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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 58





    SELENIUM









    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    World Health Orgnization
    Geneva, 1987


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CONTENTS

ENVIRONMENTAL HEATH CRITERIA FOR SELENIUM

1. SUMMARY AND RECOMMENDATIONS FOR FURTHER RESEARCH

    1.1. Summary
         1.1.1. Properties and analytical methods
         1.1.2. Sources, environmental transport, and distribution
         1.1.3. Environmental levels and exposures
         1.1.4. Selenium metabolism
                1.1.4.1  Absorption
                1.1.4.2  Total human body selenium content
                1.1.4.3  Distribution
                1.1.4.4  Metabolic pools of selenium in the body
                1.1.4.5  Metabolic conversion
                1.1.4.6  Effect of chemical form of selenium on its 
                         metabolism
                1.1.4.7  Selenium excretion
         1.1.5. Effects on animals
                1.1.5.1  Selenium toxicity
                1.1.5.2  Selenium deficiency
         1.1.6. Effects on man
                1.1.6.1  General population exposure
                1.1.6.2  Occupational exposure
    1.2. Recommendations for further activities

2. CHEMICAL AND PHYSICAL PROPERTIES; ANALYTICAL METHODS

    2.1. Properties
    2.2. Analytical methods
         2.2.1. Sample collection, processing, and storage
         2.2.2. Sample decomposition or other preliminary treatment
                2.2.2.1  Wet digestion
                2.2.2.2  Predigestion
                2.2.2.3  Combustion
                2.2.2.4  Fusion
                2.2.2.5  Concentration
         2.2.3. Removal from interfering substances
         2.2.4. Detection and identification of selenium
         2.2.5. Measurement of selenium
                2.2.5.1  Fluorometric analysis
                2.2.5.2  Neutron activation analysis
                2.2.5.3  Atomic absorption spectrometry
                2.2.5.4  Other methods

3. SOURCES, TRANSPORT, AND CYCLING OF SELENIUM IN THE ENVIRONMENT

    3.1. Natural sources
         3.1.1. Rocks and soils
         3.1.2. Natural selenium in the food chain
         3.l.3  Water and air
    3.2. Man-made sources
         3.2.1. Agriculture
         3.2.2. Industry

    3.3. Environmental transport
    3.4. Biological selenium cycle

4. LEVELS IN ENVIRONMENTAL MEDIA

    4.1. Levels and chemical forms of selenium in food
         4.1.1. Levels in food
                4.1.1.1  Natural differences among food commodities
                4.1.1.2  Effects of natural differences in the
                         availability of selenium in the 
                         environment on levels in food
                4.1.1.3  Man-induced changes in selenium levels in 
                         food
         4.1.2. Chemical forms of selenium in food
    4.2. Drinking-water
    4.3. Air

5. HUMAN EXPOSURE

    5.1. Estimate of general population exposure
         5.1.1. Food
                5.1.1.1  Geographical variation
                5.1.1.2  Food habits (consumption patterns)
                5.1.1.3  Elderly people
                5.1.1.4  Infants and children
                5.1.1.5  Special medical diets
    5.2. Occupational exposure
         5.2.1. Levels in the workplace air
         5.2.2. Biological monitoring

6. METABOLISM OF SELENIUM

    6.1. Absorption
         6.1.1. Gastrointestinal absorption
                6.1.1.1  Animal studies
                6.1.1.2  Human studies
         6.1.2. Absorption by inhalation
         6.1.3. Absorption through the skin
    6.2. Distribution in the organism
         6.2.1. Transport
         6.2.2. Organs
                6.2.2.1  Animal studies
                6.2.2.2  Human studies
         6.2.3. Blood
         6.2.4. Total-body selenium content
    6.3. Excretion in urine, faeces, and expired air
         6.3.1. Animal studies
         6.3.2. Human studies
                6.3.2.1  Excretion of selenium
                6.3.2.2  Balance studies
    6.4. Retention and turnover
         6.4.1. Animal studies
         6.4.2. Controlled human studies

    6.5. Metabolic transformation
         6.5.1. Animal studies
                6.5.1.1  Reduction and methylation
                6.5.1.2  Form in proteins
                6.5.1.3  Conversion of selenium compounds to
                         nutritionally-active forms of selenium
         6.5.2. Human studies

7. EFFECTS OF SELENIUM ON ANIMALS

    7.1. Selenium toxicity
         7.1.1. Farm animal diseases associated with a high
                selenium intake
         7.1.2. Toxicity in experimental animals
                7.1.2.1  Acute and subacute toxicity - single or 
                         repeated exposure studies with oral, 
                         intraperitoneal, or cutaneous 
                         administration
                7.1.2.2  Effects of long-term oral exposure
                7.1.2.3  Inhalation toxicity
         7.1.3. Blood levels in toxicity
         7.1.4. Effects on reproduction
         7.1.5. Effects on dental caries
         7.1.6. Factors influencing toxicity
                7.1.6.1  Form of selenium
                7.1.6.2  Nutritional factors
                7.1.6.3  Arsenic
                7.1.6.4  Sulfate
                7.1.6.5  Adaptation
         7.1.7. Mechanism of toxicity
    7.2. Selenium deficiency
         7.2.1. Animal diseases
         7.2.2. Intakes needed to prevent deficiency
                7.2.2.1  Quantitative dietary levels
                7.2.2.2  Bioavailability
         7.2.3. Blood and tissue levels in deficiency
         7.2.4. Physiological role:  glutathione peroxidase
                7.2.4.1  Function of selenium and relationship to 
                         vitamin E
                7.2.4.2  Effect of selenium intake on tissue-
                         glutathione peroxidase, activity
                7.2.4.3  Relationship between blood-selenium levels 
                         and erythrocyte-glutathione peroxidase 
                         activity
                7.2.4.4  Gluthathione peroxidase as an indicator of 
                         selenium status
         7.2.5. Other possible physiological roles
                7.2.5.1  Homeostasis of hepatic haem
                7.2.5.2  Microsomal and mitochondrial electron 
                         transport
                7.2.5.3  The immune response
                7.2.5.4  Selenium and vision
         7.2.6. Effects on reproduction
         7.2.7. Factors influencing deficiency
                7.2.7.1  Form of selenium

                7.2.7.2  Vitamin E
                7.2.7.3  Heavy metals and other minerals
                7.2.7.4  Xenobiotics
                7.2.7.5  Exercise stress
    7.3. Ratio between toxic and sufficient exposures
    7.4. Protection against heavy metal toxicity
         7.4.1. Mercury
         7.4.2. Cadmium
         7.4.3. Other heavy metals
    7.5. Cytotoxicity, mutagenicity, and anti-mutagenicity
         7.5.1. Cytotoxicity and mutagenicity
         7.5.2. Anti-mutagenicity
    7.6. Teratogenicity
    7.7. Carcinogenicity and anti-carcinogenicity
         7.7.1. Selenium as a possible carcinogen
         7.7.2. Selenium as a possible anti-carcinogen

8. EFFECTS OF SELENIUM ON MAN

    8.1. High selenium intake
         8.1.1. General population
                8.1.1.1  Signs and symptoms
                8.1.1.2  Attempts to associate high selenium intake 
                         with human diseases
         8.1.2. Reports on health effects associated with 
                occupational exposure
                8.1.2.1  Fumes and dust of selenium and its 
                         compounds
                         8.1.2.1.1  Selenium dioxide
                         8.1.2.1.2  Hydrogen selenide
                         8.1.2.1.3  Selenium oxychloride
    8.2. Low selenium intake
         8.2.1. Evidence supporting the possible essentiality of 
                selenium in man
         8.2.2. Signs and symptoms of low intake
         8.2.3. Dietary levels consistent with good nutrition
                8.2.3.1  Quantitative estimates
                8.2.3.2  Nutritional bioavailability
         8.2.4. Blood and urine levels typical of low intake
         8.2.5. Relationship between blood-selenium levels and 
                erythrocyte-glutathione peroxidase activity
         8.2.6. Attempts to associate low selenium intake with 
                human diseases
                8.2.6.1  Keshan disease
                8.2.6.2  Kashin-Beck disease
                8.2.6.3  Cancer
                8.2.6.4  Heart disease

9. EVALUATION OF THE HEALTH RISKS ASSOCIATED WITH EXCESSIVE OR 
    DEFICIENT SELENIUM EXPOSURE

    9.1. The need to consider the essentiality of selenium in 
         health risk evaluation
    9.2. Pathway of selenium exposure for the general population

    9.3. Quantitative assessment of human selenium exposure
         9.3.1. Analytical methods for selenium
         9.3.2. Food intake data
         9.3.3. Blood-selenium
         9.3.4. Hair-selenium
         9.3.5. Urine-selenium
         9.3.6. Blood-glutathione peroxidase
    9.4. Levels of dietary selenium exposure in the general
         population
    9.5. Evaluation of health risks - general population
         9.5.1. Predictive value of animal studies
         9.5.2. Studies on high-exposure effects in the general 
                population
         9.5.3. Studies on low-exposure effects in the general 
                population
         9.5.4. Evaluation of the involvement of selenium in human 
                diseases of multiple etiopathogenesis
                9.5.4.1  Keshan disease
                9.5.4.2  Kashin-Beck disease
                9.5.4.3  Ischaemic heart disease
                9.5.4.4  Studies on the involvement of selenium in 
                         cancer
                9.5.4.5  Caries
                9.5.4.6  Health effects related to reproduction
    9.6. Occupational exposure

REFERENCES

WHO TASK GROUP ON SELENIUM

 Members

Dr R.F. Burk, Jr, Department of Medicine, University of Texas
   Health Science Center, San Antonio, Texas, USA

Professor A.I. Diplock, Department of Biochemistry, Guy's
   Hospital Medical School, London, United Kingdom  (Chairman)

Dr H.N.B. Gopalan, University of Nairobi, Department of
   Botany, Nairobi, Kenya

Dr J. Chen, Department of Nutrition and Food Hygiene,
   Institute of Health, China National Centre for Preventive
   Medicine, Beijing, People's Republic of China

Dr G.N. Krasovskij, Sysir Institute of General and Community
   Hygiene, Academy of Medical Sciences of the USSR, Moscow,
   USSRa

Professor C.R. Krishna Murti, Integrated Environmental
   Programme on Heavy Metals, Centre for Environmental
   Studies, Anna University, College of Engineering, Guindy,
   Madras, Indiaa

Dr O.A. Levander, Vitamin and Mineral Nutrition Institute, US
   Department of Agriculture, Beltsville, Maryland, USA
    (Rapporteur)

Professor A. Massoud, Department of Community, Environmental
   and Occupational Medicine, Faculty of Medicine, Ain Shams
   University, Cairo, Egypta

Professor M.F. Robinson, Nutrition Department, University of
   Otago, Dunedin, New Zealand

 Secretariat

Dr J. Parizek, International Programme on Chemical Safety,
   World Health Organization, Geneva, Switzerland  (Secretary)

Dr E.S. Johnson, International Agency for Research on Cancer,
   Lyons, France

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a   Invited but unable to attend.

NOTE TO READERS OF THE CRITERIA DOCUMENTS

    Every effort has been made to present information in the 
criteria documents as accurately as possible without unduly 
delaying their publication.  In the interest of all users of the 
environmental health criteria documents, readers are kindly 
requested to communicate any errors that may have occurred to the 
Manager of the International Programme on Chemical Safety, World 
Health Organization, Geneva, Switzerland, in order that they may be 
included in corrigenda, which will appear in subsequent volumes. 



                      *    *    *



    A detailed data profile and a legal file can be obtained from 
the International Register of Potentially Toxic Chemicals, Palais 
des Nations, 1211 Geneva 10, Switzerland (Telephone no. 988400 - 
985850). 

ENVIRONMENTAL HEALTH CRITERIA FOR SELENIUM

    A WHO Task Group on Environmental Health Criteria for Selenium 
was held in Geneva on 2 - 6 December 1985.  Dr J. Parizek opened 
the meeting on behalf of the Director-General.  The Task Group 
reviewed and revised the draft criteria document and made an 
evaluation of the health risks of exposure to selenium. 

    DR O.A. LEVANDER of the US Department of Agriculture was 
responsible for the preparation of the drafts of the document. 

    The efforts of all who helped in the preparation and 
finalization of the document are gratefully acknowledged. 


                          * * *


    Partial financial support for the publication of this criteria 
document was kindly provided by the United States Department of 
Health and Human Services, through a contract from the National 
Institute of Environmental Health Sciences, Research Triangle Park, 
North Carolina, USA - a WHO Collaborating Centre for Environmental 
Health Effects. 

1.  SUMMARY AND RECOMMENDATIONS FOR FURTHER RESEARCH

1.1.  Summary

1.1.1.  Properties and analytical methods

    Selenium exists naturally in several oxidation states and some 
of its chemical forms are volatile.  Many selenium analogues of 
organic sulfur compounds exist in nature. 

    A number of procedures exist for the determination of selenium.  
However, as selenium exists in volatile and unstable forms and 
because of the inhomogeniety of many types of materials, the 
methods of sampling, preparation, and storage are equally as 
important as the analytical methods.  Great care is necessary to 
avoid contamination or loss of the element. 

    The most commonly used analytical methods depend on wet 
digestion for destroying organic matter and freeing the element.  
Some procedures depend on the formation of the piazoselenol; this 
is extracted in an organic solvent and the fluorescence determined.  
The fluorometric method with a wide variety of modifications is 
very sensitive and reliable and can be adapted for most materials.  
It is also inexpensive.  Atomic absorption spectrometry, especially 
with the atomization of the selenium as the hydride, has been 
useful, and atomic absorption methods based on the Zeeman effect 
background correction show promise for the determination of 
selenium in biological matrices, without prior sample digestion.  
Neutron activation analysis, particularly when combined with the 
chemical separation of selenium, is an excellent method, limited 
only by the cost and availability of equipment. 

1.1.2.  Sources, environmental transport, and distribution

    Selenium appears to be ubiquitous.  However, its uneven 
distribution over the face of the earth results in regions with 
very low or very high natural levels of selenium in the 
environment.  Geophysical, biological, and industrial processes are 
involved in the distribution and transport of the element and its 
cycling, but the relative importance of these processes has not 
been established.  However, the natural geophysical and biological 
processes are probably almost entirely responsible for the present 
status of selenium in the general environment.  This must be given 
primary consideration in any evaluation of the superimposed effects 
of man's activity on selenium in the environment and food chains.  
Some human activities are responsible for the redistribution of 
selenium in the environment.  Industrial sources of selenium stem 
initially from copper refining.  During this refining and the 
purification of the selenium, there can be some loss of the element 
into the environment.  In addition, industries concerned with the 
production of glass, electronic equipment, or certain metals may 
emit selenium into the environment in the immediate vicinity of the 
factories involved.  The inclusion of the element in manufactured 
products provides another avenue for its distribution.  There is 
concern in several countries with regard to the possible health 

effects of low and/or decreasing levels of selenium in the soil 
(sections 1.1.3, 1.1.5.2 and 1.1.6.1); the use of fertilizers 
containing selenium compounds in some Nordic countries is a 
remarkable example of intentional human intervention in the 
environmental distribution of selenium. 

1.1.3.  Environmental levels and exposures

    The range of selenium levels in different foods can vary 
widely, depending on the natural availability of selenium in the 
environment and on certain activities of man, such as the direct 
addition of selenium to the food supply. 

    No data are available on the chemical forms of selenium in 
foods produced under normal conditions. 

    The limited analytical data available show that the levels of 
selenium typically found in foods (on a wet-weight basis) range 
from:  0.4 - 1.5 mg/kg in liver, kidney, and seafood; 0.1 - 0.4 
mg/kg in muscle meat; < 0.1 - 0.8 mg/kg or more in cereals or 
cereal products; < 0.1 - 0.3 mg/kg in dairy products; and < 0.1 
mg/kg in most fruits and vegetables.  However, in countries with 
low selenium levels in soil, lower selenium levels than the above 
were reported, in particular in meats, cereals, and dairy products.  
The levels of selenium in baby foods tend to follow the same trends 
as in adult foods, i.e., meat and cereal products contain the 
highest levels, and fruit and vegetable products the lowest.  Meat-
based infant formulae contain more selenium than formulae based on 
milk or soy protein.  Average selenium concentrations in human milk 
range from 0.013 to 0.018 mg/litre.  However, in countries with low 
selenium levels in soil and food, lower selenium levels in breast 
milk were reported. 

    Special medical diets based on egg albumen contain more 
selenium than diets based on casein hydrolysate.  Chemically-
defined diets or total parenteral nutrition solutions based on 
amino acid mixtures contain very low levels of selenium. 

    Levels of selenium in air and water are usually very low, i.e., 
less than 10 ng/m3 in air and only a few g/litre water. 

    Food constitutes the main route of exposure to selenium for the 
general population.  Because of geochemical differences, the 
estimates of adult human exposure to selenium via the diet range 
from 11 to 5000 g/day, in different parts of the world; however, 
dietary intake more usually falls within the range of 20 - 300 
g/day.  Food consumption patterns also affect dietary-selenium 
intake, and the extreme values observed have occurred in 
populations consuming a monotonous diet comprising a limited range 
of locally-grown staple foods.  The estimated selenium intake of 
infants in different parts of the world during the first month of 
life ranges from 5 to 55 g/day, because of the variation in levels 
of selenium in milk.  Children consuming synthetic diets, as part 
of long-term diet therapy for certain metabolic diseases, such as 

phenylketonuria and maple syrup urine disease, ingest only 5 - 11 
g/day.  Adults, maintained on chemically-defined diets or total 
parenteral nutrition solutions based on amino acid mixtures, 
receive only 1 or 2 g/day.  There is growing evidence of the 
importance of the bioavailability of selenium in different foods 
for human beings. 

    Human occupational exposure to selenium is primarily via the 
air.  Exposure via direct contact is rarely of importance, unless 
local irritation or skin damage caused by vesicant selenium 
compounds facilitates cutaneous absorption.  Few quantitative data 
are available on the actual levels of occupational exposure to 
selenium.  However, it is likely that analyses carried out several 
decades ago yielded higher values (several mg/m3) than those 
carried out more recently. 

1.1.4.  Selenium metabolism

1.1.4.1.  Absorption

    Potential sites of selenium absorption from the environment 
are the gastrointestinal tract, the respiratory tract, and the 
skin.  Limited animal and no quantitative human data are available 
on the pulmonary absorption of selenium.  Nevertheless, high 
urinary-selenium levels in workers exposed to selenium in air have 
been reported and could indicate pulmonary absorption.  Selenite 
and selenium oxychloride have been shown to be absorbed through the 
skin of experimental animals.  The assessment of the possible 
pulmonary or dermal absorption rates for various selenium compounds 
must take into account differences in their physical and chemical 
properties. 

    The results of several experimental animal studies as well as 
direct measurements of selenium absorption in man indicate that 
selenium compounds can be readily absorbed in the intestinal tract 
and there appears to be no physiological control over this 
absorption.  This statement is based largely on studies of 75Se-
labelled selenite absorption in rats fed widely varying amounts of 
selenium in the diet.  All groups absorbed more than 95% of the 
75Se administered by stomach tube.  High absorption of selenium was 
reported in women given 1-mg doses of selenium as selenomethionine 
or selenite dissolved in water. 

1.1.4.2.  Total human body selenium contenta

    The reported estimates of the amount of selenium in the adult 
human body range from 3 to 14.6 mg.  The lower estimates, 3.0 or 
6.1 mg, were obtained in New Zealand by indirect techniques 
following the administration of radiolabelled selenite or 
selenomethionine, respectively, to healthy human volunteers.  The 
higher estimate, 14.6 mg, was obtained in the USA and was based on 

-------------------------------------------------------------------
a The Task Group felt that the term "body burden" might be
  misleading when applied to an essential trace element.

direct analysis of autopsy material accounting for 91.7% of the 
body mass.  The difference between these 2 estimates may be due 
either to differences in the techniques employed or to differences 
in dietary-selenium intake in New Zealand and the USA. 

1.1.4.3.  Distribution

    Under normal conditions, levels of selenium are higher in the 
kidney and liver than in the other major body tissues.  Although 
muscle-selenium levels are lower, muscle is the tissue present in 
the greatest amount in the body, and thus accounts for the highest 
proportion of the total body selenium.  It is generally assumed 
that the levels of selenium in the above tissues and in red blood 
cells and plasma are related to the total body content of selenium, 
but additional studies are needed to establish this point under 
various conditions of selenium exposure, and also in man. 

1.1.4.4.  Metabolic pools of selenium in the body

    There is no evidence of a regulated or specific storage form of 
selenium, analogous to ferritin-bound iron.  However, various data 
suggest that several body pools of selenium could be considered as 
serving a similar purpose.  Evidence for a carry-over effect of 
selenium exists.  Sheep fed plants containing adequate levels of 
selenium for 5 months and then fed low-selenium plants for 10 
months produced lambs with higher tissue-selenium contents and 
fewer signs of selenium deficiency than sheep fed only low-selenium  
plants.  North Americans moving to the low-selenium area of New 
Zealand experienced a slow drop in blood-selenium contents for 
approximately 1 year, before reaching New Zealand levels. 

    These observations could be explained by sequestration of 
selenium in the form of selenomethionine and/or other selenoamino 
acids incorporated into the primary structure of proteins 
throughout the body.  Selenium sequestered in this form would be 
released and made available at a rate corresponding to the turnover 
of proteins and the catabolism of selenomethionine.  This mechanism 
could provide selenium for animals temporarily unable to obtain it 
in sufficient amounts through their diets. 

    The Task Group concluded that present knowledge about selenium 
biochemistry was consistent with the concept of different selenium 
pools in the body, even if direct measurements of the quantitative 
aspects regarding the compartmentalization of selenium in the human 
body and the related turnover rates were not available. 

1.1.4.5.  Metabolic conversion

    Biological utilization of selenium from different chemical 
forms has usually been assessed by determining the ability of such 
compounds to prevent selenium-deficiency diseases or to increase 
glutathione peroxidase activity in selenium-deficient animals.  
Selenite and selenomethionine readily fulfil both these criteria 
and can thus be considered convertible to metabolically-active 

forms.  In addition, it should be recognized that, in several of 
the early metabolic studies on selenium, many other selenium-
containing compounds were shown to prevent dietary liver necrosis 
and thus to undergo metabolic conversion to nutritionally-active 
forms. 

    Some of the excretory metabolites of selenium have been 
identified.  Dimethylselenide is excreted in the breath at high 
levels of selenium exposure.  Trimethylselenonium ion and several 
unidentified selenium metabolites are excreted in the urine. 

1.1.4.6.  Effect of chemical form of selenium on its metabolism

    Animal studies indicate that selenite is not converted to 
selenomethionine in the body.  Nevertheless, both selenite and 
selenomethionine are able to satisfy the nutritional requirement 
for selenium. 

    The results of several studies indicate differences in the 
metabolism of these two forms of selenium.  On the basis of limited 
human studies, in which 100 g selenium/day was given, selenium in 
the form of selenomethionine was retained in larger amounts than 
selenium given as selenite; it also resulted in higher blood-
selenium levels.  Comparison of selenite and selenomethionine in 
chick studies demonstrated that retention of selenium was greater 
when given as selenomethionine than when given as selenite.  When 
mice were given toxic levels of selenium compounds, selenomethionine 
administration resulted in higher tissue-selenium levels than 
administration of the same level of selenium as selenite.  
Furthermore, manifestations of toxicity disappeared rapidly when 
selenite was withdrawn from the diet but subsided only slowly 
following withdrawal of selenomethionine.  The results of limited 
studies suggest that the metabolism of both selenium-
methylselenocysteine and selenocystine resembles that of selenite 
rather than that of selenomethionine.  These findings can be 
explained by the incorporation of a portion of the selenium 
supplied as selenomethionine into the tissue proteins as the amino 
acid. 

1.1.4.7.  Selenium excretion

    In human volunteers given tracer doses of inorganic or organic 
selenium compounds orally, excretion was mainly by the urinary 
route.  However, when people consumed naturally-occurring selenium 
in foods, approximately equal proportions were excreted in the 
urine and faeces.  Very little was excreted in the sweat, and 
animal studies have shown that significant respiratory excretion of 
volatile selenium compounds only occurs in cases of very high 
selenium exposure.  Selenium loss from the body, as judged by 
whole-body counting studies following administration of single 
doses of 75Se-labelled compounds, consisted of an initial phase of 
rapid decrease of whole body radioactivity followed, after several 
days, by a phase of more gradual 75Se excretion.  The results of 
animal studies indicate that the rate of selenium excretion in the 

initial phase is affected by the dose of selenium administered as 
well as by selenium status, whereas the second phase of excretion 
is mainly affected by selenium status. 

1.1.5.  Effects on animals

1.1.5.1.  Selenium toxicity

    A characteristic sign of acute selenium poisoning in animals is 
the odour due to the pulmonary excretion of dimethyl selenide.  
Other signs of acute selenium poisoning in dogs and rats include: 
vomiting, dyspnoea, tetanic spasms, and death from respiratory 
failure.  Pathological changes include congestion of the liver with 
areas of focal necrosis, congestion of the kidney, endocarditis, 
myocarditis, and peticheal haemorrhages of the epicardium. 

    The oral LD50 reported for sodium selenite varies from 2.3 to 
13 mg selenium/kg body weight because of species differences and 
other variables.  Inhalation exposure to various selenium 
compounds, including selenium dioxide, hydrogen selenide, and 
selenium dust, proved to be toxic, causing damage to the 
respiratory tract, liver, and other organs, lethality being 
dependent on the level and duration of exposure.  Because of the 
limited number of studies and differences in species and other 
experimental conditions used, evaluation of the dose-response 
relationships for the different compounds is difficult. 

    It has been shown that the amount of dietary selenium needed to 
cause chronic toxicity in animals is influenced by many variables 
including the form of selenium and the type of diet.  When fed in 
the diet, elemental selenium has a low order of toxicity because of 
its insolubility.  Sodium selenite or seleniferous wheat fed at a 
level of 6.4 mg selenium/kg diet caused growth inhibition, liver 
cirrhosis, and splenomegaly in young growing rats fed the diet for 
6 weeks.  Growth inhibition at 4.8 mg/kg diet was not statistically 
significant.  Levels of 8 mg/kg diet or more caused additional 
effects such as pancreatic enlargement, anaemia, elevated serum-
bilirubin levels and, in 4 weeks, death.  In another study when 
rats were fed 16 mg selenium/kg diet as sodium selenate in a 
commercial "laboratory chow" type ration, their median survival age 
was reported to be 96 days, and the predominant histopathological 
lesion was acute toxic hepatitis.  The predominant lesion at 8 
mg/kg in the chow diet was chronic toxic hepatitis and the median 
survival age was 429 days.  Only 4 mg/kg were needed to cause acute 
toxic hepatitis in rats consuming a semi-purified diet containing 
12% casein.  Increased activities of serum alkaline phosphatase (EC 
3.1.3.1) and glutamic-pyruvic transaminase (EC 2.6.1.2) were 
observed in young growing rats fed a semi-purified diet containing 
4.5 mg selenium/kg as seleniferous sesame meal. 

    By using other criteria of toxicity, some research workers have 
claimed deleterious effects of selenium at lower levels of intake, 
however, there is a need to develop and validate more sensitive and 
specific indicators of selenium poisoning.  Farm animals raised in 
regions where there are high levels of available selenium in the 

soil develop toxicity diseases as a result of consuming plants 
containing excess selenium.  The levels of dietary selenium needed 
to cause chronic toxicity are 5 mg/kg or more in cattle and 2 mg/kg 
or more in sheep.  Blood-selenium levels higher than 2 mg/litre are 
generally associated with frank chronic selenium poisoning in 
cattle, but borderline toxicity problems may be observed at levels 
between 1 and 2 mg/litre.  Blood-selenium levels of 0.6 - 0.7 
mg/litre are associated with chronic selenosis in sheep. 

    On the basis of anecdotal reports, it has been suggested that 
excess selenium may cause various practical reproduction problems 
in farm animals, such as decreased reproductive performance in 
livestock or decreased hatchability in chickens because of 
deformities, at levels that do not cause obvious manifestations of 
toxicity.  A marked deterioration in reproductive performance was 
noted in a multigeneration study in which mice were given sodium 
selenate in the drinking-water at 3 mg selenium/litre, a level that 
had no effect on growth or survival in a typical single-generation 
toxicity study.  There was a considerable decrease in the number of 
litters produced by the third-generation mice and a considerable 
increase in the number of runts among the mice that were born. 

    When monkeys were fed a cariogenic diet and given 2 mg 
selenium/litre as sodium selenite for 15 months followed by 1 
mg/litre for 45 months, the incidence of caries increased when the 
selenium was given during tooth development but not when the teeth 
were exposed post-eruptively.  On the other hand, the effect of a 
cariogenic diet given for two months after weaning was decreased in 
rats whose mothers had been given, during the second half of 
pregnancy and during lactation, drinking water containing selenium 
at the level of 0.8 mg/litre in the form of sodium selenite or 
selenomethionine. 

    In two independent studies, it was shown that, under certain 
circumstances, selenium compounds were shown to be less toxic to 
animals kept on a high dietary intake of selenium, thereby 
suggesting possible adaptation to high selenium exposures. 

1.1.5.2.  Selenium deficiency

    Animals raised in regions where there are low levels of 
available selenium in the soil develop deficiency diseases through 
consuming plants lacking adequate selenium.  These diseases can be 
prevented by feeding inorganic selenium compounds to the animals. 

    Deficiency diseases in which both selenium and vitamin E may 
play a role include nutritional muscular dystrophy in sheep and 
cattle, exudative diathesis in chickens, and liver necrosis in 
swine and rats.  Signs specific for selenium deficiency in the 
absence of vitamin E deficiency include pancreatic degeneration in 
chicks, and poor growth, reproductive failure, vascular changes, 
and cataracts in rats. 

    The level of dietary selenium needed to prevent deficiency 
diseases in animals depends on the vitamin E content of the diet.  
For example, chicks receiving a diet deficient in vitamin E need 
0.05 mg selenium/kg diet to prevent exudative diathesis whereas 
0.01 mg/kg will be sufficient to prevent the disease if the diet 
contains 100 mg vitamin E/kg. 

    Under normal vitamin E intake, the level of dietary selenium 
needed to prevent deficiency is about 0.02 mg/kg for ruminants and 
0.03 - 0.05 mg/kg for poultry. 

    Blood-selenium levels of less than 0.05 mg/litre are usually 
associated with signs of selenium deficiency in sheep.  Hepatic 
selenium levels of less than 0.21 mg/kg (dry basis) are associated 
with a high incidence of white muscle disease in lambs.  However, 
levels indicative of marginal deficiency can be influenced by the 
vitamin E status of the animal. 

    The physiological function of selenium and its nutritional 
relationship to the biological antioxidant vitamin E can be largely 
explained on the basis of its role as a component of the enzyme 
glutathione peroxidase (EC 1.11.1.9), which is responsible for the 
destruction of hydrogen peroxide and lipid peroxides. 

    There is a close association between the level of dietary 
intake of selenium and the glutathione peroxidase activity in 
several organs.  Also, the glutathione peroxidase activity of 
erythrocytes is closely associated with the selenium content of the 
blood.  Because of these close relationships, measurement of 
glutathione peroxidase offers a convenient method for assessing 
selenium intake.  However, the activity of the enzyme is influenced 
by several nutritional and environmental factors that must be 
considered when using it as an index of selenium status. 

    The ratio of the toxic level of selenium in the diet to the 
nutritional level of selenium in the diet is approximately 100, but 
this ratio can be decreased by nutritional or environmental 
factors.  For example, deficiency of vitamin E increases the 
susceptibility of animals to selenium toxicity but also increases 
the nutritional need for the element.  Furthermore, inorganic 
mercury potentiates the toxicity of methylated selenium 
metabolites, whereas methyl-mercury potentiates selenium 
deficiency. 

    Dietary selenium can protect against the toxicity of several 
heavy metals, such as mercury or cadmium, and certain xenobiotics, 
such as paraquat, but the mechanism of these protective effects is 
not known. 

    Selenium has been suspected of being a carcinogen in the past, 
but more recent research suggests that it may be able to protect 
against certain types of cancers in experimental animals. 

1.1.6.  Effects on man

1.1.6.1.  General population exposure

    As stated above, the main environmental pathway of selenium 
exposure in the general population is through food.  Nutritional 
surveys have shown that extreme dietary intakes range from 11 - 
5000 g/day, but on most diets intakes between 20 and 300 g/day 
can be considered as more typical.  The extremes in intake are 
reflected in extreme levels of selenium in blood, mean reported 
values ranging from 0.021 to 3.2 mg/litre.  The highest blood-
selenium levels ever observed in the general population were found 
in an area of the People's Republic of China in which an episode of 
intoxication reported as selenosis had occurred some years earlier.  
In this respect, as well as in at least two other studies in over-
exposed populations, hair loss and nail pathology were the most 
marked and readily documented toxic signs.  The Task Group, being 
aware of the hepatotoxicity of selenium compounds observed in 
animal studies, noted that no clinical signs of hepatotoxicity were 
observed in the studies of people exposed to high levels of dietary 
selenium, but concluded that there is a need for more thorough 
evaluation of hepatic function in persons with high selenium 
exposure.  Tooth decay was also observed in several studies on 
over-exposed populations, but in evaluating its significance the 
Task Group was unable to exclude interference by other 
environmental factors.  The Task Group recognized the difficulty in 
establishing an exact dose-response with respect to selenium in the 
above studies.  The range of blood values noted was 0.44 - 3.2 
mg/litre; in these studies no adverse effects were reported at the 
lower level, whereas clear effects on the hair and nails were 
observed at and above a level of 0.813 mg/litre. 

    The lowest blood-selenium levels ever reported in a general 
population were seen in regions of the People's Republic of China 
where Keshan disease and Kashin-Beck disease are known to be 
endemic.  The Task Group recognized the intensive research being 
carried out concerning the involvement of selenium in the 
multifactorial etiology of these diseases and the use of selenium 
compounds in their prevention. 

    The Task Group considered a large number of studies on the 
possible relationship between low levels of selenium intake and a 
high incidence of cancer.  In evaluating the available data, the 
Task Group noted both consistencies and inconsistencies, which 
made it difficult to draw a firm conclusion.  However, some recent 
case-control studies within prospective studies suggested the 
importance of this approach for a firmer evaluation of the 
involvement of the level of selenium intake in cancer prevention.  
The Task Group was aware of an intervention trial being carried out 
in China which could provide additional information on the 
association between selenium exposure and human cancer risk. 

1.1.6.2.  Occupational exposure

    As discussed above, the main environmental pathway of 
occupational exposure to selenium is through the air, or in some 
cases, by direct dermal contact.  The selenium compounds likely to 
be encountered include selenium dust, selenium dioxide, and 
hydrogen selenide.  The toxicological potential of selenium for 
human beings employed in industry, can be inferred from respiratory 
exposure studies carried out on laboratory animals and from  ad hoc 
case studies of industrial accidents. 

    Caution must be exercised when extrapolating the results of 
animal studies or industrial accidents to the industrial health 
aspects of long-term selenium exposure, because data available from 
animal studies dealing with respiratory exposure are limited, the 
exposure periods are brief, and industrial accidents involve 
situations in which the exposure was brief and at an undetermined 
level. 

    Extrapolation from general-population exposure is also quite 
difficult, since selenium ingested in the diet may have 
characteristics quite distinct from selenium encountered under 
occupational exposure conditions:  the chemical and physical forms 
are likely to be different and these forms may change after contact 
with the moist mucous membranes or with sweat.  Knowledge about the 
health effects of industrial selenium exposure is rudimentary, 
since acute exposures are accidental and must be described on an  ad 
 hoc case study basis.  The Task Group did not know of any 
epidemiological investigations of the effects of long-term 
industrial exposure to selenium that included unexposed control 
groups, nor were long-term follow-up studies with appropriate 
control groups available.  Exposure levels in short- and long-term 
exposure studies are often ill-defined and the form of selenium is 
not characterized.  Confounding factors such as simultaneous 
exposure to other toxic materials may exist. 

1.2.  Recommendations for Further Activities

1.  The Task Group recommended that further studies were needed on 
    the well-identified population segments over-exposed to 
    selenium to clarify the signs and symptoms of selenium 
    overexposure in man and establish the relevant dose-response 
    relationships.  The exclusion of hepatotoxic effects seems to 
    be of particular importance. 

2.  Further research on Keshan disease and Kashin-Beck disease 
    should be undertaken, not only to improve prevention of these 
    diseases, but also to provide basic information on the effects 
    of low selenium intake in man.

3.  Further research is needed on the relationship between the
    level of selenium intake and the incidence of cancer.

2.  CHEMICAL AND PHYSICAL PROPERTIES; ANALYTICAL METHODS

2.1.  Properties

    Selenium belongs to group VI of the periodic table, between 
sulfur and tellurium.  It has similar chemical and physical 
properties because the structure of its outer electron shells is 
similar.  Some chemical and physical properties of selenium are 
listed in Table 1. 

Table 1.  Some chemical and physical properties of seleniuma
------------------------------------------------------------------
Properties                     Values
------------------------------------------------------------------
Relative atomic mass           78.96
Atomic number                  34
Atomic radius                  0.14 nm
Covalent radius                0.116 nm
Electronegativity (Pauling's)  2.55
Electron structure             [Ar]3d104s24p4
Oxidation states               -2, 0, +2, +4, +6
Stable isotopes
 Mass                          74   76    77    78    80     82
 Natural abundance (%)         0.87 9.02  7.85  23.52 49.82  9.19
------------------------------------------------------------------
a From:  Rosenfeld & Beath (1964) and Cooper et al. (1974).

    All of the oxidation states of the element listed in Table 1 
are commonly found in nature except the +2 state.  However, 
selenium compounds containing the divalent positive ion are known. 

    The natural isotopic pattern has been useful in identifying 
selenium-containing molecular fragments produced in mass 
spectrometry.  While there are no naturally occurring radioisotopes 
of selenium, several can be produced by neutron activation.  Of 
these, 75Se has the longest half-life (120 days) and is used as a 
tracer in experiments as well as in the determination of selenium 
by neutron activation analysis.  Two relatively short-lived 
radioisotopes, 77mSe (17.5-second half-life) and 81Se (18.6 min 
half-life) have also been used in neutron activation analysis 
(Heath, 1969-70; Alcino & Kowald, 1973). 

    Selenium in the +6 or selenate state is stable under both 
alkaline and oxidizing conditions.  Thus, it occurs in alkaline 
soils, where it is soluble and easily available to plants.  It is 
also the most common form of the element found in alkaline waters.  
Because of its stability and solubility, it may be potentially the 
most environmentally dangerous form of the element. 

    Selenium in the +4 state occurs naturally as selenite.  In 
alkaline solution, it tends to oxidize slowly to the +6 state, if 
oxygen is present, but not in an acid medium.  It is readily 
reduced to elemental selenium by a number of reducing reagents, 
ascorbic acid or sulfur dioxide being commonly used for this 
purpose.  It readily reacts with certain  o-diamines, and this is 

used as the basis for some analytical methods. Selenium dioxide, 
the anhydride of selenious acid, sublimes at 317C.  This is 
important with regard to air pollution through the combustion of 
materials containing the element (Heath, 1969-70; US NAS/NRC, 
1976), and also to air sampling procedures. 

    Selenite binds tightly to iron and aluminium oxides.  Thus, it 
is quite insoluble in soils and generally not present in waters in 
any appreciable amount.  The nature of this binding has been 
suggested to be (Howard, 1971): 

    (a) hydroxylation of fracture surfaces of oxides in an 
        aqueous environment;

    (b) development of a pH-dependent charge on the surface 
        by amphoteric dissociation of the hydroxyl groups;

    (c) electrostatic attraction of ions of negative charge
        (biselenite, for instance) to the surface when it is
        positively charged; and

    (d) specific adsorption of the ion through exchange with
        surface hydroxyl groups.

    Elemental selenium (Seo), like elemental sulfur, exists in 
several allotropic forms.  At the molecular level, while several Se 
aggregates can form, only rings containing 8 selenium atoms (Se8) 
and Sen polymeric chains exist at room temperature.  Se8 is soluble 
in carbon disulfide, but Sen is not.  Both forms have a very low 
order of solubility in water and dilute acids or bases.  Seo exists 
in both amorphous and crystalline forms.  Colloidal Seo, prepared 
by reducing aqueous solutions of selenite, is an amorphous form 
with a reddish colour, used in some early methods for determining 
selenium at low concentrations.  On heating at 60 C, for a short 
time, colloidal selenium crystallizes and its colour changes to 
black.  Elemental selenium boils at 684 C, and since it, as well 
as hydrogen selenide, may form during the pyrolysis of organic 
materials, the use of dry ashing in preparing samples for analysis 
has serious limitations.  This property also contributes to the 
problem of atmospheric contamination with selenium in certain 
industrial processes (Crystal, 1973).  Elemental selenium is very 
stable and highly insoluble.  It is formed on the reduction of 
selenate as well as of selenite.  The stability and insolubility of 
elemental selenium render it unavailable to plants.  Its formation 
by natural processes might, thus, be considered one means by which 
the element is removed from active cycling in the environment. 

    In its -2 state, selenium exists as hydrogen selenide and in a 
number of metallic selenides.  Hydrogen selenide is a strong 
reducing agent and a relatively strong acid with a pKa of 3.73.  It 
is a gas at room temperature and very toxic.  Exposure to hydrogen 
selenide results in olfactory fatigue, and individuals exposed to 
it may soon be unaware of its presence.  In air, it decomposes 
rapidly to form Seo and water.  Selenides of heavy metals occur 

naturally in many minerals, and iron selenide may be one of the 
insoluble forms of the element in soils (Sindeeva, 1959; Nazarenko 
& Ermakov, 1971; Johnson, 1976; US NAS/NRC, 1976). 

    A large number of selenium analogues of organic sulfur 
compounds are known.  Many have been identified in plants, animals, 
and microorganisms.  However, although some aspects of the 
metabolism of selenium resemble those of sulfur, in many cases, 
their metabolic pathways diverge considerably (Levander, 1976a).  
As in the case of sulfur, many of the selenium compounds are 
odoriferous, volatile, and relatively unstable.  Because of this 
volatility, precautions are necessary in handling some samples for 
analysis (Klayman & Gunther, 1973; Irgolic & Kudchadker, 1974). 

2.2.  Analytical Methods

2.2.1.  Sample collection, processing, and storage

    Initially, attention must be given to the adequacy of the 
method used to analyse for selenium.  It is strongly recommended 
that the analytical method under consideration be verified against 
samples of known certified selenium content such as the standard 
reference materials available commercially from the US National 
Bureau of Standards.  Moreover, adequate analytical quality control 
measures should be standard operating practice in any laboratory 
conducting analyses for selenium.  Equally important is the proper 
collection and treatment of samples before analysis.  The sample 
collected must be representative of the material being studied, and 
must be protected from either contamination or loss of selenium 
during analysis.  These considerations are especially important in 
the processing of organic matter containing selenium and in the 
determination of trace amounts of selenium in materials of 
environmental interest such as soils, air, and water. 

    In the case of soils, it should be recognized that sampling to 
a depth of 1 m is more meaningful than shallower sampling, 
especially where soil-selenium levels are excessively high (Olson 
et al., 1942).  Also, considerable variations will occur in soils 
lying only a few metres from each other.  In air samples, both 
volatile and particulate selenium may be present and a dry filter 
with an added liquid filter has been suggested for measuring these 
two forms and the total selenium in air (Diplock et al., 1973; 
Olson, 1976).  Water samples may contain suspended solids and, in 
sampling for analysis, it must be decided whether these solids, 
which may contribute significant amounts of selenium, should be 
included in, or excluded from, the sample.  Animals are known to 
synthesize volatile selenium compounds, and so it is preferable to 
analyse animal specimens without drying. 

2.2.2.  Sample decomposition or other preliminary treatment

    Some methods of analysis can be performed without destroying 
the sample.  In others, the sample must be treated in some way to 
remove organic matter, release the selenium, and bring it to the 
proper oxidation state.  Several procedures for accomplishing this 
have been developed and are discussed below. 

2.2.2.1.  Wet digestion

    Wet digestion is most commonly used for freeing the selenium 
and destroying the organic matter.  It can be used for a wide 
variety of materials, wet or dry, and with many procedures for 
measuring the selenium.  Different mixtures of nitric, sulfuric, 
and perchloric acids, with or without such additives as hydrogen 
peroxide, mercury, molybdenum, vanadium, or persulfate, have all 
been used with equal success (Olson et al., 1973; Olson, 1976).  
Some analysts find it convenient to add nitric acid alone to their 
samples and allow them to stand overnight at room temperature.  
This procedure facilitates the later steps in the wet digestion and 
reduces the likelihood of foaming and/or clarring of the sample.  
However, reproducible recoveries of selenium are obtained only if 
all traces of nitric acid are removed from the sample digests by 
heating until the appearance of perchloric acid fumes for 15-20 min 
(Haddad & Smythe, 1974).  The trimethylselenonium ion of urine is 
somewhat resistant to decomposition by wet digestion, so an 
extended period of digestion is recommended for both urine and 
certain plant materials that may contain the trimethylselenonium 
moiety (Olson et al., 1975).  While its presence in significant 
amounts has not been demonstrated in most tissues, the 
trimethylselenonium moiety may occur in kidney in such an amount 
that extended digestion of this tissue may also be wise. 

    Wet digestion readily adapts to the predigestion procedure 
mentioned below and it can be adapted for the handling of large 
numbers of samples (Chan, 1976; Whetter & Ullrey, 1978).  Special 
care is needed to avoid explosions when using perchloric acid, 
including the use of a digestion rack with a fume manifold and a 
special fume hood.  However, a wet digestion technique with 
phosphoric acid, nitric acid, and hydrogen peroxide has been 
described that avoids the use of perchloric acid (Reamer & Veillon, 
1983a).  This procedure gives results for plasma and urine samples 
similar to those obtained with the traditional fluorometric method 
using perchloric acid digestion.  However, the method needs to be 
validated for other sample matrices. 

2.2.2.2.  Predigestion

    A predigestion process can often reduce sampling error, when 
solubilized samples or wet digestion are used in determining 
selenium.  A sample much larger than that required for the actual 
determination is heated with about 10 volumes of concentrated 
nitric acid at a slow boil for about 20 min.  After cooling and 
making to volume with water, an appropriate aliquot can be removed 
for analysis.  With samples of high fat content, the fat will rise 

to the surface on cooling and it can be avoided in sampling for 
analysis.  The fat contains essentially no selenium at this point.  
Feed samples fortified by the addition of sodium selenite or 
selenate, as well as premixes containing these compounds, can often 
be handled much more successfully with this procedure than by 
relying on fine grinding to assure a representative sample (Olson, 
1976). 

2.2.2.3.  Combustion

    Open combustion, with or without added fixatives, and low 
temperature ashing with excited oxygen have not been successfully 
used in selenium determination.  Using the Schoeniger flask for 
destroying organic matter and oxidizing the selenium gives 
excellent results, but the method is somewhat inconvenient, and 
this has limited its use (Olson et al., 1973). 

2.2.2.4.  Fusion

    Sodium carbonate or sodium peroxide fusion of soils or rocks 
and the Parr bomb fusion of some organic materials have given 
satisfactory results in selenium determination.  However, these 
methods are inconvenient in many respects and are little used 
(Olson et al., 1973). 

2.2.2.5.  Concentration

    Materials containing very small amounts of selenium may require 
a step for concentrating the element.  With water, this can usually 
be accomplished by evaporation under alkaline conditions.  Other 
methods of concentrating selenium include coprecipitation with iron 
hydroxide (selenite) and some of the techniques used for separating 
the element from interfering substances, which will be discussed in 
section 2.2.3. 

2.2.3.  Removal from interfering substances

    In many methods, it is necessary to isolate the selenium or to 
remove certain interfering substances before the selenium is 
measured.  Procedures used include:  coprecipitation with arsenic, 
tellurium, or ferric hydroxide; ion exchange column chromatography; 
solvent extraction of selenium halides, of organic selenium 
complexes, or of certain interfering metals; distillation of the 
tetrabromide; volatilization as hydrogen selenide; precipitation 
as elemental selenium; paper, thin-layer, or gas chromatography; 
and the ring oven technique (Alcino & Kowald, 1973; Cooper, 1974; 
Olson, 1976). 

    Interference by certain metal ions has been overcome, to a 
large extent, by the addition of complexing reagents such as 
oxalate or ethylenediaminetetraacetic acid. 

2.2.4.  Detection and identification of selenium

    Selenium in the form of selenite or selenate can be detected 
and identified in a number of ways (Alcino & Kowald, 1973).  Such 
qualitative tests may be useful in some industrial situations, but 
normally quantitative analysis is required for confidence in any 
interpretation, and in the end may only be slightly more time-
consuming. 

2.2.5.  Measurement of selenium

    Several reviews of methods for measuring selenium in a wide 
variety of materials (Nazarenko & Ermakov, 1971; Alcino & Kowald, 
1973; Olson et al., 1973; Cooper, 1974; Olson 1976) have been used 
as a basis for the following discussion. 

    The method used will depend on the sample to be analysed, the 
sensitivity required, the accuracy required, other analyses to be 
made, the number of samples, and the equipment and expertise 
available. 

    For samples containing high concentrations of the element, 
gravimetric or titrimetric methods may be the best.  The 
gravimetric methods have been based on precipitation of selenium as 
the element, the sulfide, the salts of certain heavy metals, an 
organic complex, or electrogravimetrically as Cu2Se.  Titrations 
have been based on iodometry, argentometry, potassium permanganate 
reductions by selenite, or back-titrations using thiourea or sodium 
thiosulfate. 

    Other methods, many of them very sensitive, can be classified 
as:  colorimetric, spectrophotometric, fluorometric, atomic 
absorption spectrometric, X-ray fluorescent, gas chromatographic, 
neutron activation, proton activation, polarographic, coulometric, 
potentiometric, spark source mass spectrometric, gas 
chromatograpic, mass spectrometric, anodic stripping voltammetric, 
and catalytic. 

    At one time, the colorimetric determination was the most used 
for the analysis of samples containing small amounts of selenium.  
The method most commonly used (Robinson, 1933) was specific for 
selenium and, for its time, quite sensitive.  The titrimetric 
method of Klein (1943) superceded it, being somewhat more 
reproducible and sensitive, until selenium was found to have a role 
as an animal nutrient, when considerably greater sensitivity was 
required.  Very sensitive methods, most commonly used, include 
fluorometry, neutron activation, and atomic absorption 
spectrophotometry. 

2.2.5.1.  Fluorometric analysis

    The methods most widely used for the determination of selenium 
in natural materials are based on fluorometry.  Selenious acid 
reacts with 1-diamines to give a piazselenol, which is fluorescent.  
The 1-diamine of choice is 2,3-diaminonaphthalene.  The piazselenol 

is extracted from an acid solution (pH 1 - 2) with either 
decahydronaphthalene or cyclohexane, in either of which the 
fluorescence yield is good.  When the organic matter is destroyed, 
the reaction can be specific for selenium.  Interference from 
copper, iron, and vanadium, and some oxidizing agents can usually 
be avoided. 

    Fluorometric methods have been applied to a number of 
materials; those for foods and plants have been subjected to 
collaborative studies (Olson, 1969; Ihnat, 1974) and have been 
accepted as official first, and final action, by the Association 
of Official Analytical Chemists (AOAC, 1975).  Critical reviews of 
fluorometric methods (Haddad & Smythe, 1974; Michie et al., 1978) 
have shown them to be reliable providing that the precautions 
described for various adaptations are followed.  The methods are 
sensitive to about 0.01 g of selenium in a sample, are adaptable 
to large numbers of samples, can be automated (Brown & Watkinson, 
1977; Szydlowski & Dunmire, 1979; Watkinson, 1979; Watkinson & 
Brown, 1979) and can be simplified (Spallholz et al., 1978; Whetter 
& Ullrey, 1978).  While isotope dilution procedures can be used 
with fluorometric methods (Cukor et al., 1964), they are not 
essential for reliable results.  Fluorometric analyses rely on 
perchloric acid digestion of the samples, and, thus, require a 
perchloric acid fume hood.  Furthermore, 2,3-diaminonaphthalene of 
adequate purity is sometimes difficult to obtain.  Improved 
sensitivity of the fluorometric analysis of water and biological 
samples was achieved by redistilling cyclohexane and extracting 
2,3-diaminonaphthalene solution in 0.1 M hydrochloric acid with two 
portions of redistilled cyclohexane (Nazarenko et al., 1975; 
Nazarenko & Kislova, 1977).  Wilkie & Young (1970) have also 
published detailed experimental procedures for purifying various 
reagents used in fluorometric analysis.  The analysis can be 
carried out with a simple fluorometer, is adaptable to a wide 
variety of materials, is reasonably rapid and reliable, and is 
relatively inexpensive to perform. 

2.2.5.2.  Neutron activation analysis

    Thermal neutron activation is the most commonly used procedure 
for irradiating samples containing selenium.  Of the radionuclides 
of selenium that it produces, 75Se (half-life 120 days), 81Se 
(half-life 18.6 min), and 77mSe (half-life 17.5 seconds) have been 
useful in analysis.  81mSe (half-life 57 min) has been used to 
measure carrier selenium after separation and reirradiation 
(Kronborg & Steinnes, 1975).  Proton-induced X-ray fluorescence 
methods have also been reported (Bearse et al., 1974; Barrette et 
al., 1976). 

    Two methods of converting radioactivity measurements to 
selenium content are: 

    (a) the direct method using calculations based on certain
        known values and constants; and

    (b) the comparator method, based on the irradiation and
        counting of a known amount of selenium, as a
        standard, together with the samples.  The comparator
        method is the most accurate and most often used, but
        the direct method is often used when short-lived
        isotopes are measured.  Ruthenium has been
        recommended as a multi-isotopic comparator when
        multi-element analysis is being performed (Van der
        Linden et al., 1974).

    Neutron activation analysis can be used without and with sample 
destruction.  When 75Se is measured by non-destructive analysis, a 
period of several weeks or months may be allowed for decay of some 
interfering radioisotopes.  The 77mSe isotope has been used without 
this type of delay with some success.  Non-destructive methods have 
been used for multi-element analysis, but they have been subject to 
more errors, because of interference, than destructive methods 
followed by chemical separation.  The use of high resolution gamma-
ray spectrometry substantially increases the specificity of the 
non-destructive methods and the complete processing of 300 - 400 
samples per month is possible (Pelekis et al., 1975).  A method has 
been developed using irradiation with epithermal neutrons and 
multiparameter analysis which eliminates the effect of spurious 
interferences in the determination of low selenium concentrations 
by instrumental neutron activation analysis.  High specificity has 
been achieved by the selective response of the system to gamma-
gamma coincidences of 75Se (Vobecky et al., 1977, 1979; Pavlik et 
al., 1979). 

    Destructive neutron activation analysis is used with the 
chemical separation of the selenium.  In most methods, 75Se is 
measured, but 77mSe measurement is not uncommon, and 81Se 
measurement has also been used.  Carrier selenium is usually added 
following the irradiation.  Destruction of the sample has been 
accomplished by wet digestion, sodium peroxide fusion, or 
combustion.  Combustion has been accomplished in a closed system, 
which provides for the dry distillation of selenium and certain 
other elements into a trapping system. Wet digestion is normally 
followed by separation of the element by distillation as the 
tetrabromide, and/or its precipitation, adsorption on an ion 
exchange material, solvent extraction of an organic selenium 
complex, or reversed phase extraction chromatography.  A semi-
automated method based on wet digestion, separation by 
distillation, and the use of ruthenium as a comparator has been 
reported (D'Hondt et al., 1977). 

    Neutron activation analysis can be very accurate, sensitive, 
and specific, especially when used with sample destruction and 
chemical separation of the selenium.  It adapts well to multi-
element analysis.  However, it requires sophisticated equipment 
that most laboratories do not have.  Furthermore, it is time-
consuming, especially when used with chemical separation.  Its most 
important use may be as a reference method against which other 
methods may be evaluated or where good reagents are not available. 

2.2.5.3.  Atomic absorption spectrometry

    Methods for selenium analysis now being most actively studied 
are those based on atomic absorption spectrometry (AAS).  A wide 
variety of techniques has been described.  Most require some type 
of wet digestion, when organic matter is present.  Flame 
atomization methods are useful for materials with a high selenium 
content.  However, other more sensitive methods have been 
developed, the most used being based on hydrogen selenide 
generation.  This has the advantages of separating the selenium 
from many other elements and measuring it using techniques that 
provide excellent sensitivity.  Ihnat (1976) compared the 
performance of hydride generation with that of a carbon furnace 
atomization-AAS method, finding hydrogen selenide generation to be 
superior.  In further studies, Ihnat & Miller (1977a,b) found that 
the sensitivity of this method was excellent and its accuracy, 
fairly good, but that its precision in a collaborative study was 
not.  McDaniel et al. (1976) found that procedures for hydrogen 
selenide generation might liberate as little as 10% of the element 
from solution.  They suggested means for optimizing hydride 
generation to give a simple and sensitive selenium determination, 
free from interferences, and using a heated graphite atomizer for 
the measurement of the element.  The hydride generation technique 
has been automated (Goulden & Brooksbank, 1974; Pierce & Brown, 
1977; Pyen & Fishman, 1978), and improved equipment for hydride 
generation has recently been described (Brodie, 1979).  Encouraging 
results with graphite furnace atomization in the presence of nickel 
(Shum et al., 1977) indicate that this method may also find 
considerable use. 

    Atomic absorption methods based on Zeeman effect background 
correction to remove spectral interferences (Pleban et al., 1982; 
Carnrick et al., 1983) are currently receiving attention.  Such 
procedures offer the promise of carrying out selenium analyses in 
certain biological matrices directly, i.e., without the need for 
sample digestion.  Development of such techniques would greatly 
increase the speed and convenience of selenium analysis. 

2.2.5.4.  Other methods

    Examples of other methods that have received recent attention 
and may find some more use in the future include:  energy 
dispersive X-ray fluorescence (Holynska & Markowicz, 1977); 
differential pulse polarography (Bound & Forbes, 1978); anodic 
(Andrews & Johnson, 1976) or cathodic (Blades et al., 1976) 
stripping voltammetry; atomic fluorescence spectrometry (Thompson, 
1975); gas-liquid chromatography (Ermakov, 1975; Poole et al., 
1977); and spark source mass spectrometric isotope dilution 
(Paulsen, 1977).  A gas chromatographic, mass spectrometric double 
isotope dilution technique based on a volatile chelate of selenium 
has recently been described, which not only determines total 
selenium in biological materials but also allows stable selenium 
isotopes to be followed as tracers in metabolic studies (Reamer & 
Veillon, 1983b). 

    A variety of methods has been proposed and used for identifying 
and measuring a number of chemical forms of selenium in different 
materials including:  paper (Hamilton, 1975) or ion exchange (Martin 
& Gerlach, 1969) chromatography for selenium compounds in plants; 
gas chromatography for volatile selenium compounds (Doran, 1976); 
and ion exchange (Shrift & Virupaksha, 1965) or solvent extraction 
separation (Kamada et al., 1978) for measuring selenite and 
selenate in solutions. 

3.  SOURCES, TRANSPORT, AND CYCLING OF SELENIUM IN THE ENVIRONMENT

3.1.  Natural Sources

    Because selenium is present in natural materials, its 
occurrence in any substance cannot be assumed to be the result of 
human activity and some knowledge of its natural distribution is 
required before evaluating its role as a pollutant. 

3.1.1.  Rocks and soils

    Several reviews of selenium geochemistry have been published 
(Sindeeva, 1959; Rosenfeld & Beath, 1964; Lakin & Davidson, 1967; 
Cooper et al., 1974).  The concentration of selenium in igneous 
rocks is low, usually much less than 1 mg/kg, and similar levels 
probably occur in metamorphic rocks.  Sedimentary rocks, such as 
sandstone, limestone, phosphorite, and shales may contain from < 1 
to > 100 mg/kg. 

    The selenium content of a soil reflects, to some extent, that 
of the parent material from which the soil has been formed.  Thus, 
in arid and semi-arid areas, soils of high selenium content have 
been derived from sedimentary rocks, usually shales and chalks 
(Moxon et al., 1950).  These soils are alkaline in reaction, 
favouring the formation of selenate (Geering et al., 1968), which 
is readily available to plants (Moxon et al., 1950).  The selenate 
is easily leached from the surface soil, but, with limited 
rainfall, it is redeposited in the subsurface soil, where it is 
still available to plants (Olson et al., 1942).  Thus, surface soil 
analysis has not been found to be a reliable measure of the 
potential of a soil to produce vegetation containing toxic levels 
of selenium. 

    Coal with an unusually high selenium content (> 80 000 mg/kg; 
average 300 mg/kg) was recently identified as the ultimate 
environmental source of selenium contaminating soils in a 
seleniferous region of Enshi county, Hubei province, the People's 
Republic of China (Yang et al., 1983).  It was thought that 
selenium passed from the coal to the soil through weathering, 
leaching, and possibly biological action, thus making it available 
to the crops.  Lime fertilizers, traditionally used in the area, 
would also render the selenium accumulated in the soil more readily 
available to plants. 

    Some soils produce crops nutritionally deficient in selenium 
(US NAS/NRC, 1971).  The most obvious factor in the formation of 
these soils is probably the parent material (Hodder & Watkinson, 
1976), but other factors such as rainfall, climate, pH, and soil 
composition contribute significantly (Gissel-Nielsen, 1976, 1986).  
As with producing plants of high selenium content, soils producing 
plants low in the element cannot be identified by analysis of the 
surface soil alone (Shacklette et al., 1974).  Because of the many 
factors affecting availability, plant analysis is also necessary 
(Kubota et al., 1967). 

    Sun et al. (1985) reported that the average total selenium 
content (112 g/kg, range 59 - 190 g/kg) in the soil of 6 low-
selenium Keshan disease areas in China was significantly lower than 
that of the 5 corresponding non-endemic areas (234 g/kg, range 142 
- 318 g/kg).  The average water-soluble selenium content and the 
percentage of water-soluble selenium in the total soil-selenium of 
the endemic areas (4.0 g/kg, range 2.2 - 8.7 g/kg and 39 g/kg, 
respectively) were also significantly lower than those of the non-
endemic areas (19.9 g/kg, range 11.4 - 38.8 g/kg and 9.2 g/kg, 
respectively).  The total soil-selenium content of a high-selenium 
area in China was 7865 g/kg (range 6390 - 10 660 g/kg), but the 
percentage of water-soluble selenium was not very high (30 - 40 
g/kg). 

3.1.2.  Natural selenium in the food chain

    All plants absorb selenium from the soil, the amount depending 
mainly on the species, the stage of growth, and the availability of 
the selenium in the soil.  Biogeochemical factors influencing the 
availability of selenium in the soil, such as pH, iron content, 
etc., have been reviewed by Ermakov & Kovalskij (1968), Allaway 
(1973), and Kovalskij (1974, 1978).  Various plant tissues contain 
different selenium levels, generally following protein content.  
Certain plants, known as selenium accumulator plants, take up 
quantities of selenium great enough to be toxic for animals.  The 
selenium content of animal tissues reflects that of the feeds 
consumed (Allaway, 1973; Kovalskij & Ermakov, 1975).  Thus, 
naturally-occurring selenium readily passes up through the food 
chain via animals to human beings, and the amount of selenium in 
the human diet is largely determined by the amount of selenium in 
the soil available for absorption by plants.  However, as discussed 
in section 7, the increased retention of selenium by animals, under 
conditions of low selenium intake, and the decreased retention 
during high selenium intake ensures that, in different geographical 
zones, the range of selenium levels in animal products is less than 
that in plant tissues.  This "buffering effect" of animals in the 
food chain tends to moderate the extremes of selenium intake to 
which human beings are exposed, whereas herbivores are subject to 
much greater fluctuations in selenium intake. 

3.1.3.  Water and air

    Under natural conditions, the concentration of selenium in 
water usually ranges from a few tenths to 2 or 3 g/litre (Ermakov 
& Kovalskij, 1974; US NAS/NRC, 1976).  The highest natural 
concentration reported to date is 9000 g/litre, almost all other 
values falling below 500 g/litre (US NAS/NRC, 1976).  A garlicky 
odour has been noted in waters containing 10 - 25 g selenium/litre 
and an astringent taste can be detected in water samples containing 
100 - 200 g/litre (Pletnikova, 1970).  In a study carried out in 
Nebraska, USA, which was biased towards finding waters with 
elevated selenium contents, it was reported that about one-third of 
161 well samples contained over 10 g selenium/litre and about 4%, 
over 100 g/litre (Engberg, 1973).  Surface waters seem much less 
likely to contain excessive levels of selenium than ground waters. 

    Soils, plants, microorganisms, animals, and volcanoes all
contribute selenium to the atmosphere.  All of these sources,
and possibly also certain sediments, produce volatile forms,
and soils and volcanoes probably contribute particulate matter
containing the element.  Some man-made activities also yield
atmospheric selenium (section 3.2.2), and it is difficult to
establish the proportion of selenium that comes from these
activities and the proportion that comes from natural sources
(US NAS/NRC, 1976).  However, data concerning atmospheric
selenium over the poles and over the Atlantic Ocean, as well
as over areas of minimal human activity (Zoller et al., 1974;
Duce et al., 1975; Dams & De Jonge, 1976) suggest that the
average concentration from natural sources should be less than
0.04 ng/m3, except close to centres of volcanic activity.

3.2.  Man-Made Sources

3.2.1.  Agriculture

    Early agricultural uses of selenium compounds as pesticides 
were very limited and short-lived.  The recent use of selenium 
compounds as feed additives or injectables for the prevention of 
selenium deficiency diseases in farm animals represents a source 
for environmental contamination, but, compared with the levels 
already present in most feeds and the amounts found in soils, even 
in the deficient areas, this source seems insignificant (US 
NAS/NRC, 1976).  In New Zealand, little increase in the selenium 
content of human foods was observed after the introduction of 
selenium supplementation for farm animals (Thomson & Robinson, 
1980).  The use of fertilizers (Koivistoinen & Huttunen, 1985) and 
foliar sprays (Gissel-Nielsen, 1973, 1986) to rectify selenium 
deficiency in feeds is being introduced, but they are unlikely to 
become a hazard in the environment.  Other fertilizers do not 
contain enough selenium to contribute significantly to the 
environment (Gissel-Nielsen, 1971).  Irrigation of seleniferous 
lands may result in an increased concentration of selenium in 
drainage waters (US NAS/NRC, 1976), but until recently there was no 
evidence to suggest that this constitutes a hazard.  However, in 
the San Joaquin Valley of California, reproductive problems have 
now been observed in aquatic birds that used irrigation drain-water 
ponds as waterfowl habitat (Ohlendorf et al., 1986).  Although the 
toxic signs reported in these birds resembled avian selenosis, the 
possible role of other water-borne toxins such as high levels of 
arsenic or boron has been pointed out. 

3.2.2.  Industry

    The main industrial sources emitting selenium into the 
environment include the mining, milling, smelting, and refining of 
copper, lead, zinc, phosphate, and uranium, the recovery and 
purification of selenium itself, the use of selenium in the 
manufacture of various products, and the burning of fossil fuels.  
Some problems from selenium emissions might arise in regions near 
selenium-producing or coal-burning industries.  For instance, in 
areas where copper sulfide ores were mined and processed, 

atmospheric selenium levels ranging from 0.15 to 6.5 g/m3 were 
reported within 0.5 - 10 km of the ore-processing plant (Seljankina 
et al., 1974).  Selenium pollution of the air may be important with 
regard to possible contamination of open-air water reservoirs; 
waterways can be contaminated directly by selenium from mining or 
industrial effluents.  For example, waste-waters of ore mines and 
effluents from a number of non-ferrous industries were reported to 
contain selenium in the concentration range of 14 - 56 g/litre.  
Residual selenium impurities in conditionally cleaned effluents 
released into open water bodies can contribute some contamination 
(Shumaev et al., 1976).  Effluents  from sewage plants can add 
selenium to waters; raw sewage has been reported to contain up to 
280 g selenium/litre, and levels of 45 - 50 g/litre have been 
reported in primary and secondary sewage effluents (Baird et al., 
1972).  Emission factors for atmospheric selenium contamination and 
solid waste generation for various industrial processes in the USA 
are shown in Table 2.  The pattern of such emissions will vary 
depending on the industrial and mining characteristics of 
individual countries.  In Canada, for example, over half of the air 
pollution due to selenium resulted from primary copper and nickel 
production, the combustion of coal contributing less than 25%. 

    When coal from deposits throughout the USA was analysed (138 
analyses), the highest selenium content was 10.65 mg/kg and the 
average, was 2.8 mg/kg, a hundred times less than the high-selenium 
coals reported in China (Yang et al., 1983) (section 3.1.1).  The 
chemical form of the element in coal is not known (US NAS/NRC, 
1976).  The selenium from the coal was released into the 
surrounding soils by natural processes, thereby contaminating the 
food chain with toxic levels of selenium. 

    Few data on the selenium content of fuel oils are available.  
Most reported values have been below 1 mg/kg (US NAS/NRC, 1976).  
Oil shale has been reported to contain selenium (Shendrikar & 
Faudel, 1978), but apparently there are no reports of its 
occurrence in natural gas. 

3.3.  Environmental Transport

    Because of the lack of quantitative data, it is impossible to 
evaluate the relative importance of various processes in the 
environmental transport of selenium.  However, Bertine & Goldberg 
(1971) have estimated that rivers move over 7 x 106 kg of selenium 
every year, even though surface waters generally contain little of 
the element.  The quantity of selenium passing via grain into the 
world feed and food supplies would be at least 105 kg, if it is 
assumed that the annual global production of cereal grains and corn 
is 109 tonnes and that these grains contain an average of 0.1 mg 
selenium/kg.  Although this simple calculation neglects all other 
plants and the large ocean flora, the quantity of selenium moved in 
grains alone is equivalent to about 7% of the average world 
production of the element for industrial purposes.  Thus, natural 
geophysical and biological processes probably play dominant roles 
in shaping the present status of selenium in the human environment 
and must be taken into account in any evaluation of the effects of 
man's activities on selenium in the environment. 

Table 2.  Estimated selenium materials balance for the 
USA for 1970a,b
---------------------------------------------------------
Source                       Selenium  Atmospheric  Solid
                             input     emissions    waste
---------------------------------------------------------
                              (---------tonne----------)
 Industrial production

Mining and milling           2900      5            1633
Smelting and refining        1270      227          181
Selenium refining            877       59           362

 Industrial consumption

Glass and ceramics           59        59
Electronics and duplicating  227       c            c
Pigments                     59        c            c
Iron and steel alloys        23        11           c
Other                        38        c            c

 Other

Coal consumption             1315      680          635
Fuel oil consumption         59        59           0
Incineration                 36        c            36
Other disposal               322       c            318

Total emissions:                       1100         3165
---------------------------------------------------------
a From:  US NAS/NRC (1976).
b The input not accounted for as atmospheric emissions or 
  solid waste would appear in intermediate or commercial 
  products.
c Less than 1 tonne.                                 

3.4.  Biological Selenium Cycle

    Several diagrammatic schemes have been presented for the 
cycling of selenium in nature (Moxon et al., 1950; Lakin & 
Davidson, 1967; Olson, 1967; Frost & Ingvoldstad, 1975; US NAS/NRC, 
1976).  None of the schemes is complete and none provides good 
quantification for the various steps in the cycle.  Indeed, a 
complete scheme is perhaps too complex to be presented 
diagrammatically with clarity, and reasonably accurate 
quantification of the various steps would demand much more 
background information than is available at present.  It appears 
that selenium has many pathways for distribution among geological 
media, biological media, the atmosphere, and waters by geophysical, 
biological, and man-made activities.  It also appears that there 
are "sinks" into which selenium may fall (elemental selenium, 
ferric hydroxy complexes, and metal selenides) from which it may be 
only very slowly recycled.  These may represent a natural 
detoxification process.  However, the fact that there are areas of 
deficiency and areas of excess of the element over the earth's 

surface is evidence that its depletion or concentration can occur 
locally.  How quickly changes in the selenium status of a region 
occur is not known, and there is a distinct need for data from 
which an evaluation could be made of the rate and impact of these 
changes as well as the influence of man's activities on them.  For 
example, Allaway (1973) concluded that any soil-plant-animal chain 
of food production on neutral or acid soils would eventually become 
depleted in biologically effective selenium, though it is not known 
how rapidly this might occur.  Shrift (1973) suggested the 
existence of a biological selenium cycle from the standpoint of 
transformations between several oxidation-reduction states, as 
shown in Fig. 1.  Reduction of the element is common and well 
established, but its biological oxidation is less well documented.  
However, a missing link on the oxidative side of the biological 
selenium cycle was found by Sarathchandra & Watkinson (1981), when 
they discovered a strain of  Bacillus megaterium, isolated from 
soil, that oxidized elemental selenium to selenite and traces of 
selenate.  The role of non-biological oxidation and reduction of 
the element has not yet been elucidated.  While a balance may be 
maintained in the redox state of selenium throughout the world, 
there are regions where oxidation prevails and others where 
reduction prevails.  Knowledge of the conditions and mechanisms 
leading to each situation is essential to understand the 
development of regions of selenium excess or deficiency. 

FIGURE 1

4.  LEVELS IN ENVIRONMENTAL MEDIA

4.1.  Levels and Chemical Forms of Selenium in Food

4.1.1.  Levels in food

    In spite of the relatively few data available, some 
generalizations concerning the selenium content of foodstuffs can 
be made.  For example, the level of selenium in food depends on 
natural differences among food commodities and the natural 
availability of selenium in the environment.  Moreover, certain of 
man's activities can influence the selenium content of human foods. 

4.1.1.1.  Natural differences among food commodities

    A wide range of values has been reported in the selenium 
content of foods (mg/kg wet weight):  liver, kidney, and seafood, 
0.4 - 1.5; muscle meats, 0.1 - 0.4; cereal and cereal products, < 
0.1 - > 0.8; diary products, < 0.1 - 0.3; and fruits and 
vegetables, < 0.1) (Oelschlager & Menke, 1969; Morris & Levander, 
1970; Schroeder et al., 1970; Suchkov, 1971; Arthur, 1972; Millar & 
Sheppard, 1972; Ferretti & Levander, 1974; Sakurai & Tsuchiya, 
1975; Abutalybov et al., 1976; Bieri & Ahmad, 1976; Kasimov et al., 
1976; Olson et al., 1978).  It should be pointed out that these 
values are given for raw foods (food as purchased) rather than 
cooked foods (food as eaten).  The effects of cooking on the 
selenium content of foods are described in section 4.1.1.3.  
Moreover, the values presented in these food composition studies 
should not be compared from one country to another, because of the 
variations in the analytical methods and sampling procedures used 
(section 2). 

    Organ meats, such as kidneys or liver, contain the highest 
levels of selenium, but some seafood products contain almost as 
much.  Muscle meats are significant sources of selenium, though 
they do not contain as much as organ meats or seafoods.  Certain 
semolina, grain, and cereal products can contribute appreciably to 
the dietary-selenium intake, but wide variations in selenium 
content have been found in different samples of the same foodstuff.  
Such variation is typical of many plant foods and the reasons for 
this are discussed below.  Milk, cheese, and egg samples from 
several countries showed low to moderate values for selenium, but 
again the results were quite variable.  Fruits and vegetables 
generally contained very low levels of selenium, though garlic and 
mushrooms contained moderate levels of the element. 

    The selenium contents of baby foods tended to show the same 
general pattern as those in adult foods (Morris & Levander, 1970; 
Arthur, 1972), i.e., meat and cereal products contained the highest 
levels and fruit and vegetable products, the lowest.  Shearer & 
Hadjimarkos (1975) analysed samples of mature human milk from 241 
subjects living in the USA and found that the overall mean selenium 
content was 0.018 mg/litre.  Over 98% of the samples contained 
between 0.007 and 0.033 mg/litre.  Grimanis et al. (1978) reported 
an average of 0.015 mg/litre in 5 samples of mature human milk 

collected in Greece.  These authors found slightly higher values in 
15 samples of human transitional milk (0.016 mg/litre) and 
colostrum (0.048 mg/litre).  A slightly lower average selenium 
concentration of 0.013 mg/litre, was reported for samples of human 
transitional milk in New Zealand (Millar & Sheppard, 1972).  The 
most extreme values for the selenium content of human milk were 
reported from China and ranged from 0.0026 mg/litre in areas where 
Keshan disease was prevalent to 0.283 mg/litre in high-selenium 
areas (Yang et al., 1986). 

    It can be seen from Table 3 that meat-based infant formulae 
have a higher selenium content than formulae based on milk or soy 
protein, and that casein-based powdered formulae for special 
medical purposes (diet therapy for errors in amino acid metabolism 
or malabsorptive states) contain low levels of selenium.  Blended 
food tube-feeding formulae containing meat tend to have higher 
selenium contents than comparable products containing only milk or 
casein and soy protein (Table 3).  Chemically-defined diets having 
egg albumen as the protein source contained more selenium than 
diets based on casein hydrolysate, which, in turn, contained more 
selenium than diets based on purified amino acids.  Total 
parenteral nutrition solutions based on casein hydrolysate also 
contain more selenium than solutions based on amino acid mixtures, 
which contain very low levels of selenium. 

Table 3.  Selenium content of commercial formula dietsa
-----------------------------------------------------------------
Product                                 Selenium content      
                                   (mg/kg wet       (mg/kg dry
                                   weight)          weight)
-----------------------------------------------------------------
 Infant formulae:

milk-based                         0.004 - 0.027
soy-based                          0.004 - 0.030
meat-based                         0.046 - 0.070
casein-based formulae for special                   0.048 - 0.120
medical purposes (powders)

 Food supplements and tube-feeding 
 formulae:

milk-based                         0.005 - 0.045
soy-casein-based                   0.013 - 0.020
blended foods                      0.037 - 0.056

 Chemically defined diets:
 (powders)

egg albumen low residue                             0.224 - 0.351
egg albumen moderate nitrogen                       0.388 - 0.886
egg albumen high nitrogen                           0.503 - 0.570
casein hydrolysate                                  0.052 - 0.071
amino acid mixture                                  0.001 - 0.011
-----------------------------------------------------------------

Table 3.  (contd.)
-----------------------------------------------------------------
Product                                 Selenium content      
                                   (mg/kg wet       (mg/kg dry
                                   weight)          weight)
-----------------------------------------------------------------
 Total parenteral nutrition 
 solutions:

casein hydrolysate                 0.037            0.324
                                   (0.032 - 0.041)
diluted 1:1 with 50% dextrose      0.019            0.093
solution                           (0.017 - 0.020)
amino acid mixture                 0.001            0.010
-----------------------------------------------------------------
a Adapted from:  Zabel et al. (1978).

    One of the factors that can influence the amount of selenium in 
plant foodstuffs is the nature of the plant itself.  Plants have 
been divided into 3 groups depending on their tendency to take up 
selenium from seleniferous soils (Rosenfeld & Beath, 1964): 

    Group 1   Primary selenium accumulators - can contain very 
              high amounts of the element (often over 1000 
              mg/kg dry weight).

    Group 2   Secondary selenium accumulators - rarely contain
              more than a few hundred mg/kg.

    Group 3   Many weeds and most crop plants, grains, and
              grasses - rarely contain more than 30 mg/kg, even
              when grown on seleniferous soils; when grown on
              normal soils generally contain less than 1 mg/kg.

    Plants from Groups 1 and 2 do not usually contribute to the 
selenium intake of human beings, since they are not consumed 
directly by people and are consumed by animals only when other 
feeds are not available.  However, plants from Group 3 can 
contribute large amounts of selenium, if they are grown in 
seleniferous areas (see below). 

    The concentrations of many nutritionally essential trace 
elements are known to be decreased by the milling of grains into 
cereals (Czerniejewski et al., 1964) and preliminary analysis of 
random supermarket samples of cereal foods suggested that refined 
products such as white flour or white bread contained less selenium 
than whole grain foods such as whole wheat flour or whole wheat 
bread (Morris & Levander, 1970).  However, a subsequent more 
controlled analytical study in which various grain fractions were 
taken from the same production batch showed that milling a variety 
of grains decreased the concentration of selenium in the consumer 
product by only 10 - 30% (Ferretti & Levander, 1974).  Thus, the 
selenium content of cereal products is somewhat less than that of 
the parent grains but the decreases in concentration are not nearly 
as great as those observed with other essential trace minerals. 

    Selenium tends to be localized mainly in the protein fraction 
of plant and animal tissues; thus, the protein content of a food 
also influences its selenium content.  For example, the 
concentration of selenium in a series of soybean products prepared 
from a given lot of soybeans increased as the protein content of 
the product increased (Ferretti & Levander, 1976).  However, 
protein content is only an expression of the potential of a food to 
contain selenium, and a food high in protein will not necessarily 
also be high in selenium.  Moreover, non-protein seleno amino acids 
occur in some foods and thus, the protein content may not always 
reflect the selenium content. 

4.1.1.2.  Effects of natural differences in the availability of
selenium in the environment on levels in food

    The most important factor in determining the selenium content 
of plant foods and feeds is the amount of selenium in the soil that 
is available for uptake by the plant.  Sun et al. (1985) reported 
that the selenium content of local crops was significantly 
correlated with the selenium content of the local soil, the 
correlation coefficients of soybean, corn, and rice being 0.9456, 
0.9953, and 0.9954, respectively.  Since the water-soluble selenium 
in the soil was directly correlated with the pH and inversely 
correlated with humin and total iron in the soil, the selenium 
content of local crops was also influenced by the amount of water-
soluble selenium in the soil.  An analytical survey carried out in 
the USA demonstrated that the level of selenium in alfalfa plants 
varied from less than 0.01 to more than 5.0 mg/kg, and it was 
assumed that these levels reflected the amount of available 
selenium in the soil (Kubota et al., 1967).  A variation in the 
selenium content of wheat from 0.04 to 21.4 mg/kg, depending on 
where the plant was grown, was reported by Schroeder et al. (1970). 
Samples of several foods bought in local markets in Caracas, 
Venezuela contained much more selenium than similar foods purchased 
in supermarkets in the eastern USA (Table 4).  The likely source of 
selenium in the milk, eggs, and meat from Caracas is sesame cake, 
since sesame is produced mostly in the seleniferous area of 
Venezuela and the pressed cake is widely used as an ingredient in 
animal feed.  Selenium levels as high as 14 mg/kg in corn and 18 
mg/kg in rice have also been observed in certain food samples taken 
from high-selenium regions in Venezuela (Jaffe, 1976).  These 
concentrations of selenium are as high as those reported in foods 
from seleniferous zones of the USA (Smith & Westfall, 1937). 

    Great extremes in the selenium content of staple foods have 
also been reported recently from China (Yang et al., 1983).  For 
example, samples of corn, rice, and soybeans, taken from a high-
selenium area with a history of human intoxication reported as 
chronic selenosis (section 8.1.1.1) contained average selenium 
levels of 8.1, 4.0, and 11.9 mg/kg, respectively, whereas samples 
of the same staples collected in a low-selenium area where Keshan 
disease was prevalent (a human selenium-deficiency disease) 
(section 8.2.2) contained average selenium levels of only 0.005, 
0.007, and 0.010 mg/kg, respectively (Table 5).  A low selenium 
content in food has also been reported in other countries with low 

selenium soils, such as New Zealand and Finland.  Typical ranges 
for selenium contents in food in such countries include (mg/kg wet 
weight): liver, kidney, and seafood, 0.09 - 0.92; muscle meats, 
0.01 - 0.06; cereal and cereal products, 0.01 - 0.07; milk, < 
0.01; and fruits and vegetables, < 0.01 - 0.02 (Koivistoinen, 
1980; Thomson & Robinson, 1980).  Samples of staple foods collected 
in areas where soils contained intermediate levels of selenium also 
contained intermediate levels of selenium. 

Table 4.  Comparison of selenium contents 
of selected foods available in Caracas, 
Venezuela, and Beltsville, Maryland, USA 
(mg selenium/kg wet weight)a
-----------------------------------------
Food                  Caracas  Beltsville
-----------------------------------------
Powdered milk         0.417    0.169

Whole milk            0.115    0.012

American-type cheese  0.425    0.090

Swiss-type cheese     0.382    0.104

Pork                  0.833    0.209

Chicken               0.702    0.106

Egg                   1.520    0.116
-----------------------------------------
a  From: Mondragon & Jaffe (1976).

    As might be expected, the selenium contents of food products of 
animal origin depend heavily on the amount of naturally-occurring 
selenium in the feed given to the animal.  In the USA, it was shown 
that the selenium content of swine muscle was highest in areas 
known to have a high level of available selenium in the soil and 
lowest in areas in which the available soil-selenium was low (Ku et 
al., 1972).  This indicates that selenium is readily passed up the 
soil-plant-animal food chain to human beings. 

4.1.1.3.  Man-induced changes in selenium levels in food

    (a)   Human activities that increase selenium levels

    Perhaps the most direct way that man's activities can increase 
the selenium content of the food supply is the deliberate addition 
of selenium to the feeds of poultry and certain livestock.  In some 
countries, this is now accepted practice to prevent the occurrence 
of selenium-deficiency diseases, many of which cause significant 
economic losses to farmers throughout the world.  In the USA, for 
example, farmers are permitted to add 0.1 mg selenium/kg (as sodium 
selenite or selenate) complete feed for beef and dairy cattle, 
sheep, chickens, ducks, swine (0.3 mg/kg in starter and prestarter 
rations), and 0.2 mg/kg for turkeys (US Department of Health and 

Human Services, Food and Drug Administration, 1984; Subcommittee on 
Selenium - Committee on animal Nutrition, 1983).  It has been shown 
that the edible tissues of poultry, swine, and sheep, fed diets 
fortified with inorganic selenium salts at the regulated levels, 
did not contain any more selenium than the tissues of animals fed 
diets, naturally adequate in selenium (Allaway, 1973; Ullrey et 
al., 1977).  The homeostatic mechanisms that appear to limit the 
concentrations of selenium in the edible tissues of animals fed 
certain levels of sodium selenite are discussed further in section 
6. 
Table 5.  Selenium contents of staple foods grown on soils in areas of China with excess, 
moderate, and deficient levels of seleniuma
-----------------------------------------------------------------------------------------
Place                          Corn                  Rice                 Soybean      
                        Number   Se content   Number   Se content   Number   Se content
                        of       (mg/kg)      of       (mg/kg)      of       (mg/kg)
                        samples               samples               samples
-----------------------------------------------------------------------------------------
High-selenium area      44       8.1          22       4.0          17       11.9
with a history of                (0.5-28.5)b           (0.3-20.2)b           (5.0-22.2)b
intoxication reported
as chronic selenosis

High-selenium area      2        0.57         2        0.97         2        0.34
reported to be without
selenosis

Moderate-selenium-      82       0.036        76       0.035        31       0.069
adequate area                    ( 0.056)             ( 0.027)             ( 0.076)
(Beijing)

Low-selenium area       10       0.009        32       0.022        -        -
                                 ( 0.009)             ( 0.009)

Low-selenium area       195      0.005        49       0.007        150      0.010
with Keshan disease              ( 0.003)             ( 0.003)             ( 0.008)
-----------------------------------------------------------------------------------------
a Adapted from:  Yang et al. (1983).
b Mean  SD or range shown in parenthesis.
    Finland is the first country to decide to increase the selenium  
content of Finnish feed and food by the addition of sodium selenate 
to fertilizers, to be used in the whole country at a concentration 
of 16 or 6 mg/kg for cereal and grassland crops, respectively 
(Koivistoinen & Huttunen, 1985).  The manufacture of these 
selenized fertilizers began in the summer of 1984 and they will be 
used at application rates of 10 g selenium/ha per growing season.  
It is anticipated that the added selenium in the fertilizers will 
be transported to the human food chain, and the selenium level of 
the cereal and grassland crops will be raised to 0.1 and 0.15 - 
0.20 mg/kg (dry basis), respectively. 

    Another potential way in which the level of selenium in the 
food chain might be increased by man's activities is the proposed 
use of selenium-bearing fly ash as a soil supplement.  Furr et al. 
(1977) analysed cabbages grown on potted soil supplemented with 
several different fly ashes and found that the selenium levels in 
the cabbages were closely correlated with those in the respective 
fly ashes in which the plants were cultured.  The ready 
bioavailability to animals of the selenium in plants grown on fly 
ash was demonstrated in a study (Stoewsand et al., 1978) in which 
Japanese quail were fed a complete diet containing 60% winter wheat 
that had been grown to maturity on either soil or a deep bed of fly 
ash.  The soil contained 2.1 mg selenium/kg and the wheat grown 
thereon contained 0.02 mg/kg, a level typical of wheat from 
selenium-deficient areas.  The fly ash contained 21.3 mg 
selenium/kg, and the wheat grown on it contained 5.7 mg/kg, a level 
sometimes found in wheat from naturally seleniferous areas.  The 
levels of selenium in the tissues of the quail fed the wheat grown 
on fly ash were much higher than those of quail fed the wheat grown 
on soil (Table 6).  Moreover, the selenium contents of eggs from 
quail fed the wheat grown on fly ash were 3.5 mg/kg in the yolk and 
almost 10 mg/kg in the white compared with 0.5 and 0.2 mg 
selenium/kg, respectively, in eggs from quail fed the control 
wheat.  Obviously, the use of selenium-bearing fly ash as a soil 
supplement to provide nutritionally desirable levels of selenium in 
plants should be carried out with care, since inappropriate use 
could lead to an unwanted build-up of selenium residues in the food 
chain.  Also, the application of fly ash to soil at rates 
sufficient to correct selenium deficiency in animals may damage the 
soil. 

Table 6.  Selenium in tissues of male Japanese quail fed winter
wheat grown on soil or fly asha
-------------------------------------------------------------------
Wheat grown                   Tissue selenium                   
on:          brain      heart      kidney     liver       muscle
-------------------------------------------------------------------
                              (mg/kg dry weight)

Soil         0.8  0.1  0.7  0.2  3.6  0.4  1.6  0.0   0.3  0.2

Fly ash      3.4  1.6  4.4  0.7  9.5  1.1  12.7  2.4  4.1  0.6
-------------------------------------------------------------------
a From:  Stoewsand et al. (1978).

    The possibility has been raised that some selenium may be added 
to the food supply as a result of atmospheric contaminants from 
the burning of fossil fuel or industrial emissions settling out on 
the leaves of plants or on the surface of the soil.  The 
geographical pattern of selenium levels in rain-water from Denmark 
or the USA implicates airborne selenium from the industrial and 
domestic uses of fossil fuel as sources (Kubota et al., 1975).  
Total industrial emissions of selenium in the USA for the year 1970 
were estimated to be about 1.1 million kg, 62% of which was derived 
from the burning of coal (US NAS/NRC, 1976).  This level of 
industrial emission of selenium may be compared with a projected 

annual use of selenium as a feed additive for chickens and swine in 
the "low-selenium" areas of the USA of 6000 kg (US FDA, 1974).  But 
there is no evidence that the selenium deposited in rainwater has 
any influence on the concentration of selenium in forage plants 
grown in Denmark or in the heavily industrialized northeastern USA 
(Kubota et al., 1975).  Furthermore, selenium deficiency has been 
observed in farm livestock grazing near coal-burning electric power 
stations (Anonymous, 1975).  This suggests that airborne selenium 
exists in the form of inert elemental selenium, insoluble selenide 
salts, or as selenium dioxide, which would be tightly bound by 
acidic, iron-bearing soils.  In any case, the selenium would not be 
available for uptake by plants; thus, there would appear to be 
little prospect of adding appreciable selenium to the food supply 
via atmospheric contamination. 

    (b)   Human activities that decrease selenium levels in the food 
          chain

    The metabolic antagonism between sulfur and selenium (Levander, 
1976a) led early workers to suggest that borderline selenium 
deficiency might be exacerbated by sulfate fertilization (Schubert 
et al., 1961).  More recent research has demonstrated that sulfate 
fertilization can result in decreased selenium concentrations in 
forage plants (Pratley & McFarlane, 1974; Westermann & Robbins, 
1974).  In many cases, this decrease can be largely explained by a 
dilution effect caused by a growth response of the plant to the 
sulfate fertilization, but decreases in selenium concentration 
independent of crop yield have also been reported.  Such decreases 
could be the result of competitive interference by sulfate with the 
uptake of selenate by plants.  The use of phosphate fertilizers in 
parts of Australia and New Zealand has resulted in an apparent 
increase in the incidence of selenium deficiency in livestock 
(Judson & Obst, 1975), but others have reported increases in the 
selenium content of forages after fertilization with phosphorus 
(Robbins & Carter, 1970; Carter et al., 1972).  These conflicting 
results may be due to differences in the selenium content of the 
phosphatic rock from which the fertilizers were prepared. 

    Another possible way in which man's activities might decrease 
selenium in the food chain or render it less available, is through 
heavy metal pollution.  For example, silver has been demonstrated 
to antagonize selenium in a wide variety of situations (Diplock, 
1976).  In an area where there has been a large amount of silver 
mining activity, muscular dystrophy of the type usually associated 
with selenium deficiency has been reported in calves fed a ration 
based on milk powder, even though the selenium content of the milk 
seemed to be adequate.  Apparently, the milk powder was derived 
from cows that grazed land containing high levels of silver 
residues from the old mining industry.  Further research is needed 
to establish fully the role of silver in potentiating these field 
cases of apparent selenium deficiency.  Because of the many 
interactions of selenium with other environmental pollutants such 
as mercury, cadmium, or arsenic (section 7), it is possible that 
other cases of heavy metal-induced selenium deficiency will be 
discovered. 

    The influence of cooking on the selenium content of foods was 
determined because of the well-known instability and volatility of 
many selenium compounds.  Certain vegetables that normally contain 
high levels of selenium such as asparagus or mushrooms, lost up to 
40% of their selenium content as a result of boiling (Higgs et al., 
1972).  Majstruk & Suchkov (1978) reported that up to 50% of the 
original selenium was lost from vegetables and dairy products 
during cooking; the addition of salt and acid pH or extended 
cooking, particularly promoted such losses.  But, other typical 
cooking procedures such as boiling cereals, baking poultry or fish, 
or broiling meats had little effect on selenium levels in the food 
(Higgs et al., 1972).  Similar results were observed by others for 
baking fish or broiling meats, though some decrease in selenium 
concentration was caused by frying organ meats or fish (Ganapathy 
et al., 1975).  Thompson et al. (1975) determined the selenium 
contents of cooked food composites and found a rough agreement with 
the calculated values based on unprepared foods from which they 
were derived.  On the basis of all these studies, it can be 
concluded that usual cooking procedures cause little decrease in 
the selenium content of most foods. 

4.1.2.  Chemical forms of selenium in food

    There is little information on the chemical forms of selenium 
that occur in human food (Levander, 1986).  Cappon & Smith (1982) 
reported that canned tuna fish contained variable percentages of 
hexavalent selenium, ranging from 7.6 to 44.8%, which was 
independent of the total selenium content.  The other forms of 
selenium in the tuna were di- and quadrivalent selenium.  On an 
average percentage basis, hexavalent selenium was more easily 
extractable by water than di- or quadrivalent selenium.  In 
recently canned samples, an average of 55.6% of the total selenium 
content was water-extractable.  However, for the older samples, the 
corresponding average extractable level was 48.2%.  The results 
suggest that sample storage may influence the chemical form of 
selenium in canned tuna.  Olson et al. (1970) found that, in a 
certain portion of high selenium wheat (the pronase hydrolysate of 
gluten), about half of the selenium was in the form of 
selenomethionine.  About 15% of the selenium in water extracts of 
seleniferous cabbage leaves was in the form of selenomethionine, 
but appreciable amounts of other selenium compounds were also 
present (Hamilton, 1975).  The chemical forms of selenium in food 
are likely to affect the bioavailability of selenium (section 7.2.2 
and 8.2.3). 

4.2.  Drinking-Water

    Analysis of samples taken from various public water-supply 
systems in the USA showed that less than 0.5% contained selenium 
levels that exceeded the US PHS limit of 10 g/litre (Taylor, 1963; 
Lakin & Davidson, 1967; McCabe et al., 1970).  Samples from 1280 
central water sources providing water for 6.5 million Bulgarians 
contained less than 2 g selenium/litre (Gitsova, 1973).  Tap water 
from Stockholm, Sweden contained only 0.06 g/litre (Lindberg, 
1968) and tap and mineral waters from Stuttgart, Federal Republic 

of Germany contained 1.6 and 5.3 g/litre, respectively 
(Oelschlager & Menke, 1969).  Surface water sources in different 
subregions of the Cernovici region of the Ukrainian SSR contained 
selenium levels ranging from 0.09  0.01 to 3.00  0.40 g/litre; 
ground-water levels ranged from 0.07  0.0 to 4.00  0.85 g/litre 
(Suchkov & Kacap, 1971).  A few tenths to several g per litre were 
reported in non-seleniferous regions of the USSR, the maximum 
reported value being 5.1 g/litre.  In Argentina, the selenium 
content of 22 surface waters varied from < 2 to 19 g/litre with a 
median value of 3 g/litre (WHO, 1984). 

    Elevated levels of selenium (> 100 g/litre) can be found in 
seeps, springs, and shallow wells, though waters from deep wells 
contain only a few g/litre (US NAS/NRC, 1976).  Highly variable 
amounts of selenium were reported in wells from seleniferous areas 
in the USA ranging from non-detectable levels to 330 g/litre 
(Smith & Westfall, 1937).  Some well waters contained enough 
selenium to be considered as poisonous for man or livestock and 
loss of hair and nails in children was attributed to selenosis, but 
the evidence for this was not considered convincing (US NAS/NRC, 
1976). 

    The average selenium content of 11 samples of drinking-water 
taken from a high-selenium area in China with a history of disease 
reported as chronic selenosis was 54 g/litre (Yang et al., 1983).  
Four of these samples were surface water from a village with 
previous heavy intoxication and these averaged 139 (117 - 159) 
g/litre.  Such water would contribute substantial amounts of 
selenium, but would still comprise a small fraction of the total 
selenium intake in this area, since the contribution from food was 
estimated to be about 5000 g/day (section 5.1.1.1).  The other 7 
samples of drinking-water originated from several sources and 
averaged only 5 g/litre. 

    Rosenfeld & Beath (1964) concluded that selenium does not occur 
in water in sufficient amounts to produce selenium toxicity in man 
or animals, except in isolated cases.  This was confirmed and 
expanded in the statement by US NAS/NRC (1976, 1980) that waters 
are rarely a significant source of selenium from either a 
nutritional or a toxicity point of view.  The low concentrations of 
selenium in drinking-water are probably the result of several 
mechanisms that act to decrease the selenium content of waters 
(section 2.1). 

4.3.  Air

    Selenium levels in the air breathed by the general population 
are probably well below 10 ng/m3, on average (US NAS/NRC, 1976).  
Hashimoto & Winchester (1967) found 0.3 - 1.6 ng airborne 
selenium/m3 in an urbanized area.  Levels of 3.6 - 9.7 ng 
selenium/m3 were detected by Pillay et al. (1971), who showed that 
over half of the selenium was not retained on filters able to trap 
particulates greater than 0.1 g in diameter.  Zoller & Reamer 
(1976) concluded that atmospheric levels of selenium in most urban 
regions vary from 0.1 to 10 ng/m3.  Selenium levels in air around 

industries that use selenium can be higher (section 3.2.2), perhaps 
of the order of a few g/m3.  Work-place air in selenium industries 
apparently contained mg levels of selenium/m3 in the past, but more 
recent measurements have indicated lower levels (section 5.2). 

5.  HUMAN EXPOSURE

5.1.  Estimate of General Population Exposure

    As discussed in section 4, selenium levels in air are low in 
areas without selenium-emitting industries and are not likely to 
exceed 10 ng/m3.  Assuming that a person respires 20 m3 air daily, 
the contribution to daily selenium intake via this route would be 
0.2 g or less.  Since this intake is much lower than that through 
food (see below), airborne selenium makes a negligible contribution 
to the average daily selenium intake of the general population.  
However, levels of selenium may be somewhat higher in the 
atmosphere around some industrial plants using selenium (section 
3.2.2).  If it is assumed that 3 g selenium/m3 is found in the air 
near these industries, then exposure to selenium via air would be 
60 g/day. 

    Other possible exposures of the general population to selenium 
via the air include contributions from house dust and tobacco 
smoke.  Lakin & Davidson (1967) reported that house or office dust 
could contain up to 10 mg selenium/kg.  Although no data are 
available to provide an estimate of human exposure to selenium from 
this source, the possibility of such exposure should be considered 
because of the increased interest in the quality of indoor air.  
Olsen & Frost (1970) found an average of 0.08 mg selenium/kg (range 
0.03 - 0.13 mg/kg) in a variety of cigarette tobaccos.  If it is 
assumed that a cigarette contains 1 g tobacco and that all the 
selenium in tobacco is volatilized and inhaled during smoking, it 
can be calculated that a person smoking one pack of 20 cigarettes 
per day would inhale an average of 1.6 g from this source. 

    Most drinking-water supplies contain only small quantities of 
selenium, except possibly for those in certain seleniferous areas.  
As discussed in section 4.2, most public water supplies contain 
much less than 10 g selenium/litre.  Assuming that a person drinks 
2 litres of water daily, the intake via this route would be only a 
few g.  While this is considerably higher than the intake via air, 
in most areas of the world, this is still a small fraction of the 
daily intake from food. 

5.1.1.  Food

5.1.1.1.  Geographical variation

    Both the amount and the bioavailability of dietary selenium are 
determinants of its biological effects.  Bioavailability is be 
considered in sections 7.2.2 and 8.2.3.  The estimated daily intake 
of selenium from dietary sources by adult human beings varies 
considerably in different parts of the world.  The greatest 
extremes in intake have been found in China (Table 7) where both 
selenium toxicity and deficiency have been reported (section 
8.1.1.1, 8.2.2).  An average selenium intake of 4990 g/day was 
estimated in a high-selenium area of China with a history of 
intoxication reported as chronic selenosis, whereas an average 
intake of only 11 g/day was estimated in an area of China where 

Keshan disease, a cardiomyopathy related to low selenium status, 
was reported.  Intermediate intakes of selenium were found in areas 
of China that were not affected with either selenosis or Keshan 
disease.  It should be pointed out that the dietary-selenium intake 
in the high-selenium area with a history of intoxication reported 
as selenosis did not overlap with that in the high-selenium area 
reported to be without selenosis.  Likewise, the dietary-selenium 
intake in the low-selenium area with Keshan disease did not overlap 
with that in the moderate-selenium area (Beijing). 
Table 7.  Daily selenium intake of residents living in high-, medium-, and low-selenium 
areas of Chinaa
---------------------------------------------------------------------------------------
                          Number      Daily selenium intake     Se intake from staple
Place                     of        minimum  maximum  average   cereals as % of total
                          subjects           (g)               daily intake
---------------------------------------------------------------------------------------
High-selenium area with   6         3200     6690     4990      28-70%
a history of intoxication
reported as chronic
selenosis

High-selenium area        3         240      1510     750       25-45%
reported as without
selenosis

Moderate-selenium area    8         42       232      116       various sources
(Beijing)

Low-selenium area with    13        3        22       11        mainly from cereals
Keshan disease
---------------------------------------------------------------------------------------
a Adapted from:  Yang et al. (1983).
    Less extreme, but still widely diverse intakes of selenium have 
been observed in other parts of the world (Table 8).  The selenium 
intake calculated in New Zealand, a country with low levels of 
selenium in the soils in certain areas, averaged 30 g/day (Thomson 
& Robinson, 1980; Watkinson, 1981).  Similar low intakes have been 
reported by other research workers in New Zealand.  For example, 
Stewart et al. (1978) showed that the mean dietary-selenium intake 
of 4 New Zealand women consuming normal diets  ad libitum was 
24.2 g/day, and Griffiths (1973) reported that the daily intake of 
selenium by 13 young New Zealand women varied from 6 to 70 g.  
Daily intakes of 30 g or more in the latter group were associated 
with the inclusion of liver, kidney, or fish in the diet.  A low 
average dietary-selenium intake (30 g/day) has also been reported 
in Finland, another country known to have soils low in selenium 
(Varo & Koivistoinen, 1980).  Low levels of dietary selenium may 
also occur in Italy (Rossi et al., 1976) and Egypt (Waslien, 1976).  
The average daily intake of selenium in the United Kingdom was 
estimated to be 60 mg (Thorn et al., 1978).  In one study, the 
dietary-selenium intake in Japan was estimated to be 88 g/day 
(Sakurai & Tsuchiya, 1975).  A higher estimate in another study was 
arrived at largely because higher selenium contents of food staples 

were used in the calculations (Yasumoto et al., 1976).  The 
estimated dietary intake of selenium in North America ranged from 
98 to 224 g/day.  A "Market basket" survey carried out in the USA 
from 1974 to 1982 indicated an average overall selenium intake of 
108 g/day (Pennington et al., 1984).  An earlier survey had 
revealed regional differences in intake, with people living in 
western parts of the country consuming 1.3 times as much selenium 
as people in the northeastern part of the country (US FDA, 1975).  
Duplicate plate analyses of self-selected diets in Maryland, USA 
gave a mean intake of 81  41 g/day (Welsh et al., 1981).  The 
daily intake in Venezuela was estimated to be 326 g, but this 
figure requires cautious interpretation because North American food 
consumption patterns were used in its derivation (Mondragon & 
Jaffe, 1976). 

5.1.1.2.  Food habits (consumption patterns)

    Because of the wide variations in the selenium content of 
various food groups in different countries, it is possible that 
certain food habits or preferences could play an important role in 
determining whether a person is at risk with regard to a deficient 
or excessive intake of selenium.  Persons with a preference for 
foods such as fish may consume high levels of selenium in their 
diet.  Sakurai & Tsuchiya (1975) estimated that Japanese eating 
large amounts of seafish may ingest as much as 500 g of selenium 
daily.  People residing in seleniferous agricultural zones may 
consume large amounts of selenium if locally-produced foods 
constitute the bulk of their diet.  In Venezuela, for example, corn 
and rice samples from high selenium areas contained as much as 14 
and 18 mg selenium/kg, respectively (Jaffe, 1976), and values as 
high as 180 mg/kg have been reported in wheat from Colombia 
(Ancizar-Sordo, 1947).  If it is assumed that some segments of the 
population living in such seleniferous regions consume, under 
certain conditions, about half of their diet in the form of rice or 
corn with a similar selenium content to that described above, the 
daily intake of selenium from dietary sources could exceed 7000 g.  
However, it should be pointed out that only a few samples from the 
high-selenium areas showed these extreme high levels.  Obviously, 
vegetarian diets could vary tremendously in selenium content.  
Ganapathy & Dhanda (1976) showed that a vegetarian diet in the USA 
supplied 84 g selenium/day.                                       

    If a particular staple food constitutes a large fraction of the 
diet of a population, then the selenium content of that food will 
have a great influence on the overall dietary-selenium intake.  For 
example, one estimated daily dietary intake of selenium in Japan 
(Sakurai & Tsuchiya, 1975) of 88 g, was based on selenium levels 
in rice and soybeans of 0.05 and 0.02 mg/kg, respectively, whereas 
another estimated intake, 208 g, was based on rice and soybean 
selenium levels of 0.220 and 0.234 mg/kg, respectively (Yasumoto et 
al., 1976).  Low levels of selenium in rice have been reported in 
Bangladesh, and it would be particularly interesting to study the 
population there, as they depend on rice as a staple food, but they 
have a recognized poor dietary vitamin E status (Bieri & Ahmad, 
1976). 


Table 8.  Estimated human dietary intake of selenium (g/day)a
----------------------------------------------------------------------------------------------------
Food             New Zealand        Finland     United    Japanf  Canadag  USAh    USA    Venezuelaj
             Dunedinb  Hamiltonc  1975d  1979d  Kingdome                         South
                                                                                 Dakotai
----------------------------------------------------------------------------------------------------
 Plant

vegetables,
fruits,
and sugars   1         2          1      1      3         6       1-9      5     10       15

cereals      4         3          3      25     30        24      62-113   45    57       88

 Animal

dairy
products,    11        11         7      13     5         2       5-28     13    48       70
eggs

meat, fish   12        16         19     19     22        56      25-90    69    101      153

Total        28        32         30     50-60  60        88      98-224   132   216      326
----------------------------------------------------------------------------------------------------
a From:  Robinson & Thomson (1983).
b From:  Thomson & Robinson (1980).
c From:  Watkinson (1981).
d From:  Varo & Koivistoinen (1981).
e From:  Thorn et al. (1978).
f From:  Sakurai & Tsuchiya (1975).
g From:  Thompson et al. (1975).
h From:  Watkinson (1974) & Levander (1976b).
i From:  US NAS/NRC (1980).
j From:  Levander (1976b).

                                           
    The importance of the selenium content of a particular staple 
in the food supply of persons dependent on a monotonous diet 
consisting of locally-produced foods was recently pointed out in 
connection with the occurrence of Keshan disease (section 8.2.2) in 
China (Yu, 1982).  In the years in which Keshan disease was endemic 
in the Fuyu county of Heilongjiang province, about 90% of the diet 
consisted of maize, whereas, in the years in which Keshan disease 
was not endemic, only about 30% of the diet was maize with much of 
the rest coming from millet and wheat.  Thus, it seems possible 
that over-reliance on this single staple food during certain years 
helped to precipitate Keshan disease in this area. 

    Recently, there has been considerable interest in some 
countries in the use of textured soy protein products as 
substitutes for meat products.  Since meat products are such good 
dietary sources of selenium, the possible impact of this trend on 
the selenium intake of human beings was examined.  Some soy protein-
based meat analogues contained as much selenium as meat products, 
but others did not (Ferretti & Levander, 1976).  These results show 
that meat analogues made from soy or other plant proteins are not 
consistent sources of selenium, since these plant-based products 
will vary in selenium content depending on where the plant is 
grown.  In contrast, meat products are more reliable dietary 
sources of selenium, because they contain a minimum quantity 
compatible with animal life. 

5.1.1.3.  Elderly people

    Thomson et al. (1977a) studied a group of 48 elderly people 
(mean age of 78 years) in New Zealand and found that their blood-
selenium levels and red cell glutathione peroxidase (EC 1.11.1.9) 
activity were lower than those in 12 young adult controls.  It was 
not possible for the authors to conclude from the data whether the 
depressed blood-selenium levels and enzyme activity were due to 
decreased selenium intake or were a general part of the aging 
process.  Abdulla et al. (1979) analysed 7-day pooled dietary 
composites of 20 pensioners in Sweden and found that the average 
daily selenium intake was 30.8 g with a range of 8.7 - 96.3 
g/day. 

5.1.1.4.  Infants and children

    The selenium intake of infants is of interest because of their 
rapid growth rate and their heavy reliance on milk, a food that has 
a highly variable selenium content, depending on its geographical 
origin (Table 9).  Millar & Sheppard (1972) assumed that human 
and cow's milk in New Zealand contained 0.010 and 0.005 mg 
selenium/litre, respectively, and calculated that the selenium 
intake of infants for the first month of life would be 5.0 or 
2.1 g/day, depending on whether human or cow's milk was fed.  
Williams (1983) measured the selenium content of mature mother's 
milk from 10 New Zealand women and calculated an average daily 
selenium intake of 5 - 6 g for an infant consuming 700 ml milk.  
If the value for the selenium content of Venezuelan cow's milk 
shown in Table 9 is typical, it can be calculated that the selenium 

intake of infants in that country would be about 58 g/day during 
the first month of life.  The most extreme values for the selenium 
content of human milk are from low- and high-selenium areas of 
China (Yang et al., 1986) (section 4.1.1.1).  For infants consuming 
750 ml milk daily, these milks would provide 2 g and 212 g 
selenium, respectively. 

Table 9.  Estimated infant daily intake of selenium 
from dietary sources in North America (6-month-old, 
6.5-kg child)a
-----------------------------------------------------
                      Daily        Selenium  Selenium
Food                  consumption  content   intake
                      (g)          (mg/kg)   (g/day)
-----------------------------------------------------
Milk                  824          0.013     11

Orange juice          122          0.014     2

Dry mixed cereal      10           0.540     5

Egg yolk              17           0.437     7

Strained meat         28           0.097     3

Strained fruit        57           0.002     -

Strained vegetable    57           0.003     -

Total selenium intake                        28
-----------------------------------------------------
a Adapted from:  Levander (1976b).

    It was shown that milk continues to furnish a sizeable portion 
of an infant's estimated daily selenium intake of 28 g, in the 
USA, after the child starts to eat solid foods (Table 9).  The 
estimated daily intake of selenium by 3-month-old infants in the 
Federal Republic of Germany was 11 g (Lombeck et al., 1975) and a 
"market basket" survey indicated that the intake of 6-month-old 
infants in the USA was about 12 g/day (Harland et al., 1978).  On 
the basis of a caloric intake of 700 Kcal/day, infants in the USA 
consuming formula diets based on milk, soy protein, casein, or 
meat, ingested 8.5, 9.5, 12.6, or 31.5 g/day, respectively (Zabel 
et al., 1978). 

    As infants grow up in New Zealand, they continue to ingest 
relatively low levels of selenium, since the estimated daily intake 
over the age span of 6 months to 5 years was 5 - 8 g (McKenzie et 
al., 1978). 

5.1.1.5.  Special medical diets

    Infants and children suffering from metabolic diseases such as 
phenylketonuria (PKU) or maple syrup urine disease (MSUD) are fed 
synthetic diets that contain little selenium for the first 10 or 12 

years of their lives.  In New Zealand, the mean daily selenium 
intake of 12 subjects consuming such synthetic diets was 5  2 g 
with little difference between the older children and the infants 
(McKenzie et al., 1978).  The selenium content of diets of 3-month-
old infants with PKU and MSUD in the Federal Republic of Germany 
amounted to 4.7 and 5.6 g/day, respectively (Lombeck et al., 
1975). 

    A wide variation in the selenium contents of special-purpose 
medical diets for adults is related to the source of protein in the 
diet (Zabel et al., 1978).  On the basis of an intake of 2000 
Kcal/day, adults consuming food supplements or tube-feeding 
formulae would ingest 29, 47, or 98 g selenium/day, depending on 
whether the diet contained soy protein and casein, milk protein and 
casein, or blended foods.  At a similar caloric intake, chemically-
defined diets based on egg albumen provided 225 g/day, whereas 
diets based on casein hydrolysate or amino acid mixtures provided 
only 28 and 1.5 g/day, respectively.  Total parenteral nutrition 
solutions based on casein hydrolysate and amino acid mixtures also 
furnished low amounts of selenium of only 32 and < 1 g/day, 
respectively.  When levels of selenium supplied by special 
therapeutic diets were studied in the Chernovitsi region of the 
Ukrainian SSR, selenium intakes were found to vary between 99  6 
and 121  8 g/day (Majstruk & Suchkov, 1978). 

5.2.  Occupational Exposure

5.2.1.  Levels in the workplace air

    The main pathway of human occupational exposure to selenium is 
through the air.  Rarely, and under special circumstances, direct 
contact may be of importance, i.e., when cutaneous absorption might 
be facilitated by the local irritation and skin damage caused by 
vesicant selenium compounds. 

    Various mechanical processes connected with the mining of 
seleniferous ores or the grinding of selenium compounds can 
contribute selenium-containing dusts to the atmosphere.  In other 
industrial activities, the amount of selenium released into the air 
depends on the temperature to which it is heated and on the area 
available for sublimation and/or vaporization. It is well 
established that heating amorphous selenium below its melting point 
results in its sublimation.  At temperatures of 170 - 180 C, 
traces of selenium can be detected in the air and, at temperatures 
of 230 - 240 C, selenium dioxide is released.  Heating of 
amorphous selenium and selenium dioxide resulted in the release of 
substantial quantities of selenium into the air, e.g., from a 
surface of 10 cm2, 2.6 - 3.75 mg was released after 20 min at 230 - 
240C and 23 - 31.6 mg was released after 20 min at 350 - 360 C 
(Izraelson et al., 1973). 

    Little quantitative information is available in the literature 
on actual levels of human exposure to selenium in industry.  The 
levels of selenium in the workplace depend not only on the nature 
of the process involved but also on the control technology in any 

given industry.  Thus, it can be expected that analyses carried out 
several decades ago yielded higher values than analyses carried out 
more recently.  In 1948, Filatova reported air levels of selenium 
and selenium dioxide of 20.6 - 24.8 mg/m3 and 0.46 - 0.78 mg/m3, 
respectively, in working zones of selenium-heating processes in a 
selenium rectifier plant, whereas levels of 0.55 - 1.1 mg/m3 and up 
to 0.11 mg/m3, respectively, were associated with the process of 
disc smearing (Filatova, cited in Izraelson et al., 1973).  In the 
production of selenium-containing photoelements by the vacuum 
application of a photosensitive layer, selenium and selenium 
dioxide levels did not exceed 2.0 mg/m3 and 0.1 mg/m3, respectively 
(Sverdlina & Maslennikova, 1961).  Selenium grinding, sulfuric acid 
treatment, and cathode alloy coating resulted in air-selenium 
levels ranging from 0.133 to 2.0 mg/m3 (Izraelson et al., 1973).  A 
highly-dispersed aerosol selenium condensate with a particle size 
of 0.5 - 2 m was produced at a level of 0.88 - 6.13 mg/m3, as a 
result of the manufacture of selenium-containing steels (Ershov, 
1969).  In the production of rare metals, the air in industrial 
premises can contain as much as 0.4 - 750 mg metallic dust/m3, 
which, in addition to other elements, contains from 0.8 - 15.7% 
selenium (Burchanov, 1972).  During the 1950s, Glover (1967) 
carried out an extensive survey in which air-selenium levels were 
determined in areas of a selenium rectifier plant in which the 
workers had been found to have high urinary-selenium values.  In 
general, the highest air levels of 1.5 - 5.2 mg selenium/m3 were 
found in relation to the grinding process.  With the exception of 
certain "special processes", air levels in the plant due to all the 
other manufacturing activities were less than 0.5 mg/m3.  In one 
case, a level of 21.3 mg/m3 was observed, but no additional details 
were given.  In this rectifier plant, a process, in which the 
elemental selenium was heated, was used for preparing the selenium 
mixture that was later applied to the metal plate.  For this 
reason, the selenium levels in the air are likely to have been 
higher than in other factories where the selenium was deposited 
from aqueous solution.  In another selenium rectifier plant, air 
levels of between 7 and 50 g selenium/m3 were reported 
(Kinnigkeit, 1962).  However, in this case, no correlation was 
observed between the air levels in the workplace and the selenium 
levels in the blood of the workers.  Kinnigkeit felt that the air-
selenium levels were not high enough to account for the high 
urinary-selenium levels in the workers.  He suggested that the 
discrepancies might be due to incomplete collection of selenium 
during air sampling, transient peaks of selenium exposure that were 
not detected by short-term sampling, or contamination of hands, 
body, and clothing with selenium, which was then transferred to the 
mouth as a result of eating or smoking.  Another possible 
explanation is that measurements of the levels in the workroom air 
did not accurately reflect levels of selenium in the actual 
breathing zone of the workers. 

    Low air levels of selenium have been observed in factories 
involved with the use of selenium in certain photocopying devices.  
In this type of manufacturing, "clean room" techniques are used, 
because strict dust control is needed to produce the quality of 

photoreceptor surfaces required.  Cannella (1976) reported air 
levels of selenium ranging from 6 to 91 g/m3 in various locations 
in a selenium alloy plant that made such photoreceptor products. 

5.2.2.  Biological monitoring

    Although selenium levels in the work-place air have been 
determined in several instances, these measurements cannot be used 
to draw any conclusions about the exposure history of individual 
workers.  Glover (1967), who estimated occupational exposure to 
selenium indirectly by determining selenium levels in the urine of 
workers, acknowledged the limitations associated with monitoring 
based on grab samples of urine.  The Working Group also recognized 
the inadequacy of urinary-selenium concentrations as a monitoring 
tool.  However, it appears that the use of a more rigorous 
programme (e.g., total 24-h urine collections) would have resulted 
in losing the cooperation of the workers involved.  A tentative 
maximum allowable concentration of selenium in urine of 0.1 
mg/litre was proposed by Glover (1967).  The urine of the workers 
was analysed at 3-month intervals, and any employee whose urinary-
selenium value exceeded the limit was transferred to a process not 
involving selenium.  The urinary-selenium levels of these 
individuals were tested weekly. 

    Two primary factors were responsible for setting the maximum 
allowable concentration for selenium in urine at 0.1 mg/litre 
(Glover, 1970).  First, a limit lower than this would have resulted 
in a certain number of "false positives", since selenium levels in 
urine are often this high in people not industrially exposed to the 
element.  Second, it was found that values below 0.1 mg/litre were 
invariably accompanied by air levels in the work-place of less than 
0.1 mg/m3, which was below the threshold limit value of 0.2 mg/m3 
for elemental selenium and its common inorganic compounds (ACGIH, 
1971).  It must be emphasized that urinary selenium cannot be used 
to monitor exposure to such dangerous selenium compounds as 
hydrogen selenide, selenium oxychloride, or certain organic 
selenium compounds because severe damage to the lungs or skin would 
have occurred by the time that the urinary-selenium values were 
raised (Glover, 1976). 

6.  METABOLISM OF SELENIUM

    The metabolism of selenium has been most completely studied in 
animals and data from human investigations are limited.  Thus, in 
the following sections, pertinent information from selected animal 
studies is presented followed by available information from 
controlled human studies. 

6.1.  Absorption

    Since food is the primary environmental medium through which 
man and animals are exposed to selenium, most data concerning 
selenium absorption deal with the gastrointestinal pathway.  Much 
less is known about the absorption of selenium through the lungs or 
skin. 

6.1.1.  Gastrointestinal absorption

6.1.1.1.  Animal studies

    The intestinal absorption of soluble selenium compounds by rats 
is highly efficient.  It has been shown that these animals absorbed 
92, 91, and 81% of doses of selenite, selenomethionine, and 
selenocystine, respectively (Thomson & Stewart, 1973; Thomson et 
al., 1975a).  In a study on rats by Whanger et al. (1976a), the 
greatest absorption of selenite or selenomethionine occurred from 
the duodenum, with slightly less absorption from the jejunum or 
ileum.  Virtually no absorption occurred from the stomach.  The 
absorption of selenite by rats does not appear to be under 
homeostatic control, since 95% or more of the dose was absorbed, 
regardless of whether the animals were fed a selenium-deficient 
diet or a diet containing mildly toxic levels of selenium (Brown et 
al., 1972).  Wright & Bell (1966) found that selenite was absorbed 
from the gastrointestinal tract to a greater extent by monogastric 
animals (swine) than by ruminant animals (sheep).  The decreased 
absorption by sheep may have been due to reduction of the 
administered selenite to insoluble or unavailable forms by rumen 
microorganisms. 

    Only limited information is available regarding the absorption 
by animals of selenium occurring naturally in foods.  Kidney tissue 
and fish muscle were chosen for model studies, because these foods 
are relatively rich sources of dietary selenium for human beings.  
The levels of intestinal absorption by rats of radio-selenium 
administered in homogenates of rabbit kidney or fish muscle 
injected with selenite, were 87 and 64%, respectively (Thomson et 
al., 1975b; Richold et al., 1977).  The low absorbability of 
"fish selenium" agrees with other reports showing the poor 
bioavailability to animals of selenium in certain fish products 
(section 5). 

    Little is known concerning the physiological processes 
governing the absorption of even simple selenium compounds, though 
McConnell & Cho (1965) showed that selenomethionine was transported 
against a concentration gradient, whereas selenite and 
selenocystine were not. 

6.1.1.2.  Human studies

    Studies carried out in New Zealand on 3 young female volunteers 
indicated that the intestinal absorption of oral doses of 
radioactive selenite, containing not more than 10 g selenium, was 
70, 64, and 44% of the dose, respectively (Thomson & Stewart, 
1974).  In a study conducted 2 years later, in which 2 of the 4 
female volunteers were women who had participated in the earlier 
study with selenite, the intestinal absorption of oral doses of 
75Se-selenomethionine, containing less than 2 g selenium, averaged 
about 96% of the dose (Griffiths et al., 1976).  When a larger dose 
of 1 mg selenium was given orally in solution, a similar difference 
in absorption was obtained, i.e., 97% for selenomethionine (one 
subject) (Thomson et al., 1978) and about 60% for sodium selenite 
(13 subjects) (Robinson et al., 1985; Thomson & Robinson, 1986).  
This value for absorption of selenite-selenium is much lower than 
the 92% absorption reported for "selenite" in the earlier paper of 
Thomson (1974), which is now known to have been selenate-selenium 
and not selenite-selenium.  Later studies on 10 volunteers also 
showed absorption of 94% for 1 mg selenate-selenium in solution 
(Thomson & Robinson, 1986).  Thus, selenate-selenium is similar to 
selenomethionine-selenium in that it is better absorbed than 
selenite-selenium. 

    Correction of selenate-selenium for selenite selenium in the 
paper of Thomson (1974) also removes the "surprising difference" 
reported between absorption of selenite given in solid form (60% 
for 4 female volunteers) and in solution (60% and not 92%).  A 
female volunteer given a 1 mg dose of selenium as selenite in 
solution daily for 5 consecutive days absorbed 59% of the total 5 
mg dose (Thomson et al., 1978).  It would appear that human beings 
have no homeostatic control to limit their absorption of large 
single doses of these selenium compounds (Barbezat et al., 1984). 

    Robinson et al. (1978b) measured the intestinal absorption of 
selenium by a New Zealand female volunteer receiving a daily 
supplement of 100 g selenium as selenomethionine, a male volunteer 
supplemented daily with 100 g selenium as sodium selenite, and a 
second female supplemented daily with 65 g selenium, as it occurs 
naturally in mackerel  (Scomber japonieus).  The selenomethionine 
and selenite were given in solution, whereas the mackerel was given 
as canned fish.  During a 4-week supplementation period, 75% of the 
selenium given as selenomethionine was absorbed compared with only 
48% of the selenium administered as selenite.  The absorption of 
the "fish selenium" was 66%.  Details of the diets consumed by the 
3 subjects were not provided, but the subjects supplemented with 
selenomethionine or fish selenium did not consume liver or kidney 
throughout the study.  However, it was specified only that the 
subject supplemented with selenite did not eat liver, kidney, or 

fish on the days that weekly urine collections were made or on 
the day prior to the collection.  Also, the subject receiving 
selenomethionine ate fish only occasionally throughout the study.  
The subject supplemented with the fish selenium ate fish other than 
mackerel on only one occasion.  Stewart et al. (1978) found that 
the average intestinal absorption of naturally-occurring selenium 
in foods was 55% in 4 young New Zealand women freely consuming 
normal diets.  However, allowing for the endogenous faecal 
excretion (half of total faecal output) the average true absorption 
of naturally occurring selenium became 79%. 

6.1.2.  Absorption by inhalation

    Certain volatile selenium compounds, such as hydrogen selenide, 
are known to be toxic when inhaled (Dudley & Miller, 1941).  
Lipinskij (1962) observed increased selenium levels in the liver 
and kidneys after respiratory exposure of rabbits to elemental 
selenium and selenium dioxide.  More recently, Weissman et al. 
(1979, 1983) studied the distribution and retention of inhaled 
75Se-labelled selenious acid and elementary selenium aerosols.  
They used 63 Beagle dogs, which were between 3 and 4 years old at 
the time of exposure.  All inhalation exposures were through the 
nose only.  Aerosol particles of both forms were small with median 
aerodynamic diameters of 0.5 and 0.7 m and geometric standard 
deviations of 2.4 and 1.5 for selenious acid and elemental 
selenium, respectively.  The urine and faeces of 4 dogs were 
collected daily, for 32 days, and then at regular time intervals 
until sacrifice.  Selenium from exhaled breath was collected from 3 
dogs for several 4-h periods, between 2 and 10 days after exposure. 
Whole-body retention of 75Se-selenium was measured immediately 
after exposure and at regular intervals up to 320 days after 
exposure.  Two dogs exposed to each aerosol were sacrificed at 
various time intervals for over half a year. The initial 75Se-
selenium body burden (IBB) in dogs that inhaled 75Se-selenium as 
selenious acid was 40  17 g selenium/kg body weight and 22  9 g 
selenium/kg body weight in dogs inhaling elementary selenium.  For 
both forms of selenium, the retention data of 75Se-selenium could 
be expressed by a 3-component negative exponential equation: 

Selenious acid:

    %IBB = 66e-1.5t + 17e-0.089t + 17e-0.023t

Elemental selenium:

    %IBB = 66e-0.090t + 21e-0.059t + 13e-0.018t

The corresponding half time values were 0.46, 7.8, and 30 days and 
0.77, 12, and 38 days for selenious acid or elemental selenium 
exposure, respectively.  Studies on organ distribution showed that, 
2 h after exposure to selenious acid, only about 5.3% of the IBB 
was retained in the lung compared with 26% of the IBB of elemental 
selenium.  For the first 32 days following exposure, the urine 
accounted for 79 and 66% of the 75Se-selenium excreted by dogs 
exposed to selenious acid and elemental selenium aerosols, 

respectively.  Respiratory excretion of 75Se-selenium was 
negligible.  The organ distribution of 75Se-selenium as a 
percentage of the sacrifice body burden is given in Table 10. 

Table 10.  75Se-selenium distribution in organs of dogs 
128 days after respiratory exposure to 75Se-selenious acid 
or elemental 75Se-selenium aerosolsa
----------------------------------------------------------
Organ                   75Se-selenium organ distribution 
                        as % of 75Se-selenium body burden
                        at sacrifice
                        ----------------------------------
                        selenious acid  elemental selenium
                        treated         treated
----------------------------------------------------------
Lung                    1.3             6.2

Liver                   11.4            7.4

Kidney                  1.6             1.6

Blood                   19.7            21.5

Gastrointestinal tract  3.4             3.6

Pelt                    9.6             9.1
----------------------------------------------------------
a Adapted from:  Weissman et al. (1979).

    Comparison of the absorption of these two forms of selenium 
through inhalation was also studied in the rat (Medinsky et al., 
1981).  The rate of transfer of selenium into the blood was slower 
when the elemental form was administered.  However, once absorbed, 
both chemical forms behaved identically. 

6.1.3.  Absorption through the skin

    Apart from the report of Dutkiewicz et al. (1972), who found 
that 10% of a 0.1 mol solution of sodium selenite applied to rat 
skin was absorbed in 1 h, there are no quantitative data on the 
dermal absorption of water-soluble selenium compounds.  However, 
Dudley (1938) showed that selenium oxychloride was absorbed through 
the skin of rabbits.  Selenium sulfide, an insoluble selenium 
compound used in certain anti-dandruff shampoos, is not ordinarily 
absorbed through the skin, although a garlicky breath odour and 
elevated urinary excretion of selenium were noted in a patient with 
open scalp lesions who used a selenium sulfide shampoo (Ransone et 
al., 1961). 

6.2.  Distribution in the Organism

6.2.1.  Transport

    Little is known about the transport of selenium in the body.  
However, a plasma selenoprotein has been identified which one group 

postulates is involved in selenium transport (Motsenbocker & 
Tappel, 1982). 

6.2.2.  Organs

6.2.2.1.  Animal studies

    Absorbed selenium is rapidly distributed among the tissues.  
Heinrich & Kelsey (1955) found that the liver of mice injected 
subcutaneously with sodium selenite contained 17 and 30% of the 
dose, 15 and 60 min after injection, respectively.  However, 
because of the great variation in the metabolic half-time of 
selenium in various tissues (Thomson & Stewart, 1973), the 
distribution pattern observed will change markedly with the time of 
sampling after injection with radio-selenium. 

    As long as the diet provides nutritionally adequate levels of 
selenium, the relative concentrations of selenium in the various 
internal organs are quite consistant over a wide range of selenium 
intakes.  For example, Jones & Godwin (1962) studied the 
distribution of selenium in the tissues of mice fed alfalfa 
containing nutritional levels of selenium.  The concentrations of 
selenium in the internal organs decreased in the following order: 
kidneys > liver > pancreas >> lungs > heart > spleen > 
skin > brain > carcass.  Smith et al. (1937) fed toxic levels of 
sodium selenite to cats and observed the following order for the 
concentration of selenium in the internal organs:  liver > 
kidneys > spleen > pancreas > heart > lungs. 

    The distribution of selenium appears to be relatively 
independent of the form and route of administration, since the 
kidneys and adrenals contained the highest concentrations of radio-
selenium, regardless of whether the rats were given labelled 
selenite or selenomethionine orally or by intravenous injection 
(Thomson & Stewart, 1973).  The greatest amounts of radioactivity 
were in the kidneys, liver, and total muscle mass.  Similar 
distribution patterns were noted in rats dosed orally with 
homogenates of tissues from rabbits or from fish that had been 
given labelled selenium compounds (Thomson et al., 1975b; Richold 
et al., 1977). 

    The distribution of selenium in tissues was markedly different 
when rats were fed a diet deficient in selenium:  the testes, 
brain, thymus gland, and spleen took up the greatest concentrations 
of selenium from a tracer dose of selenite (Burk et al., 1972).  A 
recent report confirms the ability of the testis to retain selenium 
better than other tissues in selenium deficiency (Behne & Hofer-
Bosse, 1984). 

    The distribution of selenium in the eye was determined 
fluorometrically with 2,3-diaminonaphthalene by Gusejnov et al. 
(1974), who found the following levels in various parts of the eye 
of a bull (mg/kg fresh weight):  iris, 1.3; retinal pigment 
epithelium, 0.85; retina, 0.50; cornea, 0.3; lens, 0.03; and 
vitreous body, 0.01.  In some birds (pigeons and crows), the level 

of selenium in the retina was about 10 times higher (about 5.0 
mg/kg).  In studies in which 75Se-labelled sodium selenite in 
saline was administered intraperitoneally to frogs, rats, and 
rabbits, the distribution of radio-selenium was similar to that of 
the naturally-occurring selenium measured in the bull's eye.  The 
maximum 75Se activity in the eye (5 h after administration) was 
found in the pigment with the vascular layer of the retina, whereas 
minimum activity was found in the lens and vitreous body. 
Histoautoradiography of the eyes also indicated the highest 
radioactivity in the vascular and pigment layers (Abdullaev et al., 
1972). 

6.2.2.2.  Human studies

    The distribution of selenium in human organs was examined by 
Schroeder et al. (1970), who found the following descending order 
for selenium concentrations in tissues:  kidney > liver > 
spleen > pancreas > testes > heart  muscle > intestine > 
lung > brain.  Blotcky et al. (1976) showed that, in autopsy 
samples from 106 persons, the concentrations of selenium were 2-3 
times higher in the kidneys than in the liver. 

    Uptake of an orally-administered dose of radioselenite in the 
internal organs occurred in the following relative order:  liver > 
kidneys > lungs > muscle = articular tissue (Leeb et al., 1977).  
Other studies have shown significant accumulation of radio-selenium 
by the liver and kidneys after intravenous injections of selenite 
or selenomethionine (Lathrop et al., 1972; Falk & Lindhe, 1974; 
Nordman, 1974). 

6.2.3.  Blood

    Studies on experimental animals have shown a close correlation 
between the level of selenium in the blood and the level of 
selenium in the diet (Lindberg & Jacobsson, 1970; Cary et al., 
1973; Ermakov & Kovalskij, 1974; Oh et al., 1976a).  Analytical 
surveys on human beings have shown significant variations in blood-
selenium levels in different geographical areas, presumably because 
of differences in dietary-selenium intake.  For example, Allaway et 
al. (1968) found that selenium levels in the blood of persons 
living in areas of the USA where soils and vegetation were high in 
selenium tended to contain more selenium than that of persons 
living in areas where soils and plants were generally low in 
selenium.  Thus, geographical differences in the selenium levels in 
human blood are possible, even in a country where large-scale 
interregional food shipments would be expected to level out 
differences in the amount of selenium in the food supply.  These 
geographical differences in human blood-selenium levels in the USA 
have been confirmed by Howe (1974), who found a mean selenium 
content of 0.265 mg/litre (SD = 0.056) for 626 samples collected in 
and around the state of South Dakota (a high soil-selenium region), 
whereas Schultz & Leklem (1983) reported blood-selenium values in 
Oregon (a low soil-selenium region) that were well below those 
reported for other areas of the USA. 

    Analyses of blood samples from persons living in different 
regions of the world indicate similar correlations between the 
amount of selenium in the blood and the amount of selenium in the 
food throughout the world (Table 11).  For example, blood-selenium 
concentrations tend to be lowest in areas of the world that are 
known to have low levels of selenium in the soil (Keshan-disease 
areas of China, New Zealand, Scandinavia) and highest in areas that 
are known to have high levels of selenium in the soil (Venezuela, 
reported selenosis areas of China).  Superimposed on these 
geographical variations in effects are the effects of general 
nutritional status or effects of certain disease states.  For 
example, children suffering from Kwashiorkor have lower blood-
selenium levels than their well-nourished counterparts (Burk et 
al., 1967) and reductions in the selenium content of sera have been 
observed in patients with cancer (McConnell et al., 1975).  Lower 
blood-selenium values were associated with lower serum-albumin 
values in surgical patients with and without cancer in New Zealand 
(Robinson et al., 1979).  Akesson (1985) suggested that alterations 
in plasma-selenium may be secondary to changes in plasma-protein 
concentration.  In a study of Finnish men with one or more risk 
factors for coronary heart disease, Miettinen et al. (1983) 
observed a strong association between serum-selenium and the 
eicosapentanoic acid contents of cholesterol ester and 
phospholipids.  The authors pointed out that since eicosapentanoate 
is a fatty acid peculiar to fish such an association could reflect 
the intake of fish at the time of blood sampling. 

    Blood-selenium levels change if persons travel to countries 
with soils of different selenium content.  For example, Griffiths & 
Thomson (1974) noted that the blood-selenium levels of adults from 
the USA declined rapidly on arrival in New Zealand, but, after 1 
year, their levels were still higher than the mean value for 
permanent New Zealand residents (Fig. 2).  Rea et al. (1979) found 
that plasma-selenium levels changed with changes in selenium intake 
more rapidly than erythrocyte-selenium levels.  The latter 
reflected longer-term changes in selenium exposure, presumably 
because of the relatively long life span of erythrocytes.  In a 
controlled depletion/repletion metabolic study (section 6.3.2.2), 
Levander et al. (1980) stated that the plasma-selenium levels of 
healthy young male volunteers in the USA dropped about 19% after 
2 weeks on a low-selenium diet and then returned to their previous 
levels 11 days after consuming a high-selenium diet (Fig. 3). 

FIGURE 2

FIGURE 3

Table 11.  Comparison of selenium levels in whole-blood samples
obtained from human beings living in different parts of the world 
(values for each country are listed in decreasing numerical order)
-------------------------------------------------------------------
Country or region          Reported values      Reference
                           (mg selenium/litre
                           whole blood)
-------------------------------------------------------------------
 Canada

Ontario                    0.182                Dickson & Tomlinson
                           SD  0.036           (1967)
 The People's Republic of 
 China

high-selenium area with    3.2                  Yang et al. (1983)
a history of intoxication  (1.3-7.5)
reported to be chronic
selenosisa

high-selenium area         0.44                 Yang et al. (1983)
reported to be without     (0.35-0.58)
selenosisa

moderate-selenium          0.095                Yang et al. (1983)
area (Beijing)a            SD  0.091

low-selenium area          0.027                Yang et al. (1983)
without Keshan disease     SD  0.009

low-selenium area with     0.021                Yang et al. (1983)
Keshan diseasea            SD  0.010

 Egypt                      0.068                Maxia et al. (1972)
                           (0.054-0.079)
 Finland

Helsinki                   0.081                Westermarck et al.
                           SD  0.015           (1977)

Lappeenranta               0.056                Westermarck et al.
                           SD  0.017           (1977)

 Guatemala                  0.23                 Burk et al. (1967)
                           SD  0.05

 New Zealand

Auckland, North Island     0.083                Robinson & Thomson
                           SD  0.013           (1981)

Dunedin, South Island      0.059                Rea et al. (1979)
                           SD  0.012
-------------------------------------------------------------------

Table 11.  (contd.)
-------------------------------------------------------------------
Country or region          Reported values      Reference
                           (mg selenium/litre
                           whole blood)
-------------------------------------------------------------------
 Sweden                     0.12                 Brune et al. (1966)
                           SD  0.02

 United Kingdom             0.32                 Bowen & Cawse 
                           (0.26-0.37)          (1963)

 USA

Rapid City, South Dakota   0.256                Allaway et al. 
                           SE  0.036           (1968)

Lima, Ohio                 0.157
                           SE  0.032

 USSR

Ukrainian SSR              0.442                Suchkov (1971)
                           SE  0.034

Azerbeijan SSR             0.11                 Abdullaev (1976)
                           SE  0.007

 Venezuela

Seleniferous zone          0.813                Jaffe et al. 
Villa Bruzual                                   (1972a)
Caracas                    0.355
-------------------------------------------------------------------
a These blood samples were collected in areas corresponding to 
  those shown in Table 8.

    The Task Group was aware of one report (Kinnigkeit, 1962) that 
presented blood-selenium levels in workers occupationally exposed 
to selenium (Table 12).  The analytical method used in this study 
was a wet chemical technique based on complexing selenium with 
diaminobenzidine, and the blood-selenium values obtained by this 
procedure from a population not occupationally exposed were below 
0.5 mg/litre.  These values imply that blood-selenium levels in 
workers, at least in the past, were much higher than those found in 
the general population (Table 11).  Unfortunately no control values 
were available (Table 12) so it was not possible to compare the 
blood-selenium levels with those obtained using the more recent 
analytical technique using diaminonaphthalene instead of 
diaminobenzedine (section 2.2.5.1). 

6.2.4.  Total-body selenium content

    Schroeder et al. (1970) estimated the total-body selenium 
content of persons in New England, USA, by multiplying the mean 
values of the selenium content of human tissues obtained at autopsy 

by standard organ weights.  In this way, a total-body selenium 
content of 14.6 mg (range, 13.0 - 20.3 mg) was calculated for 91.7% 
of the body.  Stewart et al. (1978) calculated the total-body 
selenium content of 4 New Zealand women by 3 different techniques: 
using the specific activity of urinary selenium and retained whole-
body radio-selenium; using plasma-selenium and the occupancy of 
radio-selenium in whole body and plasma; and using absorbed food-
selenium and the occupancy of absorbed radio-selenium in the whole 
body.  Depending on whether labelled selenomethionine or selenite 
was used in the estimation, the total-body selenium content was 
found to be either 6.1 mg (range, 4.1 - 10.0 mg) or 3.0 mg (range, 
2.3 - 5.0 mg), respectively, which was less than half that of North 
Americans.  This was consistent with the selenium contents of 
individual tissues (liver, muscle, heart) (Money, 1978; Casey et 
al., 1982) of New Zealand subjects, which also contained less than 
half that reported in North Americans. 

Table 12.  Blood-selenium levels reported in 
workers from a selenium rectifier planta
---------------------------------------------
Department            Number   Selenium level 
                      of       in blood
                      workers  (mg/litre)
---------------------------------------------
Vaporization          13       4.8  14.8

Measurement           13       15.8  11.8
field

Stamping              12       8.8  13.8

Electric fabrication  18       13.4  12.9
---------------------------------------------
a Geometric mean  standard error. From:  Kinnigkeit (1962).

6.3.  Excretion in Urine, Faeces, and Expired Air

6.3.1.  Animal studies

    Studies on rats have shown that the urinary pathway is the 
dominant route for selenium excretion, as long as the dietary 
selenium exceeds a certain critical threshold level.  For selenium 
as selenite, this threshold lies between 0.054 and 0.084 mg/kg 
(Burk et al., 1973).  As the dietary level of selenium increased 
from 0.004 to 1.000 mg/kg, the cumulative 10-day urinary excretion 
of a tracer dose of radio-selenite increased from 6 to 67% (Burk et 
al., 1972).  In contrast, the faecal excretion of selenium remained 
constant at about 10% of the dose over this range of dietary-
selenium intake.  Significant differences in the urinary excretion 
of selenium were demonstrated after dosing rats orally with various 
forms of selenium (Richold et al., 1977).  For example, the 
cumulative levels of selenium excreted in the urine, one week after 
dosing with selenite, selenocystine, selenomethionine, "rabbit 
kidney" selenium, and "fish muscle" selenium, were 14, 14, 5, 7, 
and 6% of the absorbed dose, respectively.  In many of these 

studies, the endogenous faecal excretion of selenium approached or 
exceeded urinary excretion.  These decreased urinary/faecal 
excretion ratios may have been characteristic of the different 
forms of selenium used or may have been due to the low selenium 
content of the stock diet fed to the animals (0.050 mg/kg or less). 

    The urinary-selenium excretion in animals suffering from 
chronic selenosis obviously exceeds any dietary threshold 
requirement, and cats poisoned with sodium selenite eliminated 
50 - 80% of the intake via this pathway, but only 20% or less in 
the faeces (Smith et al., 1938).  Cats poisoned with organic 
selenium in the form of seleniferous wheat protein excreted only 
40% of the ingested selenium in the urine, but this decrease in 
urinary output was more the result of increased selenium retention 
rather than increased faecal excretion. 

    The main urinary selenium metabolite of rats is trimethyl-
selenonium ion (Byard, 1969; Palmer et al., 1969).  This form 
accounts for 20 - 50% of the urinary selenium, regardless of the 
form of selenium given (Palmer et al., 1970).  A recent report 
indicates that trimethylselenonium ion accounts for a greater 
fraction of urinary selenium under conditions of high selenium 
exposure than under conditions of low exposure (Nahapetian et al., 
1983).  When selenate is injected into rats, over 35% of the 
urinary selenium is in an inorganic form, but less than 3% of the 
urinary selenium is inorganic when selenomethionine is injected 
into rats.  A major urinary metabolite that accounted for 11 - 28% 
of the total selenium in rat urine was not identified. 

    The faecal excretion of selenium is more important in ruminants 
than in non-ruminants.  For example, sheep given radio-selenite, 
orally, excreted 66% of the dose in the faeces, whereas swine 
excreted only 15% of the dose via this route (Wright & Bell, 1966).  
This increased faecal excretion of selenium by ruminants is the 
result of poor absorption rather than elevated endogenous 
excretion.  The selenite is thought to be reduced to insoluble or 
unavailable forms by rumen microorganisms. 

    The results of studies on rats have demonstrated that excretion 
of selenium by the exhalation of volatile compounds is 
quantitatively significant only when animals are injected with 
doses approaching almost lethal levels of soluble selenium salts 
(Olson et al., 1963).  A close dose-effect relationship between 
selenium exhalation and selenium exposure was observed, since the 
amount of selenium exhaled decreased as the amount of selenium 
administered decreased.  Rats fed toxic levels of selenium in the 
diet on a long-term basis, either as seleniferous wheat or sodium 
selenite, exhaled less than 2% of the selenium ingested. 

6.3.2.  Human studies

6.3.2.1.  Excretion of selenium

    Human volunteers dosed orally with microgram quantities of 
selenite or selenomethionine excreted 3 - 4 times more selenium in 
the urine than in the faeces over a 2-week collection period (Table 

13).  Subjects given selenite excreted roughly twice as much total 
selenium as subjects given selenomethionine, but the urinary 
pathway was dominant in both cases.  As might be anticipated from 
the low doses administered, losses of selenium via the dermal or 
pulmonary routes were negligible. 

Table 13.  Urinary and endogenous faecal 
excretion of radio-selenium by human beings 
over a 2-week perioda
----------------------------------------------
Labelled selenium  Urinary    Faecal excretion
compound           excretion  (endogenous)
----------------------------------------------
                       % of absorbed dose

selenite           18         5
selenomethionine   9          2
----------------------------------------------
a Adapted from:  Griffiths et al. (1976).

    Urinary excretion assumes greater importance when human beings 
ingest solutions of milligram quantities of selenium compounds that 
are soluble and also well absorbed (Table 14) (section 6.1.1.2).  
Volunteers given one milligram of selenium as selenate excreted 81% 
in the urine, over 3 times that excreted after similar sized doses 
of selenite-selenium, and was still twice as high when expressed as 
% absorbed dose.  Total excretions in urine and faeces for both 
selenite-selenium (63%) and selenate-selenium (90%) suggested that 
long-term retention of selenium was not high.  Much less of one 
milligram selenium as selenomethionine was excreted in urine and 
faeces (24% dose), which indicated that selenomethionine was 
mainly retained in comparison with selenate- and selenite-selenium.  
No pulmonary excretion was observed in one subject given one 
milligram of selenium as selenite (Thomson, 1974). 

Table 14.  Urinary and faecal excretion of one milligram 
doses of selenium by human volunteers during a 5-day 
perioda
--------------------------------------------------------
Selenium compound  Faecal excretion  Urinary excretion 
                   % dose            % dose  % absorbed
                                             dose
--------------------------------------------------------
Selenite           40                23      40

Selenate           8                 81      87

Selenomethionine   6                 18      20
--------------------------------------------------------
a Adapted from:  Thomson & Robinson (1986) (section 
  6.1.1.2).

    Urinary-selenium levels have long been used to monitor 
occupational selenium exposure (Glover, 1970), but little is known 
about the urinary excretion of selenium derived from foods.  The 

results of balance studies conducted in New Zealand suggested that 
roughly half of the dietary intake of selenium was excreted in the 
urine (Robinson et al., 1973; Stewart et al., 1978).  However, 
these subjects were ingesting small amounts of selenium (18 - 
34 g/day), and this relationship may not hold for persons with 
higher selenium intakes. 

    The importance of the kidneys in the homeostasis of selenium 
was emphasized by work from New Zealand that demonstrated that 
persons of low selenium status had low renal plasma clearances of 
selenium and excreted selenium more sparingly than others (Robinson 
et al., 1985). 

6.3.2.2.  Balance studies

    Metabolic trials, conducted on 4 New Zealand female volunteers 
in selenium balance, and consuming daily 18 - 34 g of selenium 
occurring naturally in the diet, showed that roughly equivalent 
amounts of selenium were voided in the urine and faeces.  In the 
USA, a controlled depletion/repletion study carried out on 6 
healthy young male volunteers in a metabolic unit (Levander et al., 
1980) indicated the rapidity with which both the urinary and faecal 
routes adjust to differences in selenium intake (Fig. 4, 5).  When 
the subjects were brought into the metabolic ward and given a low-
selenium formula diet providing 19 - 24 g selenium/day (depletion 
period), urinary-selenium excretion started to fall immediately and 
decreased from an initial level of 54  11 g/day to 29  5 g/day  
within 14 days.  Faecal selenium output also responded rapidly and 
declined from 33  13 g/day to 17  7 g/day, after only 3 days.  
During the time that the subjects were on the low-selenium diet and 
were in negative selenium balance, urinary excretion accounted for 
about 63% of the total selenium output (Table 15).  When the 
subjects were fed the low-selenium formula diet plus additional 
selenium in the form of seleniferous wheat and/or tuna fish (203 - 
224 g selenium/day), both urinary and faecal selenium excretion 
increased rapidly.  During this repletion period, the subjects were 
in positive selenium balance and urinary excretion comprised about 
45% of the total selenium output.  Thus, despite a 6-fold 
difference in selenium intake and a transition from negative to 
positive selenium balance, the proportion of selenium excreted in 
the urine remained relatively constant in terms of the total 
selenium output, when the selenium was supplied as it occurs 
naturally in foods. 

    The amount of selenium excreted in the sweat was found to be 
very low, and was not affected by changes in dietary-selenium 
intake (Table 16).  In agreement with these results, Griffiths et 
al. (1976) found very little radio-selenium in the sweat of 
subjects who had been given labelled selenite or selenomethionine.  
In the study by Levander et al. (1980), salivary-selenium levels 
were also very low, but appeared to reflect differences in dietary-
selenium intakes, since salivary-selenium was somewhat higher at 
the end of the repletion period than at the end of the depletion 
period (Table 16).  Hadjimarkos & Shearer (197l) found 1.1 - 5.2 g 
selenium/litre of saliva in normal children. 

FIGURE 4

FIGURE 5

Table 15.  Selenium balance during depletion and 
repletion periodsa
-----------------------------------------------------
                           Selenium balance          
                   Depletion period  Repletion period
-----------------------------------------------------
                   (g)              (g)

Urinary excretion  -1665  211       -2435  272

Faecal excretion   -985  103        -1919  228

Total excretion    -2650  257       -4354  295

Intake             +1524  173       +5424  248

Overall balance    -1126  268       +1070  482
-----------------------------------------------------
a Data expressed as mean  standard deviation.
  Adapted from:  Levander et al. (1981b).


Table 16.  Effect of selenium depletion and 
repletion on the selenium contents of saliva 
and sweat in young mena
---------------------------------------------
Body             Selenium content           
fluid   Start of       End of      End of
        study          depletion   repletion
---------------------------------------------
                (g selenium/litre)

Saliva  2.8  0.7b,c   1.4  0.4b  4.4  0.4c

Sweat   -              1.4  0.2   1.2  0.7
---------------------------------------------
a   Adapted from:  Levander et al. (1981b).
b,c Means in the same row with different 
    superscript letters differ significantly 
    ( P < 0.05, Duncan's multiple range test).  
    Data expressed as mean  SD.

6.4.  Retention and Turnover

6.4.1.  Animal studies

    Results of studies on rats have shown that the whole-body 
retention of a single injected dose of radioactive selenite is 
described by a curve that consists of an initial phase, a 
transition phase, and an extended phase (Ewan et al., 1967; Burk et 
al., 1972).  During the initial equilibration phase, there is a 
distribution of radioactive selenium throughout the tissues and a 
rapid excretion of radio-selenium in the urine, faeces, and, if the 
dose is sufficiently high, the expired air.  The initial phase is 
followed by a transition phase, during which the rate of loss of 
radio-selenium is less than that in the initial phase but greater 

than that in the final extended phase.  The extended phase consists 
of a slow constant rate of radio-selenium loss which represents the 
long-term whole-body turnover of selenium.  Increasing the dose of 
radioactive selenite administered decreased the percentage of the 
dose retained during the initial phase, but did not have any effect 
on radio-selenium retention during the extended phase.  Increasing 
the level of dietary selenium increased the turnover of radio-
selenium during both the initial and extended phases.  For example, 
supplementing the diet with 0.95 mg selenium/kg decreased the 
biological half-life of radio-selenium, during the extended phase, 
from 78 to 27 days.  The extended phase of radio-selenium retention 
in rats was shown by Richold et al. (1977) to be largely 
independent of the route of administration and the chemical form of 
selenium given.  Thus, after the initial period, it appears that 
selenium from a variety of sources is ultimately incorporated into 
the same metabolic pool in rats.  The apparent "whole-body" 
retention of radio-selenium during the extended phase is an average 
of several discrete processes, since each internal organ has its 
own characteristic rate of selenium turnover.  For example, the 
biological half-times of radio-selenium in the kidneys, whole body, 
and skeletal muscle of rats were 38, 55, and 74 days, respectively 
(Thomson & Stewart, 1973). 
                                                                     
    Information on the retention of selenium by animals became of 
practical significance when approval was sought for the use of 
selenium as a feed additive to prevent nutritional deficiency 
diseases (section 4).  Because of the toxicity of high levels of 
selenium, there was some concern about the possible build up of 
residues in the edible flesh of animals supplemented with selenium.  
Scott & Thompson (1971) noted very little increase in the 
concentrations of selenium in the tissues of chicks or poults fed 
low-selenium diets supplemented with 0.2 - 0.8 mg selenium/kg as 
sodium selenite.  However, feeding a diet naturally high in 
selenium, but not toxic (0.67 mg/kg) resulted in substantially 
increased tissue-selenium levels. 

    Scott & Thompson (1971) also showed that addition of sodium 
selenite to a diet that was naturally high in selenium did not 
produce any further increase in tissue-selenium levels.  In further 
studies on turkeys, swine, sheep, and cattle, animal feeds, 
naturally low or marginal in selenium, were supplemented with 
nutritional levels of selenium (0.1 - 0.5 mg/kg) as sodium selenite.  
Resulting tissue-selenium concentrations were not any higher than 
those that would be expected if the animals were fed diets 
naturally adequate in selenium (Groce et al., 1971; Cantor & Scott, 
1975; Ullrey et al., 1977). 

    These observations are in agreement with those from earlier 
work with toxic levels of selenium, which indicated that naturally-
occurring organically-bound selenium was retained in the tissues to 
a much greater extent than inorganic selenium (Smith et al., 1938).  
Martin & Hurlbut (1976) fed mice high levels of selenium as 
selenite, selenium-methylselenocysteine, or selenomethionine.  
After 7 weeks, the mice fed selenomethionine had much higher levels 
of selenium in their tissues than those fed either selenite or 
selenium-methylselenocysteine.  Moreover, when the various selenium 

compounds were removed from the diet, selenium was retained more 
strongly in the tissues of the mice fed the selenomethionine than 
in those of the mice fed selenite or selenium-methylselenocysteine.  
The results of this study showed that a distinction more precise 
than inorganic versus organic must be made when discussing the 
metabolism of selenium compounds, since the metabolism of selenium-
methylselenocysteine resembled that of selenite rather than that of 
selenomethionine. 

    Differences in the retention of selenite compared with 
selenomethionine were also observed when these 2 forms of selenium 
were fed in the diet at nutritional levels.  For example, Miller et 
al. (1972) showed that the total body selenium content of chicks 
was increased by an average of 29.1%, when 0.025 - 0.500 mg of 
selenium as selenomethionine was fed per kg of diet, but was 
increased only by 17.9% when selenium as selenite was fed at 
similar levels. 

    Selenium retained by female animals can apparently be used 
later to protect their offspring against the effects of selenium 
deficiency.  Allaway et al. (1966) fed ewes alfalfa containing 
2.6 mg selenium/kg for 5 months followed by a diet low in selenium.  
The ewes were able to transmit levels of selenium to their lambs 
that protected them against White Muscle Disease, even though the 
lambs were born 10 months after the low-selenium diet was first 
administered. 

6.4.2.  Controlled human studies

    As in the case of rats, the total body retention curves of 
radioactive selenium in human beings can be resolved into 3 
components (Griffiths et al., 1976).  However, oral doses of 
75Se-selenomethionine are retained more strongly and turned over 
more slowly than oral doses of 75Se-selenite (Table 17).  This 
metabolic difference between selenomethionine and selenite holds 
true, even if the compounds are administered by intravenous 
injection (Lathrop et al., 1972; Falk & Lindhe, 1974).  These 
results differ with those obtained in rats in which several forms 
of selenium apparently were incorporated into the same long-term 
metabolic pool and were thus turned over at similar rates (Richold
et al., 1977).  On this basis, it was suggested that 
selenomethionine, or food-selenium in a form that produced 
selenomethionine after digestion, might prove more effective than 
selenite in improving a low-selenium status or in correcting 
selenium deficiency in man (Griffiths et al., 1976). 

Table 17.  Retention of oral doses of selenite and selenomethionine by 
human beingsa
----------------------------------------------------------------------
                  Whole-body selenium   Biological half-times for
Form of           retention 14 days     whole-body selenium retention 
selenium          after dose            phase 1  phase 2  phase 3
given             (% of absorbed dose)          (days)
----------------------------------------------------------------------
selenite          78                    1.0      8        103
selenomethionine  89                    1.7      18       234
----------------------------------------------------------------------
a Adapted from:  Griffiths et al. (1976).

    Thomson et al. (1982) gave 100 g doses of selenium as 
selenomethionine or sodium selenite to 12 New Zealand volunteers 
over a period of several weeks.  Blood glutathione peroxidase (EC 
1.11.19) activity increased in all subjects and, at 17 weeks, 
the response was similar in both selenomethionine and selenite 
groups.  Increases in blood-selenium levels were greater after 
supplementation with selenomethionine than with selenite.  Selenium 
levels tended to plateau in the selenite-treated subjects but kept 
increasing in the selenomethionine-treated subjects.  Similar 
differences in the retention and turnover of selenium as selenate 
compared with selenium in selenium-rich yeast or wheat were 
observed in a bioavailability trial in Finland (Levander et al., 
1983) (section 5.1.1.6).  Thus, it appears that feeding of selenium 
bound in organic form (selenomethionine, selenium-rich yeast or 
wheat) results in higher blood-selenium levels than the feeding of 
selenium as selenate or selenite, but there is no difference in the 
glutathione peroxidase activities ultimately achieved during 
supplementation.  However, when the selenium supplements were 
discontinued, the glutathione peroxidase activities remained 
somewhat elevated in the groups receiving the wheat or yeast 
compared with those receiving selenate.  Apparently, the selenium 
in the yeast or wheat retained in the tissues could be used for 
glutathione peroxidase production after the selenium supplement was 
discontinued. 

6.5.  Metabolic Transformation

    Some metabolic transformations of selenium compounds are 
outlined in Fig. 6.  This scheme tends to emphasize the central 
role of selenite, but other forms of selenium may have important 
characteristic pathways of their own, under certain conditions 
(e.g., the direct incorporation of selenomethionine as such into 
tissue proteins). 

FIGURE 6

6.5.1.  Animal studies

6.5.1.1.  Reduction and methylation

    The main flow of selenium metabolism in animals is via 
reductive pathways, which contrasts with the primarily oxidative 
metabolism of sulfur (Levander, 1976a).  Selenite can react with 
glutathione or protein sulfhydryls to form selenotrisulfides 
(Ganther, 1968; Jenkins & Hidiroglou, 1971) which, at least in the 
case of the glutathione derivatives, can be reduced further by an 
enzymatic mechanism to selenide (Ganther & Hsieh, 1974; Diplock, 
1976). 

    Under normal conditions, selenide is methylated to form 
trimethylselenonium ion, the main urinary metabolite of selenium 
(section 6.3.1).  In cases of selenium toxicity, this pathway is 
overloaded and dimethyl selenide is produced.  This is the main 
volatile selenium metabolite expired via the lungs and is 
responsible for the typical "garlicky odour" of animals poisoned 
with selenium (McConnell & Portman, 1952a).  The last 2 reactions 
could be considered detoxication steps, since the methylated end-
products are much less toxic for the organism than selenite 
(McConnell & Portman, 1952b; Obermeyer et al., 1971).  However, 
both of these methylated selenium derivatives have strong 
synergistic toxicity with other minerals (section 7) and dimethyl 
selenide toxicity in male rats was reported to be inversely related 
to the level of previous selenium intake (Parizek et al., 1980). 

6.5.1.2.  Form in proteins

    Early work with animals poisoned with selenium revealed that 
much of the selenium in the tissues was associated with protein 
(Smith et al., 1938).  Since that time there has been considerable 
controversy about the exact chemical nature of the selenium in 
tissue proteins (Levander, 1976a).  Selenomethionine may be 
incorporated initially as such into animal proteins (Ochoa-Solano 
& Gitler, 1968), but, in rats, it appears to be eventually 
catabolized to selenite or selenate (Millar et al., 1973; Thomson 
& Stewart, 1973).  Non-ruminant animals cannot synthesize 
selenomethionine from inorganic selenium compounds (Cummins & 
Martin, 1967; Olson & Palmer, 1976), but rabbits and rats can 
convert selenite into selenocysteine tissue proteins (Godwin & 
Fuss, 1972; Olson & Palmer, 1976).  Forstrom et al. (1978) have 
proposed that seleno-cysteine is the form of selenium located at 
the catalytic site of glutathione peroxidase and others have shown 
that selenocysteine is essential for the activity of clostridial 
glycine reductase (Cone et al., 1976).  The mechanism by which 
selenocysteine is formed from selenite is not known but 
incorporation of preformed selenocysteine and post-translational 
modification of the protein have been considered (Sunde, 1984).  
Other possible forms of selenium in proteins include 
selenotrisulfides (Ganther & Corcoran, 1969) and "acid-labile" 
selenium (Diplock et al., 1973). 

6.5.1.3.  Conversion of selenium compounds to nutritionally-active 
forms of selenium

    The pioneering studies of Schwarz & Foltz (1958) demonstrated 
that a variety of selenium compounds could protect against dietary 
liver necrosis in vitamin E- and selenium-deficient rats.  Sodium 
selenite, sodium selenate, selenium dioxide, selenic acid, and 
potassium selenocyanate were all more or less equally active, but 
elemental gray selenium was essentially inactive.  Selenocystine 
and selenomethionine were about as effective as the active 
inorganic selenium compounds, but an organic selenium fraction 
isolated from pig kidney powder (Factor 3) was shown to be even 
more active.  A number of organic derivatives of selenium have 
shown some protective effect against liver necrosis, but none was 
superior to Factor 3 (Schwarz et al., 1972).  However, certain 
simple amino-acid derivatives of monoseleno diacetic acid showed 
some promise in that they combined high nutritional potency with a 
low order of toxicity (Schwarz, 1976).  The effects of selenite and 
selenomethionine were shown to be roughly similar in inducing 
glutathione peroxidase activity in the tissues of rats fed a diet 
deficient in selenium (Pierce & Tappel, 1977). 

    Cantor et al. (1975a) found that while selenite and 
selenocystine were equally effective in preventing exudative 
diathesis in vitamin E- and selenium-deficient chicks, seleno-
methionine was less effective.  This suggests a difference between 
rats and chicks in the metabolism of selenomethionine.  The degree 
of protection against exudative diathesis and the level of plasma 
glutathione peroxidase activity were highly correlated, suggesting 
that nutritional potency depended on the ability of the chick to 
convert various selenium compounds to the enzymatically active 
form. 

6.5.2.  Human studies

    Few studies have been carried out to investigate the metabolic 
transformation of selenium compounds in human beings, but the 
limited data available suggest certain similarities in the 
metabolism of selenium by man and animals.  For example, human 
beings overexposed to selenium develop breath with a smell of 
garlic, which is presumably due to the exhalation of dimethyl 
selenide (Glover, 1976).  Also, the chromatographic pattern of 
urinary-selenium metabolites is the same in man and the rat (Burk, 
1976).  However, species differences in selenium metabolism do 
exist, since human beings retain selenomethionine to a much greater 
extent than selenite, whereas the retention of the 2 compounds in 
rats is about the same (section 6.4.2). 

7.  EFFECTS OF SELENIUM ON ANIMALS

    The considerable biological importance of selenium was first 
recognized in the 1930s when it was discovered that certain well-
defined and economically important farm animal diseases were 
actually the result of chronic selenium poisoning (section 7.1).  
These animal diseases were restricted to agricultural areas in 
which large amounts of selenium in the soil were available for 
uptake by the plants, which were then consumed by the animals.  
Research, over the last 20 years, showed that selenium was an 
essential trace element (section 7.2), and selenium deficiency 
diseases were rapidly recognized in several species of farm 
animals.  These deficiency diseases are significant economic 
problems in areas of the world where the soil levels of the 
element available for uptake by plants are low. 

7.1.  Selenium Toxicity

7.1.1.  Farm animal diseases associated with a high selenium intake

    On the basis of field experience, Rosenfeld & Beath (1964) 
delineated 3 different types of selenium poisoning in livestock: 

    (a)  acute;

    (b)  chronic, of the blind staggers type; and

    (c)  chronic, of the alkali disease type.

    Acute poisoning is due to the ingestion of toxic quantities of 
selenium in the form of highly seleniferous accumulator plants.  
The animal has severe signs of distress such as laboured breathing, 
abnormal movement and posture, prostration, and diarrhoea.  Death 
often follows within a few hours.  This type of selenium poisoning 
is rather rare under field conditions, since grazing animals 
generally avoid the selenium accumulator plants, except in times of 
pasture shortage.  Acute selenium poisoning has also been produced 
by the experimental or accidental administration of selenium 
compounds to farm animals (US NAS/NRC, 1976). 

    Blind staggers has been reported in animals that eat a limited 
number of selenium accumulator plants over a period of weeks or 
months (Rosenfeld & Beath, 1964).  The affected animals wander, 
stumble, have impaired vision, and eventually succumb to 
respiratory failure.  Although this type of poisoning can be 
produced experimentally by the administration of water extracts of 
accumulator plants, it has not been possible to duplicate this 
syndrome by the administration of pure selenium compounds.  
Possibly alkaloids or other toxic substances found in many 
seleniferous plants may contribute to blind staggers (Maag & Glenn, 
1967; Van Kampen & James, 1978). 

    Alkali disease is associated with the consumption of grains 
containing 5 - 40 mg selenium/kg over weeks or months.  Animals 
exhibit liver cirrhosis, lameness, hoof malformations, loss of 
hair, and emaciation.  Maag & Glenn (1967) were unable to produce 
alkali disease in cattle by feeding inorganic selenium, but several 
other studies have shown that the syndrome is causally associated 
with seleniferous grains or grasses and can be produced by feeding 
inorganic selenium salts (Olson, 1978). 

    The Task Group noted that most of the work on alkali disease 
was concerned with cattle, but was aware of the report by Ermakov & 
Kovalskij (1968), which described chronic selenium toxicity of this 
type in sheep, under natural conditions.  In sheep fed feeds 
containing levels of 2 mg selenium/kg feed (fresh weight), the 
following characteristic signs were observed:  hoof deformation, 
loss of hair, hypochromic anaemia, and increases in the activity of 
both alkaline and acid phosphatases in various tissues. 

7.1.2.  Toxicity in experimental animals

    The practical significance of selenium poisoning in farm 
animals stimulated a great deal of research on both the acute and 
chronic effects of selenium in laboratory animals.  Interest in the 
toxic effects of repeated exposure to selenium via inhalation was 
stimulated by concern about the possible effects on human health of 
occupational exposure to selenium.  Also, studies were carried out 
with the aim of establishing the no-observed-adverse-effect dose 
level of selenium when administered in the drinking-water.  In some 
of the studies in which selenium was given via either the air or 
water, biochemical and/or behavioural criteria were used to assess 
the biological effects of selenium exposure.  However, as discussed 
in section 7.1.6, the toxicity of selenium compounds can be 
influenced by different variables and the results from various 
laboratories are often not comparable because of quite different  
experimental conditions.  Also, the criteria for toxicity are less 
developed than the signs of deficiency (section 7.2). 

    Reviews that deal with various aspects of selenium toxicology 
include those by Rosenfeld & Beath (1964), Muth (1966), Izraelson 
et al. (1973), Ermakov & Kovalskij (1974), US NAS/NRC (1976), and 
Lazarev (1977). 

7.1.2.1.  Acute and subacute toxicity - single or repeated exposure
studies with oral, intraperitoneal, or cutaneous administration

    Perhaps the most characteristic sign of acute selenium 
poisoning in animals is the development of the so-called "garlicky 
breath odour", which is due to the pulmonary excretion of volatile 
selenium compounds, particularly dimethyl selenide, by animals 
overexposed to selenium (section 6.3.1).  Other signs of acute 
selenium poisoning described by Franke & Moxon (1936) in dogs and 
rats included:  vomiting, dyspnoea, tetanic spasms, and death from 
respiratory failure.  Pathological changes included congestion of 
the liver with areas of focal necrosis, congestion of the kidney, 
endocarditis, myocarditis, peticheal haemorrhages of the 

epicardium, atony of the smooth muscles of the gastrointestinal 
tract, gall-bladder, and bladder, and erosion of the long bones, 
especially the tibia.  The LD50 values for sodium selenite, 
administered orally to various animal species, are given in Table 
18 (Pletnikova, 1970). 

Table 18.  Acute oral toxicity of sodium selenite for various
species of laboratory animalsa
-------------------------------------------------------------
Species              LD50             Statistical method
                     (mg selenium/kg
                     body weight)
-------------------------------------------------------------
White mouse (male)   7.75             Behrens & Schlosser
                     7.08             Litchfield & Wilcoxon

Albino rat (female)  10.50            Behrens & Schlosser
                     13.19            Diechmann & LeBlanc

Guinea-pig (female)  5.06             Deichmann & LeBlanc

Rabbit (female)      2.25             Diechmann & LeBlanc
-------------------------------------------------------------
a From:  Pletnikova (1970).
Table 19.  Acute toxicity of some selenium compounds administered to rats by 
intraperitoneal injection
----------------------------------------------------------------------------
Compound             Criterion  Toxic dose       Reference
                     of         (mg selenium/kg
                     toxicity   body weight)
----------------------------------------------------------------------------
Sodium selenite      MLD        3.25 - 3.5       Franke & Moxon (1936)

Sodium selenate      MLD        5.25 - 5.75      Franke & Moxon (1936)

DL-selenocystine     MLD        4                Moxon (1940)

DL-selenomethionine  MLD        4.25             Klug et al. (1950)

Diselenodipropionic  LD50       25 - 30          Moxon et al. (1938)
 acid

Trimethylselenonium  LD50       49.4             Obermeyer et al. (1971)
 chloride

Dimethyl selenide    LD50       1600             McConnell & Portman (1952b)
----------------------------------------------------------------------------
    For a given species, the lethal doses of sodium selenite, 
sodium selenate, DL-selenocystine, and DL-selenomethionine are 
quite similar (Table 19).  Although certain methylated metabolites 
of selenium such as dimethylselenide and trimethylselenonium 
chloride were considered relatively innocuous (see LD50 values by 
McConnell & Portman and Obermeyer et al. in Table 19), more recent 

work by Parizek et al. (1976, 1980) has shown that the toxicity of 
methylated selenium compounds depends not only on the sex of the 
animal (Parizek et al., 1974) but also on the level of previous 
selenium intake.  For example, 90% mortality was observed in male 
rats maintained on a diet containing 0.05 mg selenium/kg, when they 
were injected intraperitoneally with 20 moles dimethylselenide/kg 
body weight, i.e., by a dose of dimethylselenide that is more than 
1000 times lower than the LD50 reported by McConnell & Portman
(1952b).  Pre-treatment with a small amount of selenite (1 mol/kg 
body weight), intraperitoneally, 6 h, but not 1 h, before 
dimethylselenide injection or increased oral intake of selenite 
(Table 20), protected male rats against the toxicity of a 
subsequent dose of dimethylselenide (Parizek et al., 1976, 1980).  
Moreover, the methylated forms of selenium have strong synergistic 
toxicities with other minerals (section 7.1.6.3, 7.4.1) and 
dimethylselenide can be much more toxic for male rats than for 
female rats (section 7.1.6). 

Table 20.  Dependence of the toxicity of dimethylselenide on 
the level of previous oral intake of seleniuma
------------------------------------------------------------
Selenite        Single intraperitoneal    24-h mortality (%)
supplement in   dose of dimethylselenide  Diet A    Diet B
drinking-water
(mg selenium/   (mg mole/kg body weight)  (n = 20)  (n = 10)
litre
------------------------------------------------------------
0               20                        90        90
0.1             20                        45        30
0.5             20                        5         0
1.0             20                        0         0
------------------------------------------------------------
a Adapted from:  Parizek et al. (1976, 1980).

     Male rats (2 months old) given drinking-water with stated 
 supplement of selenite for 3 days before dimethylselenide 
 administration.  Diet A contained 0.052  0.005 mg selenium/kg and 
 diet B (semi-synthetic diet) 0.044  0.001 mg selenium/kg. 

    Smith et al. (1937) reported that the minimum lethal dose 
of selenium as sodium selenite or selenate in rabbits, rats, 
and cats was 1.5 - 3.0 mg/kg body weight, regardless of whether 
the compounds were administered orally, subcutaneously, 
intraperitoneally, or intravenously.  This lack of effect of the 
mode of administration probably reflects the rapid and complete 
absorption of soluble selenium compounds, either from the site of 
injection or from the gastrointestinal tract. 

    Cummins & Kimura (1971) described comparative studies on 
Sprague Dawley rats and dogs concerning the oral toxicity of the 
following selenium compounds:  sodium selenate, selenourea, 
biphenylselenium, selenium sulfide (1 - 30  particle size), and 
elemental selenium (1 - 30  particle size).  The oral LD50 values 
in rats for a number of selenium compounds are shown in Table 21 

and demonstrate the large variations in LD50 values that occur, 
depending on both the oxidation state of the compound and its 
aqueous solubility. 

Table 21.  Comparative solubility and toxicity of various
selenium compounds in ratsa
--------------------------------------------------------------
Compound      Solubility in 0.01 N HCl  Rat oral LD50 (95% CL)
                                        (mg/kg body weight)
--------------------------------------------------------------
Na2SeO3       700 g/litre               7 (4.4 - 11.2)

H2N-C-NH2     30 g/litre                50 (35.7 - 70.0)
    ||
    Se

SeS2          insoluble (< 1 g/litre)   138 (110 - 172)

Se            5 g/litre                 360 (308 - 421)

Elemental Se  insoluble (< 1 g/litre)  6700 (6000 - 7300)
--------------------------------------------------------------
a From:  Cummins & Kimura (1971).

     Male Sprague Dawley rats, each weighing between 50 and 100 g, 
 were given the above chemicals by gavage as 0.1 - 20% suspensions 
 in 0.5% methylcellulose.  A total of 30-36 animals was used per 
 compound, in groups of 6 animals per dose.  The LD50 values and 
 the associated confidence limits (CL) were calculated according to 
 the method of Litchfield & Wilcoxon. 

    The aqueous solubilities were carried out in 0.01 N HCl to more 
closely simulate acidic conditions in the stomach.  The least toxic 
selenium compound was insoluble elemental selenium with an LD50 of 
6.7 g/kg body weight.  Toxic signs included pilomotor activity, 
decreased body activity, dyspnoea, diarrhoea, anorexia, and 
cachexia.  Fatalities occurred within 18 - 72 h; survivors appeared 
outwardly normal, at the end of the 7-day observation period.  The 
most toxic of the selenium compounds tested was the highly soluble 
sodium selenite with an oral LD50 of 7 mg/kg body weight and the 
toxic signs were similar to those seen with high doses of elemental 
selenium.  Selenium sulfide (a component in shampoos) was about 20 
times less toxic than sodium selenite (i.e., an LD50 of 138 mg/kg 
compared with 7 mg/kg).  It was also found in this study that, with 
the exception of biphenyl selenium, toxicity could be correlated 
with blood-selenium levels.  For example, sodium selenite being the 
most toxic, gave the highest blood level followed in descending 
order by selenourea, selenium sulfide, and elemental selenium.  It 
was suggested that the blood-selenium level produced by the 
relatively non-toxic biphenyl selenium was high because this 

covalently-bound selenium compound is the most lipophilic compound, 
which is better absorbed, resists catabolism, and apparently 
circulates as the parent compound. 

    The application of 83 mg of selenium oxychloride to the skin of 
rabbits caused the death of the animals in 5 h, and application of 
4 mg caused death in 24 h (Dudley, 1938).  Lazarev (1977) reported 
a minimum lethal dose of selenium oxychloride of 7 mg/kg body 
weight, after cutaneous administration to rabbits. 

    Several papers have shown that injection of selenite in rats in 
the early postnatal period in single doses of 1.5 mg selenium/kg 
body weight, or in repeated doses of 0.5 mg/kg, induced cataracts 
(Ostadalova et al., 1979; Bhuyan et al., 1981; Shearer et al., 
1980; Bunce et al., 1985).  Similar effects have not been observed 
in hamsters (Shearer et al., 1980).  This response is dose 
dependant (Table 22) and, thus far, has been observed only when the 
selenite was given by parenteral injection. 

Table 22.  Cataractagenesis by selenite in the rata
--------------------------------------------------
Group     Daily dosageb    Frequency of cataractsc
          (mg selenium/kg  (%)
          body weight)
--------------------------------------------------
Control   0                0

Na2SeO3   0.25             13

Na2SeO3   0.50             96

Na2SeO3   0.75             96
--------------------------------------------------
a Adapted from:  Shearer et al. (1980).
b Dose given to rat pups daily on days 2-18 
  postpartum.
c Observed at 21 days of age.

7.1.2.2.  Effects of long-term oral exposure

    Moxon & Rhian (1943) summarized several older studies that 
indicated that diets containing 5 mg selenium/kg or more cause 
chronic selenosis in several species of animals, such as chickens, 
rats, and dogs.  In seleniferous areas, 5 mg selenium/kg diet is 
generally accepted as the dividing line between toxic and non-toxic 
feeds (US NAS/NRC, 1976). 

    Halverson et al. (1966) fed diets containing 0, 1.6, 3.2, 4.8, 
6.4, 8.0, 9.6, or 11.2 mg selenium/kg in the form of sodium 
selenite or seleniferous wheat to male Sprague Dawley rats, 
initially weighing 60 - 70 g.  The rats were divided into groups of 
8 and were fed the diets for 6 weeks.  The diet consisted of (g/kg) 
ground wheat, 809; purified casein 120; USP salt mixture XIV, 20; 
USP brewer's yeast, 20; corn oil, 30; and vitamin B12 mix, 1.  
Vitamins A, D, and E were provided separately.  The criteria used 

to assess toxicity were growth depression, liver cirrhosis, 
splenomegaly, pancreatic enlargement, anaemia, elevated 
serumbilirubin levels, and death.  The addition to the diet of 1.6, 
3.2, or 4.8 mg selenium/kg did not have any significant effect on 
the rats, as judged by any of these criteria.  There was a 
depression in growth in the group that received 4.8 mg dietary 
selenium/kg as sodium selenite, but this was not significant.  
Liver cirrhosis, splenomegaly, and significant growth depression 
were observed when the rats were fed levels of 6.4 mg/kg or more 
from either source of selenium.  Diets containing 8.0 mg/kg or more 
caused additional effects such as pancreatic enlargement, anaemia, 
elevated serum-bilirubin levels, and, after 4 weeks, death. 

    Diets made either with non-seleniferous or seleniferous sesame 
meal were fed to groups of 12 male Sprague Dawley rats, initially 
weighing 50 g for a period of 6 weeks (Jaffe et al., 1972b).  The 
diet made with non-seleniferous sesame meal contained 0.5 mg 
selenium/kg and consisted of (g/kg):  non-seleniferous sesame meal, 
463.3; almidon, 422.7; corn oil, 50; cod liver oil, 10; USP XVI 
salts, 40; L-lysine x HCl, 4; and vitamin mix, 10.  The diet made 
with the seleniferous sesame meal contained 10 mg selenium/kg and 
had the same composition as the previous diet except that 
seleniferous sesame, which replaced the non-seleniferous sesame 
meal, was added at a level of 490.2 g/kg, and the almidon was added 
at a level of 395.8 g/kg.  The rats fed the diet containing the 
seleniferous sesame meal showed decreased survival, impaired weight 
gain, higher incidence of liver lesions, elevated hepatic selenium 
levels, enlarged spleens, depressed haemoglobin, haematocrit, and 
fibrinogen levels, and decreased prothrombin activity (Table 23).  
In a separate study, the same workers investigated the effects of 
dietary selenium, given as seleniferous sesame meal, on the 
activities of various serum enzymes (Table 24).  The diet 
containing 4.5 mg selenium/kg had the same composition as the 
previous diets, except that the seleniferous sesame meal, non-
seleniferous sesame meal, and almidon were added at levels of 
230.8, 270.4, and 384.8 g/kg, respectively.  Feeding the diet 
containing 4.5 mg of selenium/kg for 6 weeks increased the 
activities of serum alkaline phosphatase (EC 3.1.3.1) and glutamic 
pyruvic transaminase (SGPT) (EC 2.6.1.2), whereas 10.0 mg/kg also 
increased the activity of glutamic-oxaloacetic transaminase (SGOT) 
(EC 2.6.1.1). 


Table 23.  Pathological signs in rats fed diets containing seleniferous sesame meala
--------------------------------------------------------------------------------------------------------------------
Dietary   Survival  Weight       Rats     Hepatic      Spleen        Haemo-     Haema-       Fibrinogen  Prothrombin
selenium  after     gain         with     selenium     weight        globin     tocrit                   activity
          6 weeks   after        hepatic  level                      level      value
                    6 weeks      lesions
--------------------------------------------------------------------------------------------------------------------
(mg/kg)             (g)                   (mg/kg)      (% of body    (g/litre   (volume %)   (mg/litre)
                                                       weight)       blood)

0.5       12/12     156.8  7.2  0/12     0.72  0.14  0.207  0.01  147  2.1  43.9  0.61  1664  78   963  9.5

10        8/12      61.2  7.43  10/12    7.34  0.97  0.544  0.09  123  3.5  40.8  0.82  655  78    713  76.6
--------------------------------------------------------------------------------------------------------------------
a  Adapted from: Jaffe et al. (1972b).
Table 24.  Effect of chronic selenium toxicity on the
activity of serum enzymesa
-------------------------------------------------------
Dietary    Number   Alkaline     SGOT        SGPT
selenium   of rats  phosphatase
-------------------------------------------------------
(mg/kg)             (units/ml)   (units/ml)  (units/ml)

0.5        6        6.3  0.2    66  3      20  1
4.5        10       8.8  1.3    59  2      26  2
10         8        18.9  2.3   77  5      43  6
-------------------------------------------------------
a Adapted from:  Jaffe et al. (1972b).

    Tinsley et al. (1967) and Harr et al. (1967) carried out an 
extensive study on the chronic toxicity of selenium in rats.  
Although the primary purpose of their research was to investigate 
the alleged carcinogenicity of selenium (section 7.7.1), the design 
of their study provided an opportunity to examine other aspects of 
the toxicity of selenium, such as the influence of selenium 
poisoning on growth rate and histopathology.  A total of 1437 
Wistar rats from a closed random-bred colony was used with the size 
of the experimental groups ranging from 10 - 110 animals.  The rats 
were fed one of 3 different diets:  a semipurified diet containing 
either 12 or 22% casein or a commercial "laboratory chow" type 
ration.  The casein-based diets also contained corn oil, 50 g; 
H.M.W. salts, 40 g; vitamin mix, 10 g; and glucose monohydrate 
(Cerelose) up to a weight of 1 kg.  Selenium as sodium selenite or 
sodium selenate was added at levels of 0, 0.5, 2.0, 4.0, 8.0, or 
16.0 mg/kg.  Only a small proportion of the animals fed diets 
supplemented with more than 4.0 mg/kg of selenium survived for 12 
months.  The rats fed the commercial ration were 2 - 3 times more 
resistant to the effects of selenium toxicity than the rats fed the 
semipurified diet.  A calculated maximum body weight was reported 
to be depressed by as little as 0.5 mg selenium/kg, but no 
statistical evaluation of the results was presented.  Usually 
moribund animals were killed and necropsied for histopathological 
determinations, but 136 rats were killed at specific ages. 

    Acute toxic hepatitis was the predominant histopathological 
lesion in rats fed the commercial ration supplemented with sodium 
selenate at 16 mg selenium/kg.  These rats had a median survival 
age of only 96 days.  Acute toxic hepatitis was also observed in 
rats fed the 12% casein diet supplemented with sodium selenate at 4 
or more mg selenium/kg.  The rats were emaciated, pale, and had 
poor quality hair coat.  Hydrothorax, ascites, pericardial oedema, 
and icterus were common.  Myocardial hyperaemia, fluid imbalance, 
and parenchymal degeneration were often present.  The adrenals were 
enlarged and the pancreas was oedematous.  The failure of normal 
chondrocyte proliferation observed in the metaphyses appeared to be 
different from that seen in malnutrition, since proliferation was 
irregular and not merely reduced. 

    When rats were fed the commercial ration supplemented with 
sodium selenate at 8 mg selenium/kg, the predominant lesion was 
chronic toxic hepatitis.  The median survival age in this group was 
429 days.  Other histopathological changes reported included 
pancreatic duct hyperplasia, intestinal nephritis, and myocardial 
damage, particularly in rats of more than 450 days of age and 
receiving selenite. 

    Harr et al. (1967) reported an increased proliferation of the 
hepatic parenchyma when the rats were fed the semi-purified diet 
supplemented with 0.5 - 2.0 mg selenium/kg as selenite or selenate.  
But a more detailed report from this laboratory (Weswig et al., 
1966) showed that this lesion of "chronic liver and bile duct 
hyperplasia" was observed to a greater extent in rats fed the 
commercial ration not supplemented with selenium than in rats fed 
the semi-purified diet supplemented with 0.5 mg selenium/kg.  Thus, 
this lesion may not be specifically related to selenium. 

    Harr & Muth (1972) stated that 0.25 mg/kg was the minimum toxic 
level for liver lesions, when selenium was added to a semi-purified 
diet.  The minimum toxic level was 0.75 mg/kg when the criteria 
were longevity or lesions of the heart, kidneys, or spleen.  
However, growth was normal in rats fed 0.5 mg selenium/kg diet.  
The authors estimated that the dietary threshold for physiological 
and pathological effects was 0.4 mg/kg and for pathological and 
clinical effects, 3 mg/kg. 

    Weanling rats of the Long-Evans strain were given either sodium 
selenite or selenate at 0 or 2 mg selenium/litre in the drinking-
water for 1 year (Schroeder & Mitchener, 1971b).  After 1 year, the 
selenium dosage was increased to 3 mg/litre in the selenate group.  
The weanlings were born from random-bred females that had been fed 
a low-selenium diet (0.05 mg selenium/kg) consisting of:  whole rye 
flour, 600 g; dry skim milk, 300 g; corn oil, 90 g; and iodized 
sodium chloride to which were added vitamins and iron, 1 g/kg.  The 
same diet was fed to the weanlings during the toxicity study.  The 
drinking-water was doubly deionized forest spring water to which 
had been added: zinc, 50 mg; manganese, 10 mg; chromium(III), 5 mg; 
copper, 5 mg; cobalt, 1 mg; and molybdenum, 1 mg/litre. The rats 
given the selenium compounds (plus another group not discussed here 
given sodium tellurite) were divided into groups totalling 313 
animals.  There were 105 control rats.  By 58 days, half of the 
male rats in the selenite group were dead.  Fifty percent mortality 
in the group of female rats given selenite was not achieved until 
348 days and was not achieved in the male and female groups given 
selenate until 962 and 1014 days, respectively.  On the other hand, 
Palmer & Olson (1974) gave 2 or 3 mg selenium/litre drinking-water, 
in the form of either sodium selenite or selenate to male weanling 
Sprague Dawley rats for 6 weeks and noted small decreases in weight 
gain compared with control rats receiving selenium, but no deaths.  
Two diets were used in this study, a rye diet similar to that 
described by Schroeder & Mitchener above and a corn diet that 
consisted of ground corn, 808 g; casein, 120 g; corn oil, 30 g; 
U.S.P. XIV salts, 20 g; and vitamin mix, 22 g/kg.  The trace 

elements zinc, copper, manganese, chromium, cobalt, and molybdenum 
were also added to the drinking-water, as suggested by Schroeder & 
Mitchener (1971a). 

    In a study by Jacobs & Forst (1981a), sodium selenite at 0 or 4 
mg selenium/litre drinking-water was administered to groups of 17 
and 30 male 5-week-old Sprague Dawley rats fed a commercial pellet 
ration.  After 64 weeks, survival was 94 and 63% in the control and 
selenium-treated groups, respectively.  In a second study of similar 
design, except that the rats were 8 weeks old at the start, 
survival was 90 and 95% in the control and selenium-treated groups, 
respectively, after 61 weeks. 

    Pletnikova (1970) investigated the effects of long-term, low-
level administration of sodium selenite in water to rabbits and 
rats.  For these studies, 32 rabbits and 16 rats were divided into 
4 groups and administered, orally, doses of 0, 0.005, 0.0005, or 
0.00005 mg selenium/kg body weight for periods of 7 1/2 and 6 
months, respectively.  Prolonged administration of the maximum dose 
investigated (0.005 mg/kg) produced significant alterations in the 
rabbits.  After 2 months, there was a significant increase in the 
concentration of oxidized glutathione in the blood and, after 7 
months, there was slower elimination of bromsulphalein by the 
liver, and hepatic succinic dehydrogenase activity was decreased.  
A dose of 0.0005 mg/kg caused fewer, less pronounced changes, 
whereas 0.00005 mg/kg did not produce any statistically significant 
effects in any of these tests.  A dose of 0.005 mg/kg given to rats 
caused a considerable weakening of the capacity for forming new 
conditioned reflexes.  It can be assumed that a daily dose of 0.005 
mg/kg body weight in rats is equivalent to a dietary-selenium level 
of about 0.063 mg/kg.  Since this level of selenium is within the 
physiological range needed to prevent selenium deficiency in 
animals (section 7.2.2), the toxicological significance of these 
observations is not clear, unless it is assumed that a certain dose 
of selenite given in water solution is more toxic than the same 
dose given in the diet. 

    Recently, Csallany et al. (1984) reported that giving sodium 
selenite to female mice in the drinking-water at a level of 0.1 mg 
selenium/litre increased the amount of hepatic lipid-soluble 
lipofuscin pigments, when the animals were sacrificed at 9 months 
of age.  There were 8 mice in each group and the animals were fed a 
diet adequate in vitamin E, which contained 0.05 mg selenium/kg. 

    Sodium selenite added to the drinking-water at a level of 9 mg 
selenium/litre killed all 12 rats fed a diet based on either ground 
corn or ground rye in 6 weeks (Palmer & Olson, 1974), whereas 
Halverson et al. (1966) found that sodium selenite added to a diet 
based on ground wheat, at a level of 9.6 mg/kg, killed only 1 out 
of 10 rats in the same period of time.  However, the rats used in 
the latter study were post-weanling animals weighing 60 - 70 g when 
the study started, whereas the rats used in the former study were 
21-day-old weanlings and weighed only 35 - 45 g.  Other research 
workers have shown that the resistance of rats to the toxic effects 
of selenium increases markedly after the twenty-first day of life 
(Franke & Potter, 1936). 

    Feng et al. (1985) studied the hepatoxicity of high selenium 
corn (7.12 mg/kg) produced in the Enshi county of China, where 
human selenium intoxication was reported (section 8.1.1.1).  After 
feeding a diet that contained 61% of this corn (total selenium 
concentration of 4.343 mg/kg) for 16 weeks, liver cirrhosis was 
seen in 3 out of 6 male and 5 out of 6 female rats in one group.  
No liver damage was found histologically in another group of rats 
in the same study, which had consumed a diet containing 30.5% of 
the high selenium corn (total selenium concentration of 2.35 
mg/kg). 

    At present, the best indicator of chronic selenium toxicity 
appears to be growth inhibition (US NAS/NRC, 1976), and a selenium 
level of 4 - 5 mg/kg is necessary to achieve this response in 
animals fed a normal diet.  In laboratory rats, this exposure to 
selenium represents an intake of about 200 - 250 g/kg body weight 
per day.  More sensitive and specific criteria of selenium 
poisoning to demonstrate effects at lower dose levels, such as 
biochemical or histological techniques, would obviously be highly 
desirable, but such tests are not available at present. 

7.1.2.3.  Inhalation toxicity

    The effects of respiratory exposure to selenium compounds, 
administered under conditions mimicking occupational exposure, have 
been described in several papers.  Filatova (1951) studied the 
toxic effects of respiratory exposure to selenium dioxide (SeO2) 
under conditions similar to those that occur in industry, i.e., 
heating of selenium (section 5.2.1).  In acute studies, white rats 
were exposed to air concentrations of selenium dioxide of 0.15 - 
0.6 mg/litre, and all rats died within one-half - 4 h.  
Morphological examination of the organs revealed that intraalveolar 
and perivascular oedema occurred in the lungs, and haemorrhages and 
degenerative changes in the liver, kidney, and heart.  In 4 
additional studies, all rats survived 4 h when exposed to doses of 
0.09, 0.06 - 0.07, or 0.03 - 0.04 mg selenium dioxide/litre, but 
all rats exposed to the highest dose (equal to 5 - 5.2 mg/kg body 
weight) died within 24 h.  In a series of long-term studies, rats 
were exposed to repeated doses of selenium dioxide at 0.01 - 0.03, 
0.006 - 0.009, or 0.003 - 0.005 mg/litre for 6 h, every other day, 
for one month.  The lowest dose did not produce any effects on body 
weight or on the blood picture, and all the rats survived.  
Histological examination revealed degenerative changes in the 
liver, renal tubules, dystrophy of heart muscle, and hyperaemia and 
hypertrophy of the splenic pulp.  At the dose of 0.006 - 0.009 
mg/litre, all the rats but one died within 27-33 days.  For the 
first 2 weeks, there was no difference in body weight between the 
exposed and unexposed control rats but, during the last 2 weeks, 
the exposed rats lost body weight and all but one of the exposed 
rats died.  The histopathological changes consisted of multiple 
necrosis and degeneration in the liver and myocardial fibres, and 
involvement of renal tubules.  In the third group of rats, which 
was exposed to 0.01 - 0.03 mg/litre, the animals showed respiratory 
distress, weight loss, and, in 3 rats, anaemia.  All the rats died 
between days 8 and 18 of exposure.  In the liver, kidneys, 

myocardium, and spleen, the changes observed were similar to those 
seen at lower doses, but more pronounced.  Moreover, lung oedema 
similar to that noted in the acute exposure studies was seen. 

    Lipinskij (1962) exposed 2 groups of 5 rabbits to airborne 
amorphous selenium and selenium dioxide in chambers, under 
conditions analogous to industrial exposure, except that the doses 
were higher.  In the first group, the rabbits were exposed to 20 mg 
selenium dioxide/litre and 40 mg selenium/m3, for 2 h per day, for 
one week, at which time a decrease in blood catalase (EC 1.11.1.6) 
activity was noted.  The rabbits in the second group were exposed 
to 10 g selenium dioxide/litre and 20 mg selenium/m3, for 2 h 
daily, for 12 weeks.  After 12 weeks, decreases in total and 
reduced glutathione were observed, but there was no change in 
levels of oxidized glutathione. 

    On the basis of studies on 60 white rats weighing 120 - 150 g, 
Burchanov et al. (1969) concluded that intratracheal injection of 
0.06 ml of a sterile suspension containing 50 mg of highly 
dispersed elemental selenium dust in physiological saline, for 
1 - 12 months, resulted in decreases in body weight and muscular 
strength, and morphological and biochemical alterations in the 
respiratory tract.  Burchanov (1972) obtained similar results in 
inhalation studies on rats exposed to 2 types of polymetallic dusts 
found in industry. 

    The acute toxicity of selenium dust (average mass median 
particle diameter, 1.2 ) for rats, guinea-pigs, and rabbits was 
described by Hall et al. (1951).  Exposure of these animals, for 
16 h, to an atmosphere containing approximately 30 mg selenium 
dust/m3 produced mild interstitial pneumonitis in the animals.  
Rats exposed to selenium fumes developed acute toxic effects, and 
it was suggested that the fumes might have contained some selenium 
dioxide. 

    The acute toxic effects of hydrogen selenide were investigated 
in guinea-pigs exposed for 10, 30, or 60 min to concentrations 
ranging from 0.002 to 0.57 mg/litre (Dudley & Miller, 1941).  All 
animals exposed to 0.02 mg/litre, for 60 min, died within 25 days; 
93% of those exposed to 0.043 mg/litre, for 30 min, died within 30 
days, and all exposed to 0.57 mg/litre, for 10 min, died within 5 
days.  Decreasing the concentrations of hydrogen selenide, and 
increasing the time of exposure to 2, 4, or 8 h produced death in 
50% of the guinea-pigs, within 8 h. 

    Acute studies on the toxicity of selenium hexafluoride (SeF6), 
were carried out on the rabbit, guinea-pig, rat, and mouse at 100, 
50, 25, 10, 5, and 1 ppm for 4 h.  Exposures down to and including 
10 ppm (Ct = 40 ppm/h) were uniformly fatal (Kimmerle, 1960).  
Exposure to 5 ppm (Ct = 20 ppm/h) resulted in pulmonary oedema from 
which the animals recovered, and 1 ppm did not induce any grossly 
observable effects.  However, with repeated exposure for 1 h daily 
at 5 ppm, for 5 days, there were definite signs of pulmonary 
injury. 

7.1.3.  Blood levels in toxicity

    Analyses of blood from cattle have shown that, if the average 
value of blood-selenium for a herd is over 2 mg/litre, damage from 
chronic selenium poisoning is very likely to occur (Dinkel et al., 
1957).  Average values of 1 - 2 mg/litre suggest a borderline 
problem, especially in reproduction, whereas values below 1 
mg/litre indicate that no damage from toxicity should be expected.  
Rosenfeld & Beath (1964) commented that typical concentrations of 
selenium in the blood in alkali disease, blind staggers, and acute 
selenium poisoning were 1 - 2, 1.5 - 4, and up to 25 mg/litre, 
respectively.  In studies with sodium selenite, Maag et al. (1960) 
found that severe selenium toxicity occurred in cattle when the 
selenium content of the blood exceeded 3 mg/litre.  The selenium 
levels in blood associated with chronic toxicity in sheep 
corresponded to 0.6 - 0.7 mg/litre (Ermakov & Kovalskij, 1974). 

7.1.4.  Effects on reproduction

    Franke & Potter (1936) fed 7 groups of 6 weanling rats (2 males 
and 4 females), 21 days of age, a basal diet consisting of ground 
whole wheat, 82%; commercial casein, 10%; pure leaf lard, 3%; 
dehydrated yeast, 2%; cod liver oil, 2%; and McCollum's salt 
mixture No. 185, 1%.  Group 1 was shifted immediately to a toxic 
diet in which sufficient control wheat was substituted by 
seleniferous wheat to give a final selenium concentration of 24.6 
mg/kg diet.  Groups 2, 3, 4, 5, and 6 were shifted to the toxic 
diet when the rats attained 42, 63, 84, 105, and 186 days of age, 
respectively.  Group 7 was fed the basal diet throughout the entire 
study.  No matings were successful in which both males and females 
had been fed the toxic diet for 40 days, regardless of the age at 
which the rats had been taken off the basal ration.  This was true, 
even in group 6, in which successful matings had been achieved at 
82 and 131 days, while the rats were still being fed the basal 
diet.  All male rats not placed on the toxic diet until 63 days of 
age or more were able to fertilize the normal females.  In a later 
study in which females fed the toxic diet were mated with normal 
males, there were some successful matings, but the pups that were 
born generally died or were eaten by the mother soon after birth. 

    In a study by Munsell et al. (1936), 7 groups of 4-week-old 
rats, each containing 2 males and 6 females, were fed a basal diet 
consisting of wheat, 58%; skim milk powder, 30%; yeast, 5%; butter, 
5%; and cod liver oil, 2%.  In each of the groups, a variable 
proportion of the control wheat was replaced by toxic wheat so that 
the latter contributed 8.7, 6.0, 3.0, 1.5, 0.75, 0.38, or 0 mg 
selenium/kg diet.  Compared with the controls receiving no toxic 
wheat, the number of females having young was decreased by feeding 
the diets containing 3.0 mg or more selenium/kg, and the percentage 
of young reared was decreased by the diets containing 6.0 mg or 
more/kg (Table 25).  Feeding the diet containing 0.75 mg/kg 
appeared to improve reproductive performance in terms of total 
young produced or percentage of young reared.  In the second 
generation of rats continued on their respective levels of toxic 
grain, the diet containing 6.0 mg/kg had a definite deleterious 
effect on reproduction, whereas diets containing 0.75 - 1.5 mg/kg 

had some beneficial effects.  In a second study, the percentage of 
young reared was improved in the group fed the diet containing 1.5 
mg/kg compared with the control diet group, but the average number 
of young per litter and the average number of young per bearing 
female were decreased in the group fed the diet containing 0.75 
mg/kg. 

    Halverson (1974) fed 4 groups of 70-day-old ARS/Sprague Dawley 
albino rats a basal diet containing glucose, 61.8%; purified 
casein, 25%; corn oil, 5%; minerals, 6%; and vitamins, 2.2%.  The
groups comprised 2 - 4 males and 6 - 8 females and were given the 
basal diet supplemented with sodium selenite at 0, 1.25, 2.50, or 
3.75 mg selenium/kg.  After 90 days, the rats were mated; no 
consistent effects of selenium on reproduction were observed in 
these first generation rats.  Four groups of second-generation 
young were maintained on their respective diets and used as 
breeding stock in a second life cycle.  In 2 separate studies, the 
first and second reproductions of these second generation rats were 
successful, regardless of the selenium content of the diet (Table 
26).  In the third reproduction, however, the unsupplemented rats 
showed signs of reproductive failure.  Selenium supplementation at 
all levels prevented poor litter production in the first study but 
only levels of 2.50 and 3.75 mg/kg prevented it in the second.  
Neonatal survival was improved in both studies by selenium 
administered at 3.75 mg/kg. 

    Schroeder & Mitchener (1971a) gave selenate at 3 mg 
selenium/litre, in the drinking-water, continuously, during a 
multigeneration study in mice.  Five pairs of Fo mice were given 
selenium at weaning and allowed to breed  ad libitum for 6 months.  
Controls were treated identically but did not receive any selenium 
in the water.  At weaning, F1 pairs were randomly selected from the 
first, second, and third litters and left to breed, to produce the 
F2 generation.  F2 pairs were similarly selected from the first or 
second litters to produce the F3 generation.  An increased 
male:female ratio was observed in all generations (1.30 - 1.50 
versus 0.94 - 1.03 for the controls), but the mechanism of this 
effect was not explained.  No breeding failures were seen in the 
control group, but 2 or 3 such failures occurred in each of the F1, 
F2, and F3 generations given selenate.  Only 3 litters were 
produced in the F3 generation treated with selenate and 16 of 23 
mice born were runts, whereas in the control F3 generation, 22 
litters were produced with a total of 230 mice and no runts. 

    Two groups of 5 male and 2 groups of 5 female Wistar rats were 
fed a laboratory chow diet and one group of each sex was given 
sodium selenate at 0 or 7.5 mg selenium/litre in the drinking-
water, respectively (Rosenfeld & Beath, 1954).  The rats receiving 
selenium ("selenized rats") were treated from birth to 8 months of 
age.  Mating of normal males with selenized females was totally 
unsuccessful, whereas mating of selenized males with normal females 
resulted in normal reproduction and survival.  Doses of 1.5 or 2.5 
mg/litre did not have any effect on the reproduction of breeding 
rats, the number of young reared by the mothers, or the 
reproduction of 2 successive generations of males and females. 
However, a level of 2.5 mg/litre decreased the number of young 
reared by the mothers by about 50%. 


Table 25.  Effect of seleniferous wheat on reproduction in first- and second-generation ratsa
-------------------------------------------------------------------------------------------------
Level of  Generation and          Females having  Total   Total    Average  Average  Young reared
dietary   number of females       young           young   litters  number   number
selenium  1st         2nd                                          young/   young/
(from     generation  generation                                   litter   bearing
wheat)                                                                      female
--------------------------------------------------------------------------------------------------
(mg/kg)                           Number  %       Number  Number   Number   Number   Number  %

0         6           -           6       100     70      13       5.4      11.7     30      42.9
0.38      6           -           5       83.3    72      13       5.5      14.4     23      31.9
0.75      6           -           6       100     90      18       5.0      15.0     75      83.3
1.5       6           -           5       83.3    42      10       4.2      8.4      15      35.7
3.0       6           -           3       50.0    38      7        5.4      12.7     19      50.0
6.0       6           -           4       66.7    30      8        3.8      7.5      5       16.7
8.7       6           -           2       33.3    7       2        3.5      3.5      0       0
0         -           11          10      90.9    134     19       7.1      13.4     46      34.3
0.38      -           9           6       66.7    63      10       6.3      10.5     31      49.2
0.75      -           41          29      70.7    434     52       8.3      15.0     328     75.6
1.5       -           7           7       100     100     11       9.1      14.3     72      72.0
3.0       -           7           5       71.4    61      9        6.8      12.2     25      41.0
6.0       -           2           2       100     17      3        5.7      8.5      0       0
8.7       -           0           -       -       -       -        -        -        -       -
--------------------------------------------------------------------------------------------------
a  Adapted from: Munsell et al. (1936).

Table 26.  Effect of selenium as selenite on successive reproductions of second-
generation rats maintained on a casein dieta
--------------------------------------------------------------------------------
Study  Added     Number    Measurements in first, second and third reproductions
       selenium  of brood  Number of     Number young per   2-day survival of
       in diet   females   litters born  newborn litter     litter members
                           1  2  3       1   2   3          1   2    3
--------------------------------------------------------------------------------
       (mg/kg)                                                 (%)

1      0         3         3  3  0       12  12  -          61  46   -
       1.250     6         6  6  5       12  7   8          29  21   26
       2.500     5         5  5  5       12  11  8          71  84   30
       3.750     6         6  6  6       11  9   8          79  78   78

2      0         7         7  6  2       8   10  6          74  82   33
       1.250     7         7  5  2       10  11  4          90  84   00
       2.500     9         8  8  6       9   9   5          81  85   25
       3.750     8         7  7  4       7   6   6          92  100  92
--------------------------------------------------------------------------------
a  Adapted from: Halverson (1974).
    Poley & Moxon (1938) fed 4 groups of 15 Rhode Island pullets a 
basal laying ration consisting of ground corn, 25%; ground barley, 
25%; ground wheat, 15%; wheat bran, 8%; wheat middlings, 8%; meat 
and bone scraps, 8%; alfalfa leaf meal, 5%; dried buttermilk, 5%; 
salt, 0.5%; and cod liver oil concentrate, 0.5%.  Each of the 4 
groups was mated with 2 male brothers for the entire study.  After 
2 weeks, grains containing selenium (corn, barley, and wheat) were 
substituted for normal grains in order to contribute 0, 2.5, 5, or 
10 mg selenium/kg diet fed to each of the 4 groups, respectively. 
Oyster shells and water were provided  ad libitum.  There were no 
significant differences in feed consumption, body weight, egg 
production, or egg fertility in any of the groups.  After 4 weeks 
on the toxic diets, 10 mg of selenium/kg reduced hatchability to 
zero.  Hatchability was only slightly reduced by 5 mg/kg, and a 
level of 2.5 mg/kg had no effect. 

    In a study by Wahlstrom & Olson (1959), 2 groups of 10 purebred 
Duroc gilts, 8 weeks of age, were fed a basal diet supplemented 
with sodium selenite at 10 mg selenium/kg diet.  Of the 9 gilts in 
the unsupplemented group (one was killed accidentally), 8 conceived 
with the first service and one failed to conceive after 3 services.  
Of the 10 gilts in the selenium-exposed group, 5 conceived with the 
first service, 2 with the second service and 3 failed to conceive 
after 3 services.  The selenium-exposed group farrowed fewer 
litters and fewer live pigs, and weaned fewer pigs than the control 
group (Table 27).  Moreover, the average birth weights and weaning 
weights were lower in the selenium-exposed group.  The average 
litter weight at 56 days for both litters was 131 and 227 pounds 
for the selenium-exposed and unexposed groups, respectively. 

Table 27. The effect of selenium on reproduction and lactation in swine
-------------------------------------------------------------------------
Items             Number    Average   Average   Average  Average  Average
                  litters   number    number    birth    number   weaning
                  farrowed  pigs      pigs      weight   pigs     weight
                            farrowed  farrowed  (kg)     weaned   (kg)
                                      alive
-------------------------------------------------------------------------
Basal

 First litters    7         8.0       8.0       2.95     7.3      30.5
 Second litters   6         11.2      10.5      2.89     8.0      29.0
 Average          6.5       9.6       9.25      2.92     7.65     29.75

Basal + selenium

 First litters    6         9.8       7.7       2.60b    5.7      23.1c
 Second litters   5         8.6       7.2       2.76     5.6      23.5c
 Average          5.5       9.2       7.45      2.68     5.65     23.3
-------------------------------------------------------------------------
a Adapted from:  Wahlstrom & Olson (1959).
b Significantly less than basal lot ( P < .05)
c Significantly less than basal lot ( P < .01)

    Dinkel et al. (1963) reported on the effect of early (May 1 
to mid-July) versus late (mid-July to October 1) breeding on the 
reproductive performance of beef cattle grazing on a seleniferous 
range in South Dakota.  With such a programme, it was felt that 
early conception would avoid any deleterious effects on 
reproduction of the highly seleniferous young range grasses that 
grow luxuriantly during the early summer.  Data from 152 matings, 
75 in the early and 77 in the late breeding group, collected over 
5 years, showed that the average conception rate of the early-bred 
cows was 60%, whereas that of the late-bred cows was 37.7%.  
Moreover, the average calf crop weaned was 52% in the early 
breeding group and 32.4% in the late group.  The data do not prove, 
but suggest, that selenium was the cause of the difference.  In 
addition to the early breeding effect, the very low overall 
reproductive rate should be noted.  This is considerably below the 
rate that can be attained with similar operations when chronic 
selenosis is not a problem, and it has been repeatedly observed 
that, on ranches with a selenium problem, the rate of reproduction 
is consistently low.  This led Olson (1969) to comment that the 
effect on reproduction might be the most significant effect of 
excessive amounts of the element from an economic standpoint. 

7.1.5.  Effects on dental caries

    Most studies on experimental animals have shown that high doses 
of selenium do not have any effect on caries formation when the 
selenium is given after tooth formation has already occurred.  For 
example, Muhler & Shafer (1957) fed 22 male weanling Sprague Dawley 
rats a stock corn cariogenic diet that contained 10 mg sodium 
selenite/kg.  After 6, 8, and 12 weeks, the level of sodium 
selenite was raised to 15, 20, and 30 mg/kg diet, respectively.  A 

control group of 20 rats received the same diet without added 
selenium.  The animals were given their respective diets and 
drinking-water low in fluorine (F = 0.2 mg/litre)  ad libitum for 
140 days.  The selenium-exposed group grew only about 53% as much 
as the controls, but the mean number of carious lesions was 
essentially the same in both groups (6.4 and 6.9, respectively).  
Claycomb et al. (1965) fed 2 groups of 24 weanling rats a high-
carbohydrate diet, with or without 10 mg sodium selenite/kg diet, 
for 100 days.  In this study, selenium depressed growth by only 
11%, but again the average number of carious lesions per rat was 
similar in the selenium-treated and control groups (0.92 and 1.08, 
respectively).  The rather low incidence of dental caries was 
thought to be due to genetic influences.  Wheatcroft et al. (1951) 
maintained 80 white rats, 40 males and 40 females, on a coarse corn 
cariogenic diet for 100 days.  The rats were divided into 4 groups 
of 20 and were given daily intraperitoneal doses of sodium selenite 
at 0, 0.2, 0.5, or 1.0 mg selenium/kg body weight.  The authors 
felt that there was a trend towards an increased incidence of 
caries in the group receiving the most selenium, but the 2 highest 
doses of selenium were clearly toxic, since these rats had 
diarrhoea, affected eyes, and dull, matted fur.  There was also 
histological evidence of liver damage in over half, and kidney 
damage in a third, of the rats.  Thirty new-born Wistar rats were 
divided into 3 groups receiving, intraperitoneally, 0, 0.5 - 1.0 
g, or 5 - 10 g sodium selenate, respectively, every day for 53 
days (Kaqueler et al., 1977).  The group receiving the lower dose 
of selenium had a lower total number of caries than the controls, 
while the group receiving the higher dose had more caries than the 
controls.  The authors concluded that post-eruptive administration 
of sodium selenate may have either a cariostatic or cariogenic 
influence in rats, depending on the dosage administered. 

    Attempts to induce dental caries by exposure to high levels of 
selenium were more successful when the selenium was given during 
the time of tooth development.  For example, Navia et al. (1968) 
fed sodium selenite at 4 mg selenium/kg, to groups of 21 CR-COBS 
rats in the drinking-water, in a purified caries-producing diet, or 
in the same diet gelled with equal parts of 2% aqueous agar.  The 
experimental treatments of the mothers and litters began at birth 
and continued until the pups were 50 days old.  Selenium had no 
effect on buccal, sulcal, or proximal caries, when given in the 
diet, but caused a 12% increase in sulcal lesions when administered 
in the drinking-water.  Buttner (1963) fed 3 groups of 8 female, 
caries-susceptible rats of the Wistar strain a cariogenic coarse 
stock corn diet plus 0, 5, or 10 mg sodium selenite/litre drinking-
water during mating, pregnancy, and lactation.  The offspring 
received the same concentrations of sodium selenite for 120 days.  
Thirty-one pups were born in the control group but, since the 
dosages of selenium used partially inhibited reproduction, only 20 
and 7 pups were born in the groups receiving 5 or 10 mg sodium 
selenite/litre drinking-water, respectively.  Growth of the pups 
was strongly inhibited and the number and extent of carious lesions 
were increased in both selenium-treated groups (Table 28).  In a 
study by Bowen (1972), 7 female monkeys of the species  Macaca irus 
were fed a cariogenic diet, with drinking-water sweetened with 3% 

sucrose, at night, and phosphate-free icing sugar, 4 times daily.  
A second group of 3 females of the same species was treated 
identically except that they received selenium, as sodium selenate, 
at 2 mg/litre drinking-water.  After 15 months, some of the 
selenium-treated monkeys experienced slight gastrointestinal 
trouble in the form of greenish malodorous stools and the dose of 
selenium was reduced to 1 mg/litre for another 45 months.  The 
second permanent molars and the premolars were formed during the 
period of higher selenium exposure and these teeth had a yellow 
chalky appearance in the selenium-treated monkeys.  On the other 
hand, selenium had no effect on the first permanent molars, which 
had already formed before the start of the study.  Although both 
groups of monkeys had severe dental caries, the mean caries score 
of the selenium-treated group was about twice that of the controls 
(16 and 8.4, respectively).  There was no difference between the 
times required for caries to develop in the first permanent molars 
in the controls and experimental groups, but carious lesions in the 
second permanent molars developed more rapidly in the selenium-
exposed group (6.7 versus 21 months for mean caries development 
time in selenium-treated compared with control groups).  The author 
concluded that selenium had a cariogenic effect, when administered 
during tooth development and a moderate anti-cariogenic effect, 
when given posteruptively. 

Table 28.  Effect of developmental and postdevelopmental 
administration of sodium selenite on dental caries in the rata
-------------------------------------------------------------------
Dose of sodium  Sex  Number  Weight gain  Mean number  Extent
selenite in          of      in 120 days  of carious   of carious
drinking-water       rats    (g)          lesions      lesions
(mg/litre)                       
-------------------------------------------------------------------
0               M    17      330  9      5.3  0.5    11.6  1.4
                F    14      207  7

5               M    13      240  5      7.2  0.7    18.7  2.2
                F    7       176  7

10              M    5       220  18     8.6  1.1    25.2  3.2
                F    2       148  3
-------------------------------------------------------------------
a Adapted from:  Buttner (1963).

    Britton et al. (1980), however, presented evidence that showed 
that, under some conditions, selenium can have a cariostatic 
effect, even when given during tooth development.  These workers 
gave 0, 0.8, or 2.4 mg selenium/litre drinking-water in the form of 
selenomethionine or sodium selenite, to rats from the 10th day of 
pregnancy until the pups were weaned.  At 17 - 19 days of age, the 
pups were given oral innoculations of  Streptococcus mutans - 6715
in thioglycollate broth.  When 19 days old, the pups were weaned, 
divided into groups of 13 - 19, and given a 67% sucrose diet and 
distilled water  ad libitum.  At 65 - 68 days of age, the young rats 
were killed and the first and second molar teeth were stained with 
murexide and scored for caries.  The high dose of selenium given to 

the mothers, as either compound, did not have any effect on 
dental caries, but the middle dose (0.8 mg/litre) had a definite 
cariostatic effect, since selenomethionine and sodium selenite 
decreased the incidence of total buccal caries by 46.1 and 40.9%, 
respectively.  The authors suggested that this cariostatic effect 
might occur because some selenium is necessary for proper enamal 
formation or because of undetermined effects on the oral 
environment. 

    The fact that high doses of selenium have an apparent 
cariogenic effect, only when given during tooth development, 
is consistent with the results of Shearer (1975) who found that 
the incorporation into teeth of radioactive selenite or 
selenomethionine given in the drinking-water at a level of 0.2 mg 
selenium/litre was much greater in rat pups undergoing dental 
development than in their mothers whose teeth had already matured.  
The mechanism of the cariogenic effect of high levels of selenium 
is not known, but an antagonism to fluoride does not seem to be 
involved (Shearer & Ridlington, 1976). 

7.1.6.  Factors influencing toxicity

7.1.6.1.  Form of selenium

    Studies comparing the toxicity of different forms of selenium 
are described in section 7.1.2.1.  This point is particularly 
relevant because the forms of selenium in foods have yet to be 
characterized. 

7.1.6.2.  Nutritional factors

    High levels of dietary protein protect against selenium 
toxicity (Gortner, 1940), but some proteins give better protection 
than others (Smith & Stohlman, 1940).  Jaffe (1976) found that the 
toxicity of seleniferous sesame meal for rats was markedly 
decreased when the diets were supplemented with L-lysine, the 
limiting essential amino acid in sesame proteins.  Lysine was 
thought to protect against selenium poisoning indirectly by 
improving the biological value of the sesame proteins. 

    Linseed meal contains a unique non-proteinaceous factor that 
is highly effective in protecting against selenium poisoning 
(Halverson et al., 1955; Levander et al., 1970).  The results of 
recent work suggest that the protective activity of linseed meal 
may reside in 2 newly-isolated cyanogenic glycosides (Palmer et 
al., 1980; Smith et al., 1980).  Cyanide has a partially protective 
effect against selenium poisoning in rats (Palmer & Olson, 1979) 
and increases the occurrence of nutritional myopathy in lambs 
(Rudert & Lewis, 1978). 

    There is conflicting evidence as to the ability of methyl-
donating compounds to protect against selenium toxicity (Rosenfeld 
& Beath, 1964).  Methionine was shown to protect against chronic 
selenite poisoning in rats, but only when vitamin E or other fat-
soluble antioxidants were in the diet (Levander & Morris, 1970). 

    Vitamin E deficiency increased the susceptibility of rats to 
chronic poisoning by selenium as selenite (Witting & Horwitt, 1964) 
and pigs deficient in vitamin E and selenium were more susceptible 
to acute selenium toxicosis than non-deficient pigs (Van Vleet et 
al., 1974). 

7.1.6.3.  Arsenic

    Selenium poisoning caused by feeding rats seleniferous wheat 
was decreased by giving sodium arsenite in the drinking-water 
(Moxon, 1938).  The protective effect of arsenic against selenium 
toxicity might be explained by the increased biliary excretion of 
selenium caused by arsenic (Levander & Baumann, 1966).  However, 
the use of arsenic compounds did not prove to be a practical way of 
controlling selenium poisoning in livestock (Olson, 1969).  Also, 
arsenic does not protect against all forms of selenium, since it 
potentiates the toxicity of the trimethylselenonium ion (Obermeyer 
et al., 1971). 

7.1.6.4.  Sulfate

    Dietary sulfate partially counteracts the toxicity of selenate 
in rats, but has little or no effect against selenite or organic 
forms of selenium (Halverson et al., 1962).  Sulfate apparently 
increases the urinary excretion of selenium fed as selenate, 
thereby reducing the retention of selenium in the internal organs 
(Ganther & Baumann, 1962). 

7.1.6.5.  Adaptation

    Ermakov & Kovalskij (1968) fed 18 adult female sheep from 
seleniferous and normal localities their own respective diets or 
these diets plus an additional 2 mg selenium, as selenite, daily 
for 28 days.  The 18 sheep were divided into 6 equal groups, 
according to their history of selenium intake and, in the case of 
the seleniferous sheep, according to the presence or absence of 
signs of selenium toxicity.  After 28 days, all the sheep were 
killed, and selenium levels and acid and alkaline phosphatase 
activities were determined in several tissues.  Selenium levels and 
alkaline phosphatase activities are presented in Table 29.  The 
increase in selenium retention in the blood, kidneys, and most of 
the other internal organs, produced by supplementing the feed with 
selenite, was less in sheep from high-selenium localities than in 
animals from control localities.  Retention in the liver seemed to 
be an exception.  The increase in alkaline phosphatase activity due 
to the selenite load was much clearer in sheep from the control 
localities than in the sheep from the seleniferous localities.  The 
alkaline phosphatase activity of the pancreas in sheep from the 
high-selenium locality, manifesting selenium toxicity signs, was an 
exception being much higher after the selenite load (370  57 
compared with 84  34).  These differences in the response of the 
sheep to selenite loading were interpreted by the authors as 
evidence of the adaptation of the animals to high levels of 
selenium exposure. 


Table 29.  Effect of high selenium (Se) load on selenium metabolism and alkaline phosphatase activity in sheep 
previously exposed to normal and high selenium intakes in foragea
----------------------------------------------------------------------------------------------------------------
History       Daily Se intake                   Skeletal                        Alkaline phosphatase activity 
of sheep   Plant  Selenite  Total   Blood       muscle    Liver     Kidney      kidney     liver      skeletal 
           Se     Se        Se      Se          Se        Se        Se                                muscle  
           (g)   (g)      (g)    (g/litre)  (g/kg)   (g/kg)   (g/kg)        (units/100 g tissue)
----------------------------------------------------------------------------------------------------------------
High       1821   2000      3821    411  18    230  24  600  44  870  69    286  148  448  43   13.0  2.7
Se-curved
hoofs

High       1944   0         1944    290  18    180  7   330  20  760  26    362  89   374  117  9.5  3.0
Se-curved
hoofs

High       1774   2000      3774    362  34    210  16  590  90  1000  174  309  103  335  18   9.4  2.9
Se-curved
hoofs

High       2038   0         2038    239  34    170  6   340  20  890  21    349  63   344  56   9.5  1.2
Se-curved
hoofs

Normal Se  376    2000      2376    408  23    170  8   450  38  950  77    496  53   457  57   14.8  3.0

Normal Se  396    0         396     100  12    89  5    190  20  780  69    143  29   254  7    5.5  0.8
----------------------------------------------------------------------------------------------------------------
a  Adapted from: Ermakov & Kovalskij (1968).
    Jaffe & Mondragon (1969) presented evidence that animals could 
adapt to long-term selenium intake.  Hepatic-selenium levels 
decreased steadily in young rats fed a diet containing 4.5 mg 
selenium/kg as seleniferous sesame meal, if the rats came from 
mothers that had been fed the same seleniferous diet, but the 
levels increased if the rats came from mothers fed a non-
seleniferous stock diet.  It was concluded that an adaptation 
mechanism existed that allowed rats exposed to long-term selenium 
ingestion to store less of this element than previously unexposed 
controls.  A later report (Jaffe & Mondragon, 1975) confirmed these 
results and also indicated that the hepatic lesions, splenomegaly, 
and other toxicity signs were significantly decreased in adapted 
rats. 

    One mechanism for a possible adaptive response to high levels 
of selenium could involve effects of selenium intake on various 
selenium metabolic pathways, since previous selenium exposure has 
been shown to have an influence on the whole body retention of 
selenium and the urinary and pulmonary excretion of selenium 
(Ganther et al., 1966; Ewan et al., 1967; Burk et al., 1973) 
(section 6.3, 6.4).  However, as discussed in section 7.1.2.1, more 
recent work has shown that previous selenium exposure directly 
influences the toxicity of final selenium metabolites such as 
dimethyl selenide and the trimethylselenonium ion (Parizek et al., 
1976, 1980). 

7.1.7.  Mechanism of toxicity

    The mechanism of selenium toxicity remains unclear and the 
modes of action of various selenium compounds, such as hydrogen 
selenide, selenomethionine, and selenium dioxide are likely to be 
quite different.  Thus, no unifying hypothesis regarding the toxic 
effects of selenium compounds is possible.  Various hypotheses 
concerning the mechanisms of selenium toxicity have been presented 
(Rosenfeld & Beath, 1964; Izraelson et al., 1973; Ermakov & 
Kovalskij, 1974; US NAS/NRC, 1976; Lazarev, 1977; Levander, 1982).  
Although it appears unlikely that selenite interferes directly with 
sulfhydryl enzymes (Tsen & Tappel, 1958; Tsen & Collier, 1959), it 
is possible that selenite may interfere with glutathione metabolism 
(Vernie et al., 1978; Chung & Maines, 1981; Vernie, 1984; Anundi et 
al., 1984) and that this may affect enzyme activities.  The 
apparent pro-oxidant nature of high levels of selenite has been 
reported by several workers (Witting & Horwitt, 1964; Csallany et 
al., 1984), and this may be related to some aspects of selenite 
toxicity. 

7.2.  Selenium Deficiency

7.2.1.  Animal diseases

    The nutritionally beneficial effects of selenium were first 
reported in 1957 by Schwarz, who discovered that sodium selenite 
prevented dietary liver necrosis in vitamin E-deficient rats 
(Schwarz & Foltz, 1957).  This discovery led to the rapid 
recognition of vitamin E-related selenium-responsive deficiency 

diseases in several species of farm animals.  Diseases such as 
white muscle disease in sheep and cattle, hepatosis dietetica in 
swine, and exudative diathesis in poultry are economically 
significant problems in areas of the world where the soil levels of 
selenium available for uptake by plants are low.  Schwarz & Foltz 
(1958) also reported that feeding a diet deficient in both selenium 
and vitamin E to mice resulted in multiple necrotic degeneration of 
several organs; more recently, Suchkov et al. (1977, 1978) found 
that feeding such diets to mice for 13 days caused a decreased 
staining intensity for zinc in the pancreas, kidneys, and testes. 

    The fact that vitamin E as well as selenium tended to protect 
against many of these diseases led some research workers to 
question whether there was any requirement for selenium in animals 
receiving adequate amounts of vitamin E.  But, the results of more 
recent work have clearly demonstrated the need for selenium, even 
in animals given nutritionally adequate levels of vitamin E.  
Deficiency signs specific for selenium included alopecia, vascular 
changes, cataract, poor growth, and reproductive failure in second 
generation selenium-deficient rats (McCoy & Weswig, 1969; Wu et 
al., 1979).  Pancreatic degeneration occurred in selenium-deficient 
chicks with a normal intake of vitamin E (Thompson & Scott, 1970), 
but the condition could be prevented by feeding very high 
levels (> 300 g/kg) of vitamin E or other antioxidants (Whiteacre 
et al., 1983). 

    Changes in the myocardial parenchyma and increases in heart 
weight have been observed in albino rats fed corn and vegetables 
grown in the areas in which Keshan disease is endemic (Su et al., 
1982), and swine fed grain from endemic areas for 6 months 
exhibited multiple myocardial necrosis as well as other lesions 
(Zhu et al., 1981).  Vitamin E deficiency exacerbated the 
pathological and histochemical changes in the heart and liver of 
piglets fed a low selenium diet composed mainly of cereals grown in 
the Keshan disease area (Zhu et al., 1981). 

7.2.2.  Intakes needed to prevent deficiency

7.2.2.1.  Quantitative dietary levels

    Schwarz (1961) showed that 0.02 - 0.03 mg selenium/kg diet, in 
the form of sodium selenate or selenite, afforded 50% protection 
against liver necrosis in vitamin E-deficient rats over an 
experimental period of 30 days.  Selenite-selenium at 0.10 mg/kg 
protected the rats over their entire life span in the absence of 
vitamin E.  Under these conditions, the rats developed severe 
tocopherol deficiency, which mainly afflicted the central nervous 
system.  Sprinker et al. (1971) noted that 0.10 mg selenium/kg, as 
selenite, prevented specific selenium deficiency lesions in rats 
that had been fed a vitamin E-supplemented diet for 2 generations.  
Thompson & Scott (1969) found that administration of 0.02 - 0.05 mg 
selenium/kg, as selenite, prevented death and exudative diathesis 
in chicks fed diets containing typical levels of vitamin E 
(sections 7.2.4.1 and 7.2.7.2 include discussions on the 
nutritional interrelationship of selenium and vitamin E). 

    Considerable field experience in New Zealand has indicated that 
feeds from pastures associated with selenium-responsive 
unthriftiness in sheep contain 0.008 - 0.030 mg selenium/kg 
(Hartley, 1967).  In areas where selenium-responsive diseases do 
not occur, the feed levels of selenium range from 0.020 - 0.098 
mg/kg.  Since there is some overlap in these selenium levels, other 
factors may be involved in the etiology of this selenium-responsive 
disease (various factors that can influence selenium deficiency 
are discussed in section 7.2.7). 

    It has been concluded that "the critical level for dietary 
selenium, below which deficiency symptoms are observed, is 
apparently about 0.02 mg/kg for ruminants and 0.03 - 0.05 mg/kg for 
poultry" (US NAS/NRC, 1971).  However, this US NAS/NRC committee 
pointed out that "when supplementary selenium is fed, higher levels 
than the minimal requirements have been proposed, both to permit 
satisfactory distribution of the element through the large feed 
mass and to overcome variations in feed intake by individual 
animals".  The final recommendation of the committee was that 0.1 
and 0.2 mg selenium should be added per kg feed to eliminate 
selenium deficiency in livestock and turkeys, respectively.  In 
laboratory rats, a dietary-selenium level of 0.1 - 0.2 mg/kg would 
be equivalent to an intake of about 5 - 10 g/kg body weight per 
day. 

7.2.2.2.  Bioavailability

7.2.3.  Blood and tissue levels in deficiency

    Hartley (1967) presented data on the blood-selenium levels of 
normal New Zealand lambs and lambs suffering from various selenium-
responsive diseases (Table 30).  The mean blood-selenium levels 
were lower in the diseased lambs than in the healthy ones, but 
there was considerable overlap between the two groups.  It was 
suggested that other unknown factors might be involved in the 
etiology of these diseases.  Jacobsson et al. (1970) found blood-
selenium levels of 0.003 mg/litre in cows afflicted with muscular 
degeneration, whereas healthy cows had an average of 0.046 
mg/litre.  Hartley (1967) estimated that blood-selenium levels of 
0.05 mg/litre in young sheep could be considered satisfactory. 

    The same authors compared liver-selenium levels found in normal 
lambs with those found in lambs with selenium-responsive 
unthriftiness (Table 31).  Again, there was some overlap between 
the two groups, but the average level of selenium in the livers 
from the deficient lambs was much lower than that from the healthy 
lambs.  Allaway et al. (1966) suggested that 0.21 mg/kg (dry 
weight) is the critical minimal hepatic-selenium level below which 
a high incidence of white muscle disease can be expected in lambs. 

Table 30.  Blood-selenium levels in normal 
and selenium-deficient lambsa
---------------------------------------------
Group                  Selenium contentb
                       (mg/litre)
---------------------------------------------
Normalc                0.026 (0.014 - 0.048)
White muscle diseased  0.016 (0.006 - 0.033)

Normale                0.06 (0.020 - 0.195)
Selenium-responsive    0.01 (0.007 - 0.030)
 unthriftinessf
---------------------------------------------
a Adapted from:  Hartley (1967).
b Mean with range in parentheses.
c Normal lambs from areas with white muscle 
  disease.
d Lambs with white muscle disease.
e Lambs from areas where selenium-responsive 
  diseases are not recognized.
f Lambs with selenium-responsive 
  unthriftiness.
                                                                    
Table 31.  Liver-selenium levels in normal 
lambs or lambs with selenium-responsive 
unthriftinessa
------------------------------------------
Group                Selenium contentb
                     (mg/kg)
------------------------------------------
Normalc              0.16 (0.03 - 0.40)

Selenium-responsive  0.018 (0.005 - 0.05)
 unthriftinessd
------------------------------------------
a Adapted from:  Hartley (1967).
b Mean with range in parentheses.
c Lambs from areas where selenium-
  responsive diseases are not
  recognized.
d Lambs with selenium-responsive 
  unthriftiness.

7.2.4.  Physiological role:  glutathione peroxidase

7.2.4.1.  Function of selenium and relationship to vitamin E

    The discovery that selenium is a component of the enzyme 
glutathione peroxidase (Rotruck et al., 1973) provides a logical 
explanation for the nutritional interaction of vitamin E and 
selenium, a puzzle that perplexed scientists for many years.  
Analysis of purified ovine erythrocyte glutathione peroxidase by 
fluorometry revealed that the protein contained 4 moles of selenium 
per mole of enzyme (Hoekstra et al., 1973) and this stoichiometry 
was also found for crystalline bovine erythrocyte-glutathione 
peroxidase analysed for selenium by neutron activation analysis 
(Flohe et al., 1973).  In the scheme postulated by Hoekstra 

(1975a), tocopherols act as intracellular antioxidants to prevent 
oxidative damage to polyunsaturated fatty acids in biological 
membranes by terminating chain reactions of lipid peroxides (Fig. 
7).  Selenium, as a part of glutathione peroxidase, protects 
against oxidative stress either by catalysing the destruction of 
hydrogen peroxide or by catalysing the decomposition of lipid 
hydroperoxides, thereby interrupting the free radical peroxidative 
chain reaction; in this latter role the free fatty acyl 
hydroperoxide must be liberated by phospholipan A2 action from the 
hydrophobic region of biological membranes, before its reduction 
can be catalysed by glutathione peroxidase (Grossman & Wendel, 
1983).  Thus, both of these nutrients play separate but 
interrelated roles in the cellular defence mechanisms against 
oxidative damage. 

FIGURE 7

    Although glutathione peroxidase accounts for many of the 
biological effects of selenium, other functions of this trace 
element in the body may yet be discovered.  Only 1/5 of the total 
selenium in rat brain is in the form of glutathione peroxidase 
(Prohaska & Ganther, 1976).  Selenium has also been shown to be a 
constituent of several enzymes in microorganisms (Stadtman, 1977). 

7.2.4.2.  Effect of selenium intake on tissue-glutathione peroxidase 
activity

    The results of several studies have shown a close dose-effect 
relationship between the dietary intake of selenium and the 
activity of glutathione peroxidase in various tissues.  For example, 
Hafeman et al. (1974) found that increased dietary selenium caused 
corresponding increases in erythrocyte-glutathione peroxidase 
activity in rats, even when toxic levels of selenium were fed (Fig. 
8).  Hepatic-glutathione peroxidase activity increased with 
increasing dietary-selenium levels up to 1 mg/kg, but then declined 
due to liver damage when toxic levels were fed (Fig. 9).  However, 
studies on hamsters have shown that consumption of excess selenium 

does not always result in increased erythrocyte-glutathione 
peroxidase activity, since feeding selenite at more than 10 mg 
selenium/kg diet did not cause increases in erythrocyte-enzyme 
activity that corresponded to increases in blood-selenium 
concentrations (Julius et al., 1980). 

FIGURE 8

FIGURE 9

    Oh et al. (1976a) investigated the effects of feeding several 
different levels of dietary selenium on the activity of glutathione 
peroxidase in various tissues in lambs.  The activity of the enzyme 
tended to plateau in all tissues examined, except red cells and 
pancreas, when 0.1 mg was fed per kg diet.  This level of dietary 
selenium approximates the presumed requirement in this species. 

7.2.4.3.  Relationship between blood-selenium levels and erythrocyte-
glutathione peroxidase activity

    A direct linear relationship between the selenium concentration 
of whole blood and the activity of erythrocyte-glutathione 
peroxidase has been demonstrated in lambs, sheep, cattle, and swine 
(Oh et al., 1976b; Wilson & Judson, 1976; Sivertsen et al., 1977).  
This linear relationship in lambs (Fig. 10) was thought to be due 
to the fact that glutathione peroxidase accounts for most of the 
total selenium in the ovine red cell and that ovine red cells 
contain a relatively constant proportion of the total blood-
selenium. 

FIGURE 10

    Under certain conditions, some investigators have not found a 
significant correlation between blood-selenium levels and blood 
glutathione peroxidase activity.  For example, Thompson et al. 
(1976) described swine that had high blood-selenium levels but low 
blood-glutathione peroxidase activities.  The reasons for this 
discrepancy are not known but could perhaps be related to an 
increased level of "non-functional" selenium in the blood, such as 
selenomethionine that has been nonspecifically incorporated into 
protein as a substitute for methionine. 

7.2.4.4.  Glutathione peroxidase as an indicator of selenium status

    As discussed by Hoekstra (1975b), the measurement of 
glutathione peroxidase activity offers several advantages as an 
indicator of selenium status.  First of all, the enzyme assay is 
easier to perform and is less time consuming than the selenium 
analysis.  Also, the enzyme assay is not subject to contamination 
problems.  Moreover, glutathione peroxidase represents only 
"functional" selenium in the tissues, not selenium that has been 
non-specifically incorporated into proteins or that has formed 
biologically inactive complexes with heavy metals.  Finally, at 
least in some tissues, the activity of the enzyme appears to taper 
off as the dietary level of selenium approaches the nutritional 
requirement of the animal.  This "plateau effect" of glutathione 
peroxidase activity does not occur in red blood cells, a biological 
material that is highly convenient for sampling purposes.  However, 
as pointed out by Hoekstra (1975b), the absence of plateauing in 
red cells may limit the usefulness of erythrocyte-glutathione 
peroxidase in accurately establishing selenium requirements, but 
does not diminish the usefulness of this source of the enzyme as an 
overall index of selenium status. 

    One complicating factor in the use of glutathione peroxidase to 
assess selenium status is the fact that the activity of the enzyme 
is influenced by many physiological variables other than selenium 
intake (Ganther et al., 1976).  Among these are the age and sex of 
the animal, starvation, exposure to certain oxidant stressors, 
toxicants, or heavy metals, and deficiency in iron and vitamin B12.  
Obviously, these variables have to be controlled, or compensated 
for, if glutathione peroxidase is to be a valid index of selenium 
status. 

    Another serious complicating factor in the use of glutathione 
peroxidase to assess selenium status is the existence of a "non 
selenium-dependent" glutathione peroxidase activity that persists, 
even in severe selenium deficiency (Lawrence & Burk, 1976).  This 
enzymic activity has been found in variable amounts in different 
rat tissues ranging from 23% of the total glutathione peroxidase 
activity in fat to 91% in testis (Lawrence & Burk, 1978).  The "non 
selenium-dependent" activity accounts for 26 - 38% of the total 
glutathione peroxidase activity in rat brain, kidneys, liver, and 
adrenals.  No such activity is found in rat erythrocytes, spleen, 
heart, thymus, intestinal mucosum, skin, or skeletal muscle.  The 
"non selenium-dependent" glutathione peroxidase activity has been 
found in the liver of several different species including the rat, 
hamster, guinea-pig, chicken, pig, sheep, and man.  In human and 
guinea-pig liver, it accounts for the major part of the total 
glutathione peroxidase activity.  The "non selenium-dependent" 
glutathione peroxidase activity differs from the selenium-
containing enzyme in substrate specificity in that it catalyses the 
reduction of a range of organic hydroperoxides but not of hydrogen 
peroxide.  The activity of the "non selenium-dependent" enzyme is 
inversely related in rat liver to the dietary level of selenium 
(Lawrence & Burk, 1978; Lawrence et al., 1978) and the glutathione-
 S-transferase enzymes are responsible for the "non selenium-
dependent" enzyme activity (Prohaska & Ganther, 1977; Lawrence et 
al., 1978).  The glutathione- S-transferases are not selenium-

containing enzymes; they are all dimeric, and their monomeric 
constituents fall into three categories of different relative 
molecular mass.  The glutathione peroxidase activity of the enzymes 
is only shown by the dimeric enzymes that contain one of the three 
subunits and, in selenium deficiency, the amount of this subunit 
alone is increased (Ketterer et al., 1982; Mehlert & Diplock, 
1985). 

    The physiological significance of the "non selenium-dependent" 
activity has been questioned because the seleno-enzyme has a much 
higher Vmax and lower KM (Prohaska & Ganther, 1977).  However, Burk 
et al. (1980a) showed that the "non selenium-dependent enzyme" 
removed organic hydroperoxides in intact rat livers perfused with a 
haemoglobin-free medium containing high concentrations of 
peroxides. 

    Obviously, any use of glutathione peroxidase activity to 
monitor selenium status has to take into account this "non 
selenium-dependent" activity.  This complication can be avoided by 
selecting a tissue for test that has little or none of the 
selenium-independent activity, such as erythrocytes, or by using 
hydrogen peroxide as the substrate, since this has little activity 
with the selenium-independent enzyme. 

7.2.5.  Other possible physiological roles

7.2.5.1.  Homeostasis of hepatic haem

    Burk et al. (1974) showed that the induction of hepatic 
cytochrome P-450 by daily intraperitoneal injections of 75 mg 
phenobarbital/kg body weight, for 4 days, was markedly impaired in 
rats that had been fed a selenium-deficient diet for at least 3 
months.  The induction of ethylmorphine demethylase activity by 
phenobarbital was also impaired in the livers of selenium-deficient 
rats.  However, no such impairment was observed in the induction of 
cytochrome b5 or of NADPH-cytochrome c reductase activity or 
biphenyl hydroxylase activity, or in pentobarbital sleeping time 
(Burk & Masters, 1975).  Treatment with phenobarbital stimulated a 
6- to 8-fold increase in hepatic microsomal haem oxygenase activity 
in selenium-deficient rats but had little or no effect in selenium-
supplemented rats (Correia & Burk, 1976).  This suggested that the 
abnormalities of cytochrome P-450 induction in selenium-deficient 
rats were related to increased degradation rather than decreased 
synthesis of hepatic haem.  Mackinnon & Simon (1976) reported an 
impaired haem synthesis in selenium-deficient phenobarbital-treated 
rats, but Burk & Correia (1977) were unable to confirm these 
results.  Apparently, the pronounced stimulation of microsomal 
haem oxygenase (EC 1.14.99.3) in the livers of selenium-deficient 
rats by phenobarbital is unrelated to the role of selenium in 
glutathione peroxidase, since pretreatment of deficient rats with 
a single dose of selenite at 50 mg selenium/rat, 4 - 6 h before 
phenobarbital administration, abolished the response in haem 
oxygenase but had no effect on cytosolic or mitochondrial 
glutathione peroxidase activity (Correia & Burk, 1978).  Moreover, 
phenobarbital failed to stimulate liver microsomal haem oxygenase 
activity or to affect cytochrome P-450 in vitamin E-deficient, 

selenium-adequate rats, so this response does not seem to be 
related to the direct effects of lipid peroxidation on haem or 
cytochrome P-450.  There is a marked sex difference in the 
phenobarbital stimulation of hepatic microsomal haem oxygenase 
activity in selenium-deficient rats.  The stimulation was greatest 
in males and least in females with intermediate values in castrated 
males and testosterone-treated females (Burk et al., 1980a).  This 
sex difference existed even though hepatic glutathione peroxidase 
activity was reduced to the same extent by selenium deficiency in 
all groups.  However, the exact mechanism by which selenium 
influences homeostasis of hepatic haem still needs to be clarified.  
Pascoe et al. (1983) showed that both intraluminal iron and 
selenium were required by the intestinal mucosa for maintenance of 
the intestinal cytochrome P-450 content, and its dependent mixed 
function oxidase activity, and that withdrawal of dietary selenium 
for one day markedly decreased the level of cytochrome P-450 in the 
small intestine, suggesting that intestinal mucosal cells derive 
their selenium from the diet rather than from the blood. 

    A report by Maines & Kappas (1976) indicated that injection of 
selenium increased hepatic haem oxygenase activity, but the doses 
of selenium used (3.94 mg/kg body weight) exceeded the MLD for 
selenium as selenite (Table 19), so that the phenomenon observed by 
these authors may have been merely an artifact of acute selenium 
poisoning. 

7.2.5.2.   Microsomal and mitochondrial electron transport

    Diplock and co-workers carried out an extensive series of 
studies, the results of which suggest a possible role for selenium 
and vitamin E in the electron-transfer system of rat-liver 
microsomes (Diplock, 1974a,b).  First, they showed that appreciable 
amounts of volatile selenium evolved from rat liver subcellular 
organelles, after acid treatment, only when the rats were adequate 
in vitamin E and the tissue homogenization medium contained large 
concentrations of anti-oxidants (Diplock et al., 1971).  The acid-
volatile selenium was later identified as selenide (Diplock et al., 
1973).  It was assumed that this compound was formed  in vivo, 
presumably by the glutathione reductase pathway (Fig. 9), but 
artifactual  in vitro formation of such selenide, because of the 
presence of mercaptoethanol in the homogenization medium, cannot be 
ruled out (Levander, 1976a).  An oxidant-labile form of non-haem 
iron, dependent on dietary vitamin E and selenium, was observed in 
rat liver microsomes (Caygill & Diplock, 1973).  It was considered 
that this supported the hypothesis that the selenide might form 
part of the active centre of a non-haem iron protein functional in 
microsomal electron transfer.  Alterations in the kinetic 
parameters of aminopyrine demethylation by the liver microsomes in 
vitamin E-deficient rats also supported this idea (Giasuddin et 
al., 1975).  However, attempts to isolate an oxidant-labile 
selenium- and vitamin E-dependent non-haem, iron-containing protein 
fraction were unsuccessful, because of the lability of the 
selenide, and it was concluded that clarification of the role of 
selenide in microsomes needed additional research (Diplock, 1976, 
1979).  The effects of prolonged selenium deficiency on a large 
number of parameters in mouse liver xenobiotic metabolism were 
studied by Reiter & Wendel (1983).  They demonstrated a 

heterogeneous pattern of effects that did not appear to involve 
glutathione peroxidase. 

    One of the earliest biochemical defects discovered in vitamin 
E- and selenium-deficient rats was the inability of liver slices or 
homogenates to maintain normal rates of respiration after prolonged 
periods of incubation  in vitro (Schwarz, 1962).  Although this so-
called respiratory decline might be explained on the basis of 
generalized mitochondrial membrane damage due to lipid peroxidation 
(Yeh & Johnson, 1973), it was also plausible that selenium might 
have a more specific role in mitochondrial metabolism.  Indeed, 
selenium added to the diet, or added  in vitro, accelerated the 
swelling of rat liver mitochondria induced by certain thiols, and 
this swelling could be blocked by the addition of cyanide (Levander 
et al., 1973a).  Selenium was in fact shown to be an excellent 
catalyst for the reduction of cytochrome c by thiols in chemically-
defined systems (Levander et al., 1973b) and a selenoprotein 
containing a haem group similar to that of cytochrome c has been 
reported in lamb muscle (Whanger et al., 1973).  However, more work 
is required to establish the possible role of selenium in 
mitochondrial electron transfer. 

7.2.5.3.  The immune response

    Dietary vitamin E in excess of nutritionally required levels 
has been shown to improve the humoral immune response of several 
different species to bacterial and viral antigens (Nockels, 1979).  
Because of the close nutritional and biochemical relationship 
between selenium and vitamin E (section 7.2.4.1), the effect of 
dietary selenium supplementation was tested on the immunological 
responses of mice (Spallholz et al., 1973).  Mice fed a laboratory 
chow diet (thought to contain 0.5 mg selenium/kg) supplemented with 
sodium selenite at 0.7 or 2.8 mg selenium/kg had approximately 7- 
and 30-fold higher antibody titres, respectively, after challenge 
with sheep red blood cells than mice fed the chow diet alone.  
Sodium selenite injected into mice intraperitoneally at doses of 
3 - 5 g per animal also increased the primary immune response to 
the sheep red-blood-cell antigen and this increase was greatest 
when the selenium was given prior to, or simultaneously with, the 
antigen (Spallholz  et al., 1975).  The mechanism by which selenium 
stimulates antibody synthesis is not known (Martin & Spallholz, 
1976), but the dose of selenium needed to elicit this response is 
clearly above the nutritionally required level.  Levander (1986) 
has reviewed the very limited data on the possible effect of 
selenium on the immune response in man. 

7.2.5.4.  Selenium and vision

    The effects of selenium on light perception were studied in 50 
male "Grey chinchilla" rabbits weighing 3 - 3.5 kg and maintained 
on a standard laboratory diet (Abdullaev et al., 1972, 1974a,b).  
Electroretinography was carried out in dark-adapted animals under 
conditions of maximally dilated pupil induced by topical 
application of 0.5% dikaine - 1% atropine.  Light stimulation was 
provided with an impulse lamp giving either single or dual flashes 
of 150 microseconds.  Eight different energy levels of light 
intensity were used ranging from 0.016 to 1.4 J.  Sodium selenite 
was administered subcutaneously at a dose of 0.45 mg selenium/kg 

body weight.  Control rabbits were injected with sodium sulfite at 
a dose of 1 mg/kg.  Sodium selenite stimulated light sensitivity, 
as judged by increases in the a and b waves of the electro-
retinogram (ERG).  The increase in the amplitude of the b wave was 
considerably greater than that of the a wave.  This stimulating 
effect of sodium selenite on light sensitivity persisted for 3 days 
in all studies.  The same effects were observed when sodium 
selenite was given via retrobulbar administration.  Sodium sulfite 
did not have any effect on the ERG.  Similar results were obtained 
by Bacharev et al. (1975). 

    The Task Group recognized that the data on the effects of 
selenium on vision were obtained in studies involving high dose 
levels (in the case of rabbits, the doses were approximately 20 - 
30% of the LD50).  The effects on vision of lower doses of selenium 
have not been elucidated so far.  The possible effect of deficiency 
of selenium on vision is also of interest.  Model studies with 
isolated retinas exposed to a 0.01% concentration of sodium 
selenite resulted in an increase in the amplitude of the ERG 
(Kulieva et al., 1978).  The effect of increased sensitivity of the 
eye to light, after administration of sodium selenite, and the rate 
of manifestation and duration of the effect are directly 
correlated with localization of the substance in the structures of 
the eye (section 6.2.2.1).  Subcutaneous administration of sodium 
selenite to rabbits, at a dose of 0.4 - 2 mg/kg body weight, 
inhibited free radical formation as indicated by electron 
paramagnetic resonance (EPR) measurements, not only in the lipid 
membrane phase but also within the melanoprotein granules of the 
retinal epithelium.  The EPR signal was decreased in intensity by 
selenite treatment in comparison with controls, but the form and 
parameters of the EPR lines were not changed (Abdullaev et al., 
1974a,b). 

7.2.6.  Effects on reproduction

    Vitamin E was discovered as a result of the isolation of an 
unknown fat-soluble dietary factor essential for reproduction in 
rats (Evans & Bishop, 1922), but selenium compounds are not active 
in preventing reproductive failure in vitamin E-deficient rats 
(Harris et al., 1958).  Moreover, female rats weighing 80 - 120 g 
and fed a selenium-deficient, but vitamin E-adequate, diet 
successfully delivered 3 litters over a period of 6 months, 
even though their blood-selenium levels dropped from 0.52 to 
0.06 mg/litre during this time (Hurt et al., 1971).  Similarly, 
McCoy & Weswig (1969) found that rats fed a low-selenium but 
adequate-vitamin E diet, for 4 months, reproduced normally.  
However, their offspring failed to reproduce if kept on the low 
selenium diet.  Immobile spermatozoa, with separation of heads from 
tails, were observed in 5 out of the 8 male progeny not given 
selenium supplements, and no spermatozoa were seen in the other 3 
males.  The 2 male and 2 female offspring, supplemented with sodium 
selenite at 0.1 mg selenium/kg diet, were fertile but delivered 
litters of only one or 2 rats, all of which died in a few days.  
The authors concluded that selenium supplementation resulted in 
some fertilization, but only a few full-term young were delivered 
and these were abnormal as they survived for only a brief period. 

    Wu et al. (1973) found that the motility of spermatozoa from 
male rats, born to females fed a selenium-deficient diet, was 
always very poor and that most of the sperm cells showed breakage 
near the midpiece of the tail.  Supplementation of the diet with 
high levels of vitamin E or various other antioxidants did not 
prevent these selenium deficiency effects.  However, in this study, 
the body and testicular weights of the rats were so markedly 
depressed by selenium deficiency that it was not possible to 
establish whether the abnormal sperm were due to a direct effect of 
selenium deficiency or to an indirect effect on overall growth and 
well-being.  In a second series of studies (Wu et al., 1979), using 
male rats born to dams fed a diet adequate in selenium, the 
depression of growth, and testes weight in the progeny caused by 
selenium deficiency was much less, even though impaired sperm 
motility and abnormal sperm morphology were still observed (Table 
32).  The authors also pointed out that there did not appear to be 
any correlation between reduction in body or testicular weights and 
the characteristic sperm midpiece abnormality among the individual 
rats in each treatment group.   However, all of the rats used by Wu 
and associates were fed diets that were probably low in zinc and 
chromium and both of these trace elements are known to play 
important roles in sperm formation (Wu et al., 1971; US NAS/NRC, 
1979; Anderson & Polansky, 1981). 
    
    The mechanism of the effects of selenium on the integrity of 
sperm morphology in the rat is not known, but Brown & Burk (1973) 
found over 40% of an injected tracer dose of radio-selenite in the 
testis-epididymis complex of selenium-deficient rats, after 3 
weeks.  Autoradiography of epididymal sperm revealed that the 
labelled selenium was heavily localized in the midpiece.  Calvin 
(1978) has isolated a selenopolypeptide, with a relative molecular 
mass of 17 000 daltons, from rat sperm, which may have a critical 
function in the normal assembly of the sperm tail. 

    Selenium cannot prevent resorption-gestation in vitamin E-
deficient rats, nor can it improve reproductive performance in 
vitamin E-deficient chickens or turkeys (Creger et al., 1960; 
Jensen & McGinnis, 1960).  However, studies in which severe 
depletion of selenium was produced by the long-term feeding of low-
selenium, high-vitamin E diets have shown the beneficial effects of 
the element on egg production and hatchability in poultry.  For 
example, Cantor & Scott (1974) fed 1-day-old Single Comb White 
Leghorn chicks semi-purified low-selenium starter, grower, and 
developer diets, all of which contained only 0.02 mg naturally-
occurring selenium/kg from 0 to 6, 7 to 12, and 13 to 25 weeks of 
age, respectively.  Because of the low selenium level, high levels 
of vitamin E (50 - 84 IU/kg) were added to the diets to prevent 
exudative diathesis during the growth period.  From 25 weeks of age 
to 10 months, the birds were fed semi-purified low-selenium layer 
diets that contained 11 IU of vitamin E/kg.  After 10 months, the 
hens were fed a low-selenium corn-soybean meal practical laying 
ration containing 0.027 mg natural selenium/kg, by analysis. The 
calculated vitamin E content was 16 IU/kg.  At 12 1/2 months of 
age, 4 replicate groups of 5 hens were continued on the low-
selenium diet, whereas a similar number of hens was fed the same 
diet supplemented with sodium selenite at 0.1 mg selenium/kg.  
Selenium supplementation had beneficial effects on both egg 
production and hatchability of fertile eggs (Table 33), but there 
was no significant effect of selenium on egg fertility, determined 
after 2 - 5 weeks (data not shown). 

Table 32.  Effects of selenium deficiency on body and testicular weights and 
spermatozoan morphology and motility in ratsa
------------------------------------------------------------------------------------
Dietary selenite  Number  Duration  Body      Testes       Sperm      Number of rats
supplement        of      (month)   weight    weight       motilityb  with sperm
(mg selenium/kg)  rats              (g)       (g)                     midpiece
                                                                      abnormality
------------------------------------------------------------------------------------
Study 1

 0                6       4         452  6   3.29  0.06  6.2        0/6
                          
 0.5              6       4         470  18  3.55  0.11  6.2        0/6

 0                4c      12        476  17  3.03  0.30  2.5        2/4

 0.5              4c      12        494  12  3.57  0.07  5.8        0/4

Study 2

 0                10c     11        456  16  3.07  0.09  3.5        5/10

 0.4              12      11        543  18  3.50  0.08  8.0        0/12
------------------------------------------------------------------------------------
a Adapted from:  Wu et al. (1979).
b Relative activity of sperm observed with a light microscope at 400x at 37 C and 
  graded from 0 - 10 with 10 representing the highest motility.
c Two rats died in each of these groups.
    
    Cantor et al. (1978) carried out a similar study on turkeys in 
which large white breeder hens and toms were raised from one day of 
age until sexual maturity on a series of Torula yeast-containing 
diets, low in selenium content (0.025 - 0.047 mg/kg).  At 32 weeks 
of age, 8 replicate groups, each comprising 6 individually-caged 
hens, were fed a low-selenium basal diet (0.033 mg/kg) or the same 
diet supplemented with sodium selenite at 0.2 mg selenium/kg.  
Eight individually-caged toms were also assigned to each dietary 
treatment at 32 weeks of age.  Neither the tom nor the hen dietary 
treatments had any effect on fertility and the tom dietary 
treatment did not have any effects on hatchability.  But the 
hatchability of fertile eggs from hens fed the unsupplemented and 
supplemented diets was about 50 and 59%, respectively.  The 
mechanism by which dietary selenium improves hatchability in 
chickens or turkeys is not known, but the improvement may be due to 
increased embryonic selenium levels or to a reduced embryonic need 
of vitamin E (Cantor & Scott, 1974). 

Table 33.  Effect of dietary selenium 
supplements on reproductive performance of 
12 1/2-month-old selenium-depleted hens fed a 
low-selenium, corn-soybean-meal practical 
rationa
----------------------------------------------
Selenium supplement  None  0.1 mg selenium as
                           Na2Se03/kg diet
----------------------------------------------
Criterion

  Egg production (%)

  Weeks  1-2         67.2  76.6
         3-4         66.4  78.5
         5-6         64.2  71.8

  Day   46-76        54.2  79.7
        77-107       55.1  76.7
        108-137      59.1  75.1

 Hatchability of fertile eggs (%)

  Week  2            57.3  93.0
        3            54.7  97.1
        4            54.5  94.9
        5            42.4  86.6
        17           0.0   90.3
        18           8.0   93.6
----------------------------------------------
a Adapted from:  Cantor & Scott (1974).

    In New Zealand, a close geographical relationship was observed 
between the presence of white muscle disease and the incidence of 
barren ewes (Table 34).  A selenium intervention trial was carried 
out on 3 farms where there was a history of white muscle disease 
and low lambing percentages (Table 35).  The selenium-treated ewes 
received 5 mg of selenium, as sodium selenite, at monthly intervals 
from one month before tupping until just before lambing; half of 
the rams were also given selenium at monthly intervals before and 
during tupping (Hartley et al., 1960; Hartley & Grant, 1961).  
Selenium-dosed groups on all farms had higher lambing percentages 
and fewer barren ewes than the controls.  Moreover, white muscle 
disease was eliminated in the lambs of the treated ewes.  Estrus, 
ovulation, fertilization, and early embryonic development all 
proceeded normally in selenium-responsive ovine infertility until 
between 3 and 4 weeks after conception (at about the time of 
implantation) when the embryos perished for unknown reasons 
(Hartley, 1963).  The actual cause of selenium-responsive 
infertility is also unknown and the geographical distribution of 
the disease is not always the same as that of other selenium 
deficiency diseases, such as white muscle disease or selenium-
responsive unthriftiness (Gardiner et al., 1962).  This suggests 
either that selenium-responsive infertility occurs only where 
intake of selenium is particularly low or that some other factors 
must be present that exacerbate the effects of low selenium intake.  

For example, mercury has a strong antagonism with selenium (section 
7.4.1), and Parizek et al. (1971) showed that inorganic mercury 
could block the transport of selenium from mother rats to the 
fetuses. 

Table 34.  Geographical relationship between 
congenital white muscle disease and incidence 
of barren ewesa
-----------------------------------------------
Congenital    Number  Incidence of barren ewes
white muscle  of      up to  11 - 30%  over
disease       farms   10%              30%
-----------------------------------------------
Present       21      3      8         10

Absent        16      12     4         0
-----------------------------------------------
a Adapted from:  Hartley et al. (1960).


Table 35.  Effects of selenium (Se) on the reproductive 
performance of sheep and white muscle disease in lambsa
-------------------------------------------------------
                                     White muscle
Farm  Lambing        Barren ewes     disease incidence
      control  Se    control  Se     control  Se
-------------------------------------------------------
               (%)            (%)             (%)

C     60.6     94.9  31.1     7.5    37.5     0
D     55.0     86.0  24.3     11.5   22.2     0
E     70.5     93.6  26.1     6.4    12.0     0
-------------------------------------------------------
a Adapted from:  Hartley et al. (1960).

7.2.7.  Factors influencing deficiency

7.2.7.1.  Form of selenium

    Schwarz (1961) pointed out that only 0.007 mg naturally-
occurring selenium/kg diet in extracts from pork kidney ("Factor 3 
Selenium") was needed to afford 50% protection against dietary 
necrotic liver degeneration in rats, whereas 0.020 - 0.030 mg/kg 
was required when the selenium was in the form of selenite, 
selenate, selenocystine, or selenomethionine.  Elemental selenium 
was essentially inactive.  Many organic derivatives were 
synthesized in an attempt to develop selenium compounds that were 
not highly toxic but still retained considerable biological potency 
against deficiency diseases (Schwarz et al., 1972).  Simple amino 
acid derivatives of monoseleno diacetic acid appeared promising in 
this regard and the hope was expressed that some of these compounds 
might make it possible to use selenium in the prevention and cure 
of disease (Schwarz, 1976). 

    Cantor et al. (1975a) studied the ability of selenium in 
various poultry feed ingredients to prevent exudative diathesis, a 
selenium deficiency disease, in chickens.  In general, the selenium 

in plant products was more readily available than that in animal 
products, but the latter consisted of highly-processed fish or 
poultry meals. 

    Selenium in the form of selenomethionine was less effective 
than selenium as sodium selenite for preventing exudative diathesis 
in chicks (Noguchi et al., 1973), but the reverse was true for the 
prevention of pancreatic fibrosis (Cantor et al., 1975b).  In fact, 
selenomethionine was four times as effective as either selenite or 
selenocystine for this purpose; this phenomenon may have been 
related to the peculiar affinity of this compound for the pancreas. 

7.2.7.2.  Vitamin E

    Vitamin E decreases the level of dietary selenium needed to 
prevent deficiency diseases in several species of animals.  For 
example, Scott & Thompson (1971) demonstrated that chicks receiving 
100 mg vitamin E/kg diet needed only 0.01 mg selenium/kg diet to 
prevent exudative diathesis, whereas chicks not receiving any added 
vitamin E needed 0.05 mg/kg.  Similarly, Scott et al. (1967) showed 
that selenium at 0.18 mg/kg protected against gizzard myopathy in 
turkey poults fed diets containing vitamin E, but that 0.28 mg/kg 
was needed to protect poults fed diets not supplemented with 
vitamin E.  Hakkarainen et al. (1978) found that 0.135 mg 
selenium/kg was insufficient to prevent deficiency signs in swine 
fed a diet containing 1.5 mg vitamin E/kg but was adequate in swine 
fed 5.0 mg vitamin E/kg.  Increasing the level of dietary vitamin E 
decreased the severity of nutritional muscular dystrophy in lambs 
fed diets containing selenium at 0.1 mg/kg (Ewan et al., 1968).  In 
lambs not receiving any supplementary dietary selenium, lambs 
receiving low levels of vitamin E died of dystrophy before their 
hepatic-selenium levels were depleted to 0.21 mg/kg, the level 
considered by Allaway et al. (1966) to be the critical 
concentration of selenium in liver for the development of 
nutritional muscular dystrophy (section 7.2.3).  With the highest 
level of vitamin E supplementation, the liver-selenium values were 
lower than the critical level suggested by Allaway et al. (1966) 
and yet the lambs still survived.  These results suggest that the 
tissue-selenium level is not the only factor involved, but that the 
levels of both tocopherol and selenium determine the appearance of 
nutritional muscular dystrophy.  The effects of vitamin E in 
reducing selenium requirements are readily explainable on the basis 
of the close biochemical relationship between these two nutrients 
discussed in section 7.2.4.1. 

7.2.7.3.  Heavy metals and other minerals

    Since selenium protects against the toxicity of several heavy 
metals (section 7.4), many scientists have examined the effect of 
heavy metals on the induction of selenium deficiency.  Silver 
accelerated the development of liver necrosis in rats (Whanger, 
1976) and increased the severity of selenium-vitamin E deficiency 
in swine (Van Vleet, 1976; McDowell et al., 1978), presumably by 
decreasing the activity of glutathione peroxidase.  Inorganic 
mercury also decreased glutathione peroxidase activity in the rat 
but did not have any effect on the rate of development of liver 

necrosis (Whanger, 1976).  However, methylmercury accentuated the 
development of selenium deficiency in pigs fed a low-selenium diet 
(Froseth et al., 1974).  In spite of the ability of arsenic to 
enhance the biliary excretion of toxic levels of selenium (section 
7.1.6.3), several attempts to induce selenium deficiency by feeding 
arsenic have been unsuccessful (Levander, 1977; McDowell et al., 
1978).  On the other hand, drenching pregnant and lactating ewes 
with potassium cyanide, which partially counteracts selenium 
toxicity in rats (section 7.1.6.2), increased the incidence of 
nutritional myopathy in their lambs (Rudert & Lewis, 1978).  It has 
been suggested that the use of sulfate fertilizers may decrease 
selenium concentrations in forage plants (Pratley & McFarlane, 
1974; Westermann & Robbins, 1974), and that this could lead to an 
increased incidence of selenium deficiency in farm animals 
(Schubert et al., 1961).  Dietary sulfate had no effect on the 
incidence of white muscle disease but increased the number of lambs 
with degenerative lesions of the heart (Whanger et al., 1969).  
Neither cadmium nor tellurium had any effect on white muscle 
disease in lambs (Whanger et al., 1976b) or vitamin E-selenium 
deficiency in swine (McDowell et al., 1978). 

7.2.7.4.  Xenobiotics

    The results of early work by Hove (1948) suggested that vitamin 
E could protect rats fed a low-protein diet from death due to 
carbon tetrachloride (CCl4) poisoning.  The establishment of a 
nutritional relationship between selenium and vitamin E stimulated 
Seward et al. (1966) to study deficiencies of these nutrients in 
relation to poisoning (Table 36).  Mortality was higher in the 
group deficient in both nutrients than in controls, but selenium 
deficiency alone did not increase mortality.  Other workers 
(Hafeman & Hoekstra, 1977a; Burk & Lane, 1979) have confirmed this 
result.  The increased mortality due to CCl4 in doubly-deficient 
animals could have been due simply to inhibition of eating.  
Fasting these animals overnight can precipitate dietary liver 
necrosis leading to death (Hafeman & Hoekstra, 1977b). 

Table 36. Protective effect of selenium and vitamin E 
against carbon tetrachloride toxicity in rats fed a 
10% soybean-protein dieta
-----------------------------------------------------
Dietary supplement  Weight gain  Survival 48 h after
                    (g/8 weeks)  CCl4 injectionb
-----------------------------------------------------
None                62  5       3/10
Vitamin Ec          77  3       9/10
Seleniumd           79  6       8/10
Vitamin E and       80  5       10/10
selenium
-----------------------------------------------------
a Adapted from:  Seward et al. (1966).
b All rats injected intraperitoneally with a single 
  dose at 2 ml/kg body weight.
c Added as a mixture of equal quantities of dl-alpha-
  tocopherol and dl-alpha-tocopheryl acetate at 200 
  mg/kg diet.
d Added at 0.1 mg selenium/kg diet, as sodium selenite.

    Paraquat is another xenobiotic that is thought to exert its 
toxic effect via increased lipid peroxidation (Bus et al., 1974).  
Selenium deficiency worsens lung injury in rats caused by paraquat 
(Omaye et al., 1978) and leads to liver injury that would not 
otherwise occur in mice exposed to this compound (Cagen & Gibson, 
1977).  Burk et al. (1980b) showed that selenium-deficient rats 
were much more susceptible to paraquat or diquat poisoning than 
controls (Table 37).  The deficient rats also produced more ethane 
and had a higher serum-glutamic-pyruvic transaminase (SGPT) 
activity, when treated with paraquat or diquat, than the controls.  
The same workers found that injected selenium protected deficient 
rats against diquat toxicity before appreciable amounts of 
glutathione peroxidase activity appeared in the tissues.  They 
suggested the existence of a selenium-dependent factor, apart from 
glutathione peroxidase which protects against lipid peroxidation. 
                                                                          
    Combs et al. (1975) noted a similarity between the oedema 
produced in chicks fed a practical diet containing polychlorinated 
biphenyls (PCBs) and that observed in chicks fed a diet deficient 
in selenium and vitamin E (exudative diathesis).  When selenium-
depleted hens were fed a diet not containing PCBs, selenite at 
0.15 mg selenium/kg diet was sufficient to prevent exudative 
diathesis in the chicks, but was not sufficient to prevent the 
disease when the hens were fed a diet containing 10 mg PCBs/kg 
(Table 38).  In another study, addition of 50 mg PCBs/kg diet 
increased the incidence of exudative diathesis in vitamin E-
deficient chicks receiving selenite at 0.04 mg selenium/kg diet 
from less than 60% in the controls to almost 90% in the PCBs group, 
14 days after hatching (Combs & Scott, 1975).  Dietary PCBs 
depressed plasma-glutathione peroxidase activity and increased the 
amount of dietary selenium required to protect liver microsomal 
fractions from peroxidation  in vitro.  On this basis, the authors 
concluded that dietary PCBs potentiate vitamin E-selenium 
deficiency in chicks by interfering with the biological utilization 
of dietary selenium, though some interference with the absorption 
and retention of vitamin E was also seen. 

Table 37.  Effect of selenium deficiency in rats treated with paraquat or 
diquata,b
-------------------------------------------------------------------------
Diet       Agent     Dose       Ethane          SGPT         Survival
group      given                produced        activity     time
-------------------------------------------------------------------------
                     (mol/kg)  (pmol/100 g/h)  (mU/ml)      (min)
Selenium-  paraquat  78         470  93        212  87     297  74
deficient

Control    paraquat  78         18  13         32  26      survived 24 h

Control    paraquat  390        92  5          45  34      106  30

Selenium-  diquat    19.5       1940  420      3490  1940  150  37
deficient

Control    diquat    230        56  50         41  5       80  12
-------------------------------------------------------------------------
a Adapted from:  Burk et al. (1980b).
b Values are mean  SD of 4 or 5 values.

    Burk & Lane (1979) pointed out the complexity of nutritional 
toxicology experimentation involving selenium, vitamin E, and 
various drugs and other chemicals.  After studying the effects of 
numerous xenobiotics on rats that were deficient in either vitamin 
E or selenium, they concluded that  in vivo lipid peroxidation, as 
assessed by ethane production, was not necessarily correlated with 
liver necrosis.  Moreover, it was concluded that selenium 
deficiency was not just a lack of glutathione peroxidase activity 
in the tissues, since this condition also elevates hepatic 
glutathione  S-transferase activity.  Thus, selenium deficiency may 
actually protect against the hepatotoxicity of certain compounds, 
(e.g., acetaminophen and iodipamide) by increasing their 
conjugation with glutathione. 

Table 38.  Effect of PCBs fed to hens on the 
incidence of exudative diathesis in progeny fed a 
sub-optimal level of seleniuma
------------------------------------------------------
Additions to diets of hensb  Exudative   Weight gain
--------------------------   diathesis   of chicks
PCBsd    Seleniume           in chicksc  (g/2 weeks)
(mg/kg)  (mg/kg)             (%)        
------------------------------------------------------
0        0                   35          89

0        0.15                0           102

10       0                   30          82

10       0.15                45          78
------------------------------------------------------
a Adapted from: Combs et al. (1975).
b Single Comb White Leghorn hens, 27 weeks old, that 
  had been reared on low-selenium, semi-purified diets 
  supplemented with high levels of vitamin E; hens 
  were on dietary treatments shown in Table for an
  additional 5 weeks.
c Determined at 2 weeks of age.  Chicks were fed a 
  selenium-deficient diet (less than 0.02 mg 
  selenium/kg) supplemented with 0.06 mg selenium, as 
  Na2Se03/kg. Diet was essentially free of tocopherols.
d Aroclor(R) 1254.
e Added as Na2Se03.

7.2.7.5.  Exercise stress

    Ancedotal observations from New Zealand suggested that selenium 
might be of value against "tying-up" in thoroughbred racehorses 
(Hartley & Grant, 1961), a condition that occurs during training 
and is associated with exercise.  Characteristics include muscle 
stiffness and tenderness and disinclination to move.  Young & 
Keeler (1962) applied mechanical restraint to one foreleg of lambs 
born to ewes fed a diet known to produce nutritional muscular 
dystrophy and found that lesions either did not occur or occurred 
to a much lesser extent in muscles of the restrained limb than in 
muscles of the unrestrained limb.  Brady et al. (1978) observed 

increased levels of malondialdehyde, a product of lipid 
peroxidation, in the erythrocytes of 6 horses, immediately after 
exercise, but were unable to reproduce this phenomenon in a second 
exercise trial with 8 horses.  Sodium selenite, given for 4 weeks 
in the trace mineral salt at a level calculated to provide 0.15 mg 
supplementary selenium/kg diet, did not have any effect on the 
elevated plasma-enzyme activities observed in exercised horses.  
Furthermore, it did not have any effect on plasma-selenium levels 
or erythrocyte-glutathione peroxidase activity.  Harthoorn & Young 
(1974) commented that the pathological picture in wild animals that 
have died following mechanical capture ("capture myopathy" or 
"overstraining syndrome") is indistinguishable from white muscle 
disease seen in cattle suffering from vitamin E deficiency, but 
pointed out that prophylactic and subsequent symptomatic treatment 
with vitamin E and selenium-containing preparations did not have 
any beneficial effects on captured animals.  Brady et al. (1979) 
expected to induce death in rats that had been fed a selenium and 
vitamin E-deficient diet for 4 weeks, after exercising them to 
exhaustion by swimming, but had no success, in spite of markedly 
depressed tissue-glutathione peroxidase activity, decreased hepatic 
stores of fat-soluble antioxidants, and increased levels of 
thiobarbituric acid-reacting substances.  The authors concluded 
that the rat might be an unsuitable model for an exercise stress-
susceptible species. 
                         
7.3.  Ratio Between Toxic and Sufficient Exposures

    The minimum level of dietary selenium that causes overt signs 
of chronic selenium toxicity in most species of animals is of the 
order of 4 - 5 mg/kg (US NAS/NRC, 1976).  The minimum level of 
dietary selenium needed to prevent selenium deficiency diseases in 
most species is in the range of 0.02 - 0.05 mg/kg (US NAS/NRC, 
1971).  Therefore, the ratio of toxic to deficient selenium 
exposures is about 100.  This difference between the harmful and 
beneficial levels of selenium is similar to that between the 
harmful and beneficial levels of several nutritionally essential 
minerals.  However, in the case of selenium, this ratio can be 
decreased by certain nutritional or environmental factors.  For 
example, a deficiency in vitamin E decreases the tolerance of 
animals to selenium toxicity (section 7.1.6.2) but increases the 
nutritional need for the element (section 7.2.7.2).  Also, 
inorganic mercury increases the toxicity of methylated selenium 
metabolites (section 7.4.1) but methylmercury potentiates selenium 
deficiency (section 7.2.7.3).  Thus, caution may have to be 
exercised in some situations to avoid a diminution in the ratio 
between harmful and beneficial intakes of selenium. 

7.4.  Protection Against Heavy Metal Toxicity

7.4.1.  Mercury

    Parizek & Ostadalova (1967) first showed that selenium could 
protect against the toxicity of mercury in short-term acute 
toxicity studies.  This led to the suggestion that one of the 
nutritional roles of selenium might be protection of the organism 
against traces of toxic metals that enter the body, even under 

normal conditions (Parizek et al., 1971).  Nutritional levels of 
dietary selenium have been demonstrated to decrease the chronic 
toxicity of the highly hazardous methylmercury (Ganther et al., 
1972) and the selenium in tuna may provide a built-in protective 
mechanism against the methylmercury in such fish (Ganther & Sunde, 
1974).  The possible practical significance of the metabolic 
interaction of selenium and mercury has been indicated by the 
strong correlations observed between the concentrations of mercury 
and selenium in the livers of marine mammals under normal 
environmental conditions (Koeman et al., 1975) and in human tissues 
following exposure to inorganic mercury (Kosta et al., 1975).  The 
mechanism by which selenium protects against the toxicity of 
methylmercury is not known, but the fact that vitamin E and certain 
antioxidants also decrease methylmercury toxicity (Welsh & Soares, 
1976; Welsh, 1979) has prompted the hypothesis that these compounds 
may diminish methylmercury toxicity by counteracting the damaging 
effects of the free radicals generated by its breakdown (Ganther, 
1978). 

    Although inorganic selenium salts protect against the toxicity 
of inorganic or methylmercury under a wide variety of conditions, 
dimethylselenide has a strong synergistic toxic action with 
mercuric chloride (Parizek et al., 1971).  The mechanism of this 
synergism is unknown. 

7.4.2.  Cadmium

    Parenterally administered selenium protects against the 
toxicity of injected doses of cadmium in rats, apparently by 
diverting the cadmium from low relative molecular mass target 
proteins to other proteins of higher relative molecular mass 
(Parizek et al., 1971; Chen et al., 1975).  However, selenium does 
not cause this diversion when given orally, so any mechanism by 
which selenium counteracts cadmium toxicity, under environmental 
conditions, is yet to be determined (Whanger, 1976).  The 
cadmium/selenium antagonism may be important for human health in 
that selenium prevents the hypertension caused by long-term cadmium 
exposure in rats (Perry et al., 1976). 

7.4.3.  Other heavy metals

    Selenium may interact with lead but the interaction appears to 
be much weaker than that with mercury or cadmium, and vitamin E 
seems to be more important than selenium in determining the effects 
of lead poisoning (Levander, 1979).  The interaction of selenium 
and silver is of theoretical interest since glutathione peroxidase 
activity is depressed by silver (Wagner et al., 1975), but this 
interaction does not appear to have any practical significance.  
Large doses of selenate protect against thallium toxicity in rats 
(Rusiecki & Brzezinski, 1966), but this interaction has not been 
investigated in any detail. 

7.5.  Cytotoxicity, Mutagenicity, and Anti-mutagenicity

7.5.1.  Cytotoxicity and mutagenicity

    Walker & Ting (1967) treated the soil around barley seedlings 
with solutions of sodium selenate to determine the effect on 
crossing over.  Hoagland's solution containing 0, 0.5, 1.6, or 
5.0 mg selenium/litre was applied 10 times, at 2-day intervals, to 
each of 4 groups of plants, each treatment consisting of the 
application of a 250 ml aliquot of the appropriate solution per 
pot.  On the day after treatment, the pots were irrigated with 
distilled water to prevent lethal accumulation of selenate.  
Genetic data indicated a significant effect of the selenate on the 
rate of crossing over, consisting of a progressive decline with 
increasing concentration. 

    Walker & Bradley (1969) reared larvae of  Drosophila 
 melanogaster on a semi-defined culture medium containing 
selenocystine at concentrations of 0, 2, 10, and 50 M.  The 
selenocystine had different effects on crossing over on various 
chromosomal segments and the authors concluded that these effects 
were mediated through a structural chromosomal protein with a role 
in the exchange process. 

    In studies by Nakamuro et al. (1976), various inorganic 
compounds of selenium exhibited clastogenic effects when added  in 
 vitro to cultures of human leukocytes (Table 39).  Quadrivalent 
selenium compounds were generally more efficient than hexavalent 
compounds in inducing chromosome aberrations.  Similarly, selenite 
was more potent than selenate in causing DNA damage to  Bacillus 
 subtilis that was subject to recombination repair.  The same 
authors also found that 1.6 x 10-3 mol H2Se03 or Se02 caused about 
a 30% inactivation of the tryptophan marker of  B. subtilis  
transforming DNA, whereas similar concentrations of Na2Se04, 
H2Se04, or Na2Se03 were without any significant effect. 
Table 39.  Chromosome aberrations in leukocytes exposed to selenium compoundsa
-------------------------------------------------------------------------------------
Compound  Dose          Occurrence of particular chromosome aberrationsb  Total
                        chromatid  chromatid  iso-chromatid  chromatid    aberrations
                        gaps       breaks     breaks         exchanges
-------------------------------------------------------------------------------------
          (x 10-5 mol)                  aberrations per 100 cells                    
Na2Se04   53            8.4        0.9        0.9            0.9          11.2
          26            9.3        0.8        0.8            0.8          11.9
          13            11.2       0          0              0            11.2

H2Se04    53            21.0       14.5       3.2            1.6          40.3
          26            11.9       0          0              0            11.9
          13            9.2        0.8        0              0            10.0

Na2Se03   26            54.0       14.5       1.6            1.6          71.8
          13            41.7       8.3        0.9            0.9          51.9

Table 39 (contd.)
-------------------------------------------------------------------------------------
Compound  Dose          Occurrence of particular chromosome aberrationsb  Total
                        chromatid  chromatid  iso-chromatid  chromatid    aberrations
                        gaps       breaks     breaks         exchanges
-------------------------------------------------------------------------------------
          (x 10-5 mol)                  aberrations per 100 cells                    

H2Se03    26            113.2      41.2       22.1           5.8          182.4
          13            92.3       42.3       12.8           2.6          150.0
          6.5           15.2       6.3        5.4            0            26.8

Se02      26            52.1       22.5       7.0            1.4          83.1
          13            24.2       2.5        3.3            0            30.0
          6.5           15.5       3.6        4.8            0            20.9
                                              
None      -             7.6        0          0              0            7.6
-------------------------------------------------------------------------------------
a  Adapted from: Nakamuro et al. (1976).
b  Number of cells examined varied from 62 - 250.
    Lo et al. (1978) showed that selenite caused chromosome 
aberrations and mitotic inhibition in cultured human fibroblasts 
and that incubation with a mouse liver S9 microsomal fraction 
increased this capacity of selenite about 5-fold at equimolar 
concentrations (Table 40).  Selenite also induced DNA fragmentation 
and repair synthesis and decreased the clone-forming capacity of 
the fibroblasts.  Incubation with the S9 fraction increased the 
last 2 effects of selenite but slightly decreased the extent of DNA 
fragmentation.  The response to selenite was similar in cultured 
fibroblasts from normal persons and from DNA repair-deficient 
xeroderma pigmentosum patients.  The ability of selenate to trigger 
DNA repair, inhibit the mitotic rate, or cause a lethal effect was 
about the same as that of selenite over concentrations varying from 
7 x 10-6 to 2 x 10-3 mol.  However, when both compounds were 
incubated with the S9 fraction, only the activity of the selenite 
was potentiated (Table 41). 

Table 40.  Effect of 1.5 h selenite treatement on chromosome
aberrations and mitotic rate of human fibroblastsa
-------------------------------------------------------------
Sodium      Metaphase plates with        Mitotic rate       
selenite    chromosome aberrations  without S-9  with S-9  
for 1.5 h   without S-9  with S-9   (%)          (%)
(mol)       (%)          (%)
-------------------------------------------------------------
Control     1.2          0.8        9.0          8.9
2 x 10-5    1.3          6.9        8.6          9.8
4 x 10-5    1.6          7.4        8.9          9.6
8 x 10-5    3.0          14.3       9.3          9.4
1 x 10-4    3.2          -          8.2          0.1
2 x 10-4    4.7          -          9.5          0.0
4 x 10-4    6.1          -          6.4          0.0
8 x 10-4    14.5         -          6.9          0.0
1 x 10-3    14.2         -          7.6          0.0
3 x 10-3    18.1         -          0.7          0.0
-------------------------------------------------------------
a   Adapted from: Lo et al. (1978).

    Another example of a tissue fraction influencing the 
cytotoxicity of selenite is provided by the work of Ray & 
associates (Ray & Altenburg, 1978; Ray et al., 1978).  These 
workers first showed that sodium selenite tripled the frequency of 
sister-chromatid exchanges (SCEs) in lymphocytes cultured with 
whole human blood (Table 42).  At the concentrations of selenite 
used, the selenite could only be present during the final 19 h of 
the 96-h culture incubation, otherwise cell death occurred, as 
measured by mitotic indices.  Later, they found that 7.90 x 10-6 
mol Na2Se03 increased SCE frequency, only when the lymphocytes were 
cultured in the presence of whole blood or separated red cells.  
Lysis of the erythrocytes indicated that the lysate rather than the 
red cell ghosts contained the activity necessary for selenite to 
raise the lymphocyte SCE frequency.  The authors suggested that 
exposure of selenite to the lysate possibly resulted in a chemical 
modification of the selenite that enabled it to induce SCEs.  This 
chemical modification of the selenite probably involves reduction 
to glutathione selenopersulfide derivatives, since Ray (1984) found 
that reduced glutathione (10-3 - 10-4 mol) could substitute for 
erythrocytes in activating sodium selenite to its SCE-inducing 
form.  Whiting et al. (1980) showed that glutathione markedly 
stimulated unscheduled DNA synthesis in cultured human skin 
fibroblasts and chromosome aberrations in Chinese hamster ovary 
cells caused by a variety of inorganic selenium compounds.  These 
research workers suggested that reduced selenium compounds are the 
ultimate mutagens and that their formation depends on reduction by 
glutathione. 

Table 41.  Effect of selenite versus selenate on human 
fibroblasts incubated with, or without, mouse liver S9 
microsomal fractiona
--------------------------------------------------------------
Treatment       DNA repair        Mitotic rate  Clone forming
                (grains/nucleus)  (%)           capacity (%)
--------------------------------------------------------------
Seleniteb       10.7              5.2           36

Selenite + S9   115.6             0.0           0

Selenate        7.0               4.8           42

Selenate + S9   9.1               3.9           32
--------------------------------------------------------------
a Adapted from:  Lo et al. (1978).
b The concentrations used for the estimation of DNA repair, 
  mitotic rate, and surviving colonies were 8 x 10-4, 2 x 10-7, 
  and 2 x 10-4 mol, respectively. Selenite and selenate were 
  applied at equimolar concentrations for 1.5 h.

Table 42.  Effect of sodium selenite on 
sister-chromatid exchange frequency and 
mitotic index in lymphocytes cultured 
with whole human blooda 
----------------------------------------
Na2Se03       Sister chromatid  Average 
added         exchanges per     mitotic 
(mol)         cellb             index 
----------------------------------------
Control       6.74              0.03 

1.58 x 10-6   7.17              0.03

3.95 x 10-6   7.49              0.03

7.90 x 10-6   20.71             0.02

1.19 x 10-5   21.51             0.03
----------------------------------------
a Adapted from:  Ray et al. (1978).
b Average of 4 studies; a total of 100 
  cells was scored for each Na2Se03 
  concentration except 75 at the highest 
  concentration.

    In a preliminary note, Lofroth & Ames (1978) stated that 
selenite did not give any indication of mutagenicity (<< 0.01 
revertants/n mol) whereas selenate gave rise to base-pair 
substitutions with about 0.03 revertants/n mol in a  Salmonella 
plate incorporation test using different histidine-requiring 
strains that are reverted to prototrophy by different mechanisms.  
On the other hand, Noda et al. (1979) found that both selenite and 
selenate were weak mutagens in a similar test, since they gave 
rise to base-pair substitution (0.2 and 0.05 revertants/n mol, 
respectively).  Ray & Altenburg (1980) showed that sodium selenide 
and sodium selenite were more active than sodium selenate in their 
ability to induce SCEs in human whole-blood cultures.  Sirianni & 
Huang (1983) found that sodium selenite was the most potent inducer 
of SCEs in Chinese hamster V79 cells when S9 mixture was present, 
whereas sodium selenide was the most effective inducer in the 
absence of S9.  For sodium selenate, there was no increase in SCE 
rate compared with controls, regardless of whether S9 was present 
or absent.  At present, it is difficult to provide a biochemical 
explanation for the contrasting cytogenic effects exhibited by the 
various selenium compounds, when studied in different  in vitro  
test systems. 

    Norppa et al. (1980) investigated the chromosomal effects 
of sodium selenite when given  in vivo.  They found that 
supplementation of human neuronal ceroid lipofuscinosis patients 
with tablets furnishing sodium selenite at a dose of 0.025 mg 
selenium/kg body weight for 1 - 13.5 months did not have any 
detectable effects on chromosomal aberrations or SCEs in peripheral 
blood lymphocytes.  Similarly, mice treated with a single dose of 
sodium selenite at 0.8 mg selenium/kg body weight did not show any 
rise in chromosomal abnormalities in bone-marrow cells or primary 

spermatocytes after 24 h.  However, there was an increased number 
of SCEs and chromosomal aberrations in the bone-marrow cells of 
Chinese hamsters, 17 - 19 h after injection with sodium selenite 
at a dose of 0.3 - 6.0 mg selenium/kg body weight.  It was thought 
that the manifestations of chromosomal damage observed in the 
second study may have been related to the general toxicity of 
selenium at the high doses used.

7.5.2.  Anti-mutagenicity

    Shamberger et al. (1973a) tested the ability of sodium selenite 
and various antioxidants to decrease the chromosomal breakage 
induced by 7,12-dimethylbenz[alpha]anthracene (DMBA) in human blood 
leukocyte cultures.  They found that 0.20 mol sodium selenite 
reduced the breaks caused by 1.6 mol DMBA by 42% (Table 43).  This 
concentration of selenite was used because 1 mol almost completely 
inhibited the growth of the cultures.  In later studies, Shamberger 
et al. (1979) found that sodium selenite at concentrations of 
0.67 mol or less was effective in reducing the mutagenic effects 
of malonaldehyde and beta-propiolactone in certain tester strains 
of  Salmonella typhimurium.  Rosin & Stich (1979) showed that sodium 
selenite at concentrations of 3 x 10-4 and 1 x 10-3 mol caused 
a 50% inhibition of mutagenesis in  S. typhimurium induced by  N-
methyl- N'-nitro- N-nitrosoguanidine or  N-acetoxy-2-acetylamino-
fluorene, respectively.  However, 10-2 mol sodium selenite was 
toxic to the bacteria in the presence of either carcinogen.  Sodium 
selenite has also been shown to suppress spontaneous mutagenesis in 
yeast cultures (Rosin, 1981). 

Table 43.  Effects of sodium selenite and various antioxidants on
chromosomal breakage induced by 7,12-dimethylbenz-(alpha)anthracene 
(DMBA) in human blood leukocyte culturesa
-----------------------------------------------------------------------
DMBA    Antioxidant            Number  Cells with    Breaks   Reduction
added   added                  of      breaks        minus    in
(mol)                         cells   number  %     control  breaks
                                                     (%)      (%)
-----------------------------------------------------------------------
0       none                   211     23      10.9  -        -

1.6     none                   290     82      28.3  17.4     -

1.6     0.20 mol Na2Se03      171     37      21.6  10.1     42.0

1.6     10 mol dl-alpha       156     28      17.9  6.4      63.2
        tocopherol

1.6     10 mol ascorbic acid  127     30      23.6  11.9     31.7

1.6     0.21 mol butylated    157     29      18.4  6.3      63.8
        hydroxytoluene
-----------------------------------------------------------------------
a Adapted from:  Shamberger et al. (1973a).

    Jacobs et al. (1977b) examined the effects of sodium selenite 
on the mutagenicity of 2-acetylaminofluorene (AAF),  N-hydroxy-2-
acetyl-aminofluorene (N-OH-AAF), and  N-hydroxy-aminofluorene 

(N-OH-AF) in the  S. typhimurium TA 1538 bacterial tester strain.  
Metabolism of AAF and N-OH-AAF to the active mutagen, N-OH-AF was 
accomplished by rat liver extracts.  Sodium selenite at 
concentrations ranging from 0.1 to 40 mmol decreased the 
mutagenicity of these compounds (Table 44).  However, in the case 
of AAF, the authors noted that further decreases in mutagenicity 
induced by concentrations of selenium higher than 40 mmol were not 
tested, partly because of the formation of a red selenium compound 
of low solubility, which can be presumed to have been elemental 
selenium. 

    Ray et al. (1978) determined the frequencies of sister 
chromatid exchange (SCE) in lymphocytes resulting from the 
simultaneous exposure of whole-blood cultures to different 
concentrations of sodium selenite plus 10-4 mol methyl 
methanesulfonate (MMS) or 2.7 x 10-5 mol  N-hydroxy-2-acetyl-
aminofluorene (N-OH-AAF).  The SCE frequency observed as a result 
of coexposure to 2 compounds was less than that expected because of 
an additive SCE frequency response to each individual compound 
(Table 45).  In their interpretive analysis of the data, the 
authors concluded that the most consistent explanation for the 
results was that sodium selenite decreased the SCE-inducing 
abilities of MMS and N-OH-AAF. 

Table 44.  Effect of sodium selenite on the mutagenicity of
2-acetylaminofluorene and its derviatives to  Salmonella 
 typhimuriuma
-------------------------------------------------------------------
Compound            Selenium  His+ revertants   Mutagenic activity
                    added     per plate ( SD)  (% of appropriate 
                    (mmol)                      control)          
-------------------------------------------------------------------
4.5 mmol AAF        -         1768  149        100
                    4         1411  41         80
                    10        1336  69         76
                    40        1148  71         65

0.45 mmol N-OH-AAF  -         2353  12         100
                    0.4       1891  210        80
                    4         1598  71         68
                    10        1247  53         53
                    40        655  43          28

0.065 mmol N-OH-AF  -         1628  41         100
                    0.1       1280  88         79
                    10        1233  31         76
                    20        999  26          61
-------------------------------------------------------------------
a Adapted from:  Jacobs et al. (1977b).

Table 45.  Effect of methyl methanesulfonate (MMS) or  N-hydroxy-2-
acetylaminofluorene (N-OH-AAF), with or without different concentrations of 
sodium selenite, on sister chromatid exchange (SCE) frequencies in whole-
blood cultures of lymphocytesa
----------------------------------------------------------------------------
Compound        Na2Se03      Total   Observed      Expected       Observed/
                (mol)        cells   SCE/cell      SCE/cellb      expected
                             scored                               (%)
----------------------------------------------------------------------------
None            none         100     6.74  0.30   -              -

10-4 mol MMS    none         100     30.17  0.75  -              -
                1.58 x 10-6  75      30.60  0.74  30.60 (0.43)   100
                3.95 x 10-6  75      30.13  0.96  30.92 (0.75)   97
                7.90 x 10-6  75      33.15  1.15  44.14 (13.97)  75
                1.19 x 10-5  75      31.60  1.17  44.94 (14.77)  70

None            none         125     7.65  0.27   -              -

2.7 x 10-5 mol  none         125     13.61  0.43  -              -
 N-OH-AAF       1.58 x 10-6  100     13.79  0.42  13.61 (0.00)   100
                7.90 x 10-6  65      22.66  1.10  27.15 (13.54)  83
                1.19 x 10-5  25      26.16  1.86  29.24 (15.63)  89
----------------------------------------------------------------------------
a Adapted from:  Ray et a1. (1978).
b The expected SCE/cell was determined by adding the observed separate 
  contributions to SCE frequency due to either MMS or N-OH-AAF to that due 
  to different concentrations of Na2Se03, as determined in a previous study 
  (shown in parentheses (see also Table 42)).
                                                           
    Martin et al. (1981) found that sodium selenite could 
protect against the mutagenic effects of acridine orange and 
7,12-dimethylbenz[alpha]anthracene (DMBA) in the Ames  Salmonella/
microsome mutagenicity test.  However, Chatterjee & Banerjee (1982) 
showed that the influence of sodium selenite on the transformation 
of mouse mammary cells, induced by DMBA added in organ culture, was 
markedly affected by the level of selenium used.  For example, 
sodium selenite at concentrations of 10-7 - 10-8 mol increased the 
transformation frequency of the cells within the glands.  At 10-5 
mol, sodium selenite caused an 18 and 84% inhibition of the 
frequency of transformed cells at the initiation and promotional 
stages, respectively.  At 10-4 mol, sodium selenite was toxic to 
the cells  in vitro.  Sodium selenite inhibited the metabolism and 
mutagenicity of benzo (a)pyrene to  S. typhimurium strain TA 100 
in rat (Teel & Kain, 1984) and hamster (Teel, 1984) liver S9 
activation systems, but had no inhibitory effect on the 
mutagenicity of 1,2-dimethylhydrazine or azoxymethane for  S. 
 typhimurium G46 in the host-mediated assay (Moriya et al., 1979).  
On the other hand, sodium selenite at 3.95 x 10-9 - 1.98 x 10-8 mol 
protected against chromosomal damage in cultured human lymphocytes 
caused by 2.3 x 10-6 mol sodium arsenite (Sweins, 1983).  However, 
this author reported that the cytotoxic concentration of sodium 
selenite in his system was very low (somewhere between 1.98 and 
3.95 x 10-8 mol).  No explanation was offered for the considerable 
variations between laboratories with respect to selenium 
cytotoxicity. 

    Several investigators have now examined the anti-mutagenic 
effects of dietary selenium in a variety of experimental systems.  
For example, Gairola & Chow (1982) fed rats either a low-selenium 
diet based on Torula yeast or the same diet supplemented with 
sodium selenite at 2 mg selenium/kg for 20 weeks.  Dietary selenium 
did not have any effect on the metabolic activation potential of 
S9 liver enzymes towards benzo( a)pyrene in the Ames  Salmonella/
microsome mutagenicity assay.  S9 mixtures from selenium-deficient 
rats were more active towards 2-aminoanthracene and less active 
towards 2-aminofluorene than mixtures from the selenium-
supplemented rats.  The authors concluded that further studies were 
needed to elucidate the role and nature of  in vitro metabolites 
causing mutations in the bacteria.  In contrast, Schillaci et al. 
(1982) did not find any differences in the mutagenic activation of 
7-12-dimethylbenz[alpha]anthracene (DMBA) by liver S9 mixtures in 
the Ames test with  S. typhimurium strain TA 98, prepared from rats 
fed Torula yeast-based diets supplemented with sodium selenite at 
0.1, 2.5, or 5.0 mg selenium/kg, from weaning for 3 weeks.  
However, if the rats were injected with 20, 50, or 100 mg 
Aroclor(R) 1254/kg body weight, 5 days before sacrifice, dietary 
selenium at 2.5 or 5.0 mg/kg in the form of sodium selenite 
markedly decreased the mutagenic activation of DMBA by liver 
microsomes. 

    Lawson & Birt (1983) measured single-strand breaks (SSB) 
produced in pancreatic DNA by injecting 20 mg  N-nitrosobis(2-
oxopropyl) amine (BOP)/kg body weight subcutaneously into hamsters 
that had been fed a Torula yeast-based diet supplemented with 
sodium selenite at 0, 0.1, or 5 mg selenium/kg, for 4 weeks 
previously.  One hour after injection with BOP, there were 2.26  
0.47, 2.83  0.43, and 1.74  0.43 SSB per 108 daltons of DNA (mean 
 SEM), respectively, in the 3 dietary groups, and the approximate 
half-lives of the SSB were 33, 30, and 8 days, respectively.  On 
this basis, the authors suggested that high levels of dietary 
selenium may stimulate the repair of carcinogen-induced DNA damage. 

    Olsson et al. (1984) used a novel isolated rat liver/cell 
culture system to study the effects of selenium deficiency and 
selenium supplementation, within the physiological range, on the 
anti-mutagenic effects of the element.  Rats were first fed a 
Torula yeast-based selenium-deficient diet for 5 - 6 weeks with or 
without sodium selenite supplementation at 0.2 mg selenium/litre 
drinking-water.  The rat livers were then connected to an isolated 
liver perfusion system.  A glass plate with cultured Chinese 
hamster V79 cells was introduced into the perfusion system 
immediately before the addition of 5 mmol dimethylnitrosamine (DMN) 
and then exposed directly to the circulating perfusate.  After 2 h, 
this glass plate was exchanged for another with fresh V79 cells, 
which were exposed during the subsequent 2 h.  This procedure was 
adopted to avoid a possible toxic effect that might influence 
mutation frequency.  As  in vitro controls, V79 cells were treated 
for 2 h in Krebs-Ringer albumin solution with or without DMN.  The 
induced mutation frequencies in the 2 successively treated cell 
populations were summarized to give the value for each liver.  It 
was found that the mutagenicity of DMN in Chinese hamster V79 
cells, after metabolic activation by the isolated perfused rat 

liver, was approximately doubled when livers from selenium-
deficient rats were used compared with livers from rats given the 
supplementary selenium.  The authors were unable to provide a 
precise biochemical explanation for the mechanism by which selenium 
deficiency increased the mutagenicity of DMN, but they noted that 
microsomal  N-oxygenation of  N,N-dimethylaniline (DMA) was 
decreased in livers from selenium-deficient rats and suggested that 
further investigation of the different enzymes involved in DMA- N-
oxygenation appeared warranted.  Another application of this liver 
perfusion/cell culture system was demonstrated by the work of Beije 
et al. (1984) who showed that bile collected from selenium-
deficient livers perfused with a medium containing 5 mmol 1,1-
dimethylhydrazine was much more mutagenic toward Chinese hamster 
V79 cells than bile from livers of rats given supplementary 
selenium and perfused in a similar manner.  The authors suggested 
that the increased biliary excretion of reactive mutagenic 
metabolites observed in their selenium-deficient rat liver 
perfusion system might furnish a potential explanation for some of 
the protective effects of selenium reported against chemically-
induced colon cancer in experimental animals. 

7.6.  Teratogenicity

    Franke & Tully (1935) obtained chicken eggs from 2 farms in 
South Dakota that had histories of low hatchability.  Hatchability 
in the 2 test groups was extremely low, being 4% in one and 12% in 
another.  Examination of the eggs revealed that about 75% of those 
that had failed to hatch on the 21st day contained deformed 
embryos.  Franke et al. (1936) then showed that injection of 
selenium salts into the air cell of eggs before incubation resulted 
in monsters similar to those occurring naturally on affected farms. 
Selenium injected as selenite to give a final concentration in the 
egg of 0.6 mg selenium/kg was the most effective in this respect, 
higher doses causing embryonic death and lower doses producing 
fewer monsters (Table 46).  When the toxicity of various selenium 
compounds for chick embryos was compared, it was found that 
selenate was about twice as toxic as selenite (Palmer et al., 1973) 
(Table 47).  The toxicity of selenomethionine was about the same as 
that of selenate but methylseleninic acid was more than twice as 
toxic.  The toxicity of trimethylselenonium chloride was relatively 
low.  The most common embryonic deformities observed in this study 
were the underdevelopment of the beak and abnormal development of 
the feet and legs, especially a fusing or webbing of the 2 outside 
toes.  Because of the metabolic relationships between selenium and 
arsenic or cadmium, Holmberg & Ferm (1969) investigated the 
teratogenic potential of these elements, administered separately or 
together to golden hamsters (Table 48).  Embryonic malformations 
were not observed when pregnant hamsters were injected 
intravenously with a barely sub-lethal dose of sodium selenite 
alone, and the 6% resorption rate observed was stated to be similar 
to the normal rate of resorption in this species.  Furthermore, 
under these conditions, sodium selenite actually gave partial 
protection against the teratogenesis induced by sodium arsenate or 
cadmium sulfate. 

Table 46.  Teratogenicity of sodium selenite 
injected into hens' eggsa
--------------------------------------------------
Sodium selenite   Total    Dead  Abnormal  Normal
(mg selenium/kg)  embryos  (%)   (%)       (%)
--------------------------------------------------
0.9               5        60.0  20.0      20.0
                                           
0.8               16       12.5  31.0      56.5

0.7               4        50.0  25.0      25.0

0.6               4        50.0  50.0      0

0.5               12       50.0  8.3       41.7

0.1               131      24.4  2.3       73.3

0.02              78       53.8  3.8       42.3

0.01              64       34.3  9.4       56.3
--------------------------------------------------
a Adapted from:  Franke et al. (1936).
Table 47.  Comparative toxicity of various selenium compounds for chick 
embryosa
----------------------------------------------------------------------------
Compound             Dose              Livability ratio   LD50 with 95%
                     (mg selenium/kg)  (live chicks/      confidence limits
                                       fertile eggs)      (mg selenium/kg)
----------------------------------------------------------------------------
sodium selenite      0.0               16/18
                     0.05              18/18
                     0.1               16/17              0.3b
                     0.2               17/18
                     0.4               2/18
                     0.8               0/18

sodium selenate      0.0               18/18
                     0.1               12/18
                     0.2               4/18               0.13
                     0.4               1/18               (0.086 - 0.17)
                     0.8               0/18                    
                     1.6               0/18

selenomethionine     0.0               17/18
                     0.05              18/18
                     0.1               13/18              0.13
                     0.15              5/18               (0.095-0.15)
                     0.2               4/18
                     0.4               0/18

Table 47 (contd.)
----------------------------------------------------------------------------
Compound             Dose              Livability ratio   LD50 with 95%
                     (mg selenium/kg)  (live chicks/      confidence limits
                                       fertile eggs)      (mg selenium/kg)
----------------------------------------------------------------------------
methylseleninic      0.0               23/24
 acid                0.025             17/18
                     0.05              9/18               0.052
                     0.1               2/24               (0.039-0.065)
                     0.2               0/24
                     0.4               0/24

trimethylselenonium  0.0               18/18
  chloride           6.0               17/18
                     12.0              13/18              15.7
                     18.0              5/17               (12.7 - 19.0)
                     24.0              5/18                    
                     30.0              3/18
----------------------------------------------------------------------------
a Adapted from:  Palmer et al. (1973).
b An estimate since the data did not allow calculation by the computer
  programme.
7.7.  Carcinogenicity and Anti-Carcinogenicity

7.7.1.  Selenium as a possible carcinogen

    Five investigations have been reported in the literature on the 
alleged carcinogenicity of selenium for laboratory animals.  Nelson 
et al. (1943) fed groups of 18 female rats of an inbred Osborne-
Mendel strain a 12% protein diet consisting of 49% corn, 44% wheat, 
3% yeast, and 1% each of cod liver oil, calcium carbonate, sodium 
chloride and dried whole liver.  The diet was supplemented with 0, 
5, 7, or 10 mg selenium/kg, as seleniferous corn or wheat, or 10 mg 
selenium/kg, as a mixed inorganic selenide containing ammonium 
potassium selenide and ammonium potassium sulfide.  Although 
cirrhosis was frequently observed after 3 months of selenium 
exposure, no tumours or advanced adenomatoid hyperplasia were seen 
in any of the 73 selenium-exposed rats that died or were sacrificed 
before 18 months.  Of the 53 selenium-exposed rats that survived 
18 - 24 months, 43 had cirrhosis and 11 developed liver cell 
adenoma or low-grade carcinoma without metastasis in cirrhotic 
livers.  There was no relationship between the extent of cirrhosis 
and tumour incidence except that there were no tumours in any of 
the 18- to 24-month-old rats that did not have cirrhosis.  The 
incidence of spontaneous adenoma and low-grade carcinoma of the 
liver in the unexposed rats was low and the incidence of 
spontaneous hepatic tumours in the rat colony was less than 1% in 
18- to 24-month-old rats. 

Table 48.  Effect of selenium, arsenic, and cadmium on embryonic death and 
malformations in the golden hamstera
------------------------------------------------------------------------------------
Treatment          Dose     Total      Number of  Number of  Malformed  Malformed
                   (mg/kg)  number of  embryos    embryos    (%)        or resorbed
                            embryos    resorbed   malformed             (%)
------------------------------------------------------------------------------------
sodium selenite    2        86         5          0          0          6

sodium arsenate    20       177        62         86         49         84

sodium arsenate    20       144        28         28         19         39
+ sodium selenite  2

cadmium sulfate    2        115        24         59         51         72

cadmium sulfate    2        82         2          3          4          6
+ sodium selenite  2
------------------------------------------------------------------------------------
a Adapted from:  Holmberg & Ferm (1969).
    The results of some of the initial studies of Volgarev & 
Tscherkes (1967) seemed to indicate an increased incidence of 
tumours in rats fed a low-protein diet supplemented with sodium 
selenate at 4.3 mg selenium/kg, but subsequent tests carried out by 
these authors failed to confirm these results.  Moreover, their 
work suffered from the fact that no control groups, consuming diets 
without additional selenium, were included in any of their trials.  
Schroeder & Mitchener (1971b) reported an increased incidence of 
tumours in rats given sodium selenate at 2 mg selenium/litre in the 
drinking-water for the first year of life followed by 3 mg/litre 
until death.  In a previous evaluation of this work (US NAS/NRC, 
1976), it was observed that the selenate-treated rats survived 
longer than the untreated rats and this could have contributed to 
the increased tumour incidence observed in the rats receiving 
selenate.  Also, as the organs and tissues did not appear to have 
been systematically searched, the type and incidence of 
histological lesions could not be known with certainty. 

    Schroeder & Mitchener (1972) carried out 2 studies in which 
mice were given selenium in the drinking-water.  In both studies, 
the mice were fed a diet composed of 60% whole rye flour, 30% dried 
skim milk, 9% corn oil, and 1% iodized sodium chloride, to which 
were added vitamins and iron.  The diet was calculated to contain 
24% protein, 65% carbohydrate, and 11% fat (dry weight).  The mice 
were given doubly deionized water for drinking, which originally 
came from a forest spring.  Certain essential trace metals were 
added to the drinking-water, as soluble salts, in the following 
concentrations (mg/litre):  zinc, 50; manganese, 10; copper, 5; 
cobalt, 1; and molybdenum 1.  All mice received these trace 
elements in their drinking-water.  In addition, chromium was added 
to the drinking-water at a level of 1 or 5 mg/litre in the first 
and second studies, respectively.  In the first study, groups of 
100 or more Swiss mice of the Charles River CD strain, containing 
equal numbers of each sex, were given, at weaning, sodium selenite 

at either 0 or 3 mg selenium/litre of the trace element-fortified 
drinking-water.  This regimen continued over the entire life span 
of the mice.  The second study was identical to the first, apart 
from the level of chromium given in the drinking-water, and the 
fact that the selenium was administered in the form of sodium 
selenate.  Of the 180 control mice autopsied from both studies, 119 
were sectioned.  Tumours were found in 23 (19%) of those sectioned 
and 10 of the tumours (43%) were malignant.  The different forms of 
selenium given did not influence the incidence of tumours and, of 
the 176 selenium-exposed mice autopsied in both studies, 88 were 
sectioned.  Tumours were found in 13 (15%) of those sectioned but 
all tumours were malignant.  It was concluded that selenium had 
little tumourigenic or carcinogenic activity in mice, though, when 
tumours did appear in the selenium-exposed mice, they were all 
malignant. 

    The results of studies of Harr et al. (1967) (section 7.1.2.2) 
failed to demonstrate any tumours attributable to selenium, but 
most of the rats fed semi-purified diets containing levels of 
selenium greater than 2 mg/kg died within 100 days and almost all 
were dead before 2 years.  Exceptions included 1 rat fed selenate 
at 4 mg selenium/kg diet containing 12% casein and 0.3% DL-
methionine, and 27 rats alternating at weekly intervals between a 
control ration and a diet containing sodium selenate at either 4 or 
8 mg selenium/kg.  However, no hepatic tumours were observed, even 
in the 71 rats that survived 2 years or longer at continuous 
dietary-selenium levels of 0.5 - 2.0 mg/kg. 

    The above studies indicate that test animals develop neoplastic 
lesions, only when they have liver cirrhosis produced by frank 
selenium toxicity (i.e., no hepatomas were observed in the absence 
of severe hepatotoxic phenomena).  For this reason, it was 
concluded that selenium was not, by reason of its capacity to 
induce liver damage when consumed at high levels, properly 
classified as carcinogenic because of its potential association 
with a higher rate of liver cancer (Gardner, 1973). 

    Jacobs & Forst (1981b) did not observe any signs of neoplasia 
in groups of 35 female Swiss mice fed a commercial pelleted diet 
and given 0, 1, 4, or 8 mg selenium/litre drinking-water, as sodium 
selenite, for 50 weeks. 

    Three studies have shown carcinogenic effects that appear to be 
more a specific effect of a particular selenium compound rather 
than an effect of selenium itself.  Seifter et al. (1946) found 
that 8 white rats that had received 0.05% bis-4-acetamino-phenyl-
selenium dihydroxide in their diet for 105 days had multiple 
adenomas of the the thyroid glands and adenomatous hyperplasia of 
the liver.  Innes et al. (1969) fed the maximal tolerated dose of 
selenium diethyldithiocarbamate (Ethyl selenac) to a group of 72 
mice containing both sexes of two hybrid strains (C57BL/6 x 
C3H/Anf)F and (C57BL/g x AKR)F1.  The mice were given this 
substance by stomach tube at a dose of 10 mg/kg body weight, 
starting at 7 days of age.  At 4 weeks of age, the chemical was 
mixed directly into the diet at a concentration of 26 mg/kg.  After 
82 weeks, all the surviving mice were sacrificed; of 69 necropsied, 

26, 13, and 5.8% had hepatomas, lymphomas, and pulmonary tumours, 
respectively.  Among 338 negative control mice, most of which were 
sacrificed between 78 and 89 weeks, the incidences of the 
corresponding tumours were 4.1, 4.1, and 6.2%, respectively. 

    A report from the US National Cancer Institute (National Cancer 
Institute, 1980) suggested that commercial selenium sulfide, an 
ingredient in certain anti-dandruff shampoos, was carcinogenic for 
rats and mice.  Elemental analysis of the test chemical used in 
this study indicated that the material was a mixture of selenium 
monosulfide and selenium disulfide.  The melting point of the test 
sample was closer to that reported for the monosulfide than that 
reported for the disulfide and the X-ray diffraction pattern was 
consistent with patterns reported for the monosulfide.  It was 
concluded that the selenium in the test substance used in this 
bioassay was present primarily as the monosulfide. 

    In the rat study, groups of 4-week-old male and female Fischer 
F344 rats were fed presterilized lab meal and were given untreated 
well water  ad libitum for 104 - 105 weeks.  During the first 103 
weeks, 50 rats of each sex were given one of 4 treatments:  
untreated control; vehicle control (received volumes of 0.5% 
aqueous carboxymethylcellulose equal to those of the test solutions 
administered); low-dose group (3 mg selenium sulfide suspended in 
0.5% aqueous carboxymethylcellulose/kg body weight, 5 days per 
week, given by gavage); or high-dose group (15 mg selenium 
sulfide/kg body weight administered by the same route and 
schedule).  The results showed an increased incidence of primary 
liver tumours in both male and female high-dose groups (Table 49). 

    Neoplastic nodules were usually single, rather well-defined 
areas characterized by altered hepatocytes.  In most instances, the 
hepatocytes were larger than normal, eosinophilic, and occasionally 
vacuolated.  The normal architecture was altered, mainly resulting 
in a solid mass of hepatocytes or a trabecular pattern rather than 
the normal hepatic cords.  The mass compressed the adjacent 
parenchyma around the periphery.  Anaplasia and mitoses were 
minimal.  Hepatocellular carcinomas were usually large multinodular 
masses, often encompassing entire liver lobes or even multiple 
lobes.  The histological appearance of these neoplasms varied from 
areas appearing normal to much more anaplastic areas.  The 
neoplastic hepatocytes varied from small basophilic cells to very 
large eosinophilic and occasionally vacuolated cells.  Mitoses were 
variable.  No distant metastases were observed in any of the rats 
bearing hepatocellular carcinomas.  No other neoplasms were found 
that could be related to the administration of the selenium 
sulfide. 

Table 49.  Effect of selenium sulfide, given orally for 103 weeks, on 
the incidence of liver tumours in Fischer F344 ratsa
------------------------------------------------------------------------
                        Initial   Selenium        Tumour incidence     
Test group         Sex  number    sulfide   Hepatocellular  Neoplastic
                        of rats   dose      carcinoma       nodules
------------------------------------------------------------------------
                                  (mg/kg)

Untreated control  M    50        0         1/48 (2%)       3/48 (6%)

Vehicle controlb   M    50        0         0/50 (0%)       1/50 (2%)

Low-dosec          M    50        3         0/50 (0%)       0/50 (0%)

High-dosec         M    50        15        14/49 (29%)     15/49 (31%)

Untreated control  F    50        0         0/50 (0%)       0/50 (0%)

Vehicle controlb   F    50        0         0/50 (0%)       1/50 (2%)

Low-dosec          F    50        3         0/50 (0%)       0/50 (0%)

High-dosec         F    50        15        21/50 (42%)     25/50 (50%)
------------------------------------------------------------------------
a Adapted from:  National Cancer Institute (1980).
b Received only vehicle for dosing (0.5% aqueous carboxymethylcellulose)
  5 days per week, by gavage.
c Received stated dose of selenium sulfide suspended in 0.5% aqueous
  carboxymethylcellulose, 5 days per week, by gavage.

    An increased incidence of focal cellular change in the liver 
was noted in high-dose male rats but was essentially comparable in 
frequency in the remaining treated and control groups of each sex. 

    A compound-related increase in pigmentation in the lungs was 
observed.  This was characterized by the accumulation of dark, 
slightly granular-appearing pigment in the interstitial areas and 
in some peribronchial areas.  In most cases, the pigment appeared 
to be located within cells, principally macrophages.  No evidence 
of inflammation, relative to the pigment deposits, was noted.  Lung 
pigmentation was found in 47/49 (96%) high-dose males, 1/50 (2%) 
low-dose males, 45/50 (90%) high-dose females, and 36/50 (72%) low-
dose females, but not in control males or females. 
                                                                      
    The protocol for the testing of selenium sulfide in B6C3F1 mice 
was similar to that used for rats, except that the doses of the 
substance under test were increased (Table 50).  There was an 
increased incidence of primary liver and lung tumours in the high-
dose female mice and a marginal increase in the incidence of these 
tumours in high-dose males. 

    Hepatocellular carcinomas varied from single nodules to 
multinodular masses, often encompassing several liver lobes. 
Individual hepatocytes varied considerably in morphology from large 
eosinophilic cells to small, darkly-staining hepatocytes.  In many 

cases, there was marked variation in cell type in different parts 
of the neoplasm.  The number of mitoses varied.  The number of 
hepatocellular carcinomas metastasizing to the lungs was comparable 
in vehicle-control and high-dose males.  No metastases were 
observed in the lung in female mice.  Alveolar/bronchiolar adenomas 
were usually small solitary lesions located in the subpleural area 
or immediately adjacent to a bronchiole.  The cells involved were 
cuboidal to tall columnar and tended to be situated perpendicular 
to the basement membrane in a single layer.  These cells were 
arranged in complex papillary projections forming discrete nodules 
and compressing adjacent alveolar walls.  Mitoses were rare.  
Alveolar/bronchiolar carcinomas, however, were less discrete 
lesions and tended to be larger and occasionally multiple, 
consisting of a confluence of two or more nodules.  The individual 
cells tended to be less rigidly arranged along basement membranes 
and were often piled up in layers or arranged in solid sheets 
without a papillary pattern.  The cells often showed increased 
basophilia and a moderate mitotic index.  Evidence of invasion into 
adjacent vessels, or extension into bronchioles and adjacent lung 
parenchyma was frequently present. 

    Other neoplasms that occurred in the mice were similar in 
number and kind to those that usually occur in aged B6C3F1 control 
mice and could not be related to the long-term administration of 
selenium sulfide. 

    In a comparison study, the effect of the dermal application of 
selenium sulfide was examined.  No increased incidence of neoplasms 
was observed that could be attributed to selenium sulfide. 

7.7.2.  Selenium as a possible anti-carcinogen

    High levels of dietary selenium have been shown to protect 
laboratory animals against chemical carcinogenesis, under a wide 
variety of conditions.  Clayton & Baumann (1949) fed 2 groups of 15 
young adult rats, weighing approximately 200 g, a basal diet 
consisting of extracted casein, 12 parts; salts, 4 parts; corn oil, 
5 parts; and glucose monohydrate (Cerelose) to 100 parts.  The diet 
was supplemented with thiamin, riboflavin, pyridoxine, calcium 
pantothenate, and choline.  Fat-soluble vitamins were provided by 
giving 2 drops of halibut liver oil per rat every 4 weeks.  During 
the initial 4-week feeding period, both groups received the basal 
diet supplemented with 0.064% 3'-methyl-4-dimethylaminoazobenzene. 
This was followed by a 4-week "interruption period" during which 
neither group received the azo dye, but one group received the 
basal diet supplemented with sodium selenite at 5 mg selenium/kg, 
and the other group received the basal diet without any added 
selenium.  During the third, 4-week feeding period, both groups 
received the basal diet supplemented with 0.048% of the azo dye, 
but no supplementary selenium.  During the final 8-week feeding 
period, both groups received the basal diet without either azo dye 
or selenium.  Two of the 9 surviving rats in the group that 
received supplementary selenium during the "interruption period" 
had liver tumours (22%), compared with 4 out of 10 survivors (40%) 
in the group not supplemented with selenium.  The results of a 
second similar study showed a liver tumour incidence of 4/13 (31%) 
in the selenium-supplemented group compared with 8 out of 13 rats 
(62%) in the unsupplemented group. 

    A preliminary study by Shamberger & Rudolph (1966) indicated 
that concomitant dermal application of sodium selenide reduced the 
tumour-promoting effect of croton oil in mice initiated with 7,12-
dimethylbenz[alpha]anthracene (DMBA).  Riley (1968) found that a 
similar application of sodium selenide prevented the mast cell 
reaction caused by an active fraction of croton oil in the skin of 
DMBA-initiated mice.  In a later set of studies (Shamberger, 1970), 
2 groups of 30 female ICR Swiss mice, 50 - 55 days old, were 
treated once on day one with 0.125 mg DMBA dissolved in 0.25 ml 
acetone.  On days 2 - 21, the shaved backs of the first group of 
mice were treated with 0.25 ml of a 20:80 water-acetone mixture 
containing 0.0005% sodium selenide, whereas the second group was 
not treated with any anti-oxidant.  Subsequently, in 3 separate, 
but essentially identical, studies, both groups of mice received 
0.25 ml of 0.04% croton oil in acetone daily for 16, 18, and 18 
weeks respectively.  After the croton oil treatment, the incidence 
of papillomas in the selenide-treated groups was 17, 63, and 45%, 
respectively, in 3 separate studies, compared with an incidence in 
the non-treated groups of 43, 63, and 89%, respectively.  The 
corresponding number of papillomas per mouse in the 3 studies was 
1.5, 3.0, and 1.5, respectively, in the selenide-treated groups and 
3.2, 6.0, and 2.3 in the non-treated groups.  No papillomas were 
observed in 3 DMBA-initiated control groups, which did not receive 
either antioxidant or croton oil.  A similar protective effect of 
sodium selenide was observed in 3 additional studies in which the 
promoting agents were croton oil, croton resin, and phenol and in 
which the selenide was applied concomitantly with the promoter. 

    In another study, 0.25 ml of 0.01% 3-methylcholanthrene (MCA) 
was applied daily to the shaved backs of one group of mice for 19 
weeks; a second group received 0.0005% sodium selenide together 
with the MCA.  After 19 weeks, the incidence of papillomas was 68% 
in the selenide-treated group and 87% in the untreated group, and 
the number of papillomas per mouse was 3.2 and 2.2, respectively.  
After 30 weeks, the number of mice with cancers was 17/28 and 25/30 
in the selenide-treated and untreated groups, respectively, the 
total number of cancers per group being 29 and 71, respectively. 


Table 50.  Effect of selenium sulfide given orally for 103 weeks on the incidence of liver and lung 
tumours in B6C3F1 micea
----------------------------------------------------------------------------------------------------
                                                                            Lung tumour incidence  
                        Initial  Selenium      Liver tumour incidence      Alveolar/    Alveolar/
Test group         Sex  number   sulfide   hepatocellular  hepatocellular  bronchiolar  bronchiolar
                        of mice  dose      carcinoma       adenoma         carcinoma    adenoma
                                 (mg/kg)
----------------------------------------------------------------------------------------------------
Untreated control  M    50       0         17/49 (35%)     3/49 (6%)       1/49 (2%)    8/49 (16%)

Vehicle controlb   M    50       0         15/50 (30%)     0/50 (0%)       1/50 (2%)    3/50 (6%)

Low-dosec          M    50       20        11/50 (22%)     3/50 (6%)       2/50 (4%)    8/50 (16%)

High-dosec         M    50       100       23/50 (46%)     0/50 (0%)       2/50 (4%)    12/50 (24%)

Untreated control  F    50       0         2/50 (4%)       1/50 (2%)       0/50 (0%)    2/50 (4%)

Vehicle controlb   F    50       0         0/49 (0%)       0/49 (0%)       0/49 (0%)    0/49 (0%)

Low-dosec          F    50       20        1/50 (2%)       1/50 (2%)       1/50 (2%)    2/50 (4%)

High-dosec         F    50       100       22/49 (45%)     6/49 (12%)      4/49 (8%)    8/49 (16%)
----------------------------------------------------------------------------------------------------
a Adapted from:  National Cancer Institute (1980).
b Received only vehicle for dosing (0.5% aqueous carboxymethylcellulose), 5 days per week, by gavage.
c Received stated dose of selenium sulfide suspended in 0.5% aqueous carboxymethylcellulose, 5 days 
  per week, by gavage.

                                                                  
    Shamberger (1970) also carried out 2 dietary studies in which 4 
groups of 36 female, albino ICR Swiss mice, 50 - 55 days old, were 
fed Torula yeast diets supplemented with sodium selenite at 0, 0.1, 
or 1.0 mg selenium/kg or sodium selenide at 0.1 mg selenium/kg.  
After 2 weeks on the test diets, 0.125 mg DMBA dissolved in acetone 
was applied once to the skin.  After 3 weeks, 0.25 ml 0.05% croton 
oil in acetone was applied daily for 17 weeks.  At this time, 26/36 
mice fed the unsupplemented diet had papillomas, compared with 
14/35 mice fed the diet supplemented with 1.0 mg selenium/kg, as 
selenite.  The incidence of papillomas was slightly elevated in the 
mice fed the diet supplemented with 0.1 mg selenium/kg, as sodium 
selenite, compared with the unsupplemented mice.  The incidence of 
papillomas in mice fed sodium selenide at 0.1 mg selenium/kg was 
intermediate between that of the unsupplemented group and the group 
fed sodium selenite at 1.0 mg selenium/kg. 

    In a second study of similar design, 4 groups of 36 mice were 
fed the test diets described above for 2 weeks.  Then 0.25 ml of 
0.03% benzo( a)pyrene in acetone was applied daily to the shaved 
backs of the mice for 27 weeks.  At this time, the incidence of 
papillomas in the groups fed the torula diet supplemented with 0, 
0.1, or 1.0 mg selenium/kg, as selenite, or 0.1 mg selenium/kg, as 
selenide, was 14/35, 22/36, 8/33, and 12/35, respectively.  The 
number of papillomas per mouse in the corresponding groups was 8.1, 
9.8, 5.0, and 6.8. 

    Harr et al. (1972) weaned 80 female OSU-Brown rats at 35 days 
of age and divided them into 4 groups of 20.  Each group was fed a 
low-selenium basal diet (0.018 g selenium/kg) that included Torula 
yeast as the protein source and contained 60 mg vitamin E/kg.  
Groups, 1, 2, 3, and 4 were fed the basal diet supplemented with 
sodium selenite at 2.5, 0.5, 0.1, and 0 mg selenium/kg, 
respectively.  All diets contained 150 mg 2-acetylaminofluorene/kg.  
The 40 rats in groups 1 and 2 were born from parents reared on a 
selenium-depleted regimen, but were clinically normal.  The 40 rats 
in groups 3 and 4 were from the second generation maintained on the 
depeletion regimen and had clinical signs of selenium deficiency.  
After 200 days of treatment, the number of mammary adenocarcinomas 
in groups 1, 2, 3, and 4 was 0, 1, 8, and 9, respectively.  After 
320 days, the number of mammary adenocarcinomas in the same groups 
was 11, 11, 13, and 12, respectively.  Mammary adenocarcinomas in 
groups 1, 2, and 3 occurred mainly (90%) in the thoracic region and 
were well circumscribed, firm, and easily removed, whereas those in 
group 4 occurred mainly (80%) in the pelvic area and were soft and 
fluid, contained little connective tissue, and were invasive.  
After 240 days of treatment, the number of hepatic carcinomas in 
groups 1, 2, 3, and 4 was 0, 1, 9, and 4, respectively.  After 320 
days, the number of hepatic carcinomas in the same groups was 8, 
12, 12, and 6, respectively.  Toxic hepatitis was observed in 18 of 
the 20 livers from group 1 (selenium added at 2.5 mg/kg), but was 
not seen in the other groups. 

    In studies of Marshall et al. (1978), 2 groups of male albino 
Sprague Dawley rats were fed diets containing 2-acetylaminofluorene 
at 0.3 g/kg, for 14 weeks.  One group received 4 mg selenium, as 

sodium selenite/litre drinking-water.  The carcinogen was withdrawn 
from the diet for an additional 4 weeks and then the rats were 
sacrificed.  The rats given selenium had about 50% fewer liver 
tumours than unsupplemented rats.  Control rats given a similar 
level of selenium in the water showed normal growth response, liver 
weight, and appearance. 

    Three groups of 15 male Sprague Dawley rats, weighing about 
250 g, were fed a basal diet of finely ground Purina Laboratory 
Chow and water  ad libitum (Griffin & Jacobs, 1977).  One group did 
not receive any supplementary selenium, a second group received 6 
mg selenium, as sodium selenite/litre drinking-water, and a third 
group received 6 mg selenium, in the form of a high selenium 
yeast/kg diet.  After one week on this regimen, all 3 groups were 
given 0.05% 3'-methyl-4-dimethyl-aminoazobenzene in the diet for 8 
weeks.  Following this, all groups were maintained on the 
carcinogen-free diets for an additional 4 weeks.  The selenium 
supplements were maintained for the second and third group 
throughout the entire study.  At sacrifice, the incidence of liver 
tumours in the surviving rats was 92% (11/12) in the unsupplemented 
group, 46% (7/15) in the group supplemented with selenite in the 
drinking-water, and 64% (9/14) in the group supplemented with 
selenium yeast in the diet.  In this study, the selenium 
supplements had little effect on the growth of the rats. 
Histopathological examination of several of the tumours revealed 
that they were bile duct adenocarcinomas and liver cell 
adenocarcinomas. 

    Jacobs et al. (1977a) injected 2 groups of 15 male, 8-week-old 
Sprague Dawley rats, weekly, with 20 mg sym,-dimethylhydrazine 
dihydrochloride (DMH)/kg body weight, for 18 weeks.  One group of 
rats received sodium selenite at 4 mg selenium/ litre drinking-
water, which was available  ad libitum one week prior to, and 
throughout, administration of the carcinogen.  The other group did 
not receive selenium added to the drinking-water.  The group 
receiving DMH and no added selenium had an 87% incidence (13/15) of 
colon tumours, whereas the group receiving both DMH and added 
selenium had a 40% incidence (6/15) of colon tumours.  The total 
number of colon tumours was 39 in rats receiving only DMH and 11 in 
rats receiving both DMH and added selenium.  In a similar study in 
which 2 groups of 15 rats were injected weekly with 20 mg of 
(methylazoxyl)-methanol acetate (MAM)/kg body weight for 18 weeks, 
no significant differences in the incidence of colon tumours were 
apparent between groups with (14/15) and without (14/14) added 
selenium in the drinking-water.  However, the number of MAM induced 
tumours was 73 in the group given MAM alone and 42 in the group 
receiving both MAM and added selenium. 

    Schrauzer and colleagues carried out a series of studies in 
which exogenous carcinogens were not used, to test the ability of 
supplemental selenium in influencing the development of spontaneous 
mouse mammary tumours, presumably of viral origin.  In study 1 
(Schrauzer & Ishmael, 1974), 2 groups of 30 virgin female C3H/St 
mice, 4 - 6 weeks old, were fed a basal diet ("Concord Maid") 
consisting of meat scraps, dried skimmed milk, oat groats, ground 

wheat, wheat germ meal, vegetable oil, cane molasses, salt, 
brewer's yeast, cereal binder, sodium propionate, and calcium 
pantothenate.  The diet contained about 150 g protein, 5 g fat, and 
0.15 mg selenium/kg.  One group of mice received plain distilled 
water for drinking, while the other group received distilled water 
fortified with 2 mg selenium, as selenium dioxide/litre.  The 
strain of mice used in this study ordinarily has a high incidence 
of spontaneous mammary adenocarcinomas and, after 16 months of 
treatment, the observed incidence in the group not given 
supplemental selenium in the water was 82%, whereas the incidence 
in the group given selenium was 10%. 

    In study 2 (Schrauzer et al., 1976), 3 groups of 30, 30, and 50 
female C3H/St mice fed the basal diet described above were also 
given selenite at 0, 5, or 15 mg selenium/litre drinking-water, 
respectively.  Toxicity due to the doses of selenium was indicated 
by the average body weights in the 3 groups at 12 months (33, 29, 
and 25 g, respectively) and by a higher tumour-unrelated mortality 
rate in the selenium-exposed mice.  After 26 months, the 
corresponding incidence of spontaneous mammary tumours in the 3 
groups was 82, 36, and 33% in the mice that survived to the age at 
which the first tumours appeared in each group.  A fourth group of 
20 mice, fed a selenium-deficient diet for 14 months and then the 
basal diet until death, had a mammary tumour incidence of 69% which 
was not judged to be different from the 82% incidence in the 
control group (basal diet throughout life span and no added 
selenium in the water). 

    In study 3 (Schrauzer et al., 1978a), 4 groups of 30 female 
C3H/St mice were fed a basal diet ("Wayne F-6 Lab Blox") that was 
different from that used in the first 2 studies and consisted of 
fish meal, animal liver meal, soybean meal, corn and wheat flakes, 
ground corn, wheat red dog, wheat middlings, soybean oil, cane 
molasses, salt, brewer's yeast, and various vitamins and minerals.  
This diet contained 244.8 g protein, 64.8 g fat, and 0.45 mg 
selenium/kg.  The 4 groups received selenium dioxide at 0, 0.1, 
0.5, or 1.0 mg selenium/litre drinking-water and, after 22 months, 
the incidence of mammary tumours was 42, 25, 19, and 10%, 
respectively.  Selenium supplementation at these levels did not 
have any noticeable adverse effects on weight-gain or survival of 
the mice.  The incidence of spontaneous mammary tumours in the 
control (unsupplemented) group was lower in this study than that 
observed in the 2 previous studies (42 compared with 82%), and this 
was attributed to the higher selenium content of the new basal diet 
used in the third study (0.45 versus 0.15 mg/kg). 

    Medina & Shepherd (1980) fed BALB/cfC3H mice Wayne Lab Blox and 
gave them selenium dioxide at 0, 2, or 6 mg selenium/litre 
drinking-water,  ad libitum, starting at 10 weeks of age and 
continuing to the end of the study.  In 12-month-old mice, 2 and 6 
mg selenium/litre decreased mammary tumour incidence from 82% in 
the untreated controls to 48 and 12%, respectively.  There were no 
effects of the selenium treatment on normal reproductive function 
or weight gain in these mice.  In another study, samples of 4 
different preneoplastic outgrowth lines (D2, C3, C4, and CD-7) 

were transplanted into the mammary gland-free fat pads of syngenic 
mice.  When the implants had filled the mammary fat pads with their 
respective outgrowths (8 weeks after implantation), the mice were 
given selenium dioxide at 4 mg selenium/litre drinking-water,  ad 
 libitum, for the rest of the study.  Such treatment with selenium 
delayed the rate of tumour formation only in line C4, increasing 
the time for half of the outgrowths to produce tumours from 34 to 
44 weeks.  In a third study, 2 - 6 mg selenium/litre drinking-water 
had no effect on the growth rate of primary tumours transplanted 
subcutaneously in BALB/c mice.  Since selenium did not have any 
effect on tumour formation rate in 3 of 4 preneoplastic mammary 
outgrowth lines or on the growth rate of established mammary 
tumours, the authors suggested that selenium might act by 
inhibiting chemical or viral transformation of normal cells or by 
inhibiting expression of initially transformed cells. 

    Because of the metabolic antagonism between arsenic and 
selenium (section 7.1.6.3), Schrauzer and co-workers also 
investigated the effect of arsenic on the genesis of the 
spontaneous mammary tumours in C3H/St female mice described above.  
In their first study on arsenic and selenium (which was part of the 
same study described above in Schrauzer & Ishmael (1974)), giving 
sodium arsenite at 10 mg arsenic/litre drinking-water to a group of 
30 C3H/St mice for 16 months, reduced the incidence of spontaneous 
mammary tumours to 27% compared with an incidence of 82% in the 
untreated controls (Schrauzer & Ishmael, 1974).  However, arsenic 
treatment markedly stimulated the growth rate of spontaneous or 
transplanted mammary tumours.  In a second study concerning 
arsenic, sodium arsenite at 80 mg arsenic/litre drinking-water, 
administered to a group of 20 C3H/St mice, reduced the incidence of 
spontaneous mammary tumours to 40% compared with an incidence of 
82% in the untreated controls (Schrauzer et al., 1976), but some of 
the tumour-inhibiting effect of arsenic appeared to be masked at 
this dose level by its toxicity. 

    In a third study relating arsenic and selenium (Schrauzer et 
al., 1978b), 4 groups of 30 female C3H/St mice were fed the Wayne 
F-6 Lab Blox diet described above, which contained 0.29 mg 
arsenic/kg.  The 4 groups received the following supplements in 
their deionized drinking-water:  none, arsenic trioxide at 2 mg 
arsenic/litre, selenium dioxide at 2 mg selenium/litre, or 2 mg of 
both arsenic and selenium.  The incidence of mammary tumours in the 
4 groups was 41, 36, 17, and 62%, respectively, and the percentage 
of multiple mammary tumours was 17, 40, 0, and 28.  The age of 
tumour onset in the corresponding groups was 4.5, 9, 16, and 8 
months.  Thus, in this case, treatment with arsenic appeared to 
diminish the cancer-protecting effect of selenium.  Arsenic also 
accelerated tumour growth and increased the incidence of multiple 
tumours. 

    Newberne & Conner (1974) fed 4 groups of male rats of the 
Charles River CD strain, weighing about 100 g each, a basal diet 
consisting of casein, 200 g/kg; sucrose, 209 g/kg; dextrose, 209 
g/kg; dextrin, 209 g/kg; stripped lard, 80 g/kg; Wesson Oil, 20 
g/kg; selenium-free salts, 50 g/kg; vitamin mix, 20 g/kg; choline, 

3 g/kg; and vitamin B12, 0.05 g/kg.  The basal diet contained about 
0.03 mg selenium/kg.  One group received the unsupplemented basal 
diet, whereas the other 3 groups received the basal diet 
supplemented with sufficient sodium selenite to attain approximate 
dietary levels of 0.1, 1.0, or 5.0 mg selenium/kg, respectively.  
Each group was fed the diet for 2 - 3 weeks, before oral 
administration of 7 mg aflatoxin B1 in dimethyl sulfoxide/kg body 
weight.  The rats continued on their respective diets for an 
additional 2 weeks, and the mortality rate after this time, in the 
groups fed the diets containing 0.03, 0.1, 1.0, and 5.0 mg 
selenium/kg was 28/29, 20/30, 7/28, and 27/29, respectively.  
Histological examination revealed that rats receiving 1.0 mg 
selenium/kg diet were partially protected against the aflatoxin B1 
and also had less severe liver lesions.  However, the groups fed 
diets containing 1.0 or 5.0 mg selenium/kg exhibited a novel renal 
lesion associated with acute aflatoxin B1 toxicity, characterized 
by marked tubular necrosis at the cortical medullary junction.  
Some tubules exhibited hyperplastic changes of the epithelium as 
well as necrosis. 

    In a second study, Grant et al. (1977) gave 25 g aflatoxin B1 
orally, 5 days/week for 4 weeks, to 140 male Sprague Dawley rats.  
The rats were fed normal or marginally lipotrope-deficient 
semisynthetic basal diets containing sodium selenite at 0.03, 0.10, 
0.50, 1.0, 2.5, or 5.0 mg selenium/kg.  After 17 months, the 
surviving rats were sacrificed and histopathological examination 
was carried out.  A very low incidence (20%) of hepatocarcinomas 
was seen in rats receiving 1.0 mg selenium/kg in the normal basal 
diet and 0.10 or 0.50 mg/kg in the lipotrope-deficient diet.  No 
other tumours were observed, and grading of the hepatic lesions 
indicated that there was no significant differences among the 
dietary selenium groups.  Dietary sodium selenite and repeated 
doses of aflatoxin B1 interacted to produce large bizarre cells in 
the renal tubules, occurring in the same region of the kidney as 
the severe necrosis seen previously in rats fed high levels of 
dietary selenium and given an acute dose of aflatoxin B1. 

    Recently, a study of the effects of selenium on aflatoxin B1-
induced enzyme altered foci in rat liver has been reported (Milks 
et al., 1985).  Male Sprague Dawley rats were fed a selenium-
deficient diet and given sodium selenite at 5, 2, 0.2, or 1 mg 
selenium/litre drinking-water for 3 weeks.  Each rat then received 
2 g mol aflatoxin B1/kg body weight by stomach tube.  For the next 
week the selenium status was "normalized".  Rats previously 
receiving 5, 2, 0.2, or 0 mg selenium/litre received, respectively, 
0. 0.2, 2, or 5 mg/litre.  Then rat chow was fed and a promoting 
regimen consisting of phenobarbital in the drinking-water, and a 
partial hepatectomy was instituted.  Eight weeks later, necropsies 
were carried out and livers were stained histochemically for 
gamma-glutamyl transpeptidase activity.  Foci of activity were 
counted.  The number of foci seen in livers from rats given 5, 2, 
0.2, or 0 mg selenium/litre during initiation were 0.62  0.22, 
1.97  0.46, 3.35  0.66, and 2.46  0.23 per cm2, respectively.  
The data suggested that 5 mg selenium/litre can protect against the 
hepatocarcinogenic effects of aflatoxin B1 in the rat. 

    On the basis of anecdotal observations, Wedderburn (1972) 
suggested that a decrease in the number of cases of intestinal 
carcinoma in autopsied sheep might be associated with the 
widespread veterinary use of selenium to prevent deficiency 
diseases in sheep.  Simpson (1972a) conducted an investigation into 
the epidemiology of carcinomas of the small intestine of sheep in 
which the viscera of 32 733 ewes were examined.  Carcinomas of the 
small intestine were diagnosed in 483 animals, but the prevalence 
of these neoplasms in ewes regularly dosed with selenium throughout 
their lives was not significantly different from the prevalence in 
ewes never treated with selenium (Simpson, 1972b).  Furthermore, no 
significant differences were found in association with differences 
in soil types on the farms from which the sheep originated.  It was 
concluded that soil-selenium levels and administration of selenium 
in the form and at the dose rates used did not have any effects on 
the development of intestinal carcinomas in sheep.  Underwood 
(1977) commented that neoplasias were not observed among the 
various lesions attributed to selenium deficiency in animals. 

    Ip has made and summarized a series of observations on selenium 
and carcinogenesis (Ip, 1985a). 

    Evidence of an interaction between dietary fat and selenium 
status in the induction of mammary tumours by dimethylbenz-
[alpha]anthracene in rats has been presented by Ip & Sinha (1981).  
They fed 8 groups of 23 - 25 female weanling Sprague Dawley rats 
one of the following diets either deficient in selenium or 
supplemented with sodium selenite at 0.1 mg selenium/kg:  1% corn 
oil, 5% corn oil, 25% corn oil, or 1% corn oil plus 24% 
hydrogenated coconut oil.  In addition to the fat, the diets 
consisted of Torula yeast, dextrose, HMW salt mix, vitamin mix, 
alphacel, and DL-methionine.  The diets were adjusted so that the 
intake of all nutrients would be the same, except for dextrose and 
fat, assuming that the rats would consume an equal number of 
calories.  The corn oil used was stripped of tocopherol and the 
unsupplemented diet was deficient in selenium (less than 0.02 mg/kg 
by fluorometry).  Mammary tumours were induced by the intragastric 
administration of 5 mg dimethylbenz[alpha]anthracene at 50 days of 
age.  Increasing the dietary polyunsaturated-fat level (corn oil) 
increased the tumour incidence in rats fed the selenium-
supplemented diets (Table 51).  However, the high-saturated-fat 
diet was much less active in stimulating tumourigenesis.  Selenium 
deficiency increased the tumour yield only in rats fed the high 
polyunsaturated-fat diet (25% corn oil).  Increased tumour 
incidence due to selenium deficiency was not seen in the rats fed 
the low-fat diets containing polyunsaturated fat (1 or 5% corn 
oil) or the high-fat diet containing primarily saturated fat (1% 
corn oil with 24% coconut oil).  Selenium deficiency, however, did 
increase the incidence of mammary tumours in rats fed a low-fat 
diet containing polyunsaturated fat (1% corn oil), when larger 
doses of dimethylbenz[alpha]anthracene were used (10 or 15 mg - 
data not shown). 

Table 51.  Incidence of palpable mammary tumours in
dimethylbenz(alpha)anthracene-treated rats fed different
levels and types of fats in the diet, with or without
selenium supplementationa
-----------------------------------------------------------
 Fats in diet   Selenium  Incidence of palpable tumours
Corn   Coconut  in diet   19 weeks after dimethylbenz
oil    oil      (mg/kg)   (alpha)-anthracene administration
(%)    (%)                Number of rats  (%)
-----------------------------------------------------------
1      0        0         4/23            17.4

1      0        0.1       3/24            12.5

5      0        0         11/25           44.0

5      0        0.1       8/24            33.3

25     0        0         24/25           96.0

25     0        0.1       15/25           60.0

1      24       0         7/24            29.2

1      24       0.1       6/25            24.0
----------------------------------------------------------
a Adapted from:  Ip & Sinha (1981).

    In a recent study, the effects of vitamin E status on the 
anticarcinogenic effect of selenium were examined (Ip, 1985b). 
Female Sprague Dawley rats were fed a 20% stripped corn oil, 
casein-based diet.  Four dietary groups were formed:  adequate 
vitamin E/adequate selenium, adequate vitamin E/high selenium, 
deficient vitamin E/adequate selenium, and deficient vitamin E/high 
selenium.  Adequate and deficient vitamin E diets contained 50 and 
10 mg vitamin E/kg diet, respectively.  Adequate and high selenium 
diets contained Na2SeO3 at 0.1 and 2.5 mg selenium/kg, 
respectively.  At 50 days of age, rats received 5 mg of 
dimethylbenz[alpha]anthracene (DMBA) each by stomach tube.  Rats 
were killed 20 weeks after DMBA administration.  The tumour 
incidences in the groups were:  adequate vitamin E/adequate 
selenium, 76%; adequate vitamin E/high selenium, 40%; deficient 
vitamin E/adequate selenium, 84%; deficient vitamin E/high 
selenium, 68%.  This suggests that selenium protection against 
carcinogenesis is decreased in vitamin E deficiency. 

    Pence & Buddingh (1985) studied the effects of selenium 
deficiency on 1,2-dimethylhydrazine (DMH)-induced colon cancer in 
the rat.  They used male Sprague Dawley rats fed Torula yeast-based 
diets containing 2% corn oil.  Sodium selenite at 0.1 mg 
selenium/kg was added to the diet of the controls.  Weanlings were 
fed the diets 3 weeks prior the institution of DMH treatment and 
were killed after 20 weeks of treatment.  No effects of selenium 
status were noted on the incidence of colon adenocarcinomas. 

    The effects of selenium on UVR-induced skin carcinogenesis were 
studied by Overvad et al. (1985).  Female hairless mice were given 
sodium selenite at 0, 2, 4, or 8 mg selenium/litre drinking-water.  
Three weeks after selenium exposure began they were exposed to UVR 
daily for 22 weeks.  Then they were examined weekly for 26 weeks 
for skin tumours, and relative tumour onset ratios were calculated.  
The 2 mg selenium/litre treatment did not affect tumour onset but 
the higher doses did.  This suggests that selenium can protect 
against UVR-induced skin cancer. 

    Birt et al. (1984) reported that high levels of selenium in the 
diet increased pancreatic carcinogenesis induced by bis-(2-
oxopropyl)-nitrosamine (BOP) in male Syrian hamsters.  Torula yeast-
based diets with either 0.1 or 2.5 mg selenium/kg were fed to 
hamsters beginning at 4 weeks of age.  BOP was given in 4 weekly 
injections of 5 mg/kg body weight, beginning at 8 weeks of age.  
Hamsters were killed at 78 weeks of age.  When dietary fat was low 
(11% calories as corn oil), the low-selenium group had 25 
pancreatic ductular carcinomas (PCDA) in 18 hamsters, and the high-
selenium group had 63 PCDA in 23 hamsters.  When dietary fat was 
high (45% of calories as corn oil), the low-selenium group had 27 
PCDA in 19 hamsters and the high-selenium group had 44 PCDA in 18 
hamsters. 

    Other studies have been reported.  Milner, who showed that 
pharmacological doses of selenium inhibited the growth of 
transplantable tumours, has recently summarized his work (Milner, 
1985), and Thompson has summarized his work on mammary 
carcinogenesis (Thompson, 1984).  The metabolism of the carcinogen 
2-acetylaminofluorene in selenium-deficient rats has been studied 
by Besbris et al. (1982).  They found that selenium-deficient rats 
excreted more N-OH-acetylaminofluorene than controls, suggesting 
that selenium might prevent the production of this carcinogenic 
metabolite or promote its detoxification. 

8.  EFFECTS OF SELENIUM ON MAN

8.1.  High Selenium Intake

8.1.1.  General population

8.1.1.1.  Signs and symptoms

    When it became apparent that selenium was the toxic factor in 
plants that caused alkali disease in livestock raised in 
seleniferous areas, public health personnel became interested in 
the possible hazards for human health in such regions, since 
seleniferous grains or vegetables grown on high-selenium soil could 
enter the human food chain.  Smith et al. (1936) reasoned that, if 
human selenosis were a problem anywhere, it would most likely occur 
in farmers living in seleniferous regions, who consumed largely 
locally-produced foodstuffs.  Therefore, they surveyed a rural 
population living on farms or ranches known to have a history of 
alkali disease.  Their survey inquired into the health status of 
111 families and also determined the actual consumption of locally-
produced foods.  Wherever possible, general physical examinations 
were made and urine samples were collected. 

    These workers were unable to find any symptom or group of 
symptoms or serious illness that could be considered characteristic 
of, or could definitely be attributed to, selenium poisoning in 
man.  However, the incidence of vague symptoms of ill health and 
symptoms suggesting damage to the liver, kidneys, skin, and joints 
was rather high.  But since the causes for such disorders are many, 
it was not possible to determine whether selenium played any role 
in their causation.  Apart from the more vague symptoms of 
anorexia, indigestion, general pallor, and malnutrition, the 
following more pronounced disease states were observed:  bad teeth, 
yellowish discoloration of the skin, skin eruptions, chronic 
arthritis, diseased nails, and subcutaneous oedema. 

    The same authors (Smith et al., 1936) were unable to 
demonstrate a very definite correlation between the clinical 
evidence of selenium intoxication in 127 subjects and the 
concentration of selenium in the urine.  In fact, they expressed 
surprise that there was not any more definite evidence of serious 
injury, particularly in subjects with high concentrations of 
selenium in the urine.  Relatively high urinary-selenium levels 
were most often associated with pathological nails, 
gastrointestinal disorders, icteroid skin, and bad teeth.  The 
incidence of high urinary-selenium in individuals with dermatitis 
and arthritis was no greater than that in individuals without 
symptoms. 

    Because of the ambiguous findings in their first study, Smith & 
Westfall (1937) carried out a second, more detailed and intensive 
survey to establish the symptomatology of human selenosis and its 
relation to the amount of selenium excreted in the urine.  For this 
purpose, they examined 100 subjects from 50 families that had high 
levels of urinary-selenium in their previous testing.  The 

percentage frequency of the various signs and symptoms observed is 
given as follows:  none, 24; gastrointestinal disturbances, 31; 
icteroid discolouration of the skin, 28; bad teeth, 27; sallow and 
pallid colour, especially in younger individuals, 17; history of 
recurrent jaundice, 5; dermatitis, 5; pigmentation of the skin 
(chloasma?), 3; pathological nails, 3; rheumatoid arthritis, 3; 
cardiorenal disease, 2; vitiligo, 2.  It was concluded that none of 
these signs or symptoms could be regarded as specific for selenium 
poisoning, and it was not certain that any one was the direct 
result of the continual ingestion of selenium.  Nonetheless, these 
workers felt that the high incidence of gastrointestinal 
disturbances was of importance.  Moreover, the high incidence of 
icteroid discolouration of the skin was thought to be related in 
some way to the ingestion of selenium, possibly as a result of 
liver dysfunction.  The possible cariogenic effects of high levels 
of selenium is discussed further in section 8.1.1.2.  The other 
symptoms occurred so infrequently that they did not seem to be 
associated with selenium.  However, it should be noted that the 
value of all these observations is in doubt since there is no 
comparative information available concerning the frequency of 
occurrence of these signs and symptoms in an appropriate control 
group. 

    Smith & Westfall (1937) estimated that most of their subjects 
living in highly seleniferous areas were probably absorbing about 
10 - 100 g/kg body weight per day and that some of their subjects 
might have absorbed as much as 200 g/kg per day.  For a 70-kg man, 
these rates of absorption would be equivalent to a dietary-selenium 
intake of 700 - 14 000 g/day, assuming that all of the selenium in 
the food had been absorbed. 

    As discussed in section 4.1.2, drinking-water rarely 
contributes much selenium to a person's total daily intake, but a 
brief note indicated that a family of North American Indians living 
in Colorado, USA, suffered hair loss, weakened nails, and 
listlessness after consuming well water reported to contain 9000 g 
selenium/litre for about 3 months (Anonymous, 1962).  This incident 
was thought to be the first authentic case of selenium poisoning in 
human beings induced exclusively from a naturally-occurring 
underground source of water.  Tsongas & Ferguson (1977) studied the 
effects of selenium in the drinking-water on the health of 2 groups 
of persons living in a rural Colorado community.  The first group 
("exposed") received a water supply that contained 50 - 125 
g/litre, whereas the second group ("unexposed") received a water 
supply that contained levels ranging from non-detectable (1 
g/litre) to 16 g/litre.  Examination of a total of 86 individuals 
revealed that there were no significant differences between the 
exposed and unexposed groups in the incidence or prevalence of any 
of 85 health variables studied. 

    Lemley (1940) presented a 58-year-old rancher from South 
Dakota, thought to be the first described case of chronic selenium 
dermatitis in a human being, caused by the ingestion of selenium 
from natural sources.  However, 2 samples of urine collected from 
this patient a week apart, contained only 0.043 and 0.040 mg 

selenium/litre, levels that are considered to be within the normal 
range.  Although some improvement in the patient's condition was 
noted when certain seleniferous foods consumed on his ranch were 
avoided, the improvement was not marked.  Administration of 
bromobenzene, now known to be a potent hepatotoxin, cleared up the 
dermatitis, but caused only a small increase in the urinary-
selenium output, which reached a peak value of about 0.100 
mg/litre, after 4 days.   Earlier work by Moxon et al. (1940) had 
shown that the rate of excretion of selenium from selenized animals 
could be increased by the administration of bromobenzene.   The 
likelihood that selenium was the cause of the dermatitis in this 
patient is doubtful, since, in a later paper, Lemley & Merryman 
(194l) claimed that a relapse in this patient's condition was cured 
when some canned meat containing 0.40 g selenium/kg (considered by 
them to be a highly toxic amount of selenium) was withdrawn from 
the patient's diet.  This figure for the level of selenium in the 
meat is almost certainly erroneous, since not only is it below that 
which would be found in animals suffering from selenium deficiency 
but it is also below the sensitivity of the analytical techniques 
available at that time. 

    Other cases of presumed human overexposure to selenium were 
reported by Lemley & Merryman (1941).  For example, urine samples 
from a ranching family living in South Dakota contained 0.200, 
0.250, 0.300, 0.550, and 0.600 mg selenium/litre for the father, 
mother, daughter, son, and uncle, respectively.  Administration of 
bromobenzene to the father resulted in a urinary output of selenium 
of 1.800 mg/litre within 24 h.  No mention of dermatitis was made 
in connection with this family.  Rather, all family members 
suffered from slight, continual dizziness and clouding of the 
sensorium, extreme lassitude accompanied by depression, and 
moderate emotional instability.  The patients tired on exertion and 
complained that their powers of concentration were markedly 
impaired.  After a course of bromobenzene, these people improved 
markedly and their general condition remained improved, since they 
were instructed not to use the various food products of the ranch 
that contained selenium.  Lemley & Merryman concluded that the 
following facts provided the basis for the diagnosis of selenium 
poisoning in these subjects: 

    (a) knowledge that the subjects lived in a seleniferous
        area;

    (b) presence of concentrations of selenium in the urine
        exceeding 0.100 mg/litre;

    (c) increased elimination of selenium in the urine after
        bromobenzene administration; and

    (d) improvement in the subject's symptoms after
        elimination of selenium from the diet.

    The same authors also described a 65-year-old rancher from 
South Dakota, who suffered alternate bouts of diarrhoea and 
constipation.  This patient's urinary-selenium concentrations were 

as high as 0.250 mg/litre.  An exploratory abdominal operation 
suggested that the patient had very early cirrhosis of the liver, 
which was confirmed by pathological examination.  The patient 
recovered from the operation and then gradually improved after 
being placed on a strict selenium-free diet and given a course of 
bromobenzene. 

    In a later paper, Lemley (1943) expressed the opinion that 
human selenium poisoning is common, widespread, and, in certain 
localities, of importance for the general public health.  More 
recently, Kilness (1973) complained that no follow-up public heath 
survey with an appropriate control group had been made in South 
Dakota since the initial surveys by the United States Public Health 
Service in highly seleniferous areas more than 30 years previously. 

    Jaffe (1976) carried out a field study in Venezuela and 
compared 111 children living in a seleniferous area (Villa Bruzual) 
with 50 living in Caracas.  The overall haemoglobin and haematocrit 
values were somewhat lower in Villa Bruzual (128 g/litre and 39 
volume %, respectively) than in Caracas (148 g/litre and 42 volume 
%, respectively), but no correlations between blood- and urine-
selenium levels and haemoglobin or haematocrit values were found.  
The children in Villa Bruzual consumed less meat and milk and had a 
higher incidence of intestinal parasite infestation (Jaffe et al., 
1972a) than those in Caracas.  Therefore, it was concluded that the 
differences in haemoglobin were probably due to differences in 
nutritional or parasitological status and not to differences in 
selenium intake.  Activities of prothrombin and serum alkaline 
phosphatase and transaminases, which altered in selenium-poisoned 
rats (Jaffe et al., 1972b), were normal in all the children and no 
correlation with blood-selenium levels was apparent.  Symptoms of 
dermatitis, loose hair, and pathological nails were reported as 
more frequent among the children in the seleniferous area than in 
those living in Caracas, but no quantitative information was given. 
The clinical signs of nausea and pathological nails appeared to be 
correlated with serum- and urine-selenium levels.  However, the 
cause of the different incidence of clinical signs was considered 
doubtful, especially in the absence of differences in the various 
biochemical tests performed (Jaffe et al., 1972a). 

    The mean blood-selenium level of 111 school children from the 
seleniferous area in Venezuela was 0.813 mg/litre (Jaffe et al., 
1972a).  A subgroup of 28 children from this area who had blood-
selenium levels of over 1 mg/litre had a mean blood-selenium level 
of more than 1.321 mg/litre.  There was one child with a blood-
selenium level of 1.8 mg/litre.  Another subgroup of 11 children 
who had blood-selenium levels of less than 0.4 mg/litre had a mean 
blood-selenium level of 0.330 mg/litre.  Urinary-selenium levels 
tended to reflect blood-selenium levels, since children in the 
high-blood-selenium subgroup (> 1 mg/litre) excreted a mean level 
of 0.657 mg/litre urine, whereas children in the low-blood-selenium 
subgroup (< 0.4 mg/litre) excreted a mean level of 0.266 mg/litre 
urine. 

    Kerdel-Vegas (1966) summarized 9 cases of acute intoxication 
due to the ingestion of nuts of the "Coco de Mono" tree  (Lecythis 
 ollaria) from the seleniferous areas of Venezuela.  Although the 
course of the poisoning differed from patient to patient (probably 
because of differences in the amount of nuts consumed and the 
length of time the nuts were present in the digestive tract), most 
cases experienced nausea, vomiting, and diarrhoea, a few hours 
after eating the nuts, followed by hair loss and nail changes, some 
weeks after the initial episode.  Two patients had foul breath that 
was described as being reminiscent of decomposed seaweed or 
phosphorus.  After a period of time, re-growth of hair and nails 
took place and most patients appeared to make a satisfactory 
recovery.  One fatality was reported, a 2-year-old boy who died, in 
spite of proper medical attention and symptomatic treatment for 
severe dehydration. 

    Dickson (1969) described his own personal experience after 
eating sapucaia nuts ( Lecythis elliptica H.B.K.) that had grown in 
Honduras.  He reported hair loss and splitting of finger and 
toenails several weeks after consuming the nuts.  Although no 
mention of selenium was made in his report, he noted that a 
peculiar odour was associated with consumption of these nuts, not 
only of his breath but of his body as well.  Kerdel-Vegas (1966) 
pointed out that the sapucaia, or chestnut of Para (which he called 
 Lecythis paraensis Ducke), is consumed as food in Brazil and other 
countries to which it is exported (i.e., Europe and the USA).  He 
also commented that there is a popular saying in northern Brazil 
that eating sapucaia leads to hair loss, but he knew of no 
scientific or medical reports from Brazil.  Signs of selenium 
toxicity have been observed in rats fed diets containing defatted 
Brazil nut flour that assayed 51 mg selenium/kg (Chavez, 1966), and 
Thorn et al. (1978) found that samples of Brazil nuts marketed in 
the United Kingdom contained an average of 22 mg selenium/kg 
(range, 2.3 - 53 mg/kg). 

    As reported recently, an unexplained intoxication characterized 
by nail deformation and the loss of hair and nails as the most 
common signs was observed in Enshi county of Hubei province of the 
People's Republic of China, more than 20 years ago, with a peak 
prevalence during the years 1961 - 64 (Yang et al., 1983).  In 5 
villages with 248 inhabitants, about half of the population was 
affected and in one particular village over 80% of the people were 
affected.  No other quantitative information about the cases was 
given but a general description of the signs and symptoms observed 
is presented below.  The hair became dry and brittle and was easily 
broken off at the scalp with retention of intact radicles so that 
depigmented and dull hair continued to grow.  A scalp rash 
accompanied by intolerable itching resulted in hard scratching 
which easily removed the hair.  The nails became brittle with white 
spots and longitudinal streaks on the surface, followed by a break 
on the wall of the nail.  With new nail growth, the broken nail 
advanced and ultimately fell off.  Effusian of fluid from around 
the nail was common in many cases.  The new nail had a rough and 
ridged surface and was fragile and thickened. 

    Other signs of intoxication included skin lesions, tooth decay, 
and abnormalities of the nervous system.  The skin became red and 
swollen and then blistered and eruptive followed, in some cases, by 
ulcerations that took a long but unstated time to heal.  The 
lesions occurred primarily on the limbs and also on the back of the 
neck.  Mottled teeth were observed in the intoxicated individuals 
but this observation may have been confounded by high exposure to 
fluoride.  In one heavily affected village, nervous system 
abnormalities were seen, including peripheral anaesthesia, 
acroparaesthesia, and pain in the extremities.  Hyperreflexia of 
the tendon commonly developed later followed by numbness, 
paralysis, and motor disturbances.  One case of hemiplegia was also 
reported.  There was an indication that this intoxication was 
related to the locally grown monotonous diet consumed, which later 
was shown to contain high levels of selenium.  No quantitative data 
regarding selenium exposure were obtained at the time of the 
outbreak.  However, because of circumstantial evidence, the 
intoxication was considered by the authors to be selenosis, and, as 
discussed in sections 5.1.1.1 and 6.2.3, current levels of exposure 
to dietary selenium in an area with a history of intoxication, as 
assessed by blood- and hair-selenium levels as well as dietary 
intake data, exceeded those ever reported in any non-occupationally 
exposed population (Table 8).  The authors estimated that the daily 
dietary intake of selenium, after the peak prevalence of the 
poisoning had subsided, averaged 5 mg, and blood- and hair-selenium 
levels averaged 3.2 mg/litre and 32.2 mg/kg, respectively.  The 
ultimate environmental source of the selenium in this episode of 
intoxication was a highly seleniferous coal (average selenium 
content of 300 g/g) which lost its selenium to the soil as a 
result of weathering processes.  Once in the soil, the selenium was 
taken up by plant crops and entered into the food chain. 

    Because of the nutritionally-beneficial effects of selenium in 
animals, some investigators have deliberately given inorganic or 
organic forms of the element to people with the aim of producing 
some desirable health benefit.  For example, Westermarck (1977) 
administered selenium, as selenite, in oral doses of 0.05 mg/kg 
body weight per day, for more than one year, to patients with 
neuronal ceroid lipofuscinosis (NCL) and did not observe any toxic 
manifestations.  On the contrary, it was felt that some of the NCL 
patients showed at least a transitory improvement in their 
condition.  In some patients, a slight increase in serum aspartate 
aminotransferase activity was observed, but apparently this is seen 
in a number of patients with NCL. 

    Schrauzer & White (1978) described 2 individuals who had been 
taking commercially-available nutritional supplements consisting of 
selenium-containing yeast at doses of 200 and 450 g selenium, 
daily, for 18 months.  Together with their dietary intakes, these 
individuals received a total of 350 and 600 g/day.  Although some 
marginal haematological changes were seen and the serum-glutamic 
oxaloacetic transaminase activities were on the borderline of high, 
it was concluded that daily intakes of up to 600 g selenium for 18 
months do not induce toxic effects in well-fed individuals. 

    In a study by Perona et al. (1978), 4 subjects were given, 
orally, a 2-mg dose of selenium, as sodium selenite, daily, for 
20 - 40 days, to determine the effects of  in vivo selenium 
administration on the activity of human erythrocyte-glutathione 
peroxidase.  It was stated that none of the subjects exhibited any 
symptoms of selenium poisoning, but the criteria used to judge any 
deleterious effects of selenium were not described. 

    Yang et al. (1983) reported the case of a 62-year-old man who 
had taken one tablet containing 2 mg sodium selenite per day for 
more than 2 years.  The subject did not have any symptoms of 
indisposition but presented with thickened, fragile and somewhat 
honeycomb-like fingernails.  After the oral intake of sodium 
selenite was stopped, the surface of the new nail growth became 
smooth and gradually recovered.  Blood-and hair-selenium levels 
were 0.179 mg/litre and 0.828 mg/kg, respectively, on the day the 
selenite tablets were discontinued.  These tissue-selenium levels 
are much lower than those reported by the same authors in Enshi 
county of the Hubei province (Yang et al., 1983) suggesting that 
the form of selenium ingested must be considered when interpreting 
tissue-selenium levels in the diagnosis of selenium poisoning. 

    Ingestion of superpotent selenium tablets, meant to be consumed 
as a "health food" supplement, resulted in 12 cases of human 
selenium toxicity in the USA in 1984 (Anonymous, 1984; Jensen et 
al., 1984; Helzlsouer et al., 1985).  Each tablet contained 27 - 31 
mg selenium by analysis (about 182 times more than the level stated 
on the label).  Approximately 25 mg of the selenium was present as 
sodium selenite whereas the rest was elemental and/or organic 
selenium.  The total doses of selenium estimated to be consumed by 
the victims ranged from 27 to 2387 mg.  Based on the limited 
information available, the symptoms reported in these cases as most 
common were nausea and vomiting, nail changes, hair loss, fatigue, 
and irritability.  Other symptoms included abdominal cramps, watery 
diarrhea, paraesthesias, dryness of hair, and garlicky breath. 
Eight of the 12 victims did not have any abnormalities in the blood 
chemistry, and the results of liver and kidney function tests were 
normal. 

    A level of 500 g has been proposed as the tentative maximum 
acceptable daily intake of selenium for the protection of human 
health (Sakurai & Tsuchiya, 1975).  This figure was derived from an 
initial estimate of the mean normal daily intake of selenium by 
human beings of between 50 and 150 g.  It was concluded that 
values of 10 - 200 times the normal intake appeared acceptable as 
an estimated range for the margin of safety within which the 
average human being could tolerate selenium.  By taking the lower 
values of both these estimates, the lowest level of potentially 
dangerous daily intake of selenium was estimated to be 500 g. 

8.1.1.2.  Attempts to associate high selenium intake with human
diseases

    (a)   Dental caries

    As already mentioned in section 8.1.1.1, bad teeth was one of 
the signs that was thought to be possibly associated with a high 
intake of selenium by a rural population living in seleniferous 
areas of South Dakota, Wyoming, and Nebraska (Smith et al., 1936) 
and by children living in a seleniferous zone in Venezuela (Jaffe, 
1976).  Several studies have been concerned with the possibility of 
a specific association between the incidence or prevalence of 
dental caries and residence in a seleniferous area, urinary 
excretion of selenium, or the selenium content of teeth.  
Hadjimarkos & Storvick (1950) and Hadjimarkos (1956) noted a 
geographical difference in the prevalence of dental caries in 2029 
children, between the ages 14 and 16 years, residing in 4 different 
counties in Oregon.  Two different counties, one with the highest 
(Clatsop), and one with the lowest (Klamath), rates of caries 
experience were selected for further study.  Urine samples from 24 
and 29 male children who were attending county seat high schools 
and who were born and residing in the respective counties were 
analysed for selenium content.  The mean levels of urinary-selenium 
were 0.049 and 0.037 mg/litre in the groups of children from the 
counties with the high (14.4 DMF (decayed, missing, or filled) 
teeth per child) and low (9.0 DMF teeth per child) prevalence of 
dental caries, respectively (Hadjimarkos et al., 1952). 

    In a second study, 2 additional counties with similar but high 
rates of caries experience (Jackson and Josephine, 13.4 and 14.4 
DMF teeth per child, respectively) were selected (Hadjimarkos & 
Bonhorst, 1958).  Analysis of 33 urine specimens from continuously-
resident, male high school children attending a county seat high 
school (Jackson) and 46 specimens from similar children attending a 
high school serving a rural area (Josephine) gave values (mean  
SE) of 0.074  0.007 and 0.076  0.005 mg/litre, respectively.  It 
was concluded that there was an association between the high 
prevalence of dental caries and the values of urinary-selenium 
excretion, which were double those seen in the previous study in 
the county with a lower rate of caries experience. 

    In order to explain the variations in urinary-selenium levels 
observed in the above studies, samples of locally-produced and -
consumed milk and eggs, as well as local drinking-water samples 
were collected from 74 farms located in Klamath, Jackson, and 
Josephine counties and analysed for their selenium content 
(Hadjimarkos & Bonhorst, 1961).  The selenium levels were almost 10 
times higher in food samples collected from the counties with high 
caries prevalence (Jackson and Josephine) than in those from the 
county with low caries prevalance (Klamath).  The selenium levels 
in the milk samples obtained in Jackson and Josephine counties were 
higher than those listed in Table 3. 

    In another study, Tank & Storvick (1960) determined the extent 
of dental caries in a population of children from 15 areas of 
Wyoming that had been identified previously as seleniferous or non-
seleniferous on the basis of the geological distribution of 
selenium, occurrence of the element in vegetation, and the 
occurrence of selenosis in livestock.  These research workers 
claimed that the dental caries rate in the permanent teeth was 
higher in children residing in seleniferous areas of Wyoming than 
in children living in non-seleniferous areas of Wyoming, but they 
were unable to demonstrate any consistent relationship between 
calculated selenium intake and caries or urinary-selenium excretion 
and caries. 

    Suchkov et al. (1973) found that the incidence of caries varied 
in 3 different geographical zones (mountainous, pre-mountainous, 
and forest-steppe) in the Chernovitsi region of the Ukraine.  
Analysis of teeth from people residing in rural areas in these 3 
zones and mainly consuming locally-produced foodstuffs revealed a 
direct correlation between the selenium content of the teeth and 
the incidence of dental caries.  The people in the mountainous zone 
had the highest level of selenium in the teeth and the greatest 
incidence of dental caries, whereas the people in the forest-steppe 
zone had the lowest level of selenium in the teeth and smallest 
incidence of dental caries.  This correlation was true for 
deciduous teeth as well as for permanent teeth.  However, as 
pointed out by the authors, the mountainous zone also had the 
softest water and the lowest content of fluorine in the drinking-
water, so that factors other than selenium might have been 
involved. 

    It was not possible to demonstrate any association between the 
urinary excretion of selenium and the incidence of dental caries in 
subjects living on the South Island of New Zealand, an area known 
to be low in selenium (Cadell & Cousins, 1960).  However, 
Hadjimarkos (1960) claimed that the levels of urinary excretion of 
selenium in this study (all less than 0.050 mg/litre) were too low 
to be associated with an increased incidence of caries. 

    As emphasized by Schwarz (1967), the levels of urinary-selenium 
excretion reported in the Hadjimarkos studies were within the 
limits generally found in the normal population without excessive 
selenium intake.  It may be recalled from section 7 that, in 
experimental animal studies, very high toxic levels were used to 
demonstrate the cariogenic effect of selenium. 

    (b)   Reproduction

    Possible effects of selenium on reproduction were suspected 
following old anecdotal reports from Colombia, South America that 
women living in areas, later shown to be seleniferous, gave birth 
to malformed babies (Rosenfeld & Beath, 1964), but there is a lack 
of reliable studies.  Robertson (1970) pointed out that, among 6 
women preparing microbiological media containing sodium selenite, 
one probable and 4 certain pregnancies all ended in abortions, save 
one that went to term.  The infant was born with bilateral club 

foot.  However, no differences in urinary-selenium levels were 
observed between this group of women and a control group living in 
the same area, and inquiries by the author at other laboratories 
carrying out comparable work did not show any evidence of similar 
trouble.  Jaffe & Velez (1973) could not demonstrate any 
correlation between the selenium level in the urine of school 
children in different Venezuelan states and the incidence of infant 
mortality due to congenital malformations, on the basis of 
published public health statistics.  Jaffe (1973) concluded that no 
recent observations of a teratogenic action of dietary selenium in 
human beings had been reported at that time. 

    (c)   Amyotrophic lateral sclerosis

    Kilness & Hochberg (1977) reported an unusual cluster of 4 
cases of amyotrophic lateral sclerosis (ALS) in male farmers living 
in a seleniferous area and indicated that selenium might be an 
environmental factor predisposing to the disease.  But Schwarz 
(1977) pointed out that the frequency of ALS was at least as high 
if not higher in areas that were selenium-deficient as in those 
with normal or elevated levels and Kurland (1977) suggested that 
the cluster was more indicative of a chance occurrence than of a 
new etiological lead in ALS.  Moreover, Norris & Sang (1978) found 
that 19 out of 20 well-established cases of ALS had urinary-
selenium levels lower than the mean for unexposed persons and 
therefore concluded that selenium exposure was of no concern in the 
average case. 

8.1.2.  Reports on health effects associated with occupational
exposure

    Although the toxicological potential of selenium for human 
beings can be inferred from studies carried out with laboratory 
animals, certain precautions must be taken in applying the results 
of animal studies to the industrial health aspects of selenium.  
First, the number of studies dealing with the respiratory exposure 
of animals to selenium compounds is limited, and the dose levels 
employed have usually been higher than those encountered in 
industry.  On the other hand, the period of exposure used in the 
studies reviewed in section 7.1.2.3 did not exceed one month.  The 
specific chemical form and physical state of the selenium must be 
considered as well as the fact that the chemical form of selenium 
may change when in contact with moist mucous membranes or with 
sweat.  These factors, plus several others, must be taken into 
account when considering the health effects of various selenium 
compounds under occupational exposure conditions. 

    The Task Group recognized that, for various reasons, knowledge 
on the health effects of industrial exposure to selenium compounds 
was not complete.  Acute exposures to selenium are the result of 
accidents and are, of necessity, described on an  ad hoc case study 
basis.  Regarding the effects of long-term selenium exposure in 
industry, there is a lack of epidemiological studies that include 
unexposed control groups.  Also, no follow-up studies are available 
comparing the health status of a sufficiently large number of 

workers, previously exposed to selenium, with that of the unexposed 
population.  Furthermore, the exposure level was not known with 
certainty in either acute or long-term studies, and, in some cases, 
the form of selenium was not established.  In many cases, 
simultaneous exposure to other noxious agents occurred.  
Nevertheless, the Task Group felt that some preliminary assessment 
of the toxicological potential of selenium in industry could be 
made on the basis of the occupational experience available with 
selenium compounds. 

    Since Hamilton's first observation on the effects of selenium 
exposure in industry in 1917 (Hamilton, 1927 - 34), several hundred 
persons have been described in the literature who have been 
directly affected by the vapour, fumes, or dust of selenium and its 
compounds.  In addition, there is a systematic study of a group of 
over 100 selenium workers for a period of 2 years (Glover, 1967).  
Systematic attention has also been given to the health of workers 
exposed to selenium in the USSR (Filatova, 1948; Monaenkova & 
Glotova, 1963; Gracianskaja & Kovshilo, 1977).  Several reviews 
evaluating the health effects of selenium from the point of view of 
occupational health have been presented (Glover, 1954 - 70, 1976; 
Cooper, 1967; Izraelson et al., 1973; Cooper & Glover, 1974). 

8.1.2.1.  Fumes and dust of selenium and its compounds

    Workers in several industries, such as the production or 
recovery of selenium itself, or the manufacture of glass or 
rectifiers can be exposed to the fumes and dust of selenium and its 
compounds.  In addition, direct contact with powders or solutions 
containing selenium compounds is possible and the biological 
effects of such contact will be discussed in this section. 

    The chemical form of selenium in the fumes and dusts found in 
the above-mentioned industries, consists of elemental selenium plus 
various amounts of selenium dioxide, the only oxide of selenium 
found in the industrial environment.  However, in some cases, the 
possible occurrence of other selenium compounds, such as hydrogen 
selenide, cannot be excluded.  Instances where hydrogen selenide 
was the main selenium compound of concern will be discussed 
separately in section 8.1.2.1.2. 

8.1.2.1.1.  Selenium dioxide

    Selenium dioxide mainly occurs in industry:

    (a) during the production of the compound, usually by the
        oxidation of elemental selenium; and

    (b) whenever selenium is heated in air, purposely or
        accidently, above its melting point.  "Selenium fume"
        rising under these conditions is a mixture containing
        red elemental selenium and about 20 - 80% of selenium
        dioxide.

    Glover (1954, 1970, 1976) has summarized the acute local, 
systemic, and possible long-term effects of occupational exposure 
to selenium dioxide.  Acute local effects are seen in the lungs, 
gastric mucosa, skin, nails, and eyes.  Sudden inhalation of large 
amounts of selenium dioxide produces pulmonary oedema, due to a 
local irritant effect on lung alveoli.  Working in an atmosphere 
containing selenium dioxide can increase indigestion.  Contact with 
the skin results in burns or dermatitis.  Occasionally, a true 
urticarial type of generalized allergic body rash may occur, in 
which case the individual must be removed from any work involving 
selenium.  The selenium dioxide may penetrate under the nails and 
cause excruciating pain in the nail beds.  If selenium dioxide 
enters the eyes, prompt flushing with water will prevent 
conjunctivitis.  "Rose eye", a pink discoloration of the skin of 
the eyelids, which often become puffy, is sometimes seen in persons 
who work in an atmosphere of selenium dioxide dust.  Systemic 
effects of selenium dioxide exposure include garlicky-smelling 
breath, metallic taste on the tongue, and indefinite 
sociopsychological effects.  The garlicky breath is the first and 
most characteristic sign and has been used by occupational 
hygienists as a way of monitoring exposure, even though the odour 
is not always a reliable index in this respect.  The metallic taste 
is an earlier symptom but, being more subtle, is often overlooked 
by workers.  Sociopsychological effects such as lassitude and 
irritability have also been associated with selenium exposure.  
Since the effects of selenium overexposure lead to hepatic damage 
in animals, Glover (1954) concluded that it would be prudent to 
watch for such damage in human beings. 

    (a)   Reports on health effects connected with short-term 
          accidental exposures

    An industrial incident in a plant engaged in smelting scrap 
aluminium and other non-ferrous metals was reported by Clinton 
(1947).  The aluminium scrap included more than 100 kg of aluminium 
rectifier plates coated on one side with metallic selenium overlaid 
with a coating of an alloy of bismuth, cadmium, and tin.  When an 
attempt was made to skim the dross prior to pouring, a cloud of 
reddish fume arose.  The fumes were intensely irritating to the 
eyes, nose, and throat and the plant was evacuated.  No workers 
were exposed for more than 2 min. 

    All exposed workers noticed immediate and intense irritation 
of the eyes, nose, and throat, and an unpleasant sour, garlic-like 
odour to the fumes.  The more heavily exposed workers complained of 
a severe burning sensation in the nostrils, and dryness of the 
throat; followed after 2 - 4 h by severe headache, mainly frontal 
in location, lasting until the following day.  Several men observed 
immediate sneezing, coughing, and headache, followed for 4 - 8 h by 
nasal congestion, dizziness, and redness of the eyes.  Most of the 
men noticed a bad taste in their mouths and an unpleasant odour to 
their skin and clothing.  Other people, however, did not note any 
unpleasant odour in the breath of the exposed workers. 

    Two labourers who had attempted to skim the dross from the 
furnace and therefore underwent intense exposure were hospitalized 
for observation.  On arrival at the hospital, they complained of 
soreness of the eyes and lachrymation, pain in the nose, slight 
difficulty in breathing, and frontal headache.  Physical 
examination on admission revealed conjunctival injection, 
congestion of the mucous membranes of the nose and throat, and 
oedema of the uvula.  One man had a few fine rales audible in the 
right base; roentgenological examination of the chest did not 
reveal any abnormalities.  The temperature, pulse, and respiration 
were normal.  Both workers were discharged 2 days after the 
accident, at which time they were asymptomatic and had no positive 
physical findings.  Another worker, a foreman, underwent a more 
severe exposure than most of the workers.  He was not hospitalized, 
but, about 8 - 12 h after the accident, he developed severe 
dyspnoea accompanied by a slight elevation in temperature, in 
addition to a headache and sore throat.  Physical examination 
revealed fine rales in both bases, as well as scattered asthmatic-
like wheezes throughout the chest.  These signs and symptoms 
cleared in about 24 h, without specific therapy.  All persons 
exposed to the fumes had recovered entirely in 3 days, and no 
sequelae have been encountered. 

    In the same year, Lauer (1947) described an episode that 
occurred when 15 men were exposed to fumes arising from an 
explosion and fire, which occurred in a pot when selenium became 
overheated in contact with aluminium.  The 2 elements produced a 
high-temperature reaction, and fumes and vapours were dispersed 
throughout the work area.  The lengths of exposure varied, some 
victims were using masks part of the time, and others were almost 
without protection. 

    The exposed men reported to the medical dispensary about 15 - 
45 min after the accident.  All complained of soreness and burning 
of the nose and throat, and 8 out of 15 cases had some dyspnoea.  
Two of these cases were moderately severe, requiring almost 
continuous oxygen therapy.  Headache and dizziness and a burning 
sensation in the eyes occurred in 6 cases.  Three others complained 
of substernal burning and tightness of the chest.  In 4 there was 
nausea and vomiting.  All were hospitalized.  Physical examination 
showed reddening of nasal and pharyngeal mucosa, wheezes, and 
musical rales in the lungs (12 cases).  These symptoms abated 
quickly.  In about 10 days, there were few subjective complaints.  
All apparently recovered satisfactorily with no known 
complications.  To assess possible liver affection, Hanger's 
cephalin cholesterol tests and Icterus Index determinations were 
performed on admission to the hospital and again at the end of the 
first, second, third, and seventh week.  On the day of admission to 
the hospital, Hanger's tests were made on 13 workers, 4 of which 
were positive and 9, negative.  At the end of the first week 
following exposure, there were 10 positives and 3 negatives.  At 
the end of the second week, there were 11 positives and 3 negatives 
out of a group of 14 tested, and the same result was obtained at 
the end of the third week.  By the end of the seventh week, only 4 
of 11 tested were positive.  The average value of the Icterus Index 

on admission to the hospital was 7.3 units.  One week after 
exposure, it was 13.5.  In 2 weeks, it averaged 20.7.  After the 
third week, it had fallen to 9.9 and, by the end of the seventh 
week, the average Icterus Index was 7.2. 

    An accident connected with a fire in a selenium rectifier plant 
was described by Wilson (1962).  Twenty-eight of the employees were 
exposed directly to the smoke and fumes containing selenium 
dioxide.  The length of exposure to the fumes varied with the 
individual, but no one was exposed for more than 20 min.  Oxygen 
was administered by mask to the men lying on the ground, who 
experienced bronchial spasm with coughing, gagging, and, in some 
instances, transient loss of consciousness. 

    The initial signs and symptoms were a feeling of constriction 
in the chest, accompanied by burning and irritation of the upper 
respiratory passages, violent coughing and gagging with nausea and 
vomiting, and a bitter acid taste in the mouth.  During the acute 
episode, there were mild signs of shock, with a drop in blood 
pressure and an elevated pulse and respiratory rate.  Other 
symptoms, experienced during this stage, were burning of the skin, 
conjunctivae, and mucous membranes of the upper respiratory 
passages.  Within 4 h, all patients had apparently recovered from 
the acute episode and a recheck of their blood pressure, pulse, 
respiratory rate, and general condition was found to be within 
normal limits. 

    Within 6 h of the exposure, the victims began complaining of 
secondary symptoms with the onset of generalized chills accompanied 
by nausea and vomiting, diarrhoea, malaise, dyspnoea, and headache.  
The onset of secondary symptoms was delayed in some of the victims 
for several hours after the initial exposure.  Within 12 h, all 
exposed personnel began experiencing the symptoms described.  The 
following morning, the first patient, a 30-year-old male, was 
admitted to the hospital.  He was cyanotic and in moderate 
respiratory distress.  He complained of chest pain bilaterally, 
and was experiencing bronchial spasms.  A chest roentgenogram 
revealed extensive bilateral consolidation of the lung fields, 
indicating pneumonia.  The white blood cell count was elevated to 
153 000 with a marked prominence of neutrophils.  He experienced a 
stormy course, requiring constant oxygen for the first 9 days of 
hospitalization.  By the fifth hospital day, X-ray films revealed a 
further extension of the previously noted bilateral pneumonic 
consolidation.  Two weeks following admission, comparison of a 
chest film with previous films revealed marked improvement 
bilaterally.  He was free of respiratory distress, his white blood 
cell count had returned to within normal limits, and he was 
discharged home for convalescence.  It is interesting to note that 
this was the only employee of the 5 hospitalized cases who did not 
receive oxygen on the afternoon of the fire.  On the same day, the 
second victim was admitted to the hospital in a similar dyspnoeic, 
cyanotic state with an elevated white blood cell count of 24 600.  
X-ray again revealed bilateral atelectasis and consolidation.  This 
patient required continuous oxygen for 6 days, and was discharged 
after 9 days of hospitalization:  his white blood cell count had 

returned to normal and a repeat roentgenogram revealed improvement.  
This was the second most involved and prolonged illness, and he 
received only about 6 breaths of oxygen following his exposure.  
Three days after the accident, a third employee was admitted to the 
hospital in less respiratory distress, with a normal white blood 
cell count and a chest film that revealed bilateral elevation of 
the diaphram with extensive peribronchial infiltration and some 
consolidation at the lung bases.  On the same day, another worker 
was admitted to the hospital with a normal white blood cell count 
and a chest film revealing bilateral increase in lung markings 
consistent with bronchitis; however, no consolidation was evident.  
The final patient to be hospitalized was admitted 4 days after the 
accident with a white cell count of 12 800 and a prominence of 
neutrophils.  The X-ray film indicated bilateral pneumonia. 

    Four days after exposure, all other employees with any upper 
respiratory complaints were examined.  Thirty-two of the 53 
employees examined were found to have a residual bronchitis, of 
minimal to moderate degree, that required medication.  These were 
treated on an outpatient basis.  Within 1 week, all were 
asymptomatic and free of any respiratory signs. 

    Both Monaenkova & Glotova (1963) and Skornjakova et al. (1969) 
have described occupational incidents of short-term selenium 
dioxide exposure.  In the former case, 6 workers, 20 - 52 years 
old, were exposed from 5 to 20 min in a room with a leaky selenium 
still.  The workers suffered acute pain in the eyes, hoarseness in 
the throat, painful cough, and a heavy feeling in the chest.  Acute 
conjuctivitis, laryngotracheitis, and bronchitis were also noted 
and gastroenterocolitis was common to all.  Transient fever was 
seen in 2 workers.  The various signs and symptoms disappeared 
within 5 - 7 days, but, on return to work involving selenium, 2 
workers developed chronic bronchitis.  In the report of acute 
selenium dioxide exposure by Skornjakova et al. (1969), there was 
irritation of the eyes and mucous membranes, coughing without 
expectoration, nasal secretion, headache, vertigo, nausea, 
vomiting, garlicky-smelling breath and skin, general weakness, loss 
of consciousness, and collapse.  Two weeks after exposure, an 
allergic whole body rash occurred that disappeared after removal of 
the worker from contact with selenium. 

    (b)   Effects of short-term and/or repeated dermal exposure

    Selenium dioxide is more than a primary irritant, it causes 
extremely painful burns on the skin which, however, always heal 
without a scar.  Theoretically, the selenium dioxide powder itself 
does not burn the skin (and if dropped on to the skin should be 
immediately brushed off dry).  However, in practice, in the 
industrial environment, there is sufficient moisture on the skin 
from sweating for this very deliquescent white solid to form a 
sticky solution of selenious acid within seconds, or at the most, 
minutes, of coming into contact with the skin.  Selenious acid is 
so soluble that, if the skin is immediately washed with a lot of 
water, there will be no burn or even rash from accidental contact.  
When the selenious acid does burn the skin, there is little to see 

or feel for several hours.  After 4 h with a 50% solution, an 
unremitting intense pain begins, small petechial areas occur, and a 
faintly orange coloration occurs, which indicates reduction of some 
of the selenious acid to elemental red selenium.  The pain and 
necrosis can be prevented by the application of a reducing solution 
or ointment, such as 10% sodium thiosulfate (Glover, 1954).  If the 
burn remains untreated it may go on to ulceration, but this is 
rare.  Hgger & Bhm (1944) described a case of a woman who 
suffered pain and reddening of the middle, ring, and little fingers 
of one hand when selenium dioxide crystals penetrated into the 
protective rubber glove that she was wearing. 

    The first accurate description of a case of selenium fumes 
causing allergic dermatitis was published by Duvoir et al. (1937).  
A chemical engineer, who had handled selenium for 3 years in the 
past, developed swelling of the face with a hard urticarial oedema 
of the nose and cheeks extending on the neck down to his shirt 
collar following a 3-day exposure to selenium vapours.  There was a 
semi-circle of vesicles on the lower lids, but the forehead and 
ears escaped completely.  His hands showed discrete lesions.  
Within 24 h, the genital oedema had disappeared, after 3 days, the 
rash started to go, and, by 9 days, there was only desquamation 
left.  The 5-cm plaque, occurring 1 h after a patch test with 10% 
potassium selenite, showed a greater than average contact 
sensitivity. 

    Another case was described (Halter, 1938) involving a glass 
worker whose job was to add a mixture of red selenium and sodium 
selenite to the glass.  This man was in daily contact with selenite 
powder for 36 years.  He complained of an oedematous erythema of 
the face and neck, and several hard infiltrated raised plaques on 
the dorsi of the hand and fingers.  On examination, his nasal and 
laryngeal mucosae were found to be reddened, and there was a very 
slight conjunctivitis.  There were no changes in the skin of areas 
protected by clothing.  His only other complaint was of headache.  
There were no symptoms or signs referrable to the nervous or 
gastrointestinal systems.  Selenium was detected in the urine (no 
actual values were given).  His liver was found to be enlarged and 
there was an increase of porphyrins in the urine. 

    Pringle (1942) has described several cases of acute dermatitis 
resulting from contact with dry selenium dioxide or selenium 
dioxide dissolved in water, and 2 cases of acutely painful 
paronychia after accidental contact with dry selenium dioxide.  In 
addition, several cases of mild rash on the anterior surface of 
both forearms, but principally affecting the bend of the elbows, 
were seen among employees working with heated selenium dioxide in 
the fume cupboards.  Only their fingers, protected at that time 
with gloves, entered the fume cupboard, which apparently was 
adequately protected.  The dermatitis resembled a seborrhoeic 
condition and there was frequently a thin watery discharge.  In the 
course of a year, 2 cases developed a high degree of sensitivity to 
selenium dioxide, so that working in the same department, though 
not actually on selenium, caused repeated recurrences and they had 
to be removed permanently to another part of the factory. 

    (c)   Studies on the health effects of long-term exposure

    Filatova (1948) reported that workers exposed over a long 
period of time to selenium aerosols containing elemental selenium 
at levels of 0.35 - 24.8 mg/m3 and selenium dioxide at levels of 
0.11 - 0.78 mg/m3 developed rhinitis, nasal bleeding, headaches, 
loss of weight, irritability, and pain in the extremities 
(Izraelson et al., 1973). 

    Conditions of exposure and the related health effects in a 
rectifier factory were investigated by Kinnigkeit (1962).  Air-
selenium levels were determined in various workplaces and blood-
selenium levels were measured in 62 workers exposed to selenium.  
Urinary-selenium levels were also determined in 22 workers.  The 
reported air-selenium levels did not exceed 0.05 mg/m3 and were 
less than the threshold limit value.  However, as discussed in 
section 5.2.1 there was a clearcut discrepancy between the air 
values and the selenium levels observed in blood and urine, 
indicating that the actual workers' exposure must have been 
considerably higher.  Of 62 workers, over half (35) complained of 
irritability, sleeplessness, loss of appetite, and nausea.  Twenty 
six had headaches and 3 had cramplike pains in their limbs.  
Clinical examination revealed irritation of the mucosa in 9 
workers, with conjunctivitis and slight tracheal bronchitis.  Of 
the 2 workers that had unavoidable skin contact with selenium, one 
had excematous lesions of the forearms and the other had bluish-red 
urticarial exanthema. 

    The Takata reaction and the thymol test were performed on 61 of 
these workers, and the results were within the normal range in all 
employees, with the remarkable exception of workers engaged in the 
electrical testing of the rectifier plates.  In this group of 13 
people, abnormal results suggesting impaired liver function, were 
obtained in 8 workers, the only employees from the plant showing 
this pathological reaction.  As underlined by Kinnigkeit, workers 
carrying out this process handled the plates by hand and were 
frequently directly exposed to fumes containing selenium dioxide 
arising from the burning out of plates during electrical testing.  
As discussed previously, this group was characterized by a very 
high mean blood-selenium level (geometrical mean  SE: 15.8  11.8 
mg/litre).  A great interindividual variability in selenium-blood 
levels existed with this and other groups, but no attempt was made 
to relate these individual values to the results of liver function 
tests.  Another group of workers had blood-selenium levels that 
were almost as high (Table 13) (section 6.2.3), but no evidence of 
liver dysfunction was observed in this group.  However, it cannot 
be assumed that the form and pathway of the exposure to selenium 
was the same in both groups. 

    Monaenkova & Glotova (1963) summed up results of clinical 
observations on 12 people, aged 30 - 50 years, who had been 
occupationally exposed to selenium for 3 - 16 years and who 
manifested the symptoms of chronic selenium and selenium dioxide 
poisoning.  Ten of the 12 persons had been previously engaged in 
enterprises producing selenium rectifiers and were exposed to both 
elementary selenium and selenium dioxide.  The patients complained 

of pain in the right hypochondrium, dyspeptic phenomena, undue 
fatigability, dyspnoea, weakness, and sleeplessness.  Several 
patients complained of cough and, in 3 of them, chronic bronchitis 
or moderate emphysaema were established.  One patient had asthmatic 
bronchitis.  Almost all patients had various impairments of the 
liver and gastrointestinal tract (toxic hepatitis in 6 patients, 
dyskinesis of gallbladder in 4 patients, cholecystis in 4 patients, 
and spastic colitis in 4 patients).  The patients showed an 
astheno-vegetative syndrome, pigmentation of exposed areas of the 
skin, and, in 8 persons signs of a hyperfunction of the thyroid 
gland (radioiodine uptake measurements) were found.  Elevation of 
the basal metabolic rate or hyperfunction of the thyroid gland were 
mentioned also briefly in a previous case report (Halter, 1938) and 
in a review (Holstein, 1951), respectively. 

    A group of selenium workers in a rectifier factory was followed 
by Glover (1967, 1970) in 1953 - 56.  Every 3 months, urinary-
selenium levels were determined, and the workers were asked about 
their health and examined for the presence of garlicky-smelling 
breath and skin rashes.  Other routine medical checks were not 
performed.  Workers complained of indigestion and epigastric pain; 
severe haematemesis (with hospitalization) occurred in one case.  
Several men noticed symptoms of lassitude and irritability, when on 
selenium work, which cleared whenever they were taken away from 
selenium.  A strong odour of garlic on the breath was detected in 
most workers with selenium-urinary levels of 0.5 - 1.0 mg litre, 
but not below these levels.  The breath odour disappeared in 7 - 10 
days following the removal of workers from contact with selenium.  
Glover (1967, 1970) was able to trace 17 deaths, occurring within 
10 years, among selenium-exposed workers in the same factory (Table 
52).  The author recognized that the list of deaths was not 
complete and that the group was too small to permit far-reaching 
conclusions.  The length of exposure to selenium in individual 
cases was not given.  Carcinomas arose in various organs:  2 
bronchus, 1 stomach, 1 colon, 1 ovary, and 1 testis. 

Table 52.  Comparison of the certified causes of death of 
seventeen selenium workers with the expected distribution 
by cause based on the experience throughout England and 
Wales
----------------------------------------------------------
International  Cause of death         Observed  Expectedb
list number
----------------------------------------------------------
001 - 019      tuberculosis           0         0.4

140 - 205      malignant neoplasms    6         5.1

330 - 334      vascular lesions       0         1.4

410 - 416      chronic rheumatic      2         0.6
               heart disease

420 - 422      arteriosclerotic       3         3.8
               heart disease
----------------------------------------------------------

Table 52.  (contd.)
----------------------------------------------------------
International  Cause of death         Observed  Expectedb
list number
----------------------------------------------------------
430 - 434      "other" heart disease  0         0.2

440 - 443      hypertensive heart     0         0.2
               disease

444 - 447      "other" hypertensive   1         0.2
               disease

450 - 456      disease of arteries    0         0.2

480 - 483      influenza              0         0.1

490 - 493      pneumonia              0         0.5

500 - 502      bronchitis             2         0.9

-              all other causes       3         3.5

-              all causes             17        17.1
----------------------------------------------------------
a From:  Glover (1967).
b Taking into consideration the age and sex of those who 
  died, and the year of death.  The Table shows no 
  evidence of excess mortality in the selenium workers 
  from any of these main groups of causes.

8.1.2.1.2.  Hydrogen selenide

    (a)   Short-term exposure

    There are few cases of occupational poisoning described in 
which hydrogen selenide was identified as the sole causative agent.  
Reported cases of occupational intoxication by hydrogen selenide 
resulted usually from short-term accidental exposures in the 
chemical laboratory or industry.  Apparently, the first account of 
an individual requiring hospital treatment after sudden exposure 
to this gas was by Senf (1941), describing the effects of the 
accidental laboratory exposure of a chemist to hydrogen selenide.  
The patient noticed the characteristic smell and the gas caused her 
eyes to weep and her nose to run.  Within a few hours, her voice 
became hoarse and increasing dyspnoea caused her admission to 
hospital.  On examination she was found to have a bluish-red 
erythema of the skin, conjunctivitis, and injection of the nasal 
mucous membrane.  The lung oedema, ECG myocardial changes, the dark 
red erythema, and porphyrinuria disappeared within 10 days.  In 
1941, Painter described a case of a single inhalation of hydrogen 
selenide.  After a brief "metallic" sensation, no ill effects were 
felt for about 4 h.  Then a copious discharge from the nasal 
passages began.  This persisted with violent sneezing for 3 or 4 
days.  No ill effects were noted later. 

    A case of pure hydrogen selenide poisoning in a works chemist, 
producing hydrogen selenide in order to form selenides, was 
described by Symanski (1950).  Apparently only one inhalation of 
the gas was followed by a sudden feeling of constriction in the 
chest with coughing, tears, and burning of the nose, all of which 
disappeared in a few moments.  The patient thought that he had lost 
his sense of smell.  Four or 5 h later, a severe cough and dyspnoea 
developed.  At medical examination (8 h after the accident) he was 
dyspnoeic and febrile.  He continued to cough up blood-stained 
frothy sputum all night, and by morning the acute symptoms had 
disappeared leaving him apparently with bronchitis and an 
irritating cough.  A week later he had a recurrence of the fever 
with chest pain and the signs of bronchopneumonia.  After 4 more 
days, the fever disappeared and 9 weeks later he was fit and well 
again.  A man, 5 h after cleaning out apparatus used for making 
hydrogen selenide, developed severe dyspnoea, difficulty in 
expiration, painful cough, and yellowish sputum (Bonard & Koralink, 
1958).  His condition became worse and the next day he was admitted 
to the hospital.  He was cyanosed, had severe expiratory dyspnoea, 
discrete rhinitis and conjunctivitis, and was in considerable 
distress.  He had no headache or visual troubles.  His pharynx was 
hyperaemic, his buccal mucosa was dry, and he had a furred tongue.  
Four days later, the chest roentgenogram was normal, but lung 
function tests were depressed.  Rohmer et al. (1950) reported the 
case of a chemist exposed to a high level of hydrogen selenide, 
calling attention to the development of severe hyperglycaemia that 
could only be controlled by increasingly large doses of insulin.  A 
24-year-old white man accidentally inhaled hydrogen selenide while 
transferring the gas from one cylinder to another (Schecter et al., 
1980).  He immediately experienced burning in his eyes and throat 
followed by coughing and wheezing.  He was given oxygen and 
improved over a period of 2 h.  However, 18 h later, because of 
recurrent cough and progressive dyspnoea, he was hospitalized.  
Pneumomediastinum developed in this patient and pulmonary function 
tests revealed restrictive and obstructive airways disease, which 
slowly improved. 

    Glover (1970), who reviewed 8 cases of acute hydrogen selenide 
poisoning (5 laboratory workers and 3 from industrial accidents; 
some of them probably identical with those mentioned above), and 
summarized the following sequence of events.  The first effects 
observed after exposure are signs of irritation of the mucous 
membranes, i.e., running nose, running eyes, cough, sneeze, 
followed by a slight tightness of the chest.  This clears, and 
there may be a latent period of 6 - 8 h.  The patient, who has 
often returned home by this time, usually wakes up in bed 
breathless with signs and symptoms of pulmonary oedema.  Glover, at 
the same time, underlined the importance of oxygen therapy in these 
intoxications, particularly with regard to the prevention of the 
development of pulmonary oedema. 

    Lazarev & Gadaskina (1977) referred to 5 cases of hydrogen 
selenide intoxication at an exposure level of approximately 
7 mg/m3.  These cases manifested nausea, vomiting, vertigo, and 
extreme tiredness, in addition to effects on the respiratory tract 

and conjunctiva.  The same author mentioned one case of laboratory 
exposure to hydrogen selenide in which a chemist developed lung 
oedema and long-lasting cyanosis with respiratory difficulties.  On 
the 22nd day, thrombophlebitis was observed and within 52 days 
signs of myocardial damage were noted. 

    (b)   Prolonged and/or repeated exposure

    An important point when considering prolonged low-level 
exposure to hydrogen selenide was recognized by Dudley & Miller 
(1941).  In their experience, acute exposure levels of 5 g/litre 
resulted in such eye and nose irritation in workers that the men 
could not continue their duties without the protection of a gas 
mask.  At 1 g/litre, this irritation did not occur for several 
minutes, though the presence of the gas was detected by its odour.  
However, continued exposure at these levels results in olfactory 
fatigue so that workers lose their ability to smell the gas and are 
thus disarmed against subsequent increases in levels of the gas in 
the work-place. 

    The effects of prolonged exposure to hydrogen selenide were 
described by Buchan (1947) in workers who were engaged in a process 
involving the etching of a pattern on steel stripping.  In this 
operation, steel stripping is passed between rubber imprinting 
wheels with a raised pattern on the periphery.  The pattern is in 
constant contact with a wick immersed in the etching ink.  After 
imprinting, the steel stripping passes between felt wipers and dips 
into a rust-preventive oil bath passing then to a reel.  The odour 
of hydrogen selenide was detectable at the etching machine and was 
particularly offensive in the sludge of the oil bath.  Selenium was 
identified, qualitatively, in the sludge.  Apparently, the hydrogen 
selenide was generated as a result of the reaction of the excess 
selenium deposited on the steel stripping in an acid medium, i.e., 
the oil bath, which was further acidified by contamination with the 
etching ink carried by the steel stripping.  Five out of 25 workers 
complained of nausea, vomiting, metallic taste in the mouth, 
dizziness, extreme lassitude, and fatigability.  The symptoms 
lasted 2 weeks and were said to be increasing in severity.  Until 
one month before the onset of symptoms, an etching ink containing 
nitric acid and silver was used, but then a new ink containing 
selenious acid at 52 mg selenium/litre was substituted. 

    Air samples were taken at 6 representative sampling points. 
During the analysis, qualitative detection of selenium was made, 
but, because of the lack of sensitivity of the titrimetric method 
used, it was not possible to measure the selenium quantitatively, 
and the results were recorded as less than 0.2 parts per million.  
Spot and 24-h specimens of workers' urine contained 0 - 131 g 
selenium/litre or an average of 61.6 g/litre.  So-called control 
specimens contained similar amounts, but the controls were the 
professional staff collecting the air samples and they had been 
exposed to the same environment as the workers for almost 5 h.  
Also, it should be realized that hydrogen selenide produces 
symptoms at exposures too low to increase the urinary excretion 

above normal values.  When the selenium ink was replaced by silver 
ink, there was a gradual regression of symptoms and, within 6 
months, all complaints had ceased and there was no recurrence. 

    The Task Group was not aware of any other reports dealing with 
the prolonged exposure of human beings to hydrogen selenide. 

8.1.2.1.3.  Selenium oxychloride

    Less than 5 g of pure selenium oxychloride on the skin of the 
hand resulted in a painful reaction within a few minutes, exythema 
surrounding the central necrotic area (Dudley, 1938).  Within 1 
month, the skin defect healed with a scar. 

8.2.  Low Selenium Intake

8.2.1.  Evidence supporting the possible essentiality of selenium in 
man

    Beneficial nutritional effects of selenium have been observed 
in several different species (Schwarz, 1976), and specific signs of 
selenium deficiency in the presence of adequate intake of vitamin E 
have been demonstrated in rats and chicks (section 7.2.1).  Thus, 
the question of whether selenium is essential for man arises.  The 
identification of any human disease due to low selenium intake is 
difficult, because selenium deficiency in animals is characterized 
by a wide variety of signs involving several different organ 
systems. 

    Although a clear-cut pathological condition attributable to 
selenium deficiency alone has not yet been demonstrated in human 
beings, certain evidence suggests that selenium may be essential 
for man. 

    For example, purified glutathione peroxidase, from human red 
blood cells, contains quantities of selenium similar to those found 
in the enzyme isolated from animals (Awasthi et al., 1975).  
Moreover, selenium is necessary for the optimal growth of human 
fibroblasts in purified cell culture media (McKeehan et al., 1976).  
Blood-selenium levels are depressed in children suffering from 
kwashiorkor (Burk et al., 1967; Levine & Olson, 1970) and Hopkins & 
Majaj (1967) obtained a reticulocyte response in malnourished 
infants treated with a physiological dose of selenium (25 g 
selenium, as sodium selenite).  Finally, on the basis of the 
distribution of selenium in various human tissues, Liebscher & 
Smith (1968) concluded that selenium must be an essential element 
for man. 


8.2.2.  Signs and symptoms of low intake

    The greatest possibility of a hazard due to inadequate selenium 
intake would be expected in low-selenium areas.  Nutritionists and 
public health officials in several countries are aware of the low-
selenium status of their populations and are attempting to identify 

any human health problems associated with it.  For instance, in 
the south island of New Zealand, one of the first regions where a 
low selenium status in animals was recognized, some farmers, noting 
supposed similarities between their own symptoms and those of the 
white muscle disease affecting their livestock, claimed improvement 
in their muscular complaints after self-medication with selenium 
(Hickey, 1968).  However, such anecdotal reports are not supported 
by the results of 3 separate trials involving a total of 120 
patients suffering from "muscular complaints", carried out in 
several low-selenium areas of the south island of New Zealand 
(Robinson et al., 198l).  In these studies, the patients were given 
either sodium selenite or selenomethionine at a number of dose 
levels and schedules for various periods of time.  Some subjects 
also received vitamin E with the selenium supplement.  In all 
subjects who received selenium, blood-selenium levels and 
glutathione peroxidase activity increased, whereas little change 
was seen in the control group.  Clinical assessment of muscular 
symptoms showed that approximately equal numbers of patients in the 
test and control groups exhibited an improvement in their muscular 
condition.  On the basis of these results, the authors concluded 
that there was no evidence of any response, under the conditions of 
the trials, to selenium supplements for the relief of muscular 
complaints. 

    Total parenteral nutrition (TPN) fluids for intravenous feeding 
contain very low levels of selenium (section 4.1.1.1), and patients 
sustained by such techniques would seem to be at risk of developing 
selenium deficiency.  One such patient on TPN in New Zealand 
developed muscular discomfort that disappeared after selenium 
supplementation (van Rij et al., 1979).  This patient was a 37-
year-old female who lived in a rural area of the south island of 
New Zealand where the soils were low in selenium and there was a 
history of endemic white muscle disease in sheep.  She presented 
with a perforated small intestine with peritonitis, after 
radiotherapy 2 years previously for carcinoma of the cervix.  Five 
days after abdominal exploration and the start of intensive 
antibiotic therapy she developed enterocutaneous and vaginal 
fistulae.  Gastric stress ulcer followed and necessitated a 1.5-
litre blood transfusion.  Elevated temperatures persisted with 
intraabdominal sepsis.  Ten days after admission to hospital, TPN 
was begun and resulted in a general improvement and a 6 kg weight 
gain over the next 20 days.  Regular plasma and albumin infusions 
treated hypoproteinemia.  After 20 days of TPN, early clinical 
signs of fatty acid deficiency (dry flaky skin on hands and feet) 
were noted, which responded rapidly to intralipid infusion.  After 
30 days of TPN, the patient complained of increasing bilateral 
muscular discomfort in her quadriceps and hamstring muscles.  
Muscle pain was present at rest as a persistent ache and with 
tenderness on palpation.  The muscle pain was aggravated by walking 
until she found it distressing, even to move beyond her room.  On 
examination, there was tenderness of the quadriceps, hamstrings, 
and less markedly of the calf muscles of both legs.  Both active 
and passive movements of these muscle groups were painful, 
particularly of the hamstrings.  The upper limb girdle was 
unaffected.  A generalized muscle wasting of all the limbs was 
observed after the prolonged catabolic stress, despite TPN.  No 
muscle fasciculation or neurological deficits were observed. 

    Supplementation with selenium was begun with no other 
modification to the patient's management.  Each day 100 g of 
selenium, as selenomethionine, was infused intravenously with the 
TPN solution.  During the next week, muscle pain at rest, 
tenderness to palpation, and pain on active and passive movement 
disappeared.  A return to full mobility followed.  This symptomatic 
response associated with selenium supplementation plus the 
extremely low blood-selenium levels initially observed in this 
patient (discussed further in section 8.2.4) led the authors to 
conclude that this case could be the first clinical report 
supporting the essential role of selenium in human nutrition. 

    Because of their increased metabolic requirements and faster 
growth rates, infants and children might be particularly vulnerable 
to selenium deficiency.  McKenzie et al. (1978) analysed blood from 
230 healthy adults and 83 healthy children from various areas of 
New Zealand and found that children in Auckland and Tapanui had 
lower blood-selenium concentrations (0.064 and 0.048 mg/litre) than 
adults from the same areas (0.083 and 0.060 mg/litre).  Red-blood-
cell glutathione peroxidase activity was also lower in Auckland 
children than in adults (10.6 versus 12.9 units/g haemoglobin).  A 
specific population of infants and children that might be 
especially at risk regarding low selenium intake includes those who 
suffer from phenylketonuria (PKU) and maple syrup urine disease 
(MSUD) and consume only special synthetic diets that are very low 
in selenium (section 4).  McKenzie et al. (1978) reported that the 
mean blood-selenium level in 12 such children was 0.038  0.013 
mg/litre.  One 13-year-old patient had 0.016 mg selenium/litre 
whole blood and 0.009 mg selenium/litre plasma, but clinical 
examination indicated that he was in good health.  Lombeck et al. 
(1978) found that the serum-selenium content in 36 children 
receiving diet therapy for PKU and MSUD in the Federal Republic of 
Germany ranged from 0.007 - 0.028 mg/litre.  The selenium content 
of the hair was lower in the patients (0.062 mg/kg) than in healthy 
children (0.429 mg/kg) and the erythrocyte glutathione peroxidase 
activity was reduced in comparison with normal values (4.6 versus 
8.8 units/g haemoglobin).  And yet all the patients thrived during 
the time of observation and did not exhibit any increased rate of 
haemolysis or oxidation of haemoglobin to methaemoglobin after 
incubation of their erythrocytes with sodium azide. 

    Gross (1976) studied 4 groups of premature infants who were fed 
4 different formulae based on cow's milk containing a high 
concentration of polyunsaturated fatty acid (PUFA), with and 
without iron, or a low PUFA concentration, with and without iron.  
The tocopherol content was the same in all 4 formulae and was 
judged adequate in terms of maintaining serum-vitamin E levels.  
Both glutathione peroxidase activity and plasma-selenium levels 
were similar in all 4 groups.  The former declined from 4.2 units/g 
haemoglobin at one week of age to 2.7 units/g haemoglobin at 7 
weeks of age, whereas the latter declined from 0.08 to 0.035 
mg/litre.  Although all infants exhibited the anaemia typical of 
the prematurely newborn, the decreases in haemoglobin and increases 
in reticulocyte levels were greatest in the group of infants given 
the formula high in PUFA and iron.  These haemolytic events in 

vitamin E-sufficient premature infants fed a diet rich in PUFA and 
iron were thought to be due to the oxidative stress of the formula 
coupled with the poor nutritional status of the infants with regard 
to selenium (Gross, 1976). 

8.2.3.  Dietary levels consistent with good nutrition

8.2.3.1.  Quantitative estimates

    Since no clear-cut pathological condition attributable to 
selenium deficiency alone has yet been observed in man, it is not 
possible to define a precise dietary requirement level for human 
beings.  However, 0.1 - 0.2 mg selenium/kg diet is a nutritionally 
generous level for most species of animals (US NAS/NRC, 1971).  If 
these animal data are extrapolated, a 70-kg man consuming 500 g of 
diet per day (dry basis), would need a daily intake of 50 - 100 g.  
The US National Research Council has estimated that the safe and 
adequate range of the daily intake of selenium for adults is 50 - 
200 g, with correspondingly lower intakes for infants and children 
(Table 53).  On this basis, the recommended intake for a 70-kg man 
would be equivalent to 0.7 - 2.8 g/kg body weight per day.  Any 
daily intake within the recommended range is considered adequate 
and safe, but the recommendations do not imply that intakes at the 
upper limit of the range are more desirable or beneficial than 
those at the lower limit.  The lower recommended intake for infants 
and children is consistent with the observation that 
supplementation of malnourished children with sodium selenite at 
30 g selenium daily, produced weight gain and reticulocyte 
responses without any untoward signs (Hopkins & Majaj, 1967). 

Table 53.  Estimated safe and 
adequate range of selenium intakea
-----------------------------------
Group     Age       Daily selenium 
          (years)   intake (g)
-----------------------------------
Infants   0 - 0.5   10 - 40
          0.5 - 1   20 - 60

Children  1 - 3     20 - 80
          4 - 6     30 - 120
          7+        50 - 200

Adults              50 - 200
-----------------------------------
a Adapted from:  US NAS/NRC (1980).

    Three approaches have now been used to estimate human 
nutritional requirements for selenium.  Nutritionists have long 
used metabolic balance studies to determine the human requirements 
for a variety of minerals.  In the case of selenium, healthy North 
American men needed about 80 g dietary selenium/day to maintain 
balance, but women needed only 57 g/day (Levander & Morris, 1984).  
The difference between men and women in the selenium intake needed 
to achieve balance was considered to be due to differences in body 

weight.  Expressing the balance data on a body weight basis 
revealed that both men and women needed about 1 g selenium per kg 
body weight per day to stay in balance.  However, other research 
groups showed that selenium balance in New Zealand women or Chinese 
men could be reached on intakes as low as 27 and 9 g/day, 
respectively (Stewart et al., 1978; Luo et al., 1985).  This 
demonstrates the great effect of prior dietary-selenium intake on 
the amount of selenium needed to achieve balance in people and 
shows that balance studies may not be valid techniques for 
estimating human selenium requirements. 

    Yang et al. (1985) estimated human selenium requirements on the 
basis of a comparison of dietary intakes in areas with and without 
Keshan disease.  Dietary-selenium intakes of 7.7 and 6.6 g/day in 
endemic and 19.1 and 13.3 g/day in non-endemic Keshan disease 
areas were reported for adult men and women, respectively.  These 
estimates should be considered minimum daily adult requirements for 
selenium. 

    The depletion/repletion study is another approach used by 
nutritionists to estimate human selenium requirements.  The 
relatively large body pool of selenium in North Americans prevented 
their plasma-selenium levels from dropping to values commonly found 
in persons from low-selenium areas (Finland, New Zealand), even 
when depleted for almost 7 weeks (Levander et al., 1981a,b).  
Chinese men of naturally-low-selenium status (dietary intake about 
10 g/day) were given graded supplements of selenomethionine and 
their plasma-glutathione peroxidase activity was followed (Yang et 
al., 1985).  The activity of the enzyme plateaued at the same level 
in all men receiving 30 g or more of supplementary selenium daily.  
From this study, a physiological selenium requirement of about 40 
g/day (diet plus supplement) was suggested for Chinese adult 
males, which may require adjustment to account for body weight 
differences in other populations including women. 

8.2.3.2.  Nutritional bioavailability

    None of the studies discussed in section 8.2.3.1 have 
specifically addressed the question concerning the nutritional 
bioavailability of the selenium in foods for human beings.  Using 
an animal model, Douglass et al. (1981) found that the selenium in 
freeze-dried, water-packed canned tuna for human consumption was 
only 57% as effective as selenite in restoring liver glutathione 
peroxidase activity in rats previously deficient in selenium, 
whereas selenium as cooked freeze-dried beef kidney or seleniferous 
wheat had 97 and 83% of the activity of selenite, respectively.  
The selenium in the tuna was also less effective than selenite in 
raising hepatic-selenium levels in the deficient rats.  Similar 
results concerning the relative bioavailability of the selenium in 
tuna compared with wheat were obtained by Alexander et al. (1983) 
in rats, using the slope-ratio technique.  On the other hand, 
Chansler et al. (1983) found that the selenium in mushrooms was 
only about 4% as available as that in selenite for restoring 
hepatic glutathione peroxidase activity in selenium-depleted rats.  
It has been pointed out that, in addition to absorption and 

retention, factors such as utilizability within the body are 
apparently important in determining selenium bioavailability 
(Levander, 1983). 

    Although data are accumulating on the absorption by human 
beings of the selenium in various compounds or in foods (section 
6.1.1.2), there have been few studies examining the bioavailability 
(i.e., utilization, consisting of transport, conversion to a 
metabolically-active form, retention, etc., in addition to 
absorption) of the selenium in foods for human beings.  One such 
study was carried out in a low-selenium area of central Finland 
(Levander et al., 1983).  Three groups of 10 men of low-selenium 
status (mean plasma-selenium level of 70 g/litre) were 
supplemented with 200 g of selenium, daily, as selenium-rich 
wheat, selenium-rich yeast, or sodium selenate, for 11 weeks.  
Twenty unsupplemented subjects served as controls.  Plasma-selenium 
levels increased steadily in the wheat and yeast groups for 11 
weeks to around 160 g/litre with no sign of plateauing, whereas, 
in the selenate group, plasma-selenium plateaued at about 110 
g/litre, after 4 weeks.  Red blood cell-selenium levels also 
increased steadily in the wheat and yeast groups for 11 weeks from 
90 to 190 g/litre, again with no sign of plateauing.  Red blood 
cell-selenium levels were unaffected in the selenate group. 
Platelet glutathione peroxidase activity (glutathione peroxidase is 
an index of selenium status) (section 7.2.4.4) roughly doubled 
after 4 weeks of supplementation with wheat or selenate and then 
plateaued.  Platelet glutathione peroxidase increased more slowly 
in the yeast group.  Plasma-glutathione peroxidase activity did not 
respond to selenium supplementation.  Ten weeks after the 
supplements were stopped, platelet glutathione peroxidase remained 
higher in the wheat and yeast groups than in the selenate group.  
This suggested that the selenium in yeast or wheat was, to some 
extent, deposited in the tissues in a form that could be used later 
for glutathione peroxidase biosynthesis, once the dietary 
supplement was discontinued.  The results of this bioavailability 
trial indicated that there are several different aspects to the 
nutritional availability of selenium.  Complete assessment may 
require several measurements including:  short-term platelet 
glutathione peroxidase activity, to estimate immediate 
availability; medium-term plasma-selenium levels, to determine 
retention; and long-term platelet glutathione peroxidase activity, 
after discontinuation of supplements, to estimate the 
convertibility of tissue-selenium stores to metabolically active 
selenium. 

    Griffiths & Thomson (1974) also noted that the blood-selenium 
levels of adults from the USA declined rapidly on arrival in New 
Zealand, but, after a year, their levels were still higher than the 
mean value for permanent New Zealand residents (Fig. 11).  When 
selenium levels were measured in the whole blood, erythrocytes, and 
plasma of postoperative surgical patients receiving TPN in New 
Zealand, selenium concentrations decreased as TPN was continued 
(Table 54) (van Rij et al., 1979).  The plasma-selenium 
concentration of the New Zealand TPN patient, discussed in section 
8.2.2, was 0.025 mg/litre and fell to 0.009 mg/litre just before 

selenium supplementation was begun.  The lowest value for blood-
selenium concentration in areas of China not affected by Keshan 
disease was around 0.040 mg/litre, while, in affected areas, the 
blood-selenium concentration often dropped below 0.010 mg/litre 
(Keshan Disease Research Group, 1979b). 

FIGURE 11

Table 54.  Effects of total parenteral nutrition on 
the concentration of selenium in whole blood, 
erythrocytes, and plasma of postoperative surgical 
patients in New Zealanda
------------------------------------------------------
Duration          Selenium concentration             
of TPN    Whole blood    Erythrocyte    Plasma
(days)    (mg/litre)     (mg/litre)     (mg/litre)
------------------------------------------------------
0         0.050  0.006  0.077  0.008  0.031  0.004

10-20     0.040  0.003  0.060  0.004  0.022  0.002

> 20     0.025  0.003  0.043  0.003  0.015  0.004
------------------------------------------------------
a Adapted from:  van Rij et al. (1979).

    The urinary excretion of selenium by New Zealand residents is 
quite low, reflects their low intake, and is related to whole 
blood-selenium levels (Fig. 11).  Similar relationships between 

24-h urinary-selenium excretion and plasma-selenium concentrations 
have been observed in New Zealand residents, New Zealand patients 
with TPN, and Swedish patients with TPN (van Rij et al., 1979). 

8.2.4.  Blood and urine levels typical of low intake

    In separate but simultaneous publications, Griffiths & Thomson 
(1974) and Watkinson (1974) reported that the mean selenium content 
of whole blood from New Zealand subjects was 0.068 and 0.069 
mg/litre, respectively.  However, even in New Zealand, where the 
residents generally have a low selenium status, it is apparently 
possible to observe regional differences in blood-selenium levels 
(Table 55). 

Table 55.  Selenium 
concentration in whole blood 
of human beings residing in 
different areas of New Zealanda
-------------------------------
Area of       Blood-selenium
New Zealand   concentration
              (mg/litre)
-------------------------------
Heriot        0.057  0.012

Dunedin       0.062  0.013

Kurow         0.070  0.009

Oamaru        0.074  0.012
-------------------------------
a Adapted from:  Griffiths & 
  Thomson (1974).

8.2.5.  Relationship between blood-selenium levels and erythrocyte-
glutathione peroxidase activity

    There is an excellent correlation between human whole blood-
selenium concentrations and glutathione peroxidase activity, at 
concentrations below about 0.10 mg/litre (Thomson et al., 1977b).  
However, above this concentration, activity of the enzyme is not 
noticeably increased (Fig. 12), which suggests either that this 
concentration of selenium is optimal and that an intake that 
maintains this concentration is adequate for function as measured 
by glutathione peroxidase activity, or, that above this 
concentration, other factors might play a greater role in 
influencing glutathione peroxidase activity.  Rea et al. (1979) 
showed that there was also an excellent correlation between human 
erythrocyte-selenium concentrations and whole blood-glutathione 
peroxidase activity, as long as the former was less than 0.14 
mg/litre (Fig. 13).  Schrauzer & White (1978) did not observe any 
correlation between glutathione peroxidase activity and selenium 
concentrations in the blood of subjects whose blood-selenium levels 
were all over 0.10 mg/litre.  Moreover, the activity of the enzyme 
did not increase after these subjects were supplemented with a 
selenized yeast preparation, even though blood-selenium levels 

responded to such treatment.  Only about 10% of the total selenium 
in human red cells is associated with glutathione peroxidase 
(Behne & Wolters, 1979) whereas, in sheep red cells, most of the 
selenium appears to be associated with the enzyme (Oh et al., 
1976b).  Thus, the role of selenium in glutathione peroxidase may 
not be the only function of the element.  Whether the non-
glutathione peroxidase selenium in human red blood cells truly 
represents other functional forms of the element or is merely non-
functional selenium non-specifically incorporated into tissue 
proteins cannot be answered at this time.  But the usefulness of 
the glutathione peroxidase assay as a means of assessing selenium 
intake in human beings whose whole blood-selenium concentration 
exceeds 0.10 mg/litre currently appears to be an open question. 

FIGURE 12
                  
FIGURE 13

8.2.6.  Attempts to associate low selenium intake with human diseases

8.2.6.1.  Keshan Disease

    Results of research in China have suggested a relationship 
between low selenium status and the prevalence of Keshan disease, 
an endemic cardiomyopathy that primarily affects children (Keshan 
Disease Research Group, 1979a,b).  Cases of Keshan disease were 
recorded as early as 1907 in Heilongjiang Province of northeastern 
China (Gu, 1983).  Since the etiology of the disease was not known, 
it was named after the locality in which it was originally 
observed, Keshan County. 

    Epidemiologically, the disease exhibits a regional distribution 
and occurs in a belt-like zone reaching from northeastern China to 
the southwestern part of the country.  There is a marked seasonal 
fluctuation in the disease with more cases appearing during winter 
in the north and during summer in the south.  There is also a great 
annual variation in the incidence of Keshan disease.  Recently, the 
incidence has decreased sharply such that from 1978 to 1980 less 
than one death was reported per 100 000 members of the population 
(Gu, 1983).  The overall recent decline in the incidence of Keshan 
disease has been attributed, at least in part, to the general 
increase in the living standards of the people, such as better 
sanitation, more medical attention, and improved quality of the 
diet (He, 1979).  There is also a shifting of epidemic foci from 
year to year.  Rural peasants constitute the population at risk 
with children below 10 years of age and women of child-bearing age 
most susceptible.  According to Gu (1983), migrants from non-
affected areas will not contract the disease unless they have lived 
in the endemic area for at least 3 months. 

    The criteria for diagnosing Keshan disease include acute or 
chronic cardiac insufficiency, heart enlargement, gallop rhythm, 
arrhythmia, and ECG changes (Chen et al., 1980).  The disease is 
classified into four types:  acute (cardiogenic shock), subacute, 
chronic (low output pump failure), and latent (normal heart 
function but mild enlargement).  There is no symptom or sign 
specific for identifying the disease (Gu, 1983).  
Histopathologically, Keshan disease is characterized by multifocal 
necrosis and fibrous replacement of the myocardium. 

    In the past, many different hypotheses were advanced in an 
attempt to explain the etiology of Keshan disease.  For example, 
there were theories of poisoning due to rhodamine, silica, 
digitalis, carbon monoxide, barium, nitrite, and Fusarium 
mycotoxins.  However, clear-cut proof of these toxicants as a cause 
of the disease has not been obtained despite much analytical effort 
(Yang et al., 1984).  Several nutritional problems have also been 
proposed to play a role in Keshan disease such as deficiency of 
protein, lipids, thiamin, magnesium, or molybdenum.  A hypothesis 
concerning Keshan disease etiology was proposed linking the disease 
to selenium deficiency, after it was noted that severely endemic 
areas coincided with areas where the incidence of enzootic selenium 
deficiency diseases in farm animals was also high (Zhu et al., 
1981).  On this basis, selenium supplements were used as a 
preventive measure for Keshan disease.  This hypothesis is very 
appealing since cardiomyopathy is a prime feature of selenium-
vitamin E deficiency in many species of animals, including cattle, 
sheep, and swine. 

    Since the initial proposal of the selenium-Keshan disease 
connection, much evidence has been gathered in support of this 
concept.  For example, the average blood-selenium content was 0.021 
 0.001 mg/litre for the affected areas and 0.095  0.088 mg/litre 
for non-affected areas (Yang et al., 1984).  The average hair-
selenium content was below 0.12 mg/kg in affected areas, whereas 
hair-selenium levels in neighbouring but unaffected areas ranged 
between 0.12 and 0.2 mg/kg.  Average hair-selenium contents in 
areas removed from the affected belt were between 0.25 and 0.6 
mg/kg.  The selenium level in several staple foods (rice, maize, 
wheat, soybeans, black beans, and sweet potatoes) was lower in 
areas affected with Keshan disease than in unaffected areas.  It 
was stated that an area could be considered to be unaffected 
wherever the selenium content of grains was 0.04 mg/kg or more.  
The Chinese workers stated that the amount of selenium needed to 
prevent the disease was about 20 g/day (Yang et al., 1984). 

    In some affected areas, there were highly localized pockets 
(so-called "safety islands") that were free from the disease.  
Apparently, these islands were protected because of the higher 
selenium content of their crops in the immediate vicinity.  For 
example, the average selenium contents of rice and soybeans in one 
such island were 0.020 and 0.025 mg/kg, respectively, whereas the 
values for the corresponding crops in a nearby affected area were 
0.0078 and 0.0057 mg/kg.  It was also noted that the children in 
the unaffected spot liked to catch shrimp from local streams and 
that the selenium content of these dried shrimp was as high as 1 
mg/kg (Keshan Disease Research Group, 1979b). 

    These relationships between selenium and Keshan disease led the 
Chinese workers to conduct a randomized intervention trial to test 
the possible prophylactic effect of selenium against this condition 
in the population at risk (i.e., children 1 - 9 years old).  In a 
trial in 1974, 4510 children took sodium selenite and 3985 children 
took the placebo (Table 56).  The treated children took 0.5 mg 
sodium selenite per week if 1 - 5 years old, or 1.0 mg per week if 
6 - 9 years old.  The morbidity rate due to Keshan disease was 
1.35% in the placebo group (54 cases out of 3985 children) but only 
0.22% in the treated group (10/4510).  Since a significant 
difference was also shown in the 1975 trial (0.95% morbidity rate 
in the placebo group compared with 0.1% in those treated) the 
placebo groups were abolished in 1976 and 1977.  As a result, the 
case rate dropped to 0.034% and 0% in these 2 years, respectively.  
However, in 1976, there was one case out of 212 children who failed 
to take the treatment. 

    No untoward side effects due to the sodium selenite were 
observed, except for some individual cases of nausea, which could 
be overcome by taking the medicine after meals.  Physical 
examinations and liver function tests indicated that the liver was 
undamaged after continuous ingestion of the selenium tablets for 
3 - 4 years. 

Table 56.  Effect of selenium on Keshan disease in childrena
-------------------------------------------------------------------
Treatment  Year  Number    Number   Outcome of alive cases    Death
                 of        of      Turned  Improved  Turned
                 subjects  cases   latent            chronic
-------------------------------------------------------------------
Placebo    1974  3985      54      16      9         2        27
           1975  5445      52      13      10        3        26

Sodium     1974  4510      10      9       0         1        0
selenite   1975  6767      7       6       0         0        1
-------------------------------------------------------------------
a Adapted from:  Keshan Disease Research Group (1979a).

    Since 1976, more extensive intervention trials with sodium 
selenite have been carried out in 5 counties in the same area of 
Sichuan Province (Yang et al., 1984).  All children, 1 to 12 years 
of age, in some of the most severely affected communes, were 
treated with selenium as described above, while untreated children 
in nearby communes served as controls.  The incidence rate of 
Keshan disease in the selenium-treated children was lower in each 
year of the five-year period than among the untreated children 
(Table 57). 

Table 57. Keshan disease incidence rates in selenium-treated and 
untreated children in five counties of Sichuan provincea
-------------------------------------------------------------------------
               Treated children                Untreated children        
Year   Number of  Number of  Incidence   Number of  Number of  Incidence
       subjects   cases      (per 1000)  subjects   cases      (per 1000)
-------------------------------------------------------------------------
1976   45 515     8          0.17        243 649    448        2.00

1977   67 754     15         0.22        222 944    350        1.57

1978   65 953     10         0.15        220 599    373        1.69

1979   69 910     33         0.47        223 280    300        1.34

1980   74 740     22         0.29        197 096    202        1.07

Total  323 872    88         0.27        1 107 568  1713       1.55
-------------------------------------------------------------------------
a Taken from:  Yang et al. (1984).

    Selenium intervention has proved to be very effective in the 
prophylaxis of Keshan disease and it is very likely that selenium 
insufficiency plays an important role in its etiology (Yang et al., 
1984).  Nevertheless, the Chinese workers recognized that there 
were certain epidemiological characteristics of the disease, which 
suggested that additional etiological factors were involved.  The 
selenium hypothesis, for example, does not adequately explain the 
seasonal variation in the disease, the occurrence of epidemic 
years, or the annual shifting of epidemic foci.  Such 
characteristics are more compatible with an infectious theory and, 
in fact, a hypothesis that the disease is a form of viral 
myocarditis has been put forward (He, 1979).  Perhaps the best way 
to account for all the characteristics of the disease is to assume 
that the disease has a multifactorial etiology and that a 
combination of several factors may be involved (Yang et al., 1984). 
There are some animal studies that favour such a possibility, since 
selenium-deficient mice were less resistant to the cardiotoxic 
effects of a Coxsackie B4 virus isolated from a patient with Keshan 
disease (Bai et al., 1980).  If selenium-deficient human beings are 
also less resistant to viral infection, this phenomenon could 
provide a reasonable explanation for many of the apparently 
conflicting features of Keshan disease.  In this view, selenium 
deficiency would be the fundamental underlying condition that would 
predispose persons to viral attack, possibly by impairing normal 
immune function (Yang et al., 1984). 

8.2.6.2.  Kashin-Beck disease

    Kashin-Beck disease is an endemic osteoarthropathy that occurs 
in eastern Siberia and in certain parts of China, which is 
characterized as a chronic, disabling, and degenerative 
osteoarthrosis that mainly involves children (Sokoloff, 1985). 

    Although the etiology of this disease has not been fully 
established, present works show that selenium deficiency might be 

one of the main causes.  This concept is based on the following 
evidence.  First, in China most of the endemic areas are located in 
the same low-selenium zone, from northeast to southwest, as the 
Keshan disease (section 8.2.6.1) (Tan et al., in press).  For the 
same reason, residents in these areas have low-selenium status 
characterized by low blood- and hair-selenium levels, low blood 
glutathione peroxidase activity, and low urinary-selenium 
excretion.  A survey carried out in Heilongjiang province of China 
(one of the most heavily affected province) showed that the average 
hair-selenium levels in 151 children in endemic areas (0.096  SD 
0.026 mg/kg) was significantly lower than that of the 235 children 
in the non-endemic areas (0.223  0.083 mg/kg) (Wang et al., 1985).  
The authors concluded that the low selenium status of children was 
due to the low selenium content of the locally produced staple 
food.  The average selenium content of corn, wheat, and millet in 
the endemic and non-endemic areas shown in the paper were:  0.0056 
 SD 0.0038 (n = 262) versus 0.015  0.015 (176), 0.0091  0.0096 
(225) versus 0.0235  0.022 (120), and 0.0064  0.0053 (14) versus 
0.0197  0.0144 (11) mg/kg, respectively.  Second, sodium selenite 
is reported to have both therapeutic and prophylactic effects on 
this disease.  Liang (1985) reported that 325 cases of Kashin-Beck 
disease in Shaanxi province of China were randomly divided into a 
treated and control group.  The treated group was given sodium 
selenite (1 mg/week for children 3 - 10 years of age and 2 mg/week 
for children of 11 - 13 years of age) and the control group was 
given a placebo.  After one year, X-ray examination of the 
metaphyseal changes of fingers showed that 81.9% of the cases in 
the treated group had improved, none of the cases were getting 
worse, and that 18.1% showed no change, while, in the control 
group, only 39.6% of the cases had improved, 30% were getting 
worse, and 41.5% showed no change.  Li et al. (in press) reported 
that children of 1 - 5 and 6 - 10 years of age in an endemic area 
of Gansu province in China were supplemented with 0.5 and 1.0 mg 
sodium selenite, respectively, per week over a period of 6 years.  
X-ray examination showed that the incidence of Kashin-Beck disease 
declined from 42% to 4% after the selenium intervention. 

    However, other information suggests that other factors in the 
environment may also play some role in the disease.  For example, 
the possible role of mycotoxin contamination of cereals by certain 
Fusarium strains in China and high phosphate and manganese 
contents in the soil, food, and drinking-water in endemic areas of 
the USSR have been suggested.  More studies are required to clarify 
the relationship between these hypotheses and Kashin-Beck disease. 

8.2.6.3.  Cancer

    (a)   Ecological studies

    Shamberger & Frost (1969) first pointed out the inverse 
relationship between selenium levels in forage crops and human 
blood, and cancer death rates in various regions of the USA. 
Subsequent papers expanded this concept (Shamberger & Willis, 1971; 
Shamberger et al., 1976).  From a number of comparisons, the 
cancers frequently found at one time or another to have high 
mortality associated with low-selenium areas or low blood-selenium 

levels, included cancer of the tongue, oesophagus, stomach, colon, 
rectum, liver, pancreas, larynx, lungs, kidneys, bladder, and 
Hodgkin's disease and lymphoma.  However, the high mortality of 
some of these same cancers and others, was also found to be 
associated with high-selenium areas or high blood-selenium levels; 
these include cancer of the lung, prostate, pancreas, breast, lip, 
skin, eye and dermal melanoma, and leukaemia/aleukaemia.  Some of 
these studies have been criticized as lacking strength and 
consistency, particularly because the states for which cancer 
mortality was calculated did not coincide directly with the natural 
geographical units on which the estimates of selenium levels in 
forage crops were made, thus leading frequently to 
misclassification of the different selenium areas (Allaway, 1972, 
1978).  However, in a study attempting to minimize this problem by 
using county data, similar inverse correlations were observed 
between counties classified as intermediate or high for selenium 
levels in forage, and cancers of the lung, colon, rectum, bladder, 
oesophagus, pancreas, and all sites combined, for both males and 
females, and cancers of the breast, ovary, and cervix (Clark, 
1985). 

    Schrauzer (1976) found that the mortality rates due to several 
cancers, including those of the large intestine, rectum, and breast 
(so-called Type A cancers) were directly correlated with the 
consumption of meat, eggs, milk, fat, and/or sugar and were 
inversely correlated with the consumption of cereals and fish.  
Just the opposite correlations were found for certain other cancers 
such as hepatic and stomach cancer.  Since cereals and seafoods are 
good sources of dietary selenium, it was suggested that selenium 
might be the factor in these foods that protected against Type A 
cancers.  Schrauzer et al. (1977) extended these studies to data 
from 27 countries including the USA; New Zealand was intentionally 
excluded.  Dietary intake of selenium was found to be inversely 
correlated with total age-adjusted cancer mortality, r = -0.46 ( P < 
0.01) for males and r = -0.60 ( P < 0.001) for females.  Significant 
inverse correlations were observed between dietary-selenium intake 
and mortality from cancers of the colon, rectum, prostate, female 
breast, ovary, lung (males), and from leukaemia.  Weak inverse 
relationships were found with mortality from cancers of the 
pancreas ( P = 0.06), bladder ( P = 0.1), and skin ( P = 0.1, males).  
Other cancers including those of the stomach, oesophagus, and liver 
did not show any significant direct or inverse correlations with 
dietary-selenium intake.  In this study, dietary-selenium intake 
was calculated, assuming that the same average concentration of 
selenium was present in the foods consumed in all countries (the 
Task Group questioned the validity of such an assumption).  
Mortality from cancers of the colon, rectum, prostate, lung, skin, 
bladder (all Type A), and leukaemia showed significant inverse 
correlations with blood-selenium levels in males (USA excluded).  
However in the data from the USA, this relationship was not 
observed for cancer of the prostate, lung, skin, or bladder, and 
leukaemia, and similar inconsistencies were observed for other 
cancers and in data for females. 

    Jansson et al. (1978) postulated an inverse relationship 
between dietary-selenium and the rate of colorectal and breast 
cancer, but found a direct correlation between the concentration 
of selenium in the drinking-water and the rate of colorectal 
cancer.  Moreover, these workers commented that the same 
statistical associations that indicated a protective effect of 
dietary selenium against colon, rectum, and breast cancers also 
indicated an increased risk of liver and stomach cancer due to 
selenium. 

    In a recent study in China, Yu et al. (1985) obtained a mean 
serum-selenium level in the whole blood of 1458 donors from 24 
regions, of 107 g/litre (range 22 - 314 g/litre).  Blood-selenium 
levels were inversely correlated with age-adjusted total cancer 
mortality for both males and females, r = -0.64 ( P < 0.01) and 
r = -0.60 ( P < 0.01), respectively.  Analysis by cancer sites 
revealed significant negative correlations between blood-selenium 
levels and stomach and oesophageal cancers in both sexes.  On 
reclassifying regions according to low-, moderate-, and high-
selenium areas on the basis of blood levels, significantly lower 
total cancer death rates were observed in regions with high 
selenium levels and the mortality from cancer of the stomach, 
oesophagus, and liver was particularly increased in the low-
selenium areas.  In an area where primary liver cancer was very 
common, a statistically significant negative correlation between 
primary liver cancer incidence and selenium levels in grain was 
observed (r = -0.623 for maize, and -0.631 for barley corn).  An 
inverse correlation between age-adjusted primary liver cancer and 
blood-selenium levels of residents in the area was also observed.  
The authors concluded that the results indicated that selenium 
might play an important role in the etiology of liver cancer, and 
that though selenium deficiency was not a cause of primary liver 
cancer, low selenium intake apparently reduced the ability of the 
body to withstand cancer-causing stress. 

    It has been pointed out (Levander, 1986) that the age-adjusted 
mortality rates for breast cancer and colon cancer reported in 
Finland are considerably lower than those reported in the USA, 
despite the well-documented lower dietary-selenium intakes in 
Finland. 

    (b)   Case-control studies

    Shamberger et al. (1973b) reported that blood-selenium levels 
in patients with cancer of the colon, pancreas, stomach, and in 
Hodgkin's disease and liver metastases were statistically 
significantly lower than those in normal controls.  However, of 29 
patients with rectal cancers, 6 had lower selenium levels than 
controls, and 23 had normal levels.  Similarly, normal levels were 
observed in patients with breast cancer and in patients with other 
types of carcinoma. 

    McConnell et al. (1975), compared blood-selenium levels in 110 
patients with carcinomas, 36 patients with primary neoplasm of the 
reticuloendothelial system, 28 hospitalized patients with no 
malignancy, and 18 non-hospitalized healthy individuals.  The mean 

selenium concentration for the hospitalized non-malignant patients 
was 1.49  0.06 mg/kg and for healthy controls 1.48  0.07 mg/kg.  
The mean level of 1.27  0.03 mg/kg for patients with carcinomas 
was significantly different from that of the healthy control group 
( P = 0.01).  The mean serum-selenium level of 1.14  0.08 mg/kg 
obtained for gastrointestinal cancer was significantly different 
from that of healthy controls ( P < 0.005).  In about one-third of 
the 110 cancer patients having the lowest selenium levels, 
disseminated tumour, recurrences of the primary lesions, the 
incidence of multiple primaries, and shortened patient survival 
time, were more frequently observed than in the third of the 
patients having the highest serum levels ( P > 0.001).  The mean 
serum-selenium level for the primary malignancies of the 
reticuloendothelial system was 1.76  0.24 mg/kg, which though 
higher, was not significantly different from that for the healthy 
controls. 

    Broghamer et al. (1976) reported no difference in serum-
selenium levels measured as g/ml between 110 cancer patients and 
controls.  However, patients with the lowest serum-selenium levels 
had shorter survival, higher incidence of multiple primary 
malignancies, higher rate of recurrence of the primary lesion, and 
were more likely to have dissemination of cancer than those with 
the highest serum-selenium levels. In a study of 59 patients with 
primary malignant reticuloendothelial tumours and controls, 
Broghamer et al. (1978) found no difference in serum-selenium 
levels measured as g/ml between the two groups.  McConnell et al. 
(1980) in their study found statistically significant lower levels 
of serum-selenium in 35 breast cancer patients compared with a 
control group of women free of the disease.  On the other hand, van 
Rij et al. (1979) and Robinson et al. (1978a) did not find any 
differences in the blood-selenium levels of surgical patients with 
and without cancer.  Although nutritional status, age, and severity 
and duration of disease influenced the selenium levels in the 
patients studied, low selenium levels were not characteristic for 
the cancer patients and it was suggested that the low-selenium 
status of cancer patients was more likely a consequence of their 
illness rather than the cause of the cancer. 

    Sundstrom et al. (1984a) found that 44 patients with 
gynaecological cancer had lower serum-selenium concentrations (1.15 
 0.04 mol/litre,  P < 0.05) and serum-glutathione peroxidase 
activity (404  13 units/litre,  P < 0.01) than 56 control subjects 
(1.25  0.03 mol/litre and 444  8 units/litre, respectively).  It 
was observed that in association with cytotoxic chemotherapy, 
selenium alone ( P < 0.05), vitamin E alone ( P < 0.05), and the 2 
combined ( P < 0.001) decreased the plasma concentration of lipid 
peroxides; the combination of selenium and vitamin E also increased 
the activity of serum GSH-Px ( P < 0.01).  The authors stated that 
during placebo treatment, cytotoxic chemotherapy did not affect 
plasma-lipid peroxides but decreased ( P < 0.001) the activity of 
GSH-Px.  Selenium inhibited this effect.  The authors concluded 
that this suggested that the anti-oxidative mechanisms of patients 
with these types of cancer might be defective and that treatment 
with selenium and vitamin E resulted in changes in biochemical 
factors related to lipid peroxidation. 

    In another study, Sundstrom et al. (1984b) reported that 
patients with ovarian cancer had significantly lower serum-selenium 
concentrations (mean 0.93  0.04 mol/litre,  P < 0.001) than 
matched controls (mean 1.22  0.03 mol/litre).  Clinical stage IV 
patients had lower levels of selenium (0.82  0.07 mol/litre) than 
clinical stage I and II combined (1.00  0.04 mol/litre).  
Moreover, levels tended to decrease with progressive disease and 
increase with remission, probably related to nutrition. 

    Goodwin et al. (1983) studied blood-selenium levels, and blood 
and tissue GSH-Px activity in 50 patients with untreated cancer of 
the oral cavity and oropharynx.  Mean erythrocyte-selenium and 
-glutathione peroxidase were significantly depressed compared with 
those in age-matched controls.  Mean plasma-selenium, on the other 
hand, was significantly elevated in the cancer group.  Also, 
although not significant, mean erythrocyte-selenium levels tended 
to be lower in patients who had never smoked or who had recently 
given up smoking.  No correlation between dietary selenium as 
determined by recall history and plasma- or erythrocyte-selenium 
levels in the cancer patients was observed. 

    Stead et al. (1985) reported significantly lower serum-selenium 
concentrations in 20 patients with cystic fibrosis, two of whom had 
cancer, than in controls.  The two cancer cases had mean serum-
selenium levels of 1.01 mol/litre and 0.62 mol/litre, 
respectively, compared with 1.41  0.20 mol/litre in the controls.  
Serum-vitamin E levels were also found to be low in patients, but 
did not show any correlation with serum-selenium levels. 

    (c)   Case-control studies within prospective studies

    As part of the Hypertention Detection Follow-up Programme, 
10 940 men and women with diastolic blood pressures of at least 90 
mm Hg were identified and enrolled between 1973-74, and followed-up 
for 5 years (Willett et al., 1983).  Venous blood samples were 
collected from all participants at the beginning of the study.  A 
total of 111 new cases of cancer occurred in the group during the 
period of observation.  For each case, 2 controls without cancer 
were selected who most closely matched the case in age, sex, race, 
smoking history, month of blood collection, initial blood pressure, 
hypertensive medication, randomisation assignment, and (in women) 
parity and menopausal status.  Cases and controls were comparable 
for most of the confounding factors, although serum-cholesterol and 
albumin were slightly lower among cases than controls ( P = 0.05 and 
0.06, respectively).  Serum-selenium levels did not vary with age 
or sex in controls, but black subjects had lower selenium levels 
than white.  The mean serum-selenium level in cancer cases (0.129  
0.002 mg/litre) was significantly lower than that in controls 
(0.136  0.002 mg/litre).  The  P value was 0.02.  The increased 
risk of cancer in the lowest quintile of baseline selenium was 
twice that in the highest quintile (confidence limits 1.1 to 3.3). 
Cases were too few to examine by cancer site, but a consistent 
trend of lower selenium levels among cases was observed for the 
following groups of cancers:  lung, breast, prostate, 
lymphoma/leukaemia, gastrointestinal cancer, and others.  However, 
statistically significant differences were observed only for 

gastrointestinal cancer.  Selenium level remained a significant 
predictor of risk, even when the effects of serum-retinol, vitamin 
E, and lipid levels, as well as age, sex, and race were taken into 
account.  On examination of the data according to race, sex, and 
smoking status, separately, significant differences in the mean 
serum-selenium between cases and controls were observed in blacks 
but not whites, in males but not females, and in current smokers, 
but not in past-smokers or in persons who had never smoked.  The 
risk associated with low selenium was greater among those in the 
lowest tertile of serum-vitamin E, and a similar inverse 
relationship was observed for serum-retinol.  A very strong effect 
of low selenium (relative risk = 6.2 for lowest versus highest 
tertiles) was observed for subjects who had both low serum-vitamin 
E and -retinol levels.  The authors concluded that, although their 
findings supported the overall hypothesis that low selenium intake 
increases the risk of cancer, they believed that the observed 
differences between cancer sites should be treated as hypotheses to 
be tested in other data sets, and that the differences in the 
effects of selenium according to age, race, sex, and smoking 
status, needed to be examined further (Willett et al., 1983). 

    Salonen et al. (1984b) identified a cohort of 8113 men and 
women in 1972, randomly selected from 2 counties in Finland, who 
had no history of cancer in the 12 months preceding this date.  The 
blood samples were collected from each subject at the beginning of 
the study in 1972, and stored at -20 C.  The cohort was followed-
up for cancer occurrence and death up to the end of 1978, during 
which time 43 deaths from cancer occurred and an additional 85 
persons developed cancer (total cancers = 128).  Each cancer case 
or cancer death was matched for sex, age, number of cigarettes 
smoked and total serum-cholesterol, to a control selected from the 
rest of the same population of 8113 persons.  In 1983, selenium 
concentration was estimated in blood collected from each case and 
control at the time of enrolment in the study in 1972 before the 
development of cancer.  The mean concentration of selenium was 
50.5 g/litre (SD = 12.5) for all 128 cases, and 54.3 g/litre 
(SD = 11.8) for all controls ( P < 0.012).  This difference between 
cases and control persisted for the following cancer sites: 
gastrointestinal, respiratory, and haematological cancers, 
miscellaneous cancers, and secondary cancers.  No such difference 
was observed for skin cancer, skeletal cancers, and urogenital 
cancer.  Using the lowest (35 g/litre) and third deciles as cut-
off points, relative risks were computed for the 2 lowest levels of 
serum-selenium, with the highest selenium stratum (45 g/litre) as 
the reference.  The relative risk of cancer associated with a 
serum-selenium level of less than 35 g/litre was 3.0 and that 
associated with a level of 35 - 44 g/litre was 2.4 (both 
statistically significant).  The authors concluded that their data 
provided additional support for the hypothesis that selenium 
deficiency increases the risk of most non-hormone-dependent 
cancers in middle-aged persons, though they cautioned that the 
number of cancer cases in their study was insufficient to draw 
definite conclusions about the effect of selenium for cancers at 
specific sites. 

    Salonen et al. (1985) in a further study of a subgroup of 51 
patients, who died from cancer, among the same study population as 
above, each matched to a control for age, sex, and smoking, 
obtained a mean pre-follow-up serum-selenium concentration in 
subjects who died from cancer during the study period of 53.7  1.8 
g/litre and that in controls of 60.9  1.8 g/litre; the 
difference was statistically significant.  A statistically 
significant difference in the mean serum-selenium concentration 
between cases and controls was observed in men ( P = 0.002), but not 
in women (half of the male pairs were smokers, but none of the 21 
female pairs were smokers).  Similarly, the difference in the mean 
selenium concentration was significant in smokers ( P = 0.013) but 
not significant in non-smokers.  Years of smoking showed an inverse 
correlation with serum-selenium in the cases (r = -0.30) but not in 
controls.  Analysis according to cancer site revealed that a 
statistically significant difference in serum-selenium levels 
between cases and controls was recorded only for respiratory 
cancers, though a non-significant difference also existed for 
gastrointestinal sites and other cancers.  An association between 
low serum retinol concentration and increased risk of cancer was 
observed only among smoking men.  This sex difference was 
attributed to smoking as there were no smoking women in the study. 

    Vitamin E and serum-retinol did not show any association with a 
specific cancer site, and although vitamin E had only a weak 
independent effect on the risk of cancer, it showed a strong 
synergistic relationship with selenium on the risk of fatal cancer.  
A serum-selenium concentration of 47 g/litre or less (the lowest 
tertile) was associated with a relative risk of death from cancer 
of 5.8 (95% confidence interval 1.2 - 29.0).  The authors concluded 
that, although their findings indicated that dietary-selenium 
deficiency increased the risk of cancer, owing to their study 
design, they could not rule out the possibility that the substances 
measured in the serum were not truly the protective factors but 
were merely indicators of some other compounds or nutrients that 
were directly involved in the causal relationship.  Furthermore, 
the authors recognized that there was need to investigate further 
the modification and the confounding of effects by sex, smoking, 
and other factors. 

8.2.6.4.  Heart disease

    Using the same ecological approach discussed above for cancer, 
Shamberger et al. (1975) concluded that the age-specific death 
rates for a number of heart diseases were significantly lower in 
the high-selenium regions of the USA than in the low-selenium 
regions.  However, results of a WHO/IAEA research programme showed 
no difference in tissue-selenium concentrations between patients 
who died with, or without, myocardial infarction (Masironi & Parr, 
1976).  Furthermore, Shamberger (1978) found that the kidney-
selenium levels of patients with atherosclerosis and hypertension 
did not differ from those of patients with a variety of other 
diseases.  The blood-selenium levels of patients with acute 
myocardial infarction were lower than those of healthy adults, but 
there was no difference in heart- or liver-selenium levels of 
patients who died from myocardial infarction and those who died 
from other diseases (Westermarck, 1977). 

    A recent case-control study from Finland suggested a possible 
association between the serum-selenium level and the risk of death 
from acute coronary heart disease as well as the risk of fatal and 
non-fatal myocardial infarction (Salonen et al., 1982).  The case-
control pairs were derived from 11 000 persons residing in eastern 
Finland, an area with a very high incidence of death from 
cardiovascular disease.  The cases were middle-aged persons who had 
died of coronary heart disease or other cardiovascular disease or 
suffered a non-fatal myocardial infarction over a 7-year follow-up 
period.  Attempts were made to control for potential confounding 
factors by using controls matched for 6 major coronary heart 
disease risk factors:  age, sex, serum-cholesterol, diastolic blood 
pressure, smoking, and history of angina pectoris, but the cases 
had slightly higher blood pressure than the controls.  The mean 
serum-selenium levels were 51.8 and 55.3 g/litre for cases and 
controls, respectively.  A serum-selenium level of less than 45 
g/litre was associated with an increased risk of coronary and 
cardiovascular death and myocardial infarction.  Although few 
necropsies were done, the authors felt that it was unlikely that 
the excess cardiovascular mortality observed in their subjects was 
due to Keshan disease.  The authors cautioned that the apparent 
association between low serum-selenium levels and cardiovascular 
risk might be spurious since serum-selenium might only be, for 
example, a marker for other dietary factors more directly related 
to increased coronary heart disease.  The authors also emphasized 
that, even if their results truly reflected a causal relationship 
between low selenium intake and increased ischaemic heart disease, 
most such disease is still due to the other well-known risk factors 
of elevated cholesterol, high blood pressure, and smoking.  
Moreover, it was pointed out that any association between low 
serum-selenium levels and ischaemic heart disease is likely to be 
of significance only for populations in areas where the dietary 
intake of selenium is very low. 

    In 3 other studies from Finland little or no association was 
found between the risk of death from ischemic heart disease and low 
selenium status (Miettinen et al., 1983; Salonen et al., 1985; 
Virtamo et al., 1985).  However, a critique of these studies 
(Salonen, 1985) indicated that the first and third were 
characterized by low statistical power and in the first the mean 
serum-selenium level was relatively high compared with typical 
Finnish values (73 g/litre), probably due to importation of grain 
high in selenium during the late 1970s (Mutanen & Koivistoinen, 
1983).  Salonen (1985) stated that all 4 Finnish studies discussed 
above supported the concept of an increased risk of ischemic heart 
disease due to low selenium intake as indicated by serum-selenium 
levels of less than 60 g/litre. 

    In the USA, an inverse correlation was reported between the 
plasma-selenium level and the severity of coronaryatherosclerosis 
as documented arteriographically (Moore et al., 1984).  The mean 
plasma-selenium levels of patients with "zero-vessel" disease (no 
visible narrowing as much as 50% of any coronary arteriol lumen) or 
"three-vessel" disease (as much as a more than 50% narrowing in the 
three major coronary arteries or their branches) were 136  7 or 

105  4 g/litre, respectively.  On the other hand, neither Ellis 
et al. (1984) in the United Kingdom nor Robinson et al. (1983) in 
New Zealand were able to demonstrate any correlation between the 
traditional risk factors for cardiovascular disease and blood-
selenium levels or glutathione peroxidase activity. 

9.  EVALUATION OF THE HEALTH RISKS ASSOCIATED WITH EXCESSIVE OR 
DEFICIENT SELENIUM EXPOSURE

9.1.  The Need to Consider the Essentiality of Selenium in the Health 
Risk Evaluation

    The data presented in the preceding sections show evidence that 
selenium is a functional component of an enzyme (glutathione 
peroxidase) in animals and man, and can prevent certain diseases in 
animals and responsive conditions in man.  The Task Group concluded 
that selenium meets the criteria of essentiality for man.  As is 
true for all essential elements, not only deficient but also 
excessive exposure results in adverse health effects. 

    The effects of selenium deficiency as well as toxicity are well 
known in several animal species.  In contrast to the effects seen 
in animals, health effects in man resulting from deficiency or 
excess of selenium are less well defined, but available evidence 
has been described.  They can occur at low and excessive exposure 
levels that may be expected to correspond broadly with those having 
deleterious effects on the health of animals.  Between these 
extremes is a range of safe and adequate exposures (intakes) that 
can be defined as free from toxicity and adequate to meet 
nutritional requirements.  Exposures outside this range increase 
the risk of adverse health effects.  Therefore, the health risk 
evaluation of both selenium deficiency and excess is important.  
However, it should be noted that the safe and adequate range may be 
modified by certain dietary and other environmental conditions. 

    The aim of the Task Group was not to evaluate the need for, and 
safety of, medication by selenium compounds as a preventive or 
therapeutic measure.  However, the Task Group felt that some of the 
observations presented might be of relevance whenever such a 
question might be addressed by any other body responsible for the 
appropriate risk-benefit evaluation of administration of selenium 
compounds to human beings. 

9.2.  Pathway of Selenium Exposure for the General Population

    Reproducible and accurate methods are available for the 
collection of environmental and biological samples and the 
measurement of their selenium content.  These methods, though they 
require special skills and equipment and are time-consuming, have 
been employed to assess human selenium exposure.  However, the data 
are incomplete and there are no data available on selenium exposure 
levels for the general population in many countries and regions of 
the world. 

    In spite of these limitations, it can be concluded that, for 
the general population, the main source of selenium exposure is 
food.  In nutritional surveys, extreme mean values for the 
calculated selenium intake from food by adult human beings varied 
from 11 to 5000 g/day.  However, on the basis of the data 
available from most areas, the Task Group concluded that dietary-

selenium intakes usually fall within the range of 20 - 300 g/day.  
Exposure via drinking-water is much less and rarely exceeds a few 
g/day.  Limited data on selenium levels in air indicate that about 
0.2 g can be inspired daily by individual members of the general 
population. 

9.3.  Quantitative Assessment of Human Selenium Exposure

9.3.1.  Analytical methods for selenium

    Several methods of analysis for selenium are available.  Those 
based on fluorometry, neutron activation analysis, or atomic 
absorption spectrometry have been the most thoroughly studied and 
used.  While simplified and automated procedures have been 
developed, all of these methods require skilled analysts to obtain 
consistently accurate results.  The analysis of NBS Standard 
Reference Materials and the exchange of a variety of samples with 
another laboratory known to be accomplished in analysis for this 
element, should be used to verify the adequacy of results, prior to 
any study of human exposure.  The method of choice will depend on 
the availability of equipment and of the pure chemicals that may be 
required, as well as on certain other factors.  Where a high degree 
of accuracy is required, comparison of results obtained by two or 
more different techniques is helpful. 

    The reliability of the estimate of selenium exposure will 
depend, not only on the adequacy of the method, but also on the 
adequacy of sampling, storing, subsampling, and preparing the 
subsamples for selenium determination.  Failure to plan for, and 
observe, proper practices in these steps can negate the reliability 
of results by even the most highly accurate method of measurement. 

9.3.2.  Food intake data

    Because of the wide variation in the selenium content of foods 
in different regions, special techniques must be used to assess 
human selenium exposure on the basis of food intake data.  The most 
accurate method is to determine selenium levels in duplicate diets 
(food-on-the-plate-method) made from the same food that is consumed 
by the subjects.  This method may be suitable for studies in small 
subpopulations and where a high degree of accuracy is necessary; it 
has the disadvantage of being expensive and time-consuming. 

    The use of a nutrition survey approach with calculation of 
selenium intake from food tables can be used if an important rule 
is observed, i.e., the food tables used must be formulated from 
data on the selenium contents of the food sources of the population 
being studied and of the food as eaten by the subjects under study.  
This is important to avoid the errors introduced by the wide 
variation in selenium content of a given foodstuff, depending on 
its origin. 

9.3.3.  Blood-selenium

    The selenium content of whole blood, serum, or plasma are the 
most commonly used measurements of human selenium exposure.  Blood 
is relatively easy to sample and contamination can be controlled.  
Studies on animals have shown that blood-selenium values are a good 
indication of selenium deficiency and excess.  However, variations 
in selenium deficiency signs have been observed in animals with 
similar whole blood-selenium levels.  This may be due to variations 
in the vitamin E content of the diet or exposure to other dietary 
or environmental variables.  Several factors besides selenium 
intake have been identified that may affect blood-selenium content.  
Exposure to inorganic mercury or cadmium can lead to deposition of 
selenium in the blood attached to protein in combination with the 
metal.  Human beings exposed to selenium in the form of 
selenomethionine or selenium-rich wheat or yeast, for 10 - 11 
weeks, had higher blood-selenium levels than human beings exposed 
to the same amount of selenium in the form of selenite or selenate. 

    Blood can be fractionated and plasma-selenium and red blood 
cell-selenium can be measured separately.  A recent study on the 
effects of a low-selenium diet on human beings indicated that a 
decrease in plasma-selenium content might occur before a decrease 
in red blood cell-selenium can be detected.  These data suggest 
that it may be possible to use plasma-selenium levels to assess 
short-term selenium exposure but that red blood cell- and whole 
blood-selenium reflect long-term exposure. 

9.3.4.  Hair-selenium

    Measurement of the selenium content in hair has been used in 
animals for the assessment of selenium status, with regard to both 
deficiency and excess.  It has not been generally adopted for use 
in human beings, but, in special circumstances where external 
contamination can be excluded, hair-selenium content is useful for 
assessing selenium status. 

9.3.5.  Urine-selenium

    The results of animal studies and a few human studies indicate 
that the urinary excretion of selenium can be useful for assessing 
very recent selenium exposure (i.e., within the past 24 h).  
However, determination of selenium in incomplete urine collections 
or expression of urinary-selenium per unit volume of urine cannot 
provide valid information about selenium exposure in the general 
population.  An understanding of the reservations associated with 
this technique is necessary in its application and then it may only 
be useful in conjunction with other measurements discussed in this 
section. 

9.3.6.  Blood-glutathione peroxidase

    There is no suitable, simple field method for assessing the 
selenium exposure of the general population.  The Task Group 
concluded that approaches based on the glutathione peroxidase 

activity of blood components might provide the basis for a suitable 
screening method to detect low human exposure to selenium. 

    Blood-glutathione peroxidase activity is useful for detecting 
selenium deficiency, because it represents a functional form of 
selenium and its assay is more rapid than the measurement of 
selenium in blood. 

    However, the Task Group recognized that there are several 
difficulties and limitations associated with the determination of 
glutathione peroxidase activity.  For example, the enzyme is not 
stable and hence its activity cannot be determined in samples 
stored for periods of time, whereas measurements of selenium can be 
made on stored samples.  Moreover, large differences in blood-
glutathione peroxidase activity have been reported from different 
laboratories using similar methods.  The discrepancies can be so 
great that interlaboratory comparisons are impossible without 
suitable controls.  Furthermore, results from New Zealand suggest 
that human blood-glutathione peroxidase activity may be useful in 
assessing selenium intake at low, but not necessarily at 
intermediate or high levels, because the activity of the enzyme is 
correlated with whole blood-selenium levels, only when the latter 
are less than 0.10 mg/litre.  It is not known whether excessive 
selenium exposure can increase glutathione peroxidase activity in 
human blood, above normal values.  Animal studies indicate that 
iron deficiency decreases blood glutathione peroxidase activity, 
thus possibly further confounding selenium status assessment by 
this method. 

    Human plasma contains glutathione peroxidase but its activity 
is very low and difficult to detect and haemolysis during sample 
collection should be excluded.  Nevertheless, if these reservations 
are borne in mind, the technique is promising.  Measurement of 
platelet-glutathione peroxidase is also a promising technique for 
measuring short-term changes in selenium status because of the 
short half-life of this blood component. 

9.4.  Levels of Dietary Selenium Exposure in the General Population

    The selenium content of food is highly variable in relation to 
several factors.  Levels of selenium in soil available for uptake 
by plants vary markedly in different locations and this is 
reflected in differences in the selenium contents of feeds and 
foodstuffs.  Countries in which food-stuffs are shipped between 
regions tend to avoid extremes in dietary-selenium intake by 
averaging foodstuffs with high- and low-selenium contents but some 
differences in regional intakes are still observed. 

    Animal tissues usually do not have as high a selenium content 
as the plants in high-selenium areas or as low a selenium content 
as plants in low-selenium areas.  This is probably because of the 
ability of animals to conserve selenium when it is in short supply, 
and to excrete it when an excess is present.  This may protect 
consumers of animal products from extremes of selenium intake. 

    Available analytical data show that the levels of selenium 
typically found in foods, are in the range of 0.4 - 1.5 mg/kg in 
liver, kidney, and seafood; 0.1 - 0.4 mg/kg in muscle meats; from 
less than 0.1 to over 0.8 mg/kg in cereals or cereal products; less 
than 0.1 - 0.3 mg/kg in dairy products; and less than 0.1 mg/kg in 
most fruits and vegetables.  The very large variation in the 
selenium contents of foodstuffs of the same type, depending on 
their origin, makes a food table approach to estimating dietary-
selenium intake potentially misleading as discussed in section 
9.3.2.  More accurate intake estimates could be derived from assay 
data on samples of the food items actually being consumed (food-on-
the-plate analysis). 

    The practice of supplementing the diets of livestock and 
poultry in low-selenium areas with selenite or selenate causes 
little increase in muscle-selenium content over levels encountered 
in animals raised in areas of adequate, but not excessive, selenium 
supply.  With some exceptions, food processing and preparation 
generally do not cause major losses of selenium. 

    There are few data that indicate the chemical form that 
selenium takes in normal human foods.  One available study of 
seleniferous wheat has shown that a significant fraction of the 
selenium is in the form of selenomethionine. 

    Various forms of selenium differ in their nutritional 
availability.  The absorption of selenium from foods appears quite 
efficient (about 80%). 

    Daily selenium intake can be markedly influenced by food 
consumption patterns.  For example, in many countries, consumption 
of large amounts of fish, kidney, or liver could raise an 
individual's selenium intake substantially above the highest daily 
intake shown in Table 8. 

    The greatest extremes in dietary-selenium intake have been 
reported in areas in which the diet was monotonous and consisted 
largely of locally-produced staple food. 

    The wide range of geographically-related selenium intake due to 
variations in the selenium contents of the diet is reflected in the 
wide range of selenium levels observed in human whole blood. 

    The extreme mean blood-selenium values reported for groups 
dependent on locally-grown foods of different selenium content 
ranged from 0.02 - 3.2 mg/litre (Table 11).  Limited studies from 
New Zealand have shown that children and older individuals had 
lower whole blood-selenium levels, but it is not known whether 
these lower levels are due to low dietary intakes or to changes 
connected with growth and/or aging. 

9.5.  Evaluation of Health Risks - General Population

9.5.1.  Predictive value of animal studies

    The Task Group concluded that, in view of the still fragmentary 
data concerning the possible health effects of either deficient or 
excess selenium exposure on human beings, any evaluation of the 
human health effects of selenium exposure must take into account 
results arising from animal studies.  For this purpose, these can 
be summarized as follows: 

    (a)  Selenium deficiency combined with concurrent low
         vitamin E status has resulted in deleterious effects
         in all animal species tested so far (mice, rats,
         chicks, ducks, swine, sheep, cattle, and monkeys).
         In rats, specific signs of selenium deficiency have
         been produced in animals fed diets adequate in
         vitamin E.

    (b)  Acute and chronic selenium toxicity have been
         demonstrated in a wide variety of species, under a
         wide variety of conditions (section 7.1.2).  In
         evaluating the toxic effects of different selenium
         compounds, the Task Group felt that it was useful to
         distinguish between effects that are strictly
         dependent on the selenium in the molecule and cannot
         be duplicated by, e.g., homologous compounds of
         sulfur, and compounds where the toxicity is, in
         principle, similar for homologues containing either
         selenium or sulfur.  In addition, the Task Group
         recognized that the similarity of some of the effects
         of different selenium compounds could be related to
         the formation of certain common intermediates.

    (c)  Dose-response relationships have been demonstrated in 
         acute and chronic toxicity, as well as in selenium 
         deficiency.  Comparative studies have shown that acute 
         toxicity is similar in parenteral and oral exposure 
         (section 7.1.2.1), which is in good agreement with the 
         recognized high absorbability of selenium compounds 
         from the gastrointestinal tract (section 6.1.1).

    (d)  As indicated in section 7.1.2.2, the borderline
         level of dietary selenium needed to cause growth
         depression, due to overt chronic selenium toxicity in
         rats, is in the range of 4 - 5 mg selenium/kg diet.
         However, the dietary level of selenium needed to
         cause chronic toxicity can be influenced by several
         environmental factors such as previous selenium
         intake (section 7.1.6).

    (e)  The effects of various environmental factors on
         selenium dose-response relationships is even more
         dramatically illustrated in situations of low-
         selenium intake leading to deficiency.  One of the

         primary factors influencing the nutritional 
         requirements of animals for selenium is the vitamin E
         status.  The minimum dietary level of selenium needed
         to prevent deficiency diseases in various animal
         species is in the range of 0.02 - 0.05 mg/kg diet.

    (f)  Animal diseases associated with both high- and
         low-selenium intake have been reported in certain
         areas of the world in which the animals were
         consuming feeds primarily of local origin.

    The possibility of a human disease due to selenium deficiency 
or excess should be looked for under similar conditions of 
restricted dietary consumption (monotonous diets based on locally 
grown foods).  In addition, the Task Group concluded that, in view 
of the dependence of selenium deficiency or toxicity effects on 
various environmental factors, the possible involvement of selenium 
in human diseases of multifactorial etiopathogenesis deserves 
special attention. 

9.5.2.  Studies on high-exposure effects in the general population

    Studies on this type of exposure are few and, as they are 
confined to subpopulations in high-selenium areas, some do not 
include comparison groups.  Symptoms and signs of illness elicited 
are frequently mild and not clearly related to selenium.  In 
practically all studies (section 8.1.1.1), nail pathology was 
reported and, in several studies, hair loss and increased dental 
decay.  Some of the studies included reports of gastrointestinal 
disturbances and icteroid skin.  Other possible causes of illness 
in these studies cannot be excluded and the dependence of severity 
of effects on gradation of selenium exposure cannot be evaluated.  
Examination of exposed individuals showed increased levels of 
selenium in the blood and urine. 

    Three studies on populations living in seleniferous areas and 
dependent on locally-produced food deserve particular attention.  
Examination of individuals exposed in these areas revealed highly 
increased levels of selenium in the blood and/or urine.  A study 
from South Dakota reported various signs and symptoms in people 
with long-term overexposure to selenium, as revealed by elevated 
urinary-selenium excretion.  In these areas, farm animals were 
affected by chronic selenium poisoning. 

    In a seleniferous zone of Venezuela (Villa Bruzual) 111 
children (average blood-selenium level = 0.813 mg/litre) were 
studied and compared with 50 children (blood-selenium level = 0.355 
mg/litre) not over-exposed to selenium (Caracas).  The children 
from the seleniferous area had some loss of hair and some 
abnormalities of skin and nails; the authors noted some differences 
in socio-economic factors between the 2 groups. 

    In a recent report from China, past incidents of intoxication 
were described that were thought to be due to chronic selenium 
poisoning, with hair loss and nail pathology as the most common 

signs.  No quantitative data are available from the period 1961 - 
64, which was the time of peak prevalence of the intoxication.  
Recent diet samples collected from high-selenium areas with, and 
without, a history of this intoxication showed mean daily selenium 
intakes of about 5 and 0.75 mg, respectively (Table 7).  Blood 
samples taken from the same areas had mean selenium levels of 3.2 
and 0.44 mg/litre, respectively (Table 11). 

    The above studies of populations ingesting high selenium levels 
in Venezuela and China have not revealed abnormal serum 
transaminase activity in the subjects concerned.  In individuals 
exposed to high levels of selenium in the recent outbreak in the 
USA; there was no evidence of impaired liver function, but loss of 
hair and pathological changes in the nails were observed, as well 
as some other signs and symptoms described in more detail in 
section 8.1.1.1.  However, the Task Group recognized that this is 
insufficient evidence to exclude the occurrence of liver damage and 
recognized the need for more thorough evaluation of the liver in 
persons with high selenium exposure. 

    The Task group noted that the signs and symptoms of selenium 
overexposure in human beings were not well defined.  However the 
Task Group was aware of 3 situations concerning elevated selenium 
exposure, which could form the basis for estimating a dose-response 
to high levels of selenium.  In one area of Enshi county in China, 
blood-selenium levels in adults of 0.44 mg/litre were associated 
with no reported effects.  In Venezuelan children with blood-
selenium levels of 0.813 mg/litre, hair and nail changes of an 
unspecified nature and incidence were reported.  In another area of 
Enshi county in China, definite hair and nail changes and symptoms 
and signs consistent with neuropathy were reported in adults with 
blood levels of 3.2 mg/litre.  The Task Group, however, could not 
be certain of how signs and symptoms were searched for, how their 
absence was ascertained, and how the control populations were 
selected in these studies. 

9.5.3.  Studies on low-exposure effects in the general population

    Very low blood-selenium levels observed in human subjects 
(section 8.2.4), approach those observed in animals with selenium 
responsive diseases.  One woman from a general population known to 
have a low exposure to selenium and maintained on total parenteral 
nutrition, which provided less than 1 g selenium/day, had muscular 
pain and dysfunction that responded to selenium supplementation.  
However, similar symptoms have not been observed in other patients 
with similar low blood-selenium levels.  Also, in another study, no 
muscular symptomatology was reported in children fed exclusively 
special medical diets containing very low levels of selenium, for 
long periods of time.  On the other hand, the Task Group assigned a 
high significance to recent reports describing an association 
between Keshan Disease (section 9.5.4.1) and poor selenium status 
as indicated by low selenium content of grain, low blood and hair 
levels of selenium, low blood-glutathione peroxidase activity, as 
well as a positive response to an intervention study with sodium 
selenite.  As discussed in section 9.5.1, the results of several 

experimental animal studies indicate that many different factors 
may contribute to the development of selenium deficiency diseases.  
These studies point to the conclusion that a lack of selenium may 
be only one of several causative factors responsible for the 
occurrence of certain diseases of complex multiple 
etiopathogenesis.  Such a conclusion was also fully recognized in 
the reports from China on the Keshan Disease. 

9.5.4.  Evaluation of the involvement of selenium in human diseases 
of multiple etiopathogenesis

9.5.4.1.  Keshan disease

    A suitable animal model of the Keshan disease is not available, 
even though heart damage is a feature of combined vitamin E and 
selenium deficiency in several species of animals. 

    The ecological evidence strongly favours a relationship between 
low selenium status and the incidence of Keshan disease.  Such 
evidence includes low blood-, hair-, and urine-selenium levels in 
the affected areas as well as a low selenium content in the staple 
foods raised and consumed in the affected areas.  A randomized 
intervention trial carried out in China showed that children who 
received sodium selenite had a lower incidence of Keshan disease 
than those who received a placebo.  However, in this randomized 
trial there may have been an underlying trend in the placebo group 
towards a decline in the incidence of the disease.  Also, 
information on the effectiveness of the randomization was not 
available and the incidence rates were not adjusted for age.  The 
results of the much larger but non-randomized intervention trial 
involving at least a quarter of a million children on a yearly 
basis indicated a clear-cut beneficial effect of sodium selenite in 
the prevention of the Keshan disease.  Thus, the Task Group 
concluded that Keshan disease is a condition in human beings that 
is related to low selenium status but that additional research is 
needed to clarify the role of other factors in the etiopathogenesis 
of the disease. 

    The Task Group also recognized that in section 8.2.3.1 this 
disease was used as the basis for estimating a minimal human 
nutritional selenium requirement, suggested by the authors to be 19 
and 14 g/day for men and women, respectively. 

9.5.4.2.  Kashin-Beck disease

    An additional disease found in certain low-selenium areas of 
China is an endemic osteoarthropathy known as Kashin-Beck disease 
that occurs mainly in children.  There is some evidence linking low 
selenium status with the incidence of Kashin-Beck disease, but the 
Task Group concluded that additional research, particularly in 
relation to intervention studies, is required before a definite 
statement can be made concerning the role of selenium in the 
etiology of the disease. 

9.5.4.3.  Ischaemic heart disease

    The Task Group was aware of studies that examined the 
possibility of an association between low selenium status and 
myocardial ischaemia and atherosclerosis.  However, because of the 
limited data available, the Task Group was not prepared to come to 
any conclusion regarding the role of selenium in ischaemic heart 
disease. 

9.5.4.4.  Studies on the involvement of selenium in cancer

    (a)   Carcinogenicity studies

    The Task Group concluded that the studies described in section 
7.7 suggesting a carcinogenic effect of selenite or selenate were 
invalid, because, in one study, the results were statistically 
insignificant and, in the other studies, there were no controls or 
systematic pathological examinations.  In another systematic study, 
no differences were observed in the incidence of tumours in rats 
surviving 2 years or longer and exposed to 0.5 - 2.0 mg selenium/kg 
diet. 

    The Task Group was aware of one study that demonstrated the 
carcinogenicity of ethyl selenac (selenium diethyldithiocarbamate) 
and another that showed the carcinogenicity of selenium sulfide, 
given by gavage.  The latter result is of possible interest both as 
regards human dermal exposure to selenium sulfide and/or its 
possible formation within the body, but the Task Group was not 
aware of any studies demonstrating carcinogenic effects of other 
selenium compounds. 

    The Task Group felt that the evaluation published by IARC in 
1975 was still valid in concluding that the available animal data 
were insufficient to allow an evaluation of the carcinogenicity of 
selenium compounds (IARC, 1975). 

    (b)   Experimental evidence of anticarcinogenic effects of 
          selenium compounds

    The results of studies on laboratory animals provide evidence 
of a preventive effect of selenium dioxide, sodium selenite, or 
"selenized" yeast, given in the food or drinking-water, against 
chemically-induced cancers or certain spontaneous, presumably 
viral-induced cancers (section 7.7).  Generally, the level required 
to demonstrate such effects ranges from 1 - 6 mg/kg food or per 
litre drinking-water and thus is considerably in excess of the 
animal's nutritional needs.  In one report, selenium dioxide at 
0.1 mg selenium/litre water had some beneficial effect against 
spontaneous mammary tumours in mice, but, in this case, the diet 
itself contained 0.45 mg selenium/kg.  Other studies have shown the 
beneficial effects of sodium selenide when applied concomitantly to 
the skin with certain carcinogens.  In rats fed diets high in 
polyunsaturated fats, selenium deficiency increased the incidence 
of mammary tumours, after treatment with dimethylbenz[alpha]
anthracene.  Therefore, the Task Group concluded that 

pharmacological levels of selenium compounds exhibit in many cases 
a favourable influence against the development of cancer in various 
animal model systems. However, the Task Group was aware of one 
study in which administration of high levels of selenium was 
associated with an increased incidence of chemically-induced 
cancer. 

    (c)   Epidemiological evidence regarding the possible anti-
          carcinogenic effects of selenium in human beings

    The Task Group acknowledged that apparent negative correlations 
have been drawn between cancer death rates and certain general 
population characteristics, such as blood-selenium levels or the 
average level of selenium in diets in specific geographical zones 
(section 8.2.6.1).  However, these apparent correlations have not 
been consistent with specific cancer sites and are subject to 
ecological fallacy.  Moreover, such epidemiological data are 
subject to question regarding the adequacy of sampling, the 
interpretation of blood-selenium data, and the precision of the 
estimates of dietary-selenium intake in various countries and 
different geographical areas within the USA. 

    Of the 7 case-control studies examined by the Task Group, no 
consistent association was apparent between low selenium status and 
risk of cancer.  For a given cancer site, there were few replicate 
studies.  On the majority of occasions, no association was found 
between low selenium status and cancer risk.  In fact, in at least 
one situation a positive correlation was found.  In several 
countries, low blood- or plasma-selenium levels were found in 
patients with several different types of cancer.  However, the 
effect of the malignant disease itself in lowering blood-selenium 
levels (e.g., by decreasing absorption and/or worsening the 
generally debilitated nutritional state of the patient) cannot be 
excluded as a partial or total explanation for these results. 

    The Task Group was aware of 3 studies in which blood samples 
had been taken for other purposes prior to the diagnosis of any 
cancer.  Some time later, the samples were retrieved from storage 
banks and analysed for selenium.  All 3 studies showed a consistent 
inverse association between the prediagnostic serum-selenium level 
and the risk of cancer.  This association between low serum-
selenium level and cancer risk was observed only in smokers, only 
in males, and in one study only in blacks but not in whites.  In 
one study, the association between low selenium level and cancer 
risk showed some site specificity, but the second and third studies 
were unable to confirm or rebut this because of inadequate sample 
size. 

    The Task Group was aware that in many studies showing a 
protective effect of selenium against cancer in animals 
pharmacological doses of selenium compounds were used.  Therefore, 
there were difficulties in relating the animal and human studies, 
but the Task Group was aware of an intervention trial being carried 
out in China which it is hoped will enable a more precise 
evaluation of the association between selenium status and human 
cancer risk in the future. 

    Thus, the Task Group concluded that existing data are 
insufficient to determine whether the level of selenium intake is 
indeed correlated with the incidence of cancer in man. 

9.5.4.5.  Caries

    Although an association between high selenium intake and dental 
caries has been reported in at least one animal study, there is no 
clear-cut evidence of such an association in man.  The Task Group 
concluded that difficulties associated with the interpretation of 
urinary-selenium excretion, expressed as mass-concentration per 
volume and not expressed as total daily urinary excretion of 
selenium (section 9.3.5), as well as the inability to exclude 
interference by other environmental factors such as fluoride, 
precluded any significant conclusions.  A better understanding of 
the impact of selenium on the incidence of caries will require a 
more comprehensive estimation of selenium exposure and of the other 
confounding factors in the respective subpopulations under study. 

9.5.4.6.  Health effects related to reproduction

    The Task Group concluded that at present there is no evidence 
that selenium has significant effects on reproductive function in 
man. 

9.6.  Occupational Exposure

    In contrast to general population exposure, occupational 
exposure usually occurs through direct contact and/or through 
inhalation, i.e., dermal and respiratory exposure predominate. 
Exposure to selenium and its compounds occurs in primary 
industries, i.e., those that extract, mine, treat, or process 
selenium-bearing minerals, e.g., copper, zinc, or lead ores and in 
secondary industries, i.e., those that use selenium in 
manufacturing processes.  The physical and chemical form of 
selenium under these circumstances varies and is determined by the 
industrial processes.  The Task Group recognized that industrial 
exposure has not been adequately studied with respect to levels of 
exposure and there is a need for such studies to be carried out. 

    For acute occupational selenium exposures, the effects vary 
according to to the chemical form of selenium.  In contrast to 
elemental selenium, which does not appear to be toxic unless 
oxidized or reduced, hydrogen selenide and selenium dioxide are 
highly toxic, causing irritation of the respiratory tract, which 
may be followed by pulmonary oedema. 

    The Task Group recognized that evaluation of long-term 
occupational exposure to selenium must take into account other 
dietary and environmental substances because of their recognized or 
potential interactions with selenium.  An additional factor that 
needs to be considered is the fact that preventive measures usually 
result in the removal of exposed workers with the appearance of the 
first sign of selenium over-exposure (garlic-like odour).  
Monitoring of selenium in the urine is also used to identify those 
who should be removed from further overexposure. 

    The Task Group concluded that no studies were available on the 
dose-response relationship with regard to occupational exposure to 
selenium. 

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    See Also:
       Toxicological Abbreviations
       Selenium (ICSC)
       Selenium (PIM 483)