S CIE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / s c i t o t e n v

Review

Selenium in food and the human body: A review

Miguel Navarro-Alarcon ⁎, Carmen Cabrera-Vique

Department of Nutrition and Food Science, University of Granada, 18071-Granada, Spain

AR TIC LE I N FO ABS TR ACT

Article history: Selenium levels in soil generally reflect its presence in food and the Se levels in human
Received 27 March 2008 populations. Se food content is influenced by geographical location, seasonal changes,
Received in revised form 16 June 2008 protein content and food processing. Periodic monitoring of Se levels in soil and food is
Accepted 16 June 2008 necessary. Diet is the major Se source and approximately 80% of dietary Se is absorbed
Available online 26 July 2008 depending on the type of food consumed. Se bioavailability varies according to the Se source
and nutritional status of the subject, being significantly higher for organic forms of Se. Se
Keywords: supplements can be beneficial for subjects living in regions with very low environmental
Selenium levels of Se. Several strategies have been followed: (1) employment of Se-enriched fertilizers;
Dietary intake (2) supplementation of farm animals with Se; (3) consumption of multimicronutrient
Bioavailability supplements with Se. Nevertheless, detailed investigations of possible interactions between
Supplementation Se supplements and other food components and their influence on Se bioavailability are
Biomarkers needed. Suppliers also need to provide more information on the specific type of Se used in
Disease prevention supplements. In addition, research is lacking on the mechanisms through which Se is
involved in hepatocyte damage during hepatopathies. Although Se potential as an
antioxidant for the prevention of cardiovascular diseases (CVD) is promising, additional
long-term intervention trials are necessary. As a result, indiscriminate Se supplements
cannot be reliably recommended for the prevention of CVD in human beings. Some
interesting findings reported an association of Se intake with a reduced prevalence and risk
for prostate and colon cancer. However, random trials for other cancer types are
inconclusive. As a final conclusion, the general population should be warned against the
employment of Se supplements for prevention of hepatopathies, cardiovascular or cancer
diseases, because benefits of Se supplementation are still uncertain, and their
indiscriminate use could generate an increased risk of Se toxicity.
© 2008 Elsevier B.V. All rights reserved.

Contents

1. Selenium content in foods and beverages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

1.1. Meat, chicken, fish and eggs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
1.2. Milk and dairy products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
1.3. Fruits and vegetables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
1.4. Legumes, nuts, cereals and by-products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
1.5. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

⁎ Corresponding author. Tel.: +34 958 243865; fax: +34 958 249577.
E-mail address: nalarcon@ugr.es (M. Navarro-Alarcon).

0048-9697/$ – see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.scitotenv.2008.06.024
116 SC IE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41

2. Selenium bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

3. Selenium total dietary intake. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
4. Selenium supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
5. Physiological role of selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
6. Assessment of body nutritional status on selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
7. Selenium metabolism and pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
8. Selenium deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
9. Toxicity of selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
10. Body selenium metabolism in several diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
10.1. Selenium metabolism in hepatopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
10.2. Selenium metabolism in cardiovascular diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
10.3. Selenium metabolism in cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
10.4. Influence of selenium supplementation trials on the prevention and progression of some diseases
and body limitations associated with ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

1. Selenium content in foods and beverages
Se content in food and beverages varies geographically both
within and between countries. The Se content of animal
products reflects the Se levels in their consumed diet (Barclay
et al., 1995), whereas the Se content of plants is directly
affected by Se levels in the soil in which are grown. Se in the
form of selenate or selenite is taken up by plants and mainly
transformed into Se-Met in cereal grains (Sathe et al., 1992).
Plant absorption of Se principally depends on the concentra-
tion and physicochemical forms existing in the soil. Factors
such as the type of rocks, pH and redox potential in the soil, the
existence of some organic and inorganic compounds, soil
moisture and salinity, soil sulphate concentration, plant
species, soil-management practices, oxidation state of the
element (the absorption of Se6+ is higher than that of Se4+),
nature of draining waters, and climatic conditions all influence
the distribution, status and availability of this element (Aro
et al., 1995; Barclay et al., 1995; Combs, 2001). In acid soils Se is
mainly present as selenite which has very low solubility and
plant availability. In alkaline soils, Se is oxidized to selenate,
which is more soluble and more available for uptake in the
crops. In many regions of the world Se soil levels generally
reflect the Se status in human populations (Goyer and
Clarkson, 2001; Burk and Levander, 2002). There are some
zones where Se levels in soil are very low (b0.05 ppm), such as
parts of China, Finland and New Zealand. In these regions,
diseases caused by Se deficiency in livestock and the effect on
human health are well known. Nevertheless, in regions of high
Se soil concentrations (N5 ppm), there is a net excess of this
element as observed in Canada, Ireland, some regions of the
western USA, and some zones of China, France, Germany, etc.
(Simonoff and Simonoff, 1991; Aro et al., 1995). McNaughton
and Marks (2002) reported that foods from the USA generally
have higher Se levels than Australian foods, and that foods
from United Kingdom and New Zealand have lower levels.
Efforts have been made to increase the Se content in plants by
adding Se to the soil.
Food protein content is another important factor influen-
cing Se presence in food since Se can replace sulphur in the
amino acids as selenomethionine (Se-Met), selenocysteine
(Se-Cys) and selenocystathionine due to their physicochem-
ical similarity (Simonoff and Simonoff, 1991; Navarro-Alar-
con and López-Martínez, 2000). Further, selenocompounds
would be used in the synthesis of Se-amino acids (mainly, Se-
Met and Se-Cys), and finally incorporated in vegetable
proteins. Thus, the Se forms included in the vegetable
proteins of animal feed would ultimately be employed in
the synthesis of the animal's own proteins, facilitating their
accumulation in livestock. Most plants do not have the ability
to accumulate large amounts of Se (concentrations rarely
exceed 100 μg/g, dry weight). However, various plant species
such as garlic (Allium sativum), Indian mustard (Brassica
juncea), canola (Brassica napus), and some mushrooms have
been recognized as Se accumulators. They have the ability to
take up large amounts of Se (N1000 mg Se/kg) without
exhibiting any negative effects (Dumont et al., 2006). This is
mainly due to the reduction of the intracellular Se concen-
tration of Se-Cys and Se-Met which are normally incorpo-
rated into proteins. When consumed in appropriate
amounts, these foods can be a significant food source of Se
(Dumont et al., 2006).
Industrial and agricultural activity has hastened the
release of Se compounds from geologic sources, making
them available to fish and wildlife in aquatic and terrestrial
ecosystems around the globe. In recent years, the results of
many investigations on contaminant Se conclude that Se
exhibits its toxicity in animals primarily through the food
chain (Lemly, 1999; DeForest et al., 1999; Hamilton, 2004).
Agricultural drain water, sewage sludge, fly ash from coal-
fired power plants, oil refineries, and mining of phosphates
and metal ores are all sources of Se contamination in the
aquatic environment. Specifically, bivalves (being filter-fee-
ders) have been identified as the most sensitive indicators of
Se contamination (Hamilton, 2004). Fish can take up Se from
water, plants, or by eating other marine species. Accumulation
of Se in marine animals from dietary sources (phytoplankton
ad zooplankton) is more important than that accumulated
directly from the water. In addition, Se compounds are widely
used in glass manufacture, electronic applications, photocopy
 S CIE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41 117

Table 1 – Se content in foods and beverages according to Table 1 (continued)

several authors Type of Origin Se content Reference
Type of Origin Se content Reference sample (ng/g)
sample (ng/g)
Meat, chicken, fish
fish and eggs
Milk and dairy products Salmon Australia 270–368 Marro (1996)
Cow's milk Greece 13.1–21.9 Pappa et al. (2006) Tuna (in oil)a Egypt 810.0 Akl et al. (2006)
Ireland 14–18 Murphy and Sardines Australia 570 Fardy et al. (1994)
Cashman (2001) Eggs Greece 172.8 Pappa et al. (2006)
Gouda cheese Greece 85.4 ± 10.0 Pappa et al. (2006) Australia 0.7–14.2 Marro (1996)
Yoghurt Greece 21.9–26.9 Pappa et al. (2006)
Croatia 29.9 Klapec et al. (2004) Miscellaneous
Spain 50.0 ± 30.0 Cabrera et al. (1996) Apple juice Australia 0.7–5.1 Marro (1996)
Butter Greece 4.4–13.8 Pappa et al. (2006) Beer Australia 5.00 Marro (1996)
Australia 0.7–14.2 Fardy et al. (1994) Cornflakes Greece 19.7 ± 0.6 Pappa et al. (2006)
Condensed milk Spain 75.0 ± 25.0 Cabrera et al. (1996) Australia 62.9 Marro (1996)
Ice-cream Spain 100.0 ± 40.0 Cabrera et al. (1996) Extra virgin Greece 1.1 ± 0.6 Pappa et al. (2006)
UK 15.0–17.0 Barclay et al. (1995) olive oil
Fresh buffalo milk Egypt 53 Akl et al. (2006) Olive oil Australia 5.30 Marro (1996)
Honey Greece 1.7 ± 0.004
Pappa et al. (2006)
Fruits and vegetables Herbal tea India 190 ± 18 Manjusha et al.
Apple Australia 4.5 McNaughton and (2007)
Marks (2002) Tea infusionb Australia 5.00 Marro (1996)
Australia 30.0–50.0 Marro (1996) Cardamon India 80 ± 4 Manjusha et al.
Kiwi Greece 1.4 ± 0.2 Pappa et al. (2006) (2007)
Grapes Australia 40.0–76.0 Marro (1996) Mustard seeds India 248 ± 15 Manjusha et al.
Sharon fruit Greece 3.9 ± 0.5 Pappa et al. (2006) (2007)
Mango Greece 2.6 ± 0.6 Pappa et al. (2006) Black pepper India 116 Singh and Garg
Orange Australia 5.00 Marro (1996) (2006)
Potato Australia 30.0–70.0 Marro (1996) Vinegar Spain 0.653–2.344 Díaz et al. (1997)
Greece 4.6 ± 1.4 Pappa et al. (2006) Tap water Greece 2.2 ± 0.7c Pappa et al. (2006)
Garlic Slovakia 3.5 Kadrabova et al. Sugar, raw USA 69.0 Marro (1996)
(1997) Chocolate UK 41.0 Barclay et al. (1995)
Greece 13.4–13.7 Pappa et al. (2006) USA 39.0 USDA (1999)
Celery Australia 9.3–14.2 Marro (1996) Margarine Australia 0.71–18.6 Marro (1996)
Lettuce Australia 3.0–22.8 Marro (1996) USA Ndd-10 USDA (1999)
Onion India 127 Singh and Garg New Zealand 6.00–16.0 NZ-ICFRL (2000)
(2006)
Data are referred to wet weight.
Green peas India 180 Singh and Garg a
Processed fishery food.
(2006) b
Tea, brewed 5 min.
Pepper India 150 Singh and Garg c
Data expressed as μg/l.
(2006) d
nd, Not detectable.
Greece 4.2 ± 0.3 Pappa et al. (2006)

Legumes, nuts, cereals and derivatives

Lentils USA 28.0 USDA (1999) machines, inorganic pigments, rubbers, ceramics, plastics and
New Zealand 18.0 NZ-ICFRL (2000) lubricants (Akl et al., 2006).
Bread Greece 70.0–131.8 Pappa et al. (2006) Food processing such as cooking (boiling, baking or grilling)
Pasta Greece 5.8 ± 0.2 Pappa et al. (2006) could decrease Se food content by volatilization (Dumont
Pasta, boiled Australia 35.6–50.0 Marro (1996)
et al., 2006; Sager, 2006). For example, Se losses of 40% in
Rice Greece 19.1 ± 1.4 Pappa et al. (2006)
asparagus and mushrooms were observed when boiled for
Italy 20.1 ± 45.3 Panigati et al.
(2007) some minutes (Navarro-Alarcon and López-Martínez, 2000;
Peanuts USA 75.0 USDA (1999) Dumont et al., 2006). Some Se losses have also been noted
when roasting chicken and fish (Thomson and Robinson,
Meat, chicken, fish and eggs 1990). However, other researchers did not find any decrease,
Beef, steak Australia 80–200 Tinggi (1999) and even reported that processes such as cooking, aeration or
Lamb Spain 27–30 Díaz-Alarcon et al.
lyophilization significantly increases Se content in all food
(1996a)
(Zhang et al., 1993). Considering the disparate results found in
Rabbit Spain 74–106 Díaz-Alarcon et al.
(1996a) the many studies we considered, more research in this area
Pork USA 144–450 USDA (1999) should be performed to clarify the specific influence that
Pork kidney Spain 849–1543 Díaz-Alarcon et al. different cooking processes exert on Se content of food.
(1996a) Therefore, we concluded that the content of trace elements
Pork liver Spain 256–800 Díaz-Alarcon et al. in food should not be based exclusively on food tables, but
(1996a)
should take into account loss during food processing and
Ham Australia 200 Tinggi (1999)
Oyster Australia 770 Marro (1996)
preparation, variation due to seasonal changes or geographi-
cal location, as well as food habits. Consequently, thorough
843000(continued on next page)
118 SC IE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41
and periodic determinations of trace elements such as Se is
advisable. In addition, lack of data for some foods may
introduce errors into the estimate of dietary intake of essential
elements such as Se.
1.1. Meat, chicken, fish and eggs
Data on Se content in different foods are collected in Table 1.
Meat, chicken, fish and eggs are protein-rich foods containing
high levels of Se (Klapec et al., 2004; Sirichakwal et al., 2005). In
these food groups, Ventura et al. (2007) encountered Se levels
ranging from 87.6 to 737 ng/g. Fish and eggs showed the
highest Se concentration (Pappa et al., 2006; Haratake et al.,
2007). Meat, fish and eggs contribute the major part of dietary
Se in several countries such as Greece, Portugal and Japan
(Pappa et al., 2006; Haratake et al., 2007; Ventura et al., 2007). In
Japan, fish was the greatest Se contributor (up to 60% of daily
total intake) rather than the staple foods (rice and vegetables)
(Haratake et al., 2007). Literature on Se content in fish from
different locations ranged between 62.7 and 506.7 ng/g in
Greece (Pappa et al., 2006), 120.0–632.0 ng/g in Australia
(McNaughton and Marks, 2002), 126 to 502 ng/g in the USA
(USDA, 1999), and 195 to 512 ng/g in New Zealand (NZ-ICFRL,
2000). Tinggi (1999) reported Se content in eggs from Australia
to have a mean concentration of 90 ng/g in white and 260 ng/g
in yolk (boiled eggs). Marzec et al. (2002) reported that Se levels
in meat products ranged from 55.0 to 329 ng/g. These values
were higher than those for the other food groups. Meat
showed large variations in Se concentration, reflecting the
differences in Se concentrations of the feed consumed by the
animals (McNaughton and Marks, 2002; Pappa et al., 2006).
According to Pappa et al. (2006), mean concentrations of Se in
meat from Greece ranged from 48.8 to 94.1 ng/g, with pork
measuring significantly higher beef. In sausages from Spain,
Diaz-Alarcon et al. (1996a) encountered Se levels ranging from
89.0 to 739 ng/g. These authors concluded that meat products
and cereals (mostly bread) are the main contributors to daily
Se intake in healthy individuals from South-eastern Spain. A
total of 55% of daily Se intake came from these two food
groups due to their high Se concentrations and/or consump-
tion. These findings are in agreement with other researchers
(Srikumar et al., 1992; Donovan et al., 1992) who conclude that
vegetarians and lactovegetarians suffer significantly
decreased daily Se intake, which could contribute to a
nutritional Se deficiency.
1.2. Milk and dairy products
It has been found that Se concentrations in milk from different
animal species decreases in the following order: human N
sheep N goat N cow milk. It is known that Se concentrations in
milk are negatively correlated with its fat content (Pappa et al.,
2006). A similar trend was observed by Barclay et al. (1995) in
cheeses. A survey of Se content of Australian cow milk showed
a wide variation with higher levels in summer (23.8 ± 4.6 ng/l)
than in winter milk (20.7 ± 4.2 ng/l). Cabrera et al. (1996)
determined Se content in dairy products and observed a
wide variability among the data due to the different concen-
trations of Se present in milk, eggs, cereal, fruit and other
foodstuffs used in their manufacture. These authors agree
with others such as McNaughton and Marks (2002), and Pappa
et al. (2006) who all consider that milk and dairy products
contribute a considerable fraction of the total dietary intake of
Se, particularly for infants.
1.3. Fruits and vegetables
Fruit contains low concentrations of Se (Table 1). This fact
could be explained by the low protein fraction (and therefore,
the high water content) of these products. Similarly, fresh
vegetables were also shown to be poor sources of Se
(Sirichakwal et al., 2005). Ventura et al. (2007) reported similar
Se data for fruit and vegetables from Portugal (1.7 to 24.9 ng/g).
However, it is known that vegetables such as B. juncea and the
better known species of the Brassica genus (broccoli, Brussel
sprouts, cabbage, cauliflower, collards, kohlrabi, mustards and
kale), garlic, chives and onions tend to have higher Se
concentrations and the extent to which they are consumed
is reflected in the Se content of human tissue and body fluids
(Ip and Ganther, 1994; Dumont et al., 2006; Kapolna and Fodor,
2007). These plants have a greater fraction of sulphur contain-
ing amino acids and their derivatives, but they also contain
other sulphur compounds like glycosinolates or sulfoxides.
Adequate analogues of these can be formed by substitution of
sulphur with Se, resulting in higher Se levels (Ip and Ganther,
1994). Garlic and onions seem to be a good dietary source of Se,
and both have valuable anti-carcinogenic activities. Further-
more, their intake does not result in excess accumulation of Se
in tissues; nor could any perturbation in the action of Se
enzymes be observed, even at high Se intakes (Dumont et al.,
2006). Similarly, Manjusha et al. (2007) found high Se content
in mushrooms (1340 ng/g). Some, but not all mushrooms tend
to accumulate Se because they are another vegetable species
with a high content of sulphur containing compounds. Agari-
cus bisporus is one of the most commonly studied mushrooms
for Se speciation purposes and is also the most commonly
consumed mushroom in Europe and the USA. Other mush-
rooms that accumulate Se are Boletus edulis and B. macrolepiota
(Dumont et al., 2006). Plants that accumulate Se may be used
as a natural source of mineral supplements for both animals
and human beings, especially in areas that are Se deficient.
1.4. Legumes, nuts, cereals and by-products
Pappa et al. (2006) reported that the Se content in legumes from
Greece ranged from 24.4 to 443.9 ng/g, with a mean value of
165.2 ng/g, lentils presenting the highest concentration (Table 1).
They encountered Se concentrations between 7.0 and 32.27 ng/g
in nuts. Pistachios proved to be the richest, whereas almonds
were the poorest Se source. Protein-rich nuts (pistachios,
walnuts) present higher Se concentration than other products
(Ip and Ganther, 1994; Dumont et al., 2006). Manjusha et al.
(2007) encountered a mean content of Se in Brazil nuts of
3800 ng/g. Brazil nuts (Bertholletia excelsa) are known for their
high Se concentration and one single Brazil nut could exceed the
RDA for Se (Dumont et al., 2006). The proteins found in Brazil
nuts are very high in Se-containing amino acids, mainly Se-Met.
Dumont et al. (2006), in a wide review of the literature, reported
levels of Se in cereals of 10.0–550.0 ng/g (referred to fresh
weight). Marro (1996) encountered Se levels in white bread of
 S CIE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41
80.0–109.0 ng/g (mean of 92.6 ng/g) and in whole meal bread of
100.0–152.0 ng/g (mean of 125.0 ng/g). Tinggi et al. (1992) reported
that the major source of Se in Australia comes from wheat
products such as bread (60.0–150 ng/g) and pasta (10.0–100 ng/g)
as was also reported by Diaz-Alarcon et al. (1996b). Pappa et al.
(2006) reported mean Se concentrations of bread ranging from
70.0 to 131.8 ng/g. The differences of Se content between brown,
whole-wheat and white bread were not statistically significant
(p N 0.01), although brown bread seemed to be much richer in Se
than the others.
1.5. Miscellaneous
Water Se content is usually trivial compared to the content of
this element in food (Food and Nutrition Board—Institute of
Medicine, 2000). Diaz et al. (1997) indicated that drinks and
potable water are generally poor sources of Se (Table 1).
Molnar et al. (1995) analyzed Se content in fast food from the
UK and encountered the highest levels in products based on
certain mushrooms, spinach and fish. Generally, foods
produced from Se-rich raw ingredients were themselves
high in Se. They remarked that the Se content of food varies
from sample to sample, even in cases of the same product. In
baby foods from Spain such as sole with vegetables or with
potatoes, angler fish with vegetables and hake with rice, Viñas
et al. (2000) detected Se levels that ranged from 21.5 ± 1.3 to
72.8 ± 5.3 ng/g. Roca et al. (2000) determined Se levels in virgin
olive oil, olive oil and marc oil produced in Southern Spain
ranging from undetectable to 178.51 ng/g. No statistically
significant differences were found between the three types of
oil. Singh and Garg (2006) determined Se content in Indian
spices and condiments ranging from 12 to 670 ng/g. The
highest levels were detected in turmeric (500 ng/g) and sweet
neem (670 ng/g).
Additional Se food content data from other studies and
locations are summarized in Table 1.
2. Selenium bioavailability
Selenium is one micronutrient whose deficiency and toxic
concentrations are very close each other. Therefore, it is
important to know its abundance or deficiency in food and
diet and to determine the correct balance of Se in human
beings and animals. In general, estimates of the total element
content of a given food are unreliable and the bioavailability of
the nutrient must be considered. It is a priority to know the
element bioavailability or amount absorbed and used by the
organism, because usually only a fraction is absorbed and
transformed into a biologically available form (Cabrera et al.,
1996; Cabañero et al., 2007). Ideally, a complete evaluation of
bioavailability should involve measurements of total nutrient
content, absorbable fraction, amount actually absorbed, and
percent utilized by the organism. In vivo bioaccessibility
studies are both expensive and laborious, and the possibility
of measuring certain parameters during the experiments is
often limited (Cabañero et al., 2007). In vitro bioaccessibility
methods of simulated digestion are an alternative to in vivo
bioavailability procedures for calculating the percentage of an
element that is transformed into absorbable forms in the
119
digestive tract. The results of such bioaccessibility studies are
usually expressed as the soluble fraction of the element under
given experimental conditions of pH, enzyme addition,
temperature, and duration of contact (Cabañero et al., 2007).
These bioaccessibility methods comprise a two-phase simula-
tion of gastrointestinal physiology: the stomach and intestinal
phases. In vitro bioaccessibility analytical procedures are often
useful because they are simple, rapid, inexpensive, and allow
individual experimental variables to be easily controlled
(Cabrera et al., 1996). Consequently, bioaccessibility experi-
ments offer an appealing alternative to human and animal
studies (Cabañero et al., 2007; Velasco-Reynold et al., 2008).
Se bioavailability strongly depends on the chemical form
of Se found in the food. Specifically, selenocompounds
identified in plants include selenate, selenite, selenocystine,
Se-Met, selenohomocysteine, Se-methylselenocysteine, γ-
glutamil-selenocystathionine, Se-Met selenoxide, γ-glutamyl-
Se-methylselenocysteine, selenocysteineselenic acid, Se-
proponylselenocysteine selenoxide, Se-methylselenomethionine,
selenocystathionine, dimethyl diselenide, selenosinigrin, seleno-
peptide and selenowax. However, the presence of Se-Cys in plants
is still controversial (Whanger, 2002). On the other hand,
selenocompounds in animal tissues are Se-Cys, selenotrisulfides
of cystine, selenate and selenite.
Se bioavailability is affected by its chemical form (gener-
ally, organic compounds of Se are more bioavailable than the
inorganic forms) (Thomson, 2004). The influence of other
dietary factors such as total protein, fat, and the presence of
heavy metals has been also described. Se interacts with
several trace elements, and these interactions can be additive,
antagonistic, or synergistic, and in some cases they reverse
the interaction, i.e. antagonism changed to synergism (Hamil-
ton, 2004; Akl et al., 2006). Perhaps one of the most reported
interactions between inorganic elements is the antagonistic
interaction between Hg and Se. Se is recognized to decrease Hg
toxicity when both elements are simultaneously admini-
strated (Caurant et al., 1996; Cabañero et al., 2007).
Approximately 80% of dietary Se is absorbed, although this
figure depends on the types of food consumed. Overall
absorption of all forms of Se is relatively high (70–95%), but
varies according to the source and the Se status of the subject.
Wheat and meats are the most important Se dietary sources.
Se tends to be present in relatively high concentrations and,
compared with Se salts, Se in these foods is highly bioavailable
(Finley, 2006). Several studies have shown that Se bioavail-
ability in meat is high because Se forms in foods of animal
origin are mostly Se-Cys and Se-Met (Van der Torre et al., 1991;
Dumont et al., 2006). Se-Met is an essential selenoaminoacid,
which is the major nutritional source of Se for animals, and it
is known to be highly bioavailable. It is absorbed in the small
intestine, being incorporated into the long-term body reserves
(Hinojosa et al., 2006). Although Se content in fish is high, in
some cases fish is a poor source of available Se, due in part to
its high Hg content and other heavy metals, which bind to Se
forming insoluble inorganic complexes (Van der Torre et al.,
1991; Pappa et al., 2006). However, when looking at the
bioavailability of Se in fish, source and species are important.
For example, existing data shows high Se availability from
salmon (Ornsrud and Lorentzen, 2002). Dumont et al. (2006)
reported that the order of bioavailability for Se species of
120 SC IE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41
Atlantic salmon is: Se-Met N selenite N Se-Cys N fish meal.
Absorption of Se from fish by humans is comparable to that
from plants. Fox et al. (2004) indicated that Se in fish is a highly
bioavailable source of dietary Se, and that cooking the fish did
not affect Se absorption or retention. These authors also
observed that Se from yeast is less bioavailable. Finley (2006)
observed that reports on Se bioavailability from yeast are
mixed; one group reported that Se from yeast was effective for
increasing the concentration of Se in red blood cells, but
compared with selenite and selenate, was ineffective for
increasing GPx activity. Contrarily, another group reported
that Se from yeast was almost twice as bioavailable as Se from
selenite and selenate for restoration of depleted GPx activity.
These discrepancies may reflect differences in the study
populations as well as a difference in the chemical speciation
of Se in yeast. Cabrera et al. (1996) reported a mean absorbable
fraction of Se of 80.0 ± 10.0% in dairy products such as yogurt,
custard, cream cheese, curd, crème caramel, ice-cream, and
condensed milk. Barrionuevo et al. (2003) indicated that the
goat-milk has an important and beneficial effect on the Se
bioavailability. Finley et al. (2004) concluded that the chemical
forms of Se species also differ among foods. For example, in
broccoli, which is a Se-accumulating plant that contains many
methylated forms of Se, its bioavailability has been reported to
be low. However, red meats such as pork or beef could
accumulate Se when the animal is fed high Se diets, and Se
from such meats has been reported to be highly bioavailable
for selenoprotein synthesis.
Lacour et al. (2004) reviewed 1290 valid studies providing
reliable evidence of the therapeutic benefits of Se supple-
ments in environmentally associated health disorders. They
concluded that none of the studies showed evidence of
therapeutic benefits from Se supplementation in environmen-
tally associated health disorders. Several pharmacological
factors of human Se supplements influence Se bioavailability
such as the physicochemical form, interactions with other
micronutrients in the supplement, interaction with other
medications being taken, taking the supplements in fasting or
meal conditions, and finally timing, dose and scheduling of
supplementation. These factors are very interesting because
most studies focus on the influence of dietary factors on Se
bioavailability from supplements such as fibre content,
presence of oxalate, phytate, protein, polysaccharides, and
amino acids, etc (Lacour et al., 2004). Several studies have been
conducted on the bioavailability of various Se forms (Lacour
et al., 2004; Stibilj et al., 2005). In general, animal trials
demonstrated that bioavailability of organic Se (Se-Met and
Se-yeast) was higher than inorganic forms (selenite and
selenate). The same trend was observed in human studies
(Lacour et al., 2004; Dumont et al., 2006).
3. Selenium total dietary intake
Diet is the major source of Se and intake of this essential
element depends on its concentration in food and amount of
food consumed (Navarro-Alarcon et al., 2005). Combs (2001)
indicated that an adequate adult diet should have at least
40 μg/day of Se to support the maximum expression of Se
enzymes and perhaps as much as 300 μg/day to reduce cancer
risk. Deprivation of Se is associated with reduced antioxidant
protection, redox regulation and energy production as a
consequence of suboptimal expression of one or more of the
Se-containing enzymes (Thomson, 2004). At the same time,
supranutritional intakes of Se (more than required for Se-Cys
enzyme expression) appear to reduce cancer risk (Combs et al.,
2001). Hamilton (2004) reported the existence of three Se levels
of biological activity: (1) trace concentrations are required for
normal growth and development; (2) moderate concentrations
can be stored and homeostatic functions maintained; and (3)
elevated concentrations can result in toxic effects. Accord-
ingly, low Se status is likely to contribute to morbidity and
mortality due to infectious as well as chronic diseases, and
increasing Se intakes in all parts of the world can be expected
to reduce cancer rates (Tinggi, 2003). The Recommended
Dietary Allowance (RDA) for Se for both men and woman is
55 μg/day (0.7 μmol/day) (Food and Nutrition Board—USA
Institute of Medicine, 2000). This recommendation is based on
the amount needed to maximize synthesis of the selenopro-
tein glutathione peroxidase (GPx), as assessed by the plateau
in the activity of the plasma isoform of this enzyme. The
Tolerable Upper Intake Level (UL) for adult is set at 400 μg/day
(5.1 μmol/day) based on selenosis being the adverse effect
(Food and Nutrition Board—USA Institute of Medicine, 2000).
In Finland the effect of fertilizing of soil with sodium selenate
significantly increased the daily dietary intake of Se from 39 to
92 μg per person per day (Varo et al., 1988). In Denmark the Se
dietary intake has been estimated to 343 μg/week, and meat,
fish, egg, milk, cheese and cereals have been identified as the
most important sources (Johansen et al., 2000). Marzec et al.
(2002) evaluated the average daily intake of Se in Poland to be
less than or near recommended levels, but concluded that Se
food supplements are unnecessary. Several researchers (Sri-
kumar et al., 1992; Donovan et al., 1992) revealed that
vegetarians and lactovegetarians significantly decrease daily
Se intake, and consequently could induce a deficient Se
nutritional status. Benemariya et al. (1993) determined the
daily dietary intake of Se in Burundi, Africa as 17 μg, and
concluded that rural populations risk Se deficiency. However,
data for most parts of Africa, Southern Asia, and South
America are scarce or absent. Table 2 shows the daily intake
of Se from selected countries. These data demonstrate the
wide variability between countries. But we consider that
healthy individuals with a balanced and varied diet should
have an appropriate Se nutritional level and do not need a
supranutritional intake of this element.
4. Selenium supplementation
Several authors considered that Se supplementation can be
beneficial for individuals in regions with very low environ-
mental Se levels (Simonoff and Simonoff, 1991; Chan et al.,
1998; Grashorn, 2006). In some areas where soil Se is low,
different strategies have been followed to supply the popula-
tion with sufficient Se:
(1) Use of Se-enriched fertilizers: In order to reach Se RDAs,
some countries like Finland, for example, decided in 1984
to add sodium selenate to farmlands (Varo et al., 1988).
 S CIE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41 121

Table 2 – Estimated Se intakes (μg/day) from selected exploited for the production of Se-rich plants meant
countries for export to other countries. Agricultural products are a
Country Se (μg/day) Reference rather sensitive indicator of available Se in soil (Hartikai-
nen, 2005). Experiments with tomatoes have shown that
Belgium 28–61 Robberecht et al. (1994)
Se levels can be increased by a factor of 100 by using Se-
Canada 98–224 Gissel-Nielsen (1998)
China (Keshan area) 3–11 Dumont et al. (2006) enriched fertilizer (Aro et al., 1995). Certain fertilizers,
Finland however, (sulphate, phosphorus and nitrogen) can lower
Before using Se 25 Aro et al. (1995) Se uptake and modify the synthesis of Se-containing
fertilizer amino acids (Aro et al., 1995). This technology needs
After using Se fertilizer 67–110 Anttolainen et al. (1996) further investigation since there are no data available on
Greece 39.3 Pappa et al. (2006)
the effect of Se-fertilizers on microbial population of the
Libya 13–44 El-Ghawi et al. (2005)
Lithuania 100 Golubkina et al. (1992)
soil (Surai, 2006).
México 61–73 Valentine et al. (1994) (2) Supplementation of farm animals with Se. The need for Se has
Netherlands 67 Foster and Sumar (1997) resulted in the rise of direct Se enrichment of certain
New Guinea 20 Donovan et al. (1992) foods, such as using Se-enriched fertilizer. However,
Norway 80 Meltzer et al. (1992) part of the Se in these food products is lost (volatiliza-
Scotland, United Kingdom 30–60 MacPherson et al. (1997)
tion, degradation) during harvesting and manipulation
Sweden 38 Dumont et al. (2006)
prior to consumption (Dumont et al., 2006). In Australia,
Switzerland 70 Dumont et al. (2006)
Spain (South-eastern) 72.6 Díaz-Alarcon et al. subclinical Se deficiency has largely been eliminated as
(1996a) a result of intervention programs which give Se supple-
Turkey 30 Dumont et al. (2006) ments to animals. Tinggi (2003) reported a number of
United Kingdom 34 Barclay et al. (1995) Australian Se supplement strategies to increase Se in
USA 60–160 Longnecker et al. (1991) farm animals. These strategies include: a) direct appli-
cation of Se to pastures to increase Se uptake by plants
for animal feed; b) supply of sodium selenite or selenate
incorporated into salt blocks or licks; c) direct adminis-
Hartikainen (2005) indicated that this supplement posi- tration of Se to animals by drenching with Se salt
tively affects not only the nutritive value of the entire solutions such as sodium selenite; and d) the use of Se
food chain (soil to plants to animals to humans) but also pellets that slowly release Se in the animal's gut.
improves plant yields. The level of Se addition proved Recently, a technological process to produce Se-
optimal and no abnormally high concentrations in the enriched eggs, meat and milk has been developed and
food chain were observed. In fact, plants act as effective successfully introduced in various countries worldwide
buffers, because their growth is reduced at high Se levels. (Surai, 2006). Indeed, Se-enriched eggs are produced in
They also tend to synthesize volatile compounds in order more than 25 countries worldwide. Se-pork and Se-milk
to reduce excess Se. Thus, supplementing fertilizers with are on the market shelves in Korea. Such products can
Se can be considered a very effective and readily deliver 50% RDA of Se with a single egg or portion (80–
controlled way to increase the average daily Se intake 100 g) of Se-pork or Se-chicken. Recently, a new brand of
nationwide. In 1985, the first results were observed, Se-enriched eggs called Vi-Omega-3 was developed in
showing increased Se levels in milk, meat, and eggs from Greece delivering 22 μg Se with a single egg (Pappa et al.,
7 to 8, 4 to 5, and 2 to 3 times, respectively (Varo et al., 2006). Bourre and Galea (2006) described a new natural
1988). According to Hartikainen (2005), in meat and meat multi-enriched egg as an important source of omega-3
products from Finland, Se increased 13-fold from 1985 fatty acids, vitamins D and E, carotenoids, iodine, and
to1991, and fertilization induced drastic changes in Se selenium (45% RDA). These authors remarked that these
concentrations of agricultural products. For instance, in eggs are beneficial for everyone and particularly appro-
spring cereals the increase was generally 20–30 fold priate for older people. Muñiz-Naveiro et al. (2006)
during the first years of supplementation. Milk has been indicated that it is possible to obtain Se-enriched cow
the most sensitive indicator, and was the first to reveal milk at different concentrations without altering the
changes in food quality induced by Se fertilization. Se original composition of the milk. Lyons et al. (2007)
supplementation of fertilizers has substantially affected remarked that optimizing Se nutrition for poultry and
average Se intake. Higher values of total Se intake in farm animals increased efficiency of egg, meat and milk
Japan, Australia, Finland, and the USA are partly due to production and, more importantly, improved quality.
Se-enriched fertilizers (Aro et al., 1995; Anttolainen et al., Recent advances in genomics and proteomics, along
1996; Dumont et al., 2006). In China, Se supplementation with newly described selenoproteins, will be a driving
has been widely used to control Keshan and Kashin–Beck force in reconsidering old approaches to Se nutrition
diseases (Tan et al., 1987), even though the latter disease (Kellof et al., 2000). Grashorn (2006) described the
probably is a combined result of deficiencies of two trace production of poultry enriched with conjugated linoleic
elements, Se and iodine. Hartikainen (2005) reported that acid, omega-3 fatty acids and selenium in such a way
the impact of Se fertilization on the occurrence of human that 100 g of enriched tissue provides 3 to 11%, 60 to 70%
diseases is difficult to judge. Furthermore, areas with and/or 200% and 60% of the RDA for humans, respec-
seleniferious soil (concentrations N 1 mg/kg) become tively. However, these authors indicated that some
122 SC IE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41
observed aberrations in meat quality make more
research necessary. Detailed investigations on possible
interactions between other nutrients in Se-enriched
food are still missing. Several investigations are in
progress by various research groups to measure Se
bioavailability and organoleptical properties of food
enhanced by this element (Finley, 2006).
(3) Human intake of multimicronutrient supplements containing
Se. During the last decade, the pharmaceutical market
became overwhelmed with nutritional supplements or
‘nutraceuticals’ based on Se. Two different types can be
distinguished: a) multi-vitamin and multi-mineral pre-
parations containing inorganic Se, other trace elements
and vitamins, and b) supplements based on Saccharo-
myces cerevisiae yeast. Se-enriched yeast supplements
have been widely studied (Dumont et al., 2006). Sele-
nized yeast has been the primary Se dietary supplement
and is the most attractive source of Se-Met due to its low
cost and ability to act as a precursor for Se-containing
protein synthesis (Hinojosa et al., 2006). Se-yeast can be
consumed in food or as a nutritional supplement.
Another possibility is to use selenized yeast instead of
conventional yeast for baking bread. The use of Se-yeast
for this purpose could result in higher population Se
intake since bread is such a commonly consumed
product. Moreover, Se in Se-yeast is stable even at
higher temperatures (Dumont et al., 2006). S. cerevisiae
has a high protein content which improves Se absorp-
tion. Mostly, Se is added to the growth medium as
Na2SeO3, and Se is mainly incorporated as Se-Met in
proteins. S. cerevisiae may assimilate up to 3000 μg Se/g.
Moreover, the production of Se-enriched yeast is more
manageable than the production of Se-enriched plants
(Dumont et al., 2006). Data on toxicity of Se from Se-
yeast are rather scarce (Dumont et al., 2006). These
authors remarked that the overall production of Se
supplements urgently needs control because suppliers
provide information on total Se concentration, but little
or no information on the Se species present.
Stibilj et al. (2005) investigated the advertised values of Se
in food supplements, and discovered that the difference
between the advertised and measured Se values varied by
10% in 9 out of 13 supplements. Furthermore, 2 of the 14
supplements did not comply with the recommendations
stated in the 27th edition of the USA Pharmacopoeia, which
states that minerals and vitamins in food supplements should
be within the range 90 to 200% of the declared value. B'Hymer
and Caruso (2000) evaluated six different brands of yeast-
based Se food supplements obtained from local stores in the
USA. All Se supplements were found to have near label values
based on total Se, and had reasonable uniformity in tablet to
tablet content. Nevertheless, each brand had dramatically
different profiles for the chemical form of Se present within
the supplement.
In recent years, our habits have been strongly influenced by
publicity about the necessity of multimicronutrient supple-
ments in the normal diet as a method of fortifying inadequate
diets with micronutrients such as Se. Different population
groups are considered a higher risk of deficiency, such as
infants, the elderly, athletes, and healthy people with a high
concern for diet and fitness. There is a belief that physical
activity increased vitamin and mineral requirements, mainly
those related with the oxidative stress such as Se. This could be
an important reason why a majority of athletes ingest large
doses of micronutrient supplements (Navarro-Alarcon and
López-Martínez, 2000). Additionally, the relationship between
Se, disease and degenerative pathologies related to aging has
also contributed to an increase in consumption of supplements.
5. Physiological role of selenium
Selenium is a component of several selenoproteins with
essential biological functions (Van Cauwenbergh et al., 2004)
(Table 3). This element acts as a cofactor of the GPx family of
enzymes which protect against oxidative stress. Specifically,
Se-dependent GPx enzyme recycles glutathione, reducing lipid
peroxidation by catalyzing the reduction of peroxides, includ-
ing hydrogen peroxide (Fig. 1). In general all these enzymes at
their reduced state catalyse the breakdown of lipid hydroper-
oxides and hydrogen peroxides in human cells (Navarro-
Alarcon and López-Martínez, 2000; Van Cauwenbergh et al.,
2004; Hartikainen, 2005; Navarro-Alarcon et al., 2005). From all
these associated enzymes, GPx and selenoprotein P are also
involved in the regulation of the inflammatory response (Van
Cauwenbergh et al., 2004).
Moreover, the antioxidative function of Se can help to
ameliorate the damage induced by the ultraviolet-β radiation
in humans. In farm animals diseases associated with Se
deficiency have been an important problem. White muscle
disease is a nutritional muscular dystrophy that is the most
common Se deficiency disease (Peter and Costa, 1992). Usually
actively growing animals suffer from this disease, showing
symptoms weakness, problems with feeding, and cardiac
implications that very often produce death. On the other hand,
subclinical deficiency levels are associated with poor growth,
impairment of animal production, and decrease in immune
efficiency (Peter and Costa, 1992).
On the other hand, the selenoprotein P is a plasma protein
whose source is the liver and kidney. This protein constitutes
the main plasma Se carrier carrying more than 60% of plasma
Se. Besides, it is known that the protein levels depend on the
body's Se status, such that it has been used as a biomarker of
body Se content. Particularly, the selenoprotein P acts as an
extra cellular antioxidant associated with the vascular
endothelium which diminishes the peroxinitrile (ONOO−)
level that represents reactive nitrogen specie (Li et al., 2007).
Iodothyronine-50-deiodinases (IDIs) are enzymes that con-
vert the hormone tetraiodine thyroxin (T4) to triiodine thyroxin
(T3) during the thyroid hormone metabolism (Table 3). Conse-
quently, these enzymes are involved in the synthesis of
thyroid sulphated hormones (Navarro-Alarcon et al., 2005).
An association between Se status and low plasma T3 levels
showing diminished IDI function has been reported by several
researchers (Strain et al., 1997). There exist three types of IDIs
called type I, II and III with different physiological activities:
type I is mainly responsible for the T3 levels in the blood stream
and is specifically inhibited by the propyl thiomecile. IDI type II
also participates in the transformation of T4 to T3 when the
 S CIE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41
Table 3 – More significant mammalian selenoproteins and corresponding biological function (Burk and Levander, 2002;
Sunde, 2000; Whanger, 2002)
Selenoproteins
Glutathione peroxidases [GPx1 (in erythrocytes or cystolic), GPx2 Antioxidant enzymes that protect against the oxidative stress by
(gastro intestinal), GPx3 (in plasma or extracellular) and GPx4 scavenging of hydrogen peroxide and lipid and phospolipidic
(phospholipid hidroperoxide or intracellular)]
Iodothyronine deidodinases (three isoforms: type I in liver, kidney and Synthesis and metabolic regulation of thyroid sulphated hormones (T3,
thyroid gland; type II in encephalon; and type III inactivant)
Thioredoxin reductases (also three isoforms)
Selenoprotein P
Selenoprotein W
Selenophosphate syntetase (two isoforms)
Mitochondrial capsule selenoprotein
Prostate epithelial selenoprotein
DNA-bound spermatid selenoprotein
18 kDa selenoprotein
thyroid gland is stimulated. This enzyme is the only one
composed of two Se atoms. Finally the IDI type III catalyses the
change from T4 to inverse T3 and from T3 to T2 protecting the
brain from possible plasma Se concentrations lower than
67 μg/l, which have been related to diminished peripheral
capacity for the change of T4 to T3 (Duffield et al., 1999; Thorne,
2003).
Thioredoxin reductase (TR) is also a Se-dependent enzyme
(Sunde, 2002) involved in the reduction of intracellular
substrates (Table 3). When rats were administered consider-
ably higher Se amounts than the RDA, their TR activity was
directly enhanced (Allan et al., 1999, Thorne, 2003). For some
forms of Se at very high doses, the TR enzyme has been
associated with anticancer effects (Ganther, 1999).
Several studies have also found that Se protects animals
against toxicity associated with high exposure and/or intake
of heavy metals like mercury, lead, cadmium and silver
(Levander and Burk, 1994; Caurant et al., 1996; Thorne, 2003;
Navarro-Alarcon et al., 2005; Cabañero et al., 2007; Kibriya et
al., 2007; Mousa et al., 2007). Experimental findings have
reported that Se-deficient rodents are susceptible to the
prenatal toxicity of methyl mercury. In this sense, important
changes of selenoenzymes activity, namely GPx and IDIs, have
been found in neonates (Watanabe, 2001). Kibriya et al. (2007)
suggested that long-term Se supplements may revert some of
the gene expression changes presumably induced by chronic
As exposure in individuals with pre-malignant skin lesions. In
recent years, genomic and proteomic concerns have been
considerably raised. For example, Kibriya et al. (2007) found
that in one study that many genes, after Se supplementation,
were upregulated. However, previously, these authors, in
subjects with As induced skin lesions, found the same genes
to be down-regulated. Consequently, these findings could help
to define the biological effect of Se supplementation in
123
Biological function
hydroperoxides. Finally, H202 and a wide range of organic
hydroperoxides are transformed to water and corresponding alcohols,
respectively.
T4 and T2).
Reduction of intracellular substrates like dehydroascorbic being related
with anticancer effects. Specifically it participates in the reduction of
nucleotides in the DNA synthesis as well as in the regulation of gene
expression by redox control of binding of transcription factors to DNA.
Extracellular antioxidant associated to the vascular endothelium that
protects endothelial cells against damage from peroxynitrite.
Although it is necessary for muscle function its biological function is
still unknown.
Necessary for the biosynthesis of selenophosphate and, consequently,
for that of S-Cys necessary for the selenoprotein synthesis.
GPx4 form that shields developing sperm cells from oxidative damage.
It is a 15 kDa selenoprotein that seems to have redox function that
resembles that of GPx4 in the epithelial cells of ventral prostate.
It is a 34 kDa selenoprotein with a biological activity like the GPx.
Essential selenoprotein preserved in selenium deficiency.
humans. Similarly, Mousa et al. (2007) also discovered that
the pro-angiogenesis action of sodium arsenite or stimulation
of basic fibroblast growth factor (b-FGF) was originated by the
activation of the extracellular signal-regulated kinases 1 and 2
(ERK-1/2) pathway. However, this pathway was significantly
blocked (p b 0.01) by different Se compounds (dimethyl sele-
none, diphenyl selenone, sodium selenite or Se-Methyl Se-
Cys) demonstrating that pro-angiogenesis As action was
reversed by Se-derived compounds (Mousa et al., 2007).
Wangher et al. (2001) also reported that Se even counter-
acts the neurotoxicity of Hg, Cd, Pb and V by a mechanism that
causes their accumulation in the brain, presumably in a non
toxic complex.
6. Assessment of body nutritional status on
selenium
When a Se deficiency is established, the activity of Se-
dependent enzymes diminishes depending on the enzyme
type and body tissue. Of all the enzymes, the activities of the
plasmatic and hepatic GPxs are the most dependent on the Se
supply. Therefore, they are employed as evaluation indices of
nutritional Se status. Specifically, GPx appears as 4 isoforms of
which the presence of classic or citosolic-GPx in plasma is a
good Se status indicator in humans (Persson-Moschos et al.,
1995). Additionally, several human fluids and tissues (whole
blood, plasma, serum, hair and toenails) can also be used to
assess the nutritional Se status. In fact, in most studies the Se
status has been assessed by measuring the element either in
serum or plasma erythrocytes, platelets or whole blood, and
by determining the GPx activity in whole blood or platelets.
Recently, levels of selenoprotein P, a Se-rich protein mainly
present in plasma, have also been used as good Se indicator in
124 SC IE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41

Fig. 1 – Antioxidant action of Se as cofactor of the glutathione peroxidase of the erythrocyte (taken from Navarro-Alarcon et al.,
2005). GSSG: oxidized glutathione. GSH: reduced glutathion. GSSG-R: glutathion reductase. G-6-PD: glutathion 6-phosphate
deshidrogenase. SOD: superoxide dismutase.

human beings (Persson-Moschos et al., 1995). Human nail
clippings have also been employed in epidemiological studies
as indicators of Se exposure (Slotnick and Nriagu, 2006). It is
believed that nail clippings show the exposure that occurred
over the past 6 to 12 months. On the contrary, blood and urine
are markers of shorter exposure periods (Navarro-Alarcon and
López-Martínez, 2000; Slotnick and Nriagu, 2006). In fact, urine
and blood Se levels show recent intake for no longer than
several days for urine or several weeks for blood-based
measurements, respectively.
From all biomarkers previously reported, blood, plasma
and serum Se levels are usually employed to evaluate Se
status and intake (Thomson, 2004; Batáriová et al., 2005). For
long-term Se status, toenails and hair levels are often
employed as markers (Mannisto et al., 2000; Slotnick and
Nriagu, 2006). Collecting them is non-invasive and it is easy to
store samples long-term (Slotnick and Nriagu, 2006). However,
highly variable intra hair biology and pharmacokinetics
(Harkins and Susten, 2003) as well as contamination by Se-
containing shampoos affect hair sample suitability. Nails, on
the contrary, have less external contamination and growth
rates are less variable (Slotnick and Nriagu, 2006).
On the other hand, Se urinary excretion is closely
correlated with plasma and serum and could be used to
monitor recent dietary intake of Se. Thomson (1998) reported
that Se urinary excretion constitutes between 50 and 60%
of the total amount excreted, so dietary intake could be
estimated simply by multiplying by two the daily urinary
excretion of Se.
Despite everything previously stated, tissue Se concentra-
tion may not accurately show functional activity, which varies
depending on the Se specie ingested. Therefore, more accurate
and reliable biomarkers of element status should show the Se
amounts available for functional selenoproteins (Thomson,
2004). In certain circumstances, it is also necessary to concur-
rently measure the concentration of several selenoproteins. In
 S CIE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41 125

this sense GPx activity (GPx3 and GPx1) (Table 3) is used to
assess the effect of different Se species supplementation as well
as monitoring element status in population groups (Zachara
et al., 2006) assuming that maximum enzyme activity is not
reached [approximately at 100 μg Se/l of blood (Nève, 1991;
Thomson, 2004)]. Taking into account everything previously
stated, platelet GPx seems to be a more sensitive indicator of
increased Se intake during supplementation trials, showing
enhancements in its activity after 1 to 2 weeks. Due to the fact
that Se deficiency diminishes levels of selenoproteins, they are
being used nowadays [namely selenoprotein P, tyroxine (T4) to
tri-iodothyronine (T3) ratios, TR] to monitor body Se nutritional
status (Persson-Moschos et al., 1995; Tinggi, 2003; Thomson,
2004; Xi et al., 2005; Karunasinghe et al., 2006). It has been
reported that the use of GPx as an index of Se status may not be
appropriate (Xi et al., 2005). They also found that the full
expression of selenoprotein P requires a greater Se dietary
exposure than that for plasma GPx activity. Consequently, Xi
et al. (2005) concluded that selenoprotein P is a better indicator
of Se nutritional status. Nevertheless, Wang (2006) stated that
due to the fact that selenoprotein P does not adequately focus
on the clinical specificities of different Se-responsive diseases,
the adoption of selenoprotein P as the principal standard for Se
status evaluation would not be appropriate. Therefore, biomar-
kers should be selected to match the characteristics of different
Se-responsive diseases (Wang, 2006).
Table 4 summarizes mean and range of serum, plasma and
whole blood Se levels measured in healthy individuals from
different countries as biomarkers of Se nutritional status of
defined population groups. As a general tendency, Se con-
centrations in serum and plasma were lower in females than
in males but not at a statistically significant level (p N 0.05), as
was previously reported (Navarro-Alarcon and López-Martí-
nez, 2000; Van Cauwenbergh et al., 2004). Most of the studies
collected in Table 4 (≅ 63%) reported “normal” Se concentra-
tions: serum or plasma Se levels ranging from 61–99 μg/l (Nève,
1991). Large geographical variation in Se intake due to varying
soil Se levels has been found, which correlates to the high
variability in Se serum and plasma levels measured in
different countries. This variability depends on geographical
location, climatological characteristics like annual rain, Se
species existing in soils, soil pH, type of plants cultivated, diet

Table 4 – Mean serum, plasma and whole blood Se levels measured in healthy individuals from different countries
Population group n (sex) Mean Se Se range Area (country) Reference
(age and characteristics) (μg/l) (μg/l)

Health adult individuals 130 (56 M, 74 F) 74.9 ± 27.3 30.2–175.0 Granada Navarro et al.
(South-eastern Spain) (1995)
General population 126.0 Singapore Hughes et al. (1998)
Pregnant women 158 F 76.6 46.2–106.9 Valencia Ferrer et al. (1999)
(Eastern Spain)
Healthy individuals from 6 to 75 years old 395 (187 M, 208 F) 74.7 ± 25.2 7.9–182.3 Canary Islands Díaz-Romero et al.
(Spain) (2001)
Adult population (20–40 years old) 201 (66 M, 135 F) 100.0 35.8–185.6 Mumbai (India) Raghunath et al.
(2002)
Healthy volunteers aged 19–74 years old 40 (20 M, 20 F) 67.4 ± 38.6 20.0–129.8 Lower Silesian region Luty-Frackiewicz
(Poland) et al. (2002)
Healthy adult subject aged 24–45 years old 50 89.5 ± 15.6 Bydgoszc (Poland) Czuczejko et al.
(2003)
Healthy volunteers (mean age: 39.6 years) 30 (23 M, 7 F) 73.2 ± 9.9 56.5–94.5 Rio de Janeiro Da Cunha et al.
(Brazil) (2003)
Individuals of the NHANES III (1988–1994) 14,619 (7,102 M, 124.5 ± 0.2 (M) – USA Kafai and Ganjii
7,517 F) 122.0 ± 0.2 (F) – (2003)
Healthy Caucasian volunteers sampled 26 (13 M, 13 F) 84.3 51.4–121.7 Antwerp region Van Cauwenbergh
once a month during 1 year (23–69 years) (Belgium) et al. (2004)
Healthy volunteers recruited from 31 (17 M, 14 F) 216.2 ± 7.4 Taiwan (China) Ko et al. (2005)
blood donor aged 43.2 ± 1.7 years old
Healthy individuals aged N 16 years old 160 (106 M, 24 F) 100.6 ± 13.0 75.0–134.0 Tehran (Iran) Safaralizadeh et al.
(2005)
Healthy adult blood donors 2,414 (1,781 M, 84.2 ± 20.2 b40.0–N 120.0 Czech Republic Batáriová et al. (2005)
aged 20–45 years old 633 W)
Elderly women aged 60–70 years old 187 F 92.4 ± 17.4 – Hannover Wolters et al. (2006)
(Germany)
Healthy individuals aged 18–65 years old 153 (81 M, 78 F) 85.9 ± 24.0 41.7–183.0 Vienna (Austria) Gundacker et al.
(2006)
Institutionalized elderly people 205 86.2 ± 17.0 Asturias González et al. (2006)
aged 60–80 years old (80 M, 125 W) (Northern Spain)
Healthy adult individuals 50 (25 M, 25 F) 129.0 ± 21.5 Taiwan (China) Lin et al. (2006)
aged 48.5 ± 13.2 years old
Subjects aged ≥ 15 year old and that have 401 75.0 ± 28.3 35.2–160.4 Zhou Koudian Li et al. (2007)
been living in their own for over 5 years (128 M, 272 F) (China)
Healthy adult women 41 F 105.0 66.4–137.0 Helsingborgh Rossborg et al. (2007)
(Southern Sweden)
126 SC IE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41
composition, technological and cooking treatments, as well as
additional factors influencing Se bioavailability like food
composition and other nutrients present in diet.
7. Selenium metabolism and pharmacokinetics
Although it has been reported that Se metabolism in the body
is not completely understood, it is known that Se-Cys is the
major selenocompound present in selenoproteins of body
tissues (Sunde, 2000).
The total amount of Se in the human body varies from 10 to
20 mg. Fifty percent of body Se is located in the skeletal
muscles, although organs like the kidneys, testes and liver
have the highest relative concentration of Se. On the other
hand, cells that reveal a higher consumption of Se are those of
the immune system, erythrocytes and platelets. Se is mainly
eliminated from the body by urine, although significant losses
via faeces also occurs (Burk and Levander, 2002). Additionally,
low amounts of Se are lost through the skin and respiration. It
is known that several Se species present in foods are usually
well absorbed in the gut of human beings (the usual
absorption rate ranges from 50 to 100%) (Sunde, 2000;
Navarro-Alarcon et al., 2005).
Se-Met is absorbed by the same active transport mechanism
used by methionine because Se can substitute for sulphide
atoms due to its similar ionic radius. The selenate is actively
absorbed by a mechanism common to sulphate, depending on
the Na+ gradient and maintained by the Na+/K+ ATPase. On the
other hand, Se-Cys and selenite are not absorbed by active
transport and their capture is not inhibited by similar sulphur
compounds or by body Se status (Mataix Verdu and Llopis, 2002).
Several selenocompounds exist in animal and plant tissues
(Fig. 2) (Gammelgaard et al., 2008). Specifically, selenate is the
major inorganic selenocompound found in both animal and
plant tissues (Whanger, 2002). On the other hand, Se-Met is
the predominant selenocompound in cereal grains, grassland,
legumes and soybeans, and, in some cases, Se-enriched yeast.
Finally, Se-methylselenocysteine is the major selenocom-
pound in Se enriched plants such as garlic, onions, broccoli
flowers and sprouts, and wild leeks (Whanger, 2002). Se-Cys,
mainly from meat, is directly used in the GPx synthesis.
Nevertheless, Se-Met from plants can directly replace methio-
nine amino acid during the synthesis of Se-containing
proteins (Fig. 2). On the other hand, selenate and selenite
incorporate directly into the Se pool when used in synthesis of
specific selenoproteins and Se-containing proteins, indepen-
dent of their origin (animal or vegetable) (Brody, 1999; Mataix
Verdu and Llopis, 2002; Navarro-Alarcon et al., 2005).
In general, the human body metabolizes the various Se
forms into selenide as HSe− (Fig. 2) which seems to be the
common point for regulating Se metabolism (Brody, 1999; Burk
and Levander, 2002; Mataix Verdu and Llopis, 2002; Navarro-
Alarcon et al., 2005). It has been found that animals synthesize
many different intermediary metabolites during the conver-
sion of inorganic Se to organic forms or vice versa (Ganther,
1999). As mentioned above, HSe− ion is a key metabolite
formed from inorganic sodium selenite via selenodiglu-
tathione through reduction by thiols and NADPH-dependent
reductases and released from Se-Cys by liase action (Bjorn-
stedt et al., 1992). Although the main pathway in animals is
methylation, demethylation back to inorganic Se can also
occur. Hydrogen selenide (by a previous activation to seleno-
phosphate) provides Se for synthesis of selenoproteins
(Ganther, 1999). After the catabolism of Se-containing proteins
and, subsequently, component amino acids, the Se of the Se-
Met is finally available for its specific use. In this sense, Se
entered into the upregulated metabolism and could be
incorporated in macromolecules to be transported to other
organs or even excreted (Burk and Levander, 2002).
Serum and plasma Se levels depend on the Se bioavailable
fraction present in diet. In plasma, two selenoproteins have
been cited as extracellular carriers of Se, namely selenoprotein
P and GPx-3. However both of these selenoproteins contain Se
as Se-Cys making neither of them likely carriers of Se.
Nevertheless, low molecular weight forms of Se have been
identified as possible Se carriers in plasma. Of all the organs,
the liver and kidneys show the highest capacity to accumulate
this element. High Se levels found in the liver counteract
methyl mercury toxicity by facilitating its accumulation as
mercuric selenide (Caurant et al., 1996).
Although the mechanism that regulates production of
excretory metabolites has not still been discovered, urine
excretion has been reported to be the body's mechanism for
maintaining Se homeostasis (Mataix Verdu and Llopis, 2002).
Therefore, under physiological conditions, Se homeostasis is
not regulated by absorption but rather by urinary excretion
(Gammelgaard et al., 2008). Despite this, the transporters,
receptors and enzymes involved in the absorption or move-
ment of Se across membranes of intestinal cells are generally
unknown (Sunde, 2002).
Intestinal excretion of Se is a secondary path of elimination.
It has also been observed that when the body Se status is low,
urinary Se excretion is diminished to keep element home-
ostasis in a narrow range, as reported for patients with
cardiovascular diseases (Navarro-Alarcon et al., 1999). How-
ever, when large amounts have to be excreted, respiration can
also contain volatile Se compounds, usually in the form of
dimethyl selenide (Fig. 2). In a study of healthy men confined to
a metabolic research unit and fed diets naturally high or low in
Se, Hawkes et al. (2003) reported that urinary Se measurements
responded rapidly to changes in Se intake. These researchers
remarked that urinary excretion rose rapidly in the high Se
group, but decreased only with severe Se restriction demon-
strating a low adaptation to Se excretion. Additionally, Hawkes
et al. (2003) reported that fecal excretion decreased by half in
the low Se group, a finding that indicates an underappreciated
role in metabolic adaptation to low Se. Zachara et al. (2006)
reported that losses in urine represent 50–78% of the ingested
element. These researchers also confirmed that the level of Se
excretion in urine was proportional to the level of Se intake.
Various selenocompounds are claimed to be present as
urinary Se metabolites such as selenite, selenate, methylse-
lenol, mehylselenite, trimethylselenonium ion, Se-Met, sele-
n o d i g l u ta t h i o n e , S e - C i s , s e l e n o e t h i o n i n e , S e - C y s ,
methylselenomethionine, selenocistamine, selenoadenosyl-
Met and selenosgars 1, 2 and 3 (Francesconi and Pannier,
2004). Among all of these Se compounds, only the trimethyl-
selenonium ion has been found in human urine (Francesconi
and Pannier, 2004). Suzuki (2005) and Kuehnelt et al. (2007)
 S CIE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41 127

Fig. 2 – Main Se forms in diet and human organism: Se metabolism (adapted from Navarro-Alarcon et al., 2005). 1Although in
some vegetables (cereal grains, grassland legumes and soybeans) the Se-Met is the main Se form, however the identification of
selenocysteine in vegetables is still inconclusive. Other Se forms present in vegetals are selenate, selenite, selenocystine,
selenomethionine, selenohomocysteine, Se-methylselenocysteine, γ-glutamil-selenocystathionine, selenomethionine
selenoxide, γ-glutamyl-Se-methylselenocysteine, selenocysteineselenic acid, Se-proponylselenocysteine selenoxide,
Se-methylselenomethionine, selenocystathionine, dimethyl diselenide, selenosinigrin, selenopeptide and selenowax
(Whanger, 2002). 2Selenocysteine is the predominant selenoamino acid in animal tissues while selenate is the major inorganic
selenocompound followed by selenite. Another organic Se form found in animal tissues is selenotrisulfide of cystine. 3Se
compound eliminated in the expired air in element overdosing that originates a typical garlic stink in breath. 4Selenopersulfide.
5
GS-Seleno-N-acetyl-galactosamine. 6,7,8Se-methylseleno-N-acetylgalactosamine, Se-methylseleno-N-acetylglucosamine,
Se-methylseleno- galactosamine, respectively. Additional ways of excretion. 9Trimethylselenonium.
10
Se-Methylselenocystein. 11γ-glutamil-Se-methylselenocysteine11.
128 SC IE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41
reported that new Se-containing selenosugars are the major
urinary metabolites in humans, the trimethylselenonium ion
being less significant. Specifically, the metabolite methyl-2-
acetamido-2-deoxy-1-seleno-β-D-galactopyranoside (called
selenosugar 2) has been identified (Francesconi and Pannier,
2004; Suzuki, 2005). Similarly to that stated above, Kuehnelt
et al. (2006) found during a Se supplement trial using selenite
(200 μg of Se) that selenocompounds are converted by
unknown mechanisms into trymethylselenonium and sele-
nosugars as urine metabolites in a percentage ranging from 1
to 5% and from 20 to 53% of urinary total Se, respectively.
Nevertheless, Francesconi and Pannier (2004) concluded that
even though available data shows that selenite, selenosugar 2
and selenosugar 3 (methyl 2-amino-2-deoxy-1-seleno-βD-
galactopyranoside) constitute three of the typical urinary
species, there are still species that remain unknown. Future
research is required to determine how factors such as
nutritional status and biological and chemical effects influ-
ence the type and concentration of Se urinary metabolites
(Francesconi and Pannier, 2004).
8. Selenium deficiency
Selenium is an essential mineral in human nutrition closely
associated with the population health. The element essentiality
in mammals was not discovered until 1979 due to its over-
lapping function with vitamin E (Strain and Cashman, 2002).
Low Se intake from agricultural products has negative effects on
human health. Serious health consequences have been
reported in low Se areas of China and Eastern Siberia, where
Se deficiency causes endemic Keshan disease in the Keshan
region of China. This pathology is an endemic juvenile
cardiomiopathy with myocardial insufficiency that primarily
affects children aged 2 to 10 years old, and to some extent
women of child-bearing age (Hartikainen, 2005). This disease is
caused by low soil Se levels in Keshan (mean Se content 0.125 μg/
g). Consequently, a very low Se intake from a diet of Keshan food
products was found, in some cases, lower than 10 μg Se/day.
Additionally, Se deficiency in other regions of China caused a
type of osteoarthritis called Kashin–Beck disease (Li et al., 2007).
This endemic disease is a human rheumatoid state resulting in
enlarged joints, shortened fingers and toes and dwarfism in
extreme cases (Hartikainen, 2005). In this disease, oxidative
damage attacks cartilage leading to deformation of the bone
structure (Ge and Yang, 1993). Kashin–Beck disease affects
children aged from 5 to 13 years old in certain areas of China and
the former Soviet Union. This pathology is a multiple degenera-
tion and necrosis of the hyaline cartilage, although Se's role in
the formation of this connective tissue is still unknown.
However, the interaction between the metabolism of thyroid
hormones and Se can help treat this deficiency (Nève, 1999) in
areas where the soil is Se deficient as it occurs in Zaire.
Both endemic diseases are mainly confined to the North-
east part of China. The principal characteristics of the zone are
dark brown and black soils very low in bioavailable Se as
water-soluble element fractions (Tan et al., 1994). Low Se
intake by inhabitants from these areas is caused by insuffi-
cient Se flux through the soil–plant–animal–human chain.
This finding seems to be related to the capacity of organic
matter to reduce selenate (Se6+) to selenite (Se4+), element
specie that seems to form strong inner sphere complexes with
Fe oxides. On the contrary, selenate (Se6+) is weakly adsorbed,
therefore having a higher bioavailability (Hayes et al., 1987).
On the other hand, the Se6+ is easily assimilated and bio-
available for plants and its levels increase with the alkalinity
of soils (Diaz-Alarcon et al., 1996c).
Supplementation of farmland with Se salts such as sodium
selenite in China and Finland significantly diminished the
incidence of disorders reported. This Se supplementation
exerted a prophylactic effect, raising from 2 to 8 times the Se
levels in milk, eggs, meats, etc. (Hartikainen, 2005). Since 1970,
Se in human serum has been periodically monitored in
healthy adults from Finland due to the fact that they were
among the lowest reported in the world (Hartikainen, 2005). Se
supplemented fertilizers were used which significantly
improved Se intake and serum Se levels in the Finnish
population. Nowadays, Se values in Finland (94.8 to 111.6 μg/l)
are usually higher than those of other European countries
(Navarro-Alarcon and López-Martínez, 2000; Van Cauwenbergh
et al., 2004; Hartikainen, 2005).
However, there is a seasonal aspect of Keshan disease
difficult to explain by considering only Se deficiency. Recent
literature describes a certain non-virulent strain of the poxvirus
Coxsackie (B3 strain) which, when infecting Se-deficient mice,
mutates to a virulent strain causing cardiac injuries (Beck et al.,
2003). This could explain the cardiomyopathy in children with
Keshan disease, because they usually infect with this virus type.
The genome of the virus strain codifies one GPx, which
apparently serves to protect it against the hydrogen peroxide
produced by the host's leucocytes. An absence of this enzyme
affects the virus genome. Therefore, some of the resulting
mutations increase the virus' virulence. As previously stated,
this deficiency creates some cardiac pathologies like myocardial
necrosis by injuring cellular membranes and proteins by
oxidative stress. Hartikainen (2005) deduced from animal
studies that Keshan disease produced by dietary Se deficiency
has a second aetiology of infection by enterovirus. Similarly, for
the Kashin–Beck disease, Se deficiency in diet is probably
associated with iodine intake (Nève, 1999).
9. Toxicity of selenium
Although RDA and upper limits for Se have been established by
the Food and Nutrition Board-Institute of Medicine (2000),
controversy still exists about what Se concentrations should be
considered adequate but not be toxic (Sunde, 2000). This is
because Se toxicity depends on the Se compound, method of
administration, animal species, exposure time, idiosyncrasy,
physiological status, and interaction with other metals, etc.,
(Burk and Levander, 2002).
Chronic Se toxicity in humans results in selenosis (Gold-
haber, 2003) characterized by hair loss, fingernails changes and
brittleness, gastrointestinal disturbances, skin rash, garlic
breath, and abnormal functioning of the nervous system.
Other related toxic effects are a disruption of endocrine
function, synthesis of thyroid hormones and growth hor-
mones, and an insulin-like growth factor metabolism. Parti-
cularly high levels of dietary Se were significantly associated
 S CIE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41
with diminished T3 levels, impairment of natural killer cells
and hepatotoxicity (Goldhaber, 2003). Other researchers state
that high Se levels catalyse hydrosulphide oxidation which
exerts an inhibitory effect on protein synthesis or an enhanced
risk of the cancer (Villa Eliaza et al., 1999). These toxic
symptoms are associated with Se intakes of 3200 to 6700 μg
Se/day. Milder symptoms such as fingernail changes have been
reported for Se intakes of 1260 μg Se/day (Sunde, 2000). In one
study of 400 Chinese with Se intakes up to 853 μg Se/day, and
another study of 142 subjects living in high Se areas of South
Dakota and Wyoming with Se intakes up to 724 μg Se/day, no
evidence of Se poisoning was reported (Sunde, 2000). But, other
researchers did report selenosis with Se intakes of ≥850 μg Se/
day. Consequently, the Environmental Protection Agency of
USA set a reference dose of 5 μg Se/kg/day, taking into account
an epidemiological study of 400 Chinese in which selenosis
was observed in 5. This agency defined 1262 μg Se/day as the
element intake at which clinical selenosis appeared, which
was related to a whole blood Se level of 1350 μg Se/l. As a result,
the Food and Nutrition Board—Institute of Medicine (2000)
fixed the upper Se levels (the highest daily level of Se intake
that is likely to pose no risk of adverse health effects in almost
all individuals) at 400 μg Se/day.
Although environmental toxicity of Se in humans is rare,
symptoms such as hypochromic anaemia, leucopoenia,
damaged nails, etc have been found in long-term workers
who manufacture Se rectifiers. Additionally, high accidental
ingestion of Se has been related with vomiting, diarrhoea,
mottling of the teeth as well as neurological disturbances like
acroparesthesias, weakness, convulsion, etc., (Sunde, 2000;
Mataix Verdu and Llopis, 2002; Tinggi, 2003). In any event, the
toxicity of Se depends on many factors like the Se species,
amount ingested, age, physiological status, and dietary inter-
action with other nutrients (Mataix Verdu and Llopis, 2002).
Due to the fact that the Se RDA for healthy adults (55 μg Se/
day) is not far from the established upper limits (400 μg Se/day)
(Food and Nutrition Board—Institute of Medicine, 2000), high
levels of Se dietary supplements should be considered with
caution. This conclusion correlates with other researchers
who found that Se dietary intakes of about 300 μg Se/day could
have toxic effects on growth hormone and insulin-like growth
factor-1 metabolism, as well as synthesis of thyroid hormones
(Kaprara and Krassas, 2006).
10. Body selenium metabolism in several diseases
10.1. Selenium metabolism in hepatopathies
Se deficiency has been associated with hepatocyte damage
and necrosis similar to that caused by excessive alcohol
consumption. This effect usually occurs concurrently with low
body vitamin E concentrations. Therefore, microsomal perox-
idation of hepatocytes is induced by the endoplasmic reticule
changes (Simonoff and Simonoff, 1991; Navarro-Alarcon et al.,
2002).
However, the pathologic mechanism of liver injury in
chronic alcoholic liver disease has not yet been defined
(Jablonska-Kaszewska et al., 2003). But, it seems that one
possible mechanism involves free radical reactions which
129
produce lipid, nucleic acid and protein peroxidation (Czuczejko
et al., 2003; Pemberton et al., 2005; Czeczot et al., 2006).
Specifically, alcohol metabolism in the hepatocytes increases
the lipidic oxidation of cell membranes provoking a chronic
transient state characterized by leukocyte infiltration and a
rise in collagen formation. In fact, one of the most effective
defence mechanisms is associated with the activity of several
antioxidative enzymes among which GPx has to be recognized
(Pemberton et al., 2005). This enzyme, with Se as significant
cofactor, is directly involved in numerous reactions which
protect the human organism, and specifically liver cells, from
oxidative stress. During the progression of alcoholic hepatic
disease, the liver has an initial steatosis, then it changes to
hepatitis and finally, in the last step of this process cirrhosis
develops. Cirrhosis damage is non-reversible due to intense
hepatocyte damage creating loss of liver function, compromis-
ing metabolism and overall health (Czeczot et al., 2006).
Nevertheless, the pathologic mechanisms are not well under-
stood and medical assays have generated controversial
results. However, it is known that alcohol consumption
enhances free radical production and the resulting oxidative
stress is directly implied in the disease (Pemberton et al., 2005;
Manzanares, 2007). Specifically, ethanol causes microsomal
proliferation and reactive oxygen species (ROS) like superoxide
(O2">U) and hydrogen peroxide (H2O2) generated by the ethanol-
cytochrome P450 2E1 (CYP 2E1). Additionally, the action of
aldehyde oxidase on acetaldehyde (first metabolite in ethanol
metabolism in the liver) can also produce superoxides. These
ROS, by means of the catalysed Fenton and Harber–Weiss
reaction, lead to the formation of highly reactive hydroxyl
radicals (OH">U) which have the capacity to generate 1-
hydroxy-ethyl radicals CH3–CH2O· directly from ethanol (Pem-
berton et al., 2005). Accumulation of all these alcohol-induced
ROS can overwhelm antioxidant defences causing, among
other oxidant actions, peroxidative damage to phospholipids
of membranes. ROS are capable of attacking proteins, poly-
saccharides, nucleic acids and polyunsaturated fatty acids,
resulting in cellular injury and death (Geoghegan et al., 2006).
These oxidant species may also trigger the cytokine release
from immune cells, activate inflammatory cascades and
increase the expression of adhesion molecules. The accumula-
tion of granulocytes in organs leads to enhanced generation of
ROS that amplifies the inflammatory response and tissue
injury (Geoghegan et al., 2006).
Contrarily, Bonnefont-Rousselot et al. (2006) report that
routine blood oxidative stress markers are not sensitive
indices of oxidative stress in the liver and are therefore not
good predictive markers of hepatic steatosis. However,
Czeczot et al. (2006) remarked that the antioxidant system of
cirrhosis is severely impaired.
Additionally, chronic alcoholics are frequently malnour-
ished and consequently suffer insufficient Se supply due to
diminished food intake. Since diet is the primary Se source,
excessive alcohol consumption which impairs food intake
also limits Se supply (Navarro-Alarcon et al., 2002). A
constant Se deficiency characteristic of chronic alcoholics
would develop a decrease in GPx activity and, consequently,
of catalytic elimination of hyroperoxides otherwise en-
hanced by high alcohol intake. As a result, accumulation of
toxic substances in the liver occurs progressively, along
 130
SC IE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41
Table 5 – Selenium levels in serum, plasma, whole blood, tissue and erythrocytes in healthy control subjects and patients with different pathologies
Pathology and/or Group n (sex) Mean Se Se range Age Statistical Sample Area (country) Reference
status (μg/l) (μg/l) (years) differencesa type

Hepatophathies Cirrhosis group 12 (8 M, 4 F) 41.0 ± 12.4 17.7–61.5 – Yesb Serum Motril (Spain) Navarro-Alarcon
Hepatitis group 38 (23 M, 15 F 52.4 ± 15.6. 15.8–80.5 – Yesb Serum et al. (2002)
Control group 130 (56 M, 74 F) 74.9 ± 27.3 30.2–175.0 – Serum
Chronic liver Chronic hepatitis C or 59 48.6 ± 11.8 – 54 Yesb Plasma Poland Czuczejko et al.
diseases C virus infection group 66.4 ± 14.1 – 54 Yesb Whole blood (2003)
Alcoholic, autoimmune or 64 43.0 ± 13.3 – 52 Yesb Plasma
cryptogenic chronic liver 58.4 ± 16.6 – 52 Yesb Whole blood
disease group
Healthy controls 50 67.4 ± 11.7 – 42 Plasma
89.5 ± 15.6 – 42 Whole blood
Chronic Hepatitis group 33 (20 M, 13 F) 159.1 ± 5.3 – 49.5 ± 2.4 Yesc Plasma China Ko et al. (2005)
hepatitis C ‘‘ ‘‘ 55.1 ± 3.8 – ‘‘ Yesc Erythrocyte
Control group 31 (17 M, 14 F) 216.7 ± 7.4 – 43.2 ± 1.7 Plasma
‘‘ ‘‘ 139.1 ± 5.8 – ‘‘ Erythrocyte
Alcoholic liver Cirrhosis group 24 (14M, 10 F) 46.1 31.9–60.6 46.8 ± 10.0 Yesb Serum United Kingdom Pemberton et al.
disease Control group 49 (21 M, 28 F) 100.6 92.3–105.4 45.7 ± 14.8 Serum (2005)
Hepatopathies Non-alcoholic fatty liver 17 (15 M, 5 F) 114.5 ± 15.8 – 49.5 ± 3.0 No Plasma Paris (France) Bonnefont-Rousselot
disease group et al. (2006)
Viral hepatitis group 47 (36 M, 11 F) 90.8 ± 7.1 – 43.5 ± 1.6 Plasma
Viral hepatic Hepatitis B virus carriers 50 (25 M, 25 F) 124.3 ± 22.6 – 49.9 ± 12.5 No Serum Taiwan (China) Lin et al. (2006)
diseases group
Chronic hepatitis B group 40 (20 M, 20 F) 123.5 ± 20.4 – 52.1 ± 11.6 No Serum
Hepatic cirrhosis group 20 (10 M, 10 F) 117.5 ± 25.3 – 56.3 ± 9.5 No Serum
Hepatocellular carcinoma 18 (9 M, 9 F) 108.5 ± 21.8 – 58.5 ± 10.1 Yesc Serum
group
Control group 50 (25 M, 25 F) 129.0 ± 21.5 – 48.5 ± 13.1 Serum
Hepatopathies Cirrhosis group 15 (8 M, 7 F) 0.023 ± 0.008d – 39 No Liver tissue Poland Czeczot et al. (2006)
Hepatocellular carcinoma 15 (10 M, 5 F) 0.023 ± 0.008c,d – 58 Yesb Livers tissue
group
Adjacent healthy liver group 15 (10 M, 5 F) 0.031 ± 0.015d – 58 Liver tissue
Cancer Respiratory cancer group 3 (3 M) 42.6 ± 2.42 39.8–44.2 – Yesb Serum Motril (Spain) Navarro-Alarcon
Digestive cancer group 20 (11 M, 9 F) 51.8 ± 26.6 8.85–100.0 – Yesb Serum et al. (1998)
Hematological cancer group 15 (9 M, 6 F) 59.5 ± 20.9 21.3–97.9 – Yesb Serum
Gynecological cancer group 21 (9 M, 12 F) 55.3 ± 27.3 13.2–112.5 – Yesb Serum
Control group 130 (56 M, 74 F) 74.9 ± 27.3 30.2–175.0 – Serum
Acute AMI group 36 (14 M, 22 F) 88.4 ± 16.6 – 53 No Plasma France Coudray et al. (1997)
myocardial Control group 498 (200 M, 298 F) 85.2 ± 15.0 – 65 Plasma
infarction (AMI)
AMI AMI group 683 M 86.8 ± 15.8 – b 70 Yesc Whole blood 8 European countries Kardinaal et al. (1997)
Control group 729 M 105.8 ± 13.4 – 53 Whole blood and Israel
CVD AMI group 32 (27 M, 5, F) 58.7 ± 27.2 21.6–118.5 – Yesc Serum Motril (Spain) Navarro-Alarcon
Ischemic cardiopathy 50 (38 M, 12 F) 55.5 ± 16.7 19.2–86.0 – Yesc Serum et al. (1999)
group

S CIE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41

Control group 130 (56 M, 74 F) 74.9 ± 27.3 30.2–175.0 –
AMI AMI group 27 63.7 ± 12.0 – – Yesc Plasma Turkey Bor et al. (1999)
‘‘ 0.48 ± 0.04 – – No Erythrocytes
Control group 24 (20 M, 4 F) 82.2 ± 14.6 – 51 Plasma
‘‘ 0.51 ± 0.03 – 51 Erythrocytes
AMI AMI group 49 53.8 ± 18.3 – – No Plasma Poland Zachara et al. (2001)
‘‘ 71.4 ± 18.2 – – No Whole blood
Control group 58 (35 M, 23 F) 52.5 ± 13.6 – 57 Plasma
‘‘ 73.1 ± 18.1 – 57 Whole blood
Mortality Died group 89 F 112.9 109.0–117.6 73.9 Serum Serum Baltimore (USA) Ray et al. (2006)
predictione Lived group 543 F 121.6 120.0–124.0 75 Serum Serum Baltimore (USA)
Occurrence of Group at baseline 751 (296 M, 456 F) 86.9 ± 15.8 – 65 ± 3 Plasma Nantes (France) Arnaud et al. (2007)
CV events Group at the end of the 751 (296 M, 456 F) 79.0 ± 14.2 – 74 ± 3 Yesb Plasma
study followed for 9 years
a
Statistical differences were established when compared Se levels measured in patients with those found in healthy subjects that constitute the control group.
b
p b 0.001.
c
p b 0.05.
d
Se was measured as μmol Se GPx/min per mg protein.
e
The main causes of death among the women who died (14.1%) during the 60 months of follow-up were: CVD (32.6%), cancer (18%), stroke (9.0%), infection (6.7%), chronic obstructive pulmonary disease
(5.6%), accidents (3.4%), diabetes mellitus (2.0%), renal disease (2.0%), other (13.5%) and unknown (6.7%).

131
132 SC IE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41
with alcohol toxicity. Czuczejko et al. (2003) found that
disturbances in antioxidant parameters in the blood of
patients with chronic liver disease may be the cause of the
peroxidative damage of cells.
Several case/control studies of serum, plasma and/or
whole blood Se levels and erythrocyte and/or platelet GPx
activities have been conducted in individuals with different
hepatopathies. A previous review by our research group
(Navarro-Alarcon and López-Martínez, 2000) discovered that
in 12 of 13 studies conducted between 1985 and 1998,
measured serum or plasma Se levels were significantly lower
than those of the healthy control group. In this review, six
additional studies have been discovered (Table 5), four of
which report body Se levels significantly lower in patients
with hepatopathies than for healthy subjects. The results were
independent of the Se nutritional biomarker employed,
namely serum Se (Navarro-Alarcon et al., 2002; Pemberton
et al., 2005) plasma and erythrocytes Se (Ko et al., 2005), and
plasma and whole blood Se (Czuczejko et al., 2003).
It has also been reported that the reduction of body Se
levels are more pronounced with the advance of the disease.
Therefore, as hepatitis progresses to cirrhosis, the most
pronounced Se impairment is reached in the final stages
when the highest liver injury occurs (Navarro-Alarcon et al.,
2002). This finding confirms that the severity of liver damage
is one of factors affecting the impairment in Se body status
found in patients with hepatopathies.
However, low peripheral Se levels cannot automatically be
considered as hepatopathy promoters. In fact, these diminished
Se levels are really the consequence of an impairment of body
mechanisms which control enhanced oxidative stress during
the genesis and progression of hepatopathies to more severe
stages like non-reversible cirrhosis (Navarro-Alarcon et al., 2002).
During non-invasive monitoring of oxidative stress in 24
alcoholic cirrhosis disease patients, Pemberton et al. (2005)
found that the levels of 8-isoprostane and malonaldehyde (as
markers of lipid peroxidation) were significantly increased
when compared with controls (p b 0.001). Concomitantly,
serum Se GPx, and vitamins A, C and E (as antioxidants)
were all significantly diminished (p b 0.001). Consequently
these authors conclude that oxidative stress is a significant
feature of alcoholic cirrhosis as reported for other hepatic
diseases like chronic liver disease (Czuczejko et al., 2003) or
hepatocellular carcinoma (Czeczot et al., 2006; Lin et al., 2006).
10.2. Selenium metabolism in cardiovascular diseases
As reported in our previous study, an inverse correlation exists
between the appearance of some cardiopathies and low Se
levels in the environment, diet, and blood (Navarro-Alarcon
and López-Martínez, 2000). Extreme dietary deficiencies lead
to endemic Keshan and Kashin–Beck disease. Here we review
12 serum and plasma Se level studies in patients with
cardiovascular diseases (CVDs: myocardial infarction, arterio-
sclerosis, congestive heart failure, diverse cardiopathies,
cardiomiopathies, arterial hypertension, chronic heart dis-
ease, coronary arteriosclerosis and ischemic cardiomiopathy)
versus healthy controls. In ten of the studies, Se levels were
significantly lower than normal (Navarro-Alarcon and López-
Martínez, 2000). Additionally, of the five studies showed in
Table 5, only half showed Se biomarker levels were signifi-
cantly lower for patients vs. healthy controls (p b 0.05). Wei
et al. (2004) did a prospective study of serum Se concentrations
and heart disease (HD), stroke, other diseases, and total death.
These authors measured baseline serum Se concentrations in
1103 individuals from Linxian (China) randomly selected from
a larger trial cohort. After examining the relation between
baseline serum Se and the subsequent risk of death from HD
and stroke over 15 years of follow-up (from 1986–2001). Wei
et al. (2004) only found inverse correlation trends between Se
level and death for HD (p = 0.07). Contrarily, Lewin et al. (2002)
used the human endothelial cell line EAhy 926 to determine
the importance of Se in preventing oxidation damage induced
by test-butyl hydro peroxide or oxidized low density lipopro-
tein (LDLox). These researchers showed that cells pre-treated
with 0.4 nM selenite prior to exposure to 1 μM gold tioglucose
were significantly more resistant to damage from test-BuOOH
than Se-deficient cells. These authors suggested that Se
supplementation, acting through induction of TR and GPx
has the potential to protect the human endothelium from
oxidative damage (Lewin et al., 2002).
In general, these findings demonstrate controversial results
as it still has not been determined if differences are etiological
or biological consequences of the various cardiopathies.
Nevertheless, it has been reported that a serum Se level
b55 μg/l is associated with an increased risk of coronary heart
disease. Moreover, Helmersson et al. (2005) report that low Se
levels predict mortality and CVD in some populations. These
authors investigated the longitudinal association between
serum Se and several standard indicators of oxidative stress
like F2-isoprostane and prostaglandin F2α (indicator of cycloox-
igenase-mediated inflammation) in a 27 year follow-up of
Swedish men (n = 615; 50 years old). Helmersson et al. (2005)
concluded that high concentrations of serum Se predict
reduced levels of oxidative stress (8-isoprostaglandin F2α) and
subclinical cyclooxigenase-mediated (but no cytokine-
mediated) inflammation. Therefore, the association between
Se, oxidative stress and inflammation may be related to the
cardiovascular protective properties of Se (Helmersson et al.,
2005)
Ray et al. (2006) performed a 60 month longitudinal study of
632 women (70–79 years old). They found that high serum Se
and carotenoid levels were significantly associated with a
lower risk of mortality (Table 4). Of the five major causes of
death studied, almost half were related to the cardiovascular
system. HD was the primary cause with 32.6%, and stroke was
in third place with 9% (Ray et al., 2006).
It has been reported that Se levels decrease during ageing
(De Yong et al., 2001; Arnaud et al., 2007). In a 9-year study of
an elderly French population, Arnaud et al. (2007) used
multivariate linear regression models to find the relation
between plasma Se variability and 11 risk factors (age,
education, marital status, smoking, alcohol consumption,
obesity, dislipidemia, diabetes, hypertension and personal
history of CVD). They found that cardiovascular events
(p = 0.003) and chronic obesity (p = 0.02) significantly increased
with a reduction in plasma Se (Arnaud et al., 2007). By other
means, Faure et al. (2004) also reported the importance of Se
supplementation in the prevention of CVD in type 2 diabetic
patients. It is known that the enhancement of Se GPx activity
 S CIE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41
improves the antioxidant system and results in less peroxide
formation which is indirectly implicated in the activation of
nuclear factor-kappa B (NF-κB). Activated NF-κB has been
identified in situ atherosclerotic plaques (Collins and Cybulsky,
2001), and has also been linked to development of late diabetic
macro vascular complications in humans. Antioxidants inhi-
bit NF-κB activation which, contrarily, is directly activated by
hyperglycaemia in diabetics. Specifically, Faure et al. (2004)
found that supplementing type 2 diabetic patients with Se
(n = 21; Se supplementation trial: 960 μg Se/day for 3 months)
significantly reduced NF-κB activity (p b 0.05), reaching the
same level as the non-diabetic control group (n = 10).
To the contrary, Navas-Acien et al. (2008) concluded that
current evidence is insufficient to support using Se in the role
of cardiovascular disease prevention. Additionally, these
authors stated that subjects living in high Se intake regions
should be aware that Se supplements may increase the risk of
diabetes and hypercholesterolemia. Navas-Acien et al. (2008)
concluded that large, high-quality, randomized controlled
trials (RCTs) and observational studies are needed across
populations with different Se levels intake.
It is known that homocysteine is an emerging risk factor for
CVD. Homocysteine is a metabolic product of methyl group
transfer from the amino acid methionine. After measuring
serum Se and plasma homocysteine concentrations in elderly
humans [n = 202; 85 males and 117 females] from Asturias
(Northern Spain), Gonzalez et al. (2004) reported that blood Se
levels should be considered as a potential factor to lower total
plasma homocysteine. Specifically, they found an indepen-
dent inverse association between serum Se and plasma
homocysteine (Gonzalez et al., 2004).
Thomson (2004) reported that despite significant research,
the role Se plays in protection against CVD remains incon-
clusive. Se protection found in some studies is consistent with
an apparent risk threshold of about 79 μg/l in plasma, which
corresponds with the level required to maximize antioxidant
GPx.
Although recent studies provide hopeful results, they do
not unequivocally conclude that higher Se intake decreases
risk for CVD. Although Se shows potential as an antioxidant
and its role in prevention of CVD is promising, additional long-
term intervention trials are necessary. Therefore, despite its
antioxidant action and its intervention in regulating the
human immune system, indiscriminate Se supplementation
still cannot be recommended for the prevention of CVDs.
10.3. Selenium metabolism in cancers
Solid evidence based on epidemiological studies conducted in
the last 50 years show an inverse relationship between Se
intake and cancer mortality. Thus the anticarcinogenic effect
of Se against leukaemia and cancers of the colon, rectum,
pancreas, breast ovaries, prostate, bladder, lung and skin
seems clear under at least some conditions (Sunde, 2000).
Trumbo (2005) after doing an FDA review of the evidence for Se
and cancer concluded that some evidence permits a qualified
health claim for Se and cancer. Specifically, of the 36
observational studies reviewed, approximately half supported
an association with all cancers. However, the greatest
consistency was noted for breast and prostate cancers
133
(Trumbo, 2005). Silvera and Rohan (2007) also reported
evidence to support an inverse relationship between Se
exposure and prostate cancer risk, and possibly a reduction
in risk with respect to lung cancer, although additional study
is needed. Nevertheless, these authors reported that most
studies reported no association between Se and risk of breast,
colorectal and stomach cancer (Silvera and Rohan, 2007)
Donaldson (2004) reports Se as an antioxidant nutrient and
a protective element in a cancer prevention diet along with
others like folic acid, vitamin B12, vitamin D, chlorophyll and
other antioxidants such as carotenoids. In 2000, our group
reviewed and compared 17 studies measuring Se levels in
serum or plasma from patients with different types of cancer
and in healthy adult controls (Navarro-Alarcon and López-
Martínez, 2000). Fourteen of the studies showed significantly
lower Se levels in the cancer patients compared to the control
group. Low serum Se also correlates to higher cancer risk.
Moreover, Czeczot et al. (2006) found a decrease of the GPx
activity in hepatocellular carcinoma tissue compared to
adjacent normal liver tissue. This diminishment might cause
the intensification of lipid peroxidation and the enhancement
of final peroxidation products such as malonaldehyde (MDA).
Concomitantly, increase of MDA levels in cancer tissue was
also found. Therefore, some researchers recommend Se as a
nutritional prophylaxis against cancer at a dose of 50 to100 μg
Se/day (Simonoff and Simonoff, 1991). Se has also been
recommended as a co-adjuvant to chemotherapy in cancer
treatment at a higher dose of 200 μg Se/day (Simonoff and
Simonoff, 1991). This dose is considerably higher than that
necessary to reach the maximum GPx activity. The antic-
arcinogenic effect of Se has been attributed to several
mechanisms: (a) modulation of cell division; (b) metabolic
alteration of some carcinogens; (c) cell protection against
oxidative damage by increasing TR activity (Karunasinghe
et al., 2006); (d) stimulation of the immune system; (e)
inhibition of activation of hepatic enzymes whose metabolic
activities enhance the production of toxic substances that lead
to cancer genesis.; (f) activation of the detoxifying liver
enzymes, etc.
In a study of mortality from oesophageal squamous cell
carcinoma (ESCC) and gastric cardia cancer (GCC) in Linxian
(China), a significant inverse relationship between baseline
serum Se and death from these cancers was found (p b 0.05)
(Wei et al., 2004). These researchers found a mean serum Se
concentration of 73 μg/l, which corresponds to the Se amount
present in maximally expressed plasma selenoproteins and to
the upper limits of GPx responses to Se supplements in
healthy people. On the basis of this criterion, 69% of the
subjects were Se deficient (Wei et al., 2004). They concluded
that population-wide Se supplements in regions of China with
low serum Se and high incidences of ESCC and GCC merits
serious consideration. Concomitantly with this finding, Kim et
al. (2005) found that the sera of prostate cancer subjects, after
Se supplementation, exhibited the same proteomic pattern as
prostate cancer-free subjects. Contrarily, Peters et al. (2008) in
a cohort study of long-term intake of vitamin E and Se (10-y
average intake) found no relationship with overall prostate
cancer risk. Additionally, the risk of clinically significant
advanced prostate cancer was not reduced with long-term
Se supplements.
134 SC IE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41
Connelli-Frost et al. (2006) found that high body Se was
associated with a reduced prevalence of colorectal adenoma.
Nevertheless, apoptosis did not seem to be the mechanism by
which Se was related to adenoma prevalence. They recom-
mended future clinical trials for Se as a potential chemopre-
ventive agent for colon adenomas and colon cancer. Peters
et al. (2006) studied the association of serum Se and advanced
colorectal carcinoma and concluded that Se may reduce the
risk of developing advanced colorectal adenoma, particularly
among the high risk group of smokers.
Other studies have also found a significant Se protective
effect against total and prostate cancer incidence in men at
daily dose of 200 μg Se/day via selenized yeast (Duffield-Lillico
et al., 2002). Similarly, Karunasinghe et al. (2006) demonstrated
that 6 months of Se supplements in men at high prostate
cancer risk (200 or 400 μg Se/day with selenoyeast) increased
significantly TR activity from 0.390 ± 0.050 mU/mg Hb at
baseline to 6.490 ± 0.261 mU/mg Hb by the end of the
supplementation period. However, McNaughton et al. (2005)
did a review of 26 studies of human basal cell cancer (BCC) and
squamous cell cancer (SCC) of the skin. These studies were
critically reviewed and confirmed that the evidence for
association between Se, vitamin E and vitamin C and both
BCC and SCC is weak. These authors concluded that further
well-designed and implemented studies are required to clarify
the role of diet Se in skin cancer.
Ferguson et al. (2006) stated that biomarker approaches
appear useful in assessing antioxidant activity of dietary
components like Se and may provide information relevant to
cancer protection. In some studies, it is now questioned
whether the antioxidant properties or other effects of Se
provide cancer protection. Se is significantly accumulated in
colorectal polyps (an early stage in colon cancer development)
compared to healthy tissues (Alimonti et al., 2008). This
finding is probably related to the significant drop in serum
Se in patients with gastrointestinal cancers, most of which
were colorectal cancers (Navarro-Alarcon et al., 1998) (Table 5).
10.4. Influence of selenium supplementation trials on the
prevention and progression of some diseases and body
limitations associated with ageing
Lately, various studies have been performed (Table 6) con-
cerning the influence of Se supplementation (alone or with
other antioxidant vitamins and minerals) on the prevention of
pathologies associated with oxidative stress and inflamma-
tory processes (Tomkins, 2003) like cancer, cardiovascular
diseases, rheumatoid arthritis, hepatopathies, etc. The influ-
ence of Se on the loss of body capability due to ageing is also
being studied. One study of Chinese men concludes that the
maximum dietary Se required to maximize GPx activity is
41 μg Se/day (11 μg Se/day from normal dietary intake plus a
supplement of 30 μg Se/day as Se-Met). A dose of 53 μg Se/day
is extrapolated for the for the higher body weight of USA and
Europe residents (Thomson, 2004). Nevertheless, some
research proposes that Se intakes higher than recommended
and higher than normal plasma Se concentrations may
protect against cancer, cardiovascular diseases, hepatopa-
thies, and arthritis or provide other additional health benefits.
Despite this, it is known that Se plasma and GPx levels are
normally significantly lower in patients with different types of
cancer, cardiovascular diseases, hepatopathies, rheumatoid
arthritis and osteoarthritis, etc., (Navarro-Alarcon and López-
Martínez, 2000; Navarro-Alarcon et al., 2002; Czeczot et al.,
2006; Flores-Mateo et al., 2006).
However, most reviews and studies report no disease
prevention, protection, or treatment benefits from antioxidant
supplements including Se or Se alone (Duffield-Lillico et al.,
2003; Lacour et al., 2004; Bleys et al., 2006; Flores-Mateo et al.,
2006; Stranges et al., 2006; You et al., 2006; Canter et al., 2007;
Stewart et al., 2007).
Contrarily, Etminan et al. (2005) in a systematic review and
meta-analysis of Se in the prevention of prostate cancer
concluded that Se may reduce the risk of prostate cancer.
Nevertheless, these authors are awaiting the results of
ongoing larger randomized controlled trials to confirm these
findings and definitively answer this question. Flores-Mateo
et al. (2006) after performing a meta-analysis of Se supple-
mentation and coronary heart disease concluded that the
randomized trials performed up until now are still incon-
clusive. On the other hand, Wei et al. (2004) previously
reported an inverse association between pre-diagnostic
serum Se concentrations and the risk of oesophageal squa-
mous cell carcinoma (ESCC) and gastric cardiac cancer (GCC).
Additionally, they found significant inverse associations
between baseline serum Se and death from ESCC after a 15-
year follow-up. These researchers concluded that population-
wide Se supplementation in China areas with low serum Se
and high incidences of ESCC and GCC merits serious con-
sideration. Bleys et al. (2006) did a meta-analysis of rando-
mized controlled trials (RCT) (n = 16) of the effect of vitamin–
mineral supplementation on atherosclerosis progression.
Nevertheless, only 2 trials employed antioxidants with Se as
supplements. These authors concluded that antioxidant
supplements provide no protection against atherosclerosis,
thus providing an explanation for their lack of effect on
clinical cardiovascular events (Bleys et al., 2006). Contrarily,
Vernardos and Kaye (2007) did a review summarizing the role
of myocardial antioxidant enzymes (GPx and TR). These
authors found that dietary Se supplements may provide a
safe and convenient method for increasing antioxidant
protection in aged individuals, particularly those at risk of
ischemic heart disease or undergoing clinical procedures
involving transient periods of myocardial hypoxia (Vernardos
and Kaye, 2007).
Other authors (Geoghegan et al., 2006) reported that
patients with critical illnesses were supplemented with widely
varying doses of Se (between 200 and 1000 μg) used alone or in
combination with other antioxidants. They documented a
decrease in the length of hospital stay, rate of infection, and
need or haemodialysis in these patients. Nevertheless, no trial
has demonstrated a statistically significant improvement in
mortality, despite a recent meta-analysis suggesting a trend
towards reduced mortality with Se supplementation (Geoghe-
gan et al., 2006).
In recent years, genomic and proteomic science is growing
rapidly. Because of the need to define the capacity of nutrients
like Se these sciences concern the study of nutrients like Se to
facilitate the up- or down-regulation of specific genes and
therefore to enhance or diminish protein synthesis. In this sense,
Table 6 – Supplementation studies with Se alone or with other antioxidant vitamins and minerals
Disease or status Group n (sex) Age Design and Antioxidant Results Reference Country
(years) intervention dose

Rheumatoid arthritis Selenium group 28 (7 M, 21 F) 61 ± 13 90-day double-blind, 200 μg Se/day as For Se group only arm movement Peretz et al. Belgium
Placebo group 27 (7 M, 20 F) 60 ± 13 multicentre Se-enriched yeast and health perception rose significantly (2001)
randomized (p b 0.05) from 6 test points and
controlled trial (RCT) clinical outcome measurements
Rheumatoid arthritis Selenium group 35 58 ± 13 3-month parallel 200 μg Se/day as No significant differences were found Heinle et al. –
Placebo group 30 57 ± 13 group double-blind, RCT sodium selenite for the 3 test points and (1997)
clinical outcome measurements
Precancerous Antioxidant group 1706 39–69 39-month 500 mg vitamin C, No significant differences in total, cancer, You et al. Shandong
gastric lesions Placebo group 1705 35–69 double-blind, RCT 200 IU vitamin E, 15 mg gastric cancer and cardiovascular deaths (2001) province

S CIE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41

β-carotene, 75 μg Se between the placebo and the (China)
vitamin–mineral preparation groups
Precancerous Antioxidant group 1677 35–64 7.3-year 250 mg vitamin C, No significant favourable effects were You et al. Shandong
gastric lesions Placebo group 1688 35–64 double-blind, RCT 100 IU vitamin E, seen or the diminishment of the (2006) province,
37,5 μg Se from yeast prevalence of precancerous gastric lesions China
Nonmelanoma Selenium group 621 10-year 200 μg Se/day as No association between treatment Duffield- Eastern
skin cancer Placebo group 629 double-blind, RCT Se-enriched yeast and the incidence of cancer Lillico et al. USA
(2003)
Prostate cancer Selenium group 32,400 M for 62.4 7–12 year 200 μg Se/day form Unknown results by the moment Lippman et USA,
Placebo group selenium and double-blind, RCT L-Se-Met and/or al. (2005) Puerto
placebo groups 400 UI/day vitamin E Rico and
Canada
Men at high prostate Selenium group 29 M 50–75 6-month 200 or 400 μg Se/day The TR activity of the supplemental group Karunasinghe New
cancer risk Placebo group 14 M double-blind, RCT as seleno yeast measured by 80% relative to baseline et al. (2006) Zealand
Cardiovascular disease Selenium group free 504 62.5 7.6-year 200 μg Se/day as high No overall effect of Se supplementation on Stranges et al. California,
incidence and mortality of cardiovascular (357 M, 147 F) double-blind, RCT Se baker's yeast table the primary prevention of cardiovascular (2006) USA
disease at baseline diseases
Placebo group free 500 62.1
of carviovascular (356 M, 144 F)
disease at baseline
Prevention of the Antioxidant group 79 (71 M, 8 F) 53 3.0-year 100 mg vitamin C, 800 IU Change in coronary minimal luminal Brown et al. USA and
progression of double-blind, RCT vitamin E, 100 μg Se, diameter (2001) Canada
atherosclerosis Placebo group 67 53 25 mg β-carotene
(60 M, 7 F)
Prevention of the Antioxidant group 599 53 7.2-year 120 mg vitamin C, 33 IU Carotid intima-media thickness Zureik et al. France
progression of (300 M, 299 F) double-blind, RCT vitamin E, 100 μg Se, (2004)
atherosclerosis Placebo group 563 53 6 mg β-carotene,
(281 M, 282 F) 20 mg zinc
Mood and quality of life Selenium group 336 60–74 2-year 100, 200 or 300 mg No justification for increasing Se intake Rayman et al. United
of elderly individuals Placebo group 112 60–74 double-blind, RCT Se/day as high Se-yeast to improve mood in general UK elderly (2006) Kingdom
population
Acute alcoholic Antioxidant group 36 (20 M, 16 F) 44 6-month Vitamin A, vitamin E, Se, Antioxidant therapy alone does not Stewart et al. United
hepatitis Placebo group 34 (18 M, 16 F) 44 double-blind, RCT Zn, Mn, Cu, Mg, folic acid, improve 6-mo survival (2007) Kingdom
coenzyme Q
Chronic hepatitis C Selenium group 12 43 6-month 500 mg vitamin C. 945 No consistent differences between groups Groenbaek United

135
virus-infected patients Placebo group 11 45 double-blind, RCT IU vitamin E, 200 μg or changes of activities from the baseline et al. (2006) Kingdom
selenium as Se-Met of the GPx, SOD and catalase enzymes
136 SC IE N CE OF T H E TOT AL E N V I RO N ME N T 4 0 0 ( 2 00 8 ) 1 1 5–1 41
Faure et al. (2004) concluded that in type 2 diabetic patients,
activation of NF-κβ measured in peripheral blood monocytes can
be reduced by Se supplementation, thus confirming its impor-
tance in the prevention of cardiovascular diseases (CVD). In this
Se supplement trial, type 2 diabetic patients (n = 48; age
range = 49–58 years old) were divided into two groups: 21
individuals were supplemented with 960 μg Se/day during
3 months and 27 received a placebo (Faure et al., 2004).
The impact of Se on mood and quality of life in the elderly
was studied in a randomized controlled trial by Rayman et al.
(2006). These researchers found that there was no evidence
that Se supplementation benefited mood or quality of life in
these elderly volunteers. They stated that the large sample
size and long supplementation period confirms that this is a
reliable finding. Contrarily, De Yong et al. (2001) reported that
New Zealand women aged 75 ± 3 years old in the highest third
of functional capacity index (n = 33; plasma Se = 77.4 ± 23.7 μg/l)
had significantly higher biochemical Se values than those in
the lowest third (64.7 ± 15.0 μg/l). They concluded that sub-
optimal trace element levels may be more common among
those with poor physical function, therefore promoting
consumption of high Se foods or supplements to improve Se
levels in elderly women in New Zealand may be beneficial (De
Yong et al., 2001).
Consequently, Se supplements should not be recom-
mended for the prevention of disease considering that until
now few randomized controlled trials have been conducted.
Randomized trials are inconclusive concerning the effect of Se
supplementation. Therefore, the population should be warned
against the employment of Se supplements for the prevention
of hepatopathies, rheumatoid arthritis, cardiovascular or
cancer, as the benefits are still uncertain and their indis-
criminate use could generate an increased risk of toxicity.
11. Conclusions
In the last two decades there has been much progress in our
knowledge and understanding of the biological roles of Se and its
importance in human nutrition. The current knowledge of the
role of Se in health and disease is important in order to assess the
health risk associated with low population Se levels. Diet is the
major source of Se for the general population and its bioavail-
ability comes mainly from Se organic forms (generally more than
80%). The influence of other dietary factors such as total protein,
fat and heavy metal presence, have been also described. Soil
content clearly determines the food Se content and conse-
quently the average total Se intake. High Se values for soil are
reflected in high Se concentrations in local animals and plants
and finally in body fluids as biomarkers of the nutritional status
of the population. A widely variability between Se total dietary
intakes among different countries has been found. Despite this,
healthy individuals who usually have a balanced and varied diet
should have the appropriate nutritional level of Se and hence, do
not need a supranutritional intake of this element, with the
exception of those living in geographical areas of low environ-
mental Se concentrations. Another topic of concern is the effect
of technological processing and cooking of food prior to
consumption which generally diminishes Se concentration
due to volatility and solubility. However, some researchers did
not report any effect of these processes on final Se content in
foods and meals. On the other hand few in vivo and in vitro
studies have been conducted on the influence of food technology
on Se species in prepared food and, consequently, on Se
bioavailability. Therefore, we consider that more research is
necessary in the supplementation field in order to have a better
knowledge of the amount of Se biologically available for the
human organism from Se supplements used nowadays. Efforts
to characterize Se species can be subdivided into the analyses of
the macromolecules (peptides and proteins) and small mole-
cules (amino acids, selenate, and selenite) normally associated
with Se in food (except in regions of low endemic soil Se
concentrations).
Generally, biomarker levels of nutritional Se status dimin-
ish significantly in individuals with cardiopathies, hepato-
pathies and several cancer types. Nevertheless, it is still not
clear if this low Se is a pre-existing factor promoting the
disease's genesis, or is a consequence of the disease itself.
Another conclusion is that additional scientific evidence is
needed through large high-quality RCT and observational
studies with population groups of different Se and health
levels. In addition to epidemiologic studies, basic science
research is necessary to detect mechanisms and evaluate
disease chemopreventive potential in food Se. Until that
moment, the efficacy of Se as a disease preventive agent, Se
disease health claim for specific hepatopathies, cardiopa-
thies, cancer, rheumatoid arthritis, etc., cannot be condoned
and additional study is required. Nowadays, our under-
standing of the mechanisms involved in the genesis of
hepatopathies, cardiopathies and different cancers is
increasing rapidly based on new findings in disease-related
functional genomics and proteomics. Therefore, basic and
translation research using these findings and new technology
will contribute to the definition of molecular and genomic
biomarkers that can be employed to evaluate disease risk in
cohorts and surrogate endpoints in clinical studies.
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