ArticlePDF AvailableLiterature Review

Food-chain selenium and human health: Emphasis on intake

Authors:

Abstract

Following the publication of the landmark trial of Clark et al. in 1996 that appeared to show that Se could reduce the risk of cancer, awareness of the importance of Se to human health has markedly increased. As a result, there is now much more aggressive marketing of Se supplements and functional foods, even in situations where additional consumption of Se is inappropriate. The present review addresses how Se gets into the food chain, the wide variability in Se content of foods and the very different levels of intake between countries and regions. Though it is clear that there are adverse consequences for health of both deficient and excessive intake, health effects at intermediate levels of intake are less certain. Thus it is difficult to define optimal intake which depends on a large number of factors, such as which functions of Se are most relevant to a particular disease state, which species of Se is most prominent in the Se source, which health condition is being considered, the adequacy or otherwise of intake of other nutrients, the presence of additional stressors, and lastly whether the ability to make selenoproteins may be compromised. These complexities need to be understood, particularly by policy makers, in order to make informed judgments. Potential solutions for increasing Se intake, where required, include agronomic biofortification and genetic biofortification or, for individuals, increased intake of naturally Se-rich foods, functional foods or supplements. The difficulties of balancing the risks and benefits in relation to Se intake are highlighted.
1
1
BJN-2007-011970 1
2
Food chain Se and human health: emphasis on intake 3
4
Margaret P Rayman 5
6
Nutritional Sciences Division, Faculty of Health and Medical Sciences, University of Surrey, Guildford, 7
Surrey, GU2 7XH 8
9
Address correspondence to: 10
Professor Margaret Rayman 11
Nutritional Sciences Division 12
Faculty of Health and Medical Sciences 13
University of Surrey 14
Guildford GU2 7XH 15
Tel: +44 (0)1483 686447 16
Fax +44 (0)1483 300374 17
E-mail: m.rayman@surrey.ac.uk 18
19
Key words: selenium, intake, selenium in foods, selenium and human health, optimal intake 20
21
Running head: Selenium intake in food and health 22
Reprints not available. 23
2
2
Abstract 1
Following the publication of the landmark trial of Clark and colleagues in 1996 that showed that Se 2
could reduce the risk of cancer, awareness of the importance of selenium (Se) to human health has 3
markedly increased. As a result, there is now much more aggressive marketing of Se supplements 4
and functional foods, even in situations where additional consumption of Se is inappropriate. This 5
review addresses how Se gets into the food chain, the wide variability in Se content of foods and the 6
very different levels of intake between countries and regions. Though it is clear that there are 7
adverse consequences for health of both deficient and excessive intake, health effects at 8
intermediate levels of intake are less certain. Thus it is difficult to define optimal intake which 9
depends on a large number of factors, such as which functions of Se are most relevant to a 10
particular disease state, which species of Se is most prominent in the Se source, which health 11
condition is being considered, the adequacy or otherwise of intake of other nutrients, the presence 12
of additional stressors, and lastly whether the ability to make selenoproteins may be compromised. 13
These complexities need to be understood, particularly by policy makers, in order to make informed 14
judgments. Potential solutions for increasing Se intake, where required, include agronomic 15
biofortification, genetic biofortification or for individuals, increased intake of naturally Se-rich 16
foods, functional foods or supplements. The difficulties of balancing the risks and benefits in 17
relation to Se intake are highlighted. 18
19
20
21
3
3
Introduction 1
There is a much greater awareness now of the importance of selenium (Se) to human health than 2
there was even ten years ago. This is partly due to the publication of the landmark trial of Clark and 3
colleagues
(1)
that showed that Se could reduce the risk of cancer. As a result, there is now much 4
more aggressive marketing of Se supplements and functional foods, even in situations where 5
additional consumption of Se is inappropriate. 6
Both individuals, who take a measure of responsibility for their own health and that of their 7
families, and more importantly, advisory bodies, need to be aware of the complexities surrounding 8
the issue of optimal Se intake in order to make informed judgments. The subject is often treated too 9
simplistically. This review attempts to air the issues that need to be considered. 10
Perhaps primarily, people need to be aware of the baseline intake in their country or region 11
and whether that intake is adequate or not. There are currently too few data on which to base this 12
judgment, hence companies are able to market Se supplements or functional foods to populations 13
that may already have a perfectly adequate intake of Se. Even in relatively-low Se areas, some 14
people may consume foods of good Se content (e.g. fish) or containing potent Se species (e.g. 15
garlic, onions, or broccoli) that may give them a higher or more effective intake than might be 16
predicted. An appropriate intake for an individual who is a cigarette smoker or has a family history 17
of prostate cancer may well not be the same as for an individual with a family history of squamous 18
cell carcinoma or diabetes. People may eventually learn whether they have a compromised ability 19
to make selenoproteins in which case they may need to increase their intake of Se-rich foods. 20
On the other hand, some evidence is now emerging that links the risk of more subtle adverse 21
heath effects to levels of intake well below those known to be toxic. There may even be a 22
possibility of increased risk of one condition even where risk of another is reduced. 23
An understanding of these niceties requires a certain background knowledge such as:- how 24
Se gets into the food chain; the variability of Se content of foods and how that content is affected by 25
food preparation or cooking; how intake varies according to country of region of country; health 26
effects in relation to level of intake and the factors modifying those effects. These issues are 27
addressed below, following which the potential solutions for increasing Se intake, if required, are 28
discussed. Lastly, the difficulties of balancing the risks and benefits in relation to Se intake are 29
highlighted. 30
31
How Se gets into the food chain 32
Se enters the food-chain through plants: intake through drinking water is generally trivial
(2)
. The 33
amount of Se in foods depends on a number of geological, geographical and other factors: while the 34
Se concentration of the soil is primarily controlled by the underlying geology (carbonatic vs. 35
4
4
silicatic), the bioavailability of that Se to plants is dependent on pH, redox conditions, amounts of 1
organic matter in the soil, competing ionic species such as sulphate, microbial activity, soil texture, 2
compaction and mineralogy, soil temperature, level of rainfall during the growing season, irrigation 3
and by pedoclimatic variables (temperature and rain intensity excursions) related to fluctuations of 4
soil moisture and pH
(3-10)
. The uptake of Se by the plant can be greatly inhibited by the 5
simultaneous occurrence of a high soil content of organic matter, iron hydroxides and clay minerals, 6
all of which can adsorb or bind Se
(4)
. Se speciation in soils also affects Se bioavailability: selenate 7
is more mobile, soluble and less-well adsorbed than selenite
(8)
. Thus oxidising, alkaline conditions 8
that favour the formation of selenate improve Se bioavailability, while reducing acid conditions that 9
favour the formation of selenite lower bioavailability. According to Fordyce
(8)
, it is important to 10
understand that even soils that contain adequate or high total Se concentrations can result in Se 11
deficient crops if the element is not in a form amenable to plant uptake. This is well-illustrated by 12
data from the Keshan disease area of Hebei Province, China, that showed a high soil Se content but 13
very low Se bioavailability owing to high organic matter content and lower pH than other soils in 14
the region
(8)
. 15
A further important factor is that flowering plant species (angiosperms) differ in their ability 16
to assimilate and accumulate Se: they can be divided into three groups, non-accumulators, Se-17
indicators (or secondary Se accumulators) and Se accumulators
(11)
. It appears that the transporters 18
that are responsible for the uptake or translocation of Se are selective such that the ratio of Se:S in 19
the shoots can be higher or lower than that of the solution surrounding the roots
(11)
. While non-20
accumulators rarely accumulate more than 100 μg Se/g dry weight, Se-accumulators can contain up 21
to 40,000 μg Se/g dry weight when grown in Se-rich environments
(11)
. The only Se accumulator 22
plant regularly used as a food source is the tree Bertholletia excelsa which produces Brazil nuts, but 23
some crop species of commercial importance can be described as secondary Se-accumulators e.g. 24
Brassica species (canola, broccoli), and Allium species (garlic, onions, cabbage, leeks and wild 25
leeks)
(11,12)
. Cereals crops such as wheat, oats, rye and barley are non-accumulators
(8)
. 26
The distribution of Se in various parts of the plant depends on species, phase of development 27
and physiological condition
(12)
: in Se accumulators, Se accumulates in young leaves during the early 28
vegetative stage of growth but during the reproductive stage it is found at much higher levels in 29
seeds. In non-accumulator cereal crops, there is often about the same amount in grain and roots 30
with smaller amounts in stems and leaves
(12)
. 31
32
33
34
35
5
5
Se content of foods is very variable 1
Se concentration in natural food sources has been tabulated by Rayman and colleagues
(13)
. 2
According to a WHO report
(14)
, the typical Se content of foods varies as follows:- organ meats and 3
seafood, 0.4 to 1.5 μg/g; muscle meats, 0.1 to 0.4 μg/g; most agricultural crops <1μg/g dry weight 4
e.g. cereals and grains, less than 0.1 to greater than 0.8 μg/g; dairy products, less than 0.1 to 0.3 5
μg/g; fruits and vegetables, less than 0.1 μg/g. In fact most vegetables contain a maximum of 6 6
μg/g even when grown on seleniferous soils and the level in both fruits and vegetables is more 7
likely to be < 0.01 μg/g
(15,16)
. 8
The variation in Se content of foods purchased in the upper Midwest of the US was 72-fold 9
(11-774 μg Se per 100 g) for wheat flakes, 57-fold (14-803 μg Se per 100 g) for wheat, and 11-fold 10
(19-217 μg Se per 100 g) for beef
(17)
while two brands of the same corn product purchased at the 11
same time from the same store in N America had a 10-fold difference in Se concentration
(18)
. The 12
same foods purchased in different countries may have very different Se content e.g. an average of 13
57 μg Se/100g in pasta products made in the US compared to only 6 μg Se/100g in Italian pasta
(17)
. 14
Some idea of the Se content of foods purchased in Europe may be obtained by inspecting the values 15
found by Barclay and colleagues
(19)
who measured the Se content of a range of around 100 foods 16
purchased in the UK between 1993 and 1994. Reilly
(2)
has tabulated Se levels in twelve common 17
foods from a number of countries around the world giving a good illustration of the variability that 18
exists. He also addresses in more detail the Se content of a number of individual foodstuffs:- milk, 19
bread and cereals, meat, fish, fruit, vegetables, Brazil and other nuts. 20
Brazil nuts are the richest source of food Se, but the content is very variable ranging from 21
0.03 - 512 μg/g in the studies quoted in the companion paper
(13)
. Brazil nuts are harvested from an 22
enormous area of the Amazon basin but soil levels vary from high, in the Menaus to Belem region 23
of the lower Amazon, to low, in the Acre-Rondonia region on the upper Amazon, resulting in high 24
variability in Se content
(2)
. Three studies have reported a higher Se content in unshelled than 25
shelled nuts though the reason is not known
(20-22)
. Two of these studies have drawn attention to the 26
fact that Brazil nuts are exceedingly high in barium, containing levels up to 4,000 μg barium/g. 27
Lisk and colleagues
(20)
found that a serving of three Brazil nuts (flesh weight 13.2 g) containing 290 28
μg Se, also provided 26 mg of barium. Barium can be toxic causing gastroenteritis, muscular 29
paralysis, potassium deficiency, decreased pulse rate, ventricular fibrillation and extra systoles, and 30
90% of the barium ingested in that study was retained in the body. The US Environmental 31
Protection Agency’s oral reference dose for barium based on toxicological data is 0.2 mg/kg/d, 32
which for a 75 kg person would be 15 mg/d
(23)
. It is clear that this could readily be exceeded by a 33
modest serving of Brazil nuts. Furthermore, Brazil nuts contain small amounts of radium, a 34
6
6
radioactive material. Although the amount is very small, about 1–7 pCi/g (40–260 Bq), and most of 1
it is not retained by the body, this is 1000 times higher than in other foods
(24)
. People relying on 2
Brazil nuts as their Se source, of whom there are a not-inconsiderable number, in the UK at least, 3
should be aware both of the uncertainty surrounding the quantity of Se they may be consuming and 4
of the fact that they may be inadvertently consuming barium in amounts exceeding the oral 5
reference dose and radium. 6
7
8
Effect of preparation and cooking on food Se 9
According to Fordyce
(8)
cooking reduces the Se content of most foods, and studies have shown that 10
vegetables that are normally high in Se such as asparagus and mushrooms can lose 40% during 11
boiling owing to leaching with water. Other studies have estimated that 50% of the Se content is 12
lost from vegetables and dairy products during cooking especially if salt and low pH components 13
such as vinegar are added, whereas frying foods results in much smaller Se losses
(8,14,25)
. For Se-14
enriched Allium and Brassica plants such as garlic and cabbage, recent studies have estimated that 15
85 and 89%, respectively, of the total Se is leached into boiling water (Dr Heidi Goenaga Infante, 16
personal communication, 2006). The distribution, concentration and speciation of Se in different 17
edible parts of a plant may well be different: e.g. the total Se concentration in the skin of Se-18
enriched potatoes was found to be almost three times higher than that of the flesh though the highest 19
percentage of Se as selenomethionine (73% of the total Se) was found in the flesh (Dr Heidi 20
Goenaga Infante, personal communication, 2006). Thus mode of preparation of food must be taken 21
into account when estimating magnitude or nature of Se intake. 22
23
24
Variability in Se intake by country/region 25
Intake of Se varies considerably between countries and regions of countries largely owing to the 26
variability of the Se content of plant foods (and hence of animal forage) from one part of the world 27
to another. Se intake data are summarised in Table 1
(7,24,26,27,31)
. Though the level of reliability of 28
such intake data is somewhat variable, it is clear that there is an immense range of intakes, from 29
toxic (5 mg/d) in parts of China affected by selenosis (areas of Enshi County, Hubei Province and 30
Ziyang County, Shaanxi Province), through high [Venezuela, parts of N America (N and S Dakota, 31
Montana and Wyoming) 200-724 μg/d] to high-adequate (rest of N. America, Japan 100-200 32
μg/d) to adequate/marginally adequate (Australia, Europe, New Zealand 30-90 μg/d) to low or 33
deficient (Eastern European countries, parts of China 7-30 μg/d) as judged against current 34
recommendations (tabulated by Rayman
(7)
). Though plants are the primary source of Se in the diet, 35
7
7
animals may be a more reliable source (at least for omnivores) as, unlike plants, they have an 1
absolute requirement for Se which they must get through feed or forage
(28)
. For instance, organ 2
meats such as kidney and liver are good Se sources while some sea-foods contain nearly as much. 3
In some countries, foods of animal rather than plant origin may even be a more important source of 4
dietary Se, as is the case in the UK
(29)
. 5
Human Se status is dependent not only on the Se content of locally-grown foods but on the 6
extent of use of imported foods. During the 1950s, UK wheat constituted only 15% of the grist
(11)
, 7
while wheat imported from Canada, which was much higher in Se content, made a much larger 8
contribution. This situation persisted up to the mid-1980s but by 2005, the percentage of UK wheat 9
in grists had risen to 80%
(11)
. Se intake and status in the UK has fallen in parallel with the decline 10
in imports
(30)
though increased use of sulphur fertilisers (competition of chemically similar species), 11
breeding for higher grain yield per plant, lower atmospheric deposition of Se from coal combustion 12
and the reported decline in cereal consumption are other important factors
(6,11,31)
. The opposite 13
situation has been seen in New Zealand where Australian wheat with a higher Se content has 14
recently made a significant contribution to Se intake, thereby improving Se status
(32)
. 15
16
17
Health effects of Se in relation to level of intake 18
Intake of Se ranges from clearly deficient to toxic. At intermediate levels of intake, more subtle 19
health effects have been reported. The situations of deficiency and toxicity are relatively 20
straightforward to describe and will be summarised first. The question of optimal intake for health 21
is much more difficult to address as it requires consideration of the interplay between a large 22
number of factors. 23
24
Deficient intake 25
Overt Se deficiency is associated with Keshan disease, a cardiomyopathy affecting mainly children 26
and women of child-bearing age, frequently fatal, named after the province in the extreme north-27
east of China where it was endemic
(33)
. Affected areas had soils that were subject to a strong 28
leaching effect and a high proportion of subsistence farmers who were very dependent on their local 29
food supply
(8,34)
. The disease occurred in areas where grain crops contained < 0.04 μg Se/g and 30
total daily Se intake was between 10 and 15 μg Se/d. Based on epidemiological studies in Keshan 31
disease areas, Chinese workers have suggested a deficiency threshold of 0.02 μg/g in cereal crops 32
for human consumption
(8)
. Large-scale Se supplementation (0.5-1 mg sodium selenite/week) 33
between 1974 and 1977 dramatically reduced disease incidence
(8)
. Though the disease was Se-34
responsive, it is now thought likely that it also had a viral co-factor which in the presence of Se 35
8
8
deficiency in the Keshan disease area mutated to a more virulent form that caused the heart 1
condition, as has been shown in the case of Se-deficient mice infected with coxsackie virus
(35)
. 2
Coxsackie virus has been isolated from archived heart tissue from patients with Keshan disease
(36)
. 3
Though Kashin-Beck disease, an osteoarthropathy found in rural areas of China, Tibet and 4
Siberia has also been associated with severe Se deficiency, other factors, notably low iodine status, 5
or the presence of fulvic acids or mycotoxins in foods appear likely to be more important
(37,38)
. 6
More recent data from Tibet appear to support the hypothesis that Kashin-Beck disease occurs as a 7
consequence of oxidative damage to cartilage and bone cells when associated with decreased 8
antioxidant defence, though inhibition of bone remodelling by certain mycotoxins has also been 9
suggested as a potential mechanism
(39)
. 10
While levels of Se deficiency of this magnitude are not normally seen in the West, a number 11
of cases of cardiomyopathy, some of which have been shown to be Se-responsive, have been 12
reported in subjects on intravenous nutrition receiving inadequate selenium in their infusion 13
solutions
(40,41)
. 14
15
Excessive intake 16
Overt Se toxicity in humans is far less widespread than Se deficiency
(8)
. Se toxicity has been 17
studied in animals and observed in humans where signs of selenosis are hair loss, brittle, thickened 18
and stratified nails, garlic breath and skin
(42)
. Chronic exposure to high levels of selenium has been 19
observed in several populations in seleniferous areas of the world, such as the northern great plains 20
of the United States, parts of Venezuela and Colombia, and one county in China (Enshi, Hubei 21
Province) where the average daily intake of 4.9 mg was associated with a blood Se concentration of 22
3,200 μg/l and symptoms of selenosis. In Enshi, selenosis was associated with consumption of 23
high-Se crops grown on soils derived from coal containing, on average, greater than 300 μg Se/g 24
(one sample exceeded 80,000 micrograms/g)
(43)
. Se from the coal entered the soil by weathering 25
and was available for uptake by crops because of the traditional use of lime as fertiliser in that 26
region. Morbidity rates reached 50% during peak prevalence years (1961-64) in the worst affected 27
villages which were all located in remote areas among populations of subsistence farmers
(8)
. The 28
particular outbreak of human selenosis was due to a drought that caused failure of the rice crop, 29
forcing the villagers to eat more high-Se vegetables and maize and fewer protein-rich foods
(43)
. 30
Though some plants that grow on seleniferous soils - the Se-accumulators - can take up 31
extremely large amounts of Se ranging from 1000 to 100,000 μg/g (air-dried), farm crops rarely 32
accumulate levels greater than 25-30 μg/g, even in seleniferous areas
(15,16)
. Based on 33
epidemiological studies in areas affected by selenosis, Chinese workers have suggested a toxicity 34
threshold of 1 μg/g in cereal crops for human consumption
(8)
. From published data, no health or 35
9
9
toxicity problems have been observed up to levels of intake of 819 μg Se/d in China
(44,45)
or 724 μg 1
Se/d in the USA
(45)
. If from cereal or rice, such intake is largely in the form of selenomethionine 2
(SeMet) and selenate
(46)
. By contrast, the high daily intake of Se in the Inuit of North Greenland 3
(estimated as 193-5885 μg/d), where the diet consists largely of meat and organs from marine 4
mammals, seabirds, fish, and the whales' skin delicacy, muktuk
(47)
, may include a more substantial 5
amount of selenocysteine (SeCys) from selenoproteins. Apart from the noted longitudinal striation 6
on the nails, no clinical signs of selenosis have been reported in this population, notwithstanding the 7
extremely high Se intake and blood concentrations well above 1,000 μg/L
(2)
: it would appear that Se 8
supplied through a marine diet can be tolerated at levels much higher than normally considered safe. 9
Similarly, despite the Se contamination of the Kesterson National Wildlife Refuge in California and 10
levels of 96 μg/g (wet weight) in fish, up to 130 μg/g (dry weight) in the liver of aquatic birds and 11
up to 5.3 μg/g (wet weight) in the flesh of waterfowl, no adverse health effects were seen in the 12
local population or in domestic animals
(48)
. 13
Based on the classic studies of Yang and colleagues in China, the LOAEL (Low Observed 14
Adverse Effects Level) was established as 1540 μg/d
(49)
and the NOAEL (No Observed Adverse 15
Effects Level) as 819 μg/d
(44)
. It should be noted, however, these values apply only to total Se and 16
may be inaccurate for any specific form. Applying a safety factor to the NOAEL has allowed 17
expert groups in a number of countries to define an upper level of total Se intake believed to be 18
safe. Thus for adults, the "Tolerable Upper Intake Level" for the US and Canada is 400 μg/d, based 19
on a NOAEL of 800 μg/d
(28)
. This same value has been adopted by the WHO
(50)
and is to be 20
adopted by Australia/New Zealand. The "Safe Upper Limit" in the UK is set at 450 μg/d for 21
adults
(51)
. 22
Remarkably, in Enshi, China, as described above, Keshan disease and selenosis occur within 23
20 km of one another: their incidence is dependent on the very different geologies of the two 24
relatively isolated areas
(8)
. 25
26
Optimal intake 27
Despite food supplies coming from diverse sources at least in developed countries, there is 28
evidence, that in some population groups, Se intake, while not deficient, may be sub-optimal for 29
protection against a number of adverse health conditions. Table 2 summarises studies that showed a 30
Se-associated health benefit. Use of data from these studies allows an attempt to be made to 31
estimate optimal intake in relation to specific health benefits. 32
Ascertaining the optimal intake of Se is not a trivial matter since it is dependent on a number 33
of factors. These include consideration of the mechanism by which Se is thought to act in any 34
particular situation, the species of Se ingested, which type of disease (or which type of cancer) is 35
10
10
being considered, the overall nutritional adequacy of the group or population, the extent to which 1
genomic differences between people or populations may be relevant, and what other risk or lifestyle 2
factors may be present within the population under consideration. These factors will be considered 3
separately below. 4
5
Which function of Se is being considered? 6
In the case of the many disease conditions associated with oxidative stress (e.g. asthma, rheumatoid 7
arthritis, pancreatitis, CHD), it would seem important to have an intake of Se that would at least 8
allow full expression of selenoproteins with an antioxidant function. Current recommendations for 9
intake of dietary Se (mean 57, range 30-85 μg/d
(7)
) hereinafter referred to as the RDA/RNI 10
(Recommended Dietary Allowance/Reference Nutrient Intake), have been set with this objective in 11
mind though we now know that some recommended intakes would be insufficient for the 12
expression of selenoprotein-P, a selenoprotein that appears to have a special role in scavenging 13
peroxynitrite
(91,92)
. 14
Furthermore, selenoprotein P is required for the transport of Se to a number of tissues after 15
its synthesis in the liver
(93)
and mouse knock-out studies show its absolute requirement by the brain 16
to avoid neurological dysfunction and brainstem axonal degeneration
(94,95)
. It would seem therefore 17
that Se intake needs to be sufficient to optimize the concentration of plasma selenoprotein P. 18
Though we do not yet know what level of intake that would require, we do know that current 19
intakes in some parts of Europe, specifically Eastern Europe, and parts of China are inadequate for 20
full expression of GPx let alone for full expression of selenoprotein-P
(92)
. 21
Apart from the selenoproteins, small molecular weight Se compounds such as Se-methyl 22
selenocysteine and γ-glutamyl-Se-methyl selenocysteine are thought to be precursors of the potent 23
anti-cancer agent methyl selenol
(96)
which is purported to cause apoptosis, cell-cycle arrest, 24
inhibition of tumour cell invasion and angiogenesis
(97)
. Though small amounts of these compounds 25
are found in members of the Allium and Brassica families, production of adequate amounts for 26
cancer prevention by metabolism of Se compounds more commonly found in foods probably 27
requires a considerably-larger intake, perhaps up to 290 μg Se/d, as was the case in NPC trial 28
subjects
(1)
. 29
30
Nature of Se species in food/supplements consumed 31
The predominant species of Se in the food (or supplement) consumed will affect the level of intake 32
considered to be optimal as it will affect bioavailability (absorption and retention), usefulness for 33
synthesis of selenoproteins and ability to produce methyl selenol metabolites. For instance, Se from 34
high-Se broccoli (mainly Se-methyl-selenocysteine, a precursor of methyl selenol) does not 35
11
11
accumulate in tissues or increase GPx enzyme activity to the same extent as selenite or selenoamino 1
acids
(98)
. Selenite, on the other hand, can be effectively used for selenoprotein synthesis, but it 2
cannot be stored in the body for later use. Selenomethionine (e.g. from cereals or high-Se yeast) 3
can act as a storage form of Se in body proteins from which it can slowly be released by catabolism 4
to maintain Se requirements over a longer period. Burk’s group has shown
(92)
that when Se was 5
supplemented to Chinese subjects in the form of selenomethionine, maximum enzyme activity was 6
reached with a supplement dose of 37 μg/d (on top of a background intake of 10 μg Se/d). When 7
the supplement was selenite, a daily dose of 66 μg was required to reach the same maximum level. 8
Thus, selenium in the form of selenomethionine was almost twice as effective as selenium in the 9
form of selenite in supporting plasma GPx activity. These issues are addressed in depth in the 10
companion paper
(13)
. 11
12
13
Which health condition is being considered? 14
Mortality: As mortality reflects vulnerability to a number of diseases combined, it is worthy of 15
consideration despite the fact that there have been very few studies on plasma Se and mortality in 16
elderly populations. Furthermore, such studies are particularly prone to confounding as plasma Se 17
concentrations are known to be higher in fit and well-nourished elderly people and lower in those 18
who are frail, poorly-nourished and unwell
(99)
. Such a criticism cannot be leveled at randomized 19
controlled trials (RCTs): in a meta-analysis of RCTs, Bjelakovic and colleagues
(100)
found that Se 20
supplementation tended to reduce mortality. In the 9-year longitudinal EVA study of 1389 elderly 21
French individuals living independently where various potential confounding factors 22
(sociodemographic characteristics, dietary habits, health, and cognitive factors) were controlled for, 23
low plasma selenium concentrations were associated with higher mortality i.e. for a reduction of 16 24
μg/L in plasma Se, relative risk (RR) of death was 1.54 (95% CI, 1.25-1.88)
(52)
. With a mean 25
plasma Se concentration in the EVA study population of 87 μg/L, a considerable proportion of the 26
participants may not have had a sufficient Se intake for optimal selenoprotein expression
(32)
. This 27
study therefore suggests that the RNI/RDA level of intake may benefit longevity. 28
29
Cognitive function: There can be no doubt that Se is important to the brain
(101)
: - (i) animal models 30
of neurodegenerative disease show enhanced cell loss in Se depletion; (ii) genetic inactivation of 31
cellular glutathione peroxidise (GPx) increases the sensitivity towards neurotoxins and brain 32
ischemia while increased GPx activity as a result of increased Se supply or overexpression 33
ameliorates the outcome; (iii) genetic inactivation of selenoprotein P leads to a marked reduction in 34
12
12
brain Se content with a corresponding movement disorder and spontaneous seizures in animal 1
models
(102)
. 2
Data from elderly French and Chinese populations of low-moderate Se status (mean baseline 3
plasma Se 86.0 μg/L and mean toenail Se 0.21-0.61 μg/g respectively) suggest that being at the top 4
rather than the bottom of the low-moderate range of Se status is sufficient to reduce the risk of 5
cognitive decline (see Table 2
(53-55)
). This should be achieved by an RDA/RNI level of intake. 6
In the context of cognitive function in the elderly, it should be appreciated that low plasma 7
Se may at least partly reflect a lower production of plasma glutathione peroxidase (GPx3) by a less 8
efficient kidney
(103)
. Failing kidneys also leak homocysteine, a known risk factor for dementia, into 9
the bloodstream
(104)
. Whether toenail Se would reflect plasma Se in this context is unknown. 10
11
Immune function: The studies in Table 2 show that the cell-mediated (Th1) immune response can be 12
improved by an additional 100 or 200 μg Se/d even in healthy US volunteers whose baseline Se 13
intake and status is already sufficient to optimize selenoenzyme activity
(56-59)
. In line with these 14
findings, the UK researchers concluded that in the UK population, an additional 100 μg Se/d may 15
be insufficient to support optimal function
(59)
. 16
17
Antiviral effects/HIV: Though animal studies have shown that adequate Se for antioxidant GPx1 18
activity is important for the avoidance of viral mutation to more virulent forms
(104)
, the success of 19
supplementation studies with 100 or 200 μg Se/d suggests that this level of intake on top of basic 20
diet may be necessary for anti-viral effects in humans
(59,60,62,66,67)
(Table 2). It has been suggested 21
that retroviruses such as HIV and Coxsackie B3 have the potential to deplete the host’s Se supply 22
by incorporating the Se into viral selenoproteins for their own protection, as has been demonstrated 23
for the DNA virus, Molluscum contagiosum
(106-108)
. Although unproven, this is a potential 24
explanation for the requirement for a Se intake higher than the RNI/RDA.
25
26
Fertility and reproduction: The selenoproteins phospholipid glutathione peroxidase (GPx4) and 27
sperm nuclei selenoprotein are required for sperm motility and sperm maturation 28
respectively
(109,110)
. The level of Se intake required to optimise the activities of these selenoproteins 29
is probably somewhere within the range of currently recommended intakes (RDA/RNI), say 30
between 55 and 75 μg/d, as both are high in the hierarchy of selenoprotein expression
(111,112)
. It 31
follows that the fertility of men whose Se intake is lower than that required to optimise 32
selenoenzyme activity may be improved by supplementation as was demonstrated in sub-fertile 33
Scottish men who showed a significant increase in sperm motility when supplemented with 100 μg 34
13
13
Se/d for three months
(69)
(Table 2). There is however a suggestion that relatively high intakes 1
(around 300 μg/d) may decrease sperm motility
(113)
. 2
It seems likely that the risk of miscarriage and the pregnancy disease, pre-eclampsia, may 3
also require an intake sufficient to give optimal selenoprotein expression. This can be concluded 4
from studies in UK pregnant women where those with higher Se status had a significantly lower 5
risk of first-trimester or recurrent miscarriage
(70,71)
and of pre-eclampsia
(72)
(see Table 2). As UK Se 6
intake has been measured as 29-39 μg/d
(31)
, it is clear that raising it to the RDA/RNI level of intake 7
would be sufficient to optimise female reproductive success. 8
9
Cancer: Results of the numerous prospective studies and trials are summarised in Table 2. From 10
prospective studies, the mean/median level of plasma Se required for a significant reduction in 11
cancer risk ranges from > 84 μg/L (e.g. for oesophageal and gastric cardia cancer in China
(74)
) to 12
147 μg/L (e.g. for prostate cancer in Hawaii
(114)
) according to the study, while from trial data, the 13
minimum mean plasma Se for significant reduction in cancer risk in an Eastern US population in 14
the NPC Trial ranged from 105 μg/L (all cancers)
(80)
to 123 μg/L (prostate cancer)
(81)
. The 15
minimum Se intake required to achieve these plasma concentrations ranges from just below the 16
RNI/RDA level to a total intake of around 140 μg/d from dietary Se (or Se-yeast, which is similarly 17
absorbed and retained
(115)
). This assertion is based on results of a UK supplementation study in 18
healthy volunteers with a baseline dietary intake of approximately 40 μg/d in which a further 100 19
μg Se/d as Se-enriched yeast raised plasma Se from 90.3 to 148.4 μg/L
(116)
. 20
The significant benefit of Se treatment effect in the NPC trial was restricted to males and to 21
those with baseline plasma Se 105.2 μg/L. In fact there was a non-significant increased risk of 22
cancer among those in the highest tertile (baseline plasma Se >121.6 μg/L) and a significantly-23
increased risk of squamous cell carcinoma in NPC participants with baseline plasma selenium in the 24
top two tertiles
(80,117)
. In addition, further analysis of NPC trial data has shown an increased risk of 25
self-reported Type-2 diabetes in those supplemented with Se, though the effect was significant only 26
in those in the top tertile of plasma Se at baseline
(118)
. Though such secondary end-point analyses 27
must be regarded with caution, the advisability of supplementing individuals of already-replete 28
status (say 120-125 μg/L or more
(119)
) with Se must be questioned. 29
Certainly it should be apparent that in populations that already have a mean baseline intake 30
at the level associated with reduced cancer risk e.g. the Prostate, Lung, Colorectal and Ovarian 31
Cancer Trial population where mean plasma Se was 141.3 μg/L
(120)
, no significant benefit at higher 32
intake/status should be expected, nor indeed was seen in that population. Such populations should 33
not be exposed to additional dietary Se or supplementation. 34
14
14
To date, no cancer trial has used a level of dose that would give a total intake of 140 μg Se/d 1
as suggested above, all having opted for 200 μg Se/d or more. 2
3
Thyroid effects: Since the selenoenzymes GPx and thioredoxin reductase are crucial to the 4
protection of the thyroid from the hydrogen peroxide that is produced there for thyroid hormone 5
synthesis
(121)
and the selenoenzyme iodothyronine deiodinase is required for the production of 6
active thyroid hormone, it might be expected that an intake of around the RDA/RNI which would 7
optimize the activities of these selenoproteins would be sufficient for the protective effects of Se on 8
the thyroid (see Table 2). However, it was found that a dose of 200 μg/d sodium selenite or 9
selenomethionine was required to decrease inflammation and thyroid autoantibody concentrations 10
in patients with autoimmune thyroiditis, the lower dose of 100 μg/d selenomethionine being 11
ineffective
(85)
. The reason for this rather surprising result is not known. 12
13
Coronary heart disease (CHD): Evidence that Se affects CHD risk has generally been equivocal 14
despite a good biological rationale for optimal selenoprotein activity/concentration conferring 15
benefit. However, a recent excellent meta-analyis of 25 observational studies, found the pooled 16
relative risk in a comparison of the highest with the lowest selenium concentration categories to be 17
0.85 (95% CI: 0.74, 0.99) in 14 cohort studies and 0.43 (0.29, 0.66) in 11 case-control studies
90
18
though the authors warn that observational studies have provided misleading evidence for other 19
antioxidants. Only two randomized trials have used Se as a single agent, one in Finland that found 20
a significant reduction in risk
(122)
and the other in the US that did not
(123)
, though the latter was in a 21
Se-replete population with respect to selenoprotein activity/concentration. Inspection of the 22
serum/plasma/toenail values reported in the meta-analysis together with the randomized trial 23
evidence suggests that achieving the RDA/RNI level of intake may generally be sufficient to reduce 24
CHD risk. 25
26
Conclusion on optimal intake for health effects: Partly because of the presence of potential 27
confounding in observational studies from which most of the above data is derived, it is difficult to 28
be categorical about the intake required to minimize the risk of any particular condition. However, 29
it does seem clear that the optimal intake of Se depends on the health effect being considered, the 30
risk apparently being reduced at the RDA/RNI level of intake in many cases while others such as 31
cancer and the immune response appear to require a higher intake. Results of many studies are 32
consistent with a threshold effect i.e. an intake (as represented by serum/plasma/toenail 33
concentration) of Se above which risk is uniformly decreased
(73, 74,80,124)
. 34
15
15
1
General nutritional adequacy 2
The intake of other nutrients needs to be taken into account when establishing Se requirements. If a 3
population is well-nourished, for instance, with good intake levels of vitamin E and other anti-4
oxidant micronutrients, the requirement for Se is likely to be somewhat lower than may be the case 5
for a poorly-nourished population such as some of those described in Chinese studies
(125)
. Thus, 6
the strongest effect of Se on cancer risk has been shown among those subjects with the lowest levels 7
of dietary antioxidant vitamins and carotenoids, and particularly at low α-tocopherol concentrations 8
(reviewed by Rayman
(75)
). Where the population is iodine deficient (e.g. the Democratic Republic 9
of Congo), Se intake should not be increased until iodine status has been optimized, as there may be 10
adverse effects on brain development
(126)
. 11
12
If ability to make selenoproteins is compromised, additional Se intake may be needed 13
The ability to make selenoproteins may be reduced in people with failing liver (selenoprotein P) or 14
kidney (GPx3) function
(103,127)
. To some extent, by analogy with studies in mice, increased Se 15
intake may be able to compensate for a deficit in selenoprotein activity, at least with respect to 16
colon cancer risk, by increasing the concentration of low-molecular weight selenium metabolites 17
that can produce methyl selenol
(128)
. 18
People differ substantially in their ability to increase selenoprotein activity in response to 19
additional dietary Se
(129)
. This inter-individual variation may to some extent be accounted for by 20
single nucleotide polymorphisms (SNPs) in selenoprotein genes that determine the efficiency with 21
which individuals can incorporate Se into selenoproteins
(130-132)
. Selenoprotein synthesis is a 22
complex process requiring multiple factors, many of which are encoded by polymorphic genes, for 23
the successful insertion of Se as SeCys
(133)
. This results in inter-individual and inter-racial variation 24
in the efficiency with which selenoproteins are expressed. 25
A notable example is the (GPx1) gene polymorphism at proline/leucine 198 where 26
possession of the leucine-198 allele is associated with an increased risk of bladder cancer
(134)
in a 27
Japanese population and of lung cancer in Caucasians but not among ethnic Chinese who do not 28
appear to show this polymorphism
(132)
. A Danish study found a highly significant correlation 29
between the GPx1 polymorphism and erythrocyte GPx activity such that GPx1 catalytic activity 30
was lowered 5% for each additional copy of the variant leucine-allele (P = 0.0003)
(135)
. 31
Furthermore, the activity of GPx-1 derived from the leucine-containing allele was found to be less 32
responsive to increasing Se supplementation than that from the proline-containing allele
(130)
. Thus 33
requirements for dietary Se for optimal protection against cancer may be higher in individuals 34
carrying particular functional selenoprotein SNPs (reviewed by Rayman
(75)
). 35
16
16
Epigenetic inactivation of selenoprotein gene expression may also have the potential to alter 1
Se requirements. For instance, a high frequency of GPx3 promoter hypermethylation and 2
progressive loss of GPx3 expression has been found in Barrett’s adenomacarcinomas and associated 3
lesions
(136)
. GPx3 biallelic hypermethylation and inactivation increased significantly with 4
progression toward neoplasia. It is currently unknown whether increased Se intake can compensate 5
for such loss of selenoprotein expression though the work of Irons and colleagues
(128)
suggests that 6
that may be the case. 7
8
Presence of additional stressors 9
A number of factors may increase Se requirements and need to be considered when deciding on 10
optimal intake. 11
Cigarette smokers have lower plasma Se
(99)
presumably because of higher levels of oxidative 12
stress and may therefore require a higher Se intake. Similarly exposure to arsenic, as occurs from 13
drinking water in Bangladesh and Taiwan, may increase the Se requirement since Se can interact 14
with arsenic to reduce its toxicity, possibly by the formation of a Se-arsenic-glutathione conjugate 15
formed in the liver and excreted into bile
(137)
. It is also postulated that a high mercury intake may 16
limit the availability of Se through strong chemical binding
(41)
. 17
Other factors known to be associated with lower Se status that may increase oxidative stress 18
and therefore Se requirements are obesity, occurrence of cardiovascular disease, infection or 19
inflammation
(99,138)
. 20
21
22
23
Potential solutions for increasing Se intake 24
If further evidence accrues that a certain level of Se intake or status is optimal for reduced disease 25
risk, appropriate solutions for increasing intake will vary according to whether a public-health or an 26
individual solution is envisaged. 27
Public-health solutions range from fortification of the food supply, to addition of Se to 28
fertilizers (agronomic fortification), as practiced successfully in Finland since 1984
(11,139)
, to 29
supplementation of animal feed, which is more effective if the supplement is organic. The latter 30
two solutions have the merit of introducing a biological barrier that protects the target population 31
from the effects of accidental overdose
(140)
. Genetic biofortification is a more novel solution where 32
food crops are enriched with Se by selecting or breeding crop varieties with enhanced Se-33
accumulation characteristics
(11)
. This method may also minimise the need to use Se fertilizers in all 34
but the lowest soil Se situations. It also has the potential for breeding crop varieties with higher 35
17
17
concentrations of specific forms of Se, such as Se-methyl selenocysteine or γ-glutamyl-Se-methyl 1
selenocysteine that can readily be converted to methyl selenol. 2
Individual solutions may encompass an increased intake of Brazil nuts, offal, fish or 3
shellfish which are good sources of Se
(2)
or the increasingly-available and widening-range of 4
functional foods that have been created with market demand in mind. High-Se bread, potatoes, 5
garlic, onions, broccoli, beer, tea and mussels can be sourced through the internet, Se-enriched 6
mushrooms providing a good source of bioavailable Se are now produced in N. Ireland
(141)
while 7
Korea has a chain of restaurants selling pork fed with organic selenium “Selenpork”
(142)
. Se-8
enriched eggs are produced more than in 25 countries world-wide and enjoy a substantial market 9
share in Russia (Prof Peter Surai, personal communication, 2007). Interestingly, the pork, the 10
mushrooms and the eggs are claimed to have improved shelf-life. 11
Supplements are a popular way of increasing Se intake for more affluent consumers. Se 12
from selenomethionine was found to be 1.6 times more bioavailable and much more effective in 13
raising plasma Se than was sodium selenite
(92, 119)
. Se consumed in this way appears to reach its 14
target as shown by significantly increased concentration of Se in prostate tissue in men that 15
consumed Se supplements for up to one month
(143-145)
. Se-methyl selenocystine is also available as 16
an over-the-counter supplement though there is as yet no published human data on the 17
pharmacokinetics, toxicity, or health benefits of this supplement. 18
According to Taylor and Greenwald
(146)
, at- or near-physiologic doses of Se are the 19
appropriate choice in a public-health fortification plan while higher doses might be considered if 20
individual supplementation (or consumption of functional foods) is contemplated. 21
22
23
Striking a balance 24
Though there are clearly individuals and populations that might benefit from a higher level of intake 25
of Se than they currently have, the evidence presented in this review highlights the large number of 26
factors that need to be taken into account before reaching a conclusion on optimal intake. 27
Furthermore, though full knowledge of all the relevant factors in any particular set of circumstances 28
can never be achieved, advisory bodies are obliged to do their best to make appropriate public-29
health recommendations. An attempt must be made to balance risks and benefits. While there 30
seems no downside to optimising intake to the RDA/RNI level, is it sensible to increase Se intake to 31
the level apparently required to reduce the risk of prostate cancer if it may simultaneously increase 32
the risk of squamous cell carcinoma or Type-2 diabetes
(81,117,118)
? Potential benefits in terms of 33
immune response, cancer risk, thyroid auto-immune disease must be balanced against the potential 34
risks that may be associated with a supra-physiological intake. 35
18
18
It is very important to be aware of background intake in any particular country or region as 1
what may be an appropriate additional intake in one country may well be excessive in another. For 2
instance, in those with a background level of intake that already gives them a plasma Se 3
concentration of 122 μg/L, cancer risk may potentially be increased with further Se intake
(80)
. 4
This is a concern in the current SELECT trial where US participants, of mean plasma Se 125 μg/L 5
(as found in NHANES III
(147)
) are being supplemented with 200 μg Se/d as the highly-bioavailable 6
selenomethionine. Similarly, high users of multivitamin/multimineral supplements should also be 7
aware that they may place themselves at excess risk by topping up their Se intake with additional 8
single supplements
(148)
. 9
With a view to balancing risks and benefits, it would seem sensible to aim just to reach the 10
appropriate threshold level of intake for any particular individual or indeed for a population insofar 11
as it may be judged. 12
13
14
Acknowledgements 15
Thanks are due to Dr Heidi Goenaga-Infante for sharing unpublished results. The author has no 16
conflict of interest to declare. 17
18
19
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22
30
30
Table 1. Selenium intake data for a number of countries
7,24,26,27,31
1
2
Country Selenium intake
(μg/person/d)
Information source
Australia 57-87 Fardy et al. 1989
b
Austria 48 Simma & Pfannhauser 1998
a
Belgium 28-61 Robberecht et al. 1994
b
Brazil 28-37 Maihara et al. 2004
c
Czech Republic 10-25 (estimate) Kvícala et al. 1996
b
Canada 98-224 Gissel-Nielsen 1998
a
China 7-4990 Combs, 2001
26
Croatia 27 Klapec et al. 1998
a
Denmark 38-47 Danish Government Food Agency, 1995
b
Egypt 29 Reilly 1996
c
France 29-43 Lamand et al. 1994
b
Germany 35 Alfthan G & Neve J, 1996
b
India 27-48 Mahalingam et al. 1997
c
Ireland 50 Murphy et al. 2002
c
Italy 43 Allegrini et al 1985
c
Japan 104-199 Miyazaki et al. 2001
b
Nepal 23 Moser et al. 1998
c
Netherlands 39-54
67
van Dokkum 1995
b
Kumpulainen, 1993
b
New Guinea 20 Donovan et al. 1992
c
New Zealand 55-80 Vannoort et al. 2000
b
Poland 30-40 (calculated) Wasowicz et al. 2003
b
Portugal 37 Reis et al. 1990
c
Saudi Arabia 15 Al-Saleh et al. 1997
c
Serbia 30 Djujic et al. 1995
b
Slovakia 38 Kadrabová et al 1998
b
Slovenia 30 Pokom et al. 1998
c
Spain 35 Diaz-Alarcon et al. 1996
c
Sweden 31-38 Swedish Natl Food Admin. 1989; Kumpulainen, 1993
b
Switzerland 70 Kumpulainen, 1993
b
Turkey 30-36.5 Reilly 1996; Foster & Sumar 1997; Giray & Hincal 2004
c
UK 29-39 MAFF, 1997
31
USA 106 Food and Nutrition Board 2000
24
Venezuela 200-350 Combs & Combs, 1986
a
a cited by Combs 2001
26
; b cited by Rayman 2004
7
; c cited by Surai 2006
27
3
31
31
Table 2 Summary of evidence-based health effects of Se together with an indication of the likely dose-level required 1
2
Condition/effect
(Likely protective
intake)
Evidence
Mortality
(RDA/RNI)
- After adjustment for confounding factors, low plasma Se concentration was significantly associated with higher
mortality in the 9-year longitudinal EVA study of 1389 elderly French individuals of mean baseline plasma Se =
87 μg/L)
(52)
.
Cognitive decline
(RDA/RNI)
- After adjustment for various confounding factors, a significantly increased risk of cognitive decline (OR = 1.58; CI
95% = 1.08-2.31) over a four-year period was found in French subjects aged 60 to 70 from the EVA cohort with
low plasma Se concentration at baseline
(53)
.
- After controlling for potential confounders, cognitive decline was significantly associated with the magnitude of
plasma Se decrease over a nine-year period in the EVA cohort
(54)
.
- Lower toenail Se was significantly associated with lower cognitive score in rural elderly Chinese
(55)
.
Immune system
(Additional 100-
200 μg/d,
Europe/US)
- Supplementation with 100 μg Se/d (as Se-enriched yeast) restored the age-related decline in immune response in
elderly Belgians
(56)
.
- Supplementation with 200 μg Se/d enhanced the cellular immune response of US healthy volunteers and head-and-
neck cancer patients
(57,58)
.
- Se supplementation of UK adults with 100 μg Se/d for 15 weeks in a double-blind study significantly enhanced the
cellular immune response
(59)
.
Anti-viral effects
(Additional 100-
- Low Se status increases the risk of developing primary liver cancer in hepatitis B/C positive patients while
supplementation of men carrying the hepatitis B surface antigen with 200-500 μg Se/d significantly reduced their
32
32
200 μg/d,
China/UK/US)
risk of developing liver-cancer
(60-63)
.
- Se supplementation of UK adults with 50 or 100 μg/d sodium selenite for 15 weeks in a double-blind study
resulted in faster clearance of attenuated polio virus with fewer mutations in the viral genome
59
.
- In US patients with relatively-low Se status (plasma Se <85 μg/L), HIV infection progressed more rapidly to AIDS
with higher mortality
(64,65)
.
- In a RCT in 187 HIV+ve US adults, 200 μg Se/d caused a marked decrease in hospital admission rates (RR 0.38,
p=0.002) over the two year trial
(66)
.
- In a RCT in 262 HIV-1-seropositive US men and women, the majority of whom were receiving antiretroviral
therapy, selenium supplementation (200 μg/d as Se-yeast) significantly suppressed the progression of HIV-1 viral
burden and indirectly improved CD4 count
(67)
.
- In a Tanzanian observational study involving 949 HIV-positive pregnant women, mortality decreased by 5% for
every 8 µg/L increase in plasma Se above 85 µg/L (p for trend = 0.01) over a five-year follow up period
(68)
.
Male and female
reproduction
(RNI/RDA/100
μg/d)
- Sub-fertile Scottish men supplemented with 100 μg Se per day for three months had significantly increased sperm
motility
(69).
- Significantly lower serum Se was found in UK women who suffered either first-trimester or recurrent miscarriages
compared to women who did not miscarry
(70,71).
- UK women in the bottom third of Se status were 4.4-times more likely to develop pre-eclampsia than those in the
top two-thirds
(72)
.
Anti-cancer
effects
(RDA/RNI-
additional 200
μg/d)
- Prospective studies have provided strong evidence for a beneficial effect of Se on risk of lung (meta-analysis
(73)
),
oesophageal/gastric-cardia cancers
(74)
and prostate cancer (see review
(75)
and meta-analyses
(76,77)
).
- The risk of recurrence of colorectal adenoma, a pre-cancerous condition, in US subjects with baseline serum/
plasma Se in the highest quartile (median 150 μg/L), was significantly lower than in those in the lowest quartile
(median 113 μg/L), (OR 0.66; 95% CI 0.50, 0.87)
(78)
.
- Supplementation with 200 μg Se/d reduced risk of colorectal adenomas in NPC trial subjects with plasma Se in the
33
33
bottom tertile (<105 μg/L) at baseline
(79)
.
- The Nutritional Prevention of Cancer (NPC) trial showed a significant reduction in cancer mortality and in
incidence of total cancer, prostate, colorectal and lung cancers
(1)
though in follow-up analyses, only total and
prostate cancer incidence remained significant
(80-82)
except in the bottom Se-tertile.
- Chinese trials with Se as Se-yeast (200 μg/d) or sodium selenite (500 μg/d) have shown that Se supplementation
significantly reduces the risk of hepatocellular carcinoma (RR 0.50, 95% CI 0.35, 0.71)
(63)
.
- There is some evidence that Se may affect not only cancer risk but also progression and metastasis
(75)
.
Protection of the
thyroid
(Additional 200
μg/d, Europe)
- Se supplementation decreased inflammation and thyroid autoantibody concentrations in patients with autoimmune
thyroiditis
(83-85)
.
- An inverse association was found between Se status and thyroid volume, thyroid tissue damage and goitre in
French women
(86)
.
- A positive association was found between the incidence of thyroid cancer and low prediognostic serum Se
concentration in a Norwegian population
(87,88)
.
- Se supplementation during pregnancy and the postpartum period with 200 μg/d selenomethionine in an RCT
reduced thyroid inflammatory activity and the incidence of permanent hypothyroidism
(89)
.
Coronary heart
disease
(RDA/RNI)
- A meta-analysis of 25 observational studies showed that a 50% increase in Se concentrations was associated with a
24% (95% CI 7%, 38%) reduction in coronary heart disease risk while in six randomized trials, the pooled relative
risk in a comparison of supplements containing Se with placebo was 0.89 (0.68, 1.17)
(90)
.
1
2
3
... Moreover, several reports from in vitro and animal studies have highlighted the possible mechanisms by which SeNPs might reduce or prevent oxidative stress-associated diseases including inhibiting ROS generation, regulating inflammation, and reducing vascular cell apoptosis [31]. They proved their simultaneous ability to confer cellular resistance to oxidative damage and to play a role in various neurodegenerative diseases [32,33]. ...
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Uncontrolled regulation of oxidative stress and reactive oxygen species (ROS) in living organisms might lead to the development of various diseases. Selenium is an element in antioxidant selenoproteins and is used in different forms as a food supplement. Selenium nanoparticles (SeNPs) could show improved activity and less toxicity; their bioactivity, biocompatibility, and binding to targets might be augmented by phytochemicals decorating their surfaces during green synthesis using plant extracts. Herein, the study evaluated the antioxidant activity of Moringa peregrina-mediated SeNPs (MPM-SeNPs) and the PEGylated form (PEG-MPM-SeNPs) in vivo in lipopolysaccharide (LPS)-induced oxidative stress in a mice model. LPS injection caused a reduction in enzyme activity of both oxidative stress biomarkers superoxide dismutase (SOD) and catalase (CAT) with an elevation in protein carbonyl content level in blood sera and liver homogenates of treated mice. MPM-SeNPs and PEG-MPM-SeNPs significantly recovered SOD activity in both blood sera and liver homogenates, as well as enhanced the specific activity of CAT in LPS-injected mice. Moreover, they caused a reduction in the carbonyl content in blood sera. Thus, both SeNPs complexes were able to amend the oxidation-induced damage in the body and protect its organs against necrosis and dysfunction.
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Alcoholic cardiomyopathy (ACM) is a unique disease and more familiar to physicians as “alcoholic heart disease’’ coined by William Mackenzie. Alcohol addiction exists in most societies. ‘‘Tubingen Wine Heart’’ described in 1877 and ‘‘Munich Beer Heart’’, reported by German pathologist Otto Bollinger are two popular references to harmful consequences of alcohol intemperance identified during the early 20th century. The progression of alcoholic cardiomyopathy is initiated by alcohol addiction. Alcohol-induced damage in the heart reduces blood pumping and increases myocardial apoptosis.
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Selenium is recognized as an essential element for human health and enters human body mainly via diet. Selenium is a key constituent in selenoproteins, which exert essential biological functions, including antioxidant and anti-inflammatory effects. Several selenoproteins including glutathione peroxidases, selenoprotein P and selenoprotein S are known to play roles in the regulation of type 2 diabetes. Although there is a close association between certain selenoproteins with glucose metabolism or insulin resistance, the relationship between selenium and type 2 diabetes is complex and remains uncertain. Here we review recent advances in the field with an emphasis on roles of selenium on metabolism and type 2 diabetes. Understanding the association between selenium and type 2 diabetes is important for developing clinical practice guidelines, establishing and implementing effective public health policies, and ultimately combating relative health issues.
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Selenium is a non-metal essential trace element with the symbol Se and atomic number 34. It was first described in 1818 by the Swedish chemist Jöns Jacob Berzelius (1779–1848), who began his career as a physician. He named this element after the Greek moon goddess Selene (Greek “σελήνη” (Selene) meaning Moon). Selenium seldom occurs in its elemental state or as a pure core compound in the Earth's crust and resembles sulfur in many of its chemical properties [1].
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Selenium nanoparticles (SeNPs) with unique biological properties have been suggested as a safer and more effective platform for delivering of Selenium for biological needs. In this study, we investigated the association between gut microbiota altered by SeNPs supplementation and its metabolites under oxidative stress conditions through 16S rDNA gene sequencing analysis and untargeted metabolomics. The results showed that dietary supplementation with SeNPs attenuated diquat-induced acute toxicity in mice, as demonstrated by lower levels of inflammatory effector cells, and biochemical markers in serum such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN) and lactate dehydrogenase (LDH). SeNPs also reversed the perturbed gut microbiota composition induced by diquat, decreased the Firmicutes/Bacteroidetes ratio, and increased the abundance of beneficial bacteria such as Akkermansia, Muribaculaceae, Bacteroides and Parabacteroides. Untargeted fecal metabolomics showed that SeNPs can regulate the production of steroids and steroid derivatives, organonitrogen compounds, pyridines and derivatives and other metabolites. Microbiome-metabolome correlation analysis suggested that Parabacteroides was the key bacteria for the SeNPs intervention, which might upregulate the levels of metabolites such as trimethaphan, emedastine, berberine, desoxycortone, tetrahydrocortisone. This study demonstrated that dietary SeNPs supplementation can extensively modulate the gut microbiota and its metabolism, thereby alleviating diquat-induced acute toxicity.
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Although numerous studies have explored the relationship between selenium intake and thyroid diseases, few epidemiological studies have investigated the association between selenium intake and thyroid hormones. Therefore, we conducted this analysis to investigate the association between dietary selenium intake and thyroid hormones. Our sample included 5,575 adults (age ≥ 20) years from the National Health and Nutrition Examination Survey (NHANES) 2007–2012. Thyroid hormones, including total triiodothyronine (T3), total thyroxine (T4), free T3 (FT3), free T4 (FT4), and thyroid-stimulating hormone (TSH), were detected. Multivariable linear regression models showed that log10-transformed selenium intake (LogSe) was negatively correlated with TT4 (β = −0.383, 95% CI: −0.695, −0.070) and TT4/TT3 (β = −0.003, 95% CI: −0.006, −0.0004) in U.S. adults. Besides, additional stratified analyses by sex demonstrated that LogSe was negatively associated with TT4 (β = −0.007, 95% CI: −0.013, −0.001) and TT4/TT3 (β = −0.664, 95% CI: −1.182, −0.146) and positively associated with FT4/TT4 (β = 0.031, 95% CI: 0.004, 0.059) in male adults. Meanwhile, subgroup analysis by iodine status showed that LogSe was negatively associated with TT4 (β = −0.006, 95% CI: −0.011, −0.002), FT4/FT3 (β = −0.011, 95% CI: −0.023, −0.00002) and TT4/TT3 (β = −0.456, 95% CI: −0.886, −0.026) in iodine sufficiency but not in iodine deficiency adults. Our results demonstrated that the increased dietary selenium intake was negatively correlated with TT4 and TT4/TT3 in U.S. adults. Furthermore, the association between dietary selenium intake and thyroid hormones was more pronounced in males and iodine sufficiency adults.
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The importance of daily consumed foods as affecting factors on cognition and emotion has been recognized more than ever. Due to the growing knowledge that dietary factors have a significant impact on neural functions, people become more enthusiastic about choosing good food in each phase of life. The purpose of this chapter is to give a broad overview of the effects of various kinds of nutrients including macronutrients (carbohydrates, proteins, and fats) and micronutrients (polyphenols, vitamins, and minerals) on children, adults, and the elderly. Moreover, this chapter aims to show how malnutrition impacts cognition and emotion.KeywordsCognitive functionsEmotionsNutritionMacronutrientsMicronutrients
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The soil bacterium Pseudomonas putida KT2440 has been shown to produce selenium nanoparticles aerobically from selenite; however, the molecular actors involved in this process are unknown. Here, through a combination of genetic and analytical techniques, we report the first insights into selenite metabolism in this bacterium. Our results suggest that the reduction of selenite occurs through an interconnected metabolic network involving central metabolic reactions, sulfur metabolism, and the response to oxidative stress. Genes such as sucA , D2HGDH and PP_3148 revealed that the 2- ketoglutarate and glutamate metabolism is important to converting selenite into selenium. On the other hand, mutants affecting the activity of sulfite reductase reduced the bacteria's ability to transform selenite. Other genes related to sulfur metabolism ( ssuEF , sfnCE , sqrR , sqr and pdo2 ) and stress response ( gqr , lsfA , ahpCF and sadI ) were also identified as involved in selenite transformations. Interestingly, suppression of genes sqrR , sqr and pdo2 resulted in the production of selenium nanoparticles at a higher rate than the wild-type strain, which is of biotechnological interest. The data provided in this study brings us closer to understanding the metabolism of selenium in bacteria, and offers new targets for the development of biotechnological tools for the production of selenium nanoparticles.
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Background: Despite advances in prevention and treatment, colorectal cancer remains the second most common cause of cancer death. To date, little is known about the role of prediagnostic selenium intake in colorectal cancer survival. Objective: The purpose of the study was to verify whether selenium intake in habitual diet before diagnosis is associated with survival in colorectal cancer patients. Study design: This was a prospective observation of patients primarily recruited for a case-control study between 2000 and 2012 in Cracow, Poland. A group of 671 incident cases of colorectal cancer was included. Habitual diet was assessed using a validated 148-item food questionnaire. 338 deaths were identified throughout 2017 by the Polish National Vital Registry. To evaluate the impact of dietary selenium on survival, the multivariable Cox regression model was used. Results: After standardization for several potential confounders (including key determinants, such as radical surgery, chemotherapy, tumor stage, and dietary factors), a decrease in the risk of death from colorectal cancer was observed in the group with higher dietary selenium intake (≥48.8 μg/day, group mean: 63.9 μg/day) compared to the group with lower dietary selenium intake (<48.8 μg/day, mean: 38.5 μg/day) (HR=0.73; 95% CI: 0.54–0.98) (the median was used for categorization). Conclusion: Our study suggests selenium as an additional dietary factor which may be associated with survival among colorectal cancer patients referred to surgery. Due to the observational nature of the study, the results should be taken with caution. These preliminary findings, however, provide the basis for well-structured clinical trials.
Article
While numerous laboratory investigations have shown that selenium may have anticarcinogenic activity, the epidemiological data have been inconsistent. In this report, meta-analysis was used to quantitatively summarize the existing epidemiological evidence on selenium and lung cancer and identify sources of heterogeneity among studies. When all studies were combined, the summary relative risk (RR) for subjects with higher selenium exposures was 0.74 [95% confidence interval (CI) 0.57–0.97]. In subgroup analyses based on the average selenium level in the study population, the summary RR for areas where selenium levels were low was 0.72 (95% CI 0.45–1.16), while the RR for areas where selenium levels were higher was 0.86 (95% CI 0.61–1.22). In both studies in high selenium areas where RRs were markedly below 1.0, protective effects were only found when subjects in the lowest category of selenium exposure were used as referents. No clear protective effects were seen when highly exposed subjects were compared with those in the middle exposure categories. The summary RR was lower in studies assessing selenium exposure using toenails (RR 0.46, 95% CI 0.24–0.87) than in studies using serum selenium (RR 0.80, 95% CI 0.58–1.10) or studies assessing dietary intake (RR 1.00, 95% CI 0.77–1.30). Overall, these results suggest that selenium may have some protective effect against lung cancer in populations where average selenium levels are low. The evidence for these findings is greater in studies of toenail selenium than in studies involving other measures of exposure.
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An endemic disease was discovered in 1961 in parts of the population of Enshi County, Hubei Province of the People's Republic of China. During the years of the highest prevalence, from 1961 to 1964, the morbidity was almost 50% in the 248 inhabitants of the five most heavily affected villages; its cause was determined to be selenium intoxication. The most common sign of the poisoning was loss of hair and nails. In areas of high incidence, lesions of the skin, nervous system, and possibly teeth may have been involved. A case is reported of a middle-aged, female hemiplegic, whose illness and death apparently were related to selenosis. Daily dietary intakes of selenium, estimated after the peak prevalence had subsided, averaged 4.99 (range 3.20 to 6.69) mg and hair and blood selenium levels averaged 32.2 and 3.2 µg/ml, respectively. Up to l000× differences occurred when selenium contents of vegetables, cereals, scalp hair, blood, and urine from the selenosis areas were compared with those from Keshan disease (selenium deficiency) areas. The ultimate environmental source of selenium was a stony coal of very high selenium content (average more than 300 µg/g; one sample exceeded 80,000 µg/g). Selenium from the coal entered the soil by weathering and was available for uptake by crops because of the traditional use of lime as fertilizer in that region. This particular outbreak of human selenosis was due to a drought that caused failure of the rice crop, forcing the villagers to eat more high-selenium vegetables and maize and fewer protein foods.
Article
Selenium is one of the most intensively studied of the inorganic components of the diet. Ever since it was recognised in the 1950s that the element, which effects, was also an essential had until then been known only for its toxic nutrient, it has attracted growing interest in both human and agricultural fields of science. The literature on selenium is overwhelming. Possibly 100000 publica­ tions dealing with the element have appeared since it was discovered in 1817. They continue to appear in numbers that make it difficult to keep up with even major aspects of the subject. Selenium specialisations have developed, not simply in agriculture and human studies, but also in molecular biology, metabolism, paediatric, enteral and parenteral nutrition, public health, toxicology and environmental health. All are developing their own literature and often an exclusiveness that results in loss of shared ideas and the fruitfullness of cross-boundary communication. This growth of knowledge and exclusiveness can place many readers at a disadvantage since it limits access to important new information. An appreciation of the role played by selenium in metabolism and health is far more than just an extra item in the intellectual database of modern food and health scientists. An understanding of selenium and its functions can enrich our understanding, not just of a single trace nutrient, but also of the many other food components with which selenium interacts.
Chapter
The beneficial role of selenium became apparent in the 1950’s, when it was shown to prevent a variety of diseases in animals, often when these animals were already exhibiting vitamin E deficiency. In humans, there are several examples of disease that can be attributed to selenium deficiency, and for some, the ultimate causal relationship has been established by the demonstration that symptoms can be alleviated with selenium supplementation of the at risk population. This is true both in cases where diseases associated with selenium deficiency are endemic in areas of low selenium consumption, such as Keshan disease, Keshin-Beck disease and myxedematous cretinism, as well as in circumstances where selenium deficiency results from other pre-existing health conditions. The consequences of too little dietary selenium can be considered in the context of the decline of specific selenium-containing proteins, many of which have only recently been identified.
Article
Brazil nuts (Bertholletia excelsa H.B.K.) typically contain high concentrations of selenium and barium. Four human volunteers consumed Brazil nuts for several weeks and their blood was analyzed for selenium. Brazil nut consumption was closely accompanied by a rapid increase of 100 to 350 percent in the concentration of selenium in whole blood depending on the number of nuts consumed and the period of consumption. Blood selenium decreased following Brazil nut consumption. Total excretion in urine and feces during the six days following Brazil nut consumption was, respectively, 53.89% and 12.35% of dose for selenium and 0.81% and 9.09% of dose for barium. The nutritional and toxicologic significance of these results are discussed.