Selenium is essential

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Selenium

• keeps the immune system in balance

• protects against oxidative stress

• is important for the thyroid

Updated version

Selenium: a brief overview

selenase T po 10×10 mlbiosyn Arzneimittel GmbH

AOK Bayern

106415300 A123456789 1000 12711111100 654321 10.03.2018

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Selenium is an essential trace element

Have your doctor measure your selenium status. If the selenium test reveals a selenium deficiency, the statutory health insurance covers the costs of prescription selenium drugs.

Selenium deficiency can  have negative effects on our health [C]

3

8

1 Selenium deficiency is common in Germany [A]

Selenium deficiency [B]

Serum < 80 μg/l

Whole blood < 100 μg/l

2

6 Selenium deficiency can be an indication of another disease

Examination of selenium status7

Selenium deficiency can make certain viruses more virulent [D]

4

!

Selenium administration in cases of selenium deficiency can support  the effect of vaccinations [D, E]

5

[A] Hughes DJ et al. Int J Cancer. 2015 Mar 1; 136(5): 1149-61.[B] Summary of product characteristics selenase® 50 peroral, 

biosyn Arzneimittel GmbH, November 2017.

[C] Rayman MP. Lancet. 2012 Mar 31;379(9822):1256-68.[D] Huang Z et al. Antioxid Redox Signal. 2012 Apr 1; 16(7): 705-43.[E] Broome CS et al. Am J Clin Nutr. 2004 Jul; 80(1): 154-62.

SUMMARY 3

selenase® at a glance

• corrects selenium deficiency [A]

• is safe:1) no known side effects [A]

2) few interactions with other medicines [A]

3) broad therapeutic range [A]

[A] Summary of product characteristics selenase® 100 μg peroral, biosyn Arzneimittel GmbH, November 2017.

selenase® corrects selenium deficiency

4

2 Summary

2 Selenium: a brief overview

3 selenase® at a glance

6 Selenium is essential

6 What is selenium?

7 Which organ is the most selenium-rich?

8 What do we know about selenium?

9 What makes selenium so special?

12 Why do we need selenium?

14 Selenium and the immune system

16 Selenium and the thyroid

18 Male infertility

19 Selenium and the brain

20 Selenium supply in old age

20 Selenium status in expectant mothers

23 Do we consume enough selenium?

24 Little selenium in the soil – little selenium in the food

26 A healthy diet versus an adequate supply of selenium?

28 How much selenium does an adult need?

29 Do we consume enough selenium in Germany?

30 Are there foods particularly rich in selenium?

30 Brazil nuts – ideal for selenium supply or hidden source of danger?

Contents

5

32 Selenium deficiency

32 Selenium deficiency in Germany

34 Selenium deficiency – more than just laboratory cosmetics

35 How can you tell a selenium deficiency?

35 Who has an increased risk of selenium deficiency?

38 Risk group vegetarians and vegans

39 Overweight as a risk factor

42 Selenium deficiency – possible indication of severe disease

43 What is the selenium status?

45 How is the selenium status determined?

46 Caution – check the actual selenium level

47 biosyn Service Laboratory

48 selenase® corrects selenium deficiency

51 Is selenium always the same?

51 Why sodium selenite?

52 Why not organic selenium?

56 Does selenium also have side effects?

58 Toxicity of selenium

59 Signs of acute selenium poisoning

60 Attachment

60 Bibliography

63 selenase®: application and dosage

64 selenase® pharmaceuticals: pharmacy-only

66 Information on biosyn Arzneimittel GmbH

68 Imprint

SELENIUM IS ESSENTIAL6

What is selenium?

Selenium is an essential trace element. That means selenium is essential for life. Every single cell needs selenium. At the same time, selenium only occurs in very small amounts in the body (5 – 15 milligrams). [2] However,  selenium content in the body is two-thirds lower in countries with selenium- poor soils than in countries with selenium-rich soils (Table 1). [1]

Selenium is necessary for many metabolic processes in the body

Selenium content in the body

Total amount of selenium in the body in countries with low-selenium soils

Poland approx. 5.2 mg

New Zealand approx. 3.0 – 6.1 mg

Germany approx. 6.6 mg

Total amount of selenium in the body in countries with selenium-rich soils

USA approx. 13.0 – 20.3 mg

Created according to: Zachara BA et al. Arch Environ Health. 2001 Sep-Oct; 56(5): 461-6. Tissue level, distribution, and total body selenium content in healthy and diseased humans in Poland.

Table 1

SELENIUM IS ESSENTIAL 7

Which organ is the most selenium-rich?

Regardless of the total amount of selenium in the body, there are partic-ularly selenium-rich organs in the body. [1, 3] The highest selenium concen-tration is found in the kidney and decreases in the order livertesticles

spleenheartprostatelungmusclebrain (Fig. 1). [4, 5]

Selenium in the organs

Kidney

Liver

Testicles

Spleen

Heart

Prostate

Lung

Muscle

Brain

Sel

eniu

m c

once

ntra

tion*

* measured per gram wet weight

Created according to:Oster O et al. Biol Trace Elem Res. 1988 Jan-Apr; 15: 23-45. The organ distribution of selenium in German adults.Biesalski HK. Vitamine und Minerale: Indikation, Diagnostik, Therapie. Georg Thieme Verlag, 2002.

Fig. 1

SELENIUM IS ESSENTIAL8

What do we know about selenium?

Jens Jakob Berzelius, a Swedish chemist, discovered the metal selenium in 1817. He named the newly discovered element after the Greek moon goddess Selene. Selenium wasn’t really researched until the 20th century. It was not until 1957 that it was discovered that selenium was an essential trace element. [6] In the 1970’s it became clear that selenium deficiency can cause diseases. [7]

Selenium plays a special role among the trace elements. In 1986 it was shown that selenium is incorporated into proteins as part of the amino acid selenocysteine (Fig. 2). [8] Current selenium research involving over 30,000 publications (PubMed, Nov. 2018) shows how important selenium is for our health.

The special role of selenium

Selenium

Selenocysteine

HSeNH2

O

OH

Seleno-proteins

GPx

1G

Px2

GPx3

GPx4

GPx5*

GPx6

SelK

SelRSelW

TrxR1TrxR2

TrxR3

SPS2SelT

SelVSe

lOSelISelH

SelM

SelN

Sel15

SelP

SelS

DIO3D

IO2

DIO

1

Antioxidant capacity

Redox signal transmission

Selenocysteine synthesis

Unknown functions

Protein folding

Transport & Storage

Thyroid metabolism

Classes and possible functions

* selenium independent

Created according to: Benstoem C et al. Nutrients. 2015 Apr 27; 7(5): 3094-118.  Selenium and its supplementation in cardiovascular disease--what do we know?

Fig. 2

SELENIUM IS ESSENTIAL 9

What makes selenium so special?

Selenium plays a special role among the trace elements. While, for example, iron is bound in the active center after the formation of hemoglo-bin, the incorporation of selenium takes place via a highly complicated biosynthesis process.

Proteins consist of amino acids, which in turn are encoded in the genetic code by 3 bases, the so-called codons. Start and stop codons are available for reading the mRNA. UGA (Uracil –  Guanin – Adenin) stands for a stop codon.

At least that’s what they thought for a long time. UGA also stands for the selenium-containing amino acid selenocysteine. To enable the cell to distinguish between UGA selenocysteine and a stop codon, nature has developed a highly complex biosynthesis involving several spe-cial proteins (Fig. 3). The more complicated a process is, the more error-prone it becomes. In recent years, several mutations have been found in selenium biosynthesis proteins in humans that can lead to various congenital diseases.

Complex biosynthesis of selenoproteins

StartStop©

Mou

agip

/wik

imed

ia c

omm

ons

ACU ACU

Ser

ACU

Sec

Ser Se

UGA STOPSecis

ACU

Sec

UGA STOP

ACU

Sec

Selenocysteine

L-selenocysteine

COOH

CH2

SeH

NH2 C H

Created according to: Moghadaszadeh B et al. Physiology (Bethesda). 2006 Oct; 21: 307-15. Selenoproteins and their impact on human health through diverse physiological pathways.

Fig. 3

SELENIUM IS ESSENTIAL10

Mutations in selenium biosynthesis

Congenital metabolic disorders are increasingly being recognized as the cause of diseases. The number and range of diseases due to defects in selenium use, transport and metabolism is constantly growing (Fig. 4). [11, 12]

The first congenital metabolic disorder due to a mutation in a selenopro-tein was identified in 2001. Mutations of selenoprotein N (SEPN1) cause so-called SEPN1-related myopathies. [12] Patients suffer from early-onset muscle weakness and atrophy, mainly affecting the axial muscles, leading to scoliosis.

Diseases associated with selenium deficiency  or mutations of selenoproteins and their biosynthesis

Adrenal glands

Immune system

FGD

White muscledisease

Kashin-Beckdisease

Keshandisease

Heart

HeartBones

DiseaseAffected organs

Affected selenoprotein

DCM

Muscles

Muscles

MusclesThyroid

SEPN1-relatedmyopathy

BrainBonesHeart

PCCAPCH2D

Brain

SSMD

TXNRD2

SEPS

SECISBP2

ThyroidMusclesInner earImmune systemBrainBonesTesticles

SECISBP2syndrome

SEPSECS

tRNA[Ser]Sec

SEPN1GPX4

Selenoprotein

Seleniumdeficiency

Selenoproteinbiosynthesis

A

Modified according to: Schweizer U et al. FASEB J. 2016 Nov; 30(11): 3669-81.  Why 21? The significance of selenoproteins for human health revealed by inborn errors of metabolism.

Fig. 4

Selenium is incorporated by means of a highly complicated

biosynthesis process

WHY DO WE NEED SELENIUM?12

Why do we need selenium?

Selenium is necessary for many metabolic processes in the body (Fig. 5). Selenium’s best known function is as an antioxidant. [13] Along with cat-alase and superoxide dismutase, the selenoprotein glutathione peroxi-dase is one of the three musketeers of antioxidative defense. However, seleno proteins fulfil many more important functions, some of which have not yet been fully researched. Selenium is essential for the thyroid and the brain. [14, 15] Immune system functions also suffer from an inadequate selenium supply. [16] A massive selenium deficiency can cause cardiomyo-pathy. [9] In men, sperm production suffers, which can lead to infertility. [17]

At a glance

Selenium plays an important role in the immune system [16]

Selenium is essential for the thyroid

Selenium deficiency impairs sperm quality [25]

Preferential treatment of the brain in selenium deficiency

Selenium also protects our brain in old age

Selenium is important for the brain development of the fetus

WHY DO WE NEED SELENIUM? 13

What do we need selenium for?

Antioxidant

DNArepair

Selenium

Immunesystem

ThyroidBrain

Heart

Repro-duction

Created according to:Benstoem C et al. Nutrients. 2015 Apr 27; 7(5): 3094-118. Selenium and its supplementation in cardiovascular disease--what do we know?Steinbrenner H et al. Arch Biochem Biophys. 2016 Apr 1; 595: 113-9. Selenoproteins: Antioxidant selenoenzymes and beyond.Solovyev ND. J Inorg Biochem. 2015 Dec; 153: 1-12. Importance of selenium and selenoprotein for brain function: From antioxidant protection to neuronal signalling.Köhrle J. Curr Opin Endocrinol Diabetes Obes. 2015 Oct; 22(5): 392-401. Selenium and the thyroid.Huang Z et al. Antioxid Redox Signal. 2012 Apr 1; 16(7): 705-43. The role of selenium in inflammation and immunity: from molecular mechanisms to therapeutic opportunities.Ahsan U et al. Anim Reprod Sci. 2014 Apr; 146(1-2): 55-62. Role of selenium in male reproduction – a review.

Fig. 5

WHY DO WE NEED SELENIUM?14

Selenium and the immune system

Selenium plays an essential role in the immune system. [16] Two points make this clear:

• Selenium deficiency impairs the function of the immune system. [16] • Mutations that impair the biosynthesis of selenoproteins can lead to

a defect in T cell proliferation. [12]

Selenium deficiency and risk of infection

Selenium is particularly important for the proper functioning of the acquired immune system. [16] Normally, there is a balance between a TH1 and TH2 immune response. If there is a selenium deficiency, the immune system becomes imbal-anced, which promotes autoimmune diseases and allergies (Fig. 6). [18] At the same time, the 

ability of the immune system to defend itself against viruses or tumor cells decreases. Thus selenium deficiency can increase the aggres-siveness of viruses, for example. [16] In contrast, a high dose of sodium selenite can enhance the TH1 immune response and thus protect against infections. [18, 19]

Selenium administration at vaccinations

An intact immune response is the basis for a successful vaccination. For example, the effectiveness of influenza vaccination may decrease in older people, possibly due to an age-related decrease in the immune response. [20] Selenium deficiency also reduces the functioning of the immune system. [16] There-fore it was obvious to check the effects of sele-nium supplementation before vaccination.

Several trials combined selenium supplemen-tation, alone or as part of micronutrient supple-mentation, with influenza vaccination in elderly people. [21 – 23] The result: selenium can improve the immune response in older people. [22] The selenium form and dosage, however, play a role. [21] Too little selenium (50 – 60 μg per day) showed a lower or no effect. [21, 23] Too much organic selenium (200 μg per day), as shown in a small trial with selenium yeast, was not bene-ficial either. [21]

Another trial investigated the effect of selenium supplementation at polio vaccinations. [24] In the double-blind trial, 66 adults with a serum selenium concentration of approximately 80 µg/l received a placebo, 50 or 100 µg selenium per day in the form of sodium selenite. Sodium sele-nite increased the activity of the immune system compared to the placebo group and the poliovi-rus clearance after vaccination (Fig. 7). [24] Even when the immune system was put to the test with a renewed polio vaccination using live vac-cine, the selenium group showed an increased response of the immune cells, especially the TH1 lymphocytes. [24]

WHY DO WE NEED SELENIUM? 15

High-dose sodium selenite enhances TH1 differentiation

High-dose sodium selenite

Selenium deficitNaive T-cell

Adequate selenium intake

TH1

TH2

Modified according to: Hoffmann FW et al. J Nutr. 2010 Jun; 140(6): 1155-61.  Dietary selenium modulates activation and differentiation of CD4+ T cells in mice through a mechanism involving cellular free thiols.

Fig. 6

Sodium selenite improves poliovirus clearance

Days after polio vaccination

Per

cent

age

of s

ubje

cts

with

pol

iovi

rus

in s

tool

[%]

100

80

20

40

60

90

70

10

30

50

07 14 21

Placebo

50 µg sodium selenite/day

100 µg sodium selenite/day

*

*

* **

*

*

* significant difference from placebo; p < 0.001

Created according to: Broome CS et al. Am J Clin Nutr. 2004 Jul; 80(1): 154-62.  An increase in selenium intake improves immune function and poliovirus handling in adults with marginal selenium status.

Fig. 7

WHY DO WE NEED SELENIUM?16

Selenium and the thyroid

The thyroid is the organ with the highest selenium content in the body and is therefore particularly sensitive to selenium deficiency. [15] Like iodine, selenium is essential to the thyroid. Selenoproteins are required to form active thyroid hormone (T3) and to degrade the resulting hydrogen peroxide to water.

The hormones produced by the thyroid influence overall physical develop-ment. For example, they control energy and bone metabolism, digestive function, cardiovascular functions and the mental state. Therefore, a sele-nium deficiency has a negative effect on the body due to the insufficient formation of an active thyroid hormone. In addition, an inadequate sele-nium supply leads to a lack of protective proteins and thus to destruction of thyroid tissue (Fig. 8).

The thyroid is particularly sensitive to selenium deficiency

Selenium is essential for the thyroid

WHY DO WE NEED SELENIUM? 17

Effects of selenium deficiency on the thyroid

O OH

H

O OH

H

O OH

H

O OH

H

O OH

H

O OH

H

Increasedoxidative stress

Increasedinflammation disposition

Thyroiddisorders

Impairedconversion of

thyroid hormones

T4

T3

Reduced activity of glutathione peroxidase

Lower selenium status

Reduced activity of deiodinase

Created according to: Köhrle J. Curr Opin Endocrinol Diabetes Obes. 2015 Oct; 22(5): 392-401. Selenium and the thyroid.

Fig. 8

WHY DO WE NEED SELENIUM?18

Male infertility

There is a hierarchy in the distribution of selenium in the human body. Where the selenium supply is most important, the body will always try to ensure a sufficient selenium supply. It’s the brain and the testicles.

Without selenium nothing works in sperm production. If there is a sele-nium deficiency, the sperm quality suffers (Fig. 9). [25] This can lead to infertility.

The additional intake of selenium can correct infertility due to a selenium deficiency. [26, 27]

Influence of selenium deficiency on sperm quality

Sel

eniu

m s

tatu

s

Sperms

Nor

mal

Def

icie

ncy

Quantity Morphology Mobility

Modified according to: Boitani C, Puglisi R. Adv Exp Med Biol. 2008; 636: 65-73.  Selenium, a Key Element in Spermatogenesis and Male Fertility.

Fig. 9

WHY DO WE NEED SELENIUM? 19

Selenium and the brain

Our brain is not only preferred to receive sufficient energy. The brain also gets extra attention with the selenium supply.

The brain contains only 2.3 % of the total amount of selenium in the body. [28] But if the selenium supply is insufficient, the brain retains sele-nium at the expense of other organs. Thus, the activity of the selenopro-tein glutathione peroxidase, which is one of the most important factors in reducing oxidative stress, decreases by more than 90 % in the liver when there is a selenium deficiency. In contrast, activity in the brain decreases by only 10 % (Fig. 10). [28] This is very important because brain cells are extremely sensitive to oxidative stress. Without the preferential treatment of the brain, the neuronal damage caused by oxidative stress would be immense.

Preferential treatment of the brain with selenium deficiency

Selenium deficiency

-90 % GPx

Little protectionagainst

oxidative stress

Selenium deficiency

-10 % GPx

Limited damageto neurons duringoxidative stress

Created according to: Steinbrenner H et al. Arch Biochem Biophys. 2013 Aug 15; 536(2): 152-7. Selenium homeostasis and antioxidant selenoproteins in brain: implications for disorders in the central nervous system.

Fig. 10

WHY DO WE NEED SELENIUM?20

Selenium supply in old age

Studies with older people have shown that a low selenium status is asso-ciated with a poorer result in cognitive tests. [29, 30] Conversely, this means that a long-term adequate intake of selenium is advantageous for main-taining the intellectual abilities of older people.

Selenium status in expectant mothers

But it is not only in old age that selenium protects our brain. Selenium is also important for brain development in the fetus. The fetus needs active thyroid hormone from the mother for proper brain development, as it cannot yet produce the hormone itself (Fig. 11). However, a selenoprotein is required to activate the thyroid hormones. [15] If the pregnant woman consumes too little selenium daily, this can have an effect on the cognitive development of the child, for example. [31, 32]

Selenium is important for the brain development of the fetus

Selenium is also important for the brain in old age

WHY DO WE NEED SELENIUM? 21

Maternal selenium is important for fetal brain development

before start of fetal T4 production

immature fetalT4 regulation

limited fetalT4 production

Brain development

1st trimester• visual attention• visual processing• gross motor skills

3rd trimester• language, memory• attention, IQ

2nd trimester• visual-spatial skills• fine motor skills

Dependence on maternal T4 productionFetal neonatal potential

Modified according to: La Gamma EF et al. NeoReviews 2016; 17: e394.  Transient Hypothyroxinemia of Prematurity.

Fig. 11

Selenium must be ingested through food

DO WE CONSUME ENOUGH SELENIUM? 23

Do we consume enough selenium?

At a glance

Little selenium in the soil – little selenium in the food

The healthier the diet, the lower the selenium intake

The EFSA (European Food Safety Authority) recommends an intake of 70 μg selenium per day for adults [40]

In Germany we consume too little selenium [41]

Selenium content in German food is too low overall

Brazil nuts – ideal for selenium supply or hidden source of danger?

Selenium cannot be produced by the body itself and must therefore be ingested through food. [35] Insufficient selenium intake affects up to one billion people worldwide. [34]

Up to one billion people are insufficiently 

supplied with selenium

DO WE CONSUME ENOUGH SELENIUM?24

Little selenium in the soil – little selenium in the food

Germany soils – like most of its neighbors – is poor in selenium. [35, 36] The selenium content of German arable soils is between 0.074 – 0.194 mg/kg (Fig. 12). The optimal selenium content is signifi-cantly higher at 0.6 – 4.0 mg/kg. [78] Soils with a selenium content between 0.1 – 0.6 mg/kg are classified as deficient. In the USA, the selenium content of soils is between 0.1 – 5.32 mg/kg. [37] German soils contain little selenium due to geological developments. Since plants can only absorb selenium from the soil, grain in Germany, for example, contains only about one tenth of the amount of selenium found in American grain. [79, 82]

Farm animals are largely fed with indigenous, selenium-poor feed. As a result, farm animals throughout Europe are affected by a greatly increased risk of diseases caused by selenium deficiency. [80] Therefore, EU farm animals are often fed selenium-enriched fodder. [80]

Also, selenium is added everywhere in pet food in order to avoid a sele-nium deficiency and its negative effects. [81] For humans, on the other hand, it is difficult to sufficiently cover their selenium needs with food.

German soils predominantly contain too little selenium

DO WE CONSUME ENOUGH SELENIUM? 25

Selenium content in German soils

Schleswig-Holstein0.194 mg/kg Mecklenburg-

Western Pomerania0.149 mg/kg

Bavaria0.074 mg/kg

Baden-Württemberg0.086 mg/kg

Hesse0.142 mg/kg

Rhineland-Palatine0.114 mg/kg

Optimal selenium concentration: 0.6 – 4 mg/kg

Lower Saxony0.155 mg/kg

North-Rhine-Westphalia0.121 mg/kg

The selenium content was not checked in the remaining states

Created according to:Hartfiel W, Bahners N. Biol Trace Elem Res. 1988 Jan-Apr; 15: 1-12.  Selenium deficiency in the Federal Republic of Germany.Saha U et al. International Journal of Applied Agricultural Sciences. Vol. 2, No. 6, 2016, pp. 112-125. Selenium in Animal Nutrition: Deficiencies in Soils and Forages, Requirements, Supplementation and Toxicity.

Fig. 12

DO WE CONSUME ENOUGH SELENIUM?26

A healthy diet versus an adequate supply of selenium?

Those who eat a healthy diet are able to supply the body with all the necessary minerals it needs. That is our fundamental conviction. But it appears that in fact this is not always the case. According to the German Nutrition Society, a healthy diet looks like this (Fig. 13):

Components of a healthy diet

Milk and dairy products

Meat, fish and eggs

Fats and oils

Cereals

Vegetables and salads

Fruits and berries

Beverages

Modified according to: DGE Nutrition Circle.

Fig. 13

DO WE CONSUME ENOUGH SELENIUM? 27

75 % of selenium uptake is via meat, cereals, dairy products and fish (Fig. 14). The proportion of vegetables and fruit in the selenium intake is just 7 %. [39]

The comparison with the DGE requirement for a healthy diet and the distribution of a selenium-rich diet is clearly contradictory. To put it bluntly: “The healthier the diet, the lower the selenium intake”.

Selenium uptake

Cereals

Meat

Milk and dairy products

Fish

Beverages

Fruits and vegetables

Eggs

Nuts (2 %)

Other (1 %)

27 %

27 %

11 %

11 %

10 %

7 %4 %

Created according to: Rayman MP. Lancet. 2012 Mar 31; 379(9822): 1256-68. Selenium and human health.

Fig. 14

The healthier the diet, the lower the selenium intake

DO WE CONSUME ENOUGH SELENIUM?28

How much selenium does an adult need?

The EFSA (European Food Safety Authority) recommends an intake of 70 micrograms (μg) of selenium per day for adults, and between 55 and 70 µg of selenium per day for adolescents, depending on age and weight. [40]

Recommended daily amount of selenium (RDA)

The daily recommended amount of selenium (RDA of selenium) of the German Society for Nutrition (DGE) is 60 µg per day for adult women and 70 µg per day for adult men. [76] These values are published jointly by the D-A-CH countries (Germany, Austria and Switzerland) and are based on a reference body weight of 70.7 kg for men and 60 kg for women. [77] A daily selenium intake of 1 μg/kg was assumed for healthy individuals.

EFSA, the equivalent of DGE in the EU, has similar values. The back-ground for this assessment is, among other things, a study in which an amount of 50 – 60 µg selenium per day was not sufficient to achieve an optimal concentration of the selenium transport protein selenoprotein P. [43] EFSA therefore recommends 70 μg selenium per day for adult men and women. [40]

Limitations of the RDA of selenium

Overweight people have a higher risk of selenium deficiency. The back-ground for this is the reference body weight used in the DGE recommen-dation. The average body weight in Germany in 2013 was 84.3 kg for men and 68.4 kg for women. [44] For a healthy average German, 70 µg or 60 µg of selenium per day are sufficient. With increasing body weight, the daily recommended amount of selenium may no longer be sufficient. In addition, the body can require significantly more selenium in the case of disease. In intensive care medicine, for example, up to 1,000 µg selenium per day are used to correct a selenium deficiency or to achieve a stable selenium status in the reference range. [45]

EFSA recommends 70 μg selenium per day

DO WE CONSUME ENOUGH SELENIUM? 29

Do we consume enough selenium in Germany?

EFSA recommends an intake of 70 µg selenium per day for adults and between 55 and 70 µg selenium per day for adolescents, depending on age and weight. [40] However, the estimated daily intake is only between  34 and 60 µg (Fig. 15). [40]

Insufficient daily selenium intake in Germany

Men Women40 % 50 %50 %60 %

lack of seleniumingested selenium

lack of seleniumingested selenium

Created according to:Anke M et al. Trace Elements in Man and Animals 10 (eds. Roussel AM, Anderson RA, Favrier AE), 209-14 (Kluwer Academic Publishers, 2002). Trace Element Intake and Balance in Adults in Central Europe.Kipp AP et al. J Trace Elem Med Biol. 2015 Oct; 32: 195-9. Revised reference values for selenium intake.

Fig. 15

DO WE CONSUME ENOUGH SELENIUM?30

Are there foods particularly rich in selenium?

There are selenium-accumulating plants. These plants can be divided into three groups: sodium selenite accumulators (broccoli and cucumber), selenomethionine accumulators (cereals such as wheat and mushrooms) and methylselenocysteine (garlic and onions). [35, 40] However, these plants can only enrich selenium that is present in the soil. Therefore, the sele-nium content in German food is too low overall.

Brazil nuts – ideal for selenium supply or hidden source of danger?

The question of natural selenium-rich foods is often asked. The answer is usually Brazil nuts. And it is true that no other plant enriches as much selenium in its fruit as the Brazil nut tree.

The recommendation is two Brazil nuts a day to meet an adult’s need for selenium. That sounds simple and unproblematic at first. However, there are two major problems with Brazil nuts (Fig. 16).

Brazil nuts and aflatoxins

Aflatoxins are a naturally occurring fungal toxin found in molds. Afla-toxin is one of the strongest naturally occurring toxins and carcinogenic substances. In addition, aflatoxins are heat-stable. This means that only a small part is destroyed during cooking or baking.

EU import ban on Brazil nuts

Brazil nuts in particular are susceptible to aflatoxins, as the warm and humid climate in South America is conducive to the growth of molds (see Fig. 16). The aflatoxin load of Brazil nuts often exceeds the limits set by the EU, which is why a special implementing regulation has regulated the import of Brazil nuts since 2003. [83] As a result, Brazil nuts were temporar-ily no longer imported into the EU and trade has declined to this day.

Two major problems with Brazil nuts

DO WE CONSUME ENOUGH SELENIUM? 31

Brazil nuts and radioactivity

Brazil nuts occupy a special position among foods when it comes to radio-activity. [47] Brazil nuts have a radium content per kilogram that is about 1,000 times higher than all other foods in Germany (see Fig. 16). A daily intake of two Brazil nuts results in a value of 160 microsieverts. With an average diet, radiation exposure from food amounts to 300 microsieverts per year. This means that the consumption of two Brazil nuts per day increases the radioactive load by about half. No negative health conse-quences are to be expected with these values, but the Federal Office for Radiation Protection nevertheless points out that the selenium status can also be improved by dietary supplements.

Problems with Brazil nuts: Aflatoxins and radioactivity

Accumulatesradioactivity

Highly susceptible to very carcinogenic aflatoxins

Created according to:Cardoso BR et al. Food Res Int. 2017 Oct; 100(Pt 2): 9-18. Brazil nuts: Nutritional composition, health benefits and safety aspects.Bundesamt für Strahlenschutz (The German Federal Office for Radiation Protection), access April 2018.

Fig. 16

SELENIUM DEFICIENCY32

Selenium deficiency

In Europe, for example, selenium deficiency is widespread. [48] A selenium deficit is associated with a variety of diseases. [39] Selenium deficiency diseases include the Keshan and Kashin Beck diseases, which occur in Asia, especially in certain regions of China. [49, 50] Keshan’s disease is a cardiomyopathy. The actually harmless Coxsackie virus becomes viru-lent in a selenium deficiency and can trigger Keshan disease (Fig. 17). [49] Kashin-Beck disease is a disease of the bones and joints. The preventive administration of selenium protects against both diseases. [49, 50]

At a glance

Selenium deficiency is widespread in Germany

A low selenium status may be associated with a higher mortality rate in the long term

Numerous risk groups

Risk factor – overweight

Selenium deficiency – possible indication of another disease

Selenium deficiency in Germany

Selenium deficiency is also widespread in Germany. Women in the EPIC study had a mean serum selenium concentration of 73.2 µg/l and men had 74.3 µg/l (Fig. 18). [48] A selenium deficiency is present in the serum at values below 80 µg/l. [51]

SELENIUM DEFICIENCY 33

How a selenium deficiency turns harmless viruses  unnoticed into killers

HarmlessCoxsackie

virus

VirulentCoxsackie

virus

Keshandisease(cardio-

myopathy)

Seleniumdeficiency

InfectionOxidative

stressSe

Created according to: Chen J. Asia Pac J Clin Nutr. 2012; 21(3): 320-6. An original discovery: selenium deficiency and Keshan disease (an endemic heart disease).

Fig. 17

Deficit selenium status in Germany

Ser

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Created according to: Hughes DJ et al. Int J Cancer. 2015 Mar 1; 136(5): 1149-61. Selenium status is associated with colorectal cancer risk in the European prospective investigation of cancer and nutrition cohort.

Fig. 18

SELENIUM DEFICIENCY34

Selenium deficiency – more than just laboratory cosmetics

The two selenium deficiency diseases Keshan and Kashin-Beck do not occur in Europe. Here, the effects of selenium deficiency are more subtle, but no less negative in the long run. For example, a low selenium status is associated with a higher mortality rate in the long term (Fig. 19). [39]

Relationship between selenium status and all-cause mortality

0.4

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Seleniumdeficiency

Modified according to: Rayman MP. Lancet. 2012 Mar 31; 379(9822): 1256-68.  Selenium and human health.

Fig. 19

SELENIUM DEFICIENCY 35

How can you tell a selenium deficiency?

The symptoms of selenium deficiency are non-specific and also occur in connection with other diseases. These include fatigue, poor performance, hair loss and the whitening of fingernails. [35] In addition, liver dysfunction, arthritis, muscle weakness and infertility may occur. [35] Selenium defi-ciency can limit the function of the immune system and the thyroid. The risk of cancer or cardiovascular disease is increased (Fig. 20).

Selenium deficiency symptoms

Who has an increased risk of selenium deficiency?

The risk of selenium deficiency may increase due to both limited intake and increased demand. [35] The daily intake of selenium is significantly reduced in vegetarians, vegans, alcoholics, celiac patients and dialysis patients (Fig. 21). Even with a strongly one-sided diet or patients with malabsorption, too little selenium is absorbed.

Breastfeeding women, patients with diabetes, kidney damage, bulimia, anorexia, diarrhea, obesity, maldigestion and malabsorption have an increased selenium requirement. [35, 52] In cancer patients or in event of sur-gery, the body consumes significantly more selenium, resulting in a sharp decline in selenium levels. [53, 54]

SELENIUM DEFICIENCY36

Effects of a selenium deficit

HAIRHair loss

BRAINFatigue, vitality deficiency

THYROIDImpaired thyroid function, hypothyroidism

HEARTIncreased probability of cardiovascular disease

ORGANISMImpaired function of the immune system, increased probability of cancer

LIVERLiver dysfunction

TESTICLESInfertility

MUSCLESMuscle weakness

BONESArthritis

NAILSWhite coloring of the nails

Created according to:Huang Z et al. Antioxid Redox Signal. 2012 Apr 1; 16(7): 705-43. The role of selenium in inflammation and immunity: from molecular mechanisms to therapeutic opportunities.Gärtner R et al. J Clin Endocrinol Metab. 2002 Apr; 87(4): 1687-91. Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations.Rayman MP. Lancet. 2012 Mar 31; 379(9822): 1256-68. Selenium and human health.Bundesgesundheitsblatt – Gesundheitsforschung – Gesundheitsschutz 2006. 49: 88-102.

Fig. 20

SELENIUM DEFICIENCY 37

Risk groups for selenium deficiency

vegans

celiac patients

maldigestion

one-sided nutritionobesity

dialysis patients

malabsorption

surgery

vegetarianscancer patients

alcoholics

breastfeeding mothersdiabetics

Created according to:Bundesgesundheitsblatt – Gesundheitsforschung – Gesundheitsschutz 2006. 49: 88-102.Wang Y et al. Nutrients. 2016 Jan 4; 8(1). pii: E24. Significant Beneficial Association of High Dietary Selenium Intake with Reduced Body Fat in the CODING Study.Lubinski J et al. Breast Cancer Res Treat. 2018 Jan; 167(2): 591-8. Serum selenium levels predict survival after breast cancer.Stoppe C et al. Crit Care Med. 2011 Aug; 39(8): 1879-85. The intraoperative decrease of selenium is associated with the postoperative development of multiorgan dysfunction in cardiac surgical patients.

Fig. 21

SELENIUM DEFICIENCY38

Risk group vegetarians and vegans

More and more people are changing their diet and becoming vegans or vegetarians in the belief that they are doing something good for their health. The finding of a North American trial supports this theory. [55] As a result, the risk of colorectal cancer among vegetarians in the USA is 22 % lower.

Does this also apply to Europeans?

The evaluation of European trials comes to a different conclusion. [56] European vegetarians suffer from intestinal cancer just as frequently as “omnivores”. Only vegetarians who also eat fish have a reduced risk of colon cancer.

What’s the difference?

The eating habits of Americans and Europeans are comparable. A notice-able difference can be seen in the selenium status. US vegetarians have significantly higher selenium levels than European vegetarians. [57, 58]

Risk factor vegetarian diet

Why is a vegetarian diet a risk factor for selenium deficiency? In the west-ern industrial nations, 75 % of selenium intake results from consuming meat, cereal and dairy products as well as fish. [39]

Vegetarians do not use meat and fish as selenium sources, which reduces the daily selenium intake by about 30 %. With vegans the picture looks even darker. Their daily selenium intake is reduced by about 75 %.

Considering the fact that European “omnivores” also consume too little selenium every day in most cases, selenium intake can reach danger-ously low levels.

SELENIUM DEFICIENCY 39

Overweight as a risk factor

Since the daily selenium requirement is designed for people of normal weight, a higher selenium requirement is associated with increased body weight. In addition, overweight often leads to an increase in oxidative stress (Fig. 22). [59, 60] One of the main tasks of selenoproteins is the reduc-tion of oxidative stress. Conversely, increased oxidative stress increases the daily selenium requirement.

Increased selenium requirements in obese people

Adiposity

Diabetes Cancer Asthma Heartdiseases

Mitochondrialdysfunction

Hyperglycemia

Hyperleptinemia

Hyperlipidemia

Inflammation

Unhealthy dietEndothelialdysfunction

Increased muscle activity

Lack of vitaminsand

trace elements

SeleniumOxidativestress

Lack of selenium

Modified according to: Manna P, Jain SK. Metab Syndr Relat Disord. 2015 Dec; 13(10): 423-44. Obesity, Oxidative Stress, Adipose Tissue Dysfunction, and the Associated Health Risks: Causes and Therapeutic Strategies.

Fig. 22

SELENIUM DEFICIENCY40

Selenium intake for overweight and obese people

A larger-scale clinical trial conducted in Newfoundland with over 3,000 participants was able to prove the increased need for selenium in over-weight and obese people with indisputable figures. [52] In North America, the selenium supply is usually sufficient to meet daily needs. [1] Never-theless, daily selenium intake based on body weight was 15 % lower for overweight people (BMI 25 – 29.9) and about 30 % lower for BMI over 30 (obesity) compared to people of normal weight (Fig. 23). [52]

Selenium and body fat

Body weight is composed of different elements: besides the bones and muscles, it also includes body fat. During the investigations in Newfound-land, the daily selenium intake was additionally determined in relation to the proportion of body fat. [52] As with body weight, the daily selenium intake per kilogram decreased as the proportion of body fat increased (Fig. 24). So the decisive factor is the body fat percentage, not the muscle mass. Expressed in numbers, each microgram of selenium more per kilo-gram consumed per day correlated with a 3 – 6 % decrease in body fat. [52]

Each additional microgram of selenium per kilogram correlates with a lower body fat percentage

SELENIUM DEFICIENCY 41

Reduced selenium intake in overweight patients

Classification according to BMI

Dai

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MenWomen

Created according to: Wang Y et al. Nutrients. 2016 Jan 4; 8(1). pii: E24. Significant Beneficial Association of High Dietary Selenium Intake with Reduced Body Fat in the CODING Study.

Fig. 23

Low selenium intake with higher body fat content

Daily selenium intake [µg/kg/day]

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Created according to: Wang Y et al. Nutrients. 2016 Jan 4; 8(1). pii: E24. Significant Beneficial Association of High Dietary Selenium Intake with Reduced Body Fat in the CODING Study.

Fig. 24

SELENIUM DEFICIENCY42

Selenium deficiency – possible indication  of severe disease

Regardless of the disease, the selenium status decreases with the sever-ity of the disease. [53, 61] This effect occurs in patients in intensive care as well as in cancer patients. The serum selenium concentration is therefore an independent marker for mortality in the intensive care unit or the sur-vival probability of breast cancer patients (Fig. 25). [53, 61]

A selenium deficiency is not only a sign of an inadequate selenium supply, but can also be an indication of a serious illness in which selenium con-sumption has increased sharply.

2.5-fold increase in 5-year all-cause mortality in selenium deficiency

1.0

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Quartile 1: 41.6 – 64.4 µg/l

Quartile 2: 64.4 – 72.2 µg/l

Quartile 3: 72.2 – 81.0 µg/l

Quartile 4: 81.0 – 180 µg/l

Lubinski J et al. Breast Cancer Res Treat. 2018 Jan; 167(2): 591-8. Serum selenium levels predict survival after breast cancer.

Fig. 25

WHAT IS THE SELENIUM STATUS? 43

What is the selenium status?

At a glance

Optimum selenium status in serum is approx. 130 μg/l

Average selenium status of Germans is 75 µg/l

The selenium status is determined in the blood and expressed in micro-grams per liter. An optimal selenium supply achieves the maximum activ-ity of the selenoproteins. However, the maximum activity of the different selenoproteins lies at different selenium concentrations in the blood. For the glutathione peroxidase the value is 95 μg/l, for the selenium transport protein selenoprotein P 124 μg/l selenium in serum (Fig. 26). [62, 63] If one looks at the German average with this value in mind, Germany must be regarded as an area with a pronounced selenium deficiency. The average selenium value of Germans is 75 micrograms per liter in serum. [48]

Selenium status is determined in the blood

WHAT IS THE SELENIUM STATUS?44

Selenium status

60 70 80 90 100 110 120 130 140

Serum selenium concentration [µg/ l]

Mean seleniumconcentration

in GermanyOptimal activity of glutathione peroxidase

Optimal activityof selenoprotein P

Reference rangeof selenium in Germany

Seleniumdeficiency

Created according to:Hughes DJ et al. Int J Cancer. 2015 Mar 1; 136(5): 1149-61. Selenium status is associated with colorectal cancer risk in the European prospective investigation of cancer and nutrition cohort.Thomson CD et al. Br J Nutr. 1993 Mar; 69(2): 577-88. Long-term supplementation with selenate and selenomethionine: selenium and glutathione peroxidase (EC 1.11.1.9) in blood components of New Zealand women.Hurst R et al. Am J Clin Nutr. 2010 Apr; 91(4): 923-31. Establishing optimal selenium status: results of a randomized, double-blind, placebo-controlled trial.

Fig. 26

WHAT IS THE SELENIUM STATUS? 45

How is the selenium status determined?

The selenium status is best measured with a blood test at your doctor’s office, preferably in whole blood, as this value indicates the long-term supply (Fig. 27). The serum value only reflects the current supply of selenium. It can happen that the serum value already signals a normal selenium status, while a selenium deficiency can still be detected in whole blood.

Selenium determination in whole blood*

40 %

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Fig. 27

WHAT IS THE SELENIUM STATUS?46

Caution – check the actual selenium level

Some laboratories offer selenium measurements. Do not rely on the “selenium deficiency – yes or no” assessment of the laboratory or your doctor, but check your personal selenium level carefully.

Why? Different reference ranges are used in the laboratories, which also almost always show a selenium deficiency only at values below 50 – 60 µg/l selenium in serum or whole blood. However, a selenium defi-ciency already begins at values below 80 µg/l selenium in serum or below 100 µg/l selenium in whole blood. These values were determined by the agency for medicinal products and are authoritative (Fig. 28). [51]

Selenium deficiency: < 80 µg/l selenium in serum, < 100 µg/l selenium in whole blood

When is there a selenium deficiency?

Serum

Whole blood

Reference rangeSelenium deficiency

100 µg/l1.3 µmol/l

140 µg/l1.8 µmol/l

80 µg/l1.0 µmol/l

120 µg/l1.5 µmol/l

Created according to: Summary of product characteristics selenase® T peroral, biosyn Arzneimittel GmbH, November 2017.

Fig. 28

WHAT IS THE SELENIUM STATUS? 47

biosyn Service Laboratory

The biosyn service laboratory offers you full- service range for the determination of selenium, other trace elements and heavy metals in whole blood, serum, urine or saliva. The significance of selenium determinations for selenium supply is improved by the determination in whole blood.

The analysis is carried out using modern methods such as atomic absorption spectro-scopy or photometry. The accuracy of the results is guaranteed by regular participation in official interlaboratory comparisons. Together with the measured values, you receive an evalu-ation of the results and a comparison with the reference values. Furthermore, therapy recom-mendations are given for concentrations outside the reference range.

The required material (urine tube or special blood collection system including cannula and protective sleeve, request for analysis and mail-ing bag) will be sent free of charge on request.

All information is available at http://biosyn.de/service/servicelabor/.

You can print out the complete form via the link “Analysenanforderung” (“Analysis request”).

Otherwise you can order the form as well as the required shipping material by telephone (+ 49 (0) 711 575 32 - 00) or by e-mail (information@biosyn.de).

The information provided must not be understood as a request for a specific treatment or non-treatment or for self-treatment or self-recognition of a possible illness or the like. Information is not a substitute for an examination or treatment by a doctor or a consultation in a pharmacy.

we areresearch

Information is available at:http://biosyn.de/service/servicelabor/Selenium test Amtest® *

19.90 € 39.60 €

* Heavy metal mobilization test

biosyn Arzneimittel GmbH · Schorndorfer Straße 32, 70734 Fellbach, Germany Phone: +49 (0) 711 575 32 - 00 · www.biosynpharma.com · information@biosyn.de

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Trace element and heavy metal measurement at biosyn

Certified laboratory

SELENASE® CORRECTS SELENIUM DEFICIENCY48

selenase® corrects selenium deficiency

The active ingredient in selenase® is sodium selenite pentahydrate. Sodium selenite is an inorganic form of selenium that effectively and safely corrects selenium deficiency. [51] This has been proven in numerous trials from a wide variety of disciplines (including intensive care, oncology, endocrinology) (Fig. 29). [45, 64 – 69]

Sodium selenite effectively and safely corrects selenium deficiency [51]

At a glance

GMP active ingredient: sodium selenite pentahydrate

selenase®: proven use in numerous RCT studies

SELENASE® CORRECTS SELENIUM DEFICIENCY 49

selenase® effectively corrects selenium deficiency

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et al

.

OncologyIntensive care Endocrinology

before selenase® therapy

after selenase® therapy

* converted from whole blood values

Created according to:Bloos F et al. JAMA Intern Med. 2016 Sep 1; 176(9): 1266-76. Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients With Severe Sepsis or Septic Shock: A Randomized Clinical Trial.Angstwurm MW et al. Crit Care Med. 2007 Jan; 35(1): 118-26. Selenium in Intensive Care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock.Valenta J et al. Intensive Care Med. 2011 May; 37(5): 808-15. High-dose selenium substitution in sepsis: a prospective randomized clinical trial.Muecke R, et al. Int J Radiat Oncol Biol Phys. 2010 Nov 1; 78(3): 828-35. Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology.Zimmermann T et al. Biol Trace Elem Res. 2005 Sep; 106(3): 193-203. Reduction of postoperative lymphedema after oral tumor surgery with sodium selenite.Gärtner R et al. J Clin Endocrinol Metab. 2002 Apr; 87(4): 1687-91. Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations.Eskes SA et al. Clin Endocrinol (Oxf). 2014 Mar; 80(3): 444-51. Selenite supplementation in euthyroid subjects with thyroid peroxidase antibodies.

Fig. 29

IS SELENIUM ALWAYS THE SAME? 51

Is selenium always the same?

At a glance

There are two forms of selenium:• the inorganic form – main form: sodium selenite• the organic form – main form: selenomethionine

Sodium selenite: fast and targeted dosage

Selenium is basically available in two forms, inorganic and organic. The most common inorganic form of selenium is sodium selenite. The most common organic form is selenomethionine. [2, 35] When selenium is ingested from food, the predominant form of selenium is selenomethi-onine.

Two forms of selenium

Why sodium selenite?

The advantage of sodium selenite is that it is absorbed by the body through passive diffusion and quickly converted into selenoproteins. The body also excretes it mainly via the urine, which is why it does not accu-mulate unnecessarily. [2] The complete path of sodium selenite in the body is precisely regulated by the body. [70]

IS SELENIUM ALWAYS THE SAME?52

Why not organic selenium?

Although the bioavailability of selenomethionine is higher than that of sodium selenite, absorption is much more complicated. Selenomethionine is not recognized by the body as a form of selenium, but is confused with the sulfurous amino acid methionine. As a result, selenomethionine is incorporated unspecifically and unregulated into proteins containing sul-fur. [70] Some of the sulfur-containing proteins in which selenomethionine is non-specifically incorporated can be regenerated by the body and the selenium contained can be used for the synthesis of selenoproteins. This process does not take place as required, but as a function of methionine conversion. The other part of selenomethionine is unspecifically incor-porated into non-regenerable proteins found, for example, in hair and red blood cells. This selenium can no longer be supplied to the selenium cycle, but accumulates in the body. The higher the amount of selenome-thionine absorbed, the greater the proportion of selenomethionine that is incorporated into non-regenerable proteins and can thus lead to the accumulation of selenium in the body (Fig. 30). [70]

Therefore, only sodium selenite is authorized as a medicinal product. Selenomethionine or selenium yeast (main selenium form: selenomethi-onine) may also be used in dietary supplements. It is also safer to take sodium selenite in food supplements or in combination products.

Selenomethionine – uncontrollable and unsafe

IS SELENIUM ALWAYS THE SAME? 53

Two forms of selenium: selenomethionine and sodium selenite

Reductioninto selenium-

hydrogen (H2Se)

Non-specific incorporation

in proteins (instead of

methionine)

Seleno-methionine

Degradation of excess

selenium and excretion mostly

via kidney

Synthesis of selenoproteins

Regenerable proteins

Non-regenerable

proteins

Accumulation in the body

(e.g. hair, red blood cells)

unregulated

regulated

Sodiumselenite

Created according to:EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). EFSA J. 2014; 12: 3846. Scientific Opinion on Dietary Reference Values for selenium.Summary of product characteristics selenase® T peroral, biosyn Arzneimittel GmbH, November 2017.Suzuki KT, J Health Sci. 2005 Apr; 51(2): 107-14. Metabolomics of Selenium: Se Metabolites Based on Speciation Studies.

Fig. 30

IS SELENIUM ALWAYS THE SAME?54

Effect of organic selenium on selenium status

Organic selenium increases the concentration of selenium in the blood faster than inorganic selenium. [71] However, this is largely due to the unspecific binding of selenomethionine. [70] The activity of selenoproteins, on the other hand, does not increase above the level of inorganic sele-nium using organic selenium. [71] Instead, higher doses showed the oppo-site: the activity of selenoproteins decreased significantly. [72]

The effect of organic selenium massively increasing the selenium con-centration in the blood is problematic due to the so-called U-curve, which shows the effect of the serum selenium concentration on e.g. total mortal-ity. [39] Both low and high selenium levels have a negative effect on health.

Even 200 µg selenium in the form of selenium yeast per day increases the plasma selenium concentration to an unfavorable level of over 200 µg/l (Fig. 31). [73] In a new trial, long-term intake of 300 µg selenium (selenium yeast) per day led to an increase in all-cause mortality. [72] The trial authors noted that this negative effect would probably not have occurred at the same selenium dose in the form of sodium selenite, since sodium selenite is either directly used for selenoproteins or excreted (Fig. 32). [72]

Selenium yeast increases selenium levels in the blood to an unhealthy level

0

100

50

150

200

250

300

350

Pla

sma

sele

nium

con

cent

ratio

n [µ

g/l]

100 µgselenium/day

200 µgselenium/day

300 µgselenium/day

Placebo

baseline

after 6 months

after 5 years

Reference range

Created according to: Cold F et al. Br J Nutr. 2015 Dec 14; 114(11): 1807-18.  Randomised controlled trial of the effect of long-term selenium supplementation on plasma cholesterol in an elderly Danish population.

Fig. 31

IS SELENIUM ALWAYS THE SAME? 55

Selenium is not always the same

Long-term300 µg selenium

Serum seleniumconcentration> 250 µg/l*

Total mortality***Total mortality 2.5-fold

Serum seleniumconcentration~ 160 µg/l**

Sodium seleniteSelenium yeastSelenomethionine

* after 6 months of supplementation** after 24 weeks of supplementation*** results of observational studies

Created according to:Rayman MP. Lancet. 2012 Mar 31; 379(9822): 1256-68. Selenium and human health.Rayman MP et al. Free Radic Biol Med. 2018 Feb 14. pii: S0891-5849(18)30070-4. Effect of long-term selenium supplementation on mortality: Results from a multiple-dose, randomised controlled trial.Cold F et al. Br J Nutr. 2015 Dec 14; 114(11): 1807-18. Randomised controlled trial of the effect of long-term selenium supplementation on plasma cholesterol in an elderly Danish population.Kahaly GJ et al. J Clin Endocrinol Metab. 2017 Nov 1; 102(11): 4333-41. Double-Blind, Placebo-Controlled, Randomized Trial of Selenium in Graves Hyperthyroidism.

Fig. 32

DOES SELENIUM ALSO HAVE SIDE EFFECTS?56

Does selenium also have side effects?

At a glance

High therapeutic index

300 µg selenium daily for life is a safe dose [2]

Side effects of an overdose of selenium:garlic-like breath, diarrhea, nausea, abdominal pain, fatigue, hair loss [2, 75]

Selenium poisoning is also known as selenium intoxication or selenosis. What applies to all substances also applies to selenium: it is the quantity that determines the benefit or harm of a substance. This becomes particu-larly clear when comparing selenium and common salt (Fig. 33).

For example, one takes in 6 grams of table salt per day, which is consid-ered sufficient. 210 grams of common salt, on the other hand, can also lead to death in an adult. That’s just 35 times the amount. However, no one describes table salt as toxic.

In contrast, the lethal dose of sodium selenite is 490,000 μg, almost 3,200 times the daily recommended selenium requirement.

Selenium poisoning – selenium intoxication or selenosis

DOES SELENIUM ALSO HAVE SIDE EFFECTS? 57

Therapeutic index for sodium selenite and sodium chloride

Recommended amount per day [A]

70 µg selenium corresponding to 153.3 µg sodium selenite

Amount per day for short-term high-dose therapy [B]

e.g. 2,000 µg selenium/day corresponding to 4,380 µg sodium selenite

Lethal dose [C]

490,000 µgsodium selenite

35-fold

112-fold

3,196-fold

Orientation valueper day (DGE)6 g table salt (sodium chloride)

Lethal dose [D]

210 g table salt(sodium chloride)

Sodium selenite

Table salt(sodium chloride)

[A] EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). EFSA J. 2014; 12: 3846. Scientific Opinion on Dietary Reference Values for selenium.

[B] Summary of product characteristics selenase® T peroral, biosyn Arzneimittel GmbH, November 2017.

[C] Lewis RJ, Tatken RI (Editor). Registry of Toxic effects of Chemical substances.  1978 Ed. National Institute of Occupational Safety and Health. Publ. No. 79-100. U.S. Government Printing Office, Washington, D.C., 1979.

[D] GESTIS Substance Database. Sodium chloride.

Fig. 33

DOES SELENIUM ALSO HAVE SIDE EFFECTS?58

Toxicity of selenium

Selenium poisoning is possible, but only occurs when used incorrectly and uncontrollably. The lethal toxicity of oral sodium selenite intake is 7,000 μg/kg. [75] 4,000 – 5,000 μg/kg selenium are required to acutely poison oneself with selenium. [3] Chronic poisoning with selenium is also possible. For this purpose, more than 1,000 μg selenium would have to be absorbed per day over a very long period of time, several months to years. With a lifelong daily intake of 850 μg selenium per day, there are no side effects (= NOAEL) (Fig. 34). The EU classifies the lifelong intake of 300 µg selenium as absolutely harmless. [2]

Toxicity of selenium

1,0008006004002000

Selenium quantity [μg]

Recommended daily intake [A]

Permitted level for daily intake [B]

70

300

850

1,000

Acute toxicity(280,000) [C]

Lethal toxicity(490,000) [D]

Daily intake, where adverse reactions are determined = chronic toxicity (LOAEL) [B]

Daily intake, where no adverse reactionsare determined = NOAEL [B]

[A] EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). EFSA J. 2014; 12: 3846. Scientific Opinion on Dietary Reference Values for selenium.

[B] Tolerable upper intake levels for vitamins and minerals. Scientific Committee on Food Scientific Panel on Dietetic Products, Nutrition and Allergies, February 2006.

[C] Summary of product characteristics selenase® T peroral, biosyn Arzneimittel GmbH, November 2017.

[D] Lewis RJ, Tatken RI (Editor). Registry of Toxic effects of Chemical substances.  1978 Ed. National Institute of Occupational Safety and Health. Publ. No. 79-100. U.S. Government Printing Office, Washington, D.C., 1979.

Fig. 34

Lethal selenium intoxication

DOES SELENIUM ALSO HAVE SIDE EFFECTS? 59

Signs of acute selenium poisoning

An overdose of selenium may cause side effects. First signs are garlic- like breath, diarrhea, nausea, abdominal pain, fatigue and hair loss. [2, 75] In the event of prolonged overdose, nail and hair growth may change and disturbances of the nervous system may occur.

A toxic dose cannot be achieved with products from the pharmacy. The highest dose of dietary supplements available is 200 micrograms of sele-nium per tablet. One would have to take a very large number of tablets to get into a critical range (Table 2).

Required quantities of tablets containing sodium selenite

For acute toxicity For lethal toxicity

approx. 640 tablets 200 μg  at 70 kg body weight

at least 1,120 tablets 200 μg  at 70 kg body weight

Based on:Summary of product characteristics selenase® T peroral, biosyn Arzneimittel GmbH, November 2017.Lewis RJ, Tatken RI (Editor). Registry of Toxic effects of Chemical substances.  1978 Ed. National Institute of Occupational Safety and Health. Publ. No. 79-100.  U.S. Government Printing Office, Washington, D.C., 1979.

Table 2

Only the dose makes the poison (Paracelsus)

60 ATTACHMENT

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62 ATTACHMENT

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72. Rayman MP et al. Free Radic Biol Med. 2018 Feb 14. pii: S0891-5849(18)30070-4. Effect of long-term selenium supplementation on mortality: Results from a multiple-dose, randomised controlled trial.

73. Cold F et al. Br J Nutr. 2015 Dec 14; 114(11): 1807-18. Randomised controlled trial of the effect of long-term selenium supplementation on plasma cholesterol in an elderly Danish population.

74. Kahaly GJ et al. J Clin Endocrinol Metab. 2017 Nov 1; 102(11): 4333-41. Double-Blind, Placebo-Controlled, Randomized Trial of Selenium in Graves Hyperthyroidism.

75. Lewis RJ, Tatken RI (Editor). Registry of Toxic effects of Chemical substances. 1978 Ed. National Institute of Occupational Safety and Health. Publ. No. 79-100. U.S. Government Printing Office, Washington, D.C., 1979.

76. Deutsche Gesellschaft für Ernährung. Selen: Schätzwerte für eine angemessene Zufuhr.

77. Kipp AP et al. J Trace Elem Med Biol. 2015 Oct; 32: 195-9. Revised reference values for selenium intake.

78. Saha U et al. International Journal of Applied Agricultural Sciences. Vol. 2, No. 6, 2016, pp. 112-125. Selenium in Animal Nutrition: Deficiencies in Soils and Forages, Requirements, Supplementation and Toxicity.

79. Fordyce FM. Selenium Deficiency and Toxicity in the Environment. In: Selinus O. (eds) Essentials of Medical Geology. Springer, Dordrecht, 2013.

80. EFSA FEEDAP Panel (EFSA Panel on Additives and Products or Substances used in Animal Feed), 2016. Scientific opinion on the safety and efficacy of selenium compounds (E8) as feed additives for all animal species: sodium selenite, based on a dossier submitted by Todini and Co SpA. EFSA Journal 2016; 14(3): 4442, 24 pp.

81. Davies M et al. Sci Rep. 2017 Dec 7; 7(1): 17107. Mineral analysis of complete dog and cat foods in the UK and compliance with European guidelines.

82. Rayman MP. Br J Nutr. 2008 Aug; 100(2): 254-68. Food-chain selenium and human health: emphasis on intake.

83. DURCHFÜHRUNGSVERORDNUNG (EU) Nr. 884/2014 DER KOMMISSION – vom 13. August 2014 – zur Festlegung besonderer Bedingungen für die Einfuhr bestimmter Futtermittel und Lebensmittel aus bestimmten Drittländern wegen des Risikos einer Aflatoxin-Kontamination und zur Aufhebung der Verordnung (EG) Nr. 1152/2009.

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selenase®: application and dosage

Application

Proven selenium deficiency that cannot be remedied with food

Dosage

50 μg selenium daily

A regular check of the selenium status at appropriate intervals is recommended

Summary of product characteristics selenase® 50 peroral, biosyn Arzneimittel GmbH, November 2017.

biosyn Arzneimittel GmbH

World market leader for high-dose selenium injections

biosyn Arzneimittel GmbH is a pharmaceutical and biotech company based in Fellbach, Germany. It specializes in trace elements, is a world market leader for high-dose selenium injections, developer and operator of two unique GMP manufacturing operations for producing active ingre-dients, and in the biotech sector, is actively involved in the production of glycoprotein isolated from the Megathura crenulata, a sea snail found in California. 70 percent of our sales turnover is realized outside of Ger-many – in 26 countries all around the world.

With products geared to the areas of intensive care, oncology and endo-crinology, biosyn is a partner to hospitals and physicians in private prac-tice, as well as to naturopathic physicians and holistic health practitioners. We pursue research and development and evaluate the current medical- scientific literature as well as engage in modern online marketing. Our mid-sized family enterprise places great value on an open, engaged and customer-oriented corporate culture.

GMP production of sodium selenite at biosyn: Vacuum drying facility for the selective crystallization of metal salts with defined hydrate percentages

64 ATTACHMENT

selenase®

Active substance: Sodium selenite pentahydrate. selenase® 50 Mikrogramm Injektionslösung, selenase® 50 peroral: 50 µg selenium per ml. selenase® 50 AP: 50 µg selenium per tablet. Indications: selenase® 50 Mikro-gramm Injektionslösung: Confirmed selenium deficiency that cannot be corrected by diet. Selenium deficiency can occur in conditions of maldigestion or malabsorption, as well as in malnutrition (e. g. total parenteral nutrition). selenase® 50 peroral, selenase® 50 AP: Proven selenium deficiency that cannot be offset from food sources. Selenium deficiencies may occur as a result of states of maldigestion and malabsorption, as well as in malnutrition. Composition: selenase® 50 Mikrogramm Injektionslösung: 1 ampoule of 1 ml solution for injection contains as active substance 0.167 mg sodium selenite pentahydrate corresponding to 50 μg selenium in an 0.9 % aqueous NaCl-solution. Excipients: Sodium chloride, hydrochloric acid, water for injections. selenase® 50 peroral: 1 drinking ampoule of 1 ml oral solution contains: 50 µg pure selenium as sodium selenite pentahydrate in a 0.9 % NaCl-solution. Excipients: Sodium chloride, hydrochloric acid, water for injections. selenase® 50 AP: 1 tablet contains 0.167 mg sodium selenite pentahydrate (corresponding to 50 µg selenium). Excipients: gelatin, magnesium stearate (Ph. Eur.), maize starch, sucrose, talcum. Contra-indications: Hypersensitivity to sodium selenite pentahydrate or to any of the excipients; Selenosis. Side effects: None known to date if the medicinal product is administered according to prescription. Form of administration, size of packages: selenase® 50 Mikrogramm Injektionslösung: 10 and 50 ampoules respectively of 1 ml solution for injection. selenase® 50 peroral: 50 drinking ampoules of 1 ml oral solution. selenase® 50 AP: 20 tablets, 50 tablets, 100 tablets. Subject to sale in pharmacies. 01/19 e

selenase® pharmaceuticals: pharmacy only

selenase® 50 AP

Tablets

50 µg selenium per tablet

selenase® 50 peroral

Oral solution

at difficulty with swallowing

100 μg selenium per drinking ampoule

selenase® 50 Mikrogramm Injektionslösung

Injection solution

50 μg selenium per injection ampoule

Active ingredient: sodium selenite pentahydrate. Subject to sale in pharmacies

65ADVERTISEMENT

selenase®

selenase®

during pregnancy and lactation

Our thyroid needs selenium

Helps protect cells from oxidative stress

Increases well-being

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We would be glad to send you our detailed brochure: information@biosyn.de(keyword: selenase® 100 XL /  Selenium is essential)

We would be glad to send you our detailed brochure: information@biosyn.de(keyword: selenase® 200 XXL /  Selenium is essential)

wir forschen

wir forschen

biosyn Arzneimittel GmbH Schorndorfer Straße 32, 70734 Fellbach, Germany Phone: +49 (0) 711 575 32 - 00 · www.biosynpharma.com

biosyn Arzneimittel GmbH Schorndorfer Straße 32, 70734 Fellbach, Germany Phone: +49 (0) 711 575 32 - 00 · www.biosynpharma.com

One tablet selenase® 100 XL contains 100 μg of selenium, equivalent to 182 % of the recommended daily nutrient intake (NRV).

The tablets are divisible. A varied and balanced diet as well as a healthy lifestyle are of great importance.

66 ATTACHMENT

Information on biosyn Arzneimittel GmbH

Brochures

We are happy to offer you comprehensive information on the topics of selenium, oncology and thyroid. You can order folders for yourself and your patients free of charge. Please choose from the brochures shown. Order by e-mail: information@biosyn.de (please specify desired materials).

Literature for medical experts

Information brochures for patients

Selenium and oncologyFolder for medical expertsFormat: A4, 172 pages

Selenium and the thyroid glandFolder for medical expertsFormat: A4, 132 pages

we areresearch

selenase®

• high-dose sodium selenite to improve cancer therapy

• reduces side effects by protecting healthy cells

• selectively cytotoxic against tumor cells

• improves the body’s ability to destroy tumor cells

• for effective treatment of lymphedemas

• correctsseleniumdeficiency

Selenium and oncology

Integrative OncologyFolder for medical expertsFormat: A4, 88 pages

we areresearch

• Supports the body in coping with cancer therapy

• Optimizes scientifi cally-based cancer therapy

• Reduces tumor-associated symptoms and side effects

• Improves quality of life

Integrative OncologyDiscussions with complementary physicians and background knowledge on products

we areresearch

• Selenium is important for the thyroid gland, especially for pregnant women

• Aseleniumdeficiencyimpairsthethyroidgland

• Aseleniumdeficiencyincreasestheprevalence ofthyroiditis(inflammationofthethyroid)

• Selenium requirements in patients with chronic thyroiditis are increased

• Germanyisaselenium-deficientcountry

• Selenium and iodine are an essential duo for the thyroid gland

Selenium and the thyroid gland

we areresearch

The immune system guards your health

biosynknowledge

The immune system guards your healthPatient brochureFormat: DIN long18 pages

67ATTACHMENT

© biosyn 2019

Picture creditsCover (2 ×) © Zerbor / fotoliaPages 11, 50: © kasto80 / istockphotoPage 22: © Wavebreakmedia / istockphotoPage 62: © biosyn Arzneimittel GmbH

Newsletter

Subscribe to our online newsletter “biosynNews international”  to obtain current information.

Order by e-mail: information@biosyn.de (keyword “biosynNews international”)

Further information

If you have specific questions on this topic, please call us at: + 49 (0) 711 575 32 - 00

You can also find us on coliquio, the free medical network, with our  Infocenter Selenium: www.coliquio.de

More information about us is available on our Facebook page and our YouTube channel

we areresearch

Selenium is essential

Managing Director: Dr. Thomas Stiefel and Ortwin KottwitzCommercial Register: County Court Stuttgart HRB 262712Place of performance: Fellbach, Legal venue Stuttgart

01 D01 786/B · ME / H

HP / M

id. · 10/19

biosyn Arzneimittel GmbHSchorndorfer Straße 3270734 FellbachGermany

information@biosyn.dewww.biosynpharma.comwww.biosyncorp.comwww.biosyn.de

More information about us on our Facebook page and our YouTube channel

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