Vitamin D3 till NNR5

Här kommer mitt remissvar till NNR5 rörande vitamin D3.
 
Det blev en hel del ändringar.
 
Läs remissen här http://www.slv.se/upload/NNR5/Vitamin%20D%20NNR%202012.pdf 
 
Mitt remissvar 
 

 Vitamin D – NNR 2012 Public consultation

By

Björn Hammarskjöld

2013-06-02

 

Vitamin D

50

 

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Recommendation table

Vitamin D3                                                                                  

Age group                            Minimum µg/d        Maximum µg/d

Recommended intake               RI

Children below age 10                    75 µg                       250 µg

Children above age 10                  125 µg                       500 µg

Adults                                           125 µg                       500 µg

Pregnancy and lactation                 250 µg                       500 µg

Elderly                                          125 µg                       500 µg

Average requirements             AR        125 µg                       500 µg

Lower intake level adult            LI        125 µg

Upper intake level                                                                500 µg

 

 

 

 

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Introduction

 

Vitamin D3, a seco-steroid hormone, is a prehormone essential to animals including man. The existence of a substance now named vitamin D is reported to have been known since early antiquity. The first scientific description of rickets as a deficiency was reported in the 17th century by Dr. Daniel Whistler (1645) and Professor Francis Glisson (1650).

 

Nutrition was acknowledged as an experimental science in the period 1910th – 1930th and one of the major breakthroughs in the science of nutrition was the understanding of the causative factors of rickets and the development and the appreciation of the existence of vitamins [1].

 

Traditionally, vitamin D3 is regarded as an anti rickets vitamin that is used exclusively to prevent rickets and osteoporosis. Recent research has shown that most cells in the body has Vitamin D Receptors (VDR) in the plasma membrane as well as in the cellular nuclei and that there are several hundreds of cellular reactions that are vitamin D3 dependent [2]. Also, vitamin D3 has a profound involvment in the immune systems, the endocrinological systems and a lot of other vital systems in the body [3]. Vitamin D deficiency has been linked to inflammatory and long latency diseases, such as multiple sclerosis, rheumatoid arthritis, lupus, tuberculosis, diabetes, cardiovascular disease, and various cancers, to name just a few.

 

The view of regarding vitamin D3 as a calcium regulator and rickets preventer only is an oversimplification and disregarding of true and modern science. The authorities have to have a better knowledge basis otherwise we are unable to make any decisions.

 

 

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Normal levels of vitamin D3 in the blood.

 

There has been much debate about the normal level of the vitamin D3. Clinical chemical laboratories in Sweden usually defines less than 25 nmol/L as vitamin D3 deficiency, 25-75 nmol/L as vitamin D3 insufficiency, 75-250 nmol/L as optimal level of vitamn D3 and more than 250 nmol/L as potentially toxic level of vitamin D3 [4].

 

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Physiological level of vitamin D3

There has been large debates over the physiological level of vitamin D3.

 

It is quite simple in reality.

 

There are several reports supporting that there is a linear relationship between intake of vitamin D3 and level of vitamin D3 in the blood.

 

When you increase the intake by 10 µg then the level of vitamin D3 will increase by 10 nmol/L, there is a linear relationship [5]. Also, lactating women need to have 125 nmol/L to give enough vitamin D3 in the breast milk to her baby. Parathyroid hormones are elevated when the vitamin D3 level is below 125 nmol/L. Darked skinned people living in the sun of Africa usually have a vitamin D3 level of 125-250 nmol/L

 

This shows that the physiological level of vitamin D3 is more than 125 nmol/L and that levels below 125 nmol/L must be considered as deficiency.

 

This means that the clinical chemical laboratories have to change their normal values as well.

 

Toxicity

Brohult and Jonsson showed in the beginning of 1970th that 2 500 µg vitamin D2/day for one year was without any toxic symptoms [6].

 

All toxic incidents but one is showing very large doses of vitamin D2, not vitamin D3

 

1 000 µg daily to infants gave toxicity in one to four months [7]. That is equal to 25 000 µg/day (1 000 000 IU) to an adult.

 

In Finland in 1950th up to 1964 they recommended giving 125 µg to newborns without any symptoms of toxicity [8]. 125 µg to a newborn of 2,8 kg is equivalent to 3 125 µg to a 70 kg adult per day.

 

In USA there was an accidental oversupplementation of Vitamin D in milk in the middle of 1990. The dose was up to 6 000 µg/day for half a year. The researcher found no signs of toxicity [9]

 

There are differences between vitamin D3 (animal vitamin D3 or cholecalciferol) and vitamin D2 (vegetable vitamin D2 or ergocalciferol) [10]

 

In 2008 G Jones [11] showed that an upper level of 750 nmol/L is safe.

 

In Poland the recommendation is vitamin D3 at 2,5 µgkg bodyweight, equals an adult dose of 175 µg to an adult [12].

 

In Sweden NNR4 recommends infants to have 10µg/day which equals an adult dose of 250 µg/day.

 

There is scientific information by R Vieth [13] from 1999 where the recommendation is t least 125 µg per day and a toxic dose is estimated to more than 1250 µg per day.

 

 

This means that the tolerable upper level of vitamin D3 intake is safe by a factor of at least 2, maybe a safety factor of 8, when the daily intake is below 3 500 µg/day or 50 µg*kg-1*day-1 (or 140 000 IU per day or 2 000 IU per kg and day).

 

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Vitamin D3 status in Nordic populations

According to various reports the majority of the populations in many countries have levels of vitamin D3 below the “optimal” level of minimum 75 nmol/L [14], also found in Norway by NNR5 and in Sweden [15]. But there are no reports of vitamin D3 levels below the higher physiological level of 125 nmol/L. This is embarrassing as there must be an even larger proportion of the populations that are deficient I vitamin D3. Also, the levels of vitamin D in Norway is shown to be too low, just 40 nmol/L [16]

 

 

A Finnish study giving 50 µg to newborns in 1966 reduced the incidence of diabetes type 1 by 78 % up to 30 years after birth [17]. 50 µg to a newborn of 2,8 kg is equivalent to 1 250 µg (or 50 000 IU) vitamin D3 per day to a 70 kg adult.

 

It should be remembered that the Finnish authorities in 1964 had changed the previous recommendations of 125 µg vitamin D3 from 1950th down to 50 µg per day. The recommendations previous to 1964 is equivalent to 3 125 µg (or 125 000 IU) vitamin D3 per day to an adult.

 

Now, since the Finnish recommendation was reduced to 10 µg in 1996, the number of patients with diabetes type 1 has soared in Finland.

 

 

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Summary

In most of the recent studies the results are indicating that the majority of the Nordic populations are severely deficient in vitamin 3.

 

The results of the present deficiency we are starting to see in increasing rates of diabetes type 1, multiple sclerosis, rheumatoid arthritis, lupus, tuberculosis, diabetes type 2, cardiovascular disease, and various cancers, to name just a few.

 

 

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factors such as skin surface exposed, season, latitude. Dermal
production of vitamin D3 is not affected by pigmentation. [18].

 

But the production of vitamin D3 is negatively correlated to the baseline vitamin D3 level so those with a low vitamin D3 level synthesises more vitamin D3 than those with a higher vitamin D3 level. Those with a higher S-cholesterol had a higher synthesis rate than those with a lower S-cholesterol level.

 

24 % body surface irradiated with 1.1 J/m2 10 minutes every two to three days with a total irradiation time of 40 minutes gave a mean increase of 25 nmol/L.

 

Taking in account that the half life of vitamin D3 is one to two months then the level of vitamin D3 should be well above the physiological 125 nmol/L at the beginning of autumn/fall. Otherwise the supplies formed during summer sun exposure will be insufficient during winter and spring until the summer sun can replenish the supplies.

 

 

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Supplements

 

The recommended level of vitamin D3 as more than 125 nmol/L is difficult to reach on food alone. The best source of vitamin D3 is the UVB-rays of the sun. The problem with the sun’s UVB-rays is that the sun has to be at least 35º above the horizon for the UVB to penetrate the dense atmosphere at sea level to reach the skin. At a lower inclination angle the UVB-rays are absorbed by the atmosphere and can not induce the synthesis of vitamin D3 from cholesterol. So the UVB is producing vitamin D3 only about 2-3 months before and after the summer solstice here in the Northern latitudes. The rest of the year the population has to rely on enough vitamin D3 acquired during the summer or on enough vitamin D3 in food and vitamin D3 supplementation.

 

The amount of vitamin D3 in fortified milk is 0.45 µg/dL. This means that you have to drink 277 dL milk per day. This will mean 12 500 kcal per day to obtain 125 µg vitamin D3 per day.

 

Also eating fish, salmon, then it’s necessary to eat 10 hg salmon per day to reach 125 µg

 

This means that you have to be out in the sun at least 1 h every day during summer without sunscreen or covering clothes or have a vitamin D3 supplement with at least 125 µg vitamin D3 per day year around.

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with 50 µ/d. This indicates that also children of any age must have supplement of at least 125 µg of vitamin D3 to reach the physiological level of at least 125 nmol/L.

 

 

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There seem to be a nice linear relationship between supplements of the number of µg giving about the same number of nmol/L in serum/plasma.

It should be remembered that the level of vitamin D3 on serum/plasma does not mirror the total amount of vitamin D3 in the storage volume of fat as we do not measure the concentration of vitamin D3 in fat or other tissues. This implies that obese persons will need a higher intake than lean persons until the fat tissue is saturated with vitamin D3. Then the obese person can revert to normal amounts of supplements or sunshine. We should always remember that the homeostasis in the body always will keep the body within normal limits unless we disturb the homeostasis due to sheer ignorance and maltreatment.

 

 

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osteomalacia in adults.

 

By solely focussing on vitamin D3 and bone health is a way to simplify and disregard the last decades of scientific research. We now know that vitamin D3 is indeed vital to maintain general health and that a physiological level of at least 125 nmol/L is important to breast feeding and to prevent and even treat diseases like diabetes type 1, multiple sclerosis, rheumatoid arthritis, lupus, tuberculosis, diabetes type 2, cardiovascular disease, muscle strength and various cancers, to name just a few.

 

We now know that most cells are having VDRs both at membrane levels as well as nuclear levels. This means that we do need vitamin D3 in much higher concentrations and doses than previously assumed.

 

 

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Most studies regarding vitamin D3 and mortality compares placebo (no vitamin D3 supplement) with a tiny supplement (5-40 µg) of vitamin D3 and extra calcium. You can not see any differences when you compare almost nothing with almost nothing. Previously it is shown that the physiological level of vitamin D3 is at least 125 nmol/L which means that the minimal supplement amount should be at least 125 µg of vitamin D3.

 

Most studies regarding vitamin D are using vitamin D2 (ergocalciferol). Erocalciferol is a vegetable vitamin D analogue that is not working in animals except competitively blocking the VDR thus preventing vitaminD3 (cholcecalcferol) reacting with the VDR. Also, vitamin D3 can react with sulphate thus improving the transport of vitamin D3-sulfate through cellular membranes by a factor of about 300 times [19]. Ergocalciferol can (luckily) not react with sulfate. The effect of ergocalciferol on bone health is described a hundred years ago when the knowledge was less than now. But ergocalciferol is toxic at lower levels than vitamin D3 [20].

 

What is shown is that low levels of vitamin D3 increases the mortality rate.

 

 

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A too low serum 25(OH)D3 concentration increase the risk of rickets and increase the level of parathyroid hormone. As long as the level of parathyroid hormone is above normal range is just one of several indicators of vitamin D3 deficiency. This is just one more indicator of the physiological level of 125 nmol/L o vitamin D3.

 

To try to establish a specific “fracture prone level” is just another attempt to disregard the power of homeostasis. Just follow the physiological level of vitamin D3 and there are no worries. Falls are decreased and muscle strength is improved when the level of vitamin D3 is above the physiological level of 125 nmol/L.

 

 

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In Finland it is shown that an intake of 125-50 µg per day to infants was giving a very low incidence of diabetes type 1 [21]. When the vitamin D3-supplementation decreased in 1975 to 25 µg and in 1992 to a meagre 10 µg then diabetes type 1 has soared

 

 

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Vitamin D deficiency impairs insulin secretion and induces glucose intolerance. Several vitamin D related genes are associated with different pathogenetic traits of the disease [22].

 

 

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A previously known already known in 1947 Obermer recommended: “Until further experimental evidence, adequate and incontrovertible, is made available, I submit that we should play for safety. In a climate like that of England every pregnant woman should be given a supplement of vitamin D in doses of not less than 10,000 IU per day in the first 7 months, and 20,000 IU (per day) during the 8th and 9th months.” [23]

 

Hiherto, there are no experimental evidence, adequate and incontrovertible, is published.

 

The conclusion is that pregnant women should have 250-500 µg per day to have the physiological level of at least 125 nmol/L. This secures that the child will have enough vitamin D3 via the mother’s breast milk.

 

 

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The NNR5 finds it easy to establish a physiological level of at least 125 nmol/L of vitamin D3 as shown above.

Pregnancy and lactation

E. Obermere, a British gynaecologist, issued in 1947 the following statement [24]: “Until further experimental evidence, adequate and incontrovertible, is made available, I submit that we should play for safety. In a climate like that of England every pregnant woman should be given a supplement of vitamin D in doses of not less than 10,000 IU per day in the first 7 months, and 20,000 IU (per day) during the 8th and 9th months.”

 

This is equal to 250 µg per day during the first 7 months of pregnancy and 500 µg per day the last two months of pregnancy. No experimental evidence, adequate and incontrovertible, is made available hitherto to change the recommendations from 1947. Rather, the Finnish experiences from 1950th to 1975 had shown that children should have between 125 and 50 µg vitamin D3 is not only safe but helps preventing diabetes type 1 [25]. This is approximately 4 to 8 µg vitamin D3 per day and kg bodyweight.

 

During lactation the mother’s viamin D3 level should be maintained at or more than 125 nmol/L during lactation to ensure the vitamin D3 transfer via breast milk to he child.

 

Children

The information above shows incontrovertible that children of age less than 10 years of age are recommended to have at least 125 µg Vitamin D3 as a supplement to maintain an adequate level of at least 125 nmol/L.

 

Adults

Children above 10 years age can use the same recommendations as the adults or at least 125 µg vitamin D3 per day. The safe upper limit is at least 3 500 µg per day.

 

Elderly

Elderly above 65 years of age can use the same recommendations as the adults or at least 125 µg vitamin D3 per day. The safe upper limit is at least 3 500 µg per day. This will prevent a majority of falls and bone fractures as the physiological level of vitamin D3 is maintained throughout the whole life.

 

 

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and falls and CVD outcomes. The level of vitamin D3 in NNR2004 of more than 50 nmol/L is inadequate according to both old and especially new knowledge. Many studies have shown that the physiological level of vitamin D3 is above 125 nmol/L. Also, many studies have shown that vitamin D3 levels below the physiological level of 125 nmol/L increases the risk of disease.

 

The sun induced production of vitamin D3 is limited by physical laws to about four months during summer in the Nordic countries.

 

Another limitation is the use of sunblock (contains cancer causing benzene derivates to absorb UVA and UVB) and covering clothes that blocks the synthesis of vitamin D3.

 

These sun blocking advice are not protecting against skin cancer [26], [27].

 

The supplementation level is thus set to at least 125 µg per day.

 

 

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Upper limit of vitamin D3 intake

The American IOM (Institute of Medicine) and EFSA has established an upper limit of 100 µg vitamin D3 to adults.

 

These ULs settled by IOM and EFSA seem to be too low as there are a lot of toxicity and physiological knowledge recommending a much higher Tolerable Upper Limit of vitamin D3 . See the part on toxicity.

 

Also, EFSA have recommends an upper limit intake of vitamin D3 to newborn of 25 µg per day. That is equal to 625 µg or 25 000 IU per day to an adult [28]. This mean that EFSA has settled two different upper limits, one that is 25 times higher than the next.

 

The proposed upper level of vitamin D3 intake of 500 µg is safe by a factor of at least 2, probably a safety factor of 8, when the daily intake is below 3 500 µg/day or 50 µg*kg-1*day-1 (or 140 000 IU per day or 2 000 IU per kg and day).

 

 

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Summary

Man seems, according to old and modern scientific research, to need a physiological level of at least 125 nmol/L vitamin D3 to stay healthy.

 

As sun induced synthesis of vitamin D3 has decreased due to the recommendations of the Swedish Irradiation safety authority to avoid vitamin D3 producing sunshine the proportion of individuals with vitamin D3 deficiency have increased compared to 1992.

 

The information presented here shows that the physiological level of vitamin D3 should be maintained at more than 125 nmol/L and that levels below 125 nmol/L must be considered as deficiency.

 

The sources of vitamin D3 in food are scarce so we are forced to rely on supplements of vitamin D3.

 

It is well known and established that there is a direct linear relationship between intake in µg per day and level of vitamin D3 in plasma.

 

The recommendation is therefore according to the table below to reach the population level of at least 125 nmol/L.

 

The safe upper limit of vitamin D3 intake is more than 3 125 µg per day or more than 50 µg/kg/day.

 

The recommendations to the population should thus be as shown below:

 

Recommendation table

Vitamin D3                                                                                  

Age group                            Minimum µg/d        Maximum µg/d

Recommended intake               RI

Children below age 10                    75 µg                       250 µg

Children above age 10                  125 µg                       500 µg

Adults                                           125 µg                       500 µg

Pregnancy and lactation                 250 µg                       500 µg

Elderly                                          125 µg                       500 µg

Average requirements             AR        125 µg                       500 µg

Lower intake level adult            LI        125 µg

Upper intake level                                                                500 µg

 

 

 

 

 

 



References

[1] A. Norman, University of California-Riverside, UCR, History of vitamin D 

http://vitamind.ucr.edu/about/ Accessed 2013-05-01.

[2] Vitamin D, 3rd Ed. Edited by Feldman, D., Pike, J.W, Adams, J.S. San Diego, Academic Press, pp. 1-2081 (2011).

[3] C.L. Wagner Vitamin D Recommendations during Pregnancy, Lactation and Early Infancy

http://media.clinicallactation.org/2-1/CL2-1Wagner.pdf . Accessed 2012-05-01

[4] Uppsala akademiska hospital, Akademiska laboratoriet  downloaded 2013-05-09 http://www.akademiska.se/sv/Verksamheter/Provtagningsanvisningar/

[5] R. Vieth / Journal of Steroid Biochemistry & Molecular Biology 89–90 (2004) 575–579http://www.direct-ms.org/pdf/VitDVieth/VIETH%20More%20vit%20D%20needed.pdf

[6] Brohult J, Jonson B. Effects of large doses of calciferol on patients with rheumatoid arthritis. A doubleblind clinical trial. Scand J Rheumatol. 1973;2(4):173-6.

[8] Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358:1500 –3.

[9] Scanlon et al Subclinical effects in a population exposed to excess vitamin D in milk. Am J Public Health 1995 85(10): 1418-22

[10] Lisa A Houghton and Reinhold Vieth  The case against ergocalciferol (vitamin D2) as a vitamin supplement Am J Clin Nutr 2006;84:694 –7. http://www.ajcn.org/content/84/4/694.full.pdf  

[11]  G Jones Am J Clin Nutr 2008;88(suppl):582S– 6S. http://ajcn.nutrition.org/content/88/2/582S.full.pdf

[12] Pludowski P, et al, Vitamin d supplementation and status in infants: a prospective cohort observational study.  J Pediatr Gastroenterol Nutr. 2011 Jul;53(1):93-9.

[13] Vieth, R, Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999;69:842–56.

[14] John H. Lee, MD,* James H. O’Keefe, MD,* David Bell, MD,† Donald D. Hensrud, MD, MPH,‡ Michael F. Holick, MD, PHD§, Vitamin D Deficiency An Important, Common, and Easily Treatable Cardiovascular Risk Factor? Journal of the AmericanCollege of Cardiology Vol. 52, No. 24, 2008

[15] Landin-Wilhelmsen K, Wilhelmsen L, Wilske J, Lappas G, Rosén T, Lindstedt G, Lundberg PA, Bengtsson BÅ. Sunlight increases serum 25(OH) vitamin D concentration whereas 1,25(OH)2D3 is unaffected. Results from a general population study in Göteborg, Sweden (The WHO MONICA Project). Eur J Clin Nutr. 1995;49(6):400-7.

[16] Brustad et al. Photochem. Photobiol. Sci., 2007, 6, 903–908http://www.nnc2012.is/programme.aspx

[17] Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358:1500 –3.

[18] Morten K.B. Bogh1, Anne V. Schmedes2, Peter A. Philipsen1, Elisabeth Thieden1 and Hans C. Wulf Vitamin D Production after UVB Exposure Depends on Baseline Vitamin D and Total Cholesterol but Not on Skin Pigmentation Journal of Investigative Dermatology (2010), Volume 130 p 546-53

[19] Stephanie Seneff, MIT, personal communication in 2011.

[20] Lisa A Houghton and Reinhold Vieth  The case against ergocalciferol (vitamin D2) as a vitaminsupplement Am J Clin Nutr 2006;84:694 –7.

[21] Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358:1500 –3.

[22]  Krishna G Seshadria, Bubblu Tamilselvana, Amarabalan Rajendran. Role of Vitamin D in Diabetes Journal of Endocrinology and Metabolism Volume 1, Number 2, June 2011, pages 47-56 (DOI):10.4021/jem23w http://jofem.org/index.php/jofem/article/view/23/32

[23] Obermer, E. Vitamin-D requirements in pregnancy. Br Med J. 1947 Dec 6;2(4535):927

[24] Obermer, E. Vitamin-D requirements in pregnancy. Br Med J. 1947 Dec 6;2(4535):927

[25] Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358:1500 –3.

[26] Elwood JMJopson J. Melanoma and sun exposure: an overview of published studies. Int J Cancer. 1997 Oct 9;73(2):198-203.

[27] Social and welfare board of Sweden, statistical data base, showing a sudden increase in malignant melanoma rate from 2003. There is almost no malignant melanoma cases below age 20, a steady level since 1970.

[28] Scientific Opinion on the Tolerable Upper Intake Level of vitamin D. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). EFSA Journal 2012;10(7):2813

http://www.efsa.europa.eu/en/efsajournal/doc/2813.pdf

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