Browsing by Author "Haugen, Margaretha"
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Item Assessment of Copper Intake in Relation to Tolerable Upper Intake Levels(Science Domain International, 2018-07) Strand, Tor A.; Lillegaard, Inger Therese L.; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Løvik, Martinus; Stea, Tonje Holte; Holvik, KristinThe Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of copper in the Norwegian population in relation to tolerable upper intake levels (ULs). VKM has also conducted scenario calculations to illustrate the consequences of amending maximum limits for copper to 1, 2, or 3, mg/day in food supplements. The existing maximum limit is 4 mg/day. Copper is a micronutrient essential for energy utilisation, brain function (neurotransmitter regulation), soft tissue and bone (collagen synthesis), nutrient metabolism (especially iron) and antioxidant defence against free radicals. Foods account for 90% or more of copper intake in adults when the copper content in drinking water is low (< 0.1 mg/L). If the copper content is higher (> 1-2 mg/L), water may account for up to 50% of total intake (EFSA, 2015). We reviewed four risk assessments undertaken by the Institute of Medicine (IOM), Scientific Committee on Food (SCF), Expert Committee on Vitamins and Minerals (EVM), and the Nordic Nutrition Recommendations (NNR). Liver damage was selected as a critical endpoint from which to derive a UL because it was judged to be the most reliable marker and consequence of a long-term chronic high copper intake. However, copper-related liver damage is observed almost exclusively in patients with genetic predispositions of copper accumulation. VKM suggest to use the UL at 5 mg/day (NNR Project Group, 2012; SCF, 2003). This UL was derived from human studies.In the light of the evidence, SCF decided that an uncertainty factor (UF) of 2 was adequate to allow for potential variability within the normal population, whereas the Institute of Medicine (IOM) applied a UF of 1. VKM find the higher UF suitable because human data is limited, the uncertainty of the copper content of drinking water and the potential severe and irreversible adverse effects. According to the scenario calculations, adults and 13-year-olds with high copper intakes from regular foods (95 th percentile) will exceed the ULs with supplemental copper at doses of 3 mg/day or higher. 9-year-old children will exceed the UL with use of 2 mg supplemental copper per day. For younger children the ULs will be exceeded in more than 5% without adding supplemental copper. In our calculations, copper from drinking water is not included. Copper concentrations in annual samples from waterworks are in general below 0.1 mg/L (Nordheim et al., 2016).Item Assessment of Dietary Intake of Chromium (III) in Relation to Tolerable Upper Intake Level(Science Domain International, 2018-07) Løvik, Martinus; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Stea, Tonje Holte; Strand, Tor A.; Parr, Christine Louise; Holvik, KristinThe Norwegian Scientific Committee for Food and Environment (Vitenskapskomiteen for mat og miljø, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of chromium. VKM has also conducted scenario calculations to illustrate the consequences of establishing maximum limit for chromium at 50, 125, 200 or 300 μg/day in food supplements. The former maximum limit for chromium of 125 μg/day in food supplements was revoked 30 May 2017. Chromium is present in food and supplements mainly as trivalent chromium, Cr(III), whereas in drinking water, chromium is present mainly as Cr(VI). Trivalent chromium has been reported to be an essential trace element in that it has been postulated to be necessary for the efficacy of insulin in regulation of the metabolism of carbohydrates, lipids and proteins. However, no mechanisms for these roles have been identified. Absorption of Cr(III) from food has been estimated to range from 0.4 to 2.5%, depending among other factors on the chemical properties of the ingested source and the presence of other dietary components. Absorption efficiency of supplemental Cr(III) has been reported to be between 0.1 and 5.2%, and to vary between the chromium complex ingested. In general, Cr(III) has very low toxicity by the oral route (ATSDR, 2012), and there are hardly any well-documented observations of toxicity after peroral intake in humans. In a series of animal repeat dose toxicity studies, the no observed adverse effect level (NOAEL) for general toxicity was consistently the highest dose tested (EFSA, 2014b). Chromium is ubiquitous in foods, and rich sources include meat and meat products, oils and fats, breads and cereals, fish, pulses and spices. There are no Norwegian recommendations for intake of chromium. The Nordic Nutrition Recommendations and the European Food Safety Authority (EFSA) concluded that no recommendations could be given for chromium due to lack of sufficient evidence (EFSA, 2014a; NNR Project Group, 2012). Furthermore, no tolerable upper intake levels (UL) have been established for chromium. However, the EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) suggested a tolerable daily intake (TDI) at 300 μg trivalent chromium per kg bodyweight per day based on a NOAEL in a rat study and an uncertainty factor at 1000. Due to uncertainty in the available data on developmental and reproduction toxicity, the EFSA Panel applied an uncertainty factor of 10 in addition to the default uncertainty factor of 100 for the extrapolations from rodents to humans and for human variability. The chromium intake in Norway is not known, since Norwegian food composition data are not available. VKM has therefore based this evaluation upon intake data from EFSA. Values from EFSA are likely to be valid also for Norway. Median dietary chromium intakes were 28.6 -44.0 μg/day (medians of lower and upper bound) in the category toddlers (1 to < 3 years), 55.4-76.2 μg/day in other children (3 to < 10 years), 52.1-69.4 μg/day in adolescents (≥10 to <14 years), 73.6-98.1 in adolescents (≥14 to <18 years) and 63.0-84.0 μg/day in adults (18-65 years) (EFSA, 2014b). These values are 80-300 times lower than the suggested tolerable daily intake (TDI). To illustrate the consequences of amending maximum limits for chromium to 50, 125, 200 or 300 μg per daily dose in food supplements, VKM has compared these levels and various intakes from food to the TDI at 300 μg/kg bw per day. Even with the highest level of supplemental intake and additional median levels as well as the 95 percentile intakes from food, the estimated exposure will be 16-48 times lower than the TDI of 300 μg/kg bw per day in all age groups except for the 95 th percentile intake in toddlers, where it will be about nine times lower. VKM emphasises that the current assessment of maximum limits for Cr(III) in food supplements is merely based on published reports concerning upper levels from the WHO (1996), IOM (2001, USA), SCF (2003, EU), EVM (2003, UK) , NNR (2012, Nordic countries), and EFSA (2014b). VKM has not conducted any systematic review of the literature for the current opinion, as this was outside the scope of the terms of reference from NFSA.Item Assessment of Dietary Intake of Manganese in Relation to Tolerable Upper Intake Level(Science Domain International, 2019-02) Haugen, Margaretha; Frøyland, Livar; Henjum, Sigrun; Løvik, Martinus; Stea, Tonje Holte; Strand, Tor A.; Parr, Christine Louise; Holvik, KristinThe Norwegian Scientific Committee for Food and Environment (Vitenskapskomiteen for mat og miljø, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of manganese from the diet and 1, 5 or 10 mg manganese per day in food supplements. The former maximum limit for manganese in food supplements was 5 mg per daily dose. Manganese (Mn) is an essential dietary mineral for mammals, and is a component of metalloenzymes such as superoxide dismutase, arginase and pyruvate carboxylase. Manganese is involved in amino acid-, lipid- and carbohydrate metabolism and in proteoglycan synthesis in bone formation. In 2013, the European Food Safety Authority (EFSA) suggested 3 mg/day to represent an adequate intake (AI) of manganese because data was considered insufficient to set an average requirement (AR). Reports of adverse effects resulting from manganese exposure in humans are associated primarily with inhalation in occupational settings. Excess oral exposure to manganese, especially from contaminated water sources, has been shown to cause permanent neurological disorder known as “manganism” which can be irreversible. The amount of manganese absorbed is inversely related to the concentration of manganese in the diet. This regulation seems to be part of the adaptive changes to the amount of dietary manganese intake, which allow the maintenance of manganese homeostasis over a wide range of intakes. Manganese is mainly absorbed as Mn(II), and absorption is reported to be below 10% of ingested manganese. The main route of elimination of manganese from the body is via bile to the small intestine, while very little is excreted in the urine. Half-life for manganese can vary from 13 to 37 days, with a longer half-life in women than in men, but large inter-individual variation exists. In Norway, manganese content in drinking water is low, and does not contribute to any magnitude of manganese intake. Daily dietary intake of manganese in Norway is not known, but it is proposed that manganese intake is adequate in the Scandinavian countries (NNR Project Group, 2012). Results from the Swedish Market Basket study, 2015, indicate an average daily manganese intake of 4.2 mg per person and day. Calculations based on data from Denmark, 2013 and 2015, evaluate mean dietary intake of manganese to 3.9 mg/day for adults and up to 6.9 mg/day in the higher intake groups. EFSA report on an observed mean intake in EU around 3 mg/day for adults. Main contributor to dietary manganese intake is cereals (57%) followed by fruit, vegetables, nuts and coffee/tea. Irreversible neurotoxic adverse effects from intakes of manganese close to adequate intakes have been reported in humans (SCF, 2000). The Scientific Committee on Food (SCF) could not set a no observed adverse effect level (NOAEL), because no relevant dose-response animal studies were found. Consequently SCF did not set a tolerable upper intake level (UL) for manganese. VKM considers that any dose of manganese as an ingredient in food supplements may be associated with increased risk of negative health effects. VKM emphasises that the current assessment of maximum limits for manganese in food supplements is merely based on published reports concerning upper levels from the IOM (2001, USA), SCF (2003, EU), EVM (2003, UK) and NNR (2012, Nordic countries). VKM has not conducted any systematic review of the literature for the current opinion, as this was outside the scope of the terms of reference from NFSA.Item Assessment of Dietary Intake of Molybdenum in Relation to Tolerable Upper Intake Level(Science Domain International, 2019-02) Strand, Tor A.; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Løvik, Martinus; Stea, Tonje Holte; Parr, Christine Louise; Holvik, KristinThe Norwegian Scientific Committee for Food and Environment (Vitenskapskomiteen for mat og miljø, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of molybdenum. VKM has also conducted scenario calculations to illustrate the consequences of amending maximum limits for molybdenum to 100, 250, 500 or 1000 µg/day in food supplements. The previous maximum limit was 250 µg/day. Molybdenum is as a cofactor for some important enzymes in humans. These enzymes are involved in the catabolism of sulfur amino acids and heterocyclic compounds, including purines and pyridines. A distinct molybdenum deficiency has not been described in animals when subjected to molybdenum restriction, despite considerable reduction in the activity of molybdoenzymes. Molybdenum deficiency is not observed in healthy humans. The estimated Adequate Intake (AI) proposed by the European Food Safety Authority (EFSA) is 65 µg per day for men and women. Legumes, grains, and nuts are major contributors of molybdenum in the diet. Molybdenum is a potential antagonist to copper absorption, but symptoms of copper deficiencies due to excess molybdenum intake have only been observed in ruminants. Based on the effect on reproduction and growth in animals, tolerable upper intake levels (ULs) have been estimated to be 2 mg/day by the U.S. Institute of Medicine (IOM) in 2001 and 0.6 mg/day by the Scientific Committee on Food (SCF) in 2000. These ULs were based on the same scientific evidence, but IOM used an uncertainty factor (UF) of 30 and SCF used a UF of 100 because the evidence base was considered to be weak. Because of the limited safety data on molybdenum, VKM support the use of the default uncertainty factors at 100 for extrapolation of data from animal studies to humans. Additionally, molybdenum deficiency is very rare and no studies have indicated a nutritional need for additional molybdenum from dietary supplements. The ULs for children were derived by adjusting the adult UL according to default body weights. According to the scenario estimations, only the highest suggested maximum limit of 1000 µg molybdenum from food supplements will lead to exceedance of the UL for adults. For 1-3 year old children, all the suggested maximum limits for molybdenum will lead to exceedance of the UL. In children 4-10 years, supplements with 250, 500 or 1000 µg molybdenum will lead to exceedance of the ULs, whereas for adolescents 11-17 years, the UL will be exceeded with supplemental doses at 500 or 1000 µg per day. VKM emphasises that the current assessment of maximum limits for molybdenum in food supplements is merely based on published reports concerning upper levels from the SCF (2000, EU), IOM (2001, USA), EVM (2003, UK) and NNR (2012, Nordic countries). VKM has not conducted any systematic review of the literature for the current opinion, as this was outside the scope of the terms of reference from NFSA.Item Assessment of Dietary Intake of Phosphorus in Relation to Tolerable Upper Intake Levels(Science Domain International, 2018-07) Haugen, Margaretha; Lillegaard, Inger Therese L.; Frøyland, Livar; Henjum, Sigrun; Løvik, Martinus; Stea, Tonje Holte; Strand, Tor A.; Holvik, KristinThe Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of phosphorus in the Norwegian population. VKM has also conducted scenario calculations to illustrate the consequences of amending maximum limits for phosphorus (to 1000, 2000 or 2500 mg/day) in food supplements. Phosphorus is an essential nutrient and is involved in many physiological processes, such as in the cell’s energy cycle, in regulation of the body’s acid-base balance, as a component of the cell structure, in cell regulation and signalling, and in the mineralisation of bones and teeth. In the human body, phosphorus is present in different forms. Serum contains mainly inorganic phosphates (Pi) (dihydrogen and monohydrogen phosphate), bone contains phosphorus largely in the form of hydroxyapatite, whereas the soft tissues and extracellular fluids contain organic phosphates in complex with carbohydrates, lipids and proteins. Phosphorus is the main mineral constituent of bones. About 85% of the body’s phosphorus is in bones and teeth, and together with calcium account for around 80-90% of bone composition. The remaining 15% of the body’s phosphorus is essential in functions ranging from the transfer of genetic information to energy utilisation. Phosphorus is a structural component of the nucleic acids DNA and RNA and thus involved in the storage and transmission of genetic material. It is an essential component of phospholipids (e.g. phosphatidylcholine) that form all membrane bilayers throughout the body. Phosphorus is also an essential component of adenosine triphosphate (ATP), the body’s key energy source. Currently there is no reliable biomarker of phosphorus status, and serum phosphorus increases for a short period after ingestion of a meal and then decreases and remains within a relatively narrow range as a result of homeostatic mechanisms. The EFSA recommendations (2015) for adequate intake (AI) of phosphorus is 550 mg/day for adults, both sexes, whereas the recommended intake (RI) in the Nordic Nutrition Recommendations (2012) is 600 mg/day. Adolescents have a higher requirement of phosphorous because of bone accretion (640 mg/day EFSA and 700 mg/day NNR). EFSA (2005) concluded that the available data were not sufficient to establish a tolerable upper level for phosphorus, however, data indicate that normal healthy individuals can tolerate phosphorus intakes up to 3000 mg/day. EFSA advised supplemental intake not to exceed 750 mg/day, because mild gastrointestinal symptoms have been reported when this dose was increased. EFSA gave no UL suggestions for children, lactating or pregnant women, while Institute of Medicine set a UL for total intake of phosphorous for children at 3000 mg/day and 4000 mg/day for adolescents and adults and 3500 mg/day for lactating women. In accordance with EFSA (2005), VKM suggests to use 3000 mg/day as a provisional UL for total intake of phosphorous for adults, and suggests 750 mg/day as an upper level for supplements. Because of lack of data no provisional ULs are set for adolescents or children. Accordingly, all the suggested doses from NFSA (1000, 2000 and 2500 mg/day) in supplements exceed 750 mg/day, the suggested UL for supplemental phosphorus for adults.Item Assessment of Dietary Intake of Potassium in Relation to Upper Guidance Level(Science Domain International, 2018-07) Haugen, Margaretha; Lillegaard, Inger Therese L.; Frøyland, Livar; Henjum, Sigrun; Løvik, Martinus; Stea, Tonje Holte; Strand, Tor A.; Holvik, KristinThe Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of potassium in the Norwegian population. VKM has also evaluated the consequences of amending the existing maximum limit for potassium at 1000 mg/day to 300, 2000 or 3000 mg/day in food supplements. Potassium is an essential mineral to humans and is important as the osmotically active element inside the cells, whereas sodium and chloride are the main elements outside the cells. The enzyme Na+/K+ -ATPase pumps potassium ions into the cells and sodium ions out of the cells and helps keep the intracellular potassium concentration about 30 times higher than that of plasma and interstitial fluids. The plasma potassium concentration is maintained within narrow limits (3.5 to 5.0 mmol/L) by multiple mechanisms making up the potassium homeostasis. The strict regulation is essential for a broad array of important physiological processes, like the resting cellular membrane potential and the transmission action in neuronal, muscular and cardiac tissue. Potassium is also important for hormone secretion, vascular tone, systemic blood pressure control, gastrointestinal motility, acid-base balance, glucose and insulin metabolism, mineralocorticoid action, renal concentration ability and fluid and electrolyte balance. Both hypo- and hyperkalaemia result in increased mortality. The EFSA recommendations (2016) for adequate intake (AI) of potassium is 3500 mg/day for adults, both sexes, whereas the recommended intake (RI) in the Nordic Nutrition recommendations (2012) is 3500 mg/day for men and 3100 mg/day for women. Tolerable upper intake levels have not been established for potassium from food, because intake from food has not caused adverse health effects in the healthy population. In children the renal function rapidly reaches the normal adult level in early childhood and no concern about high intake of potassium from food has been put forward. Potassium chloride supplement has, however, resulted in hyperkalaemia and case reports have described heart failure and cardiac arrest at plasma concentrations above 5.5 mmol/L and doses over 6.5 - 6.8 g supplementary potassium per day. VKM proposes to use 3000 mg/day of potassium as an upper guidance level for daily dose of supplemental potassium in adults since this dose has not been shown to cause hyperkalaemia or heart failure, and has not resulted in gastrointestinal lesions. The proposed upper guidance level for adults extrapolated for body weights corresponds to 2630 mg/day for adolescents 14 to <18 years, 1860 mg/day for children 10 to < 14 years and 990 mg/day for children 3 to 10 years. For vulnerable groups all doses of potassium supplementation could lead to hyperkalaemia. Vulnerable groups such as persons with impaired kidney function and elderly have been estimated to comprise 15-20% of the population of Norway. However, most of the vulnerable individuals will be aware of the condition and be under medical supervision. Accordingly, all the evaluated doses from NFSA (300, 1000, 2000 and 3000 mg/day of potassium in food supplements are at or below the suggested upper guidance level for supplemental potassium for adults (>18 years). In adolescents 14 to <18 years, the supplemental doses of 300, 1000 and 2000 mg/day are below the suggested upper guidance level. For the younger age groups, only 300 mg/day is below the suggested upper guidance level for supplemental potassium.Item Assessment of Dietary Intake of Vitamin C and Calcium in the Norwegian Population(Science Domain International, 2018-09) Haugen, Margaretha; Lillegaard, Inger Therese L.; Frøyland, Livar; Holvik, Kristin; Løvik, Martinus; Strand, Tor A.; Tell, Grethe S.; Iversen, Per OleThe Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of vitamin C and calcium in the Norwegian population. VKM has also conducted scenario estimations to illustrate the consequences of amending maximum limits for vitamin C (to 100, 300, 500, 600, 800 or 1000 mg/day) and calcium (to 800, 1200 or 2000 mg/day) in food supplements. Vitamin C: Vitamin C refers to both ascorbic acid and dehydroascorbic acid. Scurvy is the manifestation of vitamin C deficiency which is preventable by a daily intake of 5-10 mg/day. Fruits, berries and vegetables are important food sources of vitamin C and especially citrus fruit are important contributors. The Norwegian recommendation for dietary intake of vitamin C is 75 mg/day for adults (Helsedirektoratet, 2014). Vitamin C is absorbed from the intestine by an active process that is dose dependent. The bioavailability is at least 80% for doses up to 100 mg, 70% for doses of 200-500 mg and less than 50% for doses exceeding 1000 mg. Intestinal discomfort and diarrhea have been reported by persons using large doses (>1000 mg/day) of vitamin C supplementation. In 2000 the Institute of Medicine (IOM) in the USA proposed a tolerable upper intake level (UL) for vitamin C intake from food and supplements of 2000 mg/day for adults. ULs for children and adolescents were extrapolated based on body weight; 400 mg for children 1-3 years, 650 mg/day for children 4-8 years, 1200 mg/day for 9-13 years old adolescents, 1800 mg/day for 14-18 years old (IOM, 2000). In the assessment of vitamin C, VKM uses the Norwegian recommendations for intakes (Helsedirektoratet, 2014), and the acceptable dose for supplemental vitamin C from EFSA (2004) for adults and the tolerable upper intake levels established by the IOM (2000) for children and adolescents. Daily intakes of vitamin C from diet and supplements are estimated from nationwide dietary surveys performed in selected age groups: Adults 18-70 years, adolescents aged 13 years, and children aged 2, 4, and 9 years. Not all age-groups in the Norwegian population reach the recommended intake of vitamin C. At the 5th percentile, only 13-year-olds have an intake of vitamin C from food alone above the recommendations. At the 25th percentile, all age groups except adults have a vitamin C intake from food alone at or above the recommendations. At the 40th percentile, adults reach the recommended intake of vitamin C. The whole population would reach the recommended dietary intake with supplementation of 100 mg vitamin C per day. All the alternative maximum limits for vitamin C in food supplements listed in the terms of reference from NFSA (100, 300, 500, 600, 800 or 1000 mg/day) will be within the acceptable dose for supplemental vitamin C suggested by EFSA (2004) for adults. None of the alternative maximum limits for vitamin C in food supplements listed in the terms of reference (100, 300, 500, 600, 800 or 1000 mg/day) leads to exceedance of the tolerable upper intake levels established by IOM in adults, 13- year-olds or 9-year-olds, even with intakes from food at the 95th percentile. However, the tolerable upper intake level proposed by the IOM will be exceeded for 4-year-old children at supplemental doses above 500 mg vitamin C per day, and for 2-year-old children at doses higher than 100 mg/day. Calcium: Calcium is the most abundant mineral in the body and constitutes approximately 1200 g and 1400 g in adult women and men, respectively. More than 99% of the calcium in the body is bound to hydroxyapatite in bone and tooth enamel. Calcium is crucial for many bodily functions such as cell signalling, coagulation, muscular contraction, and neural transmission as well as skeletal integrity. Milk and dairy products are the main dietary sources of calcium, but foods such as fish, pulses, nuts, seeds (especially millet) and green vegetables may contribute to the total intake. The Norwegian recommendation for dietary intake of calcium is 800 mg/day for adults. The bioavailability of calcium is dependent on the amount of calcium ingested as well as the individual’s vitamin D status and physiological needs, like e.g. growth and pregnancy. Adverse effects of excessive calcium intake include symptoms of hypercalcaemia such as e.g. anorexia, weight loss, polyuria, heart arrhythmias, fatigue and soft tissue calcification (Jones, 2008 in IOM, 2011), deterioration of kidney function, kidney stone formation, the milk-alkali syndrome and vascular calcification. In 2012 the European Food Safety Authority (EFSA) established a tolerable upper intake level (UL) for calcium at 2500 mg/day from food and supplements for adults. No UL was set for children and adolescents. In 2011, IOM established a UL for 1-8 years old children to 2500 mg/day and 3000 mg/day for 9-18 years old children and adolescents (IOM, 2011). VKM however suggests that the UL established for adults by EFSA (2012) is used for the purpose of this VKM opinion also for children and adolescents, as the ULs from IOM for children and adolescents are considered to be high. In the assessment of calcium, VKM uses the Norwegian recommendations for intakes (Helsedirektoratet, 2014) and the tolerable upper intake levels established by the European Food Safety Authority for adults (includes both foods and supplements) (EFSA, 2012). Daily intakes of calcium from diet and supplements are estimated from nationwide dietary surveys performed in selected age groups: Adults 18-70 years, adolescents aged 13 years, and children aged 2, 4, and 9 years. Not all age groups in the Norwegian population reach the recommended intake of calcium. At the 5th percentile, no age groups fulfil the recommended daily intakes of calcium from food alone, and in the 50th percentile the 13-year-olds did not reach the recommended intake for calcium from food alone. At approximately the 65th percentile, the 13-year-olds reach the recommended intake for calcium. The whole population would reach the recommended dietary intake with supplementation of 800 mg calcium per day. For calcium, three alternative maximum limits were listed in the terms of reference (800, 1200 and 2000 mg/day). In the scenarios for high intakes of calcium, a dietary calcium intake at the 95th percentile and additionally 800 mg calcium from food supplements, will lead to an intake close to the tolerable upper intake level established by EFSA for the adult population, and supplements with 1200 or 2000 mg calcium per day will lead to exceedance of the tolerable upper intake level in adults. Children and adolescents with a dietary intake at the 95th percentile and additionally 2000 mg calcium from food supplements, will all exceed the UL suggested for adults by EFSA in 2012. All age groups except 4-year-olds will also exceed the UL with 1200 mg supplemental calcium. With 800 mg supplemental calcium 13-year-old adolescents, 9-year-old, 4 year-old and 2-year-old children will not exceed the suggested UL.Item Assessment of Dietary Intake of Vitamin K and Maximum Limits for Vitamin K in Food Supplements(Science Domain International, 2019-02) Holvik, Kristin; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Løvik, Martinus; Stea, Tonje Holte; Strand, Tor A.; Parr, Christine LouiseThe Norwegian Scientific Committee for Food and Environment (Vitenskapskomiteen for mat og miljø, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of vitamin K in the diet. VKM has also assessed the consequences of establishing maximum limits for vitamin K in food supplements at 100, 200, 300, 600 or 800 µg/day. The former maximum limit for vitamin K of 200 µg/day in food supplements was repealed 30 May 2017. Vitamin K is a fat-soluble vitamin required for the carboxylation of glutamic acid residues in proteins that regulate blood coagulation and bone metabolism. The naturally occurring forms of vitamin K present in food and supplements are phylloquinone (vitamin K1) mainly produced by plants, and a range of menaquinones (vitamin K2) mainly produced by bacteria. The chemical structure of vitamin K is characterised by a methylated naphtoquinone ring structure assumed to be responsible for its function, in addition to a side chain which differs in length and degree of saturation. Due to the varying side chains, the different forms of vitamin K are thought to behave differently with regard to absorption, metabolism, bioavailability and thereby also toxic potential. Dark green leafy vegetables are rich sources of phylloquinone. Meat and liver products provide menaquinone-4, the most common menaquinone in Western diets, while other menaquinones are found in fermented foods and cheese. An Adequate Intake (AI) of phylloquinone of 1 µg/kg body weight per day was set by the Scientific Committee on Food (SCF) in 1993 and maintained by the European Food Safety Authority (EFSA) in 2017. No dietary reference values (DRVs) have been established for menaquinones due to insufficient evidence. Furthermore, no tolerable upper intake levels (ULs) have been established for any form of vitamin K due to insufficient evidence, but previous reports stated that no adverse effects associated with vitamin K consumption from food or supplements had been reported in humans or animals. In 2003, the UK Expert Group on Vitamins and Minerals (EVM) proposed a guidance level (GL) for safe upper intake of supplemental phylloquinone of 1 mg/day in adults. The GL was set by applying an uncertainty factor of 10 for inter-individual variation to the supplemental dose of 10 mg/day that had been consumed by eight female athletes (age 20-44) for 30 days with no reported adverse effects. The UK expert group emphasised that GLs had been derived from limited data and were less secure than safe upper levels. This GL was supported by a double-blind randomised study cited in the Nordic Nutrition Recommendations (2012), in which 440 postmenopausal women with osteopenia received a daily supplement of 5 mg phylloquinone or placebo for up to four years with no difference in adverse events between the randomised groups. Corresponding GLs for children and adolescents have been derived by adjusting for reference body weights0.75 by Rasmussen et al. (2006). The distribution of intakes of vitamin K across age groups in Norway is not known, since food composition data is not available. However, habitual intakes in a representative sample of middle-aged and older adults in Western Norway were assessed in the population-based Hordaland Health Study 1997-2000, and revealed higher intakes than those estimated from dietary surveys in the other Nordic countries. Due to lack of representative estimates of vitamin K intakes in the Norwegian population, information on vitamin K intakes from other Nordic countries is included in the current opinion. This includes the distribution of vitamin K intakes in Sweden and Finland reported by EFSA, and the distribution of vitamin K intakes in Denmark, assessed by the Technical University of Denmark (DTU). In middle-aged and older Western Norwegians participating in the Hordaland Health Study 1997-2000, estimated mean intakes of total vitamin K (denoting the sum of K1+K2) ranged from 109 to 148 µg/day in four groups based on age and gender, while the 95-percentiles ranged from 261 to 329 µg/day. Average intakes of total vitamin K in the other Nordic countries are in the magnitude of 100 µg/day in adults, while 95-percentiles in adults are in the magnitude of 200 µg/day. To illustrate the consequences of establishing maximum limits for vitamin K at 100, 200, 300, 600 or 800 µg/day in food supplements, VKM has compared these levels to the age-specific GLs for supplemental phylloquinone proposed by EVM (2003). The GLs are: 1000 µg/day for adults, 870 µg/day at age 15-17 years, 670 µg/day at age 11-14 years, 500 µg/day at age 710 years, 370 µg/day at age 4-6 years and 270 µg/day at age 1-3 years. VKM concludes that: In adults and adolescents 15-17 years old, maximum limits of 100, 200, 300, 600 and 800 µg/day are below GL. In adolescents 11-14 years old, maximum limits of 100, 200, 300 and 600 µg/day are below GL while the maximum limit of 800 µg exceeds GL. In children 4-10 years old, maximum limits of 100, 200 and 300 µg/day are below GL while maximum limits of 600 µg/day and 800 µg/day exceeds GL. In children 1-3 years old, maximum limits of 100 µg/day and 200 µg/day are below GL while maximum limits of 300, 600 and 800 µg/day exceeds GL. VKM notes that the current conclusions apply to phylloquinone (vitamin K1) only, while there is insufficient evidence to appraise potential health consequences of maximum limits of menaquinones (vitamin K2). VKM emphasises that the current assessment of maximum limits for vitamin K in food supplements is merely based on published reports concerning upper levels from the IOM (2001, USA), SCF (2003, EU), EVM (2003, UK) and NNR (2012, Nordic countries). VKM has not conducted any systematic review of the literature for the current opinion, as this was outside the scope of the terms of reference from NFSA.Item Assessment of Intake of Nicotinic Acid and Nicotinamide in Relation to Tolerable Upper Intake Levels(Science Domain International, 2018-07) Stea, Tonje Holte; Lillegaard, Inger Therese L.; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Løvik, Martinus; Strand, Tor A.; Holvik, KristinThe Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the intake of niacin in the Norwegian population. NFSA has also requested that VKM conduct scenario calculations to illustrate the consequences of establishing separate maximum limits for nicotinic acid (1, 4, 8 or 10 mg/day) and nicotinamide (100, 500, 700 or 900 mg/day) in food supplements, by assessing these scenarios against existing tolerable upper intake levels (ULs). The current maximum limit for niacin added to food supplements is 32 mg/day, including nicotinic acid, nicotinamide and inositol hexanicotinate. The term niacin (vitamin B3) comprises the two main water-soluble forms nicotinic acid and nicotinamide (niacinamide). The human body can get niacin from the diet or synthesise it from the essential amino acid tryptophan. Dietary intakes are expressed as milligram niacin equivalents (NEs), which correspond to 1 mg of pure niacin or 60 mg of tryptophan. In the body, niacin primarily functions as a component of the coenzymes NAD (nicotinamide adenine dinucleotide) and NADP (nicotinamide adenine dinucleotide phosphate) which are present in all cells. These coenzymes play essential roles for the functioning of a wide range of enzymes involved in the metabolism of carbohydrates, amino acids and fat. In addition to its function in coenzymes, niacin is involved in DNA repair and gene stability. Niacin has a half-life of 20-40 minutes in the human body. Late symptoms of severe niacin deficiency (pellagra) include fatigue, headache, apathy, depression, memory loss, dementia, pigmented skin rash after sun exposure, bright red tongue, vomiting, diarrhoea, and constipation. Flushing (burning and itching of the face, arms and chest) and stomach irritation are the main side effects of moderately high supplemental intake of nicotinic acid (>35 mg/day). Long-term use of high doses (≥3000 mg/day) of nicotinic acid as a cholesterol-lowering drug can also be toxic to the liver. Nicotinamide, however, does not have these effects. In general, the risk of nicotinamide toxicity appears to be quite low. VKM proposes to adopt the ULs of nicotinic acid and nicotinamide set by the Scientific Committee for Food Safety (SCF) in 2002, which are based on one human dose-response study (nicotinic acid) and several human dose-response studies (nicotinamide), respectively. Hence, the UL for supplemental nicotinic acid is suggested to 10 mg/day for adults and the UL for supplemental nicotinamide to 900 mg/day for adults. The ULs for children and adolescents have been derived on the basis of their body weights. The ULs set for nicotinic acid and nicotinamide concern only intake from supplements since intake of nicotinic acid and nicotinamide from regular foods is considered to be without risk of negative health effects. Therefore, VKM has not conducted or evaluated scenarios with intake from both diet and the separated new maximum limits for nicotinic acid and nicotinamide in food supplements suggested by NFSA. Dietary calculations, however, have been performed for niacin intakes (includes both nicotinic acid and nicotinamide) in various percentiles (P5, P25, mean, P50, P75 and P95) in children (2-, 4- and 9-year-olds), adolescents (13-year-olds) and adults as background information. Mean and median intakes of niacin from the diet alone are above or at the recommended intakes for all age groups. Because UL for supplemental nicotinic acid is 10 mg/day for adults, none of the suggested maximum limits in food supplements (1, 4, 8, or 10 mg/day) will lead to exceedance of this UL in adults. In 13-year-olds and 9-year-olds, supplements with 8 mg nicotinic acid per day will lead to exceedance of UL, and in 4-year-olds and 2-year-olds supplementation of 4 mg nicotinic acid per day will lead to exceedance of the UL for nicotinic acid. Because UL for supplemental nicotinamide is 900 mg/day for adults, none of the suggested maximum limits in food supplements (100, 500, 700 or 900 mg/day) will lead to exceedance of UL in adults. In 13-year-olds, supplements with 700 mg nicotinamide per day will lead to exceedance of UL. In 9-year-olds, 4-year-olds and 2-year-olds, supplementation of 500 mg nicotinamide per day will lead to exceedance of the UL for nicotinic acid.Item Assessment of Iron Intake in Relation to Tolerable Upper Intake Levels(Science Domain International, 2018-09) Strand, Tor A.; Lillegaard, Inger Therese L.; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Holvik, Kristin; Løvik, Martinus; Skålhegg, Bjørn Steen; Stea, Tonje Holte; Iversen, Per OleThe Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the intake of iron in the Norwegian population in relation to tolerable upper intake levels (ULs). The existing maximum limit for iron in food supplements is 27 mg/day. VKM has also conducted scenario calculations to illustrate the consequences of amending the maximum limit to 5, 10, 20, 30, 40 or 50 mg/day. Iron deficiency is one of the most common nutritional disorders in the world. Individuals with increased iron demand such as growing children and pregnant women, those who experience blood loss such as menstruating women are particularly at risk for the consequences or iron deficiency. Iron deficiency can lead to fatigue and anaemia. The most common adverse effects of iron supplementation are reversible gastrointestinal symptoms. Chronic iron excess can lead to iron overload which is associated with several irreversible severe health outcomes such as cancers and cardiovascular diseases. Up to 1% of the population have a genetic trait that leads to accumulation of iron and renders them more vulnerable to iron excess. An adult needs approximately 10 mg iron per day to overcome daily loss. The tolerable upper intake level (UL) for iron in adults range from 45 to 60 mg/day. However, all previous reports acknowledge the challenges in defining upper levels. The Expert Group on Vitamins and minerals (EVM), UK report provided a guidance level (GL) of 17 instead of a UL and the Nordic Nutrition Recommendations (NNR) (2012) suggested an UL of 60 mg/day, but did not suggest any clear upper levels for children. Institute of Medicine (IOM), US (2001) gives the most substantiated tolerable upper intake levels based on gastrointestinal effects, which is 40 mg/day for infants and children, regardless of age, and 45 mg/day for adolescents and adults. The Joint FAO/WHO Expert Committee on Food Additives 2003 (JECFA) also took the potential serious effects of iron overload into account and suggested a GL of 50 mg/day in adults or 0.8 mg/kg per day in children and adolescents. Because the risks and consequences from overload are significant and potentially serious, VKM suggests that the GL from JECFA (2003) is used. Using the GL from JECFA (2003), none of the suggested doses can be given to 2 or 4-yearold children, 9 year olds can add 5 mg iron from supplements, 13 year olds 20, and adults 30 mg without exceeding the guidance levels.Item Assessment of Selenium Intake in Relation to Tolerable Upper Intake Levels(Science Domain International, 2018-07) Strand, Tor A.; Lillegaard, Inger Therese L.; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Løvik, Martinus; Stea, Tonje Holte; Holvik, KristinThe Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of selenium in the Norwegian population. VKM has also conducted scenario calculations to illustrate the consequences of amending maximum limits for selenium to 50, 150 or 200 μg/day in food supplements. The existing maximum limit is 100 μg/day. Selenium is a cofactor for enzymes and proteins with vital importance in antioxidant defence, thyroid hormone and insulin function and regulation of cell growth. We reviewed four risk assessments undertaken by the Institute of Medicine (IOM), Scientific Committee on Food (SCF), Expert Committee on Vitamins and Minerals (EVM), and the Nordic Nutrition Recommendations (NNR). Because of limited evidence from human studies and due to the selection of a high uncertainty factor (UF), we decided to use the tolerable upper intake levels (ULs) set by the SCF (2000) and later adopted by NNR (2012). Early signs of selenium toxicity are a garlic breath and a metallic taste. Severe selenosis results in fast hair loss and brittle nails, as well as other gastrointestinal symptoms such as nausea, vomiting, diarrhea, fatigue, irritability, and rash. Acute selenium intoxication and chronical overexposure may affect the nervous system and result in nerve damage. The SCF established a UL for selenium at 300 μg/day for adults, including pregnant and lactating women. This UL was based on a no observed adverse effect level (NOAEL) of 850 μg/day for clinical selenosis applying a UF of 3, and was supported by three studies reporting no adverse effects for selenium intake between about 200 and 500 μg/day. As there were no data to derive specific ULs for children, the SCF (2000) extrapolated the UL from adults to children based on reference body weights. The proposed UL values for children and adolescents ranged from 60 μg/day (1–3 years) to 250 μg selenium/day (15–17 years). According to the scenario estimations in adults, the dietary selenium intake at the 95th percentile and additionally 150 μg selenium from food supplements will be below the UL while 200 μg selenium from food supplements will lead to exceedance of the UL for adults. For 13- and 9-year-olds, supplemental doses of 100 and 50 μg selenium per day, respectively, do not lead to exceedance of the ULs in these age groups. For 2- and 4-year-olds, all the suggested doses in food supplements will lead to exceedance of the ULs.Item Assessment of Vitamin B6 Intake in Relation to Tolerable Upper Intake Levels(Science Domain International, 2018-09) Haugen, Margaretha; Lillegaard, Inger Therese L.; Frøyland, Livar; Henjum, Sigrun; Holvik, Kristin; Løvik, Martinus; Skålhegg, Bjørn Steen; Stea, Tonje Holte; Strand, Tor A.; Iversen, Per OleThe Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the intake of vitamin B6 (pyridoxine) in the Norwegian population in relation to tolerable upper intake levels (ULs). The existing maximum limit for vitamin B6 in food supplements is 4.2 mg/day. VKM has also conducted scenario calculations to illustrate the consequences of amending the maximum limitto 2, 6, 8, 10, 20 or 25 mg/day. Vitamin B6 is water soluble and comprises six compounds with vitamin B6 activity; pyridoxine (PN, an alcohol), pyridoxal (PL, an aldehyde) and pyridoxamine (PM, the amine) and their corresponding phosphates; pyridoxine 5’-phosphate (PNP), pyridoxal 5’ -phosphate (PLP) and pyridoaxamin 5’ –phosphate (PMP). These six forms of vitamin B6 are all present in food in addition to the glycosylated form, pyridoxine-5’-β-δ-glucoside (PNG), in some plants. In food supplements the most common vitamin B6 form is pyridoxine hydrochloride. Eighty to ninety percent of vitamin B6 in the body is found in muscles and estimated body stores in adults amount to about 170 mg with a half-life of 25-33 days. Vitamin B6 deficiency is mostly seen in combination with deficiency of other B vitamins. Symptoms of vitamin B6 deficiency are anaemia and neurological abnormalities (EFSA, 2016). Intakes of vitamin B6 from the diet alone have not been reported to cause adverse effects. Sensory neuropathy has been reported to be the most sensitive adverse health effect of vitamin B6 supplementation. VKM proposes to adopt the tolerable upper intake level (UL) set by the Scientific Committee for Food (SCF) in 2000 at 25 mg/day for vitamin B6, which was based on a lowest observed adverse effect level (LOAEL) of 100 mg/day found in one randomised controlled trial. VKM recognises that there are no well-designed dose-response studies of long-term use available. However, for adults, no adverse effects have been reported at doses with vitamin B6 up to 25 mg/day. Dietary calculations have been performed for mean intakes and in various percentiles (P5, P25, P50, P75 and P95) in children (2-, 4- and 9-year-olds), adolescents (13-year-olds) and in adults. To illustrate the consequences of amending the maximum limit for vitamin B6 in food supplements to 2, 6, 8, 10, 20 or 25 mg/day in the different age groups, VKM has used the scenarios with P95 from food and added the alternative amounts of supplements. VKM has compared these scenarios with the tolerable upper intake levels set by the Scientific Committee for Food in 2000 for adults, adolescents and children. In these scenarios, the 2- and 4-year-old children will exceed the tolerable upper intake level with use of 6 mg/day or higher vitamin B6 in supplements. The 9-year-old children will exceed the tolerable upper intake level with supplemental use of 10 mg/day. The 13-year-old adolescents will exceed the tolerable upper intake level with 20 mg/day of vitamin B6 in supplements. Adults will exceed the tolerable upper intake level with use of 25 mg/day of vitamin B6/pyridoxine in supplements.Item Assessment of Vitamin E Intake in Relation to Tolerable Upper Intake Levels(Science Domain International, 2018-09) Haugen, Margaretha; Lillegaard, Inger Therese L.; Frøyland, Livar; Henjum, Sigrun; Holvik, Kristin; Løvik, Martinus; Skålhegg, Bjørn Steen; Stea, Tonje Holte; Strand, Tor A.The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the intake of vitamin E (alpha-tocopherol) in the Norwegian population in relation to tolerable upper intake levels (ULs). The existing maximum limit for vitamin E in food supplements is 30 mg/day. VKM was also requested to conduct scenario calculations to illustrate the consequences of amending the maximum limit for alpha-tocopherol to 15, 50, 100, 150, 200 and 300 mg/day. Naturally vitamin E is a fat soluble compound synthesised by plants and consists of eight different tocopherols (α-, β-, γ- and δ- tocopherols and α-, β-, γ- and δ- tocotrienols) with varying vitamin E antioxidant activity. α-Tocopherol is recognised to meet human vitamin E requirements and accounts for 90% of the activity in human tissue. Vitamin E activity in food is expressed as α-tocopherol equivalents (α-TE) and 1 α-TE is defined as 1 mg d-αtocopherol. The physiological role of vitamin E is to react with free radicals in cell membranes and other lipid milieu, thereby preventing polyunsaturated fatty acids (PUFA) from being damaged by lipid peroxidation. This antioxidant activity is important to maintain membrane integrity and takes place in all cells in the body. Vitamin E deficiency symptoms include peripheral neuropathy, ataxia, myopathy and retinopathy. Vitamin E is dependent on lipid and lipoprotein metabolism and it takes decades for body depletion. The Norwegian recommended intakes for vitamin E for adults are 10 αTE/day for men and 8 α-TE/day for women. There is no evidence of adverse effects from the consumption of vitamin E naturally occurring in foods. Animal studies have shown that α-tocopherol is not mutagenic, carcinogenic or teratogenic. However, high doses of α-tocopherol supplements can cause haemorrhage and interrupt blood coagulation. VKM propose to adopt the tolerable upper intake level set by the Scientific Committee for Food Safety (SCF) which is based on one human dose-response study. Hence, the upper level for supplemental vitamin E is suggested to 300 mg/day for adults. The upper level for children and adolescents is derived from scaling the adult upper level based on body surface area (body weight 0.75). The tolerable upper intake levels set for vitamin E concern only intake from supplements, since intake of vitamin E from the diet is considered safe. VKM has therefore not conducted or evaluated scenarios with intake from both diet and supplements. Dietary calculations have, however, been performed for intake in various percentiles (P) P5, P25, mean, P50, P75 and P95 in children (2- 4- and 9-year-olds), adolescents (13-year-olds) and in adult men and women as background information. Mean and median intakes of vitamin E are above the recommended intakes for all age groups. No age group reaches the recommended intake at P5, and 9- and 13-year-old boys and 9-year-old girls do not reach the recommended intake at P25 from diet alone. Because the tolerable upper intake level for supplemental vitamin E for adults is 300 mg/day, none of the suggested amendments of the maximum limit in food supplements (to 15, 50, 100, 150, 200 and 300 mg/day) will lead to exceedance of this upper level in adults. In 13year-olds supplements with 300 mg/day vitamin E will lead to exceedance of the upper level. In 9-year-olds supplements with 200 mg/day vitamin E will lead to exceedance of the upper level. In 4- and 2-year-olds supplements with 150 mg/day vitamin E will lead to exceedance of the upper level. Vitamin E intake from fortified products is not included in the calculations, but are however, evaluated to be very low.Item Assessment of Zinc Intake in Relation to Tolerable Upper Intake Levels(Science Domain International, 2018-09) Strand, Tor A.; Lillegaard, Inger Therese L.; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Holvik, Kristin; Løvik, Martinus; Skålhegg, Bjørn Steen; Stea, Tonje Holte; Iversen, Per OleThe Norwegian Food Safety Authority (NFSA, Mattilsynet) has requested the Norwegian Scientific Committee for Food Safety (VKM) to assess the intake of iron zinc in the Norwegian population in relation to tolerable upper intake levels (ULs). The existing maximum limit for zinc in food supplements is 25 mg/day. VKM has also conducted scenario calculations to illustrate the consequences of amending the maximum limit to 1, 2, 5, 10, 15 or 20 mg/day. Zinc is an essential trace element required for RNA, DNA and protein synthesis, cellular division, differentiation and growth (Mac Donald, 2000). Zinc is required for catalytic function in several enzymes and participates in all major biochemical pathways in the body. The function of the immune system depends on the ability of its cells to proliferate and differentiate, which is impaired in individuals with suboptimal zinc status (Barton et al. 2000). Due to its role in cell division and differentiation, adequate zinc nutrition is particularly important in children, and the requirements per kg body weight are highest in early life. The endogenous intestinal losses can vary from 7 mmol/day (0.5 mg/day) to more than 45 mmol/day (3 mg/day), depending on zinc intake (King and Turnlund, 1989). The requirements for zinc vary according to age and bioavailability. Several bioactive compounds in food such as tannins and phytic acids interact with zinc absorption and increase zinc requirements. The requirements vary twenty-fold according to life stage and diet. Zinc supplements, even at or slightly above the recommended intakes, can cause nausea and vomiting. The main concern with chronic zinc excess is, however, copper deficiency which is associated with several chronical illnesses. However, copper deficiency is uncommon due to the ubiquitous presence of copper in the diet. VKM proposes to use the ULs set by IOM (2001) as they provide values also for children and adolescents. The tolerable upper intake level set for adults is 40 mg zinc per day from food (and water) and supplements. Based on the scenario estimations, a dietary zinc intake at the 95th percentile and additionally 20 mg zinc from food supplements will lead to an intake close to the tolerable upper intake level established by IOM for adults. For adolescents and child populations the maximum amounts are 15 and 5 mg for 13- and 9-year-olds, respectively. For 2 and 4-yearolds, P95 from intake of zinc from food alone exceeds the UL.Item Comparison of Organic and Conventional Food and Food Production Part V: Human Health – Pesticide Residues(Science Domain International, 2019-02) Bjørge, Christine; Låg, Marit; Hetland, Ragna Bogen; Christiansen, Agnethe; Skrettberg, Lise; Andreassen, Åshild K.; Arukwe, Augustine; Bøe, Knut Egil; Bernhoft, Aksel; Eklo, Ole Martin; Grung, Merete; Haugen, Margaretha; Hemre, Gro Ingrunn; Klingen, Ingeborg; Källqvist, Torsten; Krogdahl, Åshild; Lassen, Jørgen F.; Næss, Bjørn; Ropstad, Erik; Skåre, Janneche Utne; Steffensen, Inger-Lise; Sundheim, Leif; Sverdrup, Line Emilie; Torrissen, Ole; Aelxander, JanThe present report is based on data from the 2010 EFSA Report on pesticide residues in food, the Norwegian monitoring programmes 2007-2012 and data from peer reviewed literature and governmental agencies. It is a challenge to perform quantitative estimates and comparative studies of residue levels due to large variation in the measured levels, and the large number of different pesticides present in the samples. Thus, the focus is on the frequency of observed contaminations in relation to regulatory limits and to present examples to illustrate the variation in residue values and number of detected substances. Pesticide residues in conventional and organic products: Of the 12,168 samples (plant- and animal products) in the 2010 EU-coordinated programme, 1.6% exceeded the respective maximum residue level (MRL) values, and 47.7% had measurable residues above the limit of quantification (LOQ), but below or at the MRL. Of the 1168 samples analysed in Norway in 2012 (from both imported and domestic products), 1.9% exceeded MRL and 53% contained measurable pesticide residues. Direct comparison of these values is however not possible, since they contain different types of food samples, and are analysed for a different number of pesticides. When organic and conventional samples from fruit, vegetables and other plant products in the 2010 EU-coordinated programme were compared, 4.2% of the conventional and 1.0% of the organic samples exceeded the MRL values, while 43.2% of the conventional and 10.8% of the organic samples had measurable residues below or at the MRL value. Most of the pesticide residues detected in organic samples are not permitted for use in organic farming. Of the 624 organic samples analysed in Norway 2007 - 2012, 0.2% (one sample) had residues exceeding MRL, while measurable residues were detected in 1.8% of the samples (11 samples). Conventional products were often found to contain different pesticides while most organic samples were found to contain few or only one type of pesticide. Lack of data on pesticide residue levels of organic samples in the EU-coordinated programme, and few Norwegian samples do not allow for a quantitative comparison of pesticide residue levels in organic and conventional samples. Comparative estimation of pesticide residues faces a number of challenges and uncertainties. However, it seems unquestionable based on available data that organic plant products contain fewer and substantially lower amounts of pesticide residues than conventional products. Health risk associated with pesticide residues: The general level of pesticide residues in both conventional and organic food is low, and well below what is likely to result in adverse health effects. This conclusion is based on the comparison of estimated dietary exposure with toxicological reference values i.e. acceptable daily intake (ADI) for chronic effects, and acute reference dose (ARfD) for acute effects. The finding of pesticide residues that exceeds established regulatory limits in a minority of tested samples is not considered to represent a health risk. When dietary exposure that was estimated in six different food commodities in the 2010 EUcoordinated programme was compared with their relevant reference values, EFSA concluded that for 79 of 18243 conventionally grown fruit and vegetable samples, a short-term acute consumer health risk could not be excluded. The conclusion was based on the exceeding of ARfD. None of these 79 samples were organic. It is important to also consider that the exceeding of the acute reference value only occurred in 0.4% of the samples and that the scenario used for acute intake assessment is conservative, suggesting that the toxicological implications are limited. This is also reflected in the chronic exposure assessment, where none of the samples were found to exceed the toxicological reference value ADI. Dietary exposure assessments on the basis of Norwegian samples of apples, tomatoes, carrots, strawberries and lettuce did not show an exceeding of any toxicological reference value. Combined exposure and cumulative risk assessment of pesticide residues: No generally accepted methodology is at present established for cumulative risk assessment of combined exposure to pesticide residues. Available data suggest however that combined exposure is not likely to result in increased human health risk.Item Evaluation of Tolerable Upper Intake Levels for Vitamin D in Children and Adolescents(Science Domain International, 2019-02) Haugen, Margaretha; Holvik, Kristin; Iversen, Per OleIn 2012, the European Food Safety Authority (EFSA) suggested a tolerable upper intake level (UL) for vitamin D at 100 µg/day for adults based on the risk of hypercalcaemia. EFSA concluded that consumption of up to 50 µg/day does not lead to hypercalcaemia in children and adolescents (10-17 years). Furthermore, EFSA stated that there is no reason to assume that children and adolescents in the phase of rapid bone formation and growth have a lower tolerance for vitamin D compared to adults, and a UL of 100 µg/day for adolescents aged 11-17 years and 50 µg/day in children 1-10 years, taking the smaller body size into account, was proposed. The Norwegian Food Safety Authority (NFSA) is currently revising the national regulation of maximum limits in food supplements (not yet harmonised in the European Economic Area (EEA)), including maximum limits for vitamin D. NFSA has therefore requested the Norwegian Scientific Committee for Food Safety (VKM) to evaluate the assumption in the EFSA opinion that children and adolescents can tolerate the same amount of vitamin D as adults due to rapid bone formation and growth. In children and adolescents with lower weight than adults, this assumption actually implies that adolescents can tolerate more vitamin D per kg body weight than adults. VKM is therefore requested to evaluate if there is scientific evidence that a UL at 50 µg/day for children (1-10 years) and 100 µg/day for adolescents (11-17 years) is safe. The present statement is prepared by members of the Panel on Nutrition, Dietetic Products and Novel Food and Allergy in VKM. Three literature searches were performed to find new relevant studies investigating high intakes of vitamin D in children and adolescents and the role of vitamin D in bone formation and growth. No studies supporting a higher tolerance to vitamin D in children and adolescents due to rapid bone formation and growth were retrieved in the literature search. Moreover, there is apparently no firm association between bone formation and vitamin D levels in children during their growth period into adolescence and adulthood. No studies investigating high intakes of vitamin D in children 1-10 years were found. Furthermore, no studies that have examined safety issues and/or adverse effects of vitamin D supplementation in doses above 50 µg/day in adolescents were identified. It can therefore not be concluded that the UL at 50 µg/day in children (1-10 years) and 100 µg/day in adolescents (11-17 years) is safe. In the 2002 report from European Scientific Committee on Food (SCF), a UL was set at 25 µg/day for children aged 2-10 years, and 50 µg/day for adolescents aged 11-17 years (corresponding to the UL for adults at that time). To the best of knowledge no serious, harmful effects have been reported for these doses of vitamin D.Item Risk Assessment of "Other Substances" – Conjugated Linoleic Acids(Science Domain International, 2018-12) Iversen, Per Ole; Frøyland, Livar; Haugen, Margaretha; Holvik, Kristin; Løvik, Martinus; Strand, Tor A.; Tell, Grethe S.The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis for regulating the addition of "other substances" to food supplements and other foods. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any potential beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of conjugated linoleic acids (CLAs), and is based on previous risk assessments of CLAs and articles retrieved from literature searches. According to information from the NFSA, CLAs are ingredients in food supplements sold in Norway, and NFSA has requested a risk assessment of the following doses of CLAs in food supplements: 3.0, 3.25 and 3.5 g/day. The daily intakes in Norway of CLAs range between 20 and 170 mg (MoBa 2008, version 4). The CLAs are mostly studied in overweight and obese subjects because of their claimed effects to reduce body weight. CLAs constitute a group of isomeric fatty acids mostly produced by bacterial fermentation in the gut. In the human diet, meat (mainly isomers c9,t11 and t10,c12) and dairy products (mainly isomer c9,t11) are main sources of CLAs. The various isomers may have different metabolic effects. In the food supplements evaluated by EFSA (EFSA, 2010 a; EFSA, 2010 b; EFSA, 2012), Clarinol® and Tonalin®, the t10,c12 and the c9,t11 isomers are present in about equal proportions. In research articles not all authors are consistent in reporting what they have studied, so in this report we sometimes do not distinguish between these isomers; hence they are referred collectively to as CLAs if it is not specified. Most of the cited studies have tested supplemental CLAs in doses of about 3.5 g/day, but ranging from 0.7 to 6.0 g/day. In most of the randomised controlled trials (RCTs) there have been no significant differences in adverse effects between the placebo and CLA-groups. Concerns about indications of an unfavourable effect on biomarkers of lipid- and carbohydrate metabolism in obese men with metabolic syndrome as well as unfavourable effect on antioxidant status; increased markers of oxidative stress after consumption of supplemental CLAs have been reported in previous studies. No clear dose-response effects have been found. It is concluded that supplemental CLAs may impair lipid- and carbohydrate metabolism in obese men with the metabolic syndrome. Intake of supplemental CLAs by lactating women may reduce fat content in breastmilk, and intake of supplemental CLAs by pregnant women may reduce birth weight and –length among their offsprings. Only one randomised controlled trial has included children (6-10 years). These children were all overweight or obese, subjects likely to have a different CLA-metabolism/-effect than normal-weight subjects. VKM considers that current data are too incomplete to evaluate any doses of CLAs for children and adolescents. There are few long-term studies, and adverse health effects were not primary outcomes in these studies. Based on available data no conclusions can be drawn for supplemental use of CLAs longer than six months. VKM concludes that: In adults (≥18 years), the specified doses 3.0, 3.25 and 3.5 g/day CLAs in food supplements are considered to be unlikely to cause adverse health effects if used for up to six months. CLA may cause lipid- and carbohydrate disturbances in obese men with metabolic syndrome as well as in overweight/obese subjects with type 2 diabetes. Use of CLA supplements in lactating and pregnant women may cause reduction in milk production and in the content on milk fat and cause decreased birth weight andlength in their off-springs. No conclusion can be made for children and adolescents. Data are insufficient to conclude regarding use of CLAs for more than six months.Item Risk Assessment of "Other Substances" – Creatine(Science Domain International, 2018-12) Iversen, Per Ole; Frøyland, Livar; Haugen, Margaretha; Holvik, Kristin; Løvik, Martinus; Skålhegg, Bjørn Steen; Stea, Tonje Holte; Strand, Tor A.; Tell, Grethe S.The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis for regulating the addition of "other substances" to food supplements and other foods. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/ or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any potential beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of creatine as food supplement, and is based on previous risk assessments and articles retrieved in literature searches. According to information from the Norwegian Food Safety Authority (NFSA), creatine is an ingredient in food supplements sold in Norway, and NFSA has requested a risk assessment of the following doses of creatine in food supplements: 3.0, 5.0, 10.0 and 24.0 g/day. The average daily intake from the diet is about 1 g creatine, and the endogenous production also amounts to about 1 g/day. Most of the creatine supplements are in the form of creatine monohydrate. Creatine is an organic acid occurring in the body as either phosphocreatine (2/3) or as free creatine (1/3). Phosphocreatine provides phosphate groups for synthesis of adenosine triphosphate, the major energy-providing compound in the body. Previous risk assessments (AESAN, 2012; EFSA, 2004; SCF, 2000; VKM, 2010) all concluded that creatine supplementation with 3.0 g/day is unlikely to cause adverse health effects in adults. This is supported by human and animal data obtained in a literature search and assessed in the present report. Most of the studies with daily creatine intake above 3 g often (i) involved few and highly trained individuals of whom some took high daily loading doses of creatine for a short period, and (ii) were designed to test clinical benefit without emphasis on possible adverse effects. VKM therefore considers that there is insufficient evidence to conclude regarding possible adverse effects at doses of creatine above 3 g/day for the general population. VKM concludes that: In adults (≥ 18 years) the specified dose of 3.0 g/day creatine in food supplements is considered unlikely to cause adverse health effects. The documentation for absence of adverse health effects of doses 5.0, 10.0 and 24.0 g/day creatine in food supplements in the general population is limited. Hence, these doses may represent risk of adverse health effects in adults. In children (10-14 years) and adolescents (14-17 years), the specified doses of 3.0, 5.0, 10.0 and 24.0 g/day creatine in food supplements may represent a risk of adverse health effects. Children below 10 years were not included in the terms of reference.Item Risk Assessment of "Other Substances" – Glycine(Science Domain International, 2018-12) Tell, Grethe S.; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Holvik, Kristin; Løvik, Martinus; Skålhegg, Bjørn Steen; Stea, Tonje Holte; Strand, Tor A.; Iversen, Per OleThe Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating "other substances" in food supplements. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/ or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. In this series of risk assessments of "other substances" VKM has not evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of specified doses of glycine in food supplements, and it is based on previous risk assessments and articles retrieved from two literature searches. Glycine is a non-essential amino acid which is synthesised from 3-phosphoglycerate via serine, or derived from threonine, choline and hydroxyproline via inter-organ metabolism involving primarily the liver and kidneys. Endogeneous synthesis is estimated to be in the magnitude of 8 g per day in adults. Glycine is a constituent of all proteins in the human body. It also functions as a neurotransmitter, and can play both stimulatory and depressant roles in the brain. Data on dietary intake of glycine in Norway are not available. Based on NHANES III (1988-1994), the overall mean intake of glycine from food and food supplements in the United States was 3.2 g per day. Thus, the combined dietary intake and endogenous synthesis is more than 11 g per day. Because glycine is not considered an essential amino acid, a dietary requirement in healthy humans has not been established. Foods rich in glycine are generally protein rich foods such as meat, fish, dairy products and legumes. According to information from NFSA, glycine is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of 20, 50, 100, 300, 500 and 650 mg/day of glycine from food supplements. There is a lack of relevant supplementation studies with glycine in humans designed to address adverse effects and/or dose-response relationship, and none of the previous reports reviewed concluded with a no observed adverse effect level (NOAEL). For the current risk assessment, two literature searches were conducted, one for human studies and one for animal studies. No human studies were found that can be used for suggesting a "value for comparison", and there are no scientific data in the published literature suitable for assessing the specific doses in the terms of reference. The value for comparison used in this risk characterisation is 20 mg/kg per day. This value is derived from a study in rats in which the NOAEL was estimated at 2000 mg/kg per day. Using an uncertainty factor of 100, this corresponds to 20 mg/kg per day or 1.4 g per day for a person weighing 70 kg. This is more than twice as high as the highest dose for consideration in the present risk assessment, and it is far below the combined dietary intake and endogenous synthesis estimated at more than 11 g per day. No particular vulnerable groups for glycine supplements have been identified. VKM concludes that: In adults (≥18 years), the specified doses 20, 50, 100, 300, 500 and 650 mg/day of glycine from food supplements are unlikely to cause adverse health effects. In adolescents (14 to <18 years), the specified doses 20, 50, 100, 300, 500 and 650 mg/day of glycine from food supplements are unlikely to cause adverse health effects. In children (10 to <14 years), the specified doses 20, 50, 100, 300, 500 and 650 mg/day of glycine from food supplements are unlikely to cause adverse health effects. Children younger than 10 years were not within the scope of the present risk assessment.Item Risk Assessment of "Other Substances" – L-alanine(Science Domain International, 2018-10) Holvik, Kristin; Frøyland, Livar; Haugen, Margaretha; Henjum, Sigrun; Løvik, Martinus; Stea, Tonje Holte; Strand, Tor A.The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating "other substances" in food supplements. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/ or physiological e ffect . It is added mainly to food supplements, but also to energy drinks and other foods. In this series of risk assessments of "other substances" the VKM has not evaluated any claimed beneficial effects from these substances, only possible adverse effects. For the current report VKM has studied previous risk assessments and performed two systematic literature searches for any published studies assessing negative health effects of L-alanine in humans or animals. According to information from NFSA, L-alanine is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of L-alanine: 3500, 3750, 4000, 4250 and 4500 mg/day. Foods rich in alanine are generally protein rich foods such as meat, dairy products, legumes, fish, nuts, seeds, eggs and whole grains. Based on NHANES III (19881994), the overall mean intake of L-alanine from food and food supplements in the United States was 3.6 g/day. L-alanine is a naturally occurring non-essential α-amino acid belonging to the group of the 20 amino acids that are normal components of food proteins. L-alanine acts as an intermediary between protein catabolism and carbohydrate synthesis. It can be easily synthesised from the alpha keto acid pyruvate and has close links to several metabolic pathways including glycolysis, gluconeogenesis, and the citric acid cycle. Together with lactate it is capable of generating glucose from muscle protein through gluconeogenesis in the liver. Alanine thus plays a central role in the metabolism of muscle protein and is a key factor in nitrogen metabolism. Previous reports from the US Institute of Medicine (IOM) 2005, the French Food Safety Agency (AFSSA) 2007 and the Spanish Agency for Food Safety and Nutrition (AESAN) 2012 did not conclude regarding safe doses of L-alanine, but stated that data on adverse effects of L-alanine intake from supplements were not sufficient for a dose-response assessment and establishment of a tolerable upper intake level. Few studies have assessed health effects of L-alanine supplementation in humans, and these were generally not designed to evaluate potential harmful effects of L-alanine. Most human experimental studies gave single doses (up to 50 g) or short-term loading doses (e.g. 25 to 45 g/hour during exercise) to study metabolic responses such as ergogenic effects during exercise or prevention of ketosis after fasting. Adverse health effects were not reported except for abdominal discomfort and stomach cramps, nausea and diarrhea after consuming high doses. No studies assessed long-term effects of L-alanine supplementation, and no studies gave doses comparable to the doses under consideration in the present report. Only one dose-reponse toxicity study in rodents has been found (Chow et al., 1976). In that study, growing Wistar rats were fed up to 20% DL-alanine (a racemic mixture of D- and Lalanine) in their basal diet for 26 weeks, with no effect on liver and kidney weight and no pathological changes in any organs. The study was taken into account due to the otherwise scarce literature on L-alanine toxicity, and could be used since there were no adverse effects at the highest dose tested. The no observed adverse effect level (NOAEL) in mg L-alanine per kg body weight per day was not stated. VKM has therefore estimated the NOAEL using information about average reported feed consumption and average body weights of the animals, and divided by 2 to obtain a NOAEL for L-alanine, arriving at approximately 6450 mg/kg bw/day in male rats and 9700 mg/kg bw/day in female rats. A standard toxicological approach dividing by an uncertainty factor (UF) of 10 for between-species variation and an additional UF of 10 for within-species variation gives the value of 64.5 mg/kg bw per day in females and 97.0 mg/kg bw per day in males, corresponding to approximately 4500 mg/day and 6800 mg/day for a 70 kg man and woman, respectively. VKM also calculated the margins of exposure (MOE) between the estimated NOAEL and the estimated daily exposures from the five supplement doses given by the NFSA (based on default average body weights for the age groups). MOE were 100 or higher for all five doses in adults. For adolescents 14 to <18 years, the MOE was 88 for the highest dose under consideration. For children 10 to <14 years, MOE ranged from 62 for the highest dose to 80 for the lowest dose. The VKM considers that these margins are relatively high and are acceptable based on the following considerations: The highest dose tested in growing rats did not cause adverse effects, implying that the “true” NOAEL is unknown and could be considerably higher. Furthermore, L-alanine is a nutrient participating in normal energy metabolism as a substrate for glucose. It is consumed in the magnitude of 3 to 4 g/day on average in the habitual diet, and it has not been associated with harmful effects in humans beyond gastrointestinal effects when consuming very high single doses (50 g, or at a consumption rate of 30 to 45 grams per hour during exercise). VKM concludes that: In adults (≥18 years), the specified doses 3500, 3750, 4000, 4250 and 4500 mg/day L-alanine in food supplements are unlikely to cause adverse health effects. In adolescents (14 to <18 years), the specified doses 3500, 3750, 4000, 4250 and 4500 mg/day L-alanine in food supplements are unlikely to cause adverse health effects. In children (10 to <14 years), the specified doses 3500, 3750, 4000, 4250 and 4500 mg/day L-alanine in food supplements are unlikely to cause adverse health effects. Children younger than 10 years were not within the scope of the present risk assessment.