Upper Intake Level Research Articles

Guidance for establishing and applying tolerable upper intake levels for vitamins and essential minerals.

Vitamins and essential minerals are micronutrients that are required for the normal functioning of the human body. However, they may lead to adverse health effects if consumed in excess. A tolerable upper intake level (UL) is a science-based reference value that supports policy-makers and other relevant actors in managing the risks of excess nutrient intake. EFSA's principles for establishing ULs for vitamins and minerals were originally developed by the Scientific Committee on Food in 2000. This guidance from the EFSA Panel on Nutrition, Novel Foods and Food Allergens provides an updated framework for UL assessments. A draft was published in 2022 and underwent a 2-year piloting period. The present document incorporates revisions based on the experience gained through its practical implementation. It covers aspects related to the planning of the risk assessment (problem formulation and definition of methods) and its implementation (evidence retrieval, appraisal, synthesis, integration, uncertainty analysis). As in the previous framework, the general principles developed for the risk assessment of chemicals in food are applied, i.e. hazard identification, hazard characterisation, intake assessment, risk characterisation. Specific to nutrients are their biochemical and physiological roles and the specific and selective mechanisms that maintain the systemic homeostasis and accumulation of the nutrient in the body. Such considerations must also be taken into account when conducting risk assessments of nutrients.

The tolerable upper intake level of manganese alleviates Parkinson-like motor performance and neuronal loss by activating mitophagy

Manganese (Mn2+) is among the indispensable trace elements required by the human body, but high-dose Mn2+ exposure can lead to Mn poisoning. Therefore, the tolerable upper intake level (UL) for Mn2+ has been established for normal individuals in different countries. However, whether the UL of Mn2+ is suitable for the patients of Parkinson's disease (PD) is unclear.Here, we found unexpectedly that the dietary UL of Mn2+ supplement enhanced mitophagy through the PINK1/parkin-mediated ubiquitin-dependent pathway in MPTP- induced mice and cells. Mn2+ promoted mitochondrial biogenesis and dynamics, thereby increased the activity of the mitochondrial respiratory chain with restored mitochondrial function. Additionally, Mn2+ directly elevated the activity of mitochondrial superoxide dismutase (MnSOD), which contributed to the clearance of reactive oxygen species (ROS), restored dopaminergic and motor functions in the MPTP-induced PD mouse model. Similar results were also observed in SH-SY5Y cells, whereas knockdown parkin using siRNA or application of mitophagy inhibitors (Mdivi-1 or cyclosporine A), abolished the neuroprotective effects of Mn2+.These findings demonstrate that the dietary UL of Mn2+ is protective for the MPTP-induced Parkinson-like lesions with the mechanisms involving the activation of mitophagy, suggesting potential intervention of PD by moderately increasing dietary Mn2+ intake.

The Potential for Bouillon Fortification to Reduce Dietary Micronutrient Inadequacy: Modeling Analyses Using National Survey Data from Cameroon, Ghana, and Haiti

BackgroundBouillon is commonly consumed in some countries where micronutrient deficiencies are prevalent, but it has not been widely adopted as a micronutrient fortification vehicle. ObjectivesWe modeled the potential impacts of bouillon fortification on dietary micronutrient adequacy to inform future discussions around bouillon fortification programs. MethodsWe analyzed the dietary intake of women of reproductive age (WRA) and 1- to 5-y-old children from a national dietary survey in Cameroon, and “apparent intake” (using the nutrient density approach) of WRA, children, and men from 3 household surveys in Cameroon, Ghana, and Haiti. We examined (apparent) intake of bouillon and simulated the impacts of bouillon fortification with varying levels of vitamin A, folic acid, vitamin B12, iron, and zinc on inadequate intake (below the estimated average requirement) and intake above the tolerable upper intake level (UL). Scenarios accounted for current mandatory fortification programs and different assumptions about iron absorption from bouillon. ResultsBouillon was consumed by >67% of households in Ghana and >90% in Haiti and Cameroon. Median (apparent) consumption ranged from 1.6 to 2.1 g/d for WRA, 0.7 to 1.0 g/d for children, and 1.8 to 2.2 g/d for men. Bouillon fortification at the highest micronutrient concentration modeled was predicted to reduce dietary inadequacy by 21–52 percentage points (pp) for vitamin A; 3–47pp for folic acid, and 4–90pp for vitamin B12, depending on the country and population group. In contrast, predicted impacts for iron were modest (2–17pp reduction) but would increase if absorption of iron from bouillon were enhanced. Simulated zinc fortification reduced inadequacy by 12–50pp, but zinc intake above the UL exceeded 10% among children in almost all scenarios. ConclusionsModeling indicates that bouillon fortification could improve dietary micronutrient adequacy beyond existing fortification programs. Further work is needed to identify fortification levels that meet criteria for nutritional benefit, technical and commercial feasibility, affordability, and cost-effectiveness.

Contribution of fortified foods and dietary supplements to total nutrient intakes and their adequacy in Japanese adults

BackgroundThis study examined how fortified foods and dietary supplements contributed to total nutrient intakes and their adequacy in Japanese adults.MethodsNutrient intake was estimated from 4-day dietary records of 392 adults (20–69 years) in total intake considering intakes from fortified foods and dietary supplements and in base diets without considering their intake. Users were defined as participants who used at least one fortified foods and/or dietary supplements during the 4-day recording period. The proportion of participants whose intake was below the Estimated Average Requirements (EAR) or exceeded the Tolerable Upper Intake Level (UL) provided in the Dietary Reference Intakes for Japanese was calculated.ResultsIn 122 identified users (31% of participants) of fortified foods and/or dietary supplements, the mean contributions of fortified foods and dietary supplements to total intake were < 4% and < 21%, respectively, for all 25 examined nutrients. Users were more likely to meet the EAR than non-users for six nutrients in the base diets and nine nutrients in the total intake. Among the users, the prevalence of participants below the EAR decreased by ≥ 10% in the total intake compared with the base diet for five nutrients. No nutrient intake from the base diet exceeded the UL in users and non-users; however, vitamin B6 intake in 2% of users exceeded the UL of their total intake.ConclusionAlthough the users of fortified foods and/or dietary supplements had better nutrient intake than non-users in base diets, fortified foods and dietary supplements helped the Japanese users achieve adequate intakes of certain nutrients without a risk of excessive intake (except for vitamin B6).

Scientific opinion on the tolerable upper intake level for vitamin E.

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the revision of the tolerable upper intake level (UL) for vitamin E. As α-tocopherol is recognised as the only essential form of vitamin E, the Panel restricted its evaluation to α-tocopherol. Systematic reviews of the literature were conducted to assess evidence on priority adverse health effects of excess intake of vitamin E, namely risk of impaired coagulation and bleeding, cardiovascular disease and prostate cancer. The effect on blood clotting and associated increased risk of bleeding is considered as the critical effect to establish an UL for vitamin E. No new evidence has been published that could improve the characterisation of a dose-response. The ULs for vitamin E from all dietary sources, which were previously established by the Scientific Committee on Food, are retained for all population groups, i.e. 300 mg/day for adults, including pregnant and lactating women, 100 mg/day for children aged 1-3 years, 120 mg/day for 4-6 years, 160 mg/day for 7-10 years, 220 mg/day for 11-14 years and 260 mg/day for 15-17 years. A UL of 50 mg/day is established for infants aged 4-6 months and a UL of 60 mg/day for infants aged 7-11 months. ULs apply to all stereoisomeric forms of α-tocopherol. ULs do not apply to individuals receiving anticoagulant or antiplatelet medications (e.g. aspirin), to patients on secondary prevention for CVD or to patients with vitamin K malabsorption syndromes. It is unlikely that the ULs for vitamin E are exceeded in European populations, except for regular users of food supplements containing high doses of vitamin E.

Zinc Toxicity: Understanding the Limits.

Zinc, a vital trace element, holds significant importance in numerous physiological processes within the body. It participates in over 300 enzymatic reactions, metabolic functions, regulation of gene expression, apoptosis and immune modulation, thereby demonstrating its essential role in maintaining overall health and well-being. While zinc deficiency is associated with significant health risks, an excess of this trace element can also lead to harmful effects. According to the World Health Organization (WHO), 6.7 to 15 mg per day are referred to be the dietary reference value. An excess of the recommended daily intake may result in symptoms such as anemia, neutropenia and zinc-induced copper deficiency. The European Food Safety Authority (EFSA) defines the tolerable upper intake level (UL) as 25 mg per day, whereas the Food and Drug Administration (FDA) allows 40 mg per day. This review will summarize the current knowledge regarding the calculation of UL and other health risks associated with zinc. For example, zinc intake is not limited to oral consumption; other routes, such as inhalation or topical application, may also pose risks of zinc intoxication.

Scientific opinion on the tolerable upper intake level for preformed vitamin A and β‐carotene

Abstract Following two requests from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the revision of the tolerable upper intake level (UL) for preformed vitamin A and β‐carotene. Systematic reviews of the literature were conducted for priority adverse health effects of excess vitamin A intake, namely teratogenicity, hepatotoxicity and endpoints related to bone health. Available data did not allow to address whether β‐carotene could potentiate preformed vitamin A toxicity. Teratogenicity was selected as the critical effect on which to base the UL for preformed vitamin A. The Panel proposes to retain the UL for preformed vitamin A of 3000 μg RE/day for adults. This UL applies to men and women, including women of child‐bearing age, pregnant and lactating women and post‐menopausal women. This value was scaled down to other population groups using allometric scaling (body weight0.75), leading to ULs between 600 μg RE/day (infants 4–11 months) and 2600 μg RE/day (adolescents 15–17 years). Based on available intake data, European populations are unlikely to exceed the UL for preformed vitamin A if consumption of liver, offal and products thereof is limited to once per month or less. Women who are planning to become pregnant or who are pregnant are advised not to consume liver products. Lung cancer risk was selected as the critical effect of excess supplemental β‐carotene. The available data were not sufficient and suitable to characterise a dose–response relationship and identify a reference point; therefore, no UL could be established. There is no indication that β‐carotene intake from the background diet is associated with adverse health effects. Smokers should avoid consuming food supplements containing β‐carotene. The use of supplemental β‐carotene by the general population should be limited to the purpose of meeting vitamin A requirements.

Scientific opinion on the tolerable upper intake level for iron.

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the tolerable upper intake level (UL) for iron. Systematic reviews were conducted to identify evidence regarding high iron intakes and risk of chronic diseases, adverse gastrointestinal effects and adverse effects of iron supplementation in infancy, young childhood and pregnancy. It is established that systemic iron overload leads to organ toxicity, but no UL could be established. The only indicator for which a dose-response could be established was black stools, which reflect the presence of large amounts of unabsorbed iron in the gut. This is a conservative endpoint among the chain of events that may lead to systemic iron overload but is not adverse per se. Based on interventions in which black stools did not occur at supplemental iron intakes of 20-25 mg/day (added to a background intake of 15 mg/day), a safe level of intake for iron of 40 mg/day for adults (including pregnant and lactating women) was established. Using allometric scaling (body weight0.75), this value was scaled down to children and adolescents and safe levels of intakes between 10 mg/day (1-3 years) and 35 mg/day (15-17 years) were derived. For infants 7-11 months of age who have a higher iron requirement than young children, allometric scaling was applied to the supplemental iron intakes (i.e. 25 mg/day) and resulted in a safe level of supplemental iron intake of 5 mg/day. This value was extended to 4-6 month-old infants and refers to iron intakes from fortified foods and food supplements, not from infant and follow-on formulae. The application of the safe level of intake is more limited than a UL because the intake level at which the risk of adverse effects starts to increase is not defined.

Comparison study of the new national standard infant formula and dietary reference intakes 2023

To compare the relationship between the nutrient limit in new national standard Infant Formula(GB 10765-2021)(New GB)and the corresponding nutrients in Dietary Reference Intakes for China 2023(DRIs 2023), to determine the scientific and reasonable base of each nutrient in New GB, and provide supports for future revision of it. Using a data conversion method, the adequate intake(AI) of each nutrient recommended by DRIs 2023 for infants aged 0-6 months and the nutrient limit in the New GB were input into the Excel table. Based on authoritative data on the representative weight of 0-6 month infants and the recommended energy values, the conversion was done, the ratio of the lower limit of each nutrient in New GB and the AI of corresponding nutrient, as well as the ratio of the upper limit of nutrients in New GB and their tolerable upper intake level(UL) were calculated. For most nutrients in New GB for infant formula, the ratio of the lower limit to their AI is close to 1. For those nutrients with a large ratio of the lower limit to AI, or with a ratio of the upper limit to UL were greater than 1, detail analysis was conducted. Based on DRIs 2023, the nutrient limit for each nutrient in New GB for infant formula was scientific and reasonable. For some nutrients with a large ratio, more studies should be done in the future to determine whether the limit in National Standard need to be adjusted.

Trace elements in bean-to-bar chocolates from Brazil and Ecuador

BackgroundThe high quality and unique flavor and aroma of bean-to-bar chocolates have resulted in an increase in the consumption of these products. Nevertheless, cocoa beans may present inorganic contaminants from environmental and anthropogenic sources which can contribute to contamination of the chocolates, despite the fewer processing steps and few ingredients used in bean-to-bar manufacturing process compared to the industrial one. Therefore, this study aimed to evaluate the content of trace elements (As, Cd, Co, Cu, Hg, Pb, Se) in bean-to-bar chocolates and traceable cocoa beans from Brazil and Ecuador. MethodsBean-to-bar chocolate samples were acquired in Brazil (n=65) and Ecuador (n=10), considering the main products available: white, milk, semisweet and dark chocolate. Cocoa samples from dedicated farms (n=23) were analyzed for trace elements and inorganic contaminants regulated by Brazil and European agencies. Samples were mineralized using acid digestion (nitric acid and hydrogen peroxide) in a closed microwave-assisted system. Quantification of trace elements was performed using Inductively coupled plasma mass spectroscopy (ICP-MS) and Inductively coupled plasma optical emission spectroscopy (ICP OES) in optimized conditions. The analytical control was performed with certified reference materials (ERM BD512 - Dark Chocolate, Tort-2 and Tort-3 - Lobster Hepatopancreas and SRM 1547 - Peach leaves) and recoveries ranged between 84% and 105% for all elements. ResultsThe trace element levels in the bean-to-bar chocolates were (mg/kg): As (<0.022–0.023), Cd (<0.002–0.74), Cu (0.11–21.2), Co (<0.003–1.88), Hg (<0.010-<0.010), Pb (<0.007–0.22), and Se (<0.029–0.35). The exposure assessment from inorganic contaminants in chocolates revealed up to 93% of provisional tolerable monthly intake (PTMI) for Cd and 123% of tolerable upper intake level (UL) for Co for children. Inorganic contaminants were also analyzed in cocoa beans from dedicated farms and Cd and Pb levels were found above the thresholds established by Brazil health agency. ConclusionThe results observed for both bean-to-bar chocolates and raw materials (cocoa beans from dedicated farms) indicated a need for monitoring these trace elements.

Scientific opinion on the tolerable upper intake level for manganese.

Following a request from the European Commission (EC), the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the tolerable upper intake level (UL) for manganese. Systematic reviews of the literature of human and animal data were conducted to assess evidence regarding excess manganese intake (including authorised manganese salts) and the priority adverse health effect, i.e. manganese-induced neurotoxicity. Available human and animal studies support neurotoxicity as a critical effect, however, data are not sufficient and suitable to characterise a dose-response relationship and identify a reference point for manganese-induced neurotoxicity. In the absence of adequate data to establish an UL, estimated background dietary intakes (i.e. manganese intakes from natural dietary sources only) observed among high consumers (95th percentile) were used to provide an indication of the highest level of intake where there is reasonable confidence on the absence of adverse effects. A safe level of intake of 8 mg/day was established for adults ≥ 18 years (including pregnant and lactating women) and ranged between 2 and 7 mg/day for other population groups. The application of the safe level of intake is more limited than an UL because the intake level at which the risk of adverse effects starts to increase is not defined.

SAT261 Hypervitaminosis A With Hypercalcemia Without Overtly Excessive Vitamin A Intake

Abstract Disclosure: C. Chiou: None. B. Greck: None. Background: Hypervitaminosis A (hypervitA) is an uncommon cause of hypercalcemia and is due to excessive intake of preformed vitamin A (vitA), i.e., retinoids, especially in emulsified form, a common preparation in supplement. In contrast, provitamin (carotenoids) does not cause hypervitA due to limit in absorption and conversion to vitA. The tolerable upper intake level (UL) and recommended dietary allowance (RDA) of vitA for adult are 3000 and 700 (female) - 900 (male) mcg retinoid activity equivalent (RAE) respectively. While daily intake of vitA &amp;gt; UL carries risk of chronic toxicity, there are reports of hypervitA with chronic intake of vitA below UL. VitA is mainly stored in hepatic stellate cells (HSC). Liver injury can induce HSC to transform, releasing vitA, and losing capacity of vitA storage. Renal insufficiency is known with higher vitA levels in blood. Potentially, the threshold of vitA toxicity from supplement is much less in conditions with hepatic and/or renal disease. Here we report a case without history of excessive vitA intake developed hypervitA in relatively short period of time after hospitalization while in the acute and long-term care unit. Clinical Case: A 57-year male was hospitalized for alcohol related pancreatitis. It was complicated by sepsis, multi-organ failure requiring respirator, parenteral nutrition and/or tube feeding. Mild hypercalcemia was noted 4 weeks after admission, initially intermittently, then persistently and progressively higher, peak of 12.6 mg/dL at 4 months after admission. Prior calcium levels were low or normal up to 6 years before admission. Evaluation of hypercalcemia found low i-PTH, low 1,25-D, hypercalciuria, negative serum protein electrophoresis, and normal PTH-related protein. VitA was surprisingly elevated at 137 [38-98] mcg/dL. Nutritional intake was reviewed. No history of excessive vitA intake. Patient was on total parenteral nutrition (TPN) and/or tube feeding most of time, the range and average of daily preformed vitA supplement from admission to onset of hypercalcemia were 0-1309 and 1006 mcg RAE respectively; while from onset to peak of hypercalcemia, 0-3327 and 1891 mcg RAE respectively. The maximal daily preformed vitA via TPN is 1000 mcg RAE. All preformed vitA in tube feeding is from original formula without extra addition. After discovery of hypervitA, feeding formula was changed to one containing much less preformed vitA, and hypercalcemia slowly improved. Conclusion: HypervitA can develop relatively easily with tube feeding and/or parenteral nutrition with average daily preformed vitA above RDA but way below UL in a susceptible patient. In patients with liver disease and/or renal insufficiency, careful selection of feeding formula and/or nutritional supplement regarding content of preformed vitA, and alert to potential development of hypervitA are advisable. Presentation: Saturday, June 17, 2023

A Mixed Model Approach for Estimating the Optimal Food Fortification of Vitamin D: Experiment Based on Mashhad Cohort Study in Iran.

Vitamin D deficiency is a prevalent problem in worldwide healthcare related to several system disorders. Food fortification as a solution is associated with several challenges including insufficient coverage of the entire population, required degree of fortification, the vehicles used for fortification and potential toxicity. This study aimed to determine the optimal amount of vitamin D for fortification without surpassing the upper intake level (UL) of intake at the 95th percentile of the Iranian population and compare two methods of food fortification. This study is aimed to develop a model of two different fortifying approaches related to an available dataset called MASHAD cohort study. The dataset comprised demographic and nutritional data of 9704 Iranian individuals living in the Greater Mashhad region. The first approach was a computational method necessary to implement a range of eight foods and calculate the optimal approach. In the second case, we used the European formula method called ILSI. To find the appropriate value for fortification, we calculated the consumption of 400 IU and 1000 IU supplements of vitamin D. Three micrograms per 100 g in each food was the optimal output. We also used Flynn and Rasmussen's formula on our data. Using these methods, we found that 2.1 micrograms per 100 kcal provides the best result. Hence, using the two different approaches, the results appear to be consistent and promising. One interesting finding was that supplement consumption did not greatly affect the impact of fortification. This observation may support the hypothesis to determine the amount of fortification, and we can ignore the study population's supplement consumption.

Association between dietary vitamin intake and mortality in US adults with diabetes: A prospective cohort study.

To explore the association of dietary vitamin intake from food and/or supplement with mortality in US adults with diabetes. This prospective cohort study was conducted on 5418 US adults with diabetes from the National Health and Nutrition Examination Survey 1999-2018. Vitamin intake from food and supplements was estimated via dietary recall. Sufficient intake from food or food+supplement was defined as≥estimated average requirement (EAR) and≤tolerable upper intake level (UL), insufficient intake, <EAR; and excess intake, >UL. Medium supplementary intake was classified as>median level and ≤75th percentile; low intake,≤median level; and high intake, >75th percentile, as reported by supplement users. A total of 1601 deaths occurred among the participants over a median follow-up of 11.0years. Cox regression analysis of the single-vitamin model demonstrated that sufficient vitamin A and folate intake from food and food+supplement and medium vitamin A and folate intake from supplement; sufficient riboflavin, niacin, and vitamin B6 intake from food and food+supplement; and sufficient thiamin and vitamin E intake from food+supplement were significantly associated with reduced all-cause mortality (all p<0.05). In the multivitamin model, sufficient vitamin A and folate intake from food and food+supplement, medium vitamin A and folate intake from the supplement, and sufficient niacin intake from food and food+supplement were inversely associated with mortality (all p<0.05). Vitamin A and folate intake from food or supplement and niacin intake from food were significantly associated with reduced mortality in US adults with diabetes.

Iodine Nutrition in Children ≤2 years of Age in Norway

BackgroundAs a component of the thyroid hormones (THs), iodine is vital for normal neurodevelopment during early life. However, both deficient and excess iodine may affect TH production, and data on iodine status in young children are scarce. ObjectivesTo describe iodine nutrition (iodine status and intake) in children ≤2 y of age in Innlandet County (Norway) and to describe the associations with maternal iodine nutrition. MethodsA cross-sectional study was performed in a representative sample of mother–child pairs selected from 30 municipalities from November 2020 until October 2021. Iodine status [child urinary iodine concentration (UIC), maternal UIC, and breast milk iodine concentration (BMIC)] was measured. Child’s iodine intake was estimated using 2 24-h dietary recalls (24-HR) and a food frequency questionnaire. The Multiple Source Method was used to estimate the usual iodine intake distributions from the 24-HR assessments. ResultsThe median UIC in 333 children was 145 μg/L, indicating adequate iodine status according to the WHO cutoff (100 μg/L). The median usual iodine intake was 83 μg/d. Furthermore, 35% had suboptimal usual iodine intakes [below the proposed Estimated average requirement (72 μg/d)], whereas <1% had excessive usual iodine intakes [above the Upper intake level (200 μg/d)]. There was a positive correlation between children’s iodine intake and BMIC (Spearman rank correlation coefficient r = 0.67, P < 0.001), and between children’s UIC and BMIC (r = 0.43, P < 0.001), maternal UIC (r = 0.23, P = 0.001), and maternal iodine intake (r = 0.20, P = 0.004). ConclusionDespite a median UIC above the cutoff for iodine sufficiency, more than a third of the children had suboptimal usual iodine intakes. Our findings suggest that many children will benefit from iodine fortification and that risk of iodine excess in this age group is low.

Perspective: Call for Re-evaluation of the Tolerable Upper Intake Level for Magnesium Supplementation in Adults.

In 1997, the US Institute of Medicine (IOM) dietary reference intakes (DRI) Committee established a magnesium (Mg) tolerable upper intake level (UL) for adults of 350 mg/d from supplemental intake alone. Diarrhea was the limiting factor. The safety of oral Mg dietary supplements exceeding the UL is currently in debate. Increasing the UL may result in more Mg supplementation, decreasing the prevalence of undernutrition for this nutrient and thus providing additional protection against numerous chronic diseases. This perspective aims to show that more recent and comprehensive evidence-based data on the occurrence of diarrhea indicate that the Mg UL for adults should be re-evaluated. To update the literature base to re-evaluate setting the Mg UL, a PubMed search was conducted to identify intervention studies published between 1997 and 2022 that used single-ingredient Mg products reporting a priori diarrhea adverse events among adults. The Food and Drug Administration Center for Food Safety and Adverse Event Reporting System (CAERS) was also searched for adverse events caused by Mg supplementation. The PubMed search identified 10 studies, including 5 meta-analyses and 5 randomized controlled trials, that met the search criteria. Seven studies (Mg intakes of 128-1200 mg/d) found no significant differences in diarrhea occurrence between the intervention and control groups. One meta-analysis found only minor differences in gastrointestinal disturbances between groups given placebo versus 520 mg Mg/d, but withdrawals were not significantly different between groups. Another meta-analysis found that 3 of 13 studies (120-973 mg/d) reported diarrhea that led to study withdrawal, but the treatment arm was not specified in 2 studies. The CAERS search, when limited to single-ingredient suspect Mg products, found only 40 attributable cases of gastrointestinal adverse events. Only one-third of these 40 cases noted a complaint of diarrhea. These updated data indicate that doses above the current UL for Mg supplements can be consumed without adverse events.

Scientific opinion on the tolerable upper intake level for vitamin D, including the derivation of a conversion factor for calcidiol monohydrate.

Following two requests from the European Commission (EC), the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the revision of the tolerable upper intake level (UL) for vitamin D and to propose a conversion factor (CF) for calcidiol monohydrate into vitamin D3 for labelling purposes. Vitamin D refers to ergocalciferol (vitamin D2), cholecalciferol (vitamin D3), and calcidiol monohydrate. Systematic reviews of the literature were conducted to assess the relative bioavailability of calcidiol monohydrate versus vitamin D3 on serum 25(OH)D concentrations, and for priority adverse health effects of excess vitamin D intake, namely persistent hypercalcaemia/hypercalciuria and endpoints related to musculoskeletal health (i.e. falls, bone fractures, bone mass/density and indices thereof). Based on the available evidence, the Panel proposes a CF for calcidiol monohydrates of 2.5 for labelling purposes. Persistent hypercalciuria, which may be an earlier sign of excess vitamin D than persistent hypercalcaemia, is selected as the critical endpoint on which to base the UL for vitamin D. A lowest-observed-adverse-effect-level (LOAEL) of 250 μg/day is identified from two randomised controlled trials in humans, to which an uncertainty factor of 2.5 is applied to account for the absence of a no-observed-adverse-effect-level (NOAEL). A UL of 100 μg vitamin D equivalents (VDE)/day is established for adults (including pregnant and lactating women) and for adolescents aged 11-17 years, as there is no reason to believe that adolescents in the phase of rapid bone formation and growth have a lower tolerance for vitamin D compared to adults. For children aged 1-10 years, a UL of 50 μg VDE/day is established by considering their smaller body size. Based on available intake data, European populations are unlikely to exceed the UL, except for regular users of food supplements containing high doses of vitamin D.

Tolerable Upper Intake Level for Individual Amino Acids in Humans: A Narrative Review of Recent Clinical Studies.

Individual amino acids are widely popular as supplements because of various perceived and real health benefits. However, currently, there are no recommendations set by national health agencies for tolerable upper intake levels (UL) for amino acids because of a lack of well-conducted human dose-response trials. In the past decade, under the initiative of the International Council on Amino Acid Science, a nonprofit organization, a series of UL human clinical studies were conducted. The goal of this narrative review is to summarize the studies on 6 essential amino acids (leucine, tryptophan, methionine, lysine, histidine, and phenylalanine), 2 nonessential amino acids (arginine and serine), and 2 nonproteinogenic amino acids (ornithine and citrulline) and provide the first set of ULs. A brief background of the concept of the DRI framework of UL, the concept of UL for amino acids, and a perspective of the results are also provided. The data suggest that in relatively healthy adult individuals, the tested amino acids are well tolerated, and ULs, or the no-observed-adverse-effect-level (NOAEL), lowest-observed-adverse-effect-level (LOAEL), can be determined. The ULs were for leucine-young (35 g/d), tryptophan (4.5 g/d), and leucine-elderly (30 g/d); NOAEL and LOAEL for methionine at 3.2 and 6.4 g/d, respectively; NOAEL for arginine (30 g/d); NOAEL and LOAEL for lysine at 6 and 7.5 g/d, respectively; NOAEL and LOAEL for histidine at 8 and 12 g/d, respectively; and NOAEL for phenylalanine (12 g/d), serine (12 g/d), ornithine (12 g/d) and citrulline (24 g/d). This first set of human UL data are hoped to help national and international agencies set safety standards for supplemental amino acids.

Comparison of the Potential Relative Bioaccessibility of Zinc Supplements-In Vitro Studies.

The aim of this study was to determine the potential relative bioaccessibility of zinc (Zn) from selected dietary supplements during in vitro digestion. The bioaccessibility of Zn was evaluated in dietary supplements differing in the pharmaceutical form, content, dose, and chemical form of the element. The content of Zn was determined by flame atomic absorption spectrometry. The applied method was validated, and results were characterised by good linearity (R2 = 0.998), recovery (109%), and accuracy (0.02%). As a result of the tests conducted, it was found that the bioaccessibility of Zn from dietary supplements varied and ranged from 1.1% to 9.4%. The highest bioaccessibility was found for zinc diglycinate and the lowest for zinc sulphate. In 9 out of 10 tested dietary supplements, the determined Zn content was higher than the one declared by the producer (up to 161%). The estimated tolerable upper intake level (UL) was exceeded by five of the analysed dietary supplements (123-146%). The analysed dietary supplements were assessed in terms of compliance with the information contained on the product packaging, based on current Polish and European legal regulations. The qualitative assessment was performed according to the United States Pharmacopoeia (USP) guidelines.

The lack of evidence behind over-the-counter antioxidant supplements for male fertility patients: a scoping review.

What is the evidence for over-the-counter antioxidant supplements for male infertility? Less than half of over-the-counter antioxidant supplements for male fertility patients have been tested in a clinical trial, and the available clinical trials are generally of poor quality. The prevalence of male infertility is rising and, with this, the market for supplements claiming to improve male fertility is expanding. Up to now, there is limited data on the evidence for these over-the-counter supplements. Amazon, Google Shopping and other relevant shopping websites were searched on 24 June 2022 with the following terms: 'supplements', 'antioxidants', 'vitamins', AND 'male fertility', 'male infertility', 'male subfertility', 'fertility men', 'fertility man'. All supplements with a description of ingredients in English, Dutch, French, Spanish, or German were included. Subsequently, Pubmed and Google Scholar were searched for studies that included the supplements. Inclusion criteria were supplements with antioxidant properties, of which the main purpose was to improve male fertility. Included supplements must be available without a doctor's prescription. Supplements containing plant extracts were excluded, as well as supplements of which the content or dosage was not clear. The ingredients, dosage, price and health claims of the supplements were recorded. We assessed whether substances in the supplements exceeded the recommended dietary allowance (RDA) or tolerable upper intake level (UL). All clinical trials and animal studies investigating included supplements were selected for this review. Clinical trials were assessed for risk of bias with a risk of bias tool appropriate for the study design. There were 34 eligible antioxidant supplements found, containing 48 different active substances. The average price per 30 days was 53.10 US dollars. Most of the supplements (27/34, 79%) contained substances in a dosage exceeding the recommended daily allowance (RDA). All manufacturers of the supplements made health claims related to the improvement of sperm quality or male fertility. For 13 of the 34 supplements (38%), published clinical trials were available, and for one supplement, only an animal study was found. The overall quality of the included studies was poor. Only two supplements were tested in a good quality clinical trial. As a consequence of searching shopping websites, a comprehensive search strategy could not be formulated. Most supplements were excluded because they contained plant extracts or because supplement information was not available (in an appropriate language). This is the first review that gives an insight into the market of male fertility supplements as available to infertility patients and other men seeking to improve their fertility. Earlier reviews have focused only on supplements with published clinical trials. However, we show that more than half of the supplements have not been tested in a clinical trial. To our knowledge, this review is the first to assess the dosage of supplements in relation to the RDA. In agreement with the literature, we found that the evidence on male fertility supplements is generally of poor quality. This review should urge pharmaceutical companies to evaluate their products in randomized controlled trials in order to provide people with substantiated information. The research position of W.R.d.L. is funded by an unrestricted grant from Goodlife Pharma. W.R.d.L., K.F., and J.P.d.B. are in the research team of a clinical trial on Impryl®, one of the supplements included in this review. N/A.