What is the Tolerable Upper Intake Level for vitamin A

A The Tolerable UL for Vitamin D

The daily tolerable UL was established to discourage potentially dangerous self-medication [121]. The two main indicators of excess vitamin D include hypercalcemia, which can lead to calcification of soft tissues such as arteries (arteriosclerosis) and kidney (nephrocalcinosis), and hypercalciuria, which reflects the presence of excess serum calcium and could be damaging on its own. Kidney stones are sometimes raised as a concern when vitamin D intakes are increased. When incidence of kidney stones is reported from RCTs of vitamin D, there is usually calcium supplementation along with vitamin D, so it has been difficult to distinguish the cause [85]. A study of over 2000 participants who had blood 25(OH)D measured and reported, prospectively, on health outcomes. No statistically significant association between serum 25(OH)D and kidney stones was found. Serum 25(OH)D ranged between 50 and 250 nmol/L [132].

A risk assessment for vitamin D showed that based on an analysis of all published reports related to excess vitamin D ingestion up to 2007, doses of supplemental vitamin D3 ingested at levels below 10,000 IU/day were not associated with toxicity [133]. It is possible that intakes consistently above 50,000 IU/day could be linked to side effects including hypercalcemia [4].

UL values for infants 0–6 months and 6–12 months were set at 1000 and 1500 IU, respectively (Table 43.15). A no-observable-adverse-effect-level of 1800 IU was used to set these ULs as studies exist where high doses of vitamin D have produced hypercalcemia. An uncertainty factor (UF) of 1.8 was set for very young infants and a smaller UF for older infants indicting greater tolerance to vitamin D. For adults over 18 years, the committee concluded that 25(OH)D should not be above 125–150 nmol/L, and that using published data from a dosing study, determined that 4000 IU would not raise serum 25(OH)D above this threshold [4]. In that dosing study, Heaney et al. [16] gave cholecalciferol to subjects in doses up to 10,000 IU, and found no adverse effects in men treated for 5 months. The IOM indicated that attaining a 25(OH)D above 125 nmol/L had no potential benefit and possible (unknown) risk; therefore, the UL was set at 4000 IU which is an adjustment down from the 5000 IU that subjects ingested to reach 125 nmol/L with 5 months of dosing. For children, the committee chose to “scale down” the adult UL [4].

Table 43.15. Comparison of Safety Assessments for Vitamin D Based on Healthy and At-Risk Status

Organization and CriterionTolerable ULHealthy PopulationIOM, 20110–0.5 year   10000.5–1 year   15001–3 years    25004–8 years    30009–13 years   400014+ years    4000At-Risk PopulationEndocrine Society, 20110–0.5 year   20000.5–1 year   20001–3 years    40004–8 years    40009–13 years   400014+ years   10,000

Sources: From Institute of Medicine, Dietary Reference Intakes for Calcium and Vitamin D, National Academy Press, Washington, DC, 2011; M.F. Holick, N.C. Binkley, H.A. Bischoff-Ferrari, C.M. Gordon, D.A. Hanley, R.P. Heaney, M.H. Murad, C.M. Weaver, Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline, J. Clin. Endocrinol. Metab. 96 (2011) 1911–1930.

The Endocrine Society’s recommendations for UL values are higher than those of the IOM levels. The Endocrine Society uses these higher amounts, shown in Table 43.14, as they represent intakes that would be used in treatment regimens for those at high risk of vitamin D deficiency or insufficiency [51]. Unless a person is under a physician’s care, it would be prudent that the IOM values for ULs should be used as the highest safest intakes.

E Possible negative effects of dietary fiber on human health

As well as adequate TDF, also tolerable upper intake level has not been determined, yet. Potential adverse effect of high intakes of dietary fiber on mineral, vitamin, and carotenoid bioavailability has been documented (Greiner et al., 2006, 2009). The studies of effects of dietary fiber on mineral absorption were focused on the potential for the cell wall polysaccharides to act as weak cation exchangers and therefore have the capacity to bind divalent ions; moreover, they were focused on the extent of degree of their fermentability or accessibility to bacterial enzymes in the human colon (Southgate, 1987). The different affinity of dietary fiber to the formation of bonds with minerals can be predestinated from the miscellaneous chemical structures of plant cell wall polysaccharides included into the term of dietary fiber. Moreover, the extent of mineral bioavailability can depend on the presence of some antinutrients in high-fiber foods, such as oxalates, tannins, and phytates with adverse effect to mineral bioavailability (Harland, 1989; Kay, 1982). A dietary fiber–mineral–oxalate complex has been established as lowered mechanism to mineral bioavailability by binding of both oxalic acid and dietary fiber to mineral. The content of phytate in a meal has been considered as a negative factor on mineral uptake and bioavailability because of its inhibitory impairment of iron, zinc, calcium, magnesium, manganese, and copper absorption. The formation of insoluble mineral–phytate complexes at physiological pH values is regarded as the major reason for the insufficient mineral bioavailability (Afinah et al., 2010; Kumar et al., 2010). The stability and solubility of these complexes depend on the chemical forms and amounts of phytate presented in the diet, pH value, the individual cation, and the phytate to cation molar ratio and finally on the interaction with the other present compounds (Grases et al., 2001). pH is one of the major factors influencing the solubility of phytate complexes; nevertheless, its value is specific for individual minerals. Mostly, lower pH 4–5 causes the higher solubility of Ca2 +, Cd2 +, Zn2 +, and Cu2 + salts, while the Mg-phytate is soluble at acid pH up to pH 7.5. Finally, synergistic effects of different mineral cations may cause reduction of their bioavailability (Graf and Eaton, 1984; Greiner et al., 2006). In the presence of phytate and calcium, absorption of other minerals may be depressed by reason of insoluble complex formation (Kumar et al., 2010).

However, damaging effects of fiber on the mineral bioavailability have not been confirmed in all studies. Benefit effects of fermentable carbohydrates (e.g., inulin, resistant starch) on mineral absorption in rats were reported (Younes et al., 2001). Moreover, the combination of inulin and resistant starch in rat diet increased significantly the cecal-soluble Ca and Mg concentrations (Levrat et al., 1991).

The effects of lignification on the adsorption extent of mutagenic heterocyclic aromatic amines to fiber in the human intestine and colon were studied in vitro. These findings were reported by Funk et al. (2007), who indicated increase of adsorption of hydrophobic heterocyclic aromatic amines by increase of lignification degree in fiber, resulting in reduction of microbial fiber degradation. Nevertheless, shifts in pH and fermentation may somewhat reduce the adsorption of some hydrophobic heterocyclic aromatic amines during passage through the colon. In addition, consistent results were reported by Ta et al. (1999), who investigated effects of different dietary fibers on the binding capacity to pesticides, such as azinphosmethyl, chlorpropham, chlorothalonil, and permethrin under the same conditions as in the gastrointestinal tract. The most significant effect on pesticide solubility exerted lignin. Hemicellulose and cellulose have been found to bind permethrin and azinphosmethyl in the same extent as lignin, while the soluble fiber pectin had the lowest capacity to bind pesticides. Finally, diet supplementation with fiber could decrease the toxicity of food carcinogens such as pesticides and mechanism of this protective effect is the absorption and subsequently their excretion in the feces.

19.2.8.11 Boron (B)

No estimated average requirements or dietary reference intakes have been set for boron, only a tolerable upper intake level of 20 mg/day for individuals aged ≥19 years (Białek, Czauderna, Krajewska, & Przybylski, 2019). In humans, boron plays important roles in growth and maintenance of bone tissue, improvement of wound healing, and calcium metabolism (enhanced gut absorption of calcium, calcification). Boron acts together with vitamin D, calcium, and magnesium in bone metabolism. Boron has antiinflammatory effects, influences central nervous system functions, and helps regulate the hormones testosterone, estrogen, insulin, triiodothyronine, and thyroxine. It increases biological half-life and bioavailability of estradiol and vitamin D. Boron raises the abundance of antioxidant enzymes, such as superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and glucose-6-phosphate dehydrogenase. It also detoxifies reactive oxygen and nitrogen species and reduces lipid peroxidation and DNA damage (Białek et al., 2019).

In vascular plants, boron forms strong complexes with different molecules carrying cis-diol groups in appropriate spatial configurations and is essential for correct formation and stabilization of primary cell walls. Most authors consider the formation of borate diester cross links with two chains of rhamnogalacturonan-II is an essential function for growth, development, and reproduction in vascular plants (Wimmer et al., 2020). Animals lack the capacity to metabolize inorganic boron compounds (like boric acid or borates) into mono- or di-sugar–borate esters (e.g., glucose and fructose borate esters), bis-sucrose borate esters, sugar alcohol borate esters (sorbitol, mannitol), or pectic polysaccharide borate esters. In contrast, plants can convert inorganic boron into dietary sugar-borate ester complexes, which are the best chemical form for assimilation into cells. In general, plants have higher boron concentrations (from 0.1 to 0.6 mg B/100 g) than animal-based foods (from 0.01 to 0.06 mg/100 g) (Białek et al., 2019). Fresh fruits (e.g., avocado, apple, banana, and red grape), leafy vegetables, flowering heads (broccoli), dried fruits (plums, apricots, and raisins), seeds, and nuts (pecans, almonds, and hazelnuts) are primary natural dietary sources of fructoborate esters, mainly calcium fructoborate complex—an excellent source of soluble boron with many beneficial physiological properties (Gharibzahedi & Jafari, 2017).

Reference Values for Copper

Nutrient reference values for Cu have been established by scientific bodies. Table 1 shows recommended intakes and tolerable upper intake levels (UL) for Cu by life stage group established for North America (i.e., Canada and the United States) and the European Union. Depression in Cu status induces a number of quantifiable physiologic changes. Despite this, no single indicator was deemed sufficient for deriving the estimated average requirement (EAR) for Cu as part of the North American Dietary Reference Intakes due to inconsistencies in results from studies measuring similar biomarkers. For adults aged ≥ 19 years, four indicators were used to establish the EAR: serum Cu concentration, serum ceruloplasmin concentration, erythrocyte Cu/Zn superoxide dismutase (SOD1) activity, and platelet Cu concentration. The EAR for adults range from 0.7 to 1 mg day− 1 and the recommended dietary allowances (RDA) range from 0.9 to 1.3 mg day− 1. EAR and RDA are the same for males and females and these reference values are higher for pregnancy and lactation. It was determined that there were inadequate data to separately establish EAR for infants, children, and adolescents. For infants 0–12 months, adequate intakes were established based on mean Cu intake of infants fed with mainly human milk. For children and adolescents aged 1–18 years, the EAR were derived by extrapolation from the adult EAR. The European Union established population reference intakes that are slightly higher than the North American RDA.

Table 1. Reference values for coppera

Life stage groupNorth AmericabEuropean UnioncAI (mg day− 1)EAR (mg day− 1)RDA (mg day− 1)UL (mg day− 1)PRI (mg day− 1)UL (mg day− 1)0–6 months0.2–––––6–11 months––––0.3–7–12 months0.22–––––1–3 years–0.260.3410.414–6 years––––0.624–8 years–0.340.443––7–10 years––––0.739–13 years–0.540.75––11–14 years––––0.8414–18 years–0.6850.898––15–17 years––––1419–50 years–0.70.9101.1551–70 years–0.70.9101.15> 70 years–0.70.9101.1514–18 years (P)–0.785181.1–19–50 years (P)–0.81101.1–14–18 years (L)–0.9851.381.4–19–50 years (L)–11.3101.4–

There are limited data on the effects of high intakes of Cu in healthy people. Chronic high intakes of Cu result in the accumulation of Cu in the liver that can lead to liver damage. Acute ingestion of large amounts of Cu salts in drinking water has been reported to cause gastrointestinal symptoms; however, liver damage was selected as the more relevant endpoint to establish the UL for Cu. A no observed adverse effect level (NOAEL) of 10 mg day− 1 was established for adults based on data showing no liver injury in adults consuming 10 mg of supplemental Cu daily. North America applied an uncertainty factor (UF) of 1 to the NOAEL to derive a UL of 10 mg day− 1 because of the low prevalence of liver damage from Cu exposure in human populations with normal Cu homeostasis and other evidences indicating the absence of adverse effects with Cu intakes of 10–12 mg day− 1 from foods. The European Union set a more conservative UL of 5 mg day− 1, applying a UF of 2 to account for variability to Cu toxicity within the normal population. It was also concluded that the UL is not applicable during pregnancy and lactation because of limited data relating to these life stages. Given the paucity of data on Cu toxicity in healthy infants, children, and adolescents, a UL was not set for infants and UL for children and adolescents were derived by extrapolation from the adult UL.

13.7.2 Tolerable upper intake levels

In relation to high intakes, the NDA panel concluded that available data were not sufficient to establish a tolerable upper intake level for dietary LC omega-3 PUFAs (EPA, DHA and DPA individually or combined). The panel also considered that long-term supplemental intakes of EPA and DHA combined at doses up to 5 g/day, and supplemental intakes of EPA alone up to 1.8 g/day, do not raise safety concerns for the adult population. The panel noted further that observed intakes of EPA and DHA from food and food supplements in European populations are generally below these amounts.

Often cited as potentially negative effects of EPA and DHA are bleeding, lipid peroxidation, inflammation and modulation of the immune system, impaired glucose metabolism and gastrointestinal disturbances. However, the NDA panel found that long-term supplementation with amounts of EPA and DHA combined of up to 5 g/day did not increase the risk of spontaneous bleeding episodes or bleeding complications, even in subjects at high risk of bleeding by, for example, being treated with anticoagulant medication or with drugs affecting platelet function such as aspirin. Supplemental intake of doses of up to 5 g EPA + DHA/day for up to 12 weeks was shown not to affect glucose homeostasis in healthy or diabetic subjects, nor do these amounts induce changes in immune function that might raise concerns in relation to the risk of infection or inappropriate activation of inflammatory responses. Taken for up to 16 weeks, no changes in lipid peroxidation have been observed at this dose level that, otherwise, might have raised concerns about cardiovascular disease risk. It is important, however, to ensure oxidative stability of these LC omega-3 PUFAs. Gastrointestinal discomfort has frequently been reported, particularly when EPA and DHA are consumed as supplements. However, in many studies, the test material and the placebo oil caused the same type of disturbances, which would indicate that it may have been an oil effect. If gastrointestinal discomfort does occur, the symptoms are usually mild and, in many subjects, transient.

IV Vitamin E Requirements and Reference Ranges

Vitamin E has an estimated average requirement (EAR), recommended dietary allowances (RDAs), and tolerable upper intake level (UL) (Murphy and Barr, 2007). The EAR was based on the amount of 2R-α-tocopherol intake that reversed erythrocyte hemolysis in men who were vitamin E-deficient as a result of consuming a vitamin E-deficient diet for 5 years (Food and Nutrition Board, and Institute of Medicine, 2000). RDAs are designed so that, if met at a population level, almost all individuals would meet their requirements and avoid clinical deficiency symptoms (Morrissey and Sheehy, 1999). The UL is the highest level of daily nutrient intake that is likely to pose no risks of adverse health effects to most individuals in the general population (Yates et al., 1998). The functional criterion for the requirement of vitamin E for most age groups is the prevention of hydrogen peroxide (H2O2)-induced hemolysis of red blood cells (Murphy and Barr, 2007). Based on the plasma concentration of α-tocopherol to prevent significant hemolysis in vitro (14–16 μmol per L), the US/Canadian EAR is 12 mg/day; RDA for vitamin E is currently set at 15 mg/day of α-tocopherol for adults (ages above 19) (Food and Nutrition Board, and Institute of Medicine, 2000), a 50% increase on the previous RDA (National Research Council, 1989). The EAR of vitamin E in 1–3, 4–8, and 9–13 years aged children are 5, 6, 9 mg α-tocopherol per day, respectively (Eitenmiller and Lee, 2004). On the other hand, RDA levels of 1–3, 4–8, and 9–13 years aged children are 6, 7, 11 mg α-tocopherol per day, respectively (Eitenmiller and Lee, 2004). The tolerable UL was set at 1000 mg/day for vitamin E (any form of supplemental α-tocopherol) (Traber, 2007). This was one of the few UL that was set using data in rats, because sufficient and appropriate quantitative data assessing long-term adverse effects of vitamin E supplements in humans was not available (Traber, 2007). Although vitamin E seems to have very low toxicity and habitual intake of supplements of 200–600 mg/day (compared with an average dietary intake of 8–12 mg seems to be without untoward effect; Shrimpton, 1997), very high intakes may antagonize vitamin K and hence potentiate anticoagulant therapy. This is probably the result of inhibition of the vitamin K quinone reductase, but α-tocopheryl quinone may compete with vitamin K hydroquinone and hence inhibit carboxylation of glutamate in target proteins (Bender, 2003). Animal studies show that vitamin E is not mutagenic, carcinogenic, or teratogenic (Abdo et al., 1986; Dysmsza and Park, 1975; Krasavage and Terhaar, 1977). Adults tolerate relatively high doses without significant toxicity; however, muscle weakness, fatigue, double vision, emotional disturbance, breast soreness, thrombophlebitis, nausea, diarrhea, and flatulence have been reported at tocopherol intakes at 1600–3000 mg/day (Anderson and Reid, 1974; Bendich and Machlin, 1998; Food and Nutrition Board, and Institute of Medicine, 2000; Machlin, 1989; Tsai et al., 1978). The vitamin E requirement for ideal immune function depends on its interactions with other antioxidant and pro-oxidant nutrients, especially with polyunsaturated fatty acids (PUFAs), and on other factors that modulate the immune response, such as age and stress, exercise, infection, and tissue trauma all increase vitamin E requirements (Eskew et al., 1986; Meydani and Tengerdy, 1992; Nockels, 1991). Early reports suggested that vitamin E requirements increase with the intake of PUFAs (Bender, 2003), oxidizing agents, vitamin A, carotenoids, gossypol, or trace minerals and decreased with increasing levels of fat-soluble antioxidants, sulfur amino acids, or Se (Dove and Ewan, 1990; Franklin et al., 1998; Hidiroglou et al., 1992; McDowell et al., 1996). Neither the United Kingdom (Department of Health, 1991) nor the European Union (Scientific Committee for Food, 1993) set reference intakes for vitamin E, but both suggested that an acceptable intake was 0.4 mg of α-tocopherol equivalent per gram of dietary PUFA (Bender, 2003). Morrissey and Sheehy (1999) report that a consensus about the exact daily intake of vitamin E for optimal health protection has not yet been reached. Some authors believe that the scientific evidence is strong enough already, especially for cardiovascular disease (CVD), to recommend daily intakes of the order of 87–100 mg α-tocopherol per day or more (Horwitt, 1991; Packer, 1992; Weber et al., 1997). Gey (1995) has shown that there is an inverse relationship between plasma α-tocopherol and risk of ischemic heart disease over a range of 2.5–4.0 mmol per mol of cholesterol, and has suggested an optimum or desirable plasma concentration > 4 mmol of α-tocopherol per mol of cholesterol (> 3.4 μmol per gram of total plasma lipid), which corresponds an intake of 17–40 mg of α-tocopherol equivalents per day. Like the elderly, certain groups of population are at greater risk for inadequate dietary intake of vitamin E (Panemangalore and Lee, 1992; Ryan et al., 1992). Ryan et al. (1992) reported that over 40% of elderly (65–98 years) had intakes of vitamin E that were below two-thirds the 1989 RDA. In another study done by Panemangalore and Lee (1992), 37% of elderly subjects (average age of 73 years old) consumed below two-thirds RDA and 12% had low lipid adjusted plasma tocopherol status. In several studies, data have shown that elderly humans, as well as laboratory and farm animals, consuming diets that contain more than five times the RDA of vitamin E for their species had significantly increased humoral and cell-mediated immune responses and increased resistance to infectious diseases compared to nonsupplemented controls (Bendich, 1990; Bendich et al., 1986; Meydani and Blumberg, 1991; Meydani et al., 1993; Moriguchi et al., 1990; Tengerdy, 1989; Tengerdy et al., 1990). The minimum vitamin E requirement of normal animals is ~ 30 ppm of diet as in humans (McDowell, 2000). Beharka et al. (1997a) suggested that conventional methods for determining the RDA, while adequate for arriving at the level of vitamin E required to prevent clinical deficiency symptoms, may not adequately predict the optimal level of vitamin E needed to maintain immunological health.

Safe Tolerable Upper Intake Level

In the United States and Canada, an RDA or AI has not been set for boron. However, tolerable upper intake levels (ULs) were set; these were 3 mg/day for children 1–3 years of age; 6 mg/day for children 4–8 years of age; 17 mg/day for adolescents 9–18 years of age; and 20 mg/day for adults (Food and Nutrition Board, Institute of Medicine, 2001). The World Health Organization (1996) first suggested that 13 mg/day would be a safe upper intake level but later increased this to 0.4 mg/kg body weight (World Health Organization, International Program on Chemical Safety, 1998) or approximately 28 mg/day for a 70-kg person. The European Food Safety Authority (2004) established a UL for boron based on body weight that results in approximately 10 mg/day. The lack of finding adverse effects because of high boron in drinking water supports the establishment of these relatively high ULs (Nielsen and Meacham, 2011). In Turkey, populations consuming high amounts of boron via drinking water and consequently food do not exhibit any apparent adverse effects. For example, in a population exposed to drinking water up to 29 mg boron/L and to boron mining and production, no adverse effects on health and fertility were found over three generations. In another study, no adverse effects were found in 66 men (mean age of 39 years) residing in a high-boron area for 36 years with a calculated mean boron excretion of 6.77 mg/L. The drinking water from where the men resided had boron concentrations that ranged from 2.05 to 29.00 mg/L, with a mean of 10.2 ± 4.1 mg/L.

6.3.3 Wilson's disease (WD), a genetic, copper-overload disorder

Genetic predisposition disorders, like WD, may increase risk for copper toxicity even when copper intakes are well below the UL. WD is an autosomal recessive (genetic) disorder which is typified by defects in copper distribution and storage (Mak & Lam, 2008), resulting from mutations in the ATP7B gene, which encodes a copper transporter, thus disrupting copper homeostasis. A recent review provides more details on this potentially devastating human disease (Mulligan & Bronstein, 2020). The prevalence of WD is ≈ 1:30,000 individuals worldwide (Scheinberg & Sternlieb, 1984), although some genetic studies have reported much higher prevalence rates. A recent study addressed this seeming disconnect and suggested that differences in the penetrance of potentially disease-causing genetic variants may explain the discrepancy reported between epidemiological and genetic prevalence studies of WD (Wallace & Dooley, 2020). In patients with WD, redox-active copper accumulates in liver, brain, and cornea (due to impaired copper efflux), increasing the production of prooxidants and causing eventual tissue and organ damage. If the disease goes untreated, WD patients may develop hepatitis, liver fibrosis and cirrhosis, hemolytic crisis, and eventual hepatic failure. Moreover, high brain copper may cause neurological damage, and copper accumulation in the eye (i.e., so-called Kayser-Fleisher rings) may result in abnormal eye movements. Circulating CP is characteristically low in WD (since hepatic ATP7B is required for biosynthesis of CP), and urinary copper may be abnormally elevated. Early intervention can prevent development of some of these notable pathologies. Treatments for WD include high supplemental zinc dosing (which attenuates enteral copper absorption), and/or copper chelation therapy with trientine or penicillamine (LeWitt, 1999).

Nutrient adequacy and supplementation

Abbreviations

adequate intake

Dietary Reference Intakes

estimated average requirement

Institute of Medicine

recommended dietary allowance

tolerable upper intake level