Fat Soluble Vitamins. Vitamin A

Fat Soluble Vitamins Vitamin A The biochemical basis on which vitamin A requirements were established The EAR was set based on data pertaining to the assurance of adequate stores of vitamin A (Table 19). Other indicators considered, but not used, for estimating vitamin A requirements Dark Adaptation: This approach can be used to estimate the average requirement for vitamin A but without assurance of adequate tissue levels to meet non-visual needs for vitamin A. Pupillary Response Test: No data are currently available, which relate pupillary threshold sensitivity as determined by this test to usual vitamin A intakes, and, therefore, measures of papillary response cannot be used at present to establish dietary vitamin A requirements. Plasma Retinol Concentration: Because of the relatively insensitive relationship between plasma retinol concentration and liver vitamin A concentrations in the adequate range and because of the potential for confounding factors to affect the level and interpretation of plasma retinol concentration, plasma retinol was not chosen as a primary status indicator for a population for estimating an average requirement for vitamin A. Total Liver Reserves by Isotope Dilution: Although theoretically such an approach could be used to establish an EAR, no studies have been conducted in which detailed and long term dietary data have been obtained in the tested subjects. Relative Dose Response (RDR) / Modified Relative Dose Response (MRDR): Neither the RDR nor the MRDR was chosen because little data exists relating usual dietary intakes of individuals or populations to RDR or MRDR test value distributions. Conjunctival Impression Cytology (CIC): There is little data, which relate CIC-status to dietary vitamin A intake. As a result CIC was not selected as the functional indicator for establishing the EAR for vitamin A. Immune Function: There are some inherent limitations to using immune function as an indicator to establish dietary recommendations. Most changes in immune function that have been associated with a nutrient deficiency are not specific for that particular nutrient. The design of human dietary studies need, therefore, to be highly controlled with respect to the contents of potentially confounding nutrients in the diet. Additionally, the known difficulties in standardizing the methodology for immune status tests make the interpretation of such data difficult. For these reasons, immune function tests could not be used as an indicator for establishing the EAR for vitamin A. Special considerations Infant Formula: Available data indicate that the concentration of vitamin A in cow s milk is significantly lower than that in human milk. Alcohol Consumption: Excessive alcohol consumption results in depletion of liver vitamin A stores and has been shown to enhance the toxicity of vitamin A. Alcohol drinkers may be distinctly susceptible to the adverse effects of vitamin A and any increased intake to meet one s needs should be in the context of maintaining health. Parasites and Infection: The requirements for vitamin A in these clinical settings may be greater than normal requirements. Protein Energy Malnutrition: During the recovery period, the relative requirements of vitamin A are increased due to growth and tissue weight gain, which accompanies the successful dietary management of PEM. Vegetarianism: A greater amount of fruits and vegetables than previously recommended is required in order to meet the daily vitamin A requirement for vegetarians and those individuals whose primary source of vitamin A is green, leafy vegetables. 58

Populations Where the Consumption of Vitamin A Rich Foods is Limited: Populations of less developed countries may have difficulty in meeting the EAR that ensures adequate vitamin A stores. Therefore, an EAR that does not ensure adequate vitamin A stores has been determined on the basis of the level of vitamin A for correction of abnormal dark adaptation in adults in these populations. Using dark adaptation as the indicator, the EAR was established at 112µg/day for 1-3 year, 150µg/day for 4-8 year, 230µg/day for 9-13 year olds, and 300µg/day for 14 year olds and above. Toxicity Safety The UL applies to chronic intake of preformed vitamin A from food, fortified foods and supplements. Three primary adverse effects of chronic vitamin A intake were considered in determining the UL, namely reduced bone mineral density, teratogenicity and hepatic function impairment. In the case of women OF childbearing age, teratogenicity was the critical adverse effect on which the UL was based, whereas hepatic function impairment was the critical adverse effect selected in all other adult populations. The UL is not meant to apply to communities of malnourished individuals receiving vitamin A prophylactically, either periodically or through fortification as a means to prevent vitamin A deficiency or for individuals being treated for diseases, such as retinitis pigmentosa. Caution Acute toxicity has been reported, is usually transient and involves a single or short-term large dose of greater than or equal to 15 000 µg in adults and proportionately less in children. Symptoms include: - Nausea - Vomiting - Headache - Increased cerebrospinal fluid pressure - Vertigo - Blurred vision - Muscular incoordination, and - Bulging fontanelle in infants Chronic toxicity is usually associated with ingestion of large doses greater than or equal to 30 000 µg/day for months or years. Symptoms, especially in children, include: - Skeletal abnormalities - Bone tenderness and pain - Increased intracranial pressure - Desquamation - Brittle nails - Mouth fissures - Alopecia - Fever - Headache - Lethargy - Irritability - Weight loss - Vomiting, and - Hepatomegaly Distinct susceptibility to the adverse effects of excess preformed vitamin A intake includes individuals with: - High alcohol intake - Pre-existing liver disease 59

- Hyperlipidaemia, and - Severe protein malnutrition Table 19. The DRIs for vitamin A Note: Retinol Activity Equivalents (RAE) for dietary provitamin A carotenoids - β-carotene, α- carotene and β-cryptoxanthin- have been set at 12, 24 and 24µg respectively. Using RAE, the vitamin A activity of provitamin A carotenoids is half the vitamin A activity when using Retinol Equivalents (RE). This implies that a larger amount of provitamin A carotenoids is needed to meet the vitamin A requirements. Gender Age EAR RDA AI UL e NOAEL h LOAEL i Years µg/day a µg/day a µg/day a µg/day f µg/day µg/day 0 0.5 - - 400 c 600 - - 0.5 1 - - 500 d 600 - - 1 3 210 b 300-600 g - - 4 8 275 b 400-900 g - - 9 13 445 b 600-1 700 g - - 14 18 630 b 900-2 800 g - - 19 30 625 900-3 000 - - 31 50 625 900-3 000 - - 51 70 625 900-3 000 - - > 70 625 900-3 000 - - 9 13 420 b 600-1 700 g - - 14 18 485 b 700-2 800 g - - 19 30 500 700-3 000 - - 31 50 500 700-3 000 - - 51 70 500 700-3 000 - - > 70 500 700-3 000 - - Pregnancy 18 530 750-2 800 - - 19 30 550 770-3 000 - - 31 50 550 770-3 000 - - Lactation 18 880 1 200-2 800 - - 19 30 900 1 300-3 000 - - 31 50 900 1 300-3 000 - - female male a vitamin A b extrapolated from the EAR of adults using metabolic weight c based on the average amount of Vitamin A in human milk d extrapolated from the AI for infants ages 0 through 6 months e the UL applies to chronic intake of preformed Vitamin A from food, fortified food and/or supplements f preformed Vitamin A g the UL for children and adolescents was extrapolated from those established for adults and adjusted on the basis of relative body weight h a NOAEL was established at 4 500µg/day but no age groups were identified i a LOAEL was established at 14 000µg/day, which excludes women of childbearing age 60

Vitamin D (Calciferol) The biochemical basis on which vitamin D requirements were established Serum 25(OH)D was deemed the most appropriate indicator for vitamin D adequacy, since it reflects the summation of the total cutaneous synthesis of vitamin D and the oral ingestion of vitamin D 2 or vitamin D 3. It has therefore been used in setting the AIs (Table 20). Other indicators considered, but not used, for estimating vitamin D requirements Serum Parathyroid Hormone (PTH): Serum PTH concentrations are inversely related to serum 25(OH)D levels. These two parameters in combination have been documented to be a valuable indicator of vitamin D status in specific clinical settings. Serum Vitamin D: This was not considered to be indicative of vitamin D status because of its short half-life and the effects recent dietary intake and sun exposure have on serum concentrations. Serum 1,25 (OH) 2 D: The serum concentration of this parameter is tightly controlled by a variety of factors including serum calcium, phosphorus and PTH and as such its measurement was not considered as useful in assessing vitamin D adequacy. Evaluation of Skeletal Health: In neonates and children, bone development and the prevention of rickets either in combination with serum 25(OH)D or by itself are considered to be good indicators of vitamin D status. For adults, bone mineral content (BMC), bone mineral density (BMD), and fracture risk in combination with serum 25(OH)D and PTH concentrations, have also proven to be the most valuable indicators of vitamin D status. Such data, however, are not reliably available throughout the life cycle groups. Special considerations Infant Formula: Serum concentrations of formula fed infants have been reported to be similar to those of breastfed infants. The dietary needs of breastfed and formula fed infants are the same, when infants are not exposed to sunlight. Medications: In some clinical settings, additional vitamin D intake may be necessary in order to maintain serum 25(OH)D within the defined normal range [25 45ng/ml or (SI units) 62.5 112. 5nmol/L], e.g.: - glucocorticoid therapy can result in severe osteopaenia - antiepileptic medications (phenobarbital and dilantin) could result in osteomalacia and vitamin D deficiency; thus, institutionalized persons on antiepileptic medications should increase their intake of vitamin D to approximately 25µg/day. Toxicity Safety The UL for vitamin D, as is the case with the ULs for all other nutrients, only applies to healthy individuals. The most appropriate data that were available for deriving the UL for adults were those on the effect of vitamin D on serum calcium in humans. Hypercalcaemia was, therefore, the critical endpoint on which the UL was set. For most people, total vitamin D intake (food and supplements) is unlikely to exceed the UL. However, for those people who are at the upper range of intake from both sources of intake (those who use many supplements and have a high intake of fish or fortified milk) may be at risk of vitamin D toxicity. The endogenous synthesis of vitamin D 3 from sunlight irradiation of the skin has never been associated with vitamin D intoxication. Caution Granulomatous diseases (e.g. sarcoidosis, tuberculosis, histoplasmosis) are characterised by hypercalcaemia and/or hypercalciuria in individuals on normal or less-than-normal vitamin D 61

intakes or with exposure to sunlight. This apparent association is thought to be due to the extrarenal conversion of 25(OH)D to 1,25(OH) 2 D by activated macrophages. An intake of vitamin D between 1,250µg/week and 1,250µg/day for 6 weeks to 5 years was associated with: - Decreased renal function - Hypercalcaemia Table 20. The DRIs for vitamin D Gender Age EAR RDA AI UL NOAEL LOAEL Years - - µg a /day µg a /day µg a /day µg a /day 0 0.5 - - 5.0 b, c 25 - - 0.5-1 - - 5.0 b, c 25 - - 1 3 - - 5.0 d 50 - - 4 8 - - 5.0 d 50 - - 9 13 - - 5.0 50 - - 14 18 - - 5.0 50 - - 19 30 - - 5.0 50 60 f 95 f 31 50 - - 5.0 50 60 f 95 f 51 70 - - 10 50 60 f 95 f > 70 - - 15 50 - - 9 13 - - 5.0 50 - - 14 18 - - 5.0 50 - - 19 30 - - 5.0 50 60 f 95 f 31 50 - - 5.0 50 60 f 95 f 51 70 - - 10 50 60 f 95 f > 70 - - 15 50 - - Pregnancy 18 - - 5.0 e 50 - - 19 30 - - 5.0 e 50 - - 31 50 - - 5.0 e 50 - - Lactation 18 - - 5.0 e 50 - - 19 30 - - 5.0 e 50 - - 31 50 - - 5.0 e 50 - - female male a 5µg = 200IU b assuming that infants are not obtaining any vitamin D from sunlight c an intake of 10µg, which is supplied by 1 litre of most infant formulas would not be excessive d no data was available on requirements for these groups so data from older children was extrapolated e an intake of 10µg, which is supplied by pre- or postnatal vitamin supplements would not be excessive f a NOAEL and LOAEL were established from data derived from healthy males and females between the ages of 21-60 years 62

Vitamin E (α-tocopherol) The biochemical basis on which vitamin E requirements were established The values recommended here are based largely on induced vitamin E deficiency in humans and the correlation between hydrogen peroxide-induced erythrocyte lysis and plasma α- tocopherol concentrations. The RDA is based only on the α-tocopherol form of vitamin E as the other naturally occurring forms of vitamin E (β-, γ-, δ-tocopherols and the tocotrienols) do not contribute towards meeting the vitamin E requirement because although absorbed, they are not converted to α-tocopherol by humans and are poorly recognized by the α-tocopherol transfer protein (α-ttp) in the liver (Table 21). Other indicators considered, but not used, for estimating vitamin E requirements Lipid Peroxidation Markers: There is no evidence that lowering lipid peroxidation marker levels is associated with health benefits. Therefore, estimates of lipid peroxidation products have not been used for establishing α-tocopherol requirements. Oxidation Products of DNA or Proteins: Vitamin E has not been shown to directly protect DNA or proteins against oxidative damage, and, therefore, DNA adducts or protein carbonyls were not used to assess α-tocopherol requirements. Vitamin E Metabolite Excretion: α-cehc [2,5,7,8-tetramethyl-2-(2 corboxy-ethyl)-6- hydroxychroman] excretion has not been used as a basis for assessing the α-tocopherol requirements, since it represents only a small fraction of the α-tocopherol consumed daily and there is a paucity of data regarding its formation. Vitamin E Biokinetics: Almost no data exists on pool sizes or tissue concentrations of vitamin E, especially the various forms of vitamin E, which could be used as a guide for establishing vitamin E requirements. Vitamin E Deficiency Symptoms: Overt vitamin E deficiency is so rare in humans that signs of deficiency and comparisons of deficiency signs with dietary intakes are not available to serve as a basis for estimating requirements. Plasma α-tocopherol Concentrations: The correlation between intake and normal vitamin E plasma concentrations (greater than 16µmol/l) is not strong and could not be used as the basis for estimating the α-tocopherol requirements. However, in vitamin E- depleted subjects a linear increase in plasma α-tocopherol concentration was found with increasing vitamin E intake up to 17mg/day. Hydrogen Peroxide-Induced Haemolysis: Breath ethane, a lipid peroxidation marker, and erythrocyte susceptibility to in vitro hydrogen peroxide lysis have been inversely correlated with plasma α-tocopherol concentrations in children and adults with vitamin E deficiency as defined by low plasma vitamin E concentrations. The limited data available could not be used for the purpose of establishing vitamin E requirements. Special considerations It is not known if any adjustments in requirements are necessary for: Smokers Exercise (strenuous or regular) Extreme body size and composition Prevention of chronic disease Relationship of vitamin E intake to chronic disease A large and growing body of experimental evidence suggests that high intakes of vitamin E may lower the risk of some chronic diseases, especially heart disease. However, the limited and discordant clinical trial evidence available precludes recommendations of higher vitamin E intakes to reduce the risk for chronic diseases. Similar claims regarding the importance of vitamin E in enhancing immune function, especially in the elderly, remain to be confirmed. Whether or not increases in vitamin E intake have any effect on immune function in younger populations remains uncertain. 63

Toxicity Safety There is no evidence of adverse effects from the consumption of vitamin E naturally occurring in foods. Based on considerations of causality, relevance and the quality of the available data, heamorrhagic effects were selected as the critical endpoint on which the UL was based. There is some evidence of an increased incidence of haemorrhagic effects in premature infants receiving supplemental α-tocopherol. Some caution is recommended regarding the administration of supplemental doses of α- tocopherol over multiyear periods. Caution Vitamin K Deficiency and Anticoagulant Therapy: The UL for vitamin E pertains to individuals in the general population with adequate vitamin K intake. Individuals who are vitamin K deficient or are on anticoagulant therapy and consume vitamin E supplements are at an increased risk of coagulation defects and should be monitored regularly. Premature Infants: The small premature infant is particularly vulnerable to the toxic effects of α-tocopherol. Vitamin E supplements in these infants must be carefully controlled. The use of the adult UL of 14mg/kg/day is recommended as a guide. Pharmacologic doses of vitamin E for the prevention or treatment of retinopathy of prematurity, bronchopulmonary dysplasia, and intraventricular haemorrhage are not recommended. 64

Table 21. The DRIs for vitamin E (α-tocopherol) Gender Age EAR RDA AI UL d NOAEL h LOAEL h Years mg a /day mg a /day mg a /day mg a /day e 0-0.5 - - 4.0 c * - - 0.5-1 - - 5.0 c * - - 1 3 5.0 b 6.0 b - 200 f - - 4 8 6.0 b 7.0 b - 300 f - - 9 13 9.0 b 11 b - 600 f - - 14 18 12 b 15 b - 800 f - - 19 30 12 15-1 000 - - 31 50 12 15-1 000 - - 51 70 12 15-1 000 - - > 70 12 15-1 000 - - 9 13 9.0 b 11 b - 600 f - - 14 18 12 b 15 b - 800 f - - 19 30 12 15-1 000 - - 31 50 12 15-1 000 - - 51 70 12 15-1 000 - - > 70 12 15-1 000 - - Pregnancy 18 12 15-800 g - - 19 30 12 15-1 000 g - - 31 50 12 15-1 000 g - - Lactation 18 16 19-800 g - - 19 30 16 19-1 000 g - - 31 50 16 19-1 000 g - - female male * not possible to establish, vitamin E intake should be from food sources only i.e. breast milk, formula and food a 1mg = 2.325µmol b these values have been extrapolated from adult values based on lean body mass and need for growth. c 0.6mg/kg d there is no evidence of adverse effects from the consumption of vitamin E naturally occurring in foods. Therefore the UL applies to α-tocopherol as a supplement, food fortificant or pharmacological agent. e any form of supplementary α-tocopherol. f the UL values for toddlers, children and adolescents are extrapolated from those established for adults; it was adjusted on the basis of relative body weight, and then the calculated UL was rounded off. g due to the paucity of available data, it is recommended that the ULs for pregnant and lactating females be the same as that for non-pregnant and non-lactating females. h In the absence of human data pertaining to dose-response relationships the data used to identify a NOAEL for α-tocopherol included hemorrhagic toxicity in rats. A LOAEL of 500 mg/kg/day in rats was divided by an uncertainty factor of 36 to derive the adult UL of 14 mg/kg/day. This was then multiplied by the average reference body weights for male and female adults to establish the UL for adults. 65

Vitamin K The biochemical basis on which vitamin K requirements were established Due to the lack of data to estimate an average requirement, an AI was set based on representative dietary intake data from healthy individuals (Table 22). Other indicators considered, but not used, for estimating vitamin K requirements These indicators have been used to assess relative changes in vitamin K status but do not provide, by themselves or collectively, an adequate basis on which to estimate an average requirement for vitamin K. Prothrombin Time (PT): The classical PT used to measure the procoagulant potential of plasma is not a sensitive indicator of vitamin K status because prothrombin concentration must be decreased by approximately 50% before a value is outside of the "normal range". Furthermore PT does not respond to changes in dietary vitamin K in healthy subjects. Factor VII: In the absence of antibiotic treatment, factor VII activity is not a sensitive indicator of vitamin K status as it does not usually respond to changes in vitamin K intake in healthy individuals. Plasma and Serum Phylloquinone Concentration: Serum concentrations reflect recent intake and has been shown to respond to changes in dietary intake within 24 hours. However, given the distribution of vitamin K in the food supply, a single day plasma (serum) phylloquinone concentration may not reflect normal dietary intake. In healthy individuals, phylloquinone concentrations are also age dependent (higher in older than in younger subjects), irrespective of dietary intake. Urinary Υ-Carboxyglutamyl Residues (Gla): There is insufficient data for using urinary Gla excretion for estimating an average requirement. Undercarboxylated Prothrombin (PIVKA-II): Intervention studies using graded intakes of vitamin K and protocols of longer duration need to be conducted before this indicator can be used to establish dietary recommendations for vitamin K. Under-Υ-Carboxylated Osteocalcin (ucoc): Although there is little doubt that vitamin K intake affects the degree of osteocalcin λ-carboxylation, the technical problems associated with the current assays and uncertainty surrounding the physiological significance of diet-induced changes prevent the use of ucoc for estimating an average requirement for vitamin K. Relationship of vitamin K intake to chronic disease Osteoporosis: Whether vitamin K intake is a significant aetiological component is difficult to establish and must await the completion of on-going intervention studies. Atherosclerosis: Whether vitamin K status within the range of normal intake plays a significant role in the development of atherosclerosis remains to be confirmed. Toxicity No adverse effects associated with vitamin K consumption from food or supplements have been reported in humans or animals. Therefore, a quantitative risk assessment could not be performed and a UL could not be derived for vitamin K. 66

Table 22. The DRIs for vitamin K Gender Age EAR RDA AI UL NOAEL LOAEL Years µg/day µg/day µg/day µg/day µg/day µg/day 0 0.5 - - 2.0 a, b - - - 0.5-1 - - 2.5 b,c - - - 1 3 - - 30 d - - - 4 8 - - 55 d - - - 9 13 - - 60 d - - - 14 18 - - 75 d - - - 19 30 - - 120 d - - - 31 50 - - 120 d - - - 51 70 - - 120 d - - - > 70 - - 120 d - - - 9 13 - - 60 d - - - 14 18 - - 75 d - - - 19 30 - - 90 d - - - 31 50 - - 90 d - - - 51 70 - - 90 d - - - > 70 - - 90 d - - - Pregnancy 18 - - 75 - - - 19 30 - - 90 - - - 31 50 - - 90 - - - Lactation 18 - - 75 - - - 19 30 - - 90 - - - 31 50 - - 90 - - - female male a this value reflects a calculated mean vitamin K intake of infants principally fed human milk and provided vitamin K prophylaxis. b there is no information on the bioavailability of vitamin K in infant formula c the AI is set at the level obtained by extrapolating up from young infants d the AI is based on median intake data from NHANES III 67