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TABLE 1 Dietary Reference Intakes for Vitamin C by Life Stage Group DRI values (mg/day) EARa RDAb AIc ULd males females males females Life stage group NDe 0 through 6 mo 40 7 through 12 mo 50 ND 1 through 3 y 13 13 15 15 400 4 through 8 y 22 22 25 25 650 9 through 13 y 39 39 45 45 1,200 14 through 18 y 63 56 75 65 1,800 19 through 30 y 75 60 90 75 2,000 31 through 50 y 75 60 90 75 2,000 51 through 70 y 75 60 90 75 2,000 ≥ 70 y 75 60 90 75 2,000 Pregnancy £ 18 y 66 80 1,800 19 through 50 y 70 85 2,000 Lactation £ 18 y 96 115 1,800 19 through 50 y 100 120 2,000 a EAR = Estimated Average Requirement. b RDA = Recommended Dietary Allowance. c AI = Adequate Intake. d UL = Tolerable Upper Intake Level. Unless otherwise specified, the UL represents total intake from food, water, and supplements. e ND = Not determinable. This value is not determinable due to the lack of data of adverse effects in this age group and concern regarding the lack of ability to handle excess amounts. Source of intake should only be from food to prevent high levels of intake.

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PART III: VITAMIN C 203 VITAMIN C V itamin C (ascorbic acid) is a water-soluble nutrient that acts as an anti- oxidant and a cofactor in enzymatic and hormonal processes. It also plays a role in the biosynthesis of carnitine, neurotransmitters, collagen, and other components of connective tissue, and modulates the absorption, trans- port, and storage of iron. The adult requirements for vitamin C are based on estimates of body pool or tissue vitamin C levels that are deemed adequate to provide antioxidant pro- tection. Smokers have an increased requirement. The adverse effects upon which the Tolerable Upper Intake Level (UL) is based are osmotic diarrhea and gas- trointestinal disturbances. DRI values are listed by life stage group in Table 1. Foods rich in vitamin C include fruits and vegetables, including citrus fruits, tomatoes, potatoes, strawberries, spinach, and cruciferous vegetables. Vitamin C deficiency is by and large not a problem in the United States and Canada, and the risk of adverse effects of excess intake appears to be very low at the highest usual Vitamin C intakes. VITAMIN C AND THE BODY Function Vitamin C (ascorbic acid) is a water-soluble nutrient that acts as an antioxidant by virtue of its high reducing power. It has a number of functions: as a scaven- ger of free radicals; as a cofactor for several enzymes involved in the biosynthe- sis of carnitine, collagen, neurotransmitters, and in vitro processes; and as a reducing agent. Evidence for in vivo antioxidant functions of ascorbate include the scavenging of reactive oxidants in activated leukocytes, lung, and gastric mucosa, and diminished lipid peroxidation as measured by urinary isoprostane excretion. Absorption, Metabolism, Storage, and Excretion Vitamin C is absorbed in the intestine via a sodium-dependent active transport process that is saturable and dose-dependent. As intake increases, absorption decreases. At low intestinal concentrations of vitamin C, active transport is the primary mode of absorption. When intestinal concentrations of vitamin C are high, passive diffusion becomes the main form of absorption.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 204 Besides dose-dependent absorption, body vitamin C content is also regu- lated by the kidneys, which conserve or excrete unmetabolized vitamin C. Re- nal excretion of vitamin C increases proportionately with higher intakes of the vitamin. These processes allow the body to conserve vitamin C during periods of low intake and to limit plasma levels of vitamin C at high intakes. The amount of vitamin C stored in different body tissues widely varies. High levels are found in the pituitary and adrenal glands, leukocytes, eye tis- sues and humors, and the brain, while low levels are found in plasma and saliva. A total body pool of less than 300 mg is associated with symptoms of scurvy, a disease of severe vitamin C deficiency; maximum body pools (in adults) are limited to about 2,000 mg. With high intakes, unabsorbed vitamin C degrades in the intestine, which may account for the diarrhea and gastrointestinal upset sometimes reported by people taking large doses. At very low ascorbate intakes, essentially no ascor- bate is excreted unchanged and a minimal loss occurs. DETERMINING DRIS Determining Requirements The requirements for vitamin C are based on estimates of body pool or tissue vitamin C levels that are deemed adequate to provide antioxidant protection with minimal urinary loss. Although some studies have reported a possible protective effect of vitamin C against diseases such as cardiovascular disease, cancer, lung disease, cataracts, and even the common cold, others have failed to do so. Additionally, the majority of evidence accumulated thus far has been largely observational and epidemiological and thus does not prove cause and effect. Special Considerations Gender: Women tend to have higher blood levels of vitamin C than men of the same age, even when intake levels are the same, making the requirements for women lower than for men. The difference in vitamin C requirements of men and women is assumed based on mean differences in body size, total body water, and lean body mass. Age: No consistent differences in the absorption or metabolism of vitamin C due to aging have been demonstrated at median vitamin C intakes. This sug- gests that reports of low blood concentrations of vitamin C in elderly popula- tions may be due to poor dietary intakes, chronic disease or debilitation, or other factors, rather than solely an effect of aging. Therefore, the requirements of older adults do not differ from those of younger adults.

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PART III: VITAMIN C 205 Smoking: Studies have shown that smokers have decreased plasma and leuko- cyte levels of vitamin C compared to nonsmokers, even after adjusting for vita- min C intake from foods. Metabolic turnover of the vitamins has been shown to be about 35 mg/day greater in smokers. This means that smokers need 35 mg/ day more to maintain the same body pool as nonsmokers. The mechanism by which smoking compromises vitamin C status has not been well established. Exposure to environmental tobacco smoke: Increased oxidative stress and vita- min C turnover have been observed in nonsmokers who are regularly exposed to tobacco smoke. Although the available data were insufficient to estimate a special requirement, these nonsmokers are urged to ensure that they meet the RDA for vitamin C. Certain pregnant subpopulations: Pregnant women who smoke, abuse drugs or alcohol, or regularly take aspirin may have increased requirements for vitamin C. Individuals susceptible to adverse effects: People with hemochromatosis, glucose-6-phosphate dehydrogenase deficiency, and renal disorders may be par- ticularly susceptible to the adverse effects of excess vitamin C intake and there- fore should be cautious about ingesting vitamin C at levels greater than the RDA. Vitamin C may enhance iron absorption and exacerbate iron-induced tissue damage in individuals with hemochromatosis, while those with renal disorders may have increased risk of oxalate kidney stone formation from ex- cess vitamin C intake. Criteria for Determining Vitamin C Requirements, by Life Stage Group Life stage group Criterion 0 through 6 mo Human milk content 7 through 12 mo Human milk + solid food 1 through 18 y Extrapolation from adult 19 through 30 y Near-maximal neutrophil concentration 31 through > 70 y Extrapolation of near-maximal neutrophil concentration from 19 through 30 y Pregnancy £ 18 y through 50 y Age-specific requirement + tansfer to the fetus Lactation £ 18 y through 50 y Age-specific requirement + vitamin C secreted in human milk

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 206 The UL The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse effects for almost all people. Members of the general population should not routinely exceed the UL, which for vitamin C applies to intake from both food and supplements. Osmotic diar- rhea and gastrointestinal disturbances are the critical endpoints upon which the UL for vitamin C is based. Based on data from the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994), the highest mean intake of vitamin C from diet and supplements for any gender and lifestage group was estimated to be about 200 mg/day (for males aged 51 through 70 years and females aged 51 years and older). The highest reported intake at the 99th percentile was greater than 1,200 mg/day in males aged 31 through 70 years and in females aged 51 through 70 years. The risk of adverse effects resulting from excess intake of vitamin C from food and supplements appears to be very low. DIETARY SOURCES Foods Almost 90 percent of vitamin C found in the typical diet comes from fruits and vegetables, with citrus fruits and juices, tomatoes and tomato juice, and pota- toes being major contributors. Other sources include brussels sprouts, cauli- flower, broccoli, strawberries, cabbage, and spinach. Some foods are also forti- fied with vitamin C. The vitamin C content of foods can vary depending on growing conditions and location, the season of the year, the stage of maturity, cooking practices, and the storage time prior to consumption. Dietary Supplements Data from the Boston Nutritional Status Survey (1981–1984) estimated that 35 percent of men and 44 percent of women took some form of vitamin C supple- ments; of them, 19 percent of men and 15 percent of women had intakes greater than 1,000 mg/day. Bioavailability There does not appear to be much variability in the bioavailability of vitamin C between different foods and dietary supplements. Approximately 70–90 per- cent of usual dietary intakes of vitamin C (30–180 mg/day) is absorbed by the body. However, absorption falls to 50 percent or less as intake increases to doses of 1,000 mg/day or more.

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PART III: VITAMIN C 207 TABLE 2 Potential Interactions with Other Dietary Substances Substance Potential Interaction Notes VITAMIN C AFFECTING OTHER SUBSTANCES Iron Vitamin C may enhance Vitamin C added to meals facilitates the intestinal the absorption of absorption of nonheme iron, possibly due to nonheme iron. lowering of gastrointestinal iron to the more absorbable ferrous state or to countering the effect of substances that inhibit iron absorption. However, studies in which the vitamin was added to meals over long periods have not shown significant improvement of body iron status, indicating that ascorbic acid has a lesser effect on iron bioavailability than has been predicted from tests involving single meals. Copper Vitamin C may reduce Excess vitamin C may reduce copper absorption, but copper absorption. the significance of this potential effect in humans is questionable because the data have been mixed. Vitamin B12 Large doses of vitamin C Low serum B12 values reported in people receiving may reduce vitamin B12 megadoses of vitamin C are likely to be artifacts of the levels. effect of vitamin C on the radiotope assay for B12, and thus not a true nutrient–nutrient interaction. Dietary Interactions There is evidence that vitamin C may interact with certain nutrients and dietary substances (see Table 2). INADEQUATE INTAKE AND DEFICIENCY Severe vitamin C deficiency is rare in industrialized countries, but it is occa- sionally seen in people whose diets lack fruits and vegetables or in those who abuse alcohol or drugs. In the United States, low blood levels of vitamin C are more common in men, particularly elderly men, than in women, and in popu- lations of lower socioeconomic status. The classic disease of severe vitamin C deficiency is scurvy, which is char- acterized by the symptoms related to connective tissue defects. Scurvy usually occurs at a plasma concentration of less than 11 mmol/L (0.2 mg/dL). The signs and symptoms of scurvy include the following: • Follicular hyperkeratosis • Petechiae

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 208 • Ecchymoses • Coiled hairs • Inflamed and bleeding gums • Perifollicular hemorrhages • Joint effusions • Arthralgia • Impaired wound healing Other signs and symptoms include dyspnea, edema, Sjögren’s syndrome (dry eyes and mouth), weakness, fatigue, and depression. In experimental subjects who were made vitamin C deficient but not frankly scorbutic, gingival inflam- mation and fatigue were among the most sensitive markers of deficiency. Vitamin C deficiency in infants, known as infantile scurvy, may result in bone abnormalities, hemorrhagic symptoms, and anemia. Infantile scurvy is rarely seen because human milk provides an adequate supply of vitamin C and infant formulas are fortified with the vitamin. EXCESS INTAKE Adverse effects from vitamin C intake have been associated primarily with large doses (> 3,000 mg/day) and may include diarrhea and other gastrointestinal disturbances. There is no evidence suggesting that vitamin C is carcinogenic or teratogenic or that it causes adverse reproductive effects. Special Considerations Blood and urine tests: Vitamin C intakes of 250 mg/day or higher have been associated with false-negative results for detecting stool and gastric occult blood. Therefore, high-dose vitamin C supplements should be discontinued at least 2 weeks before physical exams to avoid interference with blood and urine tests.

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PART III: VITAMIN C 209 KEY POINTS FOR VITAMIN C Vitamin C (ascorbic acid) is a water-soluble nutrient that acts 3 as an antioxidant and a cofactor in enzymatic and hormonal processes. It also plays a role in the biosynthesis of carnitine, neurotransmitters, collagen, and other components of connective tissue, and modulates the absorption, transport, and storage of iron. Vitamin C requirements for adults are based on estimates of 3 body pool or tissue vitamin C levels that are deemed adequate to provide antioxidant protection. The adverse effects upon which the UL is based are osmotic diarrhea and gastrointestinal disturbances. Although some studies have reported a possible protective 3 effect of vitamin C against diseases such as cardiovascular disease, cancer, lung disease, cataracts, and even the common cold, others have failed to do so. Because smokers suffer increased oxidative stress and 3 metabolic turnover of vitamin C, the requirements are raised by 35 mg/day. Increased oxidative stress and vitamin C turnover have been 3 observed in nonsmokers who are regularly exposed to tobacco smoke, and thus nonsmokers are urged to ensure that they meet the RDA for vitamin C. The risk of adverse effects resulting from excess vitamin C 3 intake appears to be very low. Almost 90 percent of vitamin C found in the typical diet comes 3 from fruits and vegetables, with citrus fruits and juices, tomatoes and tomato juice, and potatoes being major contributors. Other sources include brussels sprouts, cauliflower, broccoli, strawberries, cabbage, and spinach. Low blood concentrations of vitamin C in elderly populations 3 may be due to poor dietary intakes, chronic disease or debilitation, or other factors, rather than solely an effect of aging. The classic disease of severe vitamin C deficiency is scurvy, 3 the signs and symptoms of which include follicular hyperkeratosis, petechiae, ecchymoses, coiled hairs, inflamed and bleeding gums, perifollicular hemorrhages, joint effusions, arthralgia, and impaired wound healing.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 210 Severe vitamin C deficiency is rare in industrialized countries, 3 but it is occasionally seen in people whose diets lack fruits and vegetables or in those who abuse alcohol or drugs. Adverse effects have been associated primarily with large 3 doses (> 3,000 mg/day) and may include diarrhea and other gastrointestinal disturbances.