SPECIAL COMMUNICATION

Criteria and Recommendations

for Vitamin C Intake
Mark Levine, MD Recommendations for vitamin C intake are under revision by the Food and
Steven C. Rumsey, PhD Nutrition Board of the National Academy of Sciences. Since 1989 when the
Rushad Daruwala, PhD last recommended dietary allowance (RDA) of 60 mg was published, exten-
sive biochemical, molecular, epidemiologic, and clinical data have become
Jae B. Park, PhD available. New recommendations can be based on the following 9 criteria:
Yaohui Wang, MD dietary availability, steady-state concentrations in plasma in relationship to
dose, steady-state concentrations in tissues in relationship to dose, bio-

R
ECOMMENDATIONS FOR VITA-
availability, urine excretion, adverse effects, biochemical and molecular func-
min C intake are under revi-
tion in relationship to vitamin concentration, direct beneficial effects and
sion by the Food and Nutri-
epidemiologic observations in relationship to dose, and prevention of defi-
tion Board of the National
ciency. We applied these criteria to the Food and Nutrition Board’s new guide-
Academy of Sciences. Since the last rec-
lines, the Dietary Reference Intakes, which include 4 reference values. The
ommendations for vitamin C intake is-
estimated average requirement (EAR) is the amount of nutrient estimated
sued in 1989, extensive biochemical, to meet the requirement of half the healthy individuals in a life-stage and
molecular, epidemiologic, and clini- gender group. Based on an EAR of 100 mg/d of vitamin C, the RDA is pro-
cal data have been published. This ar- posed to be 120 mg/d. If the EAR cannot be determined, an adequate intake
ticle reviews the role of vitamin C in (AI) amount is recommended instead of an RDA. The AI was estimated to
metabolic processes, discusses criteria be either 200 mg/d from 5 servings of fruits and vegetables or 100 mg/d of
used for recommended ingestion of vi- vitamin C to prevent deficiency with a margin of safety. The final classifi-
tamin C, and presents recommenda- cation, the tolerable upper intake level, is the highest daily level of nutrient
tions for vitamin C intake. intake that does not pose risk or adverse health effects to almost all indi-
VITAMIN C AND HUMAN viduals in the population. This amount is proposed to be less than 1 g of
METABOLIC PROCESSES vitamin C daily. Physicians can tell patients that 5 servings of fruits and veg-
etables per day may be beneficial in preventing cancer and providing suffi-
Vitamin C (ascorbic acid, ascorbate) is cient vitamin C intake for healthy people, and that 1 g or more of vitamin C
an essential micronutrient involved in may have adverse consequences in some people.
many biologic and biochemical func- JAMA. 1999;281:1415-1423 www.jama.com
tions. Humans cannot synthesize vita-
min C because they lack the last en-
4-hydroxyphenylpyruvate dioxygenase or amount of oxidant necessary to in-
zyme in the biosynthetic pathway.
participates in tyrosine metabolism. duce an experimental effect of vitamin
Known functions of vitamin C are ac-
Vitamin C also has non–enzymatic- C in vitro may be irrelevant in vivo be-
counted for by its action as an electron
reductive functions in chemical reac- cause that oxidant or its selected con-
donor, or reducing agent (FIGURE 1).
tions (Figure 1). Based on its redox po- centration might not occur. Although in
Vitamin C is a specific electron do-
tential, and its free radical intermediate, certain experimental systems ascorbate
nor for 8 enzymes.1,2 Three enzymes par-
vitamin C is a chemical reducing agent has pro-oxidant activity, there is little evi-
ticipate in collagen hydroxylation and 2
(antioxidant) in many intracellular and dence for such activity in vivo.3,4
participate in carnitine biosynthesis. Do-
extracellular reactions. Most have been
pamine b-monooxygenase is necessary Author Affiliations: Molecular and Clinical Nutrition
described in vitro, but because they are
for biosynthesis of the catecholamine Section, Digestive Diseases Branch, National Insti-
oxidation-reduction reactions they may tute of Diabetes and Digestive and Kidney Diseases,
hormone norepinephrine, peptidyl- National Institutes of Health, Bethesda, Md (Drs Levine,
not require vitamin C specifically in vivo.
glycine a-monooxygenase is necessary Rumsey, Daruwala, and Wang); Phytonutrients Labo-
In vitro chemical oxidation reactions in- ratory, Beltsville Human Nutrition Research Center, US
for amidation of peptide hormones, and
volving iron or copper may not be rel- Department of Agriculture, Beltsville, Md (Dr Park).
Corresponding Author and Reprints: Mark Levine,
evant in vivo because these divalentca- MD, National Institutes of Health, Bldg 10, Room
See also Patient Page.
tions are protein bound in vivo. The type 4D52, MSC1372, Bethesda, MD 20892.

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 VITAMIN C INTAKE

One example of vitamin C action as an lori gastritis. With hypochlorhydria, as sorption in iron-deficient patients. Al-
extracellular chemical reducing agent is in atrophic gastritis, vitamin C secre- though iron absorption is decreased
its prevention of low-density lipopro- tion can be absent.11 Because vitamin without gastric acid, as in atrophic gas-
tein (LDL) oxidation.5-7 Low-density li- C in the stomach or duodenum could tritis and achlorhydria, it is unknown
poprotein is atherogenic after struc- quench reactive oxygen metabolites or whether ascorbate increases iron ab-
tural modification. A major pathway of prevent formation of mutagenic N- sorption in these conditions.
LDL modification may be oxidative modi- nitroso compounds, gastric juice vita-
fication due to lipid peroxidation, and vi- min C might confer protection against INGESTION CRITERIA
tamin C inhibits metal-catalyzed LDL gastric cancers.12 However, vitamin C The current RDA for vitamin C is 60
oxidation in many experimental sys- concentrations were normal in gastric mg/d, which was set in 1980 and un-
tems in vitro.5-7 The likely mechanism is juice of patients at risk for familial gas- changed in 1989. The current RDA was
that vitamin C reduces aqueous free radi- tric cancer.13 High vitamin C dietary in- based on preventing scurvy with a 4-
cals. Regeneration of oxidized a-tocoph- take correlates with reduced gastric can- week margin of safety, on the thresh-
erol (vitamin E) on LDL by vitamin C has cer risk.14 Like other epidemiologic old of urine excretion, on estimates of
also been proposed, but this mecha- observations for vitamin C and cancer vitamin C absorption, on losses asso-
nism may have less importance for LDL risk, it is uncertain if either vitamin C ciated with food preparation, and on es-
protection.5 Vitamin C could also de- itself or other components of foods that timated rates of depletion, turnover, and
crease oxidative damage in vascular contain vitamin C confer protection. catabolism.16,17 The experimental data
walls.5 In contrast to protective effects of Vitamin C promotes iron absorption for this RDA were incomplete.1,18 Con-
ascorbate on LDL in vitro, effects in vivo in the small intestine.15 Vitamin C en- trolled inpatient data were from a deple-
are inconsistent.8-10 hances absorption of soluble nonheme tion-repletion study of 5 prisoners who
As an extracellular reducing agent, iron, either by reducing it or prevent- received limited vitamin C doses.19 Ar-
vitamin C may reduce harmful oxi- ing its chelation by phytates or other tifact and insensitivity, especially at low
dants in gastric juice. In normal hu- food ligands. Vitamin C increases iron values, limited accuracy of vitamin C
mans, vitamin C concentrations in gas- absorption 1.5- to 10-fold, depending on assays.20 Catabolism estimates were in-
tric juice are approximately 3-fold iron status, the test meal, and ascor- accurate because catabolism varied at
higher than in plasma. Ascorbate se- bate dose. Iron absorption can be different vitamin C amounts.1
cretion is impaired when gastric mu- doubled by 25- to 50-mg ascorbate in the Since the last RDA was set, abun-
cosa is inflamed, as in Helicobacter py- meal, and ascorbate can double iron ab- dant new data are at hand concerning
vitamin C biochemistry, molecular bi-
ology, epidemiology, pharmacokinet-
Figure 1. Actions of Vitamin C ics, and metabolism in different clini-
cal conditions. The following criteria
can be used as a basis for recom-
mended ingestion of vitamin C.2,18,21

Dietary Availability
Vitamin C is found in many fruits and
L-Ascorbic Acid Dehydro-L-Ascorbic Acid vegetables22 (TABLE), but is a labile mi-
Enzyme Cofactor cronutrient.15,23,24 Estimates of vitamin
2 H+
Collagen synthesis 2 e- Chemical Reductant C amounts in foods depend on season,
Carnitine synthesis e- e- transport of the food, shelf time prior to
Iron absorption in
e- e-
Norepinephrine synthesis gastrointestinal tract purchase, storage, and cooking prac-
Peptide hormone synthesis e- e-
Tyrosine metabolism tices. For example, supermarket broc-
coli compared with wholesaler broc-
Antioxidant (Reduction of Harmful Free Radicals)
coli can lose 33% of its vitamin C, and
boiling vegetables can cause 50% to 80%
Oxidative DNA and/or protein damage
Low-density lipoprotein oxidation loss. Cooking vegetables with minimal
Lipid peroxidation water or in a microwave oven will de-
Oxidants and nitrosamines in gastric juice
Extracellular oxidants from neutrophils
crease vitamin C losses.23,24
Endothelium-dependent vasodilation As a supplement, ascorbate is avail-
able in tablet and powder forms, with
Oxidation of vitamin C (L-ascorbic acid) sequentially releases 2 donor electrons that become available for bio- a wide dose range. Ascorbate is part of
chemical reactions observed in vivo and/or in vitro. In the molecular diagrams, carbon atoms are black; oxy- many multivitamin formulations and is
gen, red; and hydrogen, white. Up and down arrows mean an increase or decrease in level.
in supplements with selected vita-
1416 JAMA, April 21, 1999—Vol 281, No. 15 ©1999 American Medical Association. All rights reserved.

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 VITAMIN C INTAKE

mins, commonly sold as antioxidant followed, daily vitamin C intake will be C.29,30 Comparison of NHANES II and
supplements. Vitamin C absorption 210 to 280 mg, depending on food con- NHANES III data indicates that vita-
from supplements depends on tablet tent factors. For supplement users, vi- min C intake from foods is increasing
binders and dose. Effects of food and tamin C intake is dependent on the slightly, but a substantial number of
sustained-release preparations on ab- supplement chosen. people ingest vitamin C from foods at
sorption are uncertain. Information from the third US Na- or below the present US RDA.26,31
Vitamin C is readily available in foods tional Health and Nutrition Examina- Most intake data do not include vi-
in industrialized countries, and intake tion Survey (NHANES III, 1988- tamin C consumption from supple-
is governed by food selection. The US 1991) indicates that median vitamin C ments, used by 40% to 50% of the US
Department of Agriculture and the US consumption from foods for US men is population.32 Supplements may change
National Cancer Institute’s guidelines 84 mg/d, and for women, 73 mg/d (chil- total vitamin C intake.32 It is uncer-
are similar, with recommendations for dren excluded).26 However, approxi- tain whether individuals who take
eating at least 5 fruits and vegetables mately 25% of women and 33% of men supplements are those who already in-
daily.25 If these recommendations are ingested less than 2.5 servings of fruits gest vitamin C from foods or whose vi-
and vegetables daily. Mean vitamin C tamin C intake is otherwise low. Na-
intake for men and women was higher tional surveys have not provided
Table. Food Sources of Vitamin C than median intake, suggesting that quantitative estimates of total nutri-
Vitamin C, some people ingested much more vi- ent intakes based on food consump-
Source (Portion Size) mg
tamin C than the median. Data from tion plus dietary supplements.26
Fruit
surveys of specific populations on mean
Cantaloupe (1/4 Medium) 60 Steady-State Concentrations
Fresh grapefruit (1/2 Fruit) 40 dietary intake show that approxi-
Honeydew melon (1/8 Medium) 40 mately 25% of 9- to 10-year-old girls Before 1996, steady-state plasma vita-
Kiwi (1 Medium) 75
Mango (1 Cup, sliced) 45
had vitamin C intake below the RDA min C concentrations as a function of
Orange (1 Medium) 70 of 45 mg for their age,27 and less than dose were uncertain. Prior inpatient and
Papaya (1 Cup, cubes) 85 15% of Latino children ingested the rec- outpatient investigations of vitamin C
Strawberries (1 Cup, sliced) 95
Tangerines or tangelos (1 Medium) 25 ommended intake of fruits and veg- metabolism were incomplete or had de-
Watermelon (1 Cup) 15 etables.28 Data from NHANES II indi- sign limitations.1,2 In 1996 new phar-
Juice cated that 20% to 30% of US adults macokinetic data about vitamin C were
Grapefruit (1/2 Cup) 35 ingested less than 60 mg/d of vitamin published, based on results from 7 men
Orange (1/2 Cup) 50
aged 20 to 26 years who were inpa-
Fortified Juice tients for 4 to 6 months at the US Na-
Apple (1/2 Cup) 50 Figure 2. Plateau Vitamin C Concentrations
as a Function of Dose tional Institutes of Health.33 To solve
Cranberry juice cocktail (1/2 Cup) 45
Grape (1/2 Cup) 120 measurement problems of earlier stud-
Vegetables
100 ies, vitamin C was measured by high-
Plateau Plasma Vitamin C, µmol/L

Asparagus, cooked (1/2 Cup) 10 pressure liquid chromatography with

80
Broccoli, cooked (1/2 Cup) 60 coulometric electrochemical detec-
Brussels sprouts, 50
cooked (1/2 Cup)
tion.20 Steady-state concentration for
60
Cabbage each dose was based on the pharmaco-
Red, raw, chopped (1/2 Cup) 20 logical definition and occurs when the
Red, cooked (1/2 Cup) 25 40
Raw, chopped (1/2 Cup) 10 amount of vitamin absorbed equals the
Cooked (1/2 Cup) 15 20 amount of vitamin eliminated.34 Vita-
Cauliflower, raw or cooked 25 Current Recommended Dietary Allowance
(1/2 Cup) min C in water was administered ei-
0
Kale, cooked (1 Cup) 55 0 500 1000 1500 2000 2500 ther in the fasting state or at least 90
Mustard greens, cooked (1 Cup) 35
Pepper, red or green
Dose, mg/d minutes before meals. The pharmaco-
Raw (1/2 Cup) 65 kinetic data showed a steep sigmoidal
Cooked (1/2 Cup) 50 Subjects ingested less than 5 mg of vitamin C daily
Plantains, sliced, cooked (1 Cup) 15 from dietary sources. When subjects’ vitamin C plasma relationship between vitamin C dose
Potato, baked (1 Medium) 25 concentrations decreased to approximately 7 µmol/L, and steady-state plasma concentra-
Snow peas each of 7 repletion doses were administered in suc-
cession. Doses of 15 to 1250 mg were administered tion (FIGURE 2). Plasma concentra-
Fresh, cooked (1/2 Cup) 40
Frozen, cooked (1/2 Cup) 20 twice daily. Subjects achieved steady-state for each tions produced by the current US RDA
dose before the next dose was administered. Data rep-
Sweet potato
resent fasting morning samples. Plateau concentra-
of 60 mg were on the bottom third of
Baked (1 Medium) 30
Vacuum can (1 Cup) 50 tion was defined as the mean of 5 or more samples the steep sigmoidal portion of the curve;
Canned, syrup-pack (1 Cup) 20 drawn over at least 7 days with 10% SD or less. The the 200-mg dose was the first dose be-
Tomato first sample included in all plateau determinations was
Raw (1/2 Cup) 15 90% or more of the final plateau mean. Used with yond the steep portion of the curve; the
Canned (1/2 Cup) 35 permission from the Proceedings of the National Acad- 200-mg dose produced approximately
Juice (6 Fluid oz) 35 emy of Sciences.33
80% saturation of plasma; and plasma
©1999 American Medical Association. All rights reserved. JAMA, April 21, 1999—Vol 281, No. 15 1417

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 VITAMIN C INTAKE

saturation occurred at the 1000 mg/d tios assume that there is a constant vol- Vitamin C is not bound to plasma pro-
dose. Average plasma vitamin C con- ume of distribution and constant teins, and is dialyzable.38 Patients receiv-
centrations over 24 hours will be clearance for the test substance.34 At vi- ing dialysis require vitamin C replace-
slightly higher than the steady-state pre- tamin C doses of less than 200 mg, these ment, but ideal replacement amounts are
dose concentrations, but to calculate assumptions were not valid, probably uncertain. If vitamin C is not replaced,
them requires complex fitting of the as a consequence of multicompart- scurvy can occur. In patients with renal
data to a multicompartment model of ment distribution.35 Methods to deter- insufficiency not requiring dialysis, it is
vitamin C distribution.35 mine bioavailability at vitamin C doses unknown whether vitamin C utiliza-
The 1996 National Institutes of of less than 200 mg require complex tion is affected by metabolic abnormali-
Health study also measured vitamin C models that account for nonlinearity in ties associated with renal insufficiency
concentrations in neutrophils, mono- clearance and volume of distribution. and whether there is impaired vitamin
cytes, and lymphocytes at each total When these factors were accounted C filtration or reabsorption.
daily dose from 30 to 2500 mg.33 All cell for in a new model,35 bioavailability was Before 1996 there were few data de-
types saturated at the 100 mg/d dose. calculated as 89% for 15 mg, 80% for scribing urine excretion of vitamin C at
Cells saturated at lower doses com- 100 mg, 72% for 200 mg, 63% for 500 steady-state concentration for a given
pared with plasma. An explanation is mg, and 46% for 1250 mg. Based on the dose.2,19,37 Urine excretion of vitamin C
that ascorbate accumulation in cells is model, a total daily vitamin C dose of for each dose was measured at steady-
mediated by active transport, which 200 mg ingested in divided doses would state concentration in the National In-
saturates (achieves Vmax) at approxi- have nearly complete bioavailability. stitutes of Health study. In 6 of 7 volun-
mately 60 to 70 µmol/L. The ascor- Similar to steady-state plasma concen- teers, no urine excretion occurred at
bate dose producing a plasma concen- tration data, true bioavailability data vitamin C doses of less than 100 mg/d.
tration of approximately 60 µmol/L is for vitamin C were based on its ad- At 100 mg, approximately 25% of the
100 mg/d. In contrast, plasma satu- ministration in the fasted state as a pure dose was excreted, and at 200 mg ap-
rated at the 1000-mg/d dose, which pro- substance. There are no data for true proximately 50% of the dose was ex-
duced a plasma concentration of ap- bioavailability of vitamin C when admin- creted. At higher doses, such as of 500
proximately 80 µmol/L. Other factors istered with foods or in compounds mg and 1250 mg, only part of the in-
affecting plasma saturation are bioavail- found in foods. It remains possible that
ability and renal excretion. food components such as glucose will
inhibit vitamin C absorption, which Figure 3. Vitamin C Bioavailability in Plasma
Bioavailability would decrease bioavailability and shift
240
Bioavailability is a measure of efficiency ascorbate dose-concentration curves to
200
of gastrointestinal tract absorption. Most the right. If this occurred, to obtain the
160
investigators estimated vitamin C bio- dose-plasma concentration relation-
120
availability indirectly because of diffi- ships observed for pure vitamin C, the
Plasma Vitamin C, µmol/L

80
culty obtaining true bioavailability data.36 amounts of vitamin C ingested from 40
Oral absorption was compared with foods would have to be higher. 0
urine excretion or absorption of one form
of vitamin C vs another. In the National Urinary Excretion of Vitamin C 800
Institutes of Health study, at each steady- Vitamin C undergoes glomerular fil-
600
state, true bioavailability was studied for tration and renal reabsorption.37 Ascor-
1 dose, which was that total daily dose bate probably passes unchanged 400

producing steady-state.33 For example, through glomeruli and undergoes con- 200
the 200-mg/d dose was administered as centration-dependent active tubular re- 0
100 mg twice daily. At steady-state, bio- absorption by a vitamin C transport 0 2 4 6 8 10 12 14
Hours After Dose
availability sampling was for 200 mg protein. When the transport protein
given once. Vitamin C bioavailability at reaches saturation (achieves Vmax), re- Bioavailability is shown for 1 subject at 200 mg (top)
steady-state for each dose was approxi- maining vitamin C is not transported and at 1250 mg (bottom). For each dose, vitamin C
was administered at zero time (8 AM) orally and samples
mately 100% for 200 mg, 73% for 500 and is excreted in urine. It is un- were obtained as shown. After 24 hours the same dose
mg, and 49% for 1250 mg (FIGURE 3). known whether vitamin C is actively se- was given intravenously and samples were obtained
as shown. Dashed lines indicate baselines. Bioavail-
Although it was likely that bioavail- creted into renal tubules distal to the ability sampling was performed at steady-state for the
ability was complete at doses of less reabsorption site. There is no known total daily dose. Bioavailability was the ratio of the area
than 200 mg, calculations could not be renal mechanism for dehydroascorbic of the oral dose (area under the curvepo) divided by
the area of the intravenous dose (area under the cur-
made using direct area under the curve acid filtration and reabsorption, since veiv). See “Bioavailability” for details. Used with per-
ratios33 (Figure 3). Bioavailability cal- there is probably no dehydroascorbic mission from the Proceedings of the National Acad-
emy of Sciences.33
culations using area under the curve ra- acid in normal human plasma.
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 VITAMIN C INTAKE

gested dose was absorbed, but almost the observed than is now found. There- occurred in subjects with glucose-6-
entire absorbed amount was excreted. fore, it is unlikely that vitamin C in- phosphate dehydrogenase deficiency
These data show that at steady-state, vi- duces iron overabsorption in people who received at least 6 g of ascorbate
tamin C doses of more than 500 mg have heterozygous for hemochromatosis. as a single oral dose.60 We know of no
little impact on body stores.33 The thresh- Data are conflicting concerning the clinical indication for such doses. If it
old dose for vitamin C excretion is 100 effect of ascorbate on urate excretion. is necessary to administer ascorbate in-
mg/d, and the threshold plasma concen- Hyperuricosuria occurred when some travenously, patients should first be
tration for excretion is approximately 55 patients received a large dose of ascor- screened for glucose-6-phosphate de-
to 60 µmol/L. bate intravenously,46 although contra- hydrogenase deficiency.
dictory findings were reported.47 Tran- Harmful effects have been mistak-
Adverse Effects sient hyperuricosuria occurred when enly attributed to vitamin C, includ-
Vitamin C has few toxic effects, and ad- 3 g of vitamin C was given.48 The con- ing hypoglycemia, rebound scurvy, in-
verse effects are related to dose.39 Di- flicting findings may be due to lack of fertility, mutagenesis, and destruction
arrhea or abdominal bloating can oc- steady-state for vitamin C, differences of vitamin B12. Health professionals
cur when several grams are taken at in plasma concentrations, or duration should recognize that vitamin C does
once, although there are no indica- of vitamin C administration.33 In all re- not produce these effects.1
tions for such doses. With guaiac- ports hyperuricosuria was absent at vi-
based tests, false-negative results for de- tamin C doses of less than 1 g. Biochemical and Molecular
tecting stool occult blood occur with A product of vitamin C catabolism is Function in Relationship
intake of 250 mg of vitamin C.40 Vita- oxalate. Its excretion in relationship to to Vitamin Concentration
min C intake from all sources should vitamin C intake has been controver- There are no definitive data showing
be less than 250 mg for several days sial, in part because of oxalate assay that vitamin C concentrations directly
prior to stool testing. Vitamin C also can techniques. In assays used before 1987, enhance biochemical or molecular
cause false-negative test results in de- artificial oxalate elevation occurred due function in human tissues, or that
tecting gastric occult blood.41 to inadvertent ascorbate conversion to higher vitamin C concentrations con-
Vitamin C enhances iron absorp- oxalate in stored samples.49,50 Despite fer benefit. Only indirect information
tion. Patients may have iron overload better assays, controversy remains.33,51-56 is available regarding dose-function re-
due to hemochromatosis, thalassemia Taken together, the data show that oxa- lationships.
major, sideroblastic anemia, or other late excretion is probably increased at The plasma concentration corre-
diseases requiring multiple red blood vitamin C doses of 1 g or more daily in sponding to the current RDA of 60 mg/d
cell transfusions. 42 While theoreti- some healthy people, although conse- is 24 µmol/L and is close to Km for vita-
cally possible for vitamin C to en- quences are unclear. In people with un- min C transport. By contrast, the plasma
hance iron overload or harm individu- derlying hyperoxaluria, oxalate excre- concentration corresponding to 200
als with these disorders, patients with tion is accelerated by ascorbate doses mg/d is 66 µmol/L, a concentration at
hemochromatosis should not be dis- of 1 g or more, and for these people which vitamin C transport achieves Vmax
couraged from eating fruits and veg- megadoses could be harmful.53,55 Be- and tissues saturate.61 Whether this is
etables.42-44 Although uncertain, it is un- cause hyperoxaluria can be occult, and beneficial is unknown. Because vita-
likely that vitamin C induces iron oxalate excretion can be increased by min C saturation has no apparent ad-
overabsorption in healthy people. For vitamin C in some healthy people, safe verse consequences, ideal intake might
iron-replete subjects who consumed vitamin C intake is less than 1 g/d. be that amount producing maximum
foods that contained iron, 2 g of ascor- Hyperoxalemia in patients receiv- Vmax for beneficial biochemical func-
bate did not increase iron stores, sug- ing dialysis was induced by vitamin C tions that are vitamin C-dependent.62
gesting that ascorbate does not induce when it was administered intrave- Such functions include proline and ly-
overabsorption of iron.45 Patients with nously in repeated 1-g doses,57 but there sine hydroxylation for wound healing
hemochromatosis are homozygous for is no rationale for such use. Vitamin C and bone formation, oxidant quench-
the disease-causing gene. It is un- daily doses of 500 mg or more could ing, carnitine synthesis for fatty acid me-
known whether subjects who are het- possibly produce hyperoxalemia in pa- tabolism, and perhaps synthesis of some
erozygous for the gene have enhanced tients receiving dialysis. Ideal vitamin hormones.
iron absorption from vitamin C. How- C intake for patients receiving dialysis Oxidation of LDL in vitro is inhib-
ever, iron overload is rare compared is unknown, but intake probably should ited by vitamin C concentrations above
with the prevalence of people hetero- not exceed 200 mg/d. 40 to 50 µmol/L.6,7 However, in vitro
zygous for the disease-causing gene. If Hemolysis occurred after vitamin C oxidation assays may not be related to
ascorbate caused iron overload in het- was administered intravenously in pa- oxidation conditions in vivo, and it is
erozygotes, a higher incidence and tients with glucose-6-phosphate dehy- unproven whether vitamin C prevents
prevalence of iron overload should be drogenase deficiency.58,59 Hemolysis also LDL oxidation in vivo.
©1999 American Medical Association. All rights reserved. JAMA, April 21, 1999—Vol 281, No. 15 1419

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 VITAMIN C INTAKE

When neutrophils encounter bacte- Data describing the association of vi- ease and stroke.89 In this and another
ria, neutrophils are activated to pro- tamin C consumption with health study in which vitamin C appeared to
duce oxidants, which leak outside neu- maintenance or disease outcome are be protective,91 the measurement tech-
trophils and oxidize extracellular vitamin conflicting. For example, vitamin C niques overestimate vitamin C values
C to dehydroascorbic acid.63,64 Dehy- supplement use for more than 10 years at low concentrations,20 and the find-
droascorbic acid is immediately trans- was associated with lower cataract ings may indicate that vitamin C is pro-
ported into neutrophils by glucose trans- risk, 72 but findings were observa- tective only compared with defi-
porters and then reduced to vitamin C tional, sample size was small, and other ciency. Taken together, the data show
by the glutathione-dependent protein nutrients or behaviors could have ex- that only marked vitamin C defi-
glutaredoxin.65,66 Because ascorbate plained the results.73 Other reports con- ciency is associated with coronary heart
oxidized extracellularly is recycled intra- cerning cataract prevention by vita- disease, and although vitamin C might
cellularly, the process is called ascor- min C are inconsistent.74-81 Effects of have a protective effect against stroke,
bate recycling. During ascorbate recy- ascorbate intake on coronary heart dis- the findings are inconclusive due to im-
cling, extracellular ascorbate quenches ease are also inconclusive.9,10,82-89 perfect measurement techniques.
extracellular oxidants, and large in- Some inconsistencies may be ex- Other than to treat deficiency, benefi-
creases in intracellular vitamin C occur plained by relating results to intake cial effects of vitamin C on clinical out-
at the same time intracellular oxidants rather than to plasma or tissue concen- comes have not been conclusively dem-
are formed. Neutrophil-generated oxi- trations. Because of the steep relation- onstrated. It might be possible to
dants could damage neutrophils and ship between vitamin C plasma concen- determine such effects in clinical condi-
impair bacterial killing and also dam- tration and daily intake of 100 mg or less, tions in which vitamin C concentra-
age surrounding tissue. Thus, oxidant control subjects may have already been tions are low and then repleted. Vita-
quenching by ascorbate should be ben- close to saturation for vitamin C, addi- min C plasma concentrations compared
eficial, but it is unknown whether vita- tional doses would cause minimal in- with controls are low in smokers, patients
min C or its recycling will enhance neu- creases in concentrations, and an effect recovering from surgery, and patients
trophil function. Vitamin C recycling is would not be expected. 3 3 , 7 1 Con- with sepsis, human immunodeficiency
near maximal at an extracellular con- versely, small differences in vitamin C virus (HIV) infection, critical illnesses
centration of 75 µmol/L.64 intake of less than 100 mg have sub- requiring intensive care, acute respira-
Nitrosamines are formed in the gas- stantial consequences for plasma con- tory distress syndrome, and pancreati-
trointestinal tract under certain condi- centrations (Figure 2).33 Thus, instead tis.95-101 The significance of low vitamin
tions and can be harmful. Nitrosamine of correlating population outcomes to C concentrations in these patients is
formation may be decreased by vita- vitamin C intake, it may be preferable unknown. Circulating oxidants presum-
min C doses of 200 mg/d,67 but whether to correlate outcomes to measured vi- ably oxidize ascorbate in those who
this has clinical benefit remains to be de- tamin C concentrations in plasma or smoke, are critically ill, have acute res-
termined. tissues.90 piratory distress syndrome, or have pan-
Data relating disease outcome to vi- creatitis. It is uncertain if oxidation occurs
Beneficial Dose Effects tamin C concentrations are available for in vivo or occurs only as plasma is pre-
Diets with 200 mg or more of vitamin cardiovascular disease and stroke. Vi- pared. The effect of altered renal func-
C from fruits and vegetables are associ- tamin C plasma concentrations were tion on ascorbate economy in these
ated with lower cancer risk, especially not related to risk of death due to coro- patients is also unknown. For example,
for cancers of the oral cavity, esopha- nary heart disease but were for stroke91; low ascorbate postoperatively could be
gus, stomach, colon, and lung.11,14,68,69 were associated with increased risk caused by a transient increase in vita-
Five servings of fruits and vegetables ap- for coronary artery disease only with min C renal excretion, but this remains
pear to be protective. However, con- marked deficiency92,93; and had little94 unproven.
sumption of vitamin C as a supple- or no significant effect on ischemic heart For patients with low vitamin C con-
ment in experimental trials did not disease and stroke after adjustment for centrations, will increasing concentra-
decrease the incidence of colorectal ad- other risk factors.10,87 In one study, a tions change outcome? For many con-
enoma and stomach cancer.11,70,71 Fruit higher plasma vitamin C concentra- ditions it is either difficult to address
and vegetable intake may be associated tion was associated with lower mortal- this question directly or the issue has
with lower cancer risk not because of vi- ity only for those with high dietary plus not been considered adequately. Be-
tamin C alone but perhaps because of supplemental intake of vitamin C,82 sug- cause of complexities in identifying pa-
interactions between ascorbate and bio- gesting vitamin C itself was not respon- tients who will develop adult respira-
active compounds in these foods, or be- sible. In another study, plasma vita- tory distress syndrome, pancreatitis,
cause of compounds independent of vi- min C concentrations of more than 60 sepsis, or critical illness, it is difficult
tamin C, or because of characteristics of µmol/L vs 6 to 23 µmol/L were associ- to test effects of vitamin C prospec-
people who eat fruits and vegetables.14,69 ated with decreased risk of heart dis- tively. Whether increasing vitamin C
1420 JAMA, April 21, 1999—Vol 281, No. 15 ©1999 American Medical Association. All rights reserved.

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 VITAMIN C INTAKE

concentrations will ameliorate smok- RECOMMENDATIONS 100 mg dose half of the men would have
ing-associated diseases remains un- FOR INGESTION urine excretion above this value and
known. Preliminary evidence indi- In 1998, the Food and Nutrition Board half below. Thus, the EAR is 100 mg/d,
cated vitamin C had a small effect on of the National Academy of Sciences de- and the RDA is 120 mg/d.
decreasing viral load in patients in- veloped new classifications for provid-
fected with HIV, without altering HIV- ing estimates of nutrient intakes.106 The Adequate Intake
associated infections.98 In elderly pa- concept of RDAs was expanded to the The Food and Nutrition Board can de-
tients with decubitus ulcers and low new guidelines, the Dietary Reference cide that an EAR is indeterminate, and
vitamin C concentrations, patients who Intakes, which include the following an AI is used in place of an RDA. Ad-
received 500 mg of vitamin C had im- reference values: estimated average re- equate intake is an intake level based
proved healing compared with con- quirement (EAR), RDA, adequate in- on observed or experimentally deter-
trols.102 The effect remains unproven be- take (AI), and tolerable upper intake mined approximations of nutrient in-
cause only 8 patients were in each group level (UL). The criteria for estimating take by a group of healthy people.106 The
and vitamin C concentrations in supple- recommended ingestion of vitamin C primary use of the AI is as a goal for the
mented patients were much higher than can be applied to each of these Dietary nutrient intake of individuals.
those found by others.103 There are few Reference Intakes categories. One AI calculation uses criteria of the
data relating changes in vitamin C current RDA of 60 mg.16,17 As noted ear-
concentration to susceptibility to bac- EAR and RDA lier these criteria are (1) protection
terial or viral infections.64,104 To ad- The Food and Nutrition Board defined against deficiency for 1 month if vita-
vance understanding, conditions in the EAR as the amount of nutrient esti- min C ingestion suddenly ceased, (2) the
which vitamin C concentrations are low mated to meet the nutrient require- dose representing the threshold of urine
should be identified and tested pro- ment of half the healthy individuals in a excretion, and (3) a dose that replaces
spectively to determine whether in- life-stage and gender group.106 For the se- catabolic losses. Data are available for the
creasing vitamin C concentrations af- lected criterion used as the basis of the first 2 criteria but not the third. When
fects outcome. EAR, half the individuals would have val- these data are used as the basis of an AI,
Pauling104 advocated vitamin C doses ues above the EAR value and half be- 100 mg/d will prevent deficiency for 1
of many grams for preventing and treat- low. Using the EAR definition, the RDA month and is the threshold dose for urine
ing the common cold. However, the pa- is arbitrarily calculated by taking the EAR excretion. Catabolism calculations can-
tients who derived benefit, a slight re- plus 2 SDs. When the SDs of the EAR are not be performed because modeling can-
duction in cold incidence, were a small not known, a coefficient of variation is not account for multicompartment ca-
subset who were probably vitamin C de- arbitrarily assumed to be 10%, and the tabolism and because catabolism varies
ficient.104 Gram doses of vitamin C do RDA is therefore 1.2 3 EAR. as a function of repletion state, so that
not have a place in prevention or treat- The EAR is difficult to calculate for catabolic estimates calculated at 1 steady-
ment of colds. However, physicians can vitamin C because most clinical stud- state may not be relevant at another.1,35
screen for occult vitamin C deficiency ies have not been based on EAR prin- Another AI calculation, based on the
by asking about intake of fruits, veg- ciples. One EAR calculation is based on criteria discussed herein, is 200 mg/d
etables, and vitamin supplements. vitamin C saturation in neutrophils, provided by 5 servings of fruits and veg-
which are saturated at an intracellular etables. This amount is available in US
Prevention of Deficiency vitamin C concentration of 1.3 mmol/L. diets now.25 The first amount beyond the
The first symptom or sign of vitamin C The EAR is that dose at which 50% of steep portion of the dose-concentra-
deficiency is fatigue, the “lassitude” of subjects’ neutrophils are saturated and tion curve for plasma is 200 mg/d but
scurvy.105 Fatigue is subtle, precedes is 100 mg/d.33 The RDA calculation is: plasma saturation is not induced at this
other symptoms and signs, occurs at 100 mg (EAR) + 20 mg (0.2 3 EAR) amount and instead occurs at 1000
plasma concentrations below approxi- = 120 mg (RDA). Another EAR calcu- mg/d.33 Tissues probably will be satu-
mately 20 µmol/L, and resolves above lation is based on urine excretion of vi- rated at 200 mg/d, without apparent
this concentration.33 Steady-state plasma tamin C at steady-state. In healthy men harm. Bioavailability is near maximal for
concentrations achieved by 60 mg/d will at steady-state, vitamin C excretion first 100 mg twice daily, at least for pure vi-
prevent deficiency for 10 to 14 days if occurs at 100 mg/d.33 It is assumed that tamin C. The estimate of 200 mg/d ac-
vitamin C ingestion suddenly ceased. a selected value of urine excretion rep- counts for the possibility that vitamin C
Steady-state plasma concentrations of 55 resents the EAR, that this value occurs bioavailability from foods might de-
to 60 µmol/L, achieved by 100 mg/d, will near the threshold of urine excretion, crease compared with pure vitamin C.
probably prevent deficiency for 1 month and that the value can be considered as At the 200-mg/d dose, urine excretion
if vitamin C ingestion suddenly ceased33 fractional excretion of vitamin C. If the of vitamin C is beyond the excretion
(M. Levine, MD, and Y. Wang, MD, un- selected value of fractional excretion is threshold, but fractional excretion is less
published data, 1999). 23% excreted daily at steady-state, at the than 1. There are no known adverse ef-
©1999 American Medical Association. All rights reserved. JAMA, April 21, 1999—Vol 281, No. 15 1421

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 VITAMIN C INTAKE

fects of vitamin C at this dose.53 Al- verse health effects to almost all indi- tion. In: Paoletti R, Sies H, Bug J, Grossi E, Poli A, eds.
Vitamin C: The State of The Art in Disease Preven-
though uncertain, it is possible that there viduals in the population.106 As intake tion Sixty Years After the Nobel Prize. Milan, Italy:
are biochemical benefits due to the con- increases above UL, risk of adverse ef- Springer; 1998:41-49.
12. Correa P. Human gastric carcinogenesis. Cancer
centrations achieved by the 200-mg/d fects increases. Because patients with Res. 1992;52:6735-6740.
dose. Vitamin C transport will achieve preexisting hyperoxaluria may have in- 13. Sobala GM, Schorah CJ, Pignatelli B, et al. High
Vmax in tissues,61 LDL oxidation might creased risk of nephrolithiasis at vita- gastric juice ascorbic acid concentrations in members
of a gastric cancer family. Carcinogenesis. 1993;14:
be decreased compared with lower min C doses of 1 g or more, and be- 291-292.
doses,6,7 ascorbate recycling as a protec- cause this dose might increase oxalate 14. Byers R, Guerrieri N. Epidemiologic evidence for
vitamin C and vitamin E in cancer prevention. Am J
tive mechanism in neutrophils might be excretion in some healthy people, UL of Clin Nutr. 1995;62(suppl):1385S-1392S.
optimized,64 and decreased nitrosation vitamin C should be less than 1 g/d.33,53,55 15. Hallberg L, Brune M, Rossander-Hulthen L. Is there
a physiological role of vitamin C in iron absorption?
in the gastrointestinal tract might re- Ann N Y Acad Sci. 1987;498:324-332.
sult from this dose.67 Also, intake of 5 CONCLUSION 16. Food and Nutrition Board. Recommended Di-
servings of fruits and vegetables is as- Revised recommendations for vitamin etary Allowances. Washington, DC: National Acad-
emy Press; 1980.
sociated with decreased cancer risk.14,69 C intake are based on new data, new 17. Food and Nutrition Board. Recommended Di-
Finally, 200 mg of vitamin C will pre- criteria for devising recommenda- etary Allowances. Washington, DC: National Acad-
emy Press; 1989.
vent deficiency for more than 1 month tions, and new guidelines termed Di- 18. Levine M, Cantilena CC, Dhariwal KR. In situ ki-
if ingestion suddenly ceased.33 There is etary Reference Intakes. Recom- netics and ascorbic acid requirements. World Rev Nutr
no certain benefit from vitamin C at this mended intake of vitamin C can be Diet. 1993;72:114-127.
19. Baker EM, Hodges RE, Hood J, et al. Metabolism
dose compared with lower ones, except increased from 60 mg to 100 mg to 200 of 14C- and 3H-labeled L-ascorbic acid in human
for prevention of scurvy with a safety mg/d, depending on the criteria se- scurvy. Am J Clin Nutr. 1971;24:444-454.
20. Washko PW, Welch RW, Dhariwal KR, et al. Ascor-
margin. A recommendation of 200 mg lected and the Dietary Reference In- bic acid and dehydroascorbic acid analyses in biologi-
from 5 fruits and vegetables daily will takes guidelines. Whenever possible, vi- cal samples. Anal Biochem. 1992;204:1-14.
21. Food and Nutrition Board. How Should the Rec-
make intake recommendations similar to tamin C intake should come from fruits ommended Dietary Allowances Be Revised? Wash-
those of the US Department of Agricul- and vegetables and physicians should ington, DC: National Academy Press; 1994.
ture and National Cancer Institute.25 encourage their patients to eat 5 serv- 22. US Department of Agriculture. USDA Nutrient Da-
tabase for Standard Reference. Washington, DC: US
Mean fruit and vegetable intake for ings of fruits and vegetables daily. Vi- Dept of Agriculture; 1998. Release 12.
most people decreased slightly be- tamin C doses of 1 g or more could have 23. Vanderslice JT, Higgs DJ. Vitamin C content of foods.
Am J Clin Nutr. 1991;54(suppl):1323S-1327S.
tween 1965 and 1991.107 From 1991, adverse consequences in some people, 24. Erdman JW, Klein BP. Harvesting, processing, and
when the National Cancer Institute be- and physicians should counsel pa- cooking influences on vitamin C in foods. In: Seib PA,
gan its 5-a-day program, mean intake tients to avoid these doses. Tolbert BM, eds. Ascorbic Acid: Chemistry, Metabo-
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