होम Journal of Nutrition Ascorbate Increases Human Oxaluria and Kidney Stone Risk

Ascorbate Increases Human Oxaluria and Kidney Stone Risk

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The Journal of Nutrition
July, 2005
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Human Nutrition and Metabolism
Ascorbate Increases Human Oxaluria and Kidney Stone Risk1,2
Linda K. Massey,3 Michael Liebman,* and Susan A. Kynast-Gales
Department of Food Science and Human Nutrition, Washington State University, Spokane, WA and
*Department of Family and Consumer Sciences (Nutrition), University of Wyoming, Laramie, WY
ABSTRACT Currently, the recommended upper limit for ascorbic acid (AA) intake is 2000 mg/d. However,
because AA is endogenously converted to oxalate and appears to increase the absorption of dietary oxalate,
supplementation may increase the risk of kidney stones. The effect of AA supplementation on urinary oxalate was
studied in a randomized, crossover, controlled design in which subjects consumed a controlled diet in a university
metabolic unit. Stoneformers (n ⫽ 29; SF) and age- and gender-matched non-stoneformers (n ⫽ 19; NSF)
consumed 1000 mg AA twice each day with each morning and evening meal for 6 d (treatment A), and no AA for
6 d (treatment N) in random order. After 5 d of adaptation to a low-oxalate diet, participants lived for 24 h in a
metabolic unit, during which they were given 136 mg oxalate, including 18 mg 13C2 oxalic acid, 2 h before
breakfast; they then consumed a controlled very low-oxalate diet for 24 h. Of the 48 participants, 19 (12
stoneformers, 7 non-stoneformers) were identified as responders, defined by an increase in 24-h total oxalate
excretion ⬎ 10% after treatment A compared with N. Responders had a greater 24-h Tiselius Risk Index (TRI) with
AA supplementation (1.10 ⫾ 0.66 treatment A vs. 0.76 ⫾ 0.42 treatment N) because of a 31% increase in the
percentage of oxalate absorption (10.5 ⫾ 3.2% treatment A vs. 8.0 ⫾ 2.4% treatment N) and a 39% increase in
endogenous oxalate synthesis with treatment A than during treatment N (544 ⫾ 131 A vs. 391 ⫾ 71 ␮mol/d N). The
1000 mg AA twice each day increased urinary oxalate and TRI for calcium oxalate kidney stones in 40% of
participants, both stoneformers and non-stoneformers. J. Nutr. 135: 1673–1677, 2005; .


vitamin C


ascorbic acid



The current recommended upper limit for ascorbic acid
(AA)4 is 2000 mg/d (1). A small percentage (1.5%) of ingested AA is converted in vivo to oxalate (2), which is
excreted without further metabolism quantitatively in the
urine over 24 h. It is uncertain whether amounts higher than
typical intakes from foods increase the risk for kidney stones
(1). AA supplementation is widely practiced in the United
States; 12.4% of the U.S. adult population (3) and 12–14% of
stoneformers (4) reported taking ⱖ500 mg/d. We reported
previously (5) that mean 13C2-oxalic acid absorption was
significantly higher in stoneformers (SF) than in non-stoneformers (NSF) administered AA (treatment A; 10.7 ⫾ 3.2%
compared with 7.6 ⫾ 2.6%) but not different between these
subpopulations not given any AA (treatment N; 9.0 ⫾ 2.7%
compared with 8.5 ⫾ 2.6%). If AA supplements are taken, the
increased urinary oxalate may increase the risk of calcium
oxalate kidney stones.
Contradictory results from previous research evaluating the





effect of AA supplementation on urinary oxalate were attributed primarily to methodology that allowed in vitro degradation of urinary AA to oxalate (6). However, early case studies
suggested that genetic differences contributed to the variable
response to AA supplements (7). Small sample sizes and
insufficient dietary control have limited the identification of a
subset of individuals that respond to AA supplementation
with increased urinary oxalate.
This study examined the effect of a divided dose of 2000
mg/d AA on oxalate excretion, absorption, and endogenous
synthesis, as well as the Tiselius Risk Index (TRI) for calcium
oxalate precipitability. The study design included strict control of dietary AA and oxalate. Both SF and NSF were studied
for ascorbate-induced changes in risk; subjects were also characterized as responders or nonresponders.
Subjects. Individuals (n ⫽ 29) with a self-reported history of
calcium oxalate stones and 20 age- and gender-matched non-stoneformers were recruited from participants in previous nephrolithiasis
studies, their families, and acquaintances (Table 1). All participants
were at least 18 y old and without complicating medical conditions
(renal, urinary tract, intestinal, thyroid, parathyroid, skeletal, or nutritional disorders; uncontrolled hypertension or diabetes), or medication or supplement use that affect calcium or oxalate metabolism.
Nonprescription aspirin, antacid, and laxative use were prohibited,
but prescription medications were allowed if the dosage had been
stable for 3 mo and was the same for both study treatments. Six of the


Presented in part at the American Society for Bone and Mineral Research,
October 5, 2004, Seattle, WA [Massey, L., Kynast-Gales, S. & Liebman, M.
(2004) Ascorbic acid supplementation, urinary oxalate and risk of kidney stone
disease. J. Bone Miner. Res. 19 (suppl. 1): S465 (abs.)].
Supported by a grant from the Vitamin Settlement Fund through the Attorney General’s Office of Washington State and project 0370 Washington State
University Agricultural Research Center.
To whom correspondence should be addressed. E-mail: massey@wsu.edu.
Abbreviations used: AA, ascorbic acid; SF, stoneformers; NSF, non-stoneformers; treatment A, 2000 mg/d ascorbic acid; treatment N, no ascorbic acid
supplement; TRI, Tiselius Risk Index.

0022-3166/05 $8.00 © 2005 American Society for Nutritional Sciences.
Manuscript received 31 January 2005. Initial review completed 23 February 2005. Revision accepted 7 April 2005.
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Participant characteristics at screening1

Age, y
Weight, kg
BMI, kg/m2
Urinary calcium, mg/d
Urinary oxalate, mg/d



19 M, 10 F
49.8 ⫾ 14
88.8 ⫾ 17.2
30.5 ⫾ 5.7
217 ⫾ 118
35 ⫾ 8
1.3 ⫾ 0.6

8 M, 11 F
50.8 ⫾ 14.3
79.4 ⫾ 16.0
29.8 ⫾ 6.7
164 ⫾ 78
33 ⫾ 12
0.9 ⫾ 0.5

Values are means ⫾ SD.

29 SF and 3 of the 20 NSF habitually consumed ⱖ500 mg of AA
supplements several times each week; they were asked to discontinue
AA at least 1 wk before study participation because previous studies
showed that 3 d abstention was sufficient to eliminate the effects of
AA on urinary ascorbate and oxalate (8). Calcium supplements were
restricted to ⱕ100 mg/d, and other habitual nutrient supplements
were limited to ⱕ100% of the Recommended Dietary Allowance
during the study. All participants were screened for normal fasting
urinary calcium:creatinine ratio and normal calcium absorption determined by 4-h urinary calcium excretion after a 1000-mg oral
calcium load [1 package Carnation French Vanilla Instant Breakfast
(Nestle Food Company), 240 mL 2% low-fat milk, and 22 mL
calcium glubionate syrup (Calciquid, Breckenridge Pharmaceutical)].
Lean body mass was determined by air displacement plethysmography
(Bod Pod Body Composition System, Life Measurement) or bioelectrical impedance (Model BES 200Z, Bioelectrical Sciences) and used
for the determination of completeness of daily urinary collections by
comparing expected creatinine with actual creatinine. Procedures
were approved by the Human Subjects Review Committee at Washington State University and written informed consent was obtained
from participants.
Metabolic study design. A randomized crossover design was
employed, with each volunteer participating in two 6-d experimental
periods. Figure 1 depicts the experimental design. During one experimental period (treatment A), they consumed 1000 mg AA supplement (Nature Made Nutritional Products; no detectible oxalate by
direct assay) with the morning and evening meals during adaptation,
and with the oxalate load at 0700 h and the evening meal at 1800 h
in the metabolic unit. The alternate 6-d period (treatment N) was
exactly the same but without AA supplementation. Because the
oxaluric effect of AA reaches a plateau after 3 d (8), and urinary
composition stabilizes by d 4 and 5 of consuming a controlled diet
(9,10), 5 d of adaptation were considered sufficient. Each 6-d experimental period included 2 d of free-living adaptation with consumption of a self-selected, self-recorded low-oxalate diet (excluding the
10 highest known oxalate-containing foods: spinach, rhubarb, beets,
tea, chocolate, nuts, wheat bran, berries, parsley, beans, and other
legumes), followed by an additional 3 d free-living adaptation to a
controlled low-oxalate diet (37– 43 mg oxalate/d) provided by the
investigators, and concluded with 24 h in a metabolic unit consuming
a controlled low-oxalate diet (6 –7 mg oxalate/d) (Table 2). Urinary
AA levels were determined to verify AA supplement compliance. In
the metabolic unit, a staff member observed meals and confirmed
food, oxalate load, and AA supplement consumption by participants.
All foods were purchased from the same suppliers and lots, and were
provided to participants in weighed portions. The oxalate content of
actual lots of all plant foods was measured directly by oxalate oxidase
assay (Trinity Biotech) after acid extraction (11). Caffeinated or
decaffeinated coffee was provided in regulated quantities because the
oxalate content was determined to be low, and caffeine does not
affect oxalate excretion (12). Very low oxalate varieties of herbal tea,
but not regular tea, were also allowed in controlled amounts. Diets
were designed at both 8784 and 10,458 kJ/d to better accommodate
individual energy requirements. The nutrient composition of study
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FIGURE 1 Experimental design. Urine samples collected between
the indicated times were pooled. Ascorbic acid (1000 mg AA, twice
each day) was given during treatment A only.

diets was determined by computerized diet analysis using Nutritionist
Pro software (version 1.3, 2002, N-Squared Computing).
At 0700 h on the morning of the metabolic unit stay, after a 12-h
fast, participants were given a 136-mg oxalate load [18 mg 13C2oxalic acid (Cambridge Isotope Laboratories) plus 118 mg nonlabeled
oxalate contained in a gel capsule] with 175 g of unsweetened

Composition of daily study diets at 2 energy levels1
Adaptation diet

Energy, kJ
Protein, g
Ascorbic acid, mg
Calcium, mg
Magnesium, mg
Oxalate, mg
Sodium, mg

Metabolic unit diet

n ⫽ 20

n ⫽ 28

n ⫽ 20

n ⫽ 28





All participants consumed the same amount of food during the 2
treatments, whichever was most appropriate for their energy expenditure.


applesauce and 240 mL of deionized water. Meals in the metabolic
unit were served at 0900, 1300, and 1800 h. The low-oxalate breakfast consisted of a plain bagel, grape jam, cream cheese, yogurt, and
apple juice. Liberal deionized water intake was encouraged to promote a 24-h urine volume of ⬃2–2.5 L.
During the 5-d adaptation, urine was collected in calibrated jugs
containing 100 mL of 3 mmol/L hydrochloric acid over 24-h periods.
In the metabolic unit, urine was collected and pooled at 2-h intervals
for 8 h after the labeled oxalate load, then at two 3-h intervals, and
finally after 10 h overnight for a total of 24 h. All urine collected in
the metabolic unit was immediately acidified to pH ⬍ 2.0 by the
addition of 20 mL of 3 mmol/L HCl at each collection interval to
prevent in vitro AA degradation to oxalate. Urine volumes were
recorded, urine was filtered (#2 paper, Whatman) and aliquots were
quickly frozen at ⫺20°C until assay.
Biochemical analyses. Urine composition was determined as
follows: AA by the dinitrophenylhydrazine method (13); 13C2-oxalic
acid by GC-MS (Metabolic Solutions); oxalate, citrate, and creatinine by the microplate colorimetric oxalate oxidase (Sigma-Aldrich),
citrate lyase (14), and picric acid (15) methods, respectively, using a
Sunrise light absorbency microplate reader (Tecan); and calcium,
magnesium, and sodium by inductively coupled plasma optical emission spectrophotography (Optima 2000 DV, Perkin Elmer Instruments). Oxalate absorption from the administered oxalate loads was
determined by recovery of administered 13C2-oxalic acid as described
previously (5). Endogenous oxalate synthesis for urine samples collected postoxalate loading was approximated by subtracting the oxalate absorbed [(recovered 13C2-oxalic acid/administered 13C2-oxalic
acid) ⫻ oxalate ingested at 0700 h via the oxalate load] from the total
urinary oxalate excretion over the specified time period. TRI for 24-h
urine collections was calculated using the formula by Tiselius (16),
which relates the excretion in mmol of 4 urinary components and
urine volume in L as follows:


emesis after the combined oxalate and AA load, leaving 29 SF
and 19 NSF (Table 1) for the final analyses. Study diets (Table
2) were consumed per protocol as validated by sodium excretion for free-living adaptation days. Sodium excretion was 102
⫾ 6% of calculated dietary intake during adaptation days and
metabolic unit study, and did not differ between treatments A
and N (data not shown). Urinary creatinine excretions during
treatments A and N were 105 and 109% (during adaptation),
and 102 and 103% (during the metabolic study) of expected
urinary creatinine based on lean body mass, supporting the
completeness of the urine collections. Urine volumes did not
differ between treatments A and N, between SF and NSF, or
between responders and nonresponders during adaptation or
the metabolic study.
Ascorbate excretion decreased progressively over adaptation d 1, 3, and 5 for subjects administered treatment N,
and progressively increased over adaptation d 1, 3, and 5 for
those administered treatment A for all subjects (data not
shown). Urinary ascorbate did not differ between SF and
NSF, or between responders and nonresponders administered the same treatment. Oxalate excretion decreased progressively over adaptation d 3–5 in subjects administered
both treatments, and similarly for both SF and NSF (data
not shown). Dietary oxalate was only 40 mg/d during adaptation, less than typical intakes of 150 mg/d (17).
In SF, but not NSF, 24-h urinary oxalate was higher during
treatment A compared with treatment N (Table 3). When SF
were categorized as clinically hyperoxaluric (mean total oxalate ⱖ 450 ␮mol for the 2 screening days) or normooxaluric,
the hyperoxaluric SF had significantly higher oxalate absorption and endogenous synthesis than normooxaluric individuals
during treatment N (Table 4). However, they were nonresponsive to the effects of AA on endogenous synthesis and
absorption, in that ascorbate-induced increases in these values
were observed only in the normooxaluric group.
Nineteen of 48 participants were identified as responders,
defined by increased 24-h oxalate excretion ⬎10% after A
compared with N administration during the metabolic unit
study; 12 responders were SF and 7 were NSF. Responders
were slightly older than nonresponders (56 ⫾ 13 compared to
47 ⫾ 13 y, P ⫽ 0.02). Gender was not related to oxaluric
response to AA. Responders had higher 24-h TRI with treatment A compared with N (Table 5). The higher total oxalate
excretion in responders with AA supplementation could be
attributed to a combination of higher oxalate absorption and
higher endogenous oxalate (Table 5).

AP共CaOx兲 ⫽ 1.9 ⫻ 关Calcium兴0.84 ⫻ 关Oxalate兴 ⫻ 关Magnesium兴0.12
⫻ 关Citrate兴⫺0.22 ⫻ 关Volume兴⫺1.03

The TRI is a measure of calcium oxalate saturation, which
predicts the risk of its precipitation.
Statistical analyses. Statistical significance of differences between treatment A and treatment N, SF and NSF, and between
responders (participants with ⱖ10% greater oxalate excretion with
AA) and nonresponders, was determined by paired or 2-sample
Student’s t test using Excel software (version 10.3207.3131, 2002,
Microsoft). Repeated measures ANOVA was conducted using Number Cruncher (2001). Differences were considered significant when P
ⱕ 0.05. Values are presented as means ⫾ SD.

All 49 volunteers completed the metabolic study. Data
from 1 NSF participant was dropped from the analysis due to

Biochemistry of 24-h urine and the risk index of stoneformers and non-stoneformers when they were (A) or were not (N)
administered AA during the metabolic unit study1
Stoneformers (n ⫽ 29)

Volume, L
Ca, mmol
Citrate, mmol
Mg, mmol
Oxalate, ␮mol

Non-stoneformers (n ⫽ 19)





2.18 ⫾ 0.66
3.82 ⫾ 1.63
5.85 ⫾ 2.26
3.81 ⫾ 1.15
⫾ 103†
0.94 ⫾ 0.45

2.13 ⫾ 0.60
3.79 ⫾ 1.80
5.60 ⫾ 2.23
3.75 ⫾ 1.21
⫾ 139†
1.10 ⫾ 0.60

2.62 ⫾ 1.17
3.04 ⫾ 1.44*
6.35 ⫾ 2.26*
3.92 ⫾ 1.28
⫾ 104*
0.61 ⫾ 0.45*

2.60 ⫾ 1.53
2.76 ⫾ 1.41*
5.67 ⫾ 1.66
3.83 ⫾ 1.07
⫾ 173*
0.65 ⫾ 0.41*

Values are means ⫾ SD. * Different from stoneformers administered the same treatment; † different from those not administered AA within each

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Biochemistry of 24-h urine of hyperoxaluric and normooxaluric stoneformers when they were (A) or were not (N)
administered AA during the metabolic unit study1
Hyperoxaluric (n ⫽ 8)

Total oxalate, ␮mol
Endogenous oxalate, ␮mol
Oxalate absorption, %

Normooxaluric (n ⫽ 21)





⫾ 90
⫾ 5
10.9 ⫾ 3.1
1.11 ⫾ 0.54

⫾ 125
⫾ 10
11.2 ⫾ 3.3
1.21 ⫾ 0.90

⫾ 93*
⫾ 7*
8.2 ⫾ 2.0*
0.88 ⫾ 0.40

⫾ 147†
⫾ 10†
10.6 ⫾ 3.4†
1.06 ⫾ 0.48†

Values are means ⫾ SD. * Different from hyperoxaluric stoneformers administered the same treatment;
AA within each group.

Consumption of 1000 mg AA twice each day resulted in 2
distinctly different oxaluric responses: 40% of individuals,
including both SF and NSF, had increases in 24-h urinary
oxalate ⱖ 10%. The other 60% had essentially no oxaluric
response. It is not known what portion of a larger population
would have an AA-induced increase in urinary oxalate; the
actual proportion could be more or less than 40% when careful
sampling is done. In an early report, Briggs (7) found only 3 of
67 individuals tested had an increase in urinary oxalate. Examination of individual responses from 3 published studies in
which 1000 –2000 mg/d AA supplements were given (18 –20)
showed that 7 of the total 19 subjects (38%) had a ⬎10%
increase in urinary oxalate, a proportion similar to ours.
Results of this study concur with those of previous studies in
demonstrating mean increases in total oxalate excretion with
AA supplementation. Baxmann et al. (21) reported a 61%
urinary oxalate increase in SF after 1000 mg AA/d, 41% after
2000 mg AA/d in SF, and 56% after 2000 mg AA/d in NSF.
Chalmers et al. (22) studied 17 SF and 11 NSF consuming
2000 mg AA. They found SF excreted 12% more oxalate than
NSF without AA and 22% more with AA. Traxer et al. (23)
conducted a similar study with 12 SF and 12 NSF ingesting
1000 mg AA with each morning and evening meal. Urinary
oxalate excretion increased 33% (10 mg oxalate/d) in SF and
20% (6 mg oxalate/d) in NSF. As in our study, Traxer et al.
(23) identified responders in both SF and NSF. Although
responders would be at increased risk to form stones with AA
supplementation, SF may not necessarily be responders to AA.
Genetic susceptibility in study participants probably accounts
for most of the discordance in response to AA previously


different from those not administered

In our study, 79% of the AA-induced increase in total
urinary oxalate in responders was attributed to increased endogenous synthesis, and 21% to increased oxalate absorption.
Hatch (24) postulated the existence of 2 kinds of abnormalities leading to increased risk of kidney stones, i.e., increased
endogenous oxalate synthesis and increased oxalate absorption. In our study population, both seemed to occur together in
many individuals.
Of interest was the finding that normooxaluric SF, but not
hyperoxaluric SF, exhibited increases in endogenous oxalate
synthesis and oxalate absorption in association with AA supplementation. This was an unexpected finding because of the
supposition that stoneformers with higher urinary oxalate levels consuming their usual diets would be more sensitive to
AA-induced increases in urinary oxalate. However, a partial
explanation may relate to the fact that by virtue of being
normooxaluric, there is more potential for a physiologic effect
of AA on endogenous oxalate synthesis and/or oxalate absorption to be clinically observed as an increase in oxaluria.
If endogenous synthesis of oxalate from AA is ⬃1.5% of
supplemental loads (2), increased urinary oxalate from endogenous synthesis from two 1000-mg doses would be 30 mg or
341 ␮mol. The actual mean increase in total oxalate observed
was 72 ␮mol for the study group as a whole, 194 ␮mol in
responders and ⫺9 ␮mol in nonresponders. The increase is
likely to be limited by saturation of AA absorption and/or
tissue uptake at doses lower than the 2000 mg/d used in this
study. This assertion is supported by Baxmann et al. (21) who
reported that the increase in urinary oxalate was no greater
with 2000 than with 1000 mg/d in SF. If no more total AA was
absorbed from 2000 than from 1000 mg/d, the 194 ␮mol
response in responders is close to the 170 ␮mol increase

Biochemistry of 24-h urine of responders and nonresponders when they were (A) or were not (N) administered
AA during the metabolic unit study1
Responders (n ⫽ 19)
Total oxalate, ␮mol
Endogenous oxalate, ␮mol
Oxalate absorption, %

⫾ 97
⫾ 71
8.0 ⫾ 2.4
0.76 ⫾ 0.42

Nonresponders (n ⫽ 29)

⫾ 165*
⫾ 131*
10.5 ⫾ 3.2*
1.11 ⫾ 0.67*



⫾ 110
⫾ 80
9.3 ⫾ 2.7
0.84 ⫾ 0.40

⫾ 129†
⫾ 114
8.9 ⫾ 3.4
0.81 ⫾ 0.49†

Values are means ⫾ SD. * Different from those not administered AA within each group; † different from the responder administered the same

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predicted from a 1.5% conversion rate. The remaining increase in urinary oxalate, 24 ␮mol, would be from increased
absorption. The oxaluric effect of 500 mg AA/d could be
roughly extrapolated from previously reported data from 6
individuals to be ⬃40% less than that from a 1000-mg dose
(25). Because the health benefits of AA supplementation in
doses ⬎ 500 mg/d are not substantiated (25), 500 mg/d may be
considered the maximum dose for individuals at risk for calcium oxalate kidney stones until further research on lower
doses is completed.
The increase in TRI associated with AA supplementation
in this study was mediated primarily through increased urinary
oxalate excretion, with no effect on urinary calcium, magnesium, or citrate. Baxmann et al. (21) identified increases in
TRI and urinary oxalate in 47 SF and 20 NSF randomly
assigned to either 1000 mg AA (500 mg ingested 2 times/d) or
2000 mg AA (1000 mg ingested 2 times/d) for 3 d. Before d 1
and on d 3, a 24-h urine sample was obtained. The increase in
TRI with administration of 1000 mg AA (0.51) was similar to
that for 2000 mg AA (0.56), suggesting that lower doses of AA
than used in the present study may also be lithogenic.
Although urinary oxalate was shown to increase with AA
supplementation, a direct association of AA supplementation
with stone incidence is not clear. Taylor et al. (26) recently
reported that ⱖ1000 mg/d of supplemental vitamin C was
associated with a 16% increase in the 14-y incidence of kidney
stones in the Health Professionals Follow-up Study. In contrast, an earlier report on the women in the Nurses’ Health
Study found no association (27). Because supplementation is
often sporadic (3), supplementation data collected at 1 dietary
survey may not reflect the intake during the whole time the
individuals were followed for kidney stone occurrence. Also,
our data show that only 40% of our population had an oxaluric
response, which would also obscure the risk in a subset of
genetically susceptible people. In our study, 21% of SF and
16% of NSF reported taking AA supplements before participation. If only 12–20% of the genetically susceptible 40% were
taking supplements, it would be difficult to see an association
in an epidemiologic study.
In summary, because an individual’s response to AA supplementation is not predictable, high-dose AA supplementation should be considered cautiously, even for those individuals without a history of stone formation.
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3. Radimer, K., Bindewald, B., Hughes, J., Ervin, B., Swanson, C. & Picciano, M. F. (2004) Dietary supplement use by US adults: data from the

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