vitamins and minerals: efficacy and safety”2

Am J Cliii Niar 1997:66:427-37. Printed in USA. 0 1997 Anierican Society fuir Clinical Nutrition 427

Vitamins and minerals: efficacy and safety”2

John N Hatlu’o’k

Review Articles

ABSTRACT Safety and efficacy are crucial but separate is-

sues for vitamin and mineral supplements. Misinterpretation of

“safe and adequate” to mean “safety limit” would impose restric-

tions on vitamin and mnineral intakes that are not needed to ensure

safety. Substantial evidence indicates that intakes greater than the

recommended dietary allowances (RDAs) of’ certain vitamins and

minerals such as calcium, fblic acid, vitamin E, selenium. and

chromium reduce the risk of certain diseases for some people.

Limitation of’ intakes to the RDAs would preclude reductions iii

disease risk from these nutrients. The margin of safety between the

usual dietary intake and the intake that would produce adverse

effects varies greatly amilong the different nutrients. Very high

intakes of vitamins A and D, niacin, pynidoxine, and selenium have

produced adverse effects. Many widely discussed putative adverse

ef’fects of vitamin C. vitamiiin E, and trivalent chromium have little

factual basis. There is no evidence of adverse effects fromii a-car-

otene supplements except in current heavy smokers. Ant J

Cliii Nuir 1997:66:427-37.

KEY WORDS Vitamins, tiiinenals, benefits. ef’ficacy. safety.

adverse effects

INTRODUCTION

Efficacy and safety are the health issues that determine

whether dietary supplements should be recommended and con-

sumed. E,flk’acv is the ability of a supplement to provide a

health benefit related to either prevention of deficiency or a

reduction in the risk of chronic disease (1-4). Safrtv is a

reasonable certainty that there will be no adverse effects from

excessive intake of a nutrient ( I , 3. 5). Most consumers likely

consider both by assuming safety and judging efficacy in their

individual decisions. Moreover, safety related to avoidance of

adverse effects of excessive intake and efficacy to provide

health benefits are addressed separately under federal labeling

and safety regulations. Nonetheless. the two concepts aresometimes treated in a manner that does not clearly separate

them. For example. the Food and Nutrition Board has set

estimated safe and adequate daily dietary intakes (ESADDIs)

of selected vitamins and minerals as an alternative to recoin-

mended dietary allowances (RDAs) when the data are made-

quate for setting an RDA (6, 7). Also, the term “safe and

adequate” has been misinterpreted as “safety limit” by the

Codex Alimentarius Commission (8). A more accurate defini-

tion of “safe and adequate” and the ESADDI would be “the

recommended intake, an amount that is also safe” (5).

It has long been conventional wisdom that dietary supple-

ments are not needed by persons who eat varied diets, and also

that use of suppletiients may carry significant risk of adverse

effects if’ intakes exceed the RDAs (9-I I ). The issue of need

raises the question “Needed flr what?” The potential benefits

of nutrients in reducing the risk of diseases not recognized as

classic deficiency diseases generally have not been considered

thus far in setting the RDAs or ESADDIs. Recognizing the

important role of same vitaniins and niinenals beyond that (if

preventing deficiency. the Food and Nutrition Board is now

considering use of evidence for decreased risk of chronic

disease it-isetting the RDAs ( I).

Safety is of’ course an important issue. especially at nutrient

intakes well above the RDAs on ESADDIs. A safe intake of

any substance is one that provides an adequate margin below

amounts that cause adverse effects (4. 5). The Environmental

Protection Agency’s ref’erence dose concept of safe intakes has

been applied t(i essential minerals ( I 2). A similar approach that

takes nutritional recommendations into account before calcu-

lation of a safety limit has been applied to both vitamins andminerals (4. 5). The Food and Nutrition Board is currently

evaluating procedures and standards for identifying “safe tipper

limits” or “tipper reference intakes” for nutrients.

For selected vitamins and minerals. this paper examined the

scientific evidence fr benefits other than meeting classical

nutritional needs as well as the concepts and evidence related

to safety concerns, The nutrients reviewed fir safety were

selected because they have been the source of practical safety

problems or the subject of controversy about safety. Similarly.

the nutrients reviewed fir efficacy were selected because cur-

rent evidence on them challenges the conventional wisdom that

“the RDA is always enough.” The criteria for nutrient selection

for safety and efficacy intersect in the conclusion that if’ there

are benefits at intakes above the RDAs, the RDAs should not

be used as sal’ety limits.

EVIDENCE OF EFFICACY

Calcium and osteoporosis

The role (if dietary calcium in achieving higher bone mass

and thereby reducing the risk or delaying the onset of osteo-

porosis is iiow well recogmiized (13) and a health claim on this

nutrient-disease relation has been authorized by the Food and

I From the Council for Resptinsihle Nutrition, Washington. IX’.

2 Address reprint requests to iN Hathcock. Council for Responsible

Nutrition. 13(M) l9th Street NW. Suite 310, Washington. DC 2(8)36-1609.

E-iiiail: hathcock @crnusa.org.

Received November 19. 1996.Accepted fir publication March 6, 1997.

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428 HATHCOCK

Drug Administration ( 14). Because bone loss accompanies the

aging process, sufficient calcium intakes during early adult-

hood increase peak bone mass, thereby reducing the risk of

osteoporosis decades later. Increases in calcium intake in post-

menopausal women delay calcium loss from bone, thus low-

ering the risk of bone density declining to osteoporotic levels.

Daily calcium intakes of l0(X)-2000 mg slow the decline of

bone density. thus reducing risk of osteoporosis (13, 14). These

amounts are well above the 800-mg RDA for nonpregnant.

nonlactating adult women in the United States (7).

Folic acid and risk of neural tube defects and heart

disease

There is clear evidence that sufficient intakes of dietary folic

acid before conception and very early in pregnancy decrease

the risk of a baby developing neural tube defects (NTDs) that

include spina bifida. anencephaly, and encephalocele ( I 5). The

daily intake of folic acid thought to be effective for a sensitive

subset of the population is 400 p.g (0.4 mg), an amount above

the RDA in most countries. Although folic acid can reduce the

risk for NTDs, these defects are not solely attributable to folic

acid deficiency. Folic acid supplementation generally reduces

the risk by 50-75%.

Increasing evidence suggests that sufficient dietary folic acid

can decrease the plasma concentration of homocysteine. a

substance that is gaining scientific recognition as a risk factor

for heart disease ( 16-18). The data are not yet sufficient to

make a reliable estimate of the amount of folic acid needed to

generate this benefit, but the amount identified as possibly

effective is in the same range as that shown to be effective

against NTDs.

Antioxidant nutrients and risk of cancer and heart

disease

Vitamin E

Results from several research approaches studying the effect

of vitamin E on heart disease and its risk factors have shownprotective effects associated with intakes well above the RDA

(19-25). Epidemiologic evidence indicates a strong dose-ne-

sponse relation between decreased risk of heart disease and

increased vitamin E intakes from both diet and supplements.

Significant protection begins at daily intakes of 67 mg a-to-

copherol equivalents (19). Low-density-lipoprotein (LDL)-

cholesterol oxidation decreased significantly in blood taken

from subjects receiving � 400 IU/d but not � 200 IU/d (21). In

addition, a double-blind, placebo-controlled intervention trialshowed a significant decrease in nonfatal myocardial infarcts in

high-risk subjects consuming either 400 or 800 IU vitamin E/d

as a supplement (23).

In comparison. another clinical trial did not observe any

benefit on heart disease from a supplement of 50 mg all-rae-

a-tocopherol acetate/d given for 5-7 y to middle-aged Finnish

men who were long-term, heavy smokers (26). One recent

epidemiologic study observed a decrease in heart disease with

increased intakes from foods but not from supplements (27).

The study population involved very few who took vitamin E

supplements and there may have been insufficient statistical

power to detect any effects of supplements. The preponderanceof evidence contradicts these results. Considerable epidemio-logic evidence also links vitamin E with a reduced risk of

cancer (28). These data are supported by the results of animal

experiments (29) but the evidence is not as strong as for the

reduction of heart disease risk by vitamin E.

Vitamin C

Vitamin C inhibits chemical synthesis of nitrosamines (most

of which are animal carcinogens) in the gastric contents, but

inhibition is not complete until dietary intakes reach � 1000 mg

(30-33). Considerable evidence from both epidemiologic stud-

ies and clinical trials suggests that intakes of vitamin C much

higher than the RDA may reduce the risk or risk factors for

chronic diseases such as heart disease and cancer, especially

when combined with higher intakes of vitamin E (34-39).

13-Carotene

Epidemiologic studies have shown that people with high

intakes of 13-carotene or high blood concentrations of this

nutrient have a reduced risk of various diseases, including

cancer and heart disease (40). The chemical abilities of 13-car-

otene to quench singlet oxygen and inhibit peroxyl free radical

reactions are well established (41). In addition to this antioxi-

dant property, 13-carotene and some other carotenoids may play

an important role in facilitating normal cell-to-cell communi-

cation through gap junctions (42). Because many carcinogens

inhibit gap junction communications (43), protection of this

activity by dietary substances could be an important function in

protection against cancer.

Recent clinical trials-the Physicians’ Health Study (PHS)

(44), the Carotenoid and Retinol Efficacy Trial (CARET) (45),

and the Alpha-Tocopherol Beta-Carotene (ATBC) Cancer Pre-

vention Study (26)-failed to find any benefit of 13-carotene in

reducing the risk of cancer or heart disease. In fact, the ATBC

trial and the CARET found increases in lung cancer incidence

in smokers who were administered 13-carotene. The results of

these highly publicized clinical trials were without a doubt

disappointing to those expecting 13-carotene to lower the risk of

cancer. but the current data should not be overgeneralized. The

results do not show that 13-carotene has no anticarcinogenic

effect under any circumstance. Because the ATBC trial and the

CARET studied populations at very high risk of lung cancer,

and because the duration of treatment was far shorter than the

induction time for this cancer, these trials do not support, but

also do not disprove. the hypothesis that 13-carotene may be

anticancinogenic in early stages of cancer.

There are several credible reasons for hypothesizing that

13-carotene might reduce the risk of cancer: I) increased con-

sumption of 13-carotene is strongly associated with reduced risk

of cancer (40), 2) 13-carotene is a dietary antioxidant (4 1 , 46),

3) antioxidants inhibit early stages of carcinogenesis (47), and

4) 13-carotene reduces cancer in some experimental animal

models (48).

For modifying cancer risk. the importance of early adminis-

tration of an antioxidant in relation to the time of exposure to

the initiating carcinogen is well established through studies

with butylated hydnoxytoluene and butylated hydroxyanisole

(49, 50). It is widely thought that lung cancer requires two

decades for development from the first initiating events to

clinically diagnosed cancer. Thus, even with the most powerful

known protective action against lung cancer. cessation of

smoking. decreases in risk become significant only over a

10-l5-y period (51).

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VITAMIN AND MINERAL SAFETY 429

Seleniuni

The epidemiologic association of higher selenium intakes

with reduced cancer risk and the antioxidant role of selenium in

glutathione peroxidase (as well as several other possible mech-

anisms) have provided a basis for research on possible antican-

cinogenic effects of selenium. Several selenium compounds

have antitumorigenic activities in a variety of animal models

when administered at amounts greater than those associated

with nutritional need (52).

Only two clinical intervention trials published to date were

designed to determine whether selenium in combination with

other nutrients will reduce cancer risk. In one, 50 pg Se (in

yeast) in combination with vitamin E and 13-carotene moder-

ately reduced the risk of total mortality. total cancer mortality,

and stomach cancer mortality (53). In the other, inorganic

selenium together with a wide spectrum of other minerals and

vitamins did not significantly protect against cancer (54). An

additional placebo-controlled. randomized clinical trial was

stopped recently for ethical reasons after it became clear that

treattnent with 200 j.tg Se in yeast significantly decreased total

and lung cancer mortality and total colorectal and prostate

cancer incidence (55-57). The amount of selenium used in the

study was 200 j.�g. an amount nearly three times the RDA for

adult males (7). The primary objective of the trial was to

determine the effect of selenium on nonmelanoma skin cancer.

but there was no effect. either negative or positive, on this

disease-in contrast with effects on cancer at three other sites.

SAFETY: ISSUES AND EVIDENCE

Safety cannot be absolutely proven for any substance be-

cause such proof would require demonstration of a negative-

that an adverse effect does not occur. Any substance would be

expected to produce adverse effects if the intake were suffi-

ciently high, and therefore safety or lack of it must be related

to a specified intake. Published evidence is sufticient for safety

assessment of vitamins and minerals over a range of intakes.

This evidence is reviewed for some genuine and some bogus

safety concerns for different vitamins and minerals.

Vitamin A

The potential for adverse effects from excessive vitamin A

intake is well documented. Potential risk is based on the

ingestion of excessive amounts of preformed vitamin A in the

forms of retinol or retinyl esters. and not from provitamin A

forms such as 13-carotene or other vitamin A-forming carote-

noids. Consumption of 7500-15 000 p.g preformed netinol

equivalents (RE) daily for periods of several months or more

can produce multiple adverse effects, including liver toxicity

and possibly birth defects (58). The smallest daily supplement

of vitamin A reported to be associated with liver cirrhosis is

7500 pg RE (25 000 IU), which had been taken for 6 y (59).

The smallest daily supplement generally considered to generate

any risk of birth defects is also 7500 �g RE (25 000 IU) (58).

One recent report. however, described a significantly increased

risk of neural crest birth defects at daily supplement amounts of

> 3()00 p�g RE (> 10 000 IU) (60). The average supplement

intake by this group was 6509 �g RE (21 675 IU) but unfor-

tunately the authors did not identify individual supplement

intakes. Several issues have been raised about the validity of

the defect classification scheme used and the resulting likeli-

hood that the study overestimated the risk associated with

vitamin A at the intakes identified in this study (61-63).

Some reports suggest that there may be some risk of vitamin

A toxicity at supplement intakes < 6(X)0 �g REId (20 (XX)

IU/d). One report to the US Food and Drug Administration

suggested a characteristic birth defect associated with maternal

supplementation at 5400 �g REid (18 000 IU/d) (64). Another

report found marginal indications in elderly subjects of adverse

effects on the liver associated with chronic supplementation

providing intakes of 1500-3000 �g REId (5(XX)-l() (XX) IU/d

(65). However, the same laboratory was unable to repeat this

finding in later research (66).

In summary. there is no evidence that vitamin A supplements

of 3 0(X) i,�g RE (10000 IU) are harmful to normal adults.

including pregnant women and the elderly. Adverse effects of

vitamin A are sometimes observed when supplement intakes

reach 7500 p�g RE (25 000 IU) and one report suggests that

such effects may occur with somewhat lower intakes (60).

fl-Carotene

13-Carotene is widely considered to be virtually nontoxic

because humans tolerate high doses without apparent harm,

and animal studies have also failed to find any toxic effects (58.

67, 68). There is no evidence that conversion of 13-carotene to

vitamin A contributes to vitamin A toxicity, even when 13-can-

otene is ingested in large amounts (69).

The only consistent adverse or undesirable effect of high

13-carotene intakes has been coloration of the skin related to

hypencarotenemia, which occurs only at extremely high in-

takes. Doses as high as 180 mg/d have been given to humans

for several months without observed adverse effects other than

skin discoloration (70).

Because of the extensive safety record of 13-carotene. major

clinical trials have been designed with the implicit assumption

that the only likely effects would be benefits. But subsequently.

questions about the safety of 13-carotene have been raised by

the results of the ATBC trial (26) and the CARET (45). which

observed significant increases in lung cancer risk in high-risk

populations (long-term smokers or asbestos workers) given

supplements of 13-carotene (20 mg/d in the ATBC trial and 30

mg/d in the CARET). On the other hand. there was evidence in

the CARET that 13-carotene may reduce the risk of lung cancer

in former smokers. In contrast with the results of the ATBC

trial and the CARET, no increased risk was observed in the

longer-term PHS (44), which included > 2000 smokers. or in

three other shorten-term trials (53, 71, 72). Moreover, observa-

tional studies found no risk of lung cancer or other disease

associated with increased 13-carotene intakes (20. 73, 74).

The effects of alcohol or high intakes of retinol on the liver

have been postulated to explain the adverse outcomes with

13-carotene in the ATBC trial and the CARET (75). This

hypothesis is supported by recently published subgroup anal-

yses of the ATBC and CARET data. indicating that the pro-

moting effects of 13-carotene on lung cancer were seen pniman-

ily in subjects who consumed alcohol and smoked more (76.

77). All data available suggest that heavy concurrent smoking

is a necessary condition for a promotional effect of 13-carotene

(78). Former smokers, whose tissues would presumably have

been subjected to the mutagenic and carcinogenic effects of

cigarette smoke, show decreased, not increased, rates of lung

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430 HATHCOCK

cancer with 13-carotene treatment (77). A review of all pub-

lished evidence on 13-carotene shows that the ATBC trial and

the CARET suggest adverse effects but this conclusion is not

supported by other clinical trials or epidemiologic data.

Nicotinic acid

The flushing reaction produced by nicotinic acid has been

recognized for more than half a century (79). When taken on an

empty stomach, crystalline nicotinic acid (but not nicoti-

namide) in doses as small as 10 mg may produce a mild but

noticeable flushing reaction. Although not desirable. such re-

actions produce no known adverse consequences and they are

seldom perceptible when small amounts of nicotinic acid are

taken in tablet or capsule f’orm or consumed with ftod.

Side effects such as liver toxicity and serious gastrointestinal

reactions have occurred when gram quantities of nicotinic acid

were taken to lower serum lipids (80). Gastrointestinal side

effects include indigestion, nausea, vomiting, and diarrhea.

and. in some persons necessitate discontinuation of nicotinic

acid. Liver toxicity is most commonly manifested by increases

in serum transaminase enzymes of liver origin released as a

result of damage to liver cells. High doses have produced

jaundice. fatigue. and, in at least one case, fulminant liver

failure.

There is strong agreement between the minimum adverse

effect level identified through clinical trials and that suggested

by published case reports. Many severe reactions to nicotinic

acid. especially liver toxicity, have involved ill-advised or

inadvertent switching from unmodified to slow-release formu-

lations (80). Most reported adverse reactions to niacin have

occurred with intakes of 2-6 g/d. There are only two anecdotal

cases reported in which intakes were < 1000 mg. one for

slow-release nicotinic acid at 5(X) mg/d and another for un-

iiiodified tiiacin at 750 mg/d (80). In a clinical trial two groups

of adult subjects. one taking immediate-release and one taking

slow-release nicotinic acid, were observed initially and for 6

wk at each dosage level: 500. 1000, 1500, 2000, and 3000 mg/d

(8 1 )‘ The data showed no adverse reactions at 500 mg/d for

either form of nicotinic acid, but significant effects beginning

at l(XX) irig/d (gastrointestinal effects with unmodified nico-

tinic acid and mild liver toxicity with slow-release nicotinic

acid).

Many uncertainties exist in these cases about the accuracy of

patient reports regarding the amount consumed and the pres-

ence or absence of preexisting or conf’ounding conditions such

as alcoholism or other conditions that compromise liver func-

tion (80). For these reasons, the clinical trial data are useful for

safety and risk evaluations of nicotinic acid. From the clinical

trial data it can be concluded that an intake of 10(X) mg/d

carries significant risk and that an intake of 500 mg/d carries no

identifiable risk (8 1 ). Note, however, that the adverse reactions

to 1000 mg unmodified nicotinic acidld were gastrointestinal

effects, which generally have less potential for serious out-

conies compared with the liver toxicity that can result from

1000 mg slow-release nicotinic acidld. The risks associated

with � 1(XX) mg nicotinic acid/d may be tolerable when it is

used as an antihyperlipidemic drug under the care and moni-

toring of a physician. but such risks are not acceptable for

unsupervised, selI’-selected use by consumers.

Pyridoxine

Deficient and excess intakes of pynidoxine can produce

neurologic disturbances (82). The first report of pynidoxine

neurotoxicity in humans described a sensory neuropathy of the

extremities in women with daily intakes of 2000-60(X) mg,

mostly taken in an attempt to control premenstrual symptoms

(83). The neuropathy slowly but perhaps incompletely re-

gressed after cessation of the elevated dose (84-86). Most

cases of sensory neuropathy have resulted from intakes > 60()

mg/d but some evidence suggests that neuropathy may result

from doses as low as 300-5(X) mg/d in sonic individuals (82,

87. 88). The total dose over an unspecified time may give a

better prediction of the potential for neurotoxic response than

either the daily dose or the duration of the high intake (88).

There is controversy over the validity of the single report of

adverse effects at daily intakes of � 10() mg or less (89).

Although this report is often cited as evidence that pynidoxine

intakes < 1(X) mg/d can cause sensory neuropathy. the data

showed an average intake of I 17 mg/d among women with

symptoms and an identical average intake ( I 16 mg/d) in the

control group. The group with symptoms had taken pynidoxine

longer (an average of 2.9 y) than those without symptoms ( I .6

y). Some women in each group had intakes � 50 mg/d. Pos-

sible inaccuracies in the telephone survey method and a lack of

objective neurologic assessment could have introduced bias.

The symptoms observed had no dose-response relation to pyn-

idoxine intake but did show a time-response relation.

Some reports suggest that high intakes of pynidoxine may

cause the development of oxalate kidney stones, but the re-

ported cases may have been associated with the drug pynidoxi-

late (a combination of pynidoxine and glyoxalate) (90), and a

recent prospective epidemiologic study found the relative risk

of oxalate renal stone development to be decreased for men

consuming > 40 mg pynidoxine/d compared with those con-

suniing < 3 mg/d (91).

Ascorbic acid

Many hypothetical adverse effects of high intakes of vitamin

C have been cited for decades (92-94). Most, with the excep-

tion of mild and transient gastrointestinal effects, seem to have

little or no known factual basis (82).

Co,iditioned .seu,i’v

Although this supposed phenomenon has been so widely

cited in review articles that it has become conventional wisdom

(92-94). detailed review and bibliographic tracing provide no

substantiation. Only a very few original sources can be located:

most references are secondary sources, and subsequent inter-

pretation frequently reached conclusions not supported by the

original data. The original hypothesis grew out of two cases of

infantile scurvy (95). The mothers of these infants had taken

vitamin C supplements during pregnancy and the author spec-

ulated that this might have conditioned the infants for rapid

clearance of vitamin C. resulting in scurvy. High intakes of

vitamin C can result in accelerated clearance but this does not

result in blood concentrations lower than normal (96, 97). Oral

scurvy due to withdrawal from high vitamin C intakes has been

reported but the diagnosis was not confirmed, the time to onset

was suspiciously short, and no plasma vitamin C measurements

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VITAMIN AND MINERAL SAFETY 43l

were made (98). Conditioned scurvy has been widely discussed

and speculated, but not substantiated.

Ova/ate kidney .stoize.s

Reported large increases in urinary oxalate concentrations

during periods of high vitamin C intakes appear to be an

artifact of analysis due to oxalate production from ascorbic acid

in an analytic procedure that involves heat (99). A more recent

report involving better assay methods indicated a significant

increase in oxalate excretion (still within the normal range) by

persons consuming l(XX) mg ascorbic acid/d (1(X)). It is not

clear whether this increased excretion of 10-15 mg oxalate/d

was due to the instability of ascorbic acid in the urine during

collection, storage. or analysis. Some reports assert that ascon-

bic acid is a risk factor for calcium oxalate kidney stones ( 101).

Other research involving alternative sample handling proce-

dures found fl() increase with a different preparatiomi of ascorbic

acid at intakes of up to 8 g/d ( 102). One study found that

oxalate was produced only in vitro in the urine sample itself

with daily oral ascorbic acid intakes up to 10 g ( 103). The

contribution of high ascorbic acid intakes to urinary oxalate is

not established ( 104), and the suggestion that oxalate kidney

stones are caused by high ascorbic acid intakes remains spec-

ulative ( 105). Indeed, epidemiologic evidence suggests a de-

creased risk of oxalate kidney stones with increased intakes of

vitamin C. For example, a recent prospective epidemiologic

study found the relative risk of oxalate renal stones to be

decreased for men consuming � 15(X) mg vitamin C in com-

parison with those consuming < 250 mg (91). These data

provide further support for an earlier retrospective that pro-

duced siniilar results (l()6).

Proo.vida,zt efft’ets, excessive iron absorptioiz, or exee.ssit’e

iron release

A potential for harm by high intakes of ascorbic acid through

prooxidant effects has been discussed widely ( 107. 108). An

original research paper ( 109) has been cited in a review article

(108) as showing that an asconbate-dniven free radical reaction

damages cells. The study used in vitro assays with phagocytes

and found that the release of iron from senescent erythrocytes

in the medium had adverse effects only at abnormally high

ascorbic acid concentrations. These concentrations were > I 0

tinies the highest plasma ascorbic acid concentrations of sub-

jects consuming 1000-25(X) mg ascorbic acidld ( 100). The

hypothesis that high intakes ofascorbic acid will produce direct

prooxidant ef’fects is not consistent with the data on iron

release, and contrasts with the antioxidant effects of vitamin C

observed under a wide variety ofconditions (1 10). The concept

that enhanced iron absorption by ascorbic acid leads to excess

iroti-related disease has been suggested (108) based on the

hypothesis that increased serum ferritin concentrations cause

heart disease ( I I 1 , I I 2). The hypothesis that excessive iron

causes heart disease is not supported by subsequent evidence

and evaluation ( 1 1 3- 1 1 8). Ascorbic acid intakes of’ 2 g/d for

2 y did not cause excessive iron uptake (1 19), providing

additional evidence that a high ascorbic acid intake is unlikely

to produce any iron-related increase in heart disease. Intakes of

up to 10 g/d for up to 3 y without observed side effects have

been evaluated in clinical trials ( 120).

Gastrointestinal distress

The most common adverse effects of’ high vitamin C intakes

are gastrointestinal symptoms such as nausea. abdominal

cramps. and diarrhea ( I 2 1 ). When these symptoms occur. the

vitamin C dosage is usually > 2 g/d but a few individuals

report such symptoms at intakes as low as 1 g. These symptoms

seem to be a direct osmotic effect because they can usually be

avoided by taking the vitamin as a buffered salt rather than as

a free acid. The symptoms usually disappear within a week or

two with no further consequences. At least some of the diarrhea

reportedly caused by ascorbic acid supplements may have been

produced by other components such as sorbitol ( I 22).

Folic acid

Three major concerns have been identified as possible ad-

verse effects from excessive folic acid intakes: I) the masking

of pernicious anemia. thus allowing the neurologic disease of

vitamin B- I 2 deficiency to progress unchecked; 2) the disrup-

tion of zinc function: and 3) the antagonism of medications.

especially antifolate agents.

�%‘fa.sking pernicious a�zeinia

Administration of high intakes of folic acid to patients with

pernicious anemia can mask the anemic manifestations while

allowing the neurologic disease (posterolateral spinal cord de-

generation) to progress. Although there are a few reports of the

masking effect related to amounts of f’olic acid � I mg (results

based almost entirely on studies with injected fblic acid). the

eftect is unusual at such low doses and predictable only at

doses � 5 mg (123).

!‘Oli(’ (l(’id-Zi?U’ intera(’tions

Certain folic acid-zinc interactions are well documented.

including the malabsorption of f�id folates in zinc deficiency

due to insuf’ficient activity of the folate conjugase enzyme that

must convert food pteroylpolyglutamates to the monoglutaniate

forni before absorption ( I 24). The crucial question for folic

acid safety in relation to zinc is whether higher intakes have

adverse consequences through a disruption of zinc bioavail-

ability or function, and. if so. what are the intakes of fblic acid

that are associated with such effects. Some reports suggest that

as little as 350 .tg of supplemental folic acid can adversely

affect zinc nutniture (125-127), but more recent reports mdi-

cate no adverse effects of f()lic acid at even higher intakes on

zinc uptake or function (128. 129). The suggestion that folic

acid intakes < 400 �g/d cause adverse outcomes of’ pregnancy

through the antagonism of zinc functions (125) has not been

supported by subsequent larger. multicenter studies involving

intakes that were either 4 mg ( I 30) or 800 �g ( I 3 1 ) before and

throughout pregnancy.

It is difficult to resolve differences in the scientific literature

regarding a possible adverse effect of folic acid on zinc nutni-

tune. These apparently incompatible results are likely attnibut-

able to the widely different experimental approaches used. In

general, methods based on uptake rate and plasma concentra-

tion tend to show ef’fects at lower folic acid intakes. whereas

zinc balance methods tend to show effects only at higher

intakes. Large, well-conducted clinical trials have found no

adverse effects of folic acid on pregnancy through zinc antag-

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432 HATHCOCK

onism or any other mechanism, although they have shown a

clear benefit in reducing the risk of NTDs (130, 131).

Folie u’id-drug interactions

At high intakes. folic acid has been reported to interfere with

the effectiveness of anticonvulsant drugs such as Dilantin (di-

phenylhydantoin; Parke-Davis, Division of Warner Lambert,

Morris Plains. NJ), used to control epilepsy (124). Folic acid

doses of 5-30 mg orally have produced some evidence of

increased frequency of seizures in epileptics, but there is no

evidence of such effects at lower intakes of folic acid. It might

be expected that increased folic acid intakes could interfere

with actions of folate-antagonizing drugs such as methotrexate.

In contrast, administration of I mg folic acid/d for 6 mo in

patients with rheumatoid arthritis treated with low-dose meth-

otrexate actually decreased methotrexate toxicity without af-

fecting its efficacy for therapy (132).

Selenium

Excess selenium intake from consumption of seleniferous

plants by animals produces a wide range of adverse effects

( 1 33). Chronic signs of toxicity in livestock include cirrhosis,

lameness, hoof malformations, hair loss, and emaciation. In

laboratory animals the signs commonly include liver cirrhosis.

The minimum dietary intake of selenium recognized to produce

adverse effects in farm animals is 4-5 �g/g dry wt of diet

(133).

An episode of human poisoning by selenium involved a

manufacturing error that resulted in a dietary supplement prod-

uct that actually contained 182 times the amount of selenium

declared on the label (I 34, 1 35). Adverse effects occurred

within a few weeks and included effects on hair, nails, and

liven. Human selenium poisoning in a high-selenium area of

China also produced adverse effects on nails. skin, the nervous

system, and teeth ( 1 36). These adverse effects occurred in

some persons with intakes > 910 �g/d. No adverse effects

have been associated with lower intakes, but the ratios of

plasma selenium to erythrocyte selenium have been found to

increase with dietary intakes � 750 �g/d ( 137, 138). Surveys

in selenifenous areas of the United States have failed to find any

signs of selenium intoxication in persons with intakes of up to

slightly > 700 �g/d (139). In the Chinese population with an

average lowest observed adverse effect level (LOAEL) of 910

I_Lg Se intake, the lower 95% confidence limit for the LOAEL

was 6(X) p�g/d ( 140). Because the chemical forms of selenium

in foods grown in seleniferous areas are not completely known,

the human data on adverse effects from chronically high in-

takes apply only to total dietary selenium and not to any

specific form. No adverse effects were observed in a l0-y

clinical trial at daily supplemental intakes of 200 p.g Se in

selenized yeast (55-57).

Chromium

No credible data or reports have shown adverse effects of

Cr3 � in humans, and animal data also suggest that orally

administered Cr� is extremely innocuous (5, 141, 142). In

addition, the MEDLINE database (National Library of Mcdi-

cine, Bethesda, MD) lists no published cases of adverse neac-

tions in humans. In contrast, chromate (Cr6� ) is clearly estab-

lished as a work-related etiologic agent in lung disease,

including lung cancer, in chromate and stainless steel workers

(143).

One report described clastogenesis (chromosome breakage

in vitro) from high concentrations of chromium picolinate

added directly to Chinese hamster ovarian cells in culture

( 144). Because Cr6� can be biologically reduced to � Cr4�,

and Cr3� but Cn� � is not oxidized to the higher valence states,

the authors suggest that Cn� � could be the actual carcinogen.

This suggestion seems to conflict with their data that indicated

clastogenic effects of chromium picolinate and picolinic acid,

but not chromium chloride, chromium nicotinate, or nicotinic

acid ( I 44). Also, other data from the same research group were

interpreted to show that Cr�� is the genotoxic and presumably

carcinogenic species of chromium ( 145-148). Moreover, the

criteria of the Environmental Protection Agency (EPA) for

interpreting in vitro clastogenesis data in cancer risk assess-

ment specify that evidence ofclastogenicity is meaningful only

if there is confirming mutagenicity data, and that these together

are sufficient only to recommend an animal bioassay to eval-

uate possible carcinogenicity ( I 49-151).

The EPA has reviewed all relevant data on chromium tox-

icity and calculated a reference dose, a safety limit involving a

margin of safety below the levels with evidence of adverse

effects, for Cn3� and also for Cr6�. Application ofa composite

safety factor of 1000 to the animal data for Cr�� gives a

reference dose of 1 .47 mg/kg (142), which with downward

rounding converts to 70 mg/d in adult males. The reference

dose for Cr” (70 000 p.g) is 350 times the upper value of the

ESADDI of 50-200 p.g for adults (7). Thus, trivalent chro-

mium has an extraordinarily wide margin of safety. In contrast,

hexavalent chromium-a form not normally found in the di-

et-has significant toxic potential. and accordingly the refer-

ence dose for Cn6�, calculated by the EPA for a 70-kg man, is

only 335 j.�g/d (142).

There is no evidence of toxicity in humans from orally

ingested trivalent chromium, and 1000 �tg Cr/d as chromium

picolinate produced no adverse effects in a clinical trial (R

Anderson, N Cheng, N Bryden, et al, unpublished observa-

tions, 1996). Extrapolation from animal data corroborates hu-

man data that trivalent chromium is extraordinarily safe but its

benign character should not be confused with the established

toxicity of hexavalent chromium.

CONCLUSIONS

The potential benefits of nutrients in reducing the risk of

diseases that are not recognized as classic deficiency diseases

have not been used thus far in setting the RDAs or ESADDIs.

Recognizing the important role of some vitamins and minerals

beyond that of preventing deficiency. the National Academy of

Science, in contrast with past practices, is now considering use

of evidence for decreased risk of chronic disease in setting the

RDAs ( I ). Evidence is rapidly accumulating that intakes above

the RDA for some micronutnients provide benefits in reducing

the risk of chronic disease, and these effects are moving toward

acceptance as an appropriate basis for future RDAs ( I , 152).

Also, it is well recognized that higher intakes of nutrients

necessitate careful evaluation of the safety of those intakes

(1, 5).

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Efficacy

Calcium

The benefits of calcium in reducing the risk of osteoporosis

are recognized by health claims authorized by the US Food and

Drug Administration for intakes of 1000-2000 mg/d, but the

current RDA for most women is only 800 mg (Table 1).

Folk’ cl(’id

The intake of folic acid recognized by the Food and Drug

Administration to reduce the risk of NTDs is 400 p.g/d. but the

RDA for most women is only I 80 p.g (Table 1).

Vitamin E

Intakes of 67-30() mg a-tocopherol equivalents (100-400

IU) of vitamin E have been shown to reduce oxidation of LDL

cholesterol and lower the risk of heart disease, but the RDA for

adult males is 10 mg (15 LU) (Table 1).

Seleniuni

A recent clinical trial found reduced cancer risk with a

selenium intake of 200 �g/d. but the RDA for adult males is 70

�tg/d (Table 1 ). Limiting this nutrient to the RDA precludes

benefits from higher intakes, and such limitations are not

necessary for safety.

Safety

Safety limits should be based on a standard other than the

RDA, ESADDI, on other recommendations related to nutri-

tional policy or beneficial effects. Use of a direct scientific

approach to identify safe upper levels does not impose false

safety limits related to the RDA on ESADDI.

Vitanii,i A

Most evidence of adverse effects is associated with intakes

� 7500 �.tg RE (25 000 LU). There is no evidence of adverse

effects from consumption of < 6500 p.g (2 1 600 IU). An intake

of 3000 j.tg ( 10 000 IU) is known to be safe for adults, includ-

TABLE I

Beneficial intakes of supplemetital vitamins and minerals

Nutrient RDA’ Beneficial amount Reference

Calcium (mg) 800 l00()�2(X)02 13. 14

Folic acid (�.tg) 180 4(X)� 15-18

Vitamin E (mg s-TE) 10 67-3(8) 19-25

Selenium (gig) 70 2(8) 56-58

I Recommended dietary allowance (7) selected for comparison with the

beneficial effects listed in the next column: calcium, 8(8) mg for nonpreg-

nant, nonlactating women: folic acid, I 80 .tg for nonpregnant. nonlactating

women: vitamin E. 10 mg a-tocopherol equivalents (TE) for adult males:

and selenium. 70 �zg for adult males.

2 The range kr adult women recognized in regulations for food labelinghealth claims as being beneficial in reducing the risk of osteoporosis.

3 The folic acid intake for adult women recognized in regulations for

food labeling health claims as being beneficial in reducing the risk that a

pregnancy will be affected by a neural tube defect. The RDA of400 �zg for

pregnant women is not an appropriate comparison because the neural tube

closes at �28 d of pregnancy. a time before prenatal care usually begins

(15).

ing pregnant women and the elderly. These amounts are well

above the RDA of 3000 j.�g RE for adult men (Table 2.

13-Carotene

13-Carotene is widely considered to be virtually nontoxic

because humans tolerate very high doses without apparent

undesirable effects, other than skin discoloration, and animal

studies also failed to find any toxic effects. There is no cvi-

dence that conversion of 13-carotene to vitamin A contributes to

vitamin A toxicity, even when 13-carotene is ingested in large

amounts. Two clinical trials involving 13-carotene found in-

creased lung cancer in smokers, but others found no adverse

effects. An intake of 25 mg is safe for most adults except for

heavy smokers.

Nicotinic’ (U’i(l

When taken on an empty stomach, crystalline nicotinic acid

in doses as small as 10 mg may produce a mild but noticeable

flushing reaction. Liver toxicity and serious gastrointestinal

effects can occur in persons consuming � 1000 mg nicotinic

acid/d. but clinical trials have found no adverse reactions at

intakes of 500 mg/d. an intake well above the RDA for adult

males (Table 2).

Pvridoxine

Daily intakes of 20��()-600() mg pynidoxine can cause sen-

sony neuropathy. The neuropathy slowly and perhaps incom-

pletely regresses after cessation of the elevated intake. There is

controversy over the validity of the single report of adverse

effects at daily intakes of � 100 mg or less. A pynidoxine intake

of 5(X) mg/d carries some risk of neurotoxicity. There are no

reliable reports of adverse neunologic effects with intakes of

200 mg/d. Both the NOAEL (no observed adverse effect level)

and the LOAEL are far greater than the RDA (Table 2.

Ascorbic acid

Intakes up to 1000 fig vitamin C, far above the RDA for

adults, have been consumed daily without any known adverse

TABLE 2

Safe and adverse effect intakes of vitamins and minerals

NutrientRDA or

ESADDI’NOAEL LOAEL3 Relerence

Vitamin A (ftg RE)’ 1(88) 3(8%) 65(8) 58-66

Niacin (mg) 20 5(8) 1(88) 80. 81

Pyridoxine (mg) 2 2(8) 5(8) 83-88

Ascorbic acid (mg) fit) 1(88) Unknown 82. 99-lOS

Folic acid (Mg) 180 1(88) 5(8%) 123. 124, 129-132

Selenium (Mg) 70 2(8) 910 136-140

Cr� (jig) 5()-2(X) 1(8%) Unknown 142. l43�

, The highest recommended dietary allowance for any age or sex group.

except for pregnant or lactating women. or the upper value of the estimated

safe and adequate daily dietary intake (7).

2 The no observed adverse effect level, based on the absence of a

convincing pattern of effects shown in human data or observations: an

intake that may be considered safe.

3 The lowest observed adverse effect level, based on convinctng adverse

effects as shown in human data or observations: an intake that is not safe

for all consumers.

4 RE, retinol equivalent.

S Includes unpublished observations by Anderson et al, 1996.

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434 HATHCOCK

effects (Table 2). Most of the purported adverse effects attnib-

uted to vitamin C have no factual basis.

Folic acid

Folic acid is nontoxic but concern has been raised about high

intakes masking pernicious anemia. This effect is established

only at intakes � 5000 p.g. Intakes of 1000 �g (1 mg) total

folic acid plus food folates are without identifiable risk of any

known adverse effects. This intake is well above the RDA for

women (Table 2).

Selenium

The margin of safety for selenium is relatively narrow.

Adverse effects have occurred at intakes of 9 10 �sg/d. Some

risk of adverse effects may occur with total dietary intakes as

low as 600 �g/d. Daily supplemental intakes of 200 �.tg have

been shown to be safe (Table 2).

Chromium

No credible data or reports have shown adverse effects of

dietary trivalent chromium in humans, and animal data also

suggest that orally administered trivalent chromium is cx-

tremely nontoxic. Reports of DNA damage by chromium do

not apply to oral intakes of the forms found in foods and dietary

supplements. The benign character of oral trivalent chromium

should not be confused with the established toxicity of inhaled

hexavalent chromium, which is associated with workplace-

related lung cancer. Hexavalent chromium is not normally

found in foods and is not used in dietary supplements. There is

sufficient experience with intakes of trivalent chromium, as

chromium picolinate, up to 1000 �g Cn/d, along with the wide

margin of safety in animal studies, to establish the safety of

trivalent chroniium at this intake (Table 2). A

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Erratum

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