Handbook of Minerals As Nutritional Supplements

CRC Series in Modern Nutrition Science
Handbook of Minerals as
Nutritional Supplements
Copyright 2005 by CRC Press, Inc. All Rights Reserved.

CRC Series in
Modern Nutrition Science
Series Editor
Stacey J. Bell
Ideasphere, Inc.
Grand Rapids, Michigan
Phytopharmaceuticals in Cancer Chemoprevention

Edited by Debasis Bagchi and Harry Preuss
Handbook of Minerals as Nutritional Supplements

Robert A. DiSilvestro

CRC Series in Modern Nutrition Science
Handbook of Minerals as
Nutritional Supplements
Robert A. DiSilvestro
CRC PR E S S
Boca Raton London New York Washington, D.C.

1652_C00.fm Page iv Wednesday, August 18, 2004 10:53 AM
Library of Congress Cataloging-in-Publication Data
DiSilvestro, Robert A.
Handbook of minerals as nutritional supplements / Robert DiSilvestro.
p. cm.
Includes bibliographical references and index.
ISBN 0-8493-1652-9
1. Minerals in human nutrition—Handbooks, manuals, etc. I. Title.
QP533.D55 2004
613.2′85—dc22 2004051925
This book contains information obtained from authentic and highly regarded sources. Reprinted material
is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable
efforts have been made to publish reliable data and information, but the author and the publisher cannot
assume responsibility for the validity of all materials or for the consequences of their use.
Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic
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Printed in the United States of America 1 2 3 4 5 6 7 8 9 0
Printed on acid-free paper

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Preface
The Internet, television, and magazines are flooded with nutrition supplement adver-
tisements, with many claims being made for various products. One area with an
especially large recent growth spurt is the mineral supplement area. Moreover, a
number of nutrition business trade journals are projecting that the mineral supple-
ment market should see sustained growth over the next few years. As claims continue
to be made for various mineral supplement products, major questions are arising,
such as:
• What research, if any, is behind these claims?

• Do different forms of mineral supplements have different efficacies?
• Are these supplements beneficial only for correcting deficiency, or can
there be benefits of eating more than the levels currently recommended
as adequate?
• What are the safety issues of mineral supplements?
These questions are being asked not only by the general public, but also by
many health care professionals, biomedical researchers, and people involved in the
nutrition industries themselves. This last group is especially important to public
health because their marketing can drive the sales of supplements. Therefore, the
players in nutrition industries, as well as health care professionals and researchers,
need a way to evaluate mineral supplement claims. Some information can be obtained
using a quick search of the Internet, or by using a program like Medline. However,
interpretation of the information obtained can be hampered by the lack of a special-
ized background and time available. For example, if one study says that a calcium
supplement has no effect on blood pressure, and another study says the opposite,
how does one reconcile the conflict? Someone with a good biomedical background
can search out the issue, but this can be very time consuming.
This book is intended to provide a concise, yet informative presentation and
interpretation of the current state of research on various mineral supplements. Each
of the above-noted questions are addressed. The information should be technical
enough to satisfy a biomedical audience but will avoid jargon used mainly by mineral
specialists. Even so, it’s hard to write this type of a book without using some words
for which the definition may not be known. Therefore, this book includes a glossary
for some words that appear often.
As author of this book, I have tried to present more than one perspective for
controversial areas, but I have also given my opinions on many of them. When I
have given my opinion, I have tried to clearly state that this is what I am doing.
There is no doubt that more research is needed in almost all the areas I cover
in this book. In that regard, I have pointed out some of what I think should come

1652_C00.fm Page vi Wednesday, August 18, 2004 10:53 AM
next in research. At the same time, I recognize that a lot of people, from the general
public to the most dedicated researcher, sometimes get frustrated if a report on
nutrition or any other subject is totally noncommittal. So, I state what I feel is safe
to conclude right now, and I provide some conjectures.
My hope is that this book can spur many of us to further consider how mineral
supplements should and should not be used for health promotion and health care.

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Acknowledgments and
Conflicts of Interest
I would like to thank Gordon Wardlaw for reading and giving feedback on every
chapter, and Elizabeth Joseph for a great deal of assistance with the reference aspects
of the book preparation. I would also like to thank Emily Dy for help with references
in the chapter on iron. In addition, I appreciate the help of each of the following for
comments on individual subjects: Michael Bergeron, Priscilla Clarkson, Steve
Abrams, Connie Weaver, Greg Miller, and Greg Wiet. I also appreciate my wife,
Janet, and children, David, Daniel, and Lisa, for allowing me the enormous amount
of time it took to complete this writing. Finally, I want to express great appreciation
to Stacey Bell for having the original concept for the book and helping me get it
off the ground.
I endeavored to present the issues in this book as honestly as I could, without
trying to make any product supplier look better or worse than reality dictated. Even
so, I do want to note the companies that have supported parts of my own mineral
research: Albion Laboratories, Nutrition 21, Glanbia, and Purac of America.

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Author
Dr. Robert DiSilvestro is professor of nutrition at The Ohio State University.
He earned his Ph.D. in Biochemistry from Texas A&M University in 1982 after
receiving his Bachelor of Science from Purdue University, where he majored in
Biochemistry.
DiSilvestro is the author or co-author of more than 70 peer-reviewed, reseach
journal articles. He has also authored several reviews, including an invited review
of a trace mineral manual for Free Radical Biology & Medicine, a journal.
He’s been a featured speaker for a National Institute of Health workshop on the
current state of zinc research as well as speaking on minerals for a functional food
symposium at an annual meeting of the Institute of Food Technology.
This is his first book.

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Table of Contents
Chapter 1 Calcium
Overview of Function
Overview of Metabolism
Nutritional Status Assessment
Bioavailability from Foods and Supplements
Typical Intakes versus Needs
Current Research on Supplement Use
Rickets
Bone in Children and Adolescents without Rickets
Osteoporosis Prevention and Treatment in Adults
Hyperparathyroidism
Blood Pressure
Blood Lipid Alterations
Colon Cancer
Weight Loss
Toxicity
Summary and Conclusions
Chapter 2 Magnesium
Typical Intakes Versus Needs
Parenteral Pharmacological Uses
Overt Hypomagnesemia (Low Serum Magnesium)
Blood Pressure
Serum Lipids in Non-Diabetic Subjects
Prevention of Cardiovascular Disease in Non-Diabetic Subjects
Diabetes
Stress.
Exercise
Negative
Positive
Osteoporosis Prevention or Restriction
Chronic Fatigue
Asthma

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Beta-Thalassemia/Sickle Cell Anemia

Kidney Stones
Pregnancy: Premature/Low Birth Weight Outcomes
Premenstrual Syndrome (PMS)
Mitral Valve Prolapse
Other Applications
Toxicity
Chapter 3 Potassium
Overview of Physiology
Hypertension
Kidney Stones
Cramps
Potassium and Exercise Performance
Potassium and Stroke Risk
Potassium and Osteoporosis
Toxicity
Chapter 4 Iron
General Comments on Doses and Uses
Treatment and Prevention of Anemia in Individuals without
Other Discernable Health Problems
Community Interventions for Anemia Treatment and Prevention
Premature/Low Birth Weight Infants
Renal Dialysis Patients
Cancer Patients
The Elderly
Iron Deficiency without Anemia
Pregnancy
Cognitive and Behavioral Development
Infections

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Exercise Performance
Miscellaneous Health Problems
Toxicity
Chapter 5 Zinc
Overt Deficiency Correction in Children
Correction of Marginal Zinc Deficiency in Young Children
Selected Breast-Fed Infants
Premature Infants
Immune Function
Down’s Syndrome
Macular Degeneration
Acne
Wound Healing
Zinc–Carnosine and Ulcers
Rheumatoid Arthritis/Crohn’s Disease
Cancer Prevention
Exercise
Hepatitis
Osteoporosis Prevention
Renal Dialysis Patients
Cardiovascular Disease
Diabetes
Pregnancy
Zinc Lozenges and Colds
Toxicity
Copper Deficiency
Immunosupression
Prostate Cancer
Alzheimer’s Disease
Chapter 6 Copper

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Toxicity
Chapter 7 Selenium
Geographical Populations with Severe Selenium Deficiency
Cancer
Cardiovascular Disease
Arthritis
Pancreatitis
Human Immunodeficiency Virus (HIV)
Male Infertility
Pregnancy Miscarriages
Mood
Immune Function
Asthma
Ketogenic Diet in Epilepsy Patients
Miscellaneous Health Problems
General Antioxidant Effects
Toxicity
Chapter 8 Manganese
Manganese and Epilepsy
Toxicity
Chapter 9 Chromium

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Body Weight and Composition Alterations
Improved Glucose Tolerance
Beneficial Alterations in Blood Lipid Profiles
Indirect Antioxidant Actions
Toxicity
Chapter 10 Other Minerals

Phosphorus
Iodine
Ultratrace Minerals
Glossary

1652_C01.fm Page 1 Tuesday, August 17, 2004 7:47 AM
1 Calcium
Calcium is currently one of the most used nutritional supplements. Most of this
interest comes in relation to osteoporosis prevention or treatment, though other uses
also spring up. There are many types of supplements on the market and different
messages on how they should be taken. One thing seems certain: Calcium supple-
mentation will remain popular for the foreseeable future.
OVERVIEW OF FUNCTION
Calcium, as part of calcium phosphate, is the main structural component of bones
and teeth.1 In addition, calcium is involved in a long list of reversible activating and
regulatory actions.1 In fact, calcium movements in and out of cells or cell organelles
are essential to many basic physiological functions, including neurological actions
and cardiac muscle contraction.2 Part of calcium’s functions inside cells is to act as
what is called a “second messenger.”2 This name arises because the shifting of
calcium between pools is often a way that a hormone or other signaling molecule
starts a process within a cell. In addition to intracellular second messenger functions,
calcium also seems to serve as an extracellular messenger outside cells.3 Calcium
is well suited to the activator/regulator roles, because this metal is a strong enough
chelate former to complex with a signaling molecule, such as a receptor, but a weak
enough chelate former to also fall back off the molecule.
The bone function of calcium seems to be better preserved than the activator/reg-
ulator functions, since bone releases some calcium if the body’s supply falls off.1
However, not all activating/regulatory functions are necessarily preserved perfectly
in times of low calcium supply.
OVERVIEW OF METABOLISM
The activator/regulator functions are so essential to life, and are so sensitive to
changes in calcium concentrations, that the body needs powerful mechanisms to
maintain calcium homeostasis. These mechanisms exist especially for plasma cal-
cium levels, and for the transport of calcium in and out of cells and in and out of
cell organelles.4 This movement maintains the cytoplasmic concentration of ionized
calcium (calcium ion in a relatively unbound state) in the micromolar range (over
a thousand-fold less than plasma calcium concentrations). This low cytoplasmic
calcium ion concentration is essential to calcium’s second messenger functioning.

Otherwise, small calcium ion fluxes would not impact the cellular environment
enough to send signals.
About 1% of bone calcium exchanges freely with extracellular fluid and, there-
fore, is available for resisting changes in plasma calcium concentrations.5 Normally,
about 40% of blood calcium is bound to plasma proteins, primarily albumin. The
remaining 60% includes ionized calcium plus calcium complexed with phosphate
and citrate.
Calcium absorption from the intestine, as well as movement between bone and
blood, revolves around vitamin D-derived hormones, parathyroid hormone, and, to
a lesser extent, calcitonin.4,5 Parathyroid hormone is released into the blood in
response to decreases in plasma calcium. This action rapidly increases plasma
calcium due to actions such as increased intestinal absorption of calcium, increased
calcium retention by the kidney, and release of calcium from bone (bone resorption).
Vitamin D hormones, especially 1′25-dihydroxycholecalciferol, also increase intes-
tinal calcium absorption and bone resorption. The intestinal effect works in part by
increasing calcium binding proteins, which increase calcium absorption. This type
of absorption regulation is the opposite of what is seen for iron or zinc. With these
metals, intestinal binding proteins decrease absorption. Thus, calcium absorption is
increased by active regulation, but iron and zinc absorption is increased passively
by diminishing barriers to absorption.
Calcitonin tends to lower plasma calcium concentration by increasing cell
uptake, renal excretion, and bone formation.4,5 The effects of calcitonin on bone are
much weaker than those of either PTH or vitamin D.
Vitamin D hormones, in addition to regulating calcium absorption and bone
resorption, are involved in promoting some of calcium’s regulatory functions.5
NUTRITIONAL STATUS ASSESSMENT

Plasma or serum total or ionized calcium is sometimes used to assess calcium
nutritional status and for short-term assessments of calcium absorption. When there
are large changes in calcium status, such as with the correction of severe calcium-
deficiency rickets, serum calcium can show small changes.6 However, usually serum
calcium measurement is not useful for assessing calcium status because, as just
mentioned, serum calcium levels are regulated heavily.5 Sometimes, parathyroid
hormone readings are done since they respond to fluxes in plasma calcium, though
this is not the only influence.5 Other alternatives are reviewed by Cashman and
Flynn.7 One is a calcium retention test, which utilizes urinary calcium. Another
approach is the use of functional indices such as blood and urine markers of bone
metabolism. Since these markers are affected by multiple factors, their prime use is
for monitoring calcium intervention studies (i.e., to compare values before and after
increased calcium intake). For population, long-term calcium status assessment,
sometimes diet analysis is used, with the results compared to bone density or markers
of bone metabolism.6

BIOAVAILABILITY FROM FOODS AND SUPPLEMENTS

Calcium absorption from different foods is known to vary. The classic “high bio-
availability” food group is diary products, while the classic “low bioavailability”
food is spinach, where most calcium is in the water-insoluble oxalate form.1 Some
food components, such as the compound phytate, are known to inhibit calcium
absorption.1
High dietary protein has been said to both increase and decrease calcium balance,
and consequently bone strength.8 One attempt to reconcile this conflict has been
made by Dawson-Hughes.9 She notes that on the one hand, dietary protein stimulates
the production of insulin-like growth factor-1 (IGF-1), which promotes osteoblast-
mediated bone formation. On the other hand, dietary protein also increases urinary
calcium losses by several proposed mechanisms. According to the Dawson-Hughes
hypothesis, the influence that predominates depends on dietary calcium intake (at
high intake, the positive effect is more prominent). By that author’s own admission,
some but not all studies support the hypothesis. Possibly, the hypothesis is generally
true, but some other factors may come into play.
In this author’s opinion, the key to the protein–calcium issue is to eat adequate
calcium. If that is done, then even if high protein intake does have negative effects,
they may not be enough to seriously affect calcium functional status.
Many different calcium complexes have been marketed for pill or capsule
consumption or to fortify foods. A number of these have been used in studies
where the supplement produces some effect associated with improved bone health
(Table 1.1).
TABLE 1.1
Examples of Calcium
Complexes That Give
Positive Results in Bone
Studies
Carbonate*
Citrate
Citrate malate
Acetate
Phosphate
Gluconate
Lactate
* Calcium carbonate can be in a rela-

tively isolated form or part of a natural
preparation such as eggshell or coral
calcium.

The fact that all forms of calcium named in Table 1.1 have been able to produce
positive effects on bone health suggests that all can be used effectively by people.
There are also a few studies that show similarities in absorption rates between
different calcium supplements. For example, in rats, the apparent calcium absorption
is reported to be the same from carbonate, gluconate, oyster shell, and bovine bone.10
On the other hand, calcium citrate has been reported to have better absorption than
calcium carbonate, though this finding is not completely uniform.11,12,13 One reason
for the diverse results could be that a number of different evaluation criteria have
been used. It has also been suggested that the vitamin D and estrogen status of the
subjects may affect comparisons between different types of calcium supplements.13
Whatever the reason for the differing results, some health care professionals and
some researchers emphasize the better absorption potential of calcium citrates, while
others point out that carbonate, at worst, still works nearly as well, is cheaper, and
requires smaller delivery vehicle mass (due to more calcium per total complex
weight). Another consideration can be GI tract tolerability. Some people have some
distress with carbonate, though this may be lessened by splitting the daily dose into
two ingestion times. Also, the GI tract distress may be temporary in many people.
However, for people with health problems, the antacid effect of calcium carbonate
may be undesirable in the long term.
Another kind of calcium supplement is milk extract calcium, such as that sold
by Glanbia Ingredients Inc. This author’s laboratory has completed a small pilot
study with this product. In a short intervention (six weeks), the milk calcium product
produced a small decrease in a marker of bone degradation, which was not seen for
calcium carbonate (Figure 1.1).
Calcium phosphate, due to its high water solubility, is used to fortify drinks like
soy milk and is part of the calcium fortification in some orange juices. This form
of calcium is also used in some pills because it is well tolerated by people who may
have GI tract issues with calcium carbonate.
Calcium lactate finds its way into some food and pharmaceutical applications,
sometimes mixed with calcium gluconate. For food applications, calcium lactate has
desirable properties in terms of neutral flavor and stability. Calcium lactate is well
absorbed14 and, in a rat study,15 shows better bone-stimulating activity than calcium
carbonate or citrate. Calcium lactate is also sold as pills and as powder that a
consumer can mix into drinks at home. This can be an economical alternative to
some other forms of calcium supplementation.
Coral calcium, which is a type of calcium carbonate supplement, has been the
subject of many extravagant claims. Along these lines, some Internet sites state that
the many merits of coral calcium have been extensively researched. However, the
papers cited on these websites generally do not actually involve studies of coral
calcium. Instead, the research deals with calcium function in general, including many
regulatory functions that are not even known to be affected by typical variations in
calcium intake. In reality, only one original research paper relevant to coral calcium
supplements appears in a Medline search of “coral + calcium + human.”16 This paper
reports that in an acute test of calcium uptake, in a small number of people, one
type of coral calcium preparation fares better than another type of calcium carbonate.

22
20
18 *
16
14
12
10
0
PRE POST PRE POST
CaCarbonate Milk Ca
FIGURE 1.1 Bone specific alkaline phosphatase response to calcium supplementation as calcium carbonate or a milk calcium extract. Young adult
females were given about 700 mg calcium/day for six weeks. Values are Units/L ± SEM. *Significantly different from pretreatment (p < 0.05, paired t-test).

However, this study does not compare coral calcium with calcium citrate, which
may be better absorbed than calcium carbonate.
Some coral calcium advertisements claim superiority to other calcium supple-
ments based partly on the inclusion of magnesium. However, the amount of mag-
nesium varies. Moreover, there is no data presented to demonstrate how well this
magnesium is absorbed in the presence of the calcium. Another highly advertised
claim of coral calcium is that it can affect various aspects of health by manipulating
body pH. This claim has no research backing. In regard to another issue, coral
calcium is often presented as the reason for the longevity of certain Okinawans.
However, there is no actual research data to indicate that coral calcium intake is
what is responsible for any of the longevity. Therefore, considering all these issues
related to coral calcium, there is no clear research justification for the extra expense
compared to other calcium supplements.
Some calcium complexes have found a niche for specialized applications. In
these applications, attention must often be given to the effects of calcium complex
on pH as well as other chemical actions. For example, calcium gluconate is used
for some infant formulas and TPN solutions. On the other hand, this form of calcium
has not had tremendous popularity in pill or capsule form because of the relatively
low percentage of calcium. This means a person has to take more or bigger calcium
gluconate pills per dose compared to calcium carbonate. Even so, based on a rat
study,10 calcium gluconate may have one selling point: Rats fed a calcium gluconate
diet had a higher apparent absorption of magnesium than the rats fed the other
calcium supplements, possibly because the gluconate stimulates magnesium
absorption.
This observation for gluconate contrasts a concern that calcium supplements can
antagonize magnesium absorption. For this reason, some people avoid taking a
mixture of the two minerals, since each mineral may impair the absorption of the
other. In contrast, some people take supplements that mix calcium and magnesium.
The feeling is that the possible loss in absorption of each mineral is compensated
by the increased intake of each. There is also another reason why some people feel
that if one takes calcium, then one should also take magnesium. This reason is that
high body calcium-to-magnesium ratios have been stated to be problematic. The
concerns about this ratio, as well as possible impairment of magnesium absorption
by calcium, are covered below in the Toxicity section. The opposite issue, magnesium
impairing calcium absorption, is covered in the Magnesium chapter under Toxicity.
Calcium supplement bioavailability may be affected by the ability of the pill
itself to dissolve. A website put out by Kansas State University (http://www.oznet.
ksu.edu/ext_f&n/_timely/calcium.htm) suggests buying brand-name calcium supple-
ments because the solubility may be better. The site also suggests testing the ability
of a calcium pill to dissolve in 6 ounces of vinegar in 30 minutes.
Two other factors have been considered in regard to calcium supplement bio-
availability. These are the timing around meals and the splitting of the daily dose
into different ingestion times. The latter seems to help with calcium absorption,8
with 500 mg or less per single ingestion time as a common recommendation. The
timing with meals is a less-settled issue. Calcium carbonate may be better taken

with meals, since the acid involved in food digestion can help dissolve calcium
carbonate. Some groups, including an NIH panel, have recommended between meals
as the time to take other calcium supplements. For these other forms of calcium, an
empty stomach may work fine, but is it an advantage to taking between meals? One
advantage may be avoiding food components that may interfere with calcium absorp-
tion. However, it should be noted that some calcium supplements have shown good
absorption properties even when taken with a meal.17 Thus, this author feels that at
present, as far as calcium supplement absorption goes, there is no compelling reason
to favor either with meals or between meals. On the other hand, for people prone
to kidney stones, taking calcium with meals may present a distinct advantage (see
below).
TYPICAL INTAKES VERSUS NEEDS

There has been considerable debate as to what constitutes “needs” for calcium. It
is safe to say that many people of different ages and circumstances do not eat RDA
levels of calcium consistently.8 Possible consequences of such eating behavior are
being elucidated by supplement studies (considered in the next section).
Calcium is rather unique among nutrient minerals in that when discussing this
mineral, the phrase “deficiency” is not mentioned very often. This is a little strange
since, in essence, most proposed calcium supplement uses are primarily intended as
correction of marginal calcium deficiency. Even so, this term is not brought up much.
Severe calcium deficiency is not reported to any large degree in the biomedical
literature. The one exception pertains to childhood rickets. Although vitamin D
deficiency is the typical diagnosed cause of this,1 calcium deficiency can also play
a role.6 The use of calcium supplements in this situation is discussed in the next
section.
CURRENT RESEARCH ON SUPPLEMENT USE

RICKETS
Rickets is a name for a pattern of bone development impairment generally ascribed
to a vitamin D deficiency.1 Since vitamin D promotes calcium absorption, it stands
to reason that calcium deficiency can also cause or contribute to rickets. If this is
the case, then calcium supplementation can reverse, or help reverse, rickets in some
situations. This concept has been verified by a series of studies in children in
Nigeria.6,18 It remains to be seen whether similar findings would occur in other
settings.
BONE IN CHILDREN AND ADOLESCENTS WITHOUT RICKETS

Calcium supplements are often given to children by parents, with or without the
advice of their physicians, because it makes sense to be concerned about calcium
intake. The feeling is that adequate calcium intake is important to reach full bone
growth, plus to help prevent osteoporosis later in life. There are studies to support

TABLE 1.2
Questions Concerning Calcium Supplementation in Children Without
Rickets
At what level of dietary calcium intake would supplements become helpful?
Would dairy intervention have a bigger effect than calcium supplements?
If supplements are used, what is the ideal dose?
Do calcium supplements create currently undetected magnesium deficits in children?
Can the effects of calcium supplements on bone growth be improved by adding other interventions
(e.g., weight bearing exercises, increased vitamin D intake, etc.)?
Are the gains in bone lost if calcium supplementation is discontinued?
this feeling. One review19 notes that a number of studies show that in children and
adolescents, increased calcium intake, via supplement or foods, impacts at least one
measure of bone mass and growth. Despite these successes, there are a number of
unanswered questions, which are summarized in Table 1.2.
As far as the first question in Table1.2, some early returns are in. In a Chinese
study, calcium supplements are effective in children with a mean starting calcium
intake of 567 mg/day.20 In a U.S. study, calcium supplementation is more effective
if the mean calcium intake is below about 900 mg/day.21 Since this intake is not
extremely low, perhaps even a relatively good calcium intake does not preclude a
benefit of supplements. On the other hand, a different study of calcium supplemen-
tation in adolescent girls finds an effect on bone across a wide range of habitual
calcium intakes.22 In fact, the starting average calcium intake is over 900 mg. The
different results may be partly age-dependent, though this may not be the whole story.
This last study22 is also relevant to another issue raised in Table 1.2. In this
study, exercise did not enhance the calcium effect. However, since exercise–diet
interactions can vary with different circumstances, many more trials are needed
before conclusions can be reached.
As far as the last question in Table 1.2, retention of the benefits of calcium
supplementation after termination, a few results are available. What is available
presents a conflicting picture.23,24 In fact, in one study, it appears that an increased
bone acquisition rate during the supplement phase is almost balanced by a reduced
acquisition rate after supplement withdrawal.23 Unfortunately, there is just not
enough data to make a conclusion at present.
OSTEOPOROSIS PREVENTION AND TREATMENT IN ADULTS

The term “osteoporosis” describes a certain condition of low bone density that can
have multiple causes and ages of onset. However, this term is most often used to
describe a specific state that occurs in older women and sometimes in older men.1
Prevention is preferable to treatment, since it is impossible to produce high bone
density once osteoporosis is present. Treatment is limited to inhibiting disease
progression.1
It makes sense that calcium intake can be a factor in osteoporosis prevention,
since calcium is so intimately connected to bone health. Still, it should be noted that

osteoporosis is very multifactorial in nature,1 and the relative contributions of various

factors are not well characterized. The general strategy for osteoporosis prevention
is to maximize bone mass gain at younger ages and minimize bone loss at older
ages. Bone mass tends to peak about age 30, and bone loss accelerates in women
after menopause.1 Thus, most studies on osteoporosis prevention look at bone gain
in young adult women or bone loss in postmenopausal women. In this light, it can
be asked: How much does calcium intake contribute to osteoporosis prevention?
This is not an easy question to answer. When examining the pre-30-year-old popu-
lation, one is looking into a crystal ball (predicting future osteoporosis development).
When examining older women, and asking what caused or prevented osteoporosis,
one is taking a trip in a time machine (interpreting distant past history’s contribution
to a current state). What is generally done for intervention studies, such as those for
calcium supplementation, is one of two approaches. One approach is to study
postmenopausal women for slowing of bone loss and reduction of fracture incidence.
The other approach is to examine bone mass gain in young adult women, even
though we cannot quantitatively translate a given gain into a degree of osteoporosis
risk reduction.
Calcium intervention studies in older women are not easy to conduct because
bone density changes occur slowly, while health states can be constantly changing.
In addition, previous long-term history prior to study initiation could conceivably
influence how well calcium interventions work. Nonetheless, studies have been
carried out. Along these lines, a meta-analysis concludes that intake of calcium,
from supplement or foods, can have a small effect on bone loss after two or more
years.25 Moreover, the data shows a non-statistically significant trend toward reduc-
tion in vertebral fractures, though the variation is high. The variation is even more
of a problem for non-vertebral fractures, where no conclusion is reached. Therefore,
this analysis paper suggests that in postmenopausal women, a good calcium intake,
from diet or supplements, can be a factor in reducing risk of osteoporosis. However,
this analysis cannot really say just how important the calcium intake is by itself, or
how it might synergize with other factors, such as vitamin D intake. In fact, it may
be hard for any study to do this unless it includes a very large subject number, uses
interventions that last several years, examines calcium plus and minus many com-
binations of other dietary and non-dietary interventions, considers women with
different starting bone densities and histories, compares different supplement doses,
and controls the diet for calcium intake and factors that influence calcium absorption.
Such a research project would be quite an ambitious undertaking, which would be
enormously expensive, and would require incredible effort by a lot of researchers.
This explains why such a study has never been done.
As hard as it would be to do the project just described, it would even be harder
to directly study premenopausal women in regard to calcium and osteoporosis risk.
Such a project would have all the issues noted for postmenopausal women, plus
there would be a lag time of decades before osteoporosis evaluation. So, such a
study has never been done. Instead, studies on calcium supplementation and bone
in premenopausal women have focused on bone mass gains for a year or more. Some
studies have also used evaluations of urine/blood markers of bone metabolism, which
can also be used in short-term studies of intervention effects on bone turnover.

There are studies in young adult women that say that adequate calcium intake,
by supplements or diet, can increase peak bone mass.26 In addition, a meta-analysis
finds that calcium supplementation of approximately 1000 mg/day in premenopausal
women can prevent the loss of 1% of bone/year at all bone sites except in the ulna.27
Once again, though, an exact value for optimal intake and an exact effect on
osteoporosis risk is unknown. Also, we don’t have a good handle on how the
effectiveness of any given calcium intake varies with race, genetics (especially in
regard to bone density), exercise and other lifestyle issues, and dietary factors other
than calcium.
Although the research emphasis on calcium and osteoporosis has been on
women, there are a few studies on bone density in men. For example, in a placebo-
controlled study, in both men and women over 65 years of age, three-year daily
supplementation with calcium and vitamin D moderately reduces bone loss at several
sites.28 In addition, this treatment significantly decreases the rate of non-vertebral
fractures. In two other studies, calcium plus hormone treatment increases bone
mineral density in male patients with osteoporosis.29,30 However, these studies do
not examine placebo or calcium alone. There are also some studies that show that
calcium supplementation can have short-term effects on markers of bone metabolism
in men.31
HYPERPARATHYROIDISM
Certain medical situations produce high plasma concentrations of parathyroid hor-
mone. This could produce a degree of calcium deficiency, since parathyroid hormone
reduces calcium absorption and increases calcium excretion.5 Thus, it would make
sense that a moderately high calcium intake would help prevent calcium deficiency
during hyperparathyroidism. It would also make sense that a moderately high cal-
cium intake can reduce high plasma concentrations of parathyroid hormone. This is
stated because parathyroid hormone secretion increases when serum calcium starts
to fall.5 Therefore, keeping calcium intake high would prevent stimulation of par-
athyroid hormone secretion.
The ability of calcium supplementation, especially in conjunction with vitamin
D, to normalize parathyroid hormone levels is still controversial, but the efficacy
may depend on the nature of the hyperparathyroidism.32 For hyperparathyroidism
that is secondary to another disease, such as renal failure, (calcium supplementation
sometimes plus vitamin D) may be able to serve as a sole treatment. Good adherence
to treatment seems to be a necessity. Calcium supplementation also may help with
bone health in secondary hyperparathyroidism. For instance, a calcium–vitamin D
combination reverses senile secondary hyperparathyroidism, and reduces hip bone
loss and risk of hip fracture in elderly institutionalized women.33
For primary hyperparathyroidism, calcium or vitamin D supplementation is
not considered a practical alternative to surgical parathyroidectomy, though some
other non-surgical treatments are under consideration.32 However, calcium supple-
mentation may be useful for mild, primary hyperparathyroidism. In 17 such people
with a calcium intake below 450 mg/day,34 calcium supplementation (500 mg)
gives a significant increase in femoral neck bone mineral density and a decrease

in circulating parathyroid hormone values. It would be interesting to see what

would have happened with subjects eating more calcium. At present, we don’t
know if there is a minimum dietary calcium intake where supplements would no
longer be helpful.
When surgery is used for primary hyperparathyroidism, there can be a need for
calcium supplementation after surgery. One study has concluded that an ionized
calcium reading after surgery can identify the need for calcium treatment in the
majority of patients.35
BLOOD PRESSURE
The regulatory functions of calcium can affect blood pressure,4,5 but a practical
question asks: Are typical variations in calcium intake a major factor in regulating
blood pressure in many people? A number of years ago, there was a rush of interest
in this question following an epidemiological study published in a prominent jour-
nal.36 However, over time the findings of this study became thought to be more
relevant to intake just before the survey rather than long-term diet patterns. However,
other epidemiological studies support relationships of chronic calcium intake to
blood pressure.37 In addition, some intervention studies examine blood pressure
responses to increased calcium intake via foods or supplements. Three meta-analyses
of calcium intervention–blood pressure studies find a statistically significant
effect.38,39,40 However, in each of these analyses, the conclusion is that any effect is
small.
These results suggest that calcium supplementation would not make a good
standalone (or even adjuvant) treatment for high blood pressure. However, it is
possible that the effects of supplemental calcium on blood pressure could be
enhanced greatly by some co-treatment. However, this author questions the value
of a search for such a possibility when there are already known, non-pharmacological
strategies to lowering blood pressure. These strategies are good not only for lowering
blood pressure but for health in general. Therefore, the public may be better served
by being encouraged to follow these strategies rather than search for some way to
make calcium supplements work better.
A special class of hypertension is pre-eclampsia of pregnancy. The results for
calcium supplementation in this regard are mixed.41,42,43 One review contends that
calcium supplementation may not show effects in groups with no demonstrated risk
of pre-eclampsia, but may show effects in high-risk groups.41 However, the review
notes that this contention is based on negative results in a large study and positive
results in a small number of subjects for this type of issue. Another review concludes
that positive results have occurred primarily where there is low calcium intake, but
also points to low subject numbers in these studies.42
In this author’s opinion, calcium status is not the prime factor in dividing
someone into a high-risk or low-risk category for pre-eclampsia. However, for
someone in the high-risk category, marginally low calcium intake may increase the
risk even more. If this is true, then eating adequate calcium may prevent pre-
eclampsia in some women, but adequate calcium intake does not guarantee preven-
tion of pre-eclampsia. In this author’s opinion, pregnant women should try to eat

adequate calcium via food (and in some cases, supplements) because this intake is
a good idea in general, and it may sometimes prevent pre-eclampsia. However, at
present, the basis for eating high amounts of calcium to prevent pre-eclampsia is
still speculative.
BLOOD LIPID ALTERATIONS

A high calcium intake is proposed to reduce serum cholesterol and produce other
desirable blood lipid changes.37 The mechanisms are thought to involve calcium
binding to lipids and forming insoluble complexes. This action can inhibit intestinal
absorption of cholesterol, reduce re-uptake of bile acids (which could accelerate
cholesterol degradation), and lower fat absorption.
There are a series of experimental animal studies and human intervention trials
that support the concept that high calcium intake, via supplements or foods, can
affect lipid profiles.37 However, the picture is not completely clear cut. Epidemio-
logical work is not fully supportive, and two large intervention studies in hyperten-
sive and non-hypertensive people don’t find an effect for calcium.37,44,45 In addition,
among the intervention studies showing an effect, in some cases, the effect is small,
or is studied in a small number of people.46,47 Nonetheless, this author feels that the
calcium effect could be real, at least in some people. This opinion is based on the
fact that effects are seen by different research groups, and there is a considerable
effect seen in some studies. Since the effect is not totally consistent between studies,
either in terms of whether an effects is seen at all, or whether the effect is small or
large, possibly a strong effect will only occur when certain processes are strongly
affecting serum lipid profiles. More research should be done to determine if this
notion is true and, if so, to identify the relevant processes.
COLON CANCER
Calcium has been considered as an influence on colon cancer risk. The exact mech-
anism by which calcium would work is not known. However, is it expected to involve
a complex series of signaling events that affect the structural and functional orga-
nization of colon cells.48 There is also the possibility that calcium can work through
intraluminal precipitation of hydrophobic, cytotoxic substances, in particular fatty
and bile acids, which can promote colorectal cancer development.49 The idea that
calcium intake is inversely correlated with colon cancer risk is supported by some,
though not all, epidemiological population studies and work in experimental ani-
mals.49,50 A calcium–colon cancer prevention relationship is also supported by a
number of calcium intake intervention studies, which measure precancer cellular
and biochemical parameters.51 For example, in one study, subjects considered at
high risk for colon cancer took 900 mg calcium/day as either calcium carbonate
supplement or as low fat dairy products. Both interventions lower epithelial cell
proliferation indexes from a higher- to a lower-risk pattern.52 However, not all studies
on calcium and cell proliferation in humans have shown a clear-cut effect, and some
studies are not very large or may not be well controlled.53 On the other hand, some
differences in results may be due to how the proliferation is evaluated.

In this author’s opinion, at present, the calcium–colon cancer connection is

interesting but unconfirmed. Full confirmation would require an actual calcium
intervention–cancer incidence study, which would be a lengthy and costly under-
taking with ethical issues to consider. In addition, there are questions about how
many and what doses of calcium should be tested, and whether maximal effects
would require attention to vitamin D intake. Thus, in this author’s opinion, there is
not yet a clear picture of the role of calcium intake and colon cancer prevention,
but the picture is worth clarifying by further precancer intervention research.
WEIGHT LOSS
Low dietary calcium has been theorized to influence fat weight gain by increasing
secretion of hormones such as 1,25-OH-vitamin D and parathyroid hormone, which
in turn influence fat production and breakdown.37,54 In addition, high dietary calcium
may decrease digestive tract absorption of fat.37
A number of epidemiological and experimental animal studies have shown an
inverse relationship between adiposity and calcium intake.37,55 There have also been
some retroactive weight loss analyses of observational studies.37,55 Although these
studies were not set up to evaluate weight loss, it is interesting that retroactive analysis
yields a statistically significant negative association between calcium intake and body
weight. Some of these studies involve dairy interventions and some involve calcium
supplementation. Most of these studies do not report very large promotion of weight
loss (e.g., 0.346 kg/year). One could argue that such a small weight loss continued
over a long period of time is still valuable. One could also speculate the weight loss
could be bigger if the study were actually designed to examine weight loss.
In another study, published as a meeting abstract,56 three-day records of diet,
supplements, and activity for adolescent girls are examined for calcium intake from
diet and supplements. The most striking finding is that in girls with similar calorie
intake and physical activity, girls who consumed more calcium tended to weigh less
and have lower values for certain body fat measures. This interesting study can be
evaluated more fully when a full publication appears.
Conspicuously absent from the current published research is calcium interven-
tion studies designed specifically to examine weight loss. This should change soon.
In fact, one meeting abstract57 reports that in an intervention study, both calcium
supplements and low-fat dairy products stimulate weight loss, with the dairy products
being more effective. Dairy products have also been a little more effective than
calcium alone in promoting weight differences in mice.55
Certainly, this area merits more study. It is doubtful that calcium intake alone
can overcome the fat-producing effects of extreme overeating and lack of physical
activity. Nonetheless, calcium intake, via supplement or dairy products, may be able
to make an important long-term contribution to body weight control.
TOXICITY
High-dose calcium supplementation can definitely cause problems and has been said
to have done so in a few people. However, unlike many other minerals, there has

not been a lot of emphasis put on direct toxic effects of calcium intakes that are
many times the RDA. This lack of concern occurs mainly because not that many
people are likely to take calcium supplements at those doses. One reason is that
such doses would require taking a lot of pills or capsules. In addition, the media
and Internet has not encouraged high doses of calcium relative to the RDA as much
as has been done for some other micronutrients. Nonetheless, there have been
concerns about safety issues for calcium supplements: One has been lead contami-
nation. At one time, this concern was expressed primarily for dolomite and bone
meal as calcium supplements. More recently, though, a study found lead in other
calcium supplements, especially the ones that are natural product extracts.58 The
reaction to this has varied from one extreme to another. On one side, the attitude is
that the lead in most supplements is still not that high. On the other side is the
attitude that one should avoid any lead that one can. If consumers want to be on the
safe side, they can look for calcium supplement labels that say “lead free.” Seeing
a USP designation on the label is also a good sign.
Calcium supplements have also been reported to antagonize absorption of iron
and zinc. The iron issue is controversial because the data is both pro and con on the
idea.59 However, many of the pro-antagonism results are for short, highly controlled,
experimental studies, which use test meals. Most long-term studies do not see an
effect.59 In contrast, one three-day record study does see a weak inverse correlation
between calcium intake and iron status.60 However, this study can’t really account
for many factors that would restrict or enhance a calcium effect on iron absorption.
Thus, it is hard to reach a final conclusion in this area. As with other nutrient
antagonism issues presented in this book, in this author’s opinion, getting adequate
amounts of each nutrient should minimize problems. If a person takes calcium
supplements, and is concerned with effects on iron absorption, the person can take
the calcium at a different time than an iron pill or a high-iron meal.
As far as calcium supplements and zinc, in postmenopausal women, chronically
high calcium intake affects net zinc absorption and zinc balance,61 and acute calcium
carbonate supplementation lowers acute zinc absorption.62 The chronic phase uses
a calcium dose that is not all that high (under 500 mg) as a supplement or as milk.
The acute study uses 600 mg, which exceeds what is usually recommended for
single ingestion (see the Bioavailability from Foods and Supplements section).
Some negative effects of calcium supplementation are also seen for zinc status
and absorption in rats.63,64 In contrast, in a study of human female girls (average age
11 years), adding 1000 mg/day calcium to a dietary intake of about 700 mg does
not affect zinc balance.65 Similarly, in postmenopausal women, acute whole-body
retention of zinc-65 is not affected by 500 mg of calcium as carbonate.66 In this
author’s opinion, it is reasonable to say that calcium can antagonize zinc absorption,
but we do not fully know when this is a problem and when it is not. Factors that
may affect the situation include the age of the subjects, the type of calcium complex,
the exact level of total calcium and zinc intake, and the zinc complexes ingested as
foods or supplements. At present, this author recommends getting adequate intake
of both minerals, with an emphasis on well-absorbed forms of zinc (see the Zinc
chapter).

Another issue for calcium supplement safety is the concept that dietary calcium-
to-magnesium ratios should not become too high. There are three concerns that have
been raised. One, high intake of calcium can inhibit magnesium absorption and
increase magnesium excretion, which can lead to marginal magnesium deficiencies.
Two, if body calcium gets very high compared to the magnesium, hormonal changes
can cause excess deposition of calcium in soft tissues and cause calcium loss from
bones. Three, if dietary calcium-to-magnesium ratios get too high, this could alter
normal extracellular Mg(2+)/Ca(2+) antagonism, which is needed for a variety of
regulatory activities.67
Although all three of these concerns are theoretically possible, are they of
practical importance? As for the last concern, abnormal extracellular Mg(2+)/Ca(2+)
antagonism, there is little direct study of this except for one rat study.68 In this work,
there is some evidence that abnormalities in this extracellular antagonism are respon-
sible for the pro-inflammatory state in magnesium-deficient rats. Even so, it should
be recognized that this study deals with severely magnesium-deficient rats. Thus,
this may not apply to more moderate states that are apt to exist in most human
situations.
As far as high dietary calcium-to-magnesium ratios causing calcification of soft
tissues or bone calcium loss, this is known primarily for magnesium-deficient
rats.69–73 There is no data to say that this happens with marginally magnesium-
deficient rats, or with humans where calcium supplementation is superimposed over
a moderately low-magnesium diet. This does not mean that problems could not
occur, only that these problems have not been ruled in or out yet.
The other issue, calcium supplements producing marginal magnesium by low-
ering magnesium absorption, could be true. However, the idea is unconfirmed for
the typical situations that would be found in most people. It is known that in rats,
high calcium intake lowers apparent magnesium absorption, as well as bone and
serum magnesium, with the effect being worse if the rats are also fed low magne-
sium.74 Also, in an acute study, calcium can lower magnesium absorption in rat ileum
in vivo.75 Once more, the applicability of these results to common human situations
is unknown. In fact, in a controlled feeding study in humans, two types of calcium
supplements and milk do not show strong depressions of magnesium absorption,
and small effects are somewhat balanced by effects on magnesium excretion.76
Similarly, in another human study, magnesium balance is not affected by moderately
high calcium intake (intake elevated with calcium citrate malate).77
Thus, there is still a question as to whether typical calcium supplementation
practices and typical magnesium intakes can produce marginal magnesium defi-
ciency in a good number of people. To make matters more complicated, the answer
may depend on the interactions of magnesium with other dietary components. In
support of this concept, a rat study shows that calcium inhibition of magnesium
absorption is abolished by manipulating the diet’s fiber content.78 In addition, high
calcium intake does not impair absorption of magnesium in rats fed a soy-maize-
based diet.79 On the other hand, in rats, the combination of high calcium and
phosphorus can induce magnesium deficiency.80 In contrast, in this same study,
feeding a certain polysaccharide inhibited the calcium plus phosphorus effect on
magnesium status. In human very-low-birth-weight infants, when moderately low

magnesium intake is mixed with calcium and phosphorus supplementation, there is

reduced magnesium absorption and retention. 81 This occurs to the extent that the
infants go into negative magnesium balance. Nonetheless, doubling magnesium
intake negates the problem.
At present, it appears that calcium can impair magnesium absorption in some
circumstances, but not in others. Thus, more research is needed to better characterize
when this is a concern and when it is not. This author suspects that if people take
in RDA levels of both calcium and magnesium via a balanced diet, they will likely
avoid problems with balancing the two minerals. If calcium supplements are used,
then people should pay attention to their dietary magnesium, or take a well-absorbed
magnesium supplement. This could be done at a different time than calcium, though
it is not yet certain if this separation is always necessary.
Another concern about calcium supplements is possible stimulation of kidney
stone formation in susceptible individuals. At one time, people with a history of
stone formation were told to eat as little calcium as possible. At the simplest level,
this advice seemed reasonable since most kidney stones are made partly of calcium,
especially calcium oxalate. Even so, the idea of a low-calcium diet for stone formers
has now fallen into disfavor in most circles. In support of this disfavor, in a study
of postmenopausal Thai women, calcium supplementation for three months, with or
without vitamin D, has no group effects on urine markers considered relevant to
stone formation.82
Low dietary calcium may actually promote stone formation. For example, an
epidemiological study in men finds low calcium intake to be associated with higher
risk of stone formation.83 Similarly, in an epidemiology study of nurses, those
with the highest dietary calcium intakes are much less likely to develop stones
compared with the lowest intake group.84 However, in the nurse study, this rela-
tionship seems more related to calcium from diet rather than for supplements. In
fact, the women taking supplemental calcium are rated 20% more likely to develop
stones. One explanation is that the seeming protective effect of calcium from foods
is not due to the calcium, but rather to other factors in the high-calcium foods.
Alternatively, as noted in the paper on the nurse study,84 the timing of calcium
intake may be the key.
This rationale on timing involves one proposed mechanism by which calcium
may prevent stone formation. According to this rationale, a fraction of dietary
calcium, while in the GI tract, binds to oxalates from foods. This binding prevents
the absorption of oxalates, which reduces their presence in the kidneys, which lowers
the chances of calcium and oxalate forming stone crystals in the kidney. For this to
happen, presumably, the calcium has to be eaten at the same time as the oxalate-
containing foods. In the nurse study, the calcium supplements were generally not
taken with meals, or were taken with breakfast, which may have less oxalates than
other meals. Therefore, the supplemented calcium may not have done much oxalate
binding in the GI tract. Unfortunately, these ideas on meal timing have not actually
been verified directly. However, there is a study that shows that when calcium
supplements and an oxalate load are given at the same time, both calcium carbonate
and calcium citrate malate reduce urinary oxalate.85 It would have been interesting
to see what would have happened if the calcium and oxalate were given at different

TABLE 1.3
Calcium Supplements at a Glance
Adult RDA: 1000 mg
Typical dose in supplement studies: 400–1000 mg (optimal doses for each application are not well
characterized)
Best supplement complex: several acceptable for most people; for some circumstances, there may
be advantages for one over another
Applications: helpful in some rickets treatments; likely helpful for other bone health promotions
(though dairy calcium is often a good alternative); weight loss and blood lipid applications are
promising but not settled; blood pressure is a likely benefit, but how much of a benefit is debatable
Upper Level: none set
Safety issues: negative interactions with other mineral status possible, but practical importance
controversial
times. Nonetheless, this study does support the concept that calcium supplements
may actually help prevent kidney stones.
There is one additional concern with some people for calcium supplementation.
Calcium carbonate supplements can produce GI tract problems that can range from
minor to serious,86 and can have some negative interactions with some drugs.87 For
the former problems, a person can replace calcium carbonate with calcium citrate
or another form of calcium. For the latter problem, professional guidance should be
given based on the specific drug.
SUMMARY AND CONCLUSIONS

Calcium supplements are likely to remain among the most popular dietary supple-
ments for quite some time. Their use seems to have some benefits in some circum-
stances, while some other applications are still speculative. An interesting future
question for applications like weight loss is whether dairy products work better than
calcium supplements. Calcium supplements may involve some risks, though at
present, for most people, these risks have not been clearly verified.
REFERENCES
1. Wardlaw, G.M., Hampl, J.S., and DiSilvestro, R.A., Perspectives in Nutrition, 6th
ed., McGraw-Hill, New York, 2004, chap. 11.
2. Berridge, M.J., Bootman, M.D., and Roderick, H.L., Calcium signalling: dynamics,
homeostasis and remodelling, Nat. Rev. Mol. Cell Biol., 4, 517, 2003.
3. Hofer, A.M. and Brown, E.M., Extracellular calcium sensing and signalling, Nat.
Rev. Mol. Cell Biol., 4, 530, 2003.
4. Bronner, F., Calcium, in Handbook of Nutritionally Essential Mineral Elements,
O’Dell, B.L., and Sunde, R.A., Eds., Marcel Dekker, New York, 1997, chap. 18.
5. Beers, M.H. and Berkow, R., The Merck Manual of Diagnosis and Therapy, 17th ed.,
Merck & Company, Whitehouse Station, NJ, 2003.

6. Kudlacek, S., Schneider, B., Peterlik, M., Leb, G., Klaushofer, K., Weber, K.,
Woloszczuk, W., and Willvonseder, R., Assessment of vitamin D and calcium status
in healthy adult Austrians, Eur. J. Clin. Invest, 33, 323, 2003.
7. Cashman, K.D. and Flynn, A., Optimal nutrition: calcium, magnesium and phospho-
rus, Proc. Nutr. Soc., 58, 477, 1999.
8. Weaver, C.M., Calcium, in Present Knowledge in Nutrition, 8th ed., Bowman, B.A.,
and Russell, R.M., Eds., ILSI Press, Washington, 2001, chap. 26.
9. Dawson-Hughes, B., Interaction of dietary calcium and protein in bone health in
humans, J. Nutr., 133, 852S, 2003.
10. Chonan, O., Takahashi, R., Yasui, H., and Watanuki, M., The effect of calcium
gluconate and other calcium supplements as a dietary calcium source on magnesium
absorption in rats, Int. J. Vitam. Nutr. Res., 67, 201, 1997.
11. Heaney, R.P., Dowell, M.S., and Barger-Lux, M.J., Absorption of calcium as the
carbonate and citrate salts, with some observations on method, Osteoporos. Int., 9,
19, 1999.
12. Hansen, C., Werner, E., Erbes, H.J., Larrat, V., and Kaltwasser, J.P., Intestinal calcium
absorption from different calcium preparations: influence of anion and solubility,
Osteoporos. Int., 6, 386, 1996.
13. Heller, H.J., Poindexter, J.R., and Adams-Huet, B., Effect of estrogen treatment and
vitamin D status on differing bioavailabilities of calcium carbonate and calcium
citrate, J. Clin. Pharmacol., 42, 1251, 2002.
14. Martin, B.R., Weaver, C.M., Heaney, R.P., Packard, P.T., and Smith, D.L., Calcium
absorption from three salts and CaSO(4)-fortified bread in premenopausal women,
J. Agric. Food Chem., 50, 3874, 2002.
15. Hamalainen, M.M., Bone repair in calcium-deficient rats: comparison of xylitol+cal-
cium carbonate with calcium carbonate, calcium lactate and calcium citrate on the
repletion of calcium, J. Nutr., 124, 874, 1994.
16. Ishitani, K., Itakura, E., Goto, S., and Esashi, T., Calcium absorption from the
ingestion of coral-derived calcium by humans, J. Nutr. Sci. Vitaminol. (Tokyo), 45,
509, 1999.
17. Martini, L. and Wood, R.J., Relative bioavailability of calcium-rich dietary sources
in the elderly, Am. J. Clin. Nutr., 76, 1345, 2002.
18. Thacher, T.D., Fischer, P.R., Pettifor, J.M., Lawson, J.O., Isichei, C.O., Reading, J.C.,
and Chan, G.M., A comparison of calcium, vitamin D, or both for nutritional rickets
in Nigerian children, N. Engl. J. Med., 341, 563, 1999.
19. French, S.A., Fulkerson, J.A., and Story, M., Increasing weight-bearing physical
activity and calcium intake for bone mass growth in children and adolescents: a
review of intervention trials, Prev. Med., 31, 722, 2000.
20. Lee, W.T., Leung, S.S., Leung, D.M., Tsang, H.S., Lau, J., and Cheng, J.C., A
randomized double-blind controlled calcium supplementation trial, and bone and
height acquisition in children, Br. J. Nutr., 74, 125, 1995.
21. Bonjour, J.P., Carrie, A.L., Ferrari, S., Clavien, H., Slosman, D., Theintz, G., and
Rizzoli, R., Calcium-enriched foods and bone mass growth in prepubertal girls: a
randomized, double-blind, placebo-controlled trial, J. Clin. Invest, 99, 1287, 1997.
22. Stear, S.J., Prentice, A., Jones, S.C., and Cole, T.J., Effect of a calcium and exercise
intervention on the bone mineral status of 16-18-year-old adolescent girls, Am. J.
Clin. Nutr., 77, 985, 2003.
23. Lee, W.T., Leung, S.S., Leung, D.M., Wang, S.H., Xu, Y.C., Zeng, W.P., and Cheng,
J.C., Bone mineral acquisition in low calcium intake children following the with-
drawal of calcium supplement, Acta Paediatr., 86, 570, 1997.

24. Dibba, B., Prentice, A., Ceesay, M., Mendy, M., Darboe, S., Stirling, D.M., Cole,
T.J., and Poskitt, E.M., Bone mineral contents and plasma osteocalcin concentrations
of Gambian children 12 and 24 mo after the withdrawal of a calcium supplement,
Am. J. Clin. Nutr., 76, 681, 2002.
25. Shea, B., Wells, G., Cranney, A., Zytaruk, N., Robinson, V., Griffith, L., Ortiz, Z.,
Peterson, J., Adachi, J., Tugwell, P., and Guyatt, G., Meta-analyses of therapies for
postmenopausal osteoporosis. VII. Meta-analysis of calcium supplementation for the
prevention of postmenopausal osteoporosis, Endocr. Rev., 23, 552, 2002.
26. Anderson, J.J., and Rondano, P.A., Peak bone mass development of females: can
young adult women improve their peak bone mass?, J. Am. Coll. Nutr., 15, 570, 1996.
27. Welten, D.C., Kemper, H.C., Post, G.B., and van Staveren, W.A., A meta-analysis of
the effect of calcium intake on bone mass in young and middle aged females and
males, J. Nutr., 125, 2802, 1995.
28. Dawson-Hughes, B., Harris, S.S., Krall, E.A., and Dallal, G.E., Effect of calcium
and vitamin D supplementation on bone density in men and women 65 years of age
or older, N. Engl. J. Med., 337, 670, 1997.
29. Gillberg, P., Mallmin, H., Petren-Mallmin, M., Ljunghall, S., and Nilsson, A.G., Two
years of treatment with recombinant human growth hormone increases bone mineral
density in men with idiopathic osteoporosis, J. Clin. Endocrinol. Metab, 87, 4900,
2002.
30. Erlacher, L., Kettenbach, J., Kiener, H., Graninger, W., Kainberger, F., and
Pietschmann, P., Salmon calcitonin and calcium in the treatment of male osteoporosis:
the effect on bone mineral density, Wien. Klin. Wochenschr., 109, 270, 1997.
31. Ginty, F., Flynn, A., and Cashman, K.D., The effect of short-term calcium supple-
mentation on biochemical markers of bone metabolism in healthy young adults, Br.
J. Nutr., 80, 437, 1998.
32. Weigel, R.J., Nonoperative management of hyperparathyroidism: present and future,
Curr. Opin. Oncol., 13, 33, 2001.
33. Meunier, P., Prevention of hip fractures by correcting calcium and vitamin D insuf-
ficiencies in elderly people, Scand. J. Rheumatol. Suppl, 103, 75, 1996.
34. Jorde, R., Szumlas, K., Haug, E., and Sundsfjord, J., The effects of calcium supple-
mentation to patients with primary hyperparathyroidism and a low calcium intake,
Eur. J. Nutr., 41, 258, 2002.
35. Bergenfelz, A. and Ahren, B., Suppressibility of serum levels of PTH by calcium in
the immediate postoperative period after surgery for primary hyperparathyroidism,
World J. Surg., 17, 806, 1993.
36. McCarron, D.A., Morris, C.D., Henry, H.J., and Stanton, J.L., Blood pressure and
nutrient intake in the United States, Science, 224, 1392, 1984.
37. Vaskonen, T., Dietary minerals and modification of cardiovascular risk factors, J.
Nutr. Biochem., 14, 492, 2003.
38. Allender, P.S., Cutler, J.A., Follmann, D., Cappuccio, F.P., Pryer, J., and Elliott, P.,
Dietary calcium and blood pressure: a meta-analysis of randomized clinical trials,
Ann. Intern. Med., 124, 825, 1996.
39. Bucher, H.C., Cook, R.J., Guyatt, G.H., Lang, J.D., Cook, D.J., Hatala, R., and Hunt,
D.L., Effects of dietary calcium supplementation on blood pressure. A meta-analysis
of randomized controlled trials, JAMA, 275, 1016, 1996.
40. Griffith, L.E., Guyatt, G.H., Cook, R.J., Bucher, H.C., and Cook, D.J., The influence
of dietary and nondietary calcium supplementation on blood pressure: an updated
metaanalysis of randomized controlled trials, Am. J. Hypertens., 12, 84, 1999.

41. DerSimonian, R. and Levine, R.J., Resolving discrepancies between a meta-analysis

and a subsequent large controlled trial, JAMA, 282, 664, 1999.
42. Villar, J. and Belizan, J.M., Same nutrient, different hypotheses: disparities in trials
of calcium supplementation during pregnancy, Am. J. Clin. Nutr., 71, 1375S, 2000.
43. Levine, R.J., Hauth, J.C., Curet, L.B., Sibai, B.M., Catalano, P.M., Morris, C.D.,
DerSimonian, R., Esterlitz, J.R., Raymond, E.G., Bild, D.E., Clemens, J.D., and
Cutler, J.A., Trial of calcium to prevent preeclampsia, N. Engl. J. Med., 337, 69, 1997.
44. Karanja, N., Morris, C.D., Rufolo, P., Snyder, G., Illingworth, D.R., and McCarron,
D.A., Impact of increasing calcium in the diet on nutrient consumption, plasma lipids,
and lipoproteins in humans, Am. J. Clin. Nutr., 59, 900, 1994.
45. Karanja, N., Morris, C.D., Illingworth, D.R., and McCarron, D.A., Plasma lipids and
hypertension: response to calcium supplementation, Am. J. Clin. Nutr., 45, 60, 1987.
46. Groot, P.H., Grose, W.F., Dijkhuis-Stoffelsma, R., Fernandes, J., and Ambagtsheer, J.J.,
The effect of oral calcium carbonate administration on serum lipoproteins of children
with familial hypercholesterolaemia (type II-A), Eur. J. Pediatr., 135, 81, 1980.
47. Yacowitz, H., Fleischman, A.I., and Bierenbaum, M.L., Effects of oral calcium upon
serum lipids in man, Br. Med. J., 5446, 1352, 1965.
48. Lamprecht, S.A. and Lipkin, M., Chemoprevention of colon cancer by calcium,
vitamin D and folate: molecular mechanisms, Nat. Rev. Cancer, 3, 601, 2003.
49. Kleibeuker, J. H., van der, M.R., and de Vries, E.G., Calcium and vitamin D: possible
protective agents against colorectal cancer?, Eur. J. Cancer, 31A, 1081, 1995.
50. Pence, B.C., Role of calcium in colon cancer prevention: experimental and clinical
studies, Mutat. Res., 290, 87, 1993.
51. Lipkin, M., and Newmark, H., Calcium and the prevention of colon cancer, J. Cell
Biochem. Suppl., 22, 65, 1995.
52. Holt, P.R., Wolper, C., Moss, S.F., Yang, K., and Lipkin, M., Comparison of calcium
supplementation or low-fat dairy foods on epithelial cell proliferation and differen-
tiation, Nutr. Cancer, 41, 150, 2001.
53. Bostick, R.M., Human studies of calcium supplementation and colorectal epithelial
cell proliferation, Cancer Epidemiol. Biomarkers Prev., 6, 971, 1997.
54. Zemel, M.B., Mechanisms of dairy modulation of adiposity, J. Nutr., 133, 252S, 2003.
55. Zemel, M.B., Role of dietary calcium and dairy products in modulating adiposity,
Lipids, 38, 139, 2003.
56. Novotny, R., Acharya, S., Grove, J.S., Daida, Y.G., and Vogt, T.M., Higher dairy
intake is associated with lower body fat during adolescence, FASEB Journal, 17,
A453, 2003.
57. Zemel, M.B., et al., Dairy (yogurt) augments fat loss and reduces central adiposity
during energy restriction in obese subjects, FASEB, A1088:679, 2003.
58. Scelfo, G.M. and Flegal, A.R., Lead in calcium supplements, Environ. Health Per-
spect., 108, 309, 2000.
59. Bendich, A., Calcium supplementation and iron status of females, Nutrition, 17, 46,
2001.
60. Soh, P., Ferguson, E.L., McKenzie, J.E., Skeaff, S., Parnell, W., and Gibson, R.S.,
Dietary intakes of 6-24-month-old urban South Island New Zealand children in
relation to biochemical iron status, Public Health Nutr., 5, 339, 2002.
61. Wood, R.J. and Zheng, J.J., High dietary calcium intakes reduce zinc absorption and
balance in humans, Am. J. Clin. Nutr., 65, 1803, 1997.
62. Wood, R.J. and Zheng, J.J., High dietary calcium intakes reduce zinc absorption and
balance in humans, Am. J. Clin. Nutr., 65, 1803, 1997.

63. Walter, A., Rimbach, G., Most, E., and Pallauf, J., Effect of calcium supplements to
a maize-soya diet on the bioavailability of minerals and trace elements and the
accumulation of heavy metals in growing rats, J. Vet. Med. A Physiol Pathol. Clin.
Med., 47, 367, 2000.
64. Dursun, N. and Aydogan, S., Comparative effects of calcium deficiency and supple-
ments on the intestinal absorption of zinc in rats, Jpn. J. Physiol, 44, 157, 1994.
65. McKenna, A.A., Ilich, J.Z., Andon, M.B., Wang, C., and Matkovic, V., Zinc balance
in adolescent females consuming a low- or high-calcium diet, Am. J. Clin. Nutr., 65,
1460, 1997.
66. Dawson-Hughes, B., Seligson, F.H., and Hughes, V.A., Effects of calcium carbonate
and hydroxyapatite on zinc and iron retention in postmenopausal women, Am. J. Clin.
Nutr., 44, 83, 1986.
67. Muir, K.W., Magnesium in stroke treatment, Postgrad. Med. J., 78, 641, 2002.
68. Bussiere, F.I., Gueux, E., Rock, E., Mazur, A., and Rayssiguier, Y., Protective effect
of calcium deficiency on the inflammatory response in magnesium-deficient rats, Eur.
J. Nutr., 41, 197, 2002.
69. Inagaki, O., Syono, T., Nakagawa, K., Nishian, Y., Takenaka, Y., and Takamitsu, Y.,
Influence of magnesium deficiency on concentration of calcium in soft tissue of
uremic rats, Ren Fail., 18, 847, 1996.
70. Koh, E.T., Reiser, S., and Fields, M., Dietary fructose as compared to glucose and
starch increases the calcium content of kidney of magnesium-deficient rats, J. Nutr.,
119, 1173, 1989.
71. Ericsson, Y., Luoma, H., and Ekberg, O., Effects of calcium, fluoride and magnesium
supplementations on tissue mineralization in calcium- and magnesium-deficient rats,
J. Nutr., 116, 1018, 1986.
72. Schmiedl, A., Schwille, P.O., Berge, B., Markovic, M., and Dvorak, O., Reappraisal
of the quantity and nature of renal calcifications and mineral metabolism in the
magnesium-deficient rat. Effects of treatment with potassium citrate or the combina-
tion magnesium citrate and potassium citrate, Urol. Int., 61, 76, 1998.
73. Rude, R.K., Kirchen, M.E., Gruber, H.E., Stasky, A.A., and Meyer, M.H., Magnesium
deficiency induces bone loss in the rat, Miner. Electrolyte Metab, 24, 314, 1998.
74. Chonan, O., Takahashi, R., Kado, S., Nagata, Y., Kimura, H., Uchida, K., and
Watanuki, M., Effects of calcium gluconate on the utilization of magnesium and the
nephrocalcinosis in rats fed excess dietary phosphorus and calcium, J. Nutr. Sci.
Vitaminol. (Tokyo), 42, 313, 1996.
75. Brink, E.J., Beynen, A.C., Dekker, P.R., van Beresteijn, E.C., and van der, M.R.,
Interaction of calcium and phosphate decreases ileal magnesium solubility and appar-
ent magnesium absorption in rats, J. Nutr., 122, 580, 1992.
76. Lewis, N.M., Marcus, M.S., Behling, A.R., and Greger, J.L., Calcium supplements
and milk: effects on acid-base balance and on retention of calcium, magnesium, and
phosphorus, Am. J. Clin. Nutr., 49, 527, 1989.
77. Andon, M.B., Ilich, J.Z., Tzagournis, M.A., and Matkovic, V., Magnesium balance
950, 1996.
78. Watkins, D.W., Jahangeer, S., Floor, M.K., and Alabaster, O., Magnesium and calcium
absorption in Fischer-344 rats influenced by changes in dietary fibre (wheat bran),
fat and calcium, Magnes. Res., 5, 15, 1992.

79. Walter, A., Rimbach, G., Most, E., and Pallauf, J., Effect of calcium supplements to
a maize-soya diet on the bioavailability of minerals and trace elements and the
accumulation of heavy metals in growing rats, J. Vet. Med. A Physiol Pathol. Clin.
Med., 47, 367, 2000.
80. Chonan, O., Takahashi, R., Yasui, H., and Watanuki, M., Effects of beta 1—>4 linked
galactooligosaccharides on use of magnesium and calcification of the kidney and
heart in rats fed excess dietary phosphorous and calcium, Biosci. Biotechnol. Bio-
chem., 60, 1735, 1996.
81. Giles, M.M., Laing, I.A., Elton, R.A., Robins, J.B., Sanderson, M., and Hume, R.,
Magnesium metabolism in preterm infants: effects of calcium, magnesium, and phos-
phorus, and of postnatal and gestational age, J. Pediatr., 117, 147, 1990.
82. Domrongkitchaiporn, S., Ongphiphadhanakul, B., Stitchantrakul, W., Piaseu, N.,
Chansirikam, S., Puavilai, G., and Rajatanavin, R., Risk of calcium oxalate nephroli-
thiasis after calcium or combined calcium and calcitriol supplementation in post-
menopausal women, Osteoporos. Int., 11, 486, 2000.
83. Curhan, G.C., Willett, W.C., Rimm, E.B., and Stampfer, M.J., A prospective study
of dietary calcium and other nutrients and the risk of symptomatic kidney stones, N.
Engl. J. Med., 328, 833, 1993.
84. Curhan, G.C., Willett, W.C., Speizer, F.E., Spiegelman, D., and Stampfer, M.J.,
Comparison of dietary calcium with supplemental calcium and other nutrients as
factors affecting the risk for kidney stones in women, Ann. Intern. Med., 126, 497,
1997.
85. Liebman, M. and Chai, W., Effect of dietary calcium on urinary oxalate excretion
after oxalate loads, Am. J. Clin. Nutr., 65, 1453, 1997.
86. Green, F.W., Norton, R.A., and Kaplan, M.M., Pharmacology and clinical use of
antacids, Am. J. Hosp. Pharm., 32, 425, 1975.
87. Pletz, M.W., Petzold, P., Allen, A., Burkhardt, O., and Lode, H., Effect of calcium
carbonate on bioavailability of orally administered gemifloxacin, Antimicrob. Agents
Chemother., 47, 2158, 2003.

2 Magnesium
Magnesium biomedical research is currently both very exciting and very frustrating.
It is exciting because there is the possibility that many people can benefit their health
by increasing their magnesium intake. This excitement is reflected by the current
and recent past existence of journals solely or mostly dedicated to magnesium
research. On the other hand, magnesium research can be frustrating for two reasons.
One, funding for nutrition-related magnesium research has not been a high priority
among potential sources of research support. Two, in many areas of magnesium
biomedical research, conclusions are hard to draw due to seemingly contradictory
results. In fact, this author found this chapter to be the most difficult to write because
hardly any issue is clear cut (including even relative bioavailabilities of different
supplement forms).
The need for more research on magnesium is blatant, considering that there are
a number of reports contending that marginal magnesium deficiency is not uncom-
mon. In addition, a number of health applications are backed by some evidence, but
need more research to make a definitive judgment.
Magnesium affects a multitude of physiological processes. The basis for these effects
can be put into several categories. One category is that magnesium is needed as a
cofactor for a large number of enzyme-catalyzed reactions, especially reactions that
require ATP for energy.1 These ATP-requiring enzymes include those that add phos-
phate to other enzymes (enzyme phosphorylation) and the formation of the cell
signaling molecule cyclic adenosine monophosphate (cAMP). Both these actions
regulate many processes within cells. Another broad category of magnesium bio-
chemical function is intracellular free magnesium ions acting as a physiological
modulator.1,2 These modulations include competing with calcium for entrance into
cells via cell membrane channel passage. Generally, mineral competitions are viewed
from a negative perspective (i.e., one mineral competes with another for intestinal
absorption, which can create a deficiency). In contrast, a competition between
calcium and magnesium for cell membrane channels seems to keep many cellular
processes in balance. This balancing act may also occur outside cells where mag-
nesium is thought to antagonize calcium promotion of blood clotting.3
Besides affecting calcium function, magnesium also modulates potassium func-
tion, though the effects are quite different. One action of magnesium on potassium
is to block channels where potassium can leave cells.4 This helps maintain the

unequal distribution of intracellular and extracellular potassium in favor of the

former. Magnesium also influences this potassium distribution via the need for
magnesium for the enzyme Na,K-ATPase.4 This enzyme pumps sodium out of cells
and potassium in. There may also be other ways that magnesium affects potassium
distribution. These relationships between magnesium and potassium are manifest in
severe magnesium deficiency, where there are body potassium depletion and low
serum potassium readings.2
The impact of intracellular magnesium ion concentrations on cellular processes
appears to be far reaching, including effects on the synthesis of membrane phos-
pholipids and lipid second messengers.5 These synthesis patterns are thought to be
altered by low magnesium intake in a manner that can produce profound disturbances
on cell function, especially in cardiac cells.6
Magnesium also stabilizes certain structures by binding to phosphate groups.
Examples include binding to the phospholipids in cell membranes and to the phos-
phates in nucleic acids.2,7,8
Magnesium has indirect antioxidant functions, which are likely mediated by the
biochemical functions already mentioned. Although magnesium had not been tradi-
tionally viewed as an antioxidant, magnesium-deficient animals show signs of a pro-
oxidant state.9–12 These signs include: high sensitivity of lipoproteins to oxidation,
above-normal serum values for molecules associated with a pro-inflammatory state,
high values for lipid peroxides, low plasma values for radical scavenging capacity,
and activities for antioxidant enzymes, high magnitude of neurogenic oxidative
responses in vivo, and poor myocardial tolerance to oxidant stress. In addition,
magnesium deficiency in cultured cells can increase production of free radicals and
the radical precursor hydrogen peroxide.13,14 The exact biochemical mechanisms
responsible for each magnesium indirect antioxidant action are hard to identify since
there are so many possibilities. Among these is the ability of magnesium to influence
the stability and lipid composition of cell membranes, which in turn may influence
cell tendencies to produce certain radicals. Another possibility is that since magne-
sium is needed for regulation of so many processes, some of these processes likely
control production of pro-oxidant and antioxidant molecules. A lot of this regulation
may be mediated by the pro-inflammatory molecule substance P, which reaches high
levels in magnesium-deficient rats.11
The magnesium functions just discussed only involve about a third of the body’s
magnesium. This statement is made because about two thirds of the body’s magne-
sium is found in bone.15 This has led to the reasonable supposition that magnesium
function includes a role or roles in bone health. The exact nature of this function
has not been clear, but there is evidence for several possible functions.15,16 These
functions include magnesium affecting hydroxyapatite crystal structure and control-
ling bone cell proliferation. Furthermore, magnesium antioxidant effects could
restrict bone resorption. In addition, magnesium may affect bone health via effects
that occur outside the bone. For example, magnesium affects secretion of parathyroid
hormone (PTH)1,2 and insulin-like growth factor,17 both of which influence bone
metabolism. The effects of magnesium deficiency on PTH are unusual. As a defi-
ciency progresses, serum PTH levels can rise or fall at different times, but during
the rise, there can be poor receptor reactivity to the hormone.1

Magnesium absorption occurs by both a saturable carrier-mediated process and
simple diffusion.1 Absorption does not appear to be regulated in the way that occurs
for minerals such as calcium.18 There is some evidence that vitamin D status affects
magnesium absorption, but in most circumstances, magnesium absorption appears
to occur largely independent of vitamin D hormone influence.1,19 In addition, any
increase in magnesium absorption due to vitamin D hormones may often be largely
balanced by increased urinary excretion.20
The main regulation of body magnesium content is via control of kidney mag-
nesium reabsorption.1,18 This process is responsive to serum magnesium, which is
responsive to magnesium intake. However, kidney reabsorption of magnesium can
also be influenced by other factors such as certain drugs and hormonal changes. In
fact, many situations that cause severe magnesium deficiency involve excess renal
loss of magnesium.18
As noted earlier, about two thirds of the body’s magnesium is found in the
bone.2,15 Part of this magnesium is in equilibrium with the serum, while the majority
is more stable.2 After bone, the biggest area of magnesium accumulation is the
muscle, which has about a fourth of the body’s magnesium.1 Part of this magnesium
is also in equilibrium with the plasma. Extracellular magnesium accounts for only
1% of total body magnesium.2 In the serum, over half the magnesium is ionized,
while a third is bound to protein (especially albumin), and the rest is bound to low
molecular weight anions.2

By far, the most common means of assessing magnesium status is serum total
magnesium.2,21,22 Serum is generally preferred over plasma due to possible magne-
sium contamination and interferences with some assays due to the anticoagulants
in the collection tubes. Serum magnesium is definitely influenced by dietary mag-
nesium and short-term changes in renal magnesium losses. However, serum mag-
nesium values do not always reflect intracellular magnesium content or total-body
magnesium content. Low tissue magnesium contents can sometimes occur despite
normal serum magnesium values, and short-term changes in magnesium status are
not always reflected by changes in serum magnesium. In addition, factors such as
fluctuations in albumin or pH can affect serum magnesium. Nonetheless, serum
magnesium is the starting point for any evaluation of magnesium status, and values
under 0.7 mM usually mean that substantial magnesium depletion has taken place.22
Note that this is not a tremendously low value relative to the normal range, which
is 0.70 to 1.05 mM.22 This reflects that as magnesium stores drop, homeostatic
mechanisms work against big changes in serum values.
Muscle biopsy magnesium contents would seem to be an appropriate way to
assess magnesium status, since over a fourth of the body’s magnesium is typically
found in muscle.1 The main limitations for this method are that sample collection
is rather uncomfortable for the subjects, and the sampling requires skill on the part
of the person doing it. There have been rumblings that nuclear magnetic resonance

(NMR) spectroscopy may eventually be used regularly as a non-invasive means of

determining muscle-ionized magnesium. The basic method already exists,23 but has
not yet been widely applied as a magnesium status assessment tool.
Total erythrocyte magnesium contents can respond to dietary magnesium inter-
ventions,2 but values do not always correlate with other tissue pools of magnesium.2,21
In addition, genetics may have a substantial influence.24 Also, anything that affects
erythrocyte cell age distribution can affect mean magnesium values.25
Mononuclear blood cell (MNC) total magnesium contents appear to reflect
magnesium status in some but not all circumstances.1,2,26 For example, in some
subjects, MNC magnesium correlates with muscle magnesium.27 In contrast, MNC
magnesium values are reported as normal for a group of subjects with severe
magnesium depletion.28 In other work, mononuclear cell magnesium is not a good
marker of magnesium status in a study of short-term magnesium depletion in rats.27
In human magnesium supplementation studies, mononuclear cell magnesium is
increased in some studies.29,30 In contrast, values are not increased in some other
supplementation studies, though presupplementation magnesium status may have
already been good in these studies.31 Thus, the utility of MNC magnesium for status
assessment is still debatable. Two contributors to the variability in results could be
technical considerations in the sample preparation1,32 and the effects of illness on
the composition and size of the cells.33
In contrast to total blood cell magnesium contents, erythrocyte-ionized magnesium
seems to be a very good indicator of magnesium status.1,34 Although the utility of these
measures has not been verified by an enormous number of studies, the existing work
is generally supportive. Although there is some oscillation in erythrocyte-ionized mag-
nesium content as the cells circulate,25 it may be small enough to still use this approach
for magnesium status assessment. The most direct way to measure erythrocyte-ionized
magnesium is by an NMR technique.34–36 The main drawbacks are that most laboratories
are not fluent in this methodology and the amount of blood needed is substantial. Two
alternative approaches are the use of fluorescent probes and a so-called zero point
titration, which involves measuring total magnesium after sample fractionations. The
fluorescent probe approach requires navigation around a number of procedural and
interpretation pitfalls.20,37 The zero point titration approach has compared favorably with
the NMR measures in three studies, especially for relative results.34–36 Thus, the zero
point titration may be a viable option, though more comparisons to NMR results under
more circumstances would be helpful.
Serum-ionized magnesium shows considerable promise in assessing magnesium
status.20,36,38 Even so, there are still some researchers who question how often serum-
ionized magnesium values can diagnose a marginal magnesium deficiency that would
not be detected by total serum magnesium measurement.2 More research is needed
to resolve this question.
Serum-ionized magnesium is usually done by means of a magnesium-specific
electrode,20,36,38 though the quality of such electrodes may not be a constant.20,21
Another practical problem is that values for serum-ionized magnesium may change
if blood samples are not centrifuged fairly quickly20 and, possibly, if not analyzed
shortly after that. However, some studies use frozen serum samples,38 and others
claim that serum samples can be refrigerated for a substantial time.20 Until this

conflict is resolved, rapid analysis would be the safest approach, though this may
have some practical problems for some studies. Another concern is circadian rhythms
in values during the day, which cause some magnesium researchers to recommend
blood collection be carried out between 6 and 10 AM.39 There are also other technical
considerations including even the position of the subject during blood collection.20
Even if all the known technical concerns of sample collection and treatment are
addressed, there is still room for improvement in sensitivity and specificity of the
electrode method.20 Efforts on such improvement are supposed to be under way.
Another aspect of this methodology that could use improvement is electrode avail-
ability. Commercial purchase of an electrode requires the simultaneous purchase of
other apparatus that may be of no use to many researchers.
There is an alternative to the electrode approach for measuring serum-ionized
magnesium. This alternative approach uses ultrafiltration, followed by a total mag-
nesium reading in the low molecular weight fraction.40 Unfortunately, there can be
a lot of technical pitfalls in this methodology, such as the magnesium partitioning
during ultrafiltration being affected by pH changes.36,40 There seem to be ways of
preventing this problem, or correcting for it during calculations, though the details
of these approaches are still under some debate.
Urinary total magnesium is also used for assessing magnesium status, especially
following an acute parenteral magnesium load (a type of magnesium tolerance test).
For the measurements without the acute load, the applicability to status assessment can
be rationalized by the fact that nearly all absorbed magnesium is eventually excreted
in the urine.1 Thus, urinary excretion of magnesium in healthy subjects can be directly
proportional to dietary intake and magnesium stores. However, this is not always true.
High urinary magnesium can occur when there is excessive renal losses of magnesium.22
Thus, high urinary magnesium values can indicate either good or bad magnesium status.
However, a combination of high urinary magnesium with low serum magnesium can
serve as an indication of magnesium depletion due to excessive renal losses.1
The magnesium loading test (also called magnesium tolerance test) is based on
the assumption that a person in good magnesium status will excrete almost all of a
parenterally administered magnesium load within 24 hours.2 On the other hand,
someone with poor magnesium status will retain a good portion of the magnesium
load. The test is run by collecting urine after infusion of a set amount of magnesium.
The test is considered a good indicator of magnesium status in most circumstances.
There are some exceptions, such as where there are problems with renal function.
Still, this does not preclude use in most types of people. The main disadvantage to
this approach is that it is not always possible from a practical standpoint.
In summary, serum magnesium is the most used magnesium assessment method,
though it has some diagnostic limitations. Several other methods may be more
reliable in some circumstances, though technical and practical considerations can
affect their use.

There is not a lot of data on magnesium absorption from different foods and diets
in humans, though a few studies exist. Balance studies have set the percent absorption

at anywhere from about 20% up to about 70%.2 However, this would depend on the
amount of magnesium being consumed, with low percent absorptions at higher acute
intakes. However, an absorption of about 40 to 50% is often viewed as normal for
children and young adults with Western diets, based on some balance studies.41–44
For a high-magnesium mineral water, the percent absorption on an empty stomach
is about 46%, while the percent absorption jumps up to over 52% when consumed
with a meal.45 All these percentages have to be interpreted with care, since values
can vary with technique used, the subjects studied, and the amount of magnesium
given. However, these percent absorptions show that magnesium is generally
absorbed better than minerals like iron, and that magnesium from a number of
sources have somewhat similar absorptions.
There is some work on food factors that influence magnesium absorption. Some
carbohydrates, such as fructose, and fermentable carbohydrate polymers can increase
magnesium absorption.46,47 Dietary fiber, which depresses absorption of some min-
erals, has shown mixed results for magnesium. Where there is inhibition, it does not
seem to be as much as for some other minerals.48 In fact, fermentable polysaccharides
actually increase absorption.48 In a worst-case scenario, even if high-fiber foods have
a small negative effect on magnesium absorption, this effect could often be offset
by these foods containing a relatively good amount of magnesium.49
Phytates and oxalates can negatively affect magnesium absorption, though the
actual impact these compounds have can vary. For example, spinach, which is high
in oxalates, provides well-absorbed magnesium in studies of rats and humans.50–52
On the other hand, in rats, spinach can somewhat inhibit the absorption of magnesium
added to the spinach-containing diet.52 One explanation is that the added magnesium
binds to the oxalates in spinach, but the magnesium in the spinach itself is not
predominantly bound to oxalates. Instead, most spinach magnesium may be present
in complexes such as chlorophyll. The chlorophyll magnesium may be absorbed
relatively independently of oxalate effects. In the case of phytates, the effects on
magnesium absorption do not seem to be as strong as for other minerals, though at
high phytate intakes, the effect on magnesium could be substantial.48,53,54
Calcium is often stated to exert negative effects on magnesium absorption, but
a major effect for most human circumstances is unconfirmed (see the chapter on
calcium). On the other hand, high-dose zinc supplements may be an underappreci-
ated cause of poor magnesium absorption.55 This concern is based primarily on just
one study, but the study merits follow-up.
Magnesium supplements are available in many different complexes. All seem
to be capable of impacting magnesium status, though there can be differences in
bioactivity in certain studies. There is the general attitude that organic magnesium
supplements are absorbed better than are inorganic versions, in part because the
organic forms are more water soluble.56,57 However, this idea may not be clear cut.
Many of the results are conflicting for organic versus inorganic supplements, as well
as for comparisons between different organic magnesium complexes. A possible
cause of the inconsistencies is that most studies lack a precise tool for measuring
acute bioavailability. Short-term serum magnesium changes are not reliable due to
renal adjustment of serum in the short run.57,58 For this reason, many studies examine
acute responses of urinary magnesium. However, these measures may have variable

responses for different types of people in different circumstances.57 It is noteworthy

that one paper recommends that if this approach is used, then it should be preceded
by a prestudy magnesium saturation period.59 This idea has some rationale, since
magnesium absorption is not regulated by magnesium status, and saturated tissues
will push magnesium toward urine. However, most studies on urinary magnesium
don’t use this saturation pretreatment. Alternatively, stable isotope studies may
provide better answers,58 but they have not been done much for this issue. Thus, at
present, it is very difficult to make definitive statements about absorption differences
for one supplement type versus another.
An indirect approach to this issue, which has not been used much, is to compare
different magnesium complexes for long-term effects on magnesium status or some
health benefit. A problem with this approach is that it requires far more time and
money than acute studies. In addition, it is harder to use the same people for each
supplement to be tested, which is typically done for acute studies. Therefore, for
longer studies, either well-matched groups must be studied, or a single group must
be committed for a substantial amount of time (to do multiple treatments and washout
periods). In the latter case, compliance and lack of changes in diet would have to
be monitored carefully. A very limited amount of this type of work has led to the
idea that for some specialized effects, some forms of magnesium complexes may
work better than others (discussed later in this section).
In addition to possible efficacy differences between supplement types, there may
also be some differences in GI tract side effects. However, this is not well docu-
mented by extensive published studies. The limited data is discussed at the end of
this section.
The inorganic magnesium supplement that tends to draw the most criticism for
poor absorption is magnesium oxide. This complex is by far the most common form
of magnesium supplement sold in a supermarket or drugstore setting, and is used
for a lot of food-fortification applications. The attitude that magnesium oxide is not
well absorbed derives in part from its low solubility in water.56 In addition, in two
human studies of urinary magnesium responses, this form of magnesium shows less
bioavailability than some other forms of magnesium.60,61 In fact, in one of these
studies, the effect on urinary magnesium is so small that it is not significantly
different from baseline.60 In the other study, magnesium citrate is absorbed 4.5 times
as well as magnesium oxide.61 One drawback of the last study is that it is based on
two-hour urines, which may underestimate total absorption for a slowly absorbed
molecule. However, there is also an additional study reporting that magnesium
absorption from magnesium oxide is less than from magnesium aspartate.62 In
addition, in a four-week rat feeding study, magnesium oxide, when compared to
magnesium citrate and two other magnesium complexes, shows lesser long-term
effects on urinary magnesium and on diet-induced kidney stone formation.63
Despite what was just said, the story on magnesium oxide is not as clear as it
would first seem. For example, some finely ground preparations of magnesium oxide
can dissolve to a good extent in water.64 Moreover, in a cattle study, different versions
of magnesium oxide produced availabilities that paralleled their water solubility.64
In another cattle study, magnesium oxide preparations with small particle size have
a better effect on urinary magnesium than do other magnesium oxide preparations.65

Even so, one problem with applying these cattle studies to humans is that ruminant
digestive processes differ from humans, which may cause differences in handling
of magnesium oxide. Still, there are human studies of magnesium oxide supplemen-
tation where some desired health effect has been produced.66,67 Thus, it would be
very helpful to have more human comparisons between different versions of mag-
nesium oxide, as well as more comparisons of these versions vs. other types of
magnesium supplements. These comparisons should include stable isotope absorp-
tion studies, long-term effects on magnesium status, and health effect end points.
Magnesium carbonate is another supplement that is very water insoluble. At
present, magnesium carbonate is not used a lot in supplements or food fortifications,
though it is sometimes used in both these fashions. The predominant human use for
magnesium carbonate is as an antacid. Magnesium carbonate is not considered to
be a well-absorbed form of magnesium,56 though actual studies of this point are very
limited. In two studies, one in rats and one in humans, sustained magnesium car-
bonate supplementation actually decreases the magnesium content for plasma or
certain tissues.68,69 In contrast, in a rat study,70 magnesium carbonate appears to be
well absorbed, though that is in comparison to magnesium oxide and chloride, which
are not considered “gold standards.” On the other hand, a different line of argument
can be used to support a reasonably good bioavailability for magnesium carbonate.
This argument is that in a human study, a magnesium carbonate supplement produces
a small increase in serum magnesium and some apparent health benefits.71 This study
is done with subjects with symptomatic mitral valve prolapse (MVP). However, an
unanswered question is whether the benefits are due to improved magnesium status
or just antacid effects. There is precedent that antacid use can have beneficial effects
on a subcategory of subjects with mitral valve prolapse.72
Magnesium sulfate is used for intramuscular and intravenous magnesium admin-
istration, and is sold as a laxative (e.g., under the name Epsom Salts). For the non-
oral applications, there has not been much research consideration as to whether or
not this is the optimal form of magnesium to use, but this form has certainly been
the predominant one used. In the oral use area, magnesium sulfate laxative products
are sometimes prescribed as magnesium supplements. In addition, to a limited extent,
magnesium sulfate is marketed specifically for use as magnesium supplements, or
used in powder form for food fortifications. There is little study on the efficacy of
oral magnesium sulfate for impacting human magnesium status. Some researchers
recommend against magnesium sulfate for supplementation purposes due to possible
low absorption, though this has not been confirmed directly in humans. However,
two rat studies are consistent with this idea. In one study,70 retention and absorption
of magnesium sulfate is considerably less than magnesium carbonate, which may
not be well absorbed itself.56 Similarly, in a four-week rat feeding study, magnesium
sulfate, when compared to magnesium citrate and two other magnesium complexes,
shows a lesser effect on urinary magnesium and on diet-induced kidney stone
formation.63
Another inorganic magnesium supplement with antacid and laxative properties
is magnesium hydroxide (e.g., sold under the name of Maalox). Due to its poor
water solubility, this form has been stated to have poor bioavailability.56 However,
in one human study, magnesium hydroxide has the same acute effect on urinary

magnesium as some organic magnesium supplements.73 Still, as already noted above,

there is some debate as to the value of this approach, though it is the way most
studies of magnesium absorption are done. A selling point for supplement use of
magnesium hydroxide is a beneficial effect on bone density in a human study.74
However, as discussed below in another section, there are some questions about this
study. Another concern about magnesium hydroxide supplementation is that long-
term use seems to increase the risk of developing a cardiac event in certain subjects.75
In this author’s opinion, magnesium hydroxide can be a source of absorbable
magnesium. However, since there are some unknowns about its bioactivity and
safety, it would seem prudent to choose another magnesium complex if the goal is
simply to increase magnesium intake. On the other hand, there may be some situa-
tions where the antacid effects of magnesium hydroxide on the stomach or urine
may be useful. By the same token, there may be situations where those effects are
not desirable. This same type of situational benefit–detriment effect can be true for
another effect of magnesium hydroxide. This magnesium compound can influence
the solubility and absorption of various agents such as drugs.76
Magnesium chloride is another inorganic magnesium supplement, but it has
better solubility properties than the others discussed so far.56 In one rat study,
magnesium chloride is not as effective at raising serum magnesium as an organic
form (magnesium gluconate).77 However, the study design, serum magnesium read-
ings three days postsupplementation, is not a common approach to this area. In fact,
short-term changes in serum magnesium following increased intake tend to be of
limited use due to renal excretion responses.58 The time point in the rat study (three
days) is somewhat longer than what would usually be termed “short term” in this
context. Still, it is well below what would be called “long term.” In a human study,
a magnesium chloride liquid has comparable acute effects on urinary magnesium to
some organic magnesium supplements.73
One way magnesium chloride is sometimes sold as a supplement is as an enteric-
coated tablet under the trade name Slow-Mag®. The enteric coating on a magnesium
chloride pill is intended to reduce stomach upset and provide a slow, steady absorp-
tion. In one study, this type of preparation shows equal bioavailability to magnesium
gluconate.78 However, the comparison is based on serum magnesium 24 hours after
ingestion. As just noted, acute serum magnesium changes are not considered a good
way to assess relative magnesium absorption.58 In another study, which is based on
a GI tract lavage fluid collection, there is much less absorption with enteric-coated
magnesium compared to magnesium from almonds, or compared to an acetate
supplement.79 In other work, onetime supplementation with enteric-coated magne-
sium chloride does not affect urinary magnesium as much as liquid magnesium
chloride or a magnesium gluconate tablet.80 However, there is some concern about
this study. Neither the enteric-coated magnesium chloride nor the magnesium glu-
conate produce a statistically significant rise vs. no supplement. This is unexpected
for gluconate, which casts doubt on the interpretation of the whole study. Therefore,
the bioavailability of enteric-coated magnesium chloride is still an open question.
Even so, it should be noted that in a study of cardiac rehabilitation patients, this
form of magnesium does raise serum and urinary magnesium, as well as produce
cardiovascular benefits.81

There are many organic forms of magnesium supplements including lactate,

fumarate, acetate, malate, citrate, picolinate, pidolate, glycinate, other amino acid
chelates, taurate, gluconate, and orotate. There are not a lot of direct comparisons
between the various organic complexes. A number of the individual complexes have
been able to produce apparent benefits in human supplementation trials. Magnesium
lactate may have especially good absorption based on very high water solubility,
and a report of a very high percent absorption for a slow-release version.56 However,
this report must be interpreted cautiously. The comparison made for different com-
plexes uses different studies. In addition, the comparison is not based on very large-
scale research. Moreover, two studies of urinary magnesium do not show any dif-
ference between magnesium lactate and some other types of magnesium supple-
ment.60,73 Again, though, it must be remembered that acute urinary magnesium
change has been questioned as the final word on magnesium bioavailability. There-
fore, it can be said that magnesium lactate appears to have very good absorption,
which is proposed, but not confirmed, to be better than some other organic magne-
sium complexes.
Magnesium citrate is also considered a well-absorbed complex.56 As noted
earlier, in one study, magnesium citrate is absorbed 4.5 times as well as magnesium
oxide.61
Magnesium taurate has some theoretical appeal because magnesium and taurine
have been speculated to exert complementary roles in counteracting some health
problems.82 However, to this author’s knowledge, no published human studies com-
pare magnesium taurine to other types of magnesium supplements. There is an
animal study of magnesium acetyltaurinate where this complex inhibits audiogenic
seizures in magnesium-deficient mice.83 This effect is not completely duplicated by
magnesium chloride plus vitamin B-6. There is also a rat study of magnesium
acetyltaurinate in comparison to other magnesium complexes. In this case, magne-
sium acetyltaurinate is more effective than a variety of magnesium complexes in
blocking symptoms caused by the combination of kainic acid plus magnesium
deficiency.84 This is one of several examples where a particular magnesium complex
may have an advantage for a specialized bioactivity. A few others are noted in this
and other sections.
Magnesium pidolate may provide another example of where one magnesium
complex shows better specialized bioactivity than other magnesium complexes. In
rats, although magnesium deficiency-induced aggressive behavior is suppressed by
a number of magnesium salts (chloride, pidolate, aspartate, gluconate, lactate),
magnesium pidolate is the best at some subcategory measures.85 In another study,
which examined some reactions to activity-altering drugs, magnesium as pidolate,
but not as lactate or aspartate, induced a neurosedative effect.86
Some Internet sites tout magnesium malate as a superior form of magnesium
for certain applications. The main published study to support this concept is work
in fibromyalgia patients where this complex reduces pain and tenderness measures.87
However, the positive results were obtained in an unblinded fashion, were not
compared to specific effects on magnesium status, and were not compared to any
other form of magnesium. Thus, at present, no special benefits can be ascribed to
magnesium malate.

Magnesium diglycinate chelate has shown much better absorption properties

than magnesium oxide in a subgroup of subjects who have undergone ileal resec-
tion.88 Ileal resection makes people prone to magnesium deficiency, but oral mag-
nesium treatment is difficult due to sensitivity to the laxative effects of magnesium
complexes. A crossover study was done in this population using stable isotope
methodology.88 Magnesium absorption from magnesium diglycinate chelate is much
better than from oxide in a subgroup of patients with the greatest impairment of
magnesium absorption. A possible explanation for the better absorption is that the
magnesium diglycinate chelate may be absorbed intact, possibly via a dipeptide
transport pathway. However, it should be noted that this magnesium complex did
not show a different absorption from the oxide form for the group as a whole. Despite
this observation, and despite the fact that the subject number is not very large, the
study does raise the possibility that magnesium diglycinate may be especially useful
for these types of subjects. This usefulness is further enhanced by the good tolera-
bility shown in this study in subjects with high sensitivity to GI distress.
This leads to the general subject of GI tract distress due to different forms of
magnesium supplements. Unfortunately, there is no study that provides an extensive
direct comparison of different magnesium complexes in this regard. The above-noted
results for magnesium diglycinate suggest that this complex is one of the better
magnesium complexes for GI tract tolerability. There is also a report of no diarrhea
effect of magnesium aspartate at doses a little above the RDA.89 In addition, slow
release preparations, such as some versions of magnesium lactate and enteric-coated
magnesium chloride, would seem by design to be less irritating than most magnesium
preparations. However, it is possible that one could produce some of the same effect
as slow-release preparations by spacing out magnesium supplement ingestion
(though this is more effort for the consumer). A number of Internet sites say that
magnesium oxide produces 2 times, and magnesium chloride 3 times, the incidence
of diarrhea than from an equal dose of magnesium gluconate. However, this author
has been unable to find a published report on this comparison.

There are no commonly eaten foods that have extremely large percentages of the
adult RDAs for magnesium.90 Among commonly eaten foods, nuts and seeds are
the most concentrated per unit weight,90 but for most people, these foods are not a
consistently eaten source of magnesium. Other relatively good sources of magnesium
are whole grains and dark green leafy vegetables, due to the high content of chlo-
rophyll, which contains magnesium. Milk and dairy products, though not outstanding
sources of magnesium per serving, if consumed in high amounts, can contribute a
reasonable amount of magnesium to the diet. Other reasonable sources are legumes,
a few other vegetables, and a few fruits. Whole-grain products can also make some
contribution if substantial amounts are eaten.
Estimates of magnesium intake from various dietary surveys indicate that many
people eat less than recommended amounts of magnesium.91–93 One concern with
such surveys is that they may not account for supplement use, though most multi-
type supplements either omit magnesium or do not add a high percentage of the

RDA. Another issue is that most surveys do not account for the fact that some local
drinking water can be a substantial magnesium source.94 Nonetheless, even if sup-
plements and drinking water do cause an underestimation of some people’s magne-
sium intake, that would still leave many people consuming below recommended
amounts.
The exact consequences of this seemingly widespread moderately low magne-
sium intake are not fully known yet. One concern is that this produces high suscep-
tibility to acute magnesium depletion. Such depletion can be caused by impairment
of intestinal magnesium, or more often, excess renal magnesium losses.18 In extreme
cases, a serious magnesium deficit could occur even if previous magnesium intake
had been very good. Still, if magnesium intake has not been very good, then depletion
may occur more easily. Although the causes of such depletion are not extremely
common, they can be a concern for some people. Examples of situations that can
cause magnesium depletion are given below in the Overt Hypomagnesemia subsec-
tion. In other situations, marginal magnesium deficiency may have other conse-
quences, especially when combined with physiological stress. These possible con-
sequences come up in various supplementation studies that are discussed in the next
section.

PARENTERAL PHARMACOLOGICAL USES
Parenteral magnesium has been proposed as helpful for a number of uses that are
not intended primarily to correct magnesium deficiency. Examples include treatment
and prevention of eclampsia and for treatment of acute myocardial infarction.95,96
Since this book is directed toward oral mineral supplements, the topic of parenteral
magnesium for pharmacological purposes will not be covered here.
OVERT HYPOMAGNESEMIA (LOW SERUM MAGNESIUM)

Substantially low serum magnesium usually indicates magnesium deficiency due to
excess renal losses. Examples of situations that can cause magnesium depletion are
as follows:2,22,57,97
• Very low calorie intakes (including self-imposed situations such as anor-

exia nervosa and so-called protein-sparing fasts)
• Parathyroid disease
• Chronic alcoholism
• Chronic diarrhea
• Certain drugs, especially some diuretics, certain antibiotics, and selected
cancer chemotherapy drugs such as cisplatin
• Gitelman syndrome
• Uncontrolled diabetes (though body magnesium redistribution can also
be a factor)

Besides being caused by renal magnesium losses, magnesium deficiency can

also occur due to poor absorption, though this reason is less common.22 Examples
of causes of poor magnesium absorption are gastrointestinal problems, such as
malabsorption disorders as well as excessive vomiting and diarrhea.22
On the basis of experimental magnesium depletion in human volunteers, the
clinical manifestations of magnesium deficiency include anorexia, nausea, vomiting,
lethargy, weakness, personality change, tetany (e.g., positive Trousseau’s or
Chvostek’s sign or spontaneous carpopedal spasm), and tremor and muscle fascic-
ulations.2,22 The neurological signs, particularly tetany, correlate with the develop-
ment of low serum calcium and potassium.
In cases of substantial hypomagnesemia, oral magnesium supplements can often
be effective, though in very severe cases, parenteral administration can be justified.
It can also be important to treat the root cause of the problem, if possible. A first
clue to the cause can be a measure of urinary magnesium to distinguish a case of
excessive losses from poor absorption.
BLOOD PRESSURE
In theory, magnesium function could affect blood pressure via a number of different
mechanisms. For example, magnesium effects on the sodium–potassium pump and
on calcium ion flow can affect vascular tone and reactivity as well as dilation of
blood vessels.1,2,36 Blood pressure could also be affected by the magnesium antiox-
idant actions named in the Function section, since oxidant stress is thought to
contribute to hypertension.98 In addition, magnesium affects secretion of hormones,
which can impact blood pressure.1,2 In light of these possible functional connections
of magnesium to blood pressure, it is not surprising that in animals, magnesium
deficiency can promote hypertension.99,100 However, these studies may depict situa-
tions that are more severe than would occur in most humans with hypertension. Still,
a good number of human epidemiological studies show correlations between mag-
nesium intake and blood pressure.101–104 In addition, there are some correlations
between parameters of magnesium status assessment and blood pressure, though the
results do not give a totally clear-cut relationship.105–109 Even with good results,
epidemiological relationships may not actually reflect a major role for typical vari-
ations in magnesium intake and blood pressure. This statement is made because
high-magnesium diets are typically high in other minerals as well as phytochemicals
that could affect blood pressure. Thus, the apparent relationships of blood pressure
with magnesium may just be a coincidental relationship that reflects other dietary
patterns. One way to tease out what, if any, relationship magnesium has to blood
pressure is the use of magnesium supplementation studies.
Unfortunately, studies of magnesium supplementation and blood pressure have
not yielded consistent results.67,89,110–118 One problem can simply be that many studies
have a small sample size for a blood pressure study. Blood pressure studies typically
require a good number of subjects because the main end point is not very stable,
and it is affected by many factors including emotional ones. Another reason for the
variable results could be that magnesium intake may impact blood pressure only

under a combination of certain conditions. Such a circumstance combination could

be as follows:
• Subjects initially have at least a marginal magnesium deficiency.

• The deficiency is corrected by the given dose of the given magnesium
complex.
• The subjects initially have high blood pressure, but it is not so far advanced
that physical changes do not allow magnesium to make an impact.
• The high blood pressure is due to a specific process that responds to
magnesium.
For the last issue, one proposition is that the specific process involves the
renin–angiotensin-aldosterone system.108 Another proposition, based on a study com-
paring responders and non-responders, is that reduction in intraerythrocyte sodium
is a discriminating factor.119
The above-proposed scenario is supported by much of the research that has been
done so far. However, in some cases, the study publications do not supply enough
information to judge if this scenario is holding, especially for the last contention.
Examples of where the scenario is supported, at least in part, are as follows:
• Virtually all studies on magnesium supplementation of people with normal

blood pressure have not shown an effect.110,113
• One study reports that responders to magnesium tended to have recently
acquired hypertension.119
• Some studies reporting no effect on blood pressure also report no effect
on some markers of magnesium status.120–122
• Some of the studies showing improvements in blood pressure also report
increases in serum or plasma magnesium.67,111
• One study separates responders and non-responders by starting urinary
magnesium,123 while another study correlates rises in serum magnesium
and falls in blood pressure.67
A number of studies with positive results have used forms of magnesium that
are considered well absorbed or have used above-RDA doses of magnesium
oxide.111,119
In a study where responders and non-responders are compared, discriminations
can be found for starting plasma renin activities;115 in another study, discriminations
can be found based on the reduction in intraerythrocyte sodium.119
This response model may not be 100% true but it does seem to have some
explanatory power. Even so, not all studies directly support the model, though they
may not actually contradict it. For example, magnesium aspartate supplementation
lowers blood pressure in a study where there is no predictive value for starting
magnesium status or dietary intake.118 However, dietary intake does not necessarily
predict status if some types of hypertensive subjects have high magnesium needs.
In addition, in this study,118 magnesium intake may have been low in most subjects,

which would mean that most would be good responders. The last comment can also
apply to urinary magnesium data.
Two points should be clarified about the notion that already having high blood
pressure may be a prerequisite to seeing a magnesium supplement effect on blood
pressure. First, although this may be a general rule, some individuals with normal
blood pressure may still respond to magnesium. This idea is supported by a study
of normotensive subjects with signs of marginal magnesium deficiency.113 Magne-
sium supplementation does not produce a statistically significant decrease in blood
pressure, but the mean value does decrease in two groups given magnesium. Another
point about normotensive subjects is that even if increased magnesium intake doesn’t
lower blood pressure, a good magnesium intake may help prevent future hyperten-
sion in some people.
If magnesium can affect blood pressure, how much of a change can be
expected? In some studies, the change has been small, but in some cases, the
systolic change has been in double digits.111 The difference may be in part due
to starting blood pressure and change in magnesium status. It should also be
recognized that blood pressure is affected by many factors, and maximal control
is achieved by multiple interventions. This author recommends that people start
by addressing the biggest known influences on blood pressure, then consider
factors such as magnesium intake.
At present, it is still difficult to absolutely say specifically who, if anyone, can
benefit blood pressure-wise from increasing magnesium intake. What is really
needed is a study with large subject numbers of differing characteristics. It may be
hard to get such a study funded while many people are not committed to changes
already known to impact blood pressure. In the meantime, eating a diet high in
magnesium is probably a good idea from multiple health perspectives, including
boosting intake of other factors that can affect blood pressure. In addition, if people
are in a high-risk group for low magnesium intake, or if they wonder if they have
high magnesium needs, they should consult with a physician and a dietitian. In that
case, a test of serum magnesium could be done, and if that is low, a trial of
magnesium supplementation could be done. If blood pressure is lowered, and the
dose of magnesium is modest and well tolerated, there is probably no danger in
continuing this course (unless the patient tries to use this treatment to compensate
for poor health habits).
SERUM LIPIDS IN NON-DIABETIC SUBJECTS

In some animal studies, moderately high magnesium intake affects serum or tissue
lipid compositions in a manner that would be considered beneficial in humans.6,124,125
This effect does not necessarily involve prevention of a magnesium deficiency. One
mechanism could be magnesium binding to lipids and bile salts in the GI tract and
reducing their absorption.125 There also could be separate actions of magnesium on
serum lipids that does involve correction of a marginal magnesium deficiency. Along
these lines, in a few studies, serum- or platelet-ionized magnesium values show
inverse correlations with certain serum lipid values.126–128 This could mean that
marginal magnesium deficiency affects serum cholesterol. Alternatively, it could

reflect a comparison between moderately high magnesium intake vs. low to adequate
intake. Another possibility is that the correlations just reflect other dietary factors
that coincide with high magnesium intake.
There are two studies by overlapping authors that look at the response of serum
lipids to increased magnesium intake.129,130 In these studies, which each involve
about 400 subjects, magnesium intake is increased from about 400 mg/day to about
1000 mg by dietary intervention. The increased intake produces about a 10%
decrease in serum cholesterol, LDL cholesterol, and triglycerides. Unfortunately, it
is hard to decide whether these effects are due to magnesium alone, other dietary
factors, or the combination of magnesium plus other dietary factors. This is one
reason why supplementation studies can often make for cleaner results than diet
intervention, though the latter can sometimes be the more effective treatment. There
is one existing study on high-dose magnesium oxide that does not show lowered
serum cholesterol.131
In the just-discussed pair of studies,129,130 HDL cholesterol is not affected in the
total subject population, but rises in subjects with initially low values for serum
magnesium. This could mean that the effect on HDL cholesterol, unlike the effects
on the other lipid parameters, involves correction of marginal magnesium deficiency.
Although the average magnesium intake of the study subjects is reported to be above
the adult RDAs, some individual subjects could have moderately low intake. Possi-
bly, the HDL effect only occurs in the subjects with initially low magnesium intake,
or in those with unusually high magnesium needs. Alternatively, low serum magne-
sium may just be a marker for a poor diet from other perspectives, which is corrected
by the non-magnesium aspects of the diet intervention.
There is one other study where magnesium supplementation is reported to
increase HDL cholesterol values.116 The initial magnesium status of the subjects is
uncertain.
In another study, four weeks of magnesium supplementation (500 mg) plus a
low-calorie, low-cholesterol diet is examined in subjects with hyperlipidemia of
Frederickson types IV and IIb.132 The magnesium lowers serum triglycerides com-
pared to the diet alone, but not serum cholesterol. There is also a study where
magnesium aspartate does not alter total or HDL cholesterol when given at a dose
a little above the RDA for six months.118 Possibly, the dose of magnesium has to be
fairly high to see cholesterol effects.
In a final study, 1000 mg magnesium oxide supplementation of hyperlipidemic
subjects actually increases serum cholesterol slightly due to an increase in LDL
cholesterol.133 Values return to pretreatment levels after a washout period.
In summary, there is not yet conclusive evidence that high doses of magnesium
can consistently produce beneficial effects on serum lipids, though this is a possi-
bility. If this action exists, it may not always require correction of marginal magne-
sium deficiency.
PREVENTION OF CARDIOVASCULAR DISEASE IN NON-DIABETIC SUBJECTS

The possible relationship of magnesium to serum lipids and blood pressure would
impact risk of cardiovascular diseases. In addition, magnesium could affect this risk

via its antioxidant and anti-inflammatory actions.134 For example, magnesium-defi-

cient rats have lipoproteins with high susceptibility to atherosclerosis-related oxida-
tion.135 Magnesium also impacts cardiac muscle integrity, in part via regulatory
effects on antioxidant enzymes,10 and cardiac phospholipid composition.6 Further-
more, magnesium restricting of calcium movements can affect heart beat, vasospasm
tendencies, platelet aggregation, vasodilatation, and other cardiovascular-relevant
processes.103,134 There is also an idea, though still controversial, that magnesium is
part of a preischemia conditioning process that promotes later heart recovery from
ischemic stress.11,103
A number of epidemiological studies have found correlations between magne-
sium intake, or blood magnesium status indicators, and risk of certain types of
cardiovascular disease including stroke and ischemic heart disease.94,102,136–140 These
studies have included analysis of geographical regions with high magnesium contents
in drinking water.94,138 In one notable recent epidemiological study, done in Honolulu,
initial magnesium intake is correlated with later risk of coronary events in over 7000
men for over 15 years.141 There have also been autopsy studies showing lower
myocardial and skeletal magnesium contents in subjects dying from ischemic heart
disease rather than accidents.138 However, as already noted for other contexts, these
studies do not distinguish direct effects of magnesium intake from magnesium intake
just being a marker for other good dietary habits. On the other hand, studies in
experimental animals with induced atherosclerosis show directly that low magne-
sium intake can enhance atherosclerosis progress.124,125 However, such studies usu-
ally use more severe magnesium deficiency than is common in humans.
Direct studies of magnesium supplementation have not been forthcoming. This
is because studies of cardiac events in apparently healthy people require a lot of
subjects and a long time. For such studies to receive funding, there has to be a sense
of urgency, which has not yet happened in this area. One means of doing studies
that cut down on subject numbers and reduce study time is to consider survivors of
cardiovascular events. These types of studies can look at symptoms associated with
risk of further occurrence of cardiovascular events. These symptoms can develop
more quickly than major cardiac events in initially disease-free subjects. The
approach of studying people who already have cardiovascular disease provides
information useful for people in recovery, but may also have some predictive value
for first-time events.
Several of these types of studies have been done in subjects with coronary artery
disease. One such study finds that magnesium citrate supplementation (at about RDA
levels) improves exercise tolerance, exercise-induced chest pain, and an index of
quality of life.142 Similarly, in an earlier small pilot study, magnesium orotate
improves left ventricular function and exercise tolerance.143 One problem with inter-
preting this study is that orotate itself may protect against cardiac stress.144 In another
study, magnesium supplementation plus aspirin improves brachial artery endothelial
function and exercise tolerance.145 In a different study, magnesium oxide (800 to
1200 mg/day), but not placebo, inhibits platelet-dependent thrombosis without
affecting platelet aggregation.146 In one other study, enteric-coated magnesium chlo-
ride supplementation is alternated with placebo for six weeks.81 The subjects are 21
patients with stable congestive heart failure secondary to coronary artery disease,

who are treated with long-term loop diuretics, and who have initially low or normal
serum magnesium concentrations. The magnesium treatment raises serum magne-
sium values, and decreases blood pressure, vascular resistance, the frequency of
isolated ventricular premature complexes, couplets, and non-sustained ventricular
tachycardia episodes.
One question about the above-mentioned studies is whether the apparent benefits
involve correcting a marginal magnesium deficiency or not. In the study with the
patients on diuretics,81 the mean value for serum magnesium increases, but not all
subjects start with low values. Thus, it is hard to know if low serum magnesium is
a prerequisite for seeing the changes. In the study on magnesium oxide effects on
platelet-dependent thrombosis, serum magnesium is reported as normal, and it is
not increased by magnesium supplementation.146 Although serum magnesium is not
always an infallible guide to magnesium status, this study does raise the possibility
that in this trial, the action of magnesium is not correcting a marginal deficiency. In
one of the other studies,145 magnesium supplementation improves magnesium status
based on sublingual cell ionic magnesium measured by x-ray dispersion. Unfortu-
nately, it is hard to interpret this finding, since the method is not a common way to
assess magnesium status (though it may ultimately prove to be a good method).
Another issue with this study is that the magnesium supplement-induced increases
in cell values are fairly small. In addition, even if magnesium status is improved,
there is no direct evidence that the magnesium supplementation could not have
worked if starting magnesium status was good. Thus, in subjects with coronary artery
disease, any or all of the apparent benefits of magnesium supplementation may or
may not depend on correcting marginal deficiency.
In contrast to the above results, in subjects with dilated cardiomyopathy, mag-
nesium supplementation does not improve left ventricular ejection fraction nor
prognosis compared to placebo.147 However, the co-treatments used in both groups
already give substantial improvement in left ventricular ejection fraction. Thus,
improvement may be somewhat “maxed out” in these subjects. Moreover, the par-
ticular magnesium treatment used does not increase serum magnesium. Thus, if
improved magnesium status is needed to see the hypothesized benefits, then that
improvement did not occur.
One study of magnesium supplementation in subjects with cardiovascular dis-
ease actually produces negative results.75 The study is done with survivors of an
acute myocardial infarction. By one statistical analysis, though not another, cardiac
events are higher in the magnesium group than in the placebo group. However, the
magnesium supplement is the hydroxide form, which, as noted earlier, may not
always be a good choice as a magnesium supplement due to antacid effects.
In summary, for subjects who have cardiovascular disease, magnesium supple-
mentation produces apparent benefits in several studies. These results are promising
but could use bolstering by more studies in more people. Some physicians may feel
that there is already enough evidence to try a modest dose of magnesium in cardiac
rehabilitation patients. Other physicians may be more cautious due to the possible
detriment in one study. The detrimental actions, if they are a real concern, may
possibly be avoided by not using magnesium hydroxide as the supplement, though
this idea is unconfirmed.

It is not yet clear what, if anything, the studies discussed in this section imply
for prevention of a first cardiac episode. One study along these lines does exist.130
The study involves 400 high-risk individuals consuming either a magnesium-rich
diet or a control diet for 10 years. The group on the magnesium-rich diet shows less
total complications, sudden deaths, and total mortality, and higher serum magnesium.
These results are interesting, though this study should not be taken as a last word.
One concern is that the subject number is not large for a study with prime end points
of life expectancy and cardiac events. In addition, compliance tracking could have
been challenging, though the difference in serum magnesium confirms at least some
compliance. Finally, even if the study could be reproduced in more people, there
would be doubt whether the benefits are due to magnesium, magnesium plus other
dietary factors, or just the other dietary factors. For the moment, this study could
inspire anyone concerned about initial or reoccurring cardiovascular disease to
consume a magnesium-rich diet. This may help reduce cardiovascular risk, but if
not, it still provides good amounts of magnesium for other uses, and it is likely to
be high in many nutrients and phytochemicals.
DIABETES
Several lines of reasoning suggest that marginal magnesium deficiency occurs in a
good number of diabetic subjects. For example, a number of studies report low
serum magnesium values in many, though not all, subjects with type 1 or type 2
diabetes.148–150 The causes of the low serum magnesium are thought to be high renal
magnesium loss plus some magnesium distribution away from the blood into certain
tissues.149,150 Another connection between diabetes and magnesium is that erythro-
cyte-ionized magnesium, though not determined in all that many diabetic subjects,
tends to show low values.151–153 This can occur even in subjects with normal serum
magnesium values.153 Similarly, low serum-ionized magnesium can be found in type
2 diabetic adults and children, even with normal mean serum total magnesium
values.153,154 There is also a report of low muscle magnesium contents in type 1
diabetic subjects.155 Finally, a series of studies in diabetic subjects show inverse
correlations between serum magnesium and measures relevant to primary or sec-
ondary symptoms of diabetes (Table 2.1). If magnesium status is actually affecting
the symptoms listed in Table 2.1, these effects may be related, at least partly, to
insulin sensitivity. Magnesium function could have mechanistic connections to insu-
lin sensitivity via magnesium effects on insulin receptor binding, activity of the
receptors after binding, and signaling inside the cells.149,150,156
These types of observations have led to the idea that many diabetic people would
benefit from increased magnesium intake by diet or supplements. A number of
studies of magnesium supplementation have occurred with type 2 diabetic subjects
as well as a few studies with type 1 diabetic subjects (though one is not placebo
controlled). These studies give some basis for benefits of increased magnesium
intake, at least in some subjects. On the other hand, many of the studies do not
examine large numbers of subjects, and some results conflict. Representative studies
are summarized in Table 2.2.

TABLE 2.1
Inverse Correlations with Serum Magnesium in
Diabetic Subjects
Measure Type of Diabetes
Fasting glucose Type 2157

HbA(1c) Type 1158,159
Diurnal rhythms of serum glucose* Type 1 and 2160
Glucose clearance after a glucose load Type 2157
Occurrence or progression of retinopathy Type 1 and 2rev in 149
* Comparison with diurnal rhythms of serum magnesium
In addition to these results, magnesium supplementation can also improve insulin

responses and actions in elderly subjects without diabetes.178
These results suggest that at least some diabetic people could benefit from
increased magnesium intake. However, there is some doubt about the exact benefits,
in the portion of the diabetic population that would reap the benefits, and the ideal
magnesium treatment (dose, complex, length of treatment) to produce the benefits.
The doubt derives from the low subject numbers in many studies, lack of placebo
in a few studies, and conflicting results. The only way to settle these issues is a
large, multi-center trial that examines many variations in subjects and treatments.
As noted in the previous subsection, such trials are only funded where there is a
high sense of urgency. In the meantime, some unconfirmed speculations on the
causes of some of the conflicting results are given in the next few paragraphs.
For the lipid effects, there may be two different ways in which magnesium
supplements can work. The first way may involve effects mediated by intracellular
magnesium regulatory actions. For this process to be affected by increased magne-
sium intake, there may be two requirements. First, supplementation may have to
correct a marginal magnesium deficiency. Some of the negative results noted in Table
2.2 for magnesium supplementation and serum lipids come in studies where mag-
nesium status is not improved, is not reported, or is not initially poor in all the
subjects. There may also be a minimal time of treatment needed to see an effect. It
may take some time to correct magnesium deficiency and then some time for effects
on lipid metabolism to replace the existing state of lipid compositions. This time-
lag idea may also apply to some other possible effects of magnesium in diabetic
subjects. For example, in the study finding no effect of magnesium supplementation
on lipoprotein oxidation, the study’s authors propose that a longer treatment time
may be needed to see an effect.161
A second way in which magnesium may affect serum lipids is the same as that
hypothesized for effects in non-diabetic individuals. High oral magnesium intake
may decrease absorption of lipids and bile salts. Doses of magnesium are not very
high for many of the studies in Table 2.2.

TABLE 2.2
Representative Studies of Magnesium (Mg) Supplementation in Diabetic
Subjects
Type 1 Subjects
No effect on lipoprotein oxidation; improved erythrocyte Mg and Mg loading test161
Increased muscle Mg; reduced requirements for insulin (not placebo controlled)162
No effect on serum lipids or kidney function163
Substantial reduction in blood pressure164
Increased muscle potassium165
Improved Mg loading test and erythrocyte magnesium contents, but values not normalized; lipid and
glycemic parameters unchanged166
Type 2 Subjects
Reduced plasma cholesterol/LDL cholesterol; increased HDL cholesterol; no change in glycemic
control167
Reduced plasma cholesterol/LDL cholesterol; increased HDL cholesterol168
Better insulin sensitivity, fasting glucose, HbA(1c), serum Mg (initially low values)169
Increased acute insulin response after IV glucose or IV arginine170
Increases in acute insulin response, glucose disappearance rate after glucose pulse, and glucose infusion
rate (increases correlate with increases in erythrocyte magnesium)171
Reduced platelet hyperaggregability172
Increased plasma and erythrocyte Mg; improved insulin sensitivity with an acute glucoseload, but no
change in fasting glucose173
Improved insulin sensitivity with an acute glucose load; improvement correlated to increase in
erythrocyte Mg171
Normalization of erythrocyte ionized Mg and platelet reactivity174
Increased erythrocyte ionized Mg; no effect on glycemic control, markers of platelet reactivity,
hemostatic function, and endothelial function (subjects initially in good glycemic control)175
Increased mononuclear cell and plasma Mg; decreased plasma fructosamine (indicator of metabolic
control); all changes only seen with higher of two Mg doses tested176
No effect on serum lipids or glycemic control164
No effect on glycemic control, serum lipids, blood pressure164
Small increase in serum Mg; no effect on glycemic control, serum lipids, blood pressure; in subjects
with increased serum Mg (in response to either Mg or placebo), decreased diastolic blood pressure 177
The specific magnesium complex used may also be important. One of the better
effects seen on serum lipids is in a study using magnesium pidolate.168 This complex
may work better due to better bioavailability than the inorganic magnesium com-
plexes used in some of the negative studies. Alternatively, the pidolate may exert
specialized effects, either independently of the magnesium or with it.
Insulin sensitivity and insulin reaction to glucose loading are improved in a
number of studies in Table 2.2. In contrast, only one study reports any improvement
of fasting serum glucose,169 and just one reports improvement in any other indicator
of metabolic control.176 Some of the disparity for metabolic control results could be

tied to changes in magnesium status. In some negative result studies, initial magne-
sium status may not be poor for many of the subjects. In addition, in some studies,
the magnesium treatment may not have corrected any marginal deficiency that was
present. This lack of effect may be related to magnesium dose and bioavailability.
In support of these last ideas, one of the two positive studies on magnesium sup-
plementation and metabolic control notes an effect only with the higher of two doses
tested.176 In the other positive study, the supplement is liquid magnesium chloride,169
which shows good bioavailability in some studies.73,80 However, improvement in
magnesium status cannot be the only factor in magnesium-induced improvement in
metabolic control. There are studies noted in Table 2.2 where magnesium status is
improved but metabolic control is unchanged. Thus, whether magnesium supple-
mentation can help with metabolic control in many diabetic subjects is still in doubt.
In 1992, the American Diabetes Association made the following statement:179
“Adequate dietary magnesium intake can generally be achieved by a nutritionally
balanced meal plan as recommended by the American Diabetes Association … only
diabetic patients at high risk of hypomagnesemia should have total serum (blood)
magnesium assessed, and such levels should be repleted only if hypomagnesemia
can be demonstrated.” Since that statement, quite a few new studies have appeared,
but this author feels that much of the statement still makes sense. On the other hand,
this author feels that anyone with diabetes can have his or her serum magnesium
checked. If a person shows low serum magnesium, in this author’s opinion, a low-
dose supplement with high bioavailability and low GI side effects is very likely to
be safe and, possibly, could be helpful. If a diabetic person shows normal serum
magnesium, this does not guarantee adequate magnesium intake, but a more detailed
assessment of magnesium status is not available in most clinical settings. In this
author’s opinion, if serum values come back normal, a subject should still strive to
eat a moderately high magnesium diet. Supplements may or may not be helpful,
though this decision should be made in consultation with a physician and a dietitian.
STRESS
Internet sites, as well as some scientific review articles,180 tout magnesium as an
anti-stress mineral. Stress can be produced physiologically or psychologically. Mag-
nesium effects on physiological stress are part of the rationale for the possible effects
of magnesium on blood pressure and other aspects of cardiovascular disease (see
above). This is also part of the rationale for magnesium effects on exercise-related
phenomena (see below). In addition, magnesium may affect reactions to psycholog-
ical stress.
Magnesium has a lot of theoretical ties with inhibiting responses to psychological
stress. For instance, magnesium has a strong effect on neural excitability, since
magnesium deficiency is characterized by neural and neuromuscular hyperexcitabil-
ity.181 In addition, blood vessel dilation or constriction can be very much influenced
by magnesium.182 Magnesium can also have a variety of effects that involve systems
thought to be involved in the pathophysiology of depression.183 One such effect is
suppression of hippocampal kindling, which can reduce the release of adrenocorti-
cotrophic hormone (ACTH) and affect adrenocortical sensitivity to ACTH. A second

such effect is modulation of various receptors such as N-methyl-D-aspartate-antag-

onism, gamma-aminobutyric acidA-agonism, or angiotensin II-antagonism. In addi-
tion, magnesium can affect the function of the transport protein p-glycoprotein at
the level of the blood-brain barrier, which may impact access of corticosteroids to
the brain. Finally, magnesium depresses calcium ion–proteinkinase C-related neu-
rotransmission and stimulates the sodium-potassium pump, both of which can impact
neurological function.
It is of interest that magnesium and lithium, an anti-depression drug, have a
number of functional overlaps, including effects on sleep electroencephalogram
results.183
A big part of the relationship between magnesium and stress could be via
interactions with the stress-related catecholamine hormones epinephrine and nore-
pinephrine (adrenaline and noradrenaline). These hormones have three theoretically
possible interactions with magnesium:
1. Epinephrine may increase magnesium needs, which could promote mag-

nesium deficiency.
2. Norepinephrine and epinephrine secretion during stress may be inhibited
by magnesium.
3. Magnesium may limit detrimental effects caused by these two hormones
during stress.
In support of the first premise, low serum magnesium is reported for physiolog-
ical stress situations associated with high serum catecholamine levels.180,184 These
physiological stress situations include myocardial infarction, cardiac surgery, and
insulin-induced hypoglycemia stress tests. This idea that catecholamine hormones
depress serum magnesium is further supported by multiple studies showing that
epinephrine infusion in humans depresses serum magnesium.185 In addition, emo-
tional stress due to combat or threat of combat has been shown to produce low total
and ionized serum magnesium values.186 Part of the mechanism for depressed serum
magnesium in these situations has been thought to be epinephrine stimulation of
adipose tissue fat breakdown.180 This breakdown liberates free fatty acids, which
can then bind to magnesium and change its cell uptake patterns. However, this
concept is not fully confirmed, because if plasma free fatty acids are elevated from
an exogenous source, plasma magnesium does not drop.187 Thus, there may also be
other ways in which epinephrine lowers serum or plasma magnesium.
It is not known if the lowering of serum magnesium by epinephrine is actually
associated with a functional magnesium deficit. A deficit could be created by increased
urinary loss of magnesium or a type of body magnesium redistribution that tends to
deplete certain functional pools. Unfortunately, there is very little data as to whether
either of these responses actually occurs. One study finds no short-term epinephrine
infusion-induced increase of urinary magnesium,188 but there is not much additional
work building on this observation. Also, in some situations, stress can actually produce
a rise in plasma magnesium simultaneous to a loss of this element in blood cell and
heart tissue. This pattern has been demonstrated by combining data from guinea pigs,
rats, and humans undergoing noise stress.189–192 However, this rise may be temporary,

since noise stress can increase urinary magnesium.192 Thus, future studies may need to
give attention to the time course of changes in magnesium metabolism.
The second possible interaction, magnesium inhibition of stress-induced nore-
pinephrine secretion, is supported by a number of animal and human studies. Four
examples are given here. One, in people with mitral valve prolapse, magnesium
supplementation can decrease urinary norepinephrine and epinephrine, which is an
indication of lower blood levels of these hormones.71 Two, in humans, magnesium
sulfate infusion suppresses cardiac release of norepinephrine during a handgrip stress
test, which is an indirect index of sympathetic efferent neuronal activity.193 Three,
in stressed pigs, adding magnesium aspartate to a seemingly adequate diet produces
lower norepinephrine concentrations.194 Four, high-dose magnesium gluconate
reduces the catecholamine increase in response to immobilization stress.77 In the
first example, the effect is thought to coincide with correction of marginal magnesium
deficiency. On the other hand, this may not be the case in the last three examples.
This raises the possibility that above-adequate magnesium intakes may counteract
some stress effects.
On the other end of the spectrum, poor magnesium status can cause poor reaction
to stress. For example, in comparing mice with genetically low blood magnesium
to those with genetically high blood magnesium, the former have higher norepi-
nephrine levels.195 Similarly, magnesium-deficient rats show high urinary norepi-
nephrine.196 Also in rats, magnesium deprivation produces aggressive behavior.85,197
This effect can be reversed by supplementation by any of five magnesium complexes
(chloride, pidolate, aspartate, gluconate, lactate).85 However, magnesium pidolate
had the greatest efficacy by one assessment tool. The exact relationship of such
animal studies to human situations is not yet clear.
The third premise, magnesium can modulate the detrimental effects of catechola-
mine hormones, is well supported by animal work. Three examples are given here.
One, in magnesium-deficient rats, isolated aorta sensitivity to norepinephrine is
higher than in control rats.198,224 Two, vascular reactivity to norepinephrine is higher
in moderately magnesium-deficient rats than in controls.199 Three, in rats, high
magnesium intake produces low pulmonary vascular reactivity and hypoxic pulmo-
nary hypertension.200 Thus, this is another case where magnesium may have an effect
that does not involve correction of a magnesium deficiency.
Despite these mechanistic rationales for magnesium interactions with psycho-
logical stress, there is not a lot of human studies of magnesium supplementation in
this area. There is a study of magnesium supplement effects on sleep patterns, which
is done in 12 elderly subjects.201 Based on sleep electroencephalogram results and
nocturnal hormone secretion, magnesium supplementation partially reverses aging-
related changes in sleep. The authors of the study note that these effects of magne-
sium resemble those of lithium, which supports the possible efficacy of magnesium
as a mood stabilizer.
In another study, magnesium pidolate supplementation does not affect blood
pressure during sympathetic neuro-stimulation by stresses of cold, isometric action,
and tilt.112 Supplementation raises serum magnesium, though initial values are not
very low.

There has been some attempt to use noise-induced hearing-loss studies to relate
magnesium to protection against stress. In guinea pigs, and to a limited extent in
humans, magnesium intake or body fluid magnesium levels (including perilymph
values), have been shown to impact noise-induced hearing loss.189,202-208 However, the
mechanisms of action may go well beyond a limitation of the general stress response.
Instead, the magnesium effects may involve various physiological effects in the ear.
Nonetheless, even if the magnesium actions on hearing loss do not primarily relate
to general stress processes, the area of magnesium and hearing loss could use more
human research. On the other hand, avoiding excess noise, when possible, may be a
better approach to hearing maintenance than magnesium supplementation.
In conclusion, a connection between magnesium and resistance to the ill effects
of psychological stress has a strong mechanistic basis. However, there are just not
enough human intervention studies to rate the value of magnesium supplementation
for anti-stress effects. One approach to such human intervention studies could involve
noise and hearing loss, but this may not be ideal for studies on magnesium and
general stress.
EXERCISE
Since a great deal of the body’s non-bone magnesium is found in muscle, it would
be expected that there would be studies of magnesium supplementation relevant to
exercise. Such studies yield differing results. This should not be all that surprising
since many studies of a given theme in exercise give variable results. This can happen
in part because of the many variables associated with designing an exercise study
such as subject age, subject fitness, subject training level, subject motivation, the
type of exercise examined, the exercise testing duration, the timing of the supple-
mentation around the exercise tests, the project end points, how the data is analyzed
(e.g., improvement versus just final results), and background diet (both for the
component being studied and other components). In the case of magnesium supple-
mentation, not only do these variations complicate interpretation, but as discussed
below, there are also other design issues that cloud interpretation of many of the
studies.
In principle, magnesium function should have many effects on exercise. For
example, magnesium is important for regulating neuromuscular activity, excitation,
and muscle contraction, as well as for aspects of protein synthesis.1,57 Magnesium
is also needed for ATP-driven reactions, which include muscle contraction.1,57 In
addition, the antioxidant and anti-inflammatory actions of magnesium could delay
fatigue and promote muscle recovery, since fatigue and muscle recovery-related
inflammation can be accelerated by oxidant stress.209 Another way magnesium can
affect exercise capacities is via hormonal influences. For example, magnesium
impacts secretion of insulin-like growth factor, which influences muscle growth and
maintenance.210 Furthermore, magnesium promotes vasodilatation,182 which may
impact blood flow to the muscles.
Besides a mechanistic link between magnesium and exercise, body magnesium
distribution can be altered by exercise. Some short, intense exercise can increase

serum magnesium, possibly due to dehydration and movement of magnesium into

the serum from muscle and other cells.57 In contrast, sustained strenuous exercise
can reduce serum magnesium.57 Whether or not this action impacts magnesium
functional status is controversial. Reductions in serum or plasma magnesium of 5
to 25% have been reported immediately after prolonged strenuous exercise such as
a marathon run, a half Ironman triathlon, prolonged cross-country skiing, 90 minutes
of treadmill exercise, and a 120 km march.57 Some of this fall in serum magnesium
may be mediated by catecholamines, as discussed for other types of stress in the
previous subsection.
The drop in serum magnesium values seems to be especially pronounced in hot
conditions.211,212 This could imply that sweat losses contribute greatly to the depres-
sion in serum magnesium in exercise, especially in heat. However, sweat losses of
magnesium during exercise don’t appear to be big enough to account for the majority
of the drop in serum magnesium.211,213
Urinary magnesium can undergo some fluxes during and after prolonged exer-
cise, but the net result is not thought to have major acute impact on body magnesium
status.214 The effects of chronic exercise training on urinary magnesium, or on
magnesium status in general, is poorly characterized. The fall in serum magnesium
during acute, strenuous exercise may not involve body losses, but instead may be a
movement of magnesium into cells including muscle cells, adipocytes, and erythro-
cytes.57 After exercise subsides, body magnesium distribution tends to gradually
return back to normal.57 Whether or not prolonged repetition of this cycle raises
magnesium needs is not known.
Magnesium movements during short-term or prolonged strenuous exercise could
conceivably interact with dietary magnesium in the following ways:
1. If magnesium intake is chronically well below the RDA before exercise,

performance could be impaired by sub-optimal amounts of magnesium
moving to areas of need.
2. After exercise, the return to normal magnesium distribution may not be
fully effective; if training keeps repeating this process, magnesium needs
may be raised; if these increased needs are not met, exercise performance
impairment and other effects of marginal magnesium deficiency may
result.
3. An above-adequate intake of magnesium might enhance the efficiency of
magnesium redistribution during exercise, which in turn might improve
exercise performance.
The first possibility seems to be a safe assumption. Poor magnesium status has
been shown in both humans and rats to have this effect.215,216 This could be true even
in people of average fitness doing sub-maximal exercise. This contention is supported
by a study where postmenopausal women are chronically fed different levels of
magnesium.217 Marginally low intake affects sub-maximal exercise performance by
increasing energy needs and adversely affecting cardiovascular function.
Although possibility number 1 was just stated to be a safe assumption, there are
two unanswered questions. One, how bad does marginal magnesium deficiency have

to be before an effect is seen? And, two, how often does this state occur? Dietary
surveys of competitive athletes and otherwise very active people show magnesium
intake varying among different groups.57 Intakes range from well below the RDA
to levels at or a little above the RDA. What these studies don’t say is whether the
RDA is an appropriate standard for all types of athletes or highly active people. This
leads to the second possibility, which says that chronic exercise training raises
magnesium needs. As already stated, this issue has not been well addressed. A little
support for the idea of raised needs is gathered from two studies.31,218 In one, low
serum magnesium persists long after a 120 km hike has ended.218 In the other study,31
certain female athletes show low serum magnesium levels despite dietary magnesium
intakes above the RDA. Unfortunately, with both studies, it is hard to know if the
results represent a true magnesium deficit or just metabolic regulatory action. The
second study31 claims to have evidence for the latter. The contention is based on a
lack of effect of three-week supplementation with magnesium oxide given to athletes
with low to normal serum magnesium. The lack of effect is noted for both serum
and cellular magnesium contents. However, this could simply indicate that the
magnesium oxide supplement used has low bioavailability. This proposition is sup-
ported by the lack of a clear increase in urine magnesium from baseline in the
supplemented group. If the supplemented magnesium was absorbed, but did not
improve magnesium status, the urinary magnesium should increase. Thus, the ques-
tion of whether chronic exercise training raises dietary magnesium needs is not yet
answered.
The final possibility is that a dietary magnesium-induced improvement in exer-
cise performance could go beyond any correction of marginal deficiency. This
possibility is still unsettled, partly because most studies on magnesium supplemen-
tation and exercise performance do not fully address the issue of starting magnesium
status.
There have been a number of studies on magnesium supplement effects on
exercise performance. Most of these focus on just magnesium, though there are also
a few dealing with specialized products such as magnesium–creatine, and a product
that combines magnesium, zinc, and vitamin B6. These last two products are dis-
cussed briefly at the end of this subsection.
The following are brief summaries of 10 representative studies on magnesium
supplementation and exercise performance (5 negative results and 5 positive results).
In many of these studies, some details, such as magnesium status of the subjects,
are not reported. In each of these studies, a placebo control is used.
Negative
1. Three weeks of magnesium oxide supplementation gives no effect on

performance in multiple types of exercises; there is minimal impact on
urine magnesium.31
2. Magnesium aspartate supplementation has no effect on marathon race
running performance in terms of muscle damage, rate of recovery of
muscle function, or running time; no increase is seen for muscle or serum
magnesium.219

3. A 12-week exercise program plus magnesium supplementation is tried in

active men; peak oxygen uptake is increased with or without magnesium;
there is no change in urinary magnesium.220
4. Four weeks of magnesium oxide supplementation is done in young adults
with a broad range of serum ionized magnesium values; there is a small
increase in serum-ionized magnesium, but no change in exercise perfor-
mance and recovery indices.221
5. Magnesium aspartate supplementation is done for three months in healthy
young swimmers; there is no effect on performance data for laboratory
or competition settings; there is some increase in serum magnesium val-
ues, which are initially in the lower end of normal range.222
Positive
6. Magnesium oxide is given during a seven-week strength training program

for untrained subjects; both the magnesium and placebo groups gain
strength, but the magnesium group does better based on knee-extension
torque strength.223
7. Magnesium orotate is given to competitive triathletes for four weeks; there
is no change in serum magnesium, which is initially in the normal range;
swimming, cycling, and running times are lower in the magnesium group
versus placebo; hormonal and metabolic changes in the supplemented
group are more favorable than for placebo.224
8. Magnesium aspartate is given for three weeks to female rowers with
plasma magnesium values at the low end of the normal range; exercise
performance is improved.225
9. Magnesium picolinate given to moderately trained adults improves car-
diorespiratory function during sub-maximal exercise.226
10. Short-term magnesium–potassium aspartate improves endurance on a
bicycle ergometer.227
Some studies on both sides have questions about interpretation. For example, both
study number 2 on the negative side219 and number 7 on the positive side224 have no
before-intervention testing; there is just after-treatment testing. These types of studies
require careful matching for initial fitness, plus either a very consistent, clear inter-
vention effect or a high subject number. These studies have neither of the latter two
traits. Study number 2 also uses both genders, which should not be done in an exercise
study with a small number of subjects. In fairness to study number 7, the authors do
not actually make a strong claim that the study demonstrates a magnesium effect on
exercise performance. The authors present as their main goal analysis of magnesium
modulation of exercise-induced effects on hormone metabolism and various physio-
logical parameters. However, some other researchers have presented this study as a
demonstration of exercise performance enhancement by magnesium.
Two of the five negative result studies cited use magnesium oxide,31,221 which
does not always show good bioavailability. This may have been the case in both of
these studies, since one reports no clear effect on urinary magnesium,31 and the other

reports just a small change in serum-ionized magnesium.221 Another of the negative

result studies reports no effect on serum total magnesium.220 Similarly, one of the
other negative studies finds no increase in serum or muscle magnesium.219 Thus,
four of the five negative result studies do not necessarily involve improved magne-
sium status, which may be a requirement for seeing a magnesium supplement effect
on exercise.
One of the positive results studies also uses magnesium oxide but still gets an
effect on training-induced strength increase.223 It is noteworthy that pretraining
strength of the subjects is pretty well matched between the magnesium and placebo
groups. Unfortunately, this study does not report on subject magnesium status
changes, but as noted earlier, some preparations of magnesium oxide can show
enough bioavailability to affect magnesium status.
Study number 10 of the positive result studies227 has some question marks about
interpretation due to low subject number (n = 6), the short duration of supplemen-
tation (one day before the first assessment), and the possible effects of potassium
and aspartate independent of magnesium. The general idea of this last concern also
applies to study number 7 of the positive results,224 because orotate has biological
activities independent of magnesium.144
In conclusion, there are many questions about the studies of magnesium sup-
plementation and exercise. Thus, no conclusions can be reached yet.
As mentioned earlier, two atypical magnesium supplements are marketed for
exercise performance enhancement. One is a magnesium–creatine chelate. This
complex may enhance creatine effectiveness by targeting creatine to muscle, slowing
degradation of ingested creatine, and by magnesium functions complementing the
actions of creatine. This author’s laboratory finds that short-term use of this supple-
ment, at a relatively low dose for a creatine study, produces improved bench press
performance.228 However, the improvement is no better than creatine alone. The
short-term supplementation approach is used to test for a direct effect on performance
that is relatively independent of a training enhancement effect. The negative results
of this study do not rule out that magnesium–creatine might outperform creatine in
a longer term training study of low-dose supplementation. Also, the initial work
does not control for macronutrient content of the diet, which may affect the results.
One other study has been published for magnesium–creatine,229 which when com-
pared to our group’s study, uses a slightly longer intervention time and a considerably
higher dose. The magnesium–creatine chelate increases intracellular and extracellu-
lar water as well as knee extension peak torque. This increase is not seen for placebo
or for magnesium oxide mixed with creatine. The increased intracellular water may
be indicative of more muscle synthesis of creatine or protein, though this is uncon-
firmed. In conclusion, work on magnesium creatine is still in the early stages.
A popular supplement for exercisers combines magnesium, zinc, and vitamin
B6, and is called ZMA. Although one website states: “There is a large body of
scientific evidence supportive of ZMA,” there is not a single hit on Medline for the
term “ZMA.” This author is aware of one meeting abstract on ZMA.230 This author
is not aware of a follow-up as a full-length paper. Thus, it is difficult to assess the
value of ZMA at this time.

OSTEOPOROSIS PREVENTION OR RESTRICTION

Since a high portion of the body’s magnesium resides in bone,15 and since magnesium
has some possible mechanistic ties with bone health (see the Function section), it
makes sense that magnesium intake could affect osteoporosis prevention or progres-
sion. This concept is supported by animal studies,15 but human intervention studies
are very limited. The study that gets the most attention examines trabecular bone
density in 31 postmenopausal women with osteoporosis.231 After a year, bone density
is increased by magnesium supplementation as compared to a group of women who
refused osteoporosis treatment. However, there are some bothersome aspects of the
study. One concern is that bone density increases after one year, which is not a
common finding in studies of this subject group. Usually, a good result is a slowing
of bone loss. In addition, in 10 of the subjects given magnesium, continuation for
a second year of supplementation loses the magnesium effect. Another problem is
there is no placebo group. Instead, for a frame of reference, a group is used that
may have been less motivated about their bone health than the supplementation
group.
In a different study, done in healthy young adult females, the effects of 28 days
of magnesium supplementation or placebo are examined for effects on biomarkers
of bone metabolism.120 In this crossover study, values for serum and urine bone
turnover markers are not affected by magnesium supplementation, but neither is
serum magnesium. Thus, a marginal magnesium deficiency may not have existed,
or if it did, it may not have been corrected. This may be the reason for no effect on
bone turnover parameters. Alternatively, the supplementation intervention may have
been too short. Or, it’s possible that boosting magnesium intake is not an effective
way to promote bone health in this people group.
A few other studies on magnesium supplementation and bone have been done,
though low subject number or design problems cause these studies to not carry much
weight. Thus, at present, though magnesium protection against osteoporosis is the-
oretically very possible, we don’t know if increased magnesium intake would help
osteoporosis prevention or restriction to a large degree in many people.
CHRONIC FATIGUE
Magnesium status in subjects with chronic fatigue syndrome does not seem consis-
tent. One study states that erythrocyte magnesium is low,232 but a larger study does
not.233 In the latter study, normal values are also reported for a magnesium loading
test, though only six of the study subjects are tested. A different study reports normal
serum total and ionized magnesium in subjects with chronic fatigue syndrome.234 In
one other study, just under half of 97 subjects show evidence of magnesium defi-
ciency based on a magnesium loading test.235 Magnesium supplementation was tested
in 24 of these patients. Supplementation improves values for the loading test. How-
ever, not all the subjects in this study are declared to have chronic fatigue syndrome.
Some are designated as having other types of chronic fatigue. Even so, this study
adds to the idea that some degree of magnesium deficiency is not a consistent finding
in chronic fatigue syndrome.

There are two other magnesium supplementation studies. One uses six weekly
injections, which produces subjective symptom improvements in 12 of 15 subjects,
while placebo gives improvement in 3 of 17 subjects.232 In this same study, there is
also an energy scoring evaluation where seven of the supplemented group show
improvement compared to just one in the placebo group. One other study examines
a heterogeneous group of subjects, about half of which are said to have chronic
fatigue syndrome.236 About half of the total subject group are designated as having
“subclinical” magnesium deficiency based on a magnesium loading test. These
subjects show lower values for some parameters of antioxidant defense. Of these
subjects, 24 are given magnesium supplements, but only about half show improved
magnesium status. The type of supplement is not stated. Supplementation increases
serum vitamin E levels and improves one parameter of resistance to oxidant stress,
but not two others.
At present, it is hard to reach a conclusion of the value of magnesium supple-
mentation in chronic fatigue syndrome due to the inconsistency of results as to
magnesium status, the very limited testing of symptom improvement with adminis-
tered magnesium, and the mixing of different fatigue classifications in two studies.
ASTHMA
A number of Internet sites tout magnesium supplements for asthma patients. It is
true that magnesium given by various non-oral routes has been tried pharmacolog-
ically in asthmatic subjects, particularly for treating acute stress.20 However, this
does not necessarily indicate that oral supplements would be effective. There is one
study of short-term intervention effects of magnesium intake on asthma symptoms.237
In this work, subjects eat a low-magnesium diet for three weeks, and then have a
short-term treatment period for supplementation with magnesium or placebo. The
subjects then repeat the diet protocol, after which they then take whatever supple-
mentation treatment was not used the first time (magnesium or placebo). Magnesium
supplementation improves subjective, but not objective, symptoms. Thus, at present,
there is no direct, strong evidence that oral magnesium supplements would help
asthma, though there are some epidemiological links between magnesium intake
and some asthmatic symptoms.238
BETA-THALASSEMIA/SICKLE CELL ANEMIA

These two erythrocyte pathologies may be helped by magnesium supplementation.
In the case of sickle cell anemia, one of the pathogenetic mechanisms responsible
for sickling is decreased hydration of the cells.239 Erythrocytes require a high degree
of hydration to keep the large amounts of hemoglobin soluble in the cells. In sickle
cell anemia patients, a subset of the erythrocytes loses magnesium easily through
cell membranes.239 This, in turn, affects cellular electrolyte transport, which in turn
affects water movement in and out of the cells.
Besides the loss of magnesium from erythrocytes, there are reports of people
with sickle cell anemia having high urinary magnesium excretion and low plasma

or serum magnesium.240,241 However, these reports do not encompass a tremendously

large number of subjects.
A small study in humans shows beneficial effects of magnesium pidolate sup-
plementation on the erythrocytes.242 The benefits include effects on measures indic-
ative of better cell hydration. In addition, in a mouse model for this disease, a low
magnesium intake worsens the condition, and a high magnesium intake improves
it.243 There is also a non-blinded study where magnesium supplementation strongly
decreases the median number of painful days in a six-month period.244 However, as
the authors of the study note, no firm conclusion on therapeutic efficacy can be
drawn from this unblinded, open trial.
These results are certainly interesting. The next step would be large, placebo-
controlled trials. Since all of the studies mentioned in the previous paragraph involve
one particular researcher, it would be good to have some other groups also involved
in the future studies. Some attention may need to be given to the particular magne-
sium complex used for the studies.
The same researcher who led the studies on magnesium supplementation and
sickle cell anemia has also investigated magnesium in another erythrocyte disease,
beta-thalassemia.245,246 This disease is also characterized by magnesium metabolism
abnormalities, including low blood cell magnesium.246 In a small study of magnesium
supplementation in humans,246 and in a study of a mouse model for the disease,245
erythrocytes are affected in ways that are reminiscent of those found for magnesium
in sickle cell anemia. These results include effects on cell hydration, though the
clinical importance of these effects for beta-thalassemia is not totally clear yet.
KIDNEY STONES
Magnesium–potassium citrate has been used as a preventive measure against kidney
stone formation, but the main intended effect is citrate delivery. However, magnesium
as part of this or other complexes may help inhibit kidney stone formation, partic-
ularly for calcium oxalate stones. There are several theoretical possibilities for how
magnesium could work against such stone formation:
1. Inhibiting the formation of calcium oxalate crystal building in the kidney

(supported by work in vitro)247,248
2. Influencing body citrate metabolism, which influences urinary citrate,
which inhibits stone formation249,250,251
3. Non-citrate-related alkali effects in the urine, which reduce stone
development252 (this could be especially true of complexes like magne-
sium hydroxide, which is an antacid)
4. Binding to oxalate in the GI tract to prevent oxalate absorption253
5. Repression of internal oxalate production;254 this may only be relevant to
avoidance of severe magnesium deficiency, and even then, increased pro-
duction may be offset by increased oxalate secretion into the intestine255
There have been some attempts to say that some chronic stone formers often
have marginal magnesium deficiency, but the studies tend to be small and not overly

compelling. For example, in a study in Thailand, 9 of 17 subjects with kidney stones

show signs of marginal magnesium deficiency based on a magnesium tolerance test,
but so do 6 of 16 controls.249 Even so, it is possible that a stone former would not
have to have a marginal magnesium deficiency to benefit from increased magnesium
intake. Conceivably, some mechanisms noted above could be promoted by consum-
ing magnesium at levels beyond those needed to prevent or correct a marginal
deficiency. Moreover, the effects of magnesium hydroxide as a urinary antacid may
go beyond the effects of just providing extra magnesium. On the other hand, a low
magnesium intake could aggravate a predisposition to renal stone formation via
some of the possible mechanisms mentioned above. Thus, in principle, magnesium
intake could be useful for kidney stone prevention as part of antacid complex, as a
corrector of marginal magnesium deficiency, or by various actions that go beyond
either antacid actions or correction of a marginal deficiency.
There are a number of studies on magnesium supplementation in regard to stone
formation or kidney stone risk factors. Unfortunately, none make a strong case for
or against supplementation. One reason is that most of the studies do not have a lot
of subjects for the type of study done. In addition, some of the studies use end points
that really don’t rule in or out a strong effect on stone formation. Another problem
is that there is often little attention paid to the specific magnesium complex used,
which could affect the results. Finally, many of the studies do not use a placebo
control. As shown in one of the studies discussed below, a placebo effect can be
very strong in these types of investigations. One reason for a placebo effect is that
if subjects are motivated enough to be in this type of study, then they may also be
motivated to take other steps to prevent stone formation (e.g., increasing water
intake).
In one study, 13 stone formers are treated for one year with 400 mg magnesium
oxide plus another agent in a non-placebo-controlled study.256 The treatment reduces
urinary calcium to magnesium ratios, a result assumed but not confirmed to lower
risk of forming calcium oxalate stones. A big issue for this study is that serum
magnesium actually decreases with the treatment. This could mean that despite some
positive effect, magnesium oxide might not be the best way to increase body uptake
of magnesium. This concept is supported by a rat study suggesting that magnesium
oxide is somewhat “middle of the road” among magnesium complexes for fighting
kidney stone formation.63
Another study examines only four subjects.257 Magnesium oxide supplemen-
tation shows no effect on urine parameters such as a measure of calcium phosphate
complex formation tendencies. One problem with this study, besides the low
subject number, is that the parameters measured may have limited value in pre-
dicting the formation of the most common kidney stones. An additional problem
is the use of magnesium oxide, which as just mentioned may not be the best
magnesium complex for fighting kidney stones. In another study with magnesium
oxide in stone formers, there is no significant effect on urinary oxalate, while
urinary calcium is increased.258 The supplementation does not increase in urinary
magnesium, which could mean that the supplemental magnesium oxide is not
absorbed well enough to be effective.

In contrast to these studies, some studies do show positive effects of magnesium

oxide treatment. However, not one of the studies has a clear-cut interpretation. In
one study, which is reported in two articles,250,259 stone formation per year is lower
with magnesium oxide treatment. However, this assessment is based not on a blinded
placebo comparison, but based on the subjects’ previous history and in comparison
to some subjects who were not undergoing preventative treatments. As already noted,
placebo controls are very important for kidney stone studies. There is reason to
believe that the effects seen in the just-mentioned study may have been a placebo
effect, or due to the subjects making a general commitment to stone prevention steps.
This reasoning is reinforced by the fact that the magnesium supplementation did
not increase serum magnesium values long term.
The lack of a placebo group also applies to another study where magnesium
oxide is reported to decrease the number of stones occurring in stone formers.260 In
an additional study of magnesium oxide,261 the interpretation is clouded by the
treatment consisting of magnesium plus vitamin B6. Thus, the role of magnesium
versus that of the vitamin B6 in the results is not clear. The same can be said for
another study of the combination of magnesium oxide and vitamin B6.262 In this
case, stone formation is not assessed. Instead, there is a report of increased urinary
magnesium and citrate, along with a decrease in oxalate excretion in 16 calcium
oxalate stone formers. The increase in urinary magnesium differs from some studies
of magnesium oxide that don’t see a change in urinary magnesium. However, as
noted in the Bioavailability section, physical differences in magnesium oxide prep-
arations can give differences in bioavailability. In another study of urinary oxalate,
seven normal subjects and four stone formers are given magnesium oxide or citrate
for two weeks.263 If the supplements are taken with meals, urinary oxalate and urinary
saturation of calcium with oxalate decreases. The low subject number and lack of
placebo again put the results in question.
In a study of a different magnesium complex, nine subjects with low urinary
magnesium excretion are given magnesium hydroxide (500 mg/day) for up to 18
months.264 Urinary magnesium increases while urinary oxalate decreases. The stone
recurrence rate decreases from 0.75 to 0.11. Once again, though, there is no placebo
control. Also, it is not known if the effect is due to magnesium in general, or due
to the antacid effect of magnesium hydroxide.
There is a placebo-controlled study of magnesium hydroxide and kidney stone
formation.265 A large improvement is seen for stone formation, but it is not statisti-
cally different from the placebo group. This emphasizes the need for a placebo group
in this type of study. A problem with interpreting this particular study is that the
improvement in the placebo group is so good. Possibly, with such a good placebo
response, the study may have had to go longer to see a clear effect of the magnesium
hydroxide (the improvement in the magnesium hydroxide group exceeds the placebo
effect, but the difference is not statistically significant). Another question is whether
another type of magnesium supplement could do better than magnesium hydroxide.
Although the magnesium hydroxide has urine pH effects, an organic magnesium
supplement may be more bioavailable.
There is one other study relevant to this area. In this work, magnesium and
calcium are examined for short-term effects following an acute oxalate load in 24

healthy subjects.253 Magnesium is nearly as effective as calcium in reducing oxalate

absorption and urinary excretion. This does not definitively show that magnesium
supplements actually prevent kidney stone formation, but it does strengthen the case
for one of the proposed mechanisms by which this could happen (reduced GI tract
oxalate absorption).
After viewing the results and conflicting interpretations of these studies, a phy-
sician or a patient may ask: How can anyone make a decision on this issue? If one
takes the approach of “it may help and it probably won’t hurt,” then a moderately
high magnesium intake is appropriate. This could be done by diet. However, since
a number of good magnesium sources are also high in oxalates, which are not
desirable for stone formers, supplements can be a convenient option.
This issue has a practical side to this author, who has had a kidney stone. This
author’s own approach, besides drinking large volumes of water, is to take about
320 mg of magnesium per day. This is not done as magnesium hydroxide, due to
potential additive effects with one of his medications. Instead, an organic compound
such as magnesium bisglycinate or magnesium lactate is used, even though neither
has been tested in humans for kidney stone prevention. Still, these supplements at
the stated dose are likely to be safe, should be well absorbed, and have the potential
to affect most of the mechanisms noted above for magnesium and kidney stone
prevention. This author would like to see a well-designed study of various magne-
sium complexes on kidney stone formation.
PREGNANCY: PREMATURE/LOW BIRTH WEIGHT OUTCOMES

Low serum magnesium values are common during pregnancy, though this could be
a regulatory action or a hemodilution effect (increased water in the blood).266,267 On
the other hand, some work with erythrocyte-ionized magnesium suggests that preg-
nancy can tend to deplete body magnesium.268 Moreover, there are some U.S.-based
diet survey studies that show that magnesium intake by pregnant women is often
well below the pregnancy RDA.269,270 This dietary pattern is seen even in middle-
to upper-income women.269 These diet studies, plus the possibility that pregnancy
may tend to deplete body magnesium, have fueled speculation that magnesium intake
can affect pregnancy outcome. This attention has been especially focused on the
risk of premature or other low-birth-weight pregnancy outcomes. Part of this focus
has occurred because parenteral magnesium administration has been used to arrest
preterm labor.271 Although this pharmacological application of magnesium may be
very different from nutritional magnesium actions, in some people’s thoughts, the
parenteral use connects magnesium with preterm delivery.
One line of evidence does support this connection. In Taiwan, there is an inverse
relationship between risk of a very-low-birth-weight outcome and magnesium levels
in drinking water.272 There is also a study reporting that women in preterm labor
have even lower serum magnesium than most pregnant women.273 On the other hand,
other studies find that preterm labor and delivery do not correspond to differences
in dietary or serum magnesium levels.274
There have been a number of studies of magnesium supplement effects on this
type of pregnancy outcome, but they have been criticized for their design. For

instance, the author of a meta-analysis paper on this subject states that only one of
seven reviewed studies were judged to be of high quality.275 This meta-analysis does
report that oral magnesium treatment from before the 25th week of gestation is
associated with a lower frequency of preterm birth.275 However, this effect disappears
with exclusion of a cluster trial. Furthermore, the author says that the poor design
just noted is likely to produce a bias favoring magnesium supplementation.
Thus, though oral magnesium supplementation may help prevent against pre-
mature and low-birth-weight pregnancy outcome, this hypothesis has not yet been
adequately tested.
PREMENSTRUAL SYNDROME (PMS)

Due to magnesium functional ties with hormones and neurological processes, a role
for magnesium in reducing PMS symptoms seems plausible. Some studies have
reported low values of blood cell magnesium in women with PMS,276 but plasma
magnesium can be normal.276 Since blood cell total magnesium may or may not be
indicative of magnesium status, it is unclear if women with PMS are prone to
marginal magnesium deficiency. However, the absence of such deficiency may not
exclude the possibility of benefits for increased magnesium intake.
In a randomized, double-blind, placebo-controlled, crossover study, a daily sup-
plement of 200 mg magnesium (as oxide) or placebo is administered for two men-
strual cycles.66 In the second cycle, but not the first, the supplementation reduces
mild premenstrual symptoms related to fluid retention. Since this study involves
fairly low doses of a possibly poorly absorbed magnesium complex, the effects may
have been better with a higher dose of a better absorbed magnesium complex. It is
noteworthy that in this study, though urinary magnesium is increased, it is not to a
great extent. Another crossover, placebo-controlled study uses the same dose and
complex of magnesium, but also includes a treatment period where vitamin B6 is
tested (plus or minus the magnesium).277 Treatment times are all one menstrual cycle.
One type of statistical analysis finds no difference between treatments, but another
analysis shows a significant effect of the magnesium–vitamin B6 combination on
anxiety-related PMS symptoms. Urinary magnesium output is not affected by
treatment. In the authors’ own words, the effects are modest, absorption from
magnesium oxide is poor, and daily supplementation for longer than one month is
necessary for tissue repletion
In one other study, which is a double-blind, randomized design, 32 women with
PMS are given placebo or magnesium pyrrolidone carboxylic acid for two cycles.278
The Menstrual Distress Questionnaire score of the cluster “pain” is significantly reduced
during the second month in both groups, whereas magnesium treatment significantly
impacts both the total Menstrual Distress Questionnaire score and the cluster “negative
effect.” In the second month, supplementation increases lymphocyte and polymorpho-
nuclear cell magnesium, but not magnesium in the plasma or erythrocytes.
Based on these three studies, it cannot be said that magnesium supplements can
provide major PMS symptom relief, though there may be a modest effect on some
symptoms. However, the relationship of increased magnesium intake to PMS symp-
toms may not have yet been tested in an ideal design.

MITRAL VALVE PROLAPSE

MVP can be fairly asymptomatic but it can also cause discomfort in many people.
Magnesium could affect these symptoms via multiple direct effects on neurological
function and by restriction of catecholamine rises in the blood (see the Stress
subsection). There are three studies where magnesium is reported to improve symp-
toms in subjects with MVP. One of the studies only includes symptomatic MVP
patients (N = 141) and finds low serum magnesium in 60% of the patients (as
opposed to 5% of controls).71 Magnesium supplementation (five weeks) exceeds
placebo in reducing symptoms and urinary epinephrine and norepinephrine (which
indicates reduced blood levels of this hormone). However, it should be noted that
symptoms are reduced, but not eliminated. Furthermore, not every subject shows
improvement in every area. Perhaps with a longer treatment, the effects, though
already respectable, could be even better. However, another issue here is that the
form of magnesium used, magnesium carbonate, is an antacid. Antacids can relieve
some MVP symptoms in some subjects.72 Thus, some of the effects shown here may
not be due entirely to magnesium status changes. On the other hand, if antacid effects
are not the main mechanism for the benefits, then the use of a different magnesium
supplement might give better results. This contention is based on the supposition
that magnesium carbonate may not be as well absorbed as some other magnesium
complexes (see in Bioavailability from Foods and Supplements). In this study,71
magnesium carbonate does increase serum magnesium values, but the mean is still
in the very low end of the normal range.
In another study, six months of magnesium orotate supplementation in MVP patients
completely or partially reduces a variety of symptoms in more than half the patients.279
Similarly, 16 weeks of magnesium lactate supplementation, in 35 MVP patients,
improves a number of symptoms.280 One particular symptom, called the sign of Trous-
seau, disappears in the 10 subjects initially showing this symptom. The latter study is
partially placebo-controlled in that placebo is given to some of the subjects for the first
half of the treatment time. No improvement is noted for the placebo time period.
In conclusion, the studies done thus far raise the possibility that increased
magnesium intake can help with some MVP symptoms in at least some people with
symptomatic MVP. However, more study is needed, especially a placebo-controlled
study that well characterizes magnesium status before and after intervention, and
relates status changes to symptom improvement.
OTHER APPLICATIONS
There are a good number of other health applications that have been proposed for
magnesium supplements based on one or more of the following:
• Abnormal values for some measure(s) of blood or urinary magnesium in

a portion of subjects relevant to the application
• Mechanistic ties with the application
• One or a few studies on magnesium supplementation show a possible
benefit

TABLE 2.3
Magnesium Supplements at a Glance
Adult RDA: 420 mg (male), 320 mg (female)
Typical dose in supplement studies: 300–600 mg
Best supplement complex: organics are generally considered more active than inorganics, except
chloride liquid; however, actual data is conflicting, possibly due to limitations in the methodology
typically used; data is also conflicting for comparisons among the organics; amino acid chelates
and lactate are among the best for GI tolerance; certain magnesium complexes may work best for
certain specialized applications
Applications: use is established for treating substantial hypomagnesaemia; many other uses have
some rationale, but are unconfirmed; the best supported of the unconfirmed uses are producing
various benefits in diabetic subjects with low serum magnesium, modest lowering of blood pressure
in certain types of people, giving various benefits in cardiac rehabilitation patients (though one
study may show a use risk), and treatment of sickle cell anemia (though supplementation has been
studied in just a few people)
Upper Level: 350 mg from supplements (based on GI tract symptoms); people may be able to exceed
the UL without symptoms with magnesium from foods, with certain types of supplements, and
possibly by spacing out daily doses
Safety issues: typical supplement doses are considered safe for people with good kidney function
except for GI symptoms, especially diarrhea
As should be clear from the above subsections, these three types of reasoning
do not guarantee a clear demonstration of the efficacy of magnesium supplementa-
tion. This is especially true if the supplementation studies have design flaws. For
some reason, a lot of such studies seem to show up in regard to magnesium supple-
mentation. Thus, at this point, it has to be said that there are many claims for
magnesium supplementation that could be true, but are not at all confirmed.
TOXICITY
The adult Upper Level (UL) for magnesium is odd in that the value (350 mg) is
below the RDA for adult males and pregnant women.90 However, the UL for mag-
nesium is designated as supplement intake, not total intake from food plus supple-
ments. The UL is based on GI tract distress such as diarrhea rather than a toxic
magnesium build-up. The actual intake that causes GI tract symptoms likely depends
on the specific magnesium complex(es) ingested, the way the daily dose is taken
(i.e., at one time vs. spread out), and whether the supplement is taken with food.
However, none of these suppositions has been tested extensively from a published
research standpoint.
Typical oral magnesium supplement doses are RDA levels to less than twice
the RDA. These doses are not thought to generally pose an internal health
problem. One exception is for subjects with renal failure, which slows magnesium
excretion and can elevate risk for toxic build-up.2 In addition, the elderly can
sometimes be at risk for magnesium toxicity because kidney function can decline
with age.90 Also, elderly people are more likely than younger people to take

magnesium-containing laxatives and antacids. Magnesium toxicity symptoms,

besides diarrhea and nausea, include mental abnormalities, cardiac problems,
reduced reflexes, and breathing difficulties.2

Despite mounds of study on magnesium in general, and on supplementation in
particular, very little can be said about the efficacy of magnesium supplements. The
only established use for supplementation is for treatment of substantial hypo-
magnesemia due to “classical reasons” such as the use of certain diuretics. Many
other applications may be useful, but this cannot be confirmed because so many
studies are too small, too conflicting in results, too hard to interpret, too poorly
designed, or simply require more follow-up.
REFERENCES
1. Shils, M.E., Magnesium, in Handbook of Nutritionally Essential Mineral Elements,
2. Fleet, J.C. and Cashman, K.D., Magnesium, in Present Knowledge in Nutrition, 8th
ed., Bowman, B.A., and Russell, R.M., Eds., ILSI Press, Washington, 2001, chap. 28.
3. Seelig, M.S., Increased need for magnesium with the use of combined estrogen and
calcium for osteoporosis treatment, Magnes. Res., 3, 197, 1990.
4. Bara, M., Guiet-Bara, A., and Durlach, J., Regulation of sodium and potassium
pathways by magnesium in cell membranes, Magnes. Res., 6, 167, 1993.
5. Morrill, G.A., Gupta, R.K., Kostellow, A.B., Ma, G.Y., Zhang, A., Altura, B.T., and
Altura, B.M., Mg2+ modulates membrane sphingolipid and lipid second messenger
levels in vascular smooth muscle cells, FEBS Lett., 440, 167, 1998.
6. Altura, B.M., Gebrewold, A., Altura, B.T., and Brautbar, N., Magnesium depletion
impairs myocardial carbohydrate and lipid metabolism and cardiac bioenergetics and
raises myocardial calcium content in-vivo: relationship to etiology of cardiac diseases,
Biochem. Mol. Biol. Int., 40, 1183, 1996.
7. Srinivasan, C., Minadeo, N., Geraldes, C.F., and Mota, d.F., Competition between
Li+ and Mg2+ for red blood cell membrane phospholipids: A 31P, 7Li, and 6Li
nuclear magnetic resonance study, Lipids, 34, 1211, 1999.
8. Drygin, D. and Zimmermann, R.A., Magnesium ions mediate contacts between phos-
phoryl oxygens at positions 2122 and 2176 of the 23S rRNA and ribosomal protein
L1, RNA., 6, 1714, 2000.
9. Hans, C.P., Chaudhary, D.P., and Bansal, D.D., Magnesium deficiency increases
oxidative stress in rats, Indian J. Exp. Biol., 40, 1275, 2002.
10. Kumar, B.P. and Shivakumar, K., Depressed antioxidant defense in rat heart in
experimental magnesium deficiency. Implications for the pathogenesis of myocardial
lesions, Biol. Trace Elem. Res, 60, 139, 1997.
11. Kramer, J.H., Mak, I.T., Phillips, T.M., and Weglicki, W.B., Dietary magnesium intake
influences circulating pro-inflammatory neuropeptide levels and loss of myocardial
tolerance to postischemic stress, Exp. Biol. Med. (Maywood.), 228, 665, 2003.

12. Kurantsin-Mills, J., Cassidy, M.M., Stafford, R.E., and Weglicki, W.B., Marked alter-
ations in circulating inflammatory cells during cardiomyopathy development in a
magnesium-deficient rat model, Br. J. Nutr., 78, 845, 1997.
13. Wiles, M.E., Wagner, T.L., and Weglicki, W.B., Effect of acute magnesium deficiency
(MgD) on aortic endothelial cell (EC) oxidant production, Life Sci., 60, 221, 1997.
14. Zhou, Q., Olinescu, R.M., and Kummerow, F.A., Influence of low magnesium con-
centrations in the medium on the antioxidant system in cultured human arterial
endothelial cells, Magnes. Res., 12, 19, 1999.
15. Martini, L.A., Magnesium supplementation and bone turnover, Nutr. Rev., 57, 227,
1999.
16. Sojka, J.E. and Weaver, C.M., Magnesium supplementation and osteoporosis, Nutr.
Rev., 53, 71, 1995.
17. Clausen, T. and Dorup, I., Micronutrients, minerals and growth control, Bibl. Nutr.
Dieta,84, 1998.
18. Kelepouris, E. and Agus, Z.S., Hypomagnesemia: renal magnesium handling, Semin.
Nephrol., 18, 58, 1998.
19. Hardwick, L.L., Jones, M.R., Brautbar, N., and Lee, D.B., Magnesium absorption:
mechanisms and the influence of vitamin D, calcium and phosphate, J. Nutr., 121,
13, 1991.
20. Saris, N.E., Mervaala, E., Karppanen, H., Khawaja, J.A., and Lewenstam, A., Mag-
nesium. An update on physiological, clinical and analytical aspects, Clin. Chim. Acta,
294, 1, 2000.
21. Elin, R.J., Laboratory tests for the assessment of magnesium status in humans,
Magnes. Trace Elem., 10, 172, 1991.
23. Widmaier, S., Hoess, T., Jung, W.I., Staubert, A., Dietze, G.F., and Lutz, O., 31P
NMR studies of human soleus and gastrocnemius show differences in the J gamma
beta coupling constant of ATP and in intracellular free magnesium, MAGMA., 4, 47,
1996.
24. Darlu, P., Defrise-Gussenhoven, E., Michotte, Y., Susanne, C., and Henrotte, J.G.,
Possible linkage relationship between genetic markers and blood magnesium and
zinc. A twin study, Acta Genet. Med. Gemellol. (Roma.), 34, 109, 1985.
25. Flatman, P.W., The control of red cell magnesium, Magnes. Res., 1, 5, 1988.
26. Guex, E, Bussiere, F., and Rayssiguier, Y., Magnesium content of polymorphonuclear
blood cells is not an indicator of magnesium status, in Advances in Magnesium
Research, Rayssiguier, Y., Mazur, A., and Durlach, J., Eds., John Libbey, Eastleigh,
2001, chap. 40.
27. Sjogren, A., Floren, C.H., and Nilsson, A., Measurements of magnesium in mono-
nuclear cells, Sci. Total Environ., 42, 77, 1985.
28. Elin, R.J., Hosseini, J.M., and Gill, J.R., Jr., Erythrocyte and mononuclear blood cell
magnesium concentrations are normal in hypomagnesemic patients with chronic renal
magnesium wasting, J. Am. Coll. Nutr., 13, 463, 1994.
29. Facchinetti, F., Battaglia, C., Benatti, R., Borella, P., and Genazzani, A.R., Oral
magnesium supplementation improves fetal circulation, Magnes. Res., 5, 179, 1992.
30. Cohen, N., Alon, I., Almoznino-Sarafian, D., Zaidenstein, R., Weissgarten, J., Gorelik,
O., Berman, S., Modai, D., and Golik, A., Metabolic and clinical effects of oral
magnesium supplementation in furosemide-treated patients with severe congestive
heart failure, Clin. Cardiol., 23, 433, 2000.

31. Weller, E., Bachert, P., Meinck, H.M., Friedmann, B., Bartsch, P., and Mairbaurl, H.,
Lack of effect of oral Mg-supplementation on Mg in serum, blood cells, and calf
muscle, Med. Sci. Sports Exerc., 30, 1584, 1998.
32. Huijgen, H.J., van Ingen, H.E., Sanders, R., Gaffar, F.R., Oosting, J., and Sanders,
G.T., Precision of the magnesium determination in mononuclear blood cells and
erythrocytes, Clin. Biochem., 30, 203, 1997.
33. Martin, B.J., Lyon, T.D., Walker, W., and Fell, G.S., Mononuclear blood cell mag-
nesium in older subjects: evaluation of its use in clinical practice, Ann. Clin. Biochem.,
30 (Pt. 1), 23, 1993.
34. Geven, W.B., Vogels-Mentink, G.M., Willems, J.L., von Os, C.H., Hilbers, C.W.,
Joordens, J.J., Rijksen, G., and Monnens, L.A., 31P nuclear magnetic resonance and
zero-point titration compared for measuring free magnesium concentration in eryth-
rocytes, Clin. Chem., 37, 2076, 1991.
35. Malon, A., Wagner, B., Bulska, E., and Maj-Zurawska, M., Comparison of the poten-
tiometric, (31)P NMR, and zero-point titration methods of determining ionized mag-
nesium in erythrocytes, Anal. Biochem., 302, 220, 2002.
36. Altura, B.M. and Altura, B.T., Role of magnesium in patho-physiological processes
and the clinical utility of magnesium ion selective electrodes, Scand. J. Clin. Lab
Invest Suppl., 224, 211, 1996.
37. Millart, H., Durlach, V., and Durlach, J., Red blood cell magnesium concentrations:
analytical problems and significance, Magnes. Res., 8, 65, 1995.
38. Altura, B.T., Shirey, T.L., Young, C.C., Dell’Orfano, K., Hiti, J., Welsh, R., Yeh, Q.,
Barbour, R.L., and Altura, B.M., Characterization of a new ion selective electrode
for ionized magnesium in whole blood, plasma, serum, and aqueous samples, Scand.
J. Clin. Lab Invest Suppl., 217, 21, 1994.
39. Ising, H., Bertschat, F., Gunther, T., Jeremias, E., and Jeremias, A., Measurement of
free magnesium in blood, serum and plasma with an ion-sensitive electrode, Eur. J.
Clin. Chem. Clin. Biochem., 33, 365, 1995.
40. Dewitte, K., Stockl, D., and Thienpont, L.M., Reliability of measurement of ionized
magnesium in ultrafiltrate, Clin. Chem., 45, 588, 1999.
41. Knudsen, E., Sandstrom, B., and Solgaard, P., Zinc, copper and magnesium absorption
from a fibre-rich diet, J. Trace Elem. Med. Biol., 10, 68, 1996.
42. Sojka, J., Wastney, M., Abrams, S., Lewis, S.F., Martin, B., Weaver, C., and Peacock,
M., Magnesium kinetics in adolescent girls determined using stable isotopes: effects
of high and low calcium intake, Am. J. Physiol., 273, R710, 1997.
43. Coudray, C., Bellanger, J., Vermorel, M., Sinaud, S., Wils, D., Feillet-Coudray, C.,
Brandolini, M., Bouteloup-Demange, C., and Rayssiguier, Y., Two polyol, low digest-
ible carbohydrates improve the apparent absorption of magnesium but not of calcium
in healthy young men, J. Nutr., 133, 90, 2003.
44. Andon, M.B., Ilich, J.Z., Tzagournis, M.A., and Matkovic, V., Magnesium balance
950, 1996.
45. Sabatier, M., Arnaud, M.J., Kastenmayer, P., Rytz, A., and Barclay, D.V., Meal effect
on magnesium bioavailability from mineral water in healthy women, Am. J. Clin.
Nutr., 75, 65, 2002.
46. Bei, L., Wood, R.J., and Rosenberg, I.H., Glucose polymer increases jejunal calcium,
magnesium, and zinc absorption in humans, Am. J. Clin. Nutr., 44, 244, 1986.
47. Holbrook, J.T., Smith, J.C., Jr., and Reiser, S., Dietary fructose or starch: effects on
copper, zinc, iron, manganese, calcium, and magnesium balances in humans, Am. J.
Clin. Nutr., 49, 1290, 1989.

48. Coudray, C., Demigne, C., and Rayssiguier, Y., Effects of dietary fibers on magnesium
absorption in animals and humans, J. Nutr., 133, 1, 2003.
49. Brink, E.J. and Beynen, A.C., Nutrition and magnesium absorption: a review, Prog.
Food Nutr. Sci., 16, 125, 1992.
50. Kikunaga, S., Ishii, H., and Takahashi, M., The bioavailability of magnesium in
spinach and the effect of oxalic acid on magnesium utilization examined in diets of
magnesium-deficient rats, J. Nutr. Sci. Vitaminol. (Tokyo), 41, 671, 1995.
51. Schwartz, R., Grunes, D.L., Wentworth, R.A., and Wien, E.M., Magnesium absorption
from leafy vegetables intrinsically labeled with the stable isotope 26Mg, J. Nutr.,
110, 1365, 1980.
52. Takamatsu, N., Nishio, A., Nagata, S., Matsumoto, J., Kamimura, Y., Miyamoto, A.,
and Ishiguro, S., Decreased absorption and retention rates of magnesium in the rats
fed on spinach-supplemented diets: possible explanations, Magnes. Res, 14, 247,
2001.
53. Lopez, H.W., Duclos, V., Coudray, C., Krespine, V., Feillet-Coudray, C., Messager,
A., Demigne, C., and Remesy, C., Making bread with sourdough improves mineral
bioavailability from reconstituted whole wheat flour in rats, Nutrition, 19, 524, 2003.
54. Matsui, T., Ohmori, Y., Okumura, H., and Yano, H., Dietary phytate does not increase
endogenous magnesium excretion in the feces of rats, in Advances in Magnesium
Research, Rayssiguier, Y., Mazur, A., and Durlach, J., Eds., John Libbey, Eastleigh,
2001, chap. 18.
55. Spencer, H., Norris, C., and Williams, D., Inhibitory effects of zinc on magnesium
balance and magnesium absorption in man, J. Am. Coll. Nutr., 13, 479, 1994.
56. Ranade, V.V. and Somberg, J.C., Bioavailability and pharmacokinetics of magnesium
after administration of magnesium salts to humans, Am. J. Ther., 8, 345, 2001.
57. Bohl, C.H. and Volpe, S.L., Magnesium and exercise, Crit Rev. Food Sci. Nutr., 42,
533, 2002.
58. Benech, H. and Grognet, J.M., Recent data on the evaluation of magnesium bioavail-
ability in humans, Magnes. Res., 8, 277, 1995.
59. Kuhn, I., Jost, V., Wieckhorst, G., Theiss, U., and Lucker, P.W., Renal elimination of
magnesium as a parameter of bioavailability of oral magnesium therapy, Methods
Find. Exp. Clin. Pharmacol., 14, 269, 1992.
60. Firoz, M. and Graber, M., Bioavailability of US commercial magnesium preparations,
Magnes. Res, 14, 257, 2001.
61. Lindberg, J.S., Zobitz, M.M., Poindexter, J.R., and Pak, C.Y., Magnesium bioavail-
ability from magnesium citrate and magnesium oxide, J. Am. Coll. Nutr., 9, 48, 1990.
62. Muhlbauer, B., Schwenk, M., Coram, W.M., Antonin, K.H., Etienne, P., Bieck, P.R.,
and Douglas, F.L., Magnesium-L-aspartate-HCl and magnesium-oxide: bioavailabil-
ity in healthy volunteers, Eur. J. Clin. Pharmacol., 40, 437, 1991.
63. Ogawa, Y., Yamaguchi, K., and Morozumi, M., Effects of magnesium salts in pre-
venting experimental oxalate urolithiasis in rats, J. Urol., 144, 385, 1990.
64. Schonewille, J.T., van’t Klooster, A.T., and van Mosel, M., [A comparative study of
the in-vitro solubility and availability of magnesium from various sources for cattle],
Tijdschr. Diergeneeskd., 117, 105, 1992.
65. Xin, Z., Tucker, W.B., and Hemken, R.W., Effect of reactivity rate and particle size
of magnesium oxide on magnesium availability, acid-base balance, mineral metabo-
lism, and milking performance of dairy cows, J. Dairy Sci., 72, 462, 1989.
66. Walker, A.F., De Souza, M.C., Vickers, M.F., Abeyasekera, S., Collins, M.L., and
Trinca, L.A., Magnesium supplementation alleviates premenstrual symptoms of fluid
retention, J. Women’s Health, 7, 1157, 1998.

67. Kawano, Y., Matsuoka, H., Takishita, S., and Omae, T., Effects of magnesium sup-
plementation in hypertensive patients: assessment by office, home, and ambulatory
blood pressures, Hypertension, 32, 260, 1998.
68. Skrajnowska, D. and Oledzka, R., [Balance of magnesium and iron and their content
in tissues and body fluids of rats after supplementation with magnesium carbonate],
Rocz. Panstw. Zakl. Hig., 51, 403, 2000.
69. Breuer, J., Moniz, C., Baldwin, D., and Parsons, V., The effects of zero magnesium
dialysate and magnesium supplements on ionised calcium concentration in patients
on regular dialysis treatment, Nephrol. Dial. Transplant., 2, 347, 1987.
70. Cook, D.A., Availability of magnesium: balance studies in rats with various inorganic
magnesium salts, J. Nutr., 103, 1365, 1973.
71. Lichodziejewska, B., Klos, J., Rezler, J., Grudzka, K., Dluzniewska, M., Budaj, A.,
and Ceremuzynski, L., Clinical symptoms of mitral valve prolapse are related to
hypomagnesemia and attenuated by magnesium supplementation, Am. J. Cardiol.,
79, 768, 1997.
72. Woolf, P.K., Gewitz, M.H., Berezin, S., Medow, M.S., Stewart, J.M., Fish, B.G.,
Glassman, M.S., and Newman, L.J., Noncardiac chest pain in adolescents and children
with mitral valve prolapse, J. Adolesc. Health, 12, 247, 1991.
73. Bohmer, T., Roseth, A., Holm, H., Weberg-Teigen, S., and Wahl, L., Bioavailability
of oral magnesium supplementation in female students evaluated from elimination
of magnesium in 24-hour urine, Magnes. Trace Elem., 9, 272, 1990.
74. Dimai, H.P., Porta, S., Wirnsberger, G., Lindschinger, M., Pamperl, I., Dobnig, H.,
Wilders-Truschnig, M., and Lau, K.H., Daily oral magnesium supplementation sup-
presses bone turnover in young adult males, J. Clin. Endocrinol. Metab, 83, 2742,
1998.
75. Galloe, A.M., Rasmussen, H.S., Jorgensen, L.N., Aurup, P., Balslov, S., Cintin, C.,
Graudal, N., and McNair, P., Influence of oral magnesium supplementation on cardiac
events among survivors of an acute myocardial infarction, BMJ, 307, 585, 1993.
76. Neuvonen, P.J. and Kivisto, K.T., Enhancement of drug absorption by antacids. An
unrecognised drug interaction, Clin. Pharmacokinet., 27, 120, 1994.
77. Kietzmann, M., Influence of magnesium gluconate on stress reactions in rats, Dtsch.
Tierarztl. Wochenschr., 96, 292, 1989.
78. Martin, R.W., Perry, K.G., Jr., Martin, J.N., Jr., Seago, D.P., Roberts, W.E., and
Morrison, J.C., Oral magnesium for tocolysis: a comparison of magnesium glu-
conate and enteric-coated magnesium chloride, J. Miss. State Med. Assoc., 39,
180, 1998.
79. Fine, K.D., Santa Ana, C.A., Porter, J.L., and Fordtran, J.S., Intestinal absorption of
magnesium from food and supplements, J. Clin. Invest, 88, 396, 1991.
80. White, J., Massey, L., Gales, S.K., Dittus, K., and Campbell, K., Blood and urinary
magnesium kinetics after oral magnesium supplements, Clin. Ther., 14, 678, 1992.
81. Bashir, Y., Sneddon, J.F., Staunton, H.A., Haywood, G.A., Simpson, I.A., McKenna,
W.J., and Camm, A.J., Effects of long-term oral magnesium chloride replacement in
congestive heart failure secondary to coronary artery disease, Am. J. Cardiol., 72,
1156, 1993.
82. McCarty, M.F., Complementary vascular-protective actions of magnesium and tau-
rine: a rationale for magnesium taurate, Med. Hypotheses, 46, 89, 1996.
83. Bac, P., Herrenknecht, C., Binet, P., and Durlach, J., Audiogenic seizures in magne-
sium-deficient mice: effects of magnesium pyrrolidone-2-carboxylate, magnesium
acetyltaurinate, magnesium chloride and vitamin B-6, Magnes. Res., 6, 11, 1993.

84. Bac, P., Herrenknecht, C., Pages, N., Dupont, C., and Durlach, J., Reversible model
of magnesium depletion induced by systemic kainic acid injection in magnesium-
deficient rats: I—Comparative study of various magnesium salts, Magnes. Res., 9,
281, 1996.
85. Bac, P., Pages, N., Herrenknecht, C., and Teste, J.F., Inhibition of mouse-killing
behaviour in magnesium-deficient rats: effect of pharmacological doses of magnesium
pidolate, magnesium aspartate, magnesium lactate, magnesium gluconate and mag-
nesium chloride, Magnes. Res., 8, 37, 1995.
86. Teste, J.F., Decelle, T., and Henrotte, J.G., [Psychopharmacological properties of
three magnesium salts: pidolate, lactate and aspartate], Ann. Pharm. Fr., 53, 176,
1995.
87. Russell, I.J., Michalek, J.E., Flechas, J.D., and Abraham, G.E., Treatment of fibro-
myalgia syndrome with Super Malic: a randomized, double blind, placebo controlled,
crossover pilot study, J. Rheumatol., 22, 953, 1995.
88. Schuette, S.A., Lashner, B.A., and Janghorbani, M., Bioavailability of magnesium
diglycinate vs magnesium oxide in patients with ileal resection, JPEN J. Parenter.
Enteral Nutr., 18, 430, 1994.
89. Cappuccio, F.P., Markandu, N.D., Beynon, G.W., Shore, A.C., Sampson, B., and
MacGregor, G.A., Lack of effect of oral magnesium on high blood pressure: a double
blind study, Br. Med. J. (Clin. Res. Ed), 291, 235, 1985.
91. Galan, P., Preziosi, P., Durlach, V., Valeix, P., Ribas, L., Bouzid, D., Favier, A., and
Hercberg, S., Dietary magnesium intake in a French adult population, Magnes. Res,
10, 321, 1997.
92. Vaquero, M.P., Magnesium and trace elements in the elderly: intake, status and
recommendations, J. Nutr. Health Aging, 6, 147, 2002.
93. Ford, E.S. and Mokdad, A.H., Dietary magnesium intake in a national sample of U.S.
adults, J. Nutr., 133, 2879, 2003.
94. Seelig, M.S., Epidemiology of water magnesium: evidence of contributions to health,
in Advances in Magnesium Research, Rayssiguier, Y., Mazur, A., and Durlach, J.,
Eds., John Libbey, Eastleigh, 2001, chap. 32.
95. Witlin, A.G. and Sibai, B.M., Magnesium sulfate therapy in preeclampsia and eclamp-
sia, Obstet. Gynecol., 92, 883, 1998.
96. Ravn, H.B., Pharmacological effects of magnesium on arterial thrombosis—mecha-
nisms of action?, Magnes. Res., 12, 191, 1999.
97. Kobrin, S.M. and Goldfarb, S., Magnesium deficiency, Semin. Nephrol., 10, 525,
1990.
98. Elmarakby, A.A., Williams, J.M., and Pollock, D.M., Targeting sources of superoxide
and increasing nitric oxide bioavailability in hypertension, Curr. Opin. Investig.
Drugs, 4, 282, 2003.
99. Touyz, R.M., Pu, Q., He, G., Chen, X., Yao, G., Neves, M.F., and Viel, E., Effects
of low dietary magnesium intake on development of hypertension in stroke-prone
spontaneously hypertensive rats: role of reactive oxygen species, J. Hypertens., 20,
2221, 2002.
100. Laurant, P., Hayoz, D., Brunner, H.R., and Berthelot, A., Effect of magnesium defi-
ciency on blood pressure and mechanical properties of rat carotid artery, Hyperten-
sion, 33, 1105, 1999.

101. Ascherio, A., Rimm, E.B., Giovannucci, E.L., Colditz, G.A., Rosner, B., Willett,
W.C., Sacks, F., and Stampfer, M.J., A prospective study of nutritional factors and
hypertension among US men, Circulation, 86, 1475, 1992.
102. Ascherio, A., Rimm, E.B., Hernan, M.A., Giovannucci, E.L., Kawachi, I., Stampfer,
M.J., and Willett, W.C., Intake of potassium, magnesium, calcium, and fiber and risk
of stroke among US men, Circulation, 98, 1198, 1998.
103. Chakraborti, S., Chakraborti, T., Mandal, M., Mandal, A., Das, S., and Ghosh, S.,
Protective role of magnesium in cardiovascular diseases: a review, Mol. Cell Bio-
chem., 238, 163, 2002.
104. Mizushima, S., Cappuccio, F.P., Nichols, R., and Elliott, P., Dietary magnesium intake
and blood pressure: a qualitative overview of the observational studies, J. Hum.
Hypertens., 12, 447, 1998.
105. Reusser, M.E. and McCarron, D.A., Micronutrient effects on blood pressure regula-
tion, Nutr. Rev., 52, 367, 1994.
106. Resnick, L.M., Cellular calcium and magnesium metabolism in the pathophysiology
and treatment of hypertension and related metabolic disorders, Am. J. Med., 93, 11S,
1992.
107. Resnick, L.M., Bardicef, O., Altura, B.T., Alderman, M.H., and Altura, B.M., Serum
ionized magnesium: relation to blood pressure and racial factors, Am. J. Hypertens.,
10, 1420, 1997.
108. Resnick, L.M. and Laragh, J.H., Renin, calcium metabolism and the pathophysiologic
basis of antihypertensive therapy, Am. J. Cardiol., 56, 68H, 1985.
109. Rubenowitz, E., Landin, K., and Wilhelmsen, L., Skeletal muscle magnesium and
potassium by gender and hypertensive status, Scand. J. Clin. Lab Invest, 58, 47, 1998.
110. Jee, S.H., Miller, E.R., III, Guallar, E., Singh, V.K., Appel, L.J., and Klag, M.J., The
effect of magnesium supplementation on blood pressure: a meta-analysis of random-
ized clinical trials, Am. J. Hypertens., 15, 691, 2002.
111. Dyckner, T. and Wester, P.O., Effect of magnesium on blood pressure, Br. Med. J.
(Clin. Res. Ed), 286, 1847, 1983.
112. Ferrara, L.A., Iannuzzi, R., Castaldo, A., Iannuzzi, A., Dello, R.A., and Mancini, M.,
Long-term magnesium supplementation in essential hypertension, Cardiology, 81,
25, 1992.
113. Sacks, F.M., Willett, W.C., Smith, A., Brown, L.E., Rosner, B., and Moore, T.J., Effect
on blood pressure of potassium, calcium, and magnesium in women with low habitual
intake, Hypertension, 31, 131, 1998.
114. Plum-Wirell, M., Stegmayr, B.G., and Wester, P.O., Nutritional magnesium supple-
mentation does not change blood pressure nor serum or muscle potassium and mag-
nesium in untreated hypertension. A double-blind crossover study, Magnes. Res., 7,
277, 1994.
115. Haga, H., Effects of dietary magnesium supplementation on diurnal variations of
blood pressure and plasma Na+, K(+)-ATPase activity in essential hypertension, Jpn.
Heart J., 33, 785, 1992.
116. Itoh, K., Kawasaka, T., and Nakamura, M., The effects of high oral magnesium
supplementation on blood pressure, serum lipids and related variables in apparently
healthy Japanese subjects, Br. J. Nutr., 78, 737, 1997.
117. Widman, L., Wester, P.O., Stegmayr, B.K., and Wirell, M., The dose-dependent
reduction in blood pressure through administration of magnesium. A double blind
placebo controlled cross-over study, Am. J. Hypertens., 6, 41, 1993.

118. Witteman, J.C., Grobbee, D.E., Derkx, F.H., Bouillon, R., de Bruijn, A.M., and
Hofman, A., Reduction of blood pressure with oral magnesium supplementation in
women with mild to moderate hypertension, Am. J. Clin. Nutr., 60, 129, 1994.
119. Sanjuliani, A.F., de, A.F., V and Francischetti, E.A., Effects of magnesium on blood
pressure and intracellular ion levels of Brazilian hypertensive patients, Int. J. Cardiol.,
56, 177, 1996.
120. Doyle, L., Flynn, A., and Cashman, K., The effect of magnesium supplementation
on biochemical markers of bone metabolism or blood pressure in healthy young adult
females, Eur. J. Clin. Nutr., 53, 255, 1999.
121. Nowson, C.A. and Morgan, T.O., Magnesium supplementation in mild hypertensive
patients on a moderately low sodium diet, Clin. Exp. Pharmacol. Physiol, 16, 299,
1989.
122. Zemel, P.C., Zemel, M.B., Urberg, M., Douglas, F.L., Geiser, R., and Sowers, J.R.,
Metabolic and hemodynamic effects of magnesium supplementation in patients with
essential hypertension, Am. J. Clin. Nutr., 51, 665, 1990.
123. Lind, L., Lithell, H., Pollare, T., and Ljunghall, S., Blood pressure response during
long-term treatment with magnesium is dependent on magnesium status. A double-
blind, placebo-controlled study in essential hypertension and in subjects with high-
normal blood pressure, Am. J. Hypertens., 4, 674, 1991.
124. Altura, B.T., Brust, M., Bloom, S., Barbour, R.L., Stempak, J.G., and Altura, B.M.,
Magnesium dietary intake modulates blood lipid levels and atherogenesis, Proc. Natl.
Acad. Sci. U.S.A., 87, 1840, 1990.
125. Vaskonen, T., Dietary minerals and modification of cardiovascular risk factors, J.
Nutr. Biochem., 14, 492, 2003.
126. Haenni, A., Ohrvall, M., and Lithell, H., Atherogenic lipid fractions are related to
ionized magnesium status, Am. J. Clin. Nutr., 67, 202, 1998.
127. Niemela, J.E., Csako, G., Bui, M.N., and Elin, R.J., Gender-specific correlation of
platelet ionized magnesium and serum low-density-lipoprotein cholesterol concen-
trations in apparently healthy subjects, J. Lab Clin. Med., 129, 89, 1997.
128. Niemela, J.E., Snader, B.M., and Elin, R.J., Determination of ionized magnesium in
platelets and correlation with selected variables, Clin. Chem., 42, 744, 1996.
129. Singh, R.B., Rastogi, S.S., Sharma, V.K., Saharia, R.B., and Kulshretha, S.K., Can
dietary magnesium modulate lipoprotein metabolism?, Magnes. Trace Elem., 9, 255,
1990.
130. Singh, R.B., Effect of dietary magnesium supplementation in the prevention of cor-
onary heart disease and sudden cardiac death, Magnes. Trace Elem., 9, 143, 1990.
131. Marken, P.A., Weart, C.W., Carson, D.S., Gums, J.G., and Lopes-Virella, M.F., Effects
of magnesium oxide on the lipid profile of healthy volunteers, Atherosclerosis, 77,
37, 1989.
132. Kisters, K., Spieker, C., Tepel, M., and Zidek, W., New data about the effects of oral
physiological magnesium supplementation on several cardiovascular risk factors (lip-
ids and blood pressure), Magnes. Res., 6, 355, 1993.
133. Hoogerbrugge, N., Cobbaert, C., de Heide, L., and Birkenhager, J.C., Oral physio-
logical magnesium supplementation for 6 weeks with 1 g/d magnesium oxide does
not affect increased Lp(a) levels in hypercholesterolaemic subjects, Magnes. Res., 9,
129, 1996.
134. Altura, B.M. and Altura, B.T., Magnesium and cardiovascular biology: an important
link between cardiovascular risk factors and atherogenesis, Cell Mol. Biol. Res, 41,
347, 1995.

135. Gueux, E., Cubizolles, C., Bussiere, L., Mazur, A., and Rayssiguier, Y., Oxidative
modification of triglyceride-rich lipoproteins in hypertriglyceridemic rats following
magnesium deficiency, Lipids, 28, 573, 1993.
136. Ford, E.S., Serum magnesium and ischaemic heart disease: findings from a national
sample of US adults, Int. J. Epidemiol., 28, 645, 1999.
137. Booth, J.V., Phillips-Bute, B., McCants, C.B., Podgoreanu, M.V., Smith, P.K.,
Mathew, J.P., and Newman, M.F., Low serum magnesium level predicts major adverse
cardiac events after coronary artery bypass graft surgery, Am. Heart J., 145, 1108,
2003.
138. Eisenberg, M.J., Magnesium deficiency and sudden death, Am. Heart J., 124, 544,
1992.
139. Lasserre, B., Spoerri, M., Moullet, V., and Theubet, M.P., Should magnesium therapy
be considered for the treatment of coronary heart disease? II. Epidemiological evi-
dence in outpatients with and without coronary heart disease, Magnes. Res., 7, 145,
1994.
140. Liao, F., Folsom, A.R., and Brancati, F.L., Is low magnesium concentration a risk
factor for coronary heart disease? The Atherosclerosis Risk in Communities (ARIC)
Study, Am. Heart J., 136, 480, 1998.
141. Abbott, R.D., Ando, F., Masaki, K.H., Tung, K.H., Rodriguez, B.L., Petrovitch, H.,
Yano, K., and Curb, J.D., Dietary magnesium intake and the future risk of coronary
heart disease (the Honolulu Heart Program), Am. J. Cardiol., 92, 665, 2003.
142. Shechter, M., Bairey Merz, C.N., Stuehlinger, H.G., Slany, J., Pachinger, O., and
Rabinowitz, B., Effects of oral magnesium therapy on exercise tolerance, exercise-
induced chest pain, and quality of life in patients with coronary artery disease, Am.
J. Cardiol., 91, 517, 2003.
143. Geiss, K.R., Stergiou, N., Jester, Neuenfeld, H.U., and Jester, H.G., Effects of mag-
nesium orotate on exercise tolerance in patients with coronary heart disease, Cardio-
vasc. Drugs Ther., 12 Suppl. 2, 153, 1998.
144. Rosenfeldt, F.L., Metabolic supplementation with orotic acid and magnesium orotate,
Cardiovasc. Drugs Ther., 12 Suppl. 2, 147, 1998.
145. Shechter, M., Sharir, M., Labrador, M.J., Forrester, J., Silver, B., and Bairey Merz,
C.N., Oral magnesium therapy improves endothelial function in patients with coro-
nary artery disease, Circulation, 102, 2353, 2000.
146. Shechter, M., Merz, C.N., Paul-Labrador, M., Meisel, S.R., Rude, R.K., Molloy, M.D.,
Dwyer, J.H., Shah, P.K., and Kaul, S., Oral magnesium supplementation inhibits
platelet-dependent thrombosis in patients with coronary artery disease, Am. J. Car-
diol., 84, 152, 1999.
147. Fruhwald, F.M., Dusleag, J., Fruhwald, S.M., Grisold, M., Gasser, R., and Klein, W.,
A physiological oral magnesium supplement does not influence total serum magne-
sium, left ventricular ejection fraction and prognosis in patients with dilated cardi-
omyopathy, Magnes. Res., 6, 251, 1993.
148. Tosiello, L., Hypomagnesemia and diabetes mellitus. A review of clinical implica-
tions, Arch. Intern. Med., 156, 1143, 1996.
149. de Valk, H.W., Magnesium in diabetes mellitus, Neth. J. Med., 54, 139, 1999.
150. Paolisso, G., Scheen, A., D’Onofrio, F., and Lefebvre, P., Magnesium and glucose
homeostasis, Diabetologia, 33, 511, 1990.
151. Barbagallo, M., Gupta, R.K., and Resnick, L.M., Cellular ions in NIDDM: relation
of calcium to hyperglycemia and cardiac mass, Diabetes Care, 19, 1393, 1996.

152. Rude, R.K., Stephen, A., and Nadler, J., Determination of red blood cell intracellular
free magnesium by nuclear magnetic resonance as an assessment of magnesium
depletion, Magnes. Trace Elem., 10, 117, 1991.
153. Resnick, L.M., Altura, B.T., Gupta, R.K., Laragh, J.H., Alderman, M.H., and Altura,
B.M., Intracellular and extracellular magnesium depletion in type 2 (non-insulin-
dependent) diabetes mellitus, Diabetologia, 36, 767, 1993.
154. Husmann, M.J., Fuchs, P., Truttmann, A.C., Laux-End, R., Mullis, P.E., Peheim, E.,
and Bianchetti, M.G., Extracellular magnesium depletion in pediatric patients with
insulin-dependent diabetes mellitus, Miner. Electrolyte Metab, 23, 121, 1997.
155. Dyckner, T., Hagg, E., Lithner, F., Nyhlin, H., and Wester, P.O., Muscle magnesium
and capillary basement membrane thickness in diabetes mellitus, Diabete Metab, 14,
619, 1988.
156. Reis, M.A., Reyes, F.G., Saad, M.J., and Velloso, L.A., Magnesium deficiency mod-
ulates the insulin signaling pathway in liver but not muscle of rats, J. Nutr., 130, 133,
2000.
157. Yajnik, C.S., Smith, R.F., Hockaday, T.D., and Ward, N.I., Fasting plasma magnesium
concentrations and glucose disposal in diabetes, Br. Med. J. (Clin. Res. Ed), 288,
1032, 1984.
158. Gunn, I.R. and Burns, E., Plasma ultrafiltrable magnesium in insulin dependent
diabetics, J. Clin. Pathol., 40, 294, 1987.
159. Sjogren, A., Floren, C.H., and Nilsson, A., Magnesium deficiency in IDDM related
to level of glycosylated hemoglobin, Diabetes, 35, 459, 1986.
160. Mather, H.M., Levin, G.E., Nisbet, J.A., Hadley, L.A., Oakley, N.W., and Pilkington,
T.R., Diurnal profiles of plasma magnesium and blood glucose in diabetes, Diabeto-
logia, 22, 180, 1982.
161. De, L., I, Engelen, W., Aerts, P., and Schrans, S., Effect of intensive magnesium
supplementation on the in vitro oxidizability of LDL and VLDL in Mg-depleted type
1 diabetic patients, Magnes. Res, 11, 179, 1998.
162. Sjogren, A., Floren, C.H., and Nilsson, A., Oral administration of magnesium hydrox-
ide to subjects with insulin-dependent diabetes mellitus: effects on magnesium and
potassium levels and on insulin requirements, Magnesium, 7, 117, 1988.
163. Hagg, E., Carlberg, B.C., Hillorn, V.S., and Villumsen, J., Magnesium therapy in type
1 diabetes. A double blind study concerning the effects on kidney function and serum
lipid levels, Magnes. Res., 12, 123, 1999.
164. Eriksson, J. and Kohvakka, A., Magnesium and ascorbic acid supplementation in
diabetes mellitus, Ann. Nutr. Metab, 39, 217, 1995.
165. Djurhuus, M.S., Klitgaard, N.A., and Pedersen, K.K., Effect of glucose/insulin infu-
sion and magnesium supplementation on serum and muscle sodium and potassium
and muscle [3H]ouabain binding capacity in Type 1 diabetes mellitus, Scand. J. Clin.
Lab Invest, 63, 93, 2003.
166. De Leeuw, I., Engelen, W., Vertommen, J., and Nonneman, L., Effect of intensive
i.v. + oral magnesium supplementation on circulating ion levels, lipid parameters and
metabolic control in Mg-depleted insulin-dependent diabetic patients (IDDM),
Magnes. Res., 10, 135, 1997.
167. Lal, J., Vasudev, K., Kela, A.K., and Jain, S.K., Effect of oral magnesium supple-
mentation on the lipid profile and blood glucose of patients with type 2 diabetes
mellitus, J. Assoc. Physicians India, 51, 37, 2003.

168. Corica, F., Allegra, A., Di Benedetto, A., Giacobbe, M.S., Romano, G., Cucinotta,
D., Buemi, M., and Ceruso, D., Effects of oral magnesium supplementation on plasma
lipid concentrations in patients with non-insulin-dependent diabetes mellitus, Magnes.
Res., 7, 43, 1994.
169. Rodriguez-Moran, M. and Guerrero-Romero, F., Oral magnesium supplementation
improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a
randomized double-blind controlled trial, Diabetes Care, 26, 1147, 2003.
170. Paolisso, G., Passariello, N., Pizza, G., Marrazzo, G., Giunta, R., Sgambato, S.,
Varricchio, M., and D’Onofrio, F., Dietary magnesium supplements improve B-cell
response to glucose and arginine in elderly non-insulin dependent diabetic subjects,
Acta Endocrinol. (Copenh), 121, 16, 1989.
171. Paolisso, G., Sgambato, S., Pizza, G., Passariello, N., Varricchio, M., and D’Onofrio,
F., Improved insulin response and action by chronic magnesium administration in
aged NIDDM subjects, Diabetes Care, 12, 265, 1989.
172. Paolisso, G., Tirelli, A., Coppola, L., Verrazzo, G., Pizza, G., Sgambato, S., and
D’Onofrio, F., Magnesium administration reduces platelet hyperaggregability in
NIDDM, Diabetes Care, 12, 167, 1989.
173. Paolisso, G., Scheen, A., Cozzolino, D., Di Maro, G., Varricchio, M., D’Onofrio, F.,
and Lefebvre, P.J., Changes in glucose turnover parameters and improvement of
glucose oxidation after 4-week magnesium administration in elderly noninsulin-
dependent (type II) diabetic patients, J. Clin. Endocrinol. Metab, 78, 1510, 1994.
174. Nadler, J.L., Malayan, S., Luong, H., Shaw, S., Natarajan, R.D., and Rude, R.K.,
Intracellular free magnesium deficiency plays a key role in increased platelet reactivity
in type II diabetes mellitus, Diabetes Care, 15, 835, 1992.
175. Johnsen, S.P., Husted, S.E., Ravn, H.B., Stodkilde-Jorgensen, H., Peltz-Andresen, E.,
and Christensen, C.K., [Magnesium supplementation to patients with type II diabe-
tes], Ugeskr. Laeger, 161, 945, 1999.
176. Lima, M.L., Cruz, T., Pousada, J.C., Rodrigues, L.E., Barbosa, K., and Cangucu, V.,
The effect of magnesium supplementation in increasing doses on the control of type
2 diabetes, Diabetes Care, 21, 682, 1998.
177. de Valk, H.W., Verkaaik, R., van Rijn, H.J., Geerdink, R.A., and Struyvenberg, A.,
Oral magnesium supplementation in insulin-requiring Type 2 diabetic patients, Dia-
bet. Med., 15, 503, 1998.
178. Paolisso, G., Sgambato, S., Gambardella, A., Pizza, G., Tesauro, P., Varricchio, M.,
and D’Onofrio, F., Daily magnesium supplements improve glucose handling in eld-
erly subjects, Am. J. Clin. Nutr., 55, 1161, 1992.
179. Anonymous, Magnesium supplementation in the treatment of diabetes. American
Diabetes Association, Diabetes Care, 15, 1065, 1992.
180. Seelig, M.S., Consequences of magnesium deficiency on the enhancement of stress
reactions; preventive and therapeutic implications (a review), J. Am. Coll. Nutr., 13,
429, 1994.
181. Galland, L., Magnesium, stress and neuropsychiatric disorders, Magnes. Trace Elem.,
10, 287, 1991.
182. Ram, Z., Sadeh, M., Shacked, I., Sahar, A., and Hadani, M., Magnesium sulfate
reverses experimental delayed cerebral vasospasm after subarachnoid hemorrhage in
rats, Stroke, 22, 922, 1991.
183. Murck, H., Magnesium and affective disorders, Nutr. Neurosci., 5, 375, 2002.

184. Abraham, A.S., Shaoul, R., Shimonovitz, S., Eylath, U., and Weinstein, M., Serum
magnesium levels in acute medical and surgical conditions, Biochem. Med., 24, 21,
1980.
185. Belz, G.G., Matthews, J.H., Longerich, S., Butzer, R., and Volger, K.D., Epinephrine
infusion decreases magnesium plasma concentration in humans, J. Cardiovasc. Phar-
macol., 7, 1205, 1985.
186. Cernak, I., Savic, V., Kotur, J., Prokic, V., Kuljic, B., Grbovic, D., and Veljovic, M.,
Alterations in magnesium and oxidative status during chronic emotional stress,
Magnes. Res., 13, 29, 2000.
187. de Valk, H.W., Bianchi, R., van Rijn, H.J., and Erkelens, D.W., Acute exogenous
elevation of plasma free fatty acids does not influence the plasma magnesium con-
centration, Clin. Chem. Lab Med., 36, 115, 1998.
188. Ryzen, E., Servis, K.L., and Rude, R.K., Effect of intravenous epinephrine on serum
magnesium and free intracellular red blood cell magnesium concentrations measured
by nuclear magnetic resonance, J. Am. Coll. Nutr., 9, 114, 1990.
189. Vormann, J. and Gunther, T., Influence of magnesium on drug- and noise-induced
inner ear damage. Animal studies, Schriftenr. Ver. Wasser Boden Lufthyg., 88, 491,
1993.
190. Ising, H., Interaction of noise-induced stress and Mg decrease, Artery, 9, 205, 1981.
191. Gunther, T., Ising, H., and Merker, H.J., [Electrolyte and collagen content of rat heart
in chronic Mg-deficiency and stress (author’s transl.)], J. Clin. Chem. Clin. Biochem.,
16, 293, 1978.
192. Mocci, F., Canalis, P., Tomasi, P.A., Casu, F., and Pettinato, S., The effect of noise
on serum and urinary magnesium and catecholamines in humans, Occup. Med.
(Lond), 51, 56, 2001.
193. Ohtsuka, S., Oyake, Y., Seo, Y., Eda, K., and Yamaguchi, I., Magnesium sulphate
infusion suppresses the cardiac release of noradrenaline during a handgrip stress test,
Can. J. Cardiol., 18, 133, 2002.
194. D’Souza, D.N., Warner, R.D., Leury, B.J., and Dunshea, F.R., The effect of dietary
magnesium aspartate supplementation on pork quality, J. Anim. Sci., 76, 104, 1998.
195. Henrotte, J.G., Franck, G., Santarromana, M., Frances, H., Mouton, D., and Motta,
R., Mice selected for low and high blood magnesium levels: a new model for stress
studies, Physiol Behav., 61, 653, 1997.
196. Henrotte, J.G., Aymard, N., Leyris, A., Monier, C., Frances, H., and Boulu, R., Brain
weight and noradrenaline content in mice selected for low (MGL) and high (MGH)
blood magnesium, Magnes. Res., 6, 21, 1993.
197. Bac, P., Pages, N., Herrenknecht, C., Dupont, C., Maurois, P., Vamecq, J., and
Durlach, J., THC aggravates rat muricide behavior induced by two levels of magne-
sium deficiency, Physiol. Behav., 77, 189, 2002.
198. Nishio, A., Ishiguro, S., and Matsumoto, M., Ex vivo study of the vascular reactivity
to some vaso-active agents in isolated thoracic aorta from dietary magnesium-defi-
cient rats, Magnes. Res., 1, 169, 1988.
199. Luthringer, C., Rayssiguier, Y., Gueux, E., and Berthelot, A., Effect of moderate
magnesium deficiency on serum lipids, blood pressure and cardiovascular reactivity
in normotensive rats, Br. J. Nutr., 59, 243, 1988.
200. Lu, C.Y. and Wang, D.X., Effects of dietary magnesium on pulmonary vascular
reactivity and chronic hypoxic pulmonary hypertension in rats, J. Tongji Med. Univ,
11, 1, 1991.

201. Held, K., Antonijevic, I.A., Kunzel, H., Uhr, M., Wetter, T.C., Golly, I.C., Steiger,
A., and Murck, H., Oral Mg(2+) supplementation reverses age-related neuroendocrine
and sleep EEG changes in humans, Pharmacopsychiatry, 35, 135, 2002.
202. Cevette, M.J., Vormann, J., and Franz, K., Magnesium and hearing, J. Am. Acad.
Audiol., 14, 202, 2003.
203. Haupt, H., Scheibe, F., and Mazurek, B., Therapeutic efficacy of magnesium in
acoustic trauma in the guinea pig, ORL J. Otorhinolaryngol. Relat Spec., 65, 134,
2003.
204. Attias, J., Weisz, G., Almog, S., Shahar, A., Wiener, M., Joachims, Z., Netzer, A.,
Ising, H., Rebentisch, E., and Guenther, T., Oral magnesium intake reduces permanent
hearing loss induced by noise exposure, Am. J. Otolaryngol., 15, 26, 1994.
205. Joachims, Z., Netzer, A., Ising, H., Rebentisch, E., Attias, J., Weisz, G.,and Gunther,
T., Oral magnesium supplementation as prophylaxis for noise-induced hearing loss:
results of a double blind field study, Schriftenr. Ver. Wasser Boden Lufthyg., 88, 503,
1993.
206. Joachims, Z., Babisch, W., Ising, H., Gunther, T., and Handrock, M., Dependence of
noise-induced hearing loss upon perilymph magnesium concentration, J. Acoust. Soc.
Am., 74, 104, 1983.
207. Buck, D.R., Mahoney, A.W., and Hendricks, D.G., Effect of magnesium deficiency
on nonspecific excitability level (NEL) and audiogenic seizure susceptibility, Phar-
macol. Biochem. Behav., 5, 529, 1976.
208. Gunther, T., Ising, H., and Joachims, Z., Biochemical mechanisms affecting suscep-
tibility to noise-induced hearing loss, Am. J. Otol., 10, 36, 1989.
209. Kanter, M., Free radicals, exercise and antioxidant supplementation, Proc. Nutr. Soc.,
57, 9, 1998.
210. Estivariz, C.F. and Ziegler, T.R., Nutrition and the insulin-like growth factor system,
Endocrine., 7, 65, 1997.
211. Beller, G.A., Maher, J.T., Hartley, L.H., Bass, D.E., and Wacker, W.E., Changes in
serum and sweat magnesium levels during work in the heat, Aviat. Space Environ.
Med., 46, 709, 1975.
212. Stendig-Lindberg, G., Moran, D., and Shapiro, Y., How significant is magnesium in
thermoregulation?, J. Basic Clin. Physiol Pharmacol., 9, 73, 1998.
213. Lijnen, P., Hespel, P., Fagard, R., Lysens, R., Vanden Eynde, E., and Amery, A.,
Erythrocyte, plasma and urinary magnesium in men before and after a marathon, Eur.
J. Appl. Physiol Occup. Physiol, 58, 252, 1988.
214. Rayssiguier, Y., Guezennec, C.Y., and Durlach, J., New experimental and clinical
data on the relationship between magnesium and sport, Magnes. Res., 3, 93, 1990.
215. Keen, C.L., Lowney, P., Gershwin, M.E., Hurley, L.S., and Stern, J.S., Dietary mag-
nesium intake influences exercise capacity and hematologic parameters in rats, Metab-
olism, 36, 788, 1987.
216. McDonald, R. and Keen, C.L., Iron, zinc and magnesium nutrition and athletic
performance, Sports Med., 5, 171, 1988.
217. Lukaski, H.C. and Nielsen, F.H., Dietary magnesium depletion affects metabolic
responses during submaximal exercise in postmenopausal women, J. Nutr., 132, 930,
2002.
218. Stendig-Lindberg, G., Shapiro, Y., Epstein, Y., Galun, E., Schonberger, E., Graff, E.,
and Wacker, W.E., Changes in serum magnesium concentration after strenuous exer-
cise, J. Am. Coll. Nutr., 6, 35, 1987.

219. Terblanche, S., Noakes, T.D., Dennis, S.C., Marais, D., and Eckert, M., Failure of
magnesium supplementation to influence marathon running performance or recovery
in magnesium-replete subjects, Int. J. Sport Nutr., 2, 154, 1992.
220. Manore, M., Merkel, J., and Helleksen, J.M., Longitudinal changes in magnesium
status in untrained males: effect of two different 12-week exercise training programs
and magnesium supplementation, in Sports Nutrition: Minerals and Electrolytes,
Kies, C.V., and Driskell, J.A., Eds., CRC Press, Boca Raton, 1995.
221. Finstad, E.W., Newhouse, I.J., Lukaski, H.C., Mcauliffe, J.E., and Stewart, C.R., The
effects of magnesium supplementation on exercise performance, Med. Sci. Sports
Exerc., 33, 493, 2001.
222. Ruddell, H., Werner, C., and Ising, H., Impact of magnesium supplementation on
performance data in young swimmers, Magnes. Res., 3, 103, 1990.
223. Brilla, L.R. and Haley, T.F., Effect of magnesium supplementation on strength training
in humans, J. Am. Coll. Nutr., 11, 326, 1992.
224. Golf, S.W., Bender, S., and Gruttner, J., On the significance of magnesium in extreme
physical stress, Cardiovasc. Drugs Ther., 12 Suppl. 2, 197, 1998.
225. Golf, S.W., Bohmer, D., and Nowacki, P.E., Is magnesium a limiting factor in
competitive exercise? A summary of relevant scientific data, in Magnesium, Golf, S.,
Dralle, D., and Vecchiet, L., Eds., John Libbey, London, 1993.
226. Ripari, P., Pieralisi, G., Giamberardino, M.A., and Vecchiet, L., Effects of magnesium
picolinate on some cardiorespiratory submaximal effort parameters, Magnes. Res., 2,
70, 1989.
227. Ahlborg, B., Ekelund, L.G., and Nilsson, C.G., Effect of potassium-magnesium-
aspartate on the capacity for prolonged exercise in man, Acta Physiol. Scand., 74,
238, 1968.
228. Selsby, J., DiSilvestro, R.A., and Devor, S.T., Short term supplementation with creatine
or magnesium-creatine chelate on resistance exercise performance, J. Strength Condit.
Res., in press.
229. Brilla, L.R., Giroux, M.S., Taylor, A., and Knutzen, K.M., Magnesium-creatine sup-
plementation effects on body water, Metabolism, 52, 1136, 2003.
230. Brilla, L.R. and Conte, V., Effects of zinc-magnesium (ZMA) supplementation on
muscle attributes of football players, Med. Sci. Sports Exer., 31, 483, 1999.
231. Stendig-Lindberg, G., Tepper, R., and Leichter, I., Trabecular bone density in a two
year controlled trial of peroral magnesium in osteoporosis, Magnes. Res., 6, 155,
1993.
232. Cox, I.M., Campbell, M.J., and Dowson, D., Red blood cell magnesium and chronic
fatigue syndrome, Lancet, 337, 757, 1991.
233. Hinds, G., Bell, N.P., McMaster, D., and McCluskey, D.R., Normal red cell magne-
sium concentrations and magnesium loading tests in patients with chronic fatigue
syndrome, Ann. Clin. Biochem., 31 (Pt. 5), 459, 1994.
234. Altura, B.T., Burack, J.L., Cracco, R.Q., Galland, L., Handwerker, S.M., Markell,
M.S., Mauskop, A., Memon, Z.S., Resnick, L.M., and Zisbrod, Z., Clinical studies
with the NOVA ISE for IMg2+, Scand. J. Clin. Lab. Invest. Suppl., 217, 53, 1994.
235. Moorkens, G., Keenoy, B., Vertommen, J., Meludu, S., Noe, M., and De Leeuw, I.,
Magnesium deficit in a sample of the Belgian population presenting with chronic
fatigue, Magnes. Res., 10, 329, 1997.
236. Keenoy, B., Moorkens, G., Vertommen, J., Noe, M., Neve, J., and De Leeuw, I.,
Magnesium status and parameters of the oxidant-antioxidant balance in patients with
chronic fatigue: effects of supplementation with magnesium, J. Am. Coll. Nutr., 19,
374, 2000.

237. Hill, J., Micklewright, A., Lewis, S., and Britton, J., Investigation of the effect of
short-term change in dietary magnesium intake in asthma, Eur. Respir. J., 10, 2225,
1997.
238. Fogarty, A. and Britton, J., Nutritional issues and asthma, Curr. Opin. Pulm. Med.,
6, 86, 2000.
239. Zhou, G.P., Anderson, K.P., Joiner, C.H., and Gallagher, P.G., Modification of eryth-
rocyte hydration in the treatment of sickle cell disease, Blood Cells Mol. Dis., 27,
65, 2001.
240. Olukoga, A.O., Adewoye, H.O., Erasmus, R.T., and Adedoyin, M.A., Urinary mag-
nesium excretion in steady-state sickle cell anaemia, Acta Haematol., 90, 136, 1993.
241. Altura, R.A., Wang, W.C., Wynn, L., Altura, B.M., and Altura, B.T., Hydroxyurea
therapy associated with declining serum levels of magnesium in children with sickle
cell anemia, J. Pediatr., 140, 565, 2002.
242. De Franceschi, L., Bachir, D., Galacteros, F., Tchernia, G., Cynober, T., Alper, S.,
Platt, O., Beuzard, Y., and Brugnara, C., Oral magnesium supplements reduce eryth-
rocyte dehydration in patients with sickle cell disease, J. Clin. Invest, 100, 1847, 1997.
243. De Franceschi, L., Beuzard, Y., Jouault, H., and Brugnara, C., Modulation of eryth-
rocyte potassium chloride cotransport, potassium content, and density by dietary
magnesium intake in transgenic SAD mouse, Blood, 88, 2738, 1996.
244. De Franceschi, L., Bachir, D., Galacteros, F., Tchernia, G., Cynober, T., Neuberg,
D., Beuzard, Y., and Brugnara, C., Oral magnesium pidolate: effects of long-term
administration in patients with sickle cell disease, Br. J. Haematol., 108, 284, 2000.
245. De Franceschi, L., Brugnara, C., and Beuzard, Y., Dietary magnesium supplementa-
tion ameliorates anemia in a mouse model of beta-thalassemia, Blood, 90, 1283, 1997.
246. De Franceschi, L., Cappellini, M.D., Graziadei, G., Manzato, F., Olivieri, O., Corro-
cher, R., Fiorelli, G., Beuzard, Y., and Brugnara, C., The effect of dietary magnesium
supplementation on the cellular abnormalities of erythrocytes in patients with beta
thalassemia intermedia, Haematologica, 83, 118, 1998.
247. Rodgers, A., Aspects of calcium oxalate crystallization: theory, in vitro studies, and
in vivo implementation, J. Am. Soc. Nephrol., 10 Suppl. 14, S351, 1999.
248. Kohri, K., Garside, J., and Blacklock, N.J., The role of magnesium in calcium oxalate
urolithiasis, Br. J. Urol., 61, 107, 1988.
249. Reungjui, S., Prasongwatana, V., Premgamone, A., Tosukhowong, P., Jirakulsomchok,
S., and Sriboonlue, P., Magnesium status of patients with renal stones and its effect
on urinary citrate excretion, BJU. Int., 90, 635, 2002.
250. Johansson, G., Backman, U., Danielson, B.G., Fellstrom, B., Ljunghall, S., and
Wikstrom, B., Effects of magnesium hydroxide in renal stone disease, J. Am. Coll.
Nutr., 1, 179, 1982.
251. Schwartz, B.F., Bruce, J., Leslie, S., and Stoller, M.L., Rethinking the role of urinary
magnesium in calcium urolithiasis, J. Endourol., 15, 233, 2001.
252. Stemmer, C.L., Oster, J.R., Vaamonde, C.A., Perez, G.O., and Rogers, A.I., Effect of
routine doses of antacid on renal acidification, Lancet, 2, 3, 1986.
253. Liebman, M. and Costa, G., Effects of calcium and magnesium on urinary oxalate
excretion after oxalate loads, J. Urol., 163, 1565, 2000.
254. Rattan, V., Thind, S.K., Jethi, R.K., Sidhu, H., and Nath, R., Oxalate metabolism in
magnesium-deficient rats, Magnes. Res., 6, 127, 1993.
255. Straub, B., Muller, M., Schrader, M., Goessl, C., Heicappell, R., and Miller, K.,
Intestinal and renal handling of oxalate in magnesium-deficient rats. Evaluation of
intestinal in vivo 14C-oxalate perfusion, BJU. Int., 90, 312, 2002.

256. Ahlstrand, C. and Tiselius, H.G., Biochemical effects in patients with calcium oxalate
stone disease during combined treatment with bendroflumethiazide and magnesium
oxide, Br. J. Urol., 56, 125, 1984.
257. Fetner, C.D., Barilla, D.E., Townsend, J., and Pak, C.Y., Effects of magnesium oxide
on the crystallization of calcium salts in urine in patients with recurrent nephrolith-
iasis, J. Urol., 120, 399, 1978.
258. Tiselius, H.G., Ahlstrand, C., and Larsson, L., Urine composition in patients with
urolithiasis during treatment with magnesium oxide, Urol. Res., 8, 197, 1980.
259. Johansson, G., Backman, U., Danielson, B.G., Fellstrom, B., Ljunghall, S., and
Wikstrom, B., Biochemical and clinical effects of the prophylactic treatment of renal
calcium stones with magnesium hydroxide, J. Urol., 124, 770, 1980.
260. Melnick, I., Landes, R.R., Hoffman, A.A., and Burch, J.F., Magnesium therapy for
recurring calcium oxalate urinary calculi, J. Urol., 105, 119, 1971.
261. Prien, E.L., Sr., and Gershoff, S.F., Magnesium oxide-pyridoxine therapy for recurrent
calcium oxalate calculi, J. Urol., 112, 509, 1974.
262. Rattan, V., Sidhu, H., Vaidyanathan, S., Thind, S.K., and Nath, R., Effect of combined
supplementation of magnesium oxide and pyridoxine in calcium-oxalate stone form-
ers, Urol. Res., 22, 161, 1994.
263. Lindberg, J., Harvey, J., and Pak, C.Y., Effect of magnesium citrate and magnesium
oxide on the crystallization of calcium salts in urine: changes produced by food-
magnesium interaction, J. Urol., 143, 248, 1990.
264. Vagelli, G., Calabrese, G., Pratesi, G., Mazzotta, A., and Gonella, M., [Magnesium
hydroxide in idiopathic calcium nephrolithiasis], Minerva Urol. Nefrol., 50, 113,
1998.
265. Ettinger, B., Citron, J.T., Livermore, B., and Dolman, L.I., Chlorthalidone reduces
calcium oxalate calculous recurrence but magnesium hydroxide does not, J. Urol.,
139, 679, 1988.
266. Seydoux, J., Girardin, E., Paunier, L., and Beguin, F., Serum and intracellular mag-
nesium during normal pregnancy and in patients with pre-eclampsia, Br. J. Obstet.
Gynaecol., 99, 207, 1992.
267. Handwerker, S.M., Altura, B.T., and Altura, B.M., Ionized serum magnesium and
potassium levels in pregnant women with preeclampsia and eclampsia, J. Reprod.
Med., 40, 201, 1995.
268. Bardicef, M., Bardicef, O., Sorokin, Y., Altura, B.M., Altura, B.T., Cotton, D.B., and
Resnick, L.M., Extracellular and intracellular magnesium depletion in pregnancy and
gestational diabetes, Am. J. Obstet. Gynecol., 172, 1009, 1995.
269. Turner, R.E., Langkamp-Henken, B., Littell, R.C., Lukowski, M.J., and Suarez, M.F.,
Comparing nutrient intake from food to the estimated average requirements shows
middle- to upper-income pregnant women lack iron and possibly magnesium, J. Am.
Diet. Assoc., 103, 461, 2003.
270. Giddens, J.B., Krug, S.K., Tsang, R.C., Guo, S., Miodovnik, M., and Prada, J.A.,
Pregnant adolescent and adult women have similarly low intakes of selected nutrients,
J. Am. Diet. Assoc., 100, 1334, 2000.
271. Simchen, M.J., Dulitzky, M., Mashiach, S., Friedman, S.A., and Schiff, E., Adjust-
ment of magnesium sulfate infusion rate in patients with preterm labor, Am. J. Obstet.
Gynecol., 179, 994, 1998.
272. Yang, C.Y., Chiu, H.F., Tsai, S.S., Chang, C.C., and Sung, F.C., Magnesium in
drinking water and the risk of delivering a child of very low birth weight, Magnes.
Res., 15, 207, 2002.

273. Kurzel, R.B., Serum magnesium levels in pregnancy and preterm labor, Am. J.
Perinatol., 8, 119, 1991.
274. Skajaa, K., Dorup, I., and Sandstrom, B.M., Magnesium intake and status and preg-
nancy outcome in a Danish population, Br. J. Obstet. Gynaecol., 98, 919, 1991.
275. Makrides, M. and Crowther, C.A., Magnesium supplementation in pregnancy,
Cochrane. Database. Syst. Rev., CD000937, 2001.
276. Sherwood, R.A., Rocks, B.F., Stewart, A., and Saxton, R.S., Magnesium and the
premenstrual syndrome, Ann. Clin. Biochem., 23 (Pt. 6), 667, 1986.
277. De Souza, M.C., Walker, A.F., Robinson, P.A., and Bolland, K., A synergistic effect
of a daily supplement for 1 month of 200 mg magnesium plus 50 mg vitamin B6 for
the relief of anxiety-related premenstrual symptoms: a randomized, double-blind,
crossover study, J. Womens Health Gend. Based. Med., 9, 131, 2000.
278. Facchinetti, F., Borella, P., Sances, G., Fioroni, L., Nappi, R.E., and Genazzani, A.R.,
Oral magnesium successfully relieves premenstrual mood changes, Obstet. Gynecol.,
78, 177, 1991.
279. Martynov, A.I., Stepura, O.B., Shekhter, A.B., Mel’nik, O.O., Pak, L.S., and Ushak-
ova, T.I., [New approaches to the treatment of patients with idiopathic mitral valve
prolapse], Ter. Arkh., 72, 67, 2000.
280. Simoes, F.J., Pereira, T., Carvalho, J., Franca, A., Andrade, R., Nogueira, P.J., Rod-
rigues, J.C., Laires, M.J., and Halpern, M.J., Therapeutic effect of a magnesium salt
in patients suffering from mitral valvular prolapse and latent tetany, Magnesium, 4,
283, 1985.

3 Potassium
If the average person is asked about potassium and nutrition, the person is likely to
say two things. One, it is found in bananas, and two, it prevents cramps. Beyond
that, there is not a tremendous amount of public awareness of this mineral, though
there have been attempts to raise public consciousness. For example, a high-potas-
sium diet was touted as an antidote to high blood pressure in the popular press book
The High Blood Pressure Solution: Natural Prevention and Cure with the K Factor
(by Richard D. Moore, Healing Art Press, 1993).
Although there are various medical uses of potassium compounds as prescription
medicines, supplement companies have not given tremendous attention to potassium.
One reason is that consumers have to take a lot of pills or capsules to make a major
impact on their daily potassium intake. This is not an easy sell to consumers without
compelling arguments. Thus, supplement companies have generally decided to put
their efforts elsewhere. Nonetheless, there are some faint rumblings that potassium
may become of more concern to the general public and biomedical community. If
this does happen, we may see more of an advertising push for supplements, though
food fortification may become more prominent (due to the pill or capsule dose issue
just noted). The fortification approach may become especially prevalent with meal
replacement products.
Potassium is of tremendous importance from a physiology standpoint, since potas-
sium ion is the most abundant positively charged electrolyte inside cells.1 As noted
in the next section, Overview of Physiology, potassium is actively pumped into cells.
Intracellular potassium is a major determinant of intracellular osmolality.1,2 This
gradient between intra- and extra-cellular potassium is needed for cell membrane
polarization, which influences processes such as nerve impulses and muscle cell
contraction (including cardiac muscle). Inside cells, potassium is needed for normal
cell growth and protein synthesis.2 The charge movement by potassium through
channels in cells has various regulatory actions.2 In addition, potassium channels in
the kidneys participate in many diverse renal tubule functions.2
Some very interesting but underappreciated work suggests that potassium may
have indirect antioxidant actions by restricting excessive production of superoxide
radical. This contention is based on a study where low potassium is fed to rabbits.3
When arteries are removed from these rabbits, superoxide production outside the
body is very high. Unfortunately, this paper has not provoked follow-up studies in

humans, possibly due to technical limitations. Hopefully, some of the indirect

approaches to evaluating superoxide production will be applied to human studies of
potassium intake.
OVERVIEW OF PHYSIOLOGY
Since potassium acts as the prime electrolyte inside cells, this electrolyte is pumped
into cells, while sodium is pumped out, by the so-called Na,K-ATPase.4 The sodium-
potassium gradient created by this pump is essential for functions such as nerve
impulse transmission. Only about 2% of total body potassium is outside cells, with
much of the cellular potassium contained in muscle cells. Therefore, total body
potassium is roughly proportional to lean body mass. Numerous factors affect the
movement of potassium in and out of cells including insulin, which pushes potassium
into cells.2,4,5,6 Stimulation of the sympathetic nervous system also affects potassium
movement. β-agonists promote cellular uptake of potassium, while β-blockade or
stimulation by α-agonists appear to do the opposite. Plasma potassium can also be
affected by plasma pH.4 Acute metabolic acidosis increases movement of potassium
out of cells, while acute metabolic alkalosis does the opposite. However, changes
in plasma HCO3 concentration may be more important than just pH changes.
Fecal potassium losses are fairly constant and small (roughly 10% of intake).2,4
In contrast, in healthy kidneys, urinary excretion is regulated to maintain balance.
However, a large acute potassium load causes only about 50% of the load to appear
in the urine over several hours. A rise in plasma potassium is minimized by trans-
ferring most of the potassium load into cells. If elevated intake continues, renal
potassium excretion rises, probably due to aldosterone secretion.4 In renal failure,
this process is impaired, which is why potassium intake is restricted in renal patients.
During low potassium intake, potassium leaves cells, which partially maintains
plasma concentrations.2,4

Typically, serum or plasma potassium is used to assess potassium nutrition status.4,7,8
These measures can generally serve as a rough index to estimate body potassium
stores, though normal or even high values do not always exclude some potassium
depletion.4,7
Severe potassium depletion is generally diagnosed by the combination of serum
potassium readings plus medical history and symptoms often associated with potas-
sium depletion.4,8 If a severe depletion is suspected, the root cause typically needs
to be ferreted out. Then, the therapy should generally involve both potassium reple-
tion and treating the root cause directly. Monitoring of repletion is then done by
both serum potassium measures and evaluations associated with gross symptoms.
This treatment and monitoring should not be done by “amateurs” but by medical
professionals.
Besides concerns about potassium depletion, potassium status has also been
studied to some extent from the standpoint of optimal intake. For example, some

studies have asked: Is there an optimal potassium intake that can beneficially impact
blood pressure? For such purposes, potassium status is studied usually from the
perspective of dietary intake assessment, or serum or plasma potassium. Occasion-
ally, urinary potassium is also used, especially for considering short-term oral absorp-
tion of potassium from various sources. Although there may be other approaches
that should be added, so far, there has not been a strong research demand for this
addition. One possibility may be erythrocyte potassium ion content, which does
show an inverse relationship with blood pressure in Venezuelan adolescents.9

Potassium, because of its high water solubility, is generally absorbed very well, even
up to about 90%.10 There is not a lot of information on absorption from individual
foods, probably because it is assumed that potassium is absorbed well from most
foods. For supplements, many different complexes of potassium are made for oral
or intravenous use. In many cases, the molecule linked to the potassium is intended
as the main biological modulator, not the potassium. In other cases, some specific
molecule is combined with the potassium so that the complex has some specialized
characteristic. For example, potassium is combined with chloride to have the taste
characteristics suitable as a salt substitute for “shaker” use. In other cases, the binding
molecule is chosen to avoid negative effects on certain medical conditions. In still
other cases, the binding molecule is not chosen with a great deal of strategy.
As with food potassium, the potassium in supplements is assumed to be generally
well absorbed. A few studies have examined the absorption of certain types of
potassium supplements and have found the absorption to be very high.11,12,13 In some
people, the types of encapsulation used for potassium supplements may influence
tendencies for GI tract irritation.14

No RDA currently exists for potassium, and there is some question as to what
constitutes an optimal intake under various circumstances. One problem with study-
ing potassium needs is that it is hard to find a diet low or high in potassium that
does not also have several other positive or negative aspects.
The concept that bananas are a good source of potassium is partially true.
Compared to other foods, bananas contain one of the higher potassium contents per
serving.15 On the other hand, there are a good number of other foods with equal or
higher potassium per serving.15 These other foods include certain other fruits, dairy
products, and even meats. It should be noted that one serving of any of these foods
does not come close to providing most anyone’s definition of a full day’s supply.
This points to the need to consider potassium intake from a full diet standpoint,
rather than from a single food standpoint.
Since a lot of foods have some potassium, diet alone doesn’t usually cause severe
potassium deficiencies unless total food intake is very low.1 Most cases of severe
deficiency involve potassium losses.1

As noted earlier, there is some question as to what level of potassium intake is

optimal. Some nutrition texts and Internet medical sites say that potassium intake
in the U.S. tends to be fine except for extenuating circumstances (e.g., the use of
certain diuretic drugs and some severe medical conditions). These texts and sites
usually discourage potassium supplementation unless prescribed by a physician. In
contrast to this attitude, there are popular press books and Internet sites claiming
that many people in this country, especially those with high sodium intakes, do not
eat less than optimal amounts of potassium. These sentiments are even echoed
occasionally in scientific journals, though a somewhat speculative tone is often used.
In this author’s opinion, it is hard to come to any conclusions on this matter until
more creative research is done. There have been a few studies done on supplements.
Some have supported the side that says all is usually well with potassium intake,
while others have raised the possibility that increased intake may help some people.

This section will be limited to applications where potassium is playing an active
role in a chronic use. This will exclude situations where potassium is given by
infusion or oral electrolyte solution to correct acute electrolyte depletions in medical
care situations. This will also exclude applications directed by a physician to deal
with drug side effects. A prime example of the latter is to counteract the potassium-
depleting effects of certain diuretic drugs. Also excluded from this chapter will be
the use of potassium chloride as a table salt substitute. To this author’s knowledge,
there is not a lot of information on salt substitutes that differentiates the effects of
decreased sodium intake vs. those of increased potassium intake. In addition, this
section will not cover situations where potassium is given as part of a complex where
the other part is considered the active ingredient. In such situations, the role of
potassium is that of a “space filler.”
Once all these applications are eliminated, the main uses of potassium supple-
ments that have been researched or given attention by the general public are those
of Table 3.1. There could be other applications, but so far these have been given
limited attention.
TABLE 3.1
Areas of Prime Current Interest
for Potassium Supplementation
Hypertension
Athletic/exercise performance enhancement
Kidney stone prevention
Stroke prevention
Osteoporosis prevention

HYPERTENSION
The idea that potassium affects blood pressure derives from reasonable physiology
involving electrolyte movement1,2 and possibly the indirect antioxidant effects noted
earlier.3 However, just because potassium can affect blood pressure does not mean
that typical variations in potassium intake have a major impact on blood pressure
in many people. Some epidemiological studies show an inverse relationship between
blood pressure and potassium intake or urinary potassium.16–19 However, it is not
known if this relationship reflects actual potassium effects or other positive aspects
of diets that happen to be high in potassium.
As far as potassium supplement studies go, a statistical analysis of a range of
studies finds a statistically significant effect of potassium supplementation on blood
pressure.20 This effect holds even with the exclusion of the most extreme results.
This statistical analysis reports that the effects appear to be greatest when sodium
intake is high. The average change in blood pressure for all the studies analyzed is
not huge, but small average changes are not unusual for this type of overview
analysis. This is because such overviews often must include studies that may not
use the optimal conditions to see a change. This is not necessarily a negative
comment about such studies. Such studies are needed to identify what the optimal
conditions are for maximal changes. In addition, such studies define the range of
circumstances where an effect can be seen. Nonetheless, when such suboptimal
studies are included in an overview analysis, the average impact will be diminished.
Another issue here is that a new study of potassium chloride21 is not included
in the overview analysis.20 This new study has a number of strong points:
• Placebo control
• A study group that should show high compliance
• Low to moderate potassium supplement dose
• Use of both a three- and six-week treatment duration (the effect is bigger
at six weeks, which is longer than some studies showing no or low effects
of potassium on blood pressure)
• A study group with fairly uniform, non-hypertensive starting blood
pressure
An interesting speculation is brought up in the paper for this study.21 This

speculation is that the relatively low dose of potassium chloride used might be more
effective than a high dose. The reason given is that high intakes of chloride might
counteract a blood pressure-lowering effect of potassium. It would be interesting to
see a comparison of blood pressure effects between potassium chloride and potas-
sium supplements that are not chloride based (e.g., tartrate).
Another overview analysis also reports a statistically significant effect of potas-
sium supplementation on blood pressure.22 This analysis notes that the effect seems
to be bigger in people with hypertension than in people with blood pressure in the
normal range. Some studies of people with blood pressure in the normal range do
not see an effect of potassium supplementation.23,24 On the other hand, the study
discussed in the last two paragraphs does see an effect in such people.21 In addition,

another study of potassium supplementation in normotensive people also reports an

effect.25 The latter study may differ from the negative result studies in that it is
limited to subjects with moderately low potassium intakes. In these people, potas-
sium supplementation raises total intake by an average of about 65%. Importantly,
the response is specific to potassium, since raising intake of two other minerals is
not effective.
In this author’s opinion, sustained potassium supplementation can likely help at
least some people lower blood pressure. Factors in how much potassium helps, or
if it helps at all, could be starting blood pressure, dietary potassium intake, the dose
and duration of potassium supplementation, and possibly whether or not potassium
chloride is the form used. In this author’s opinion, potassium supplementation should
not be viewed as a panacea for hypertension. One reason is that there is no clear
indication that this step by itself can prevent or fully correct essential hypertension.
In fact, even when drugs are used to correct essential hypertension, there is often
the need to use more than one drug.26 Even so, increasing potassium intake can be
one part of a dietary and non-dietary combination approach to preventing or reversing
essential hypertension. With respect to the diet component, in this author’s opinion,
high-potassium foods may be superior to supplements for most people. One reason
is that unlike the case for most minerals, typical potassium supplement regimens
tend to not provide more potassium than a few servings of various foods. Moreover,
a high-potassium diet may have a variety of attributes that could aid with blood
pressure control. Along these lines, the success of the so called Dash Diet for
controlling blood pressure could be due partly to both the high potassium content
and other factors.27
KIDNEY STONES
Potassium/magnesium citrate has been used as a prescription drug to prevent kidney
stones in people prone to this problem.28 The strategy has revolved more around the
citrate part of the complex than the two minerals, but the minerals themselves may
also be important (for the magnesium aspects, see the chapter on magnesium).
Unfortunately, there are not an abundance of studies directly distinguishing the
effects of supplementation of potassium apart from when it is “accompanying”
citrate. However, there is one study that indirectly supports an effect of the potassium
itself on kidney stone formation. In this study, children with high urinary calcium
are examined for the effects of either supplemental potassium treatment or feeding
a high-potassium diet. In both cases, there is a reduction of urinary calcium to
creatinine ratios, which is considered a factor in kidney stone formation. Although
this is not the same as examining adult kidney stone formation, it does say that
potassium has the potential to reduce values for a risk factor for stone formation.
Epidemiological studies also support the idea that low-potassium intake
increases the risk of kidney stone formation in high-risk subjects. 29 Interpretation
of these results can be clouded by the fact that low-potassium diets may also have
other characteristics that influence stone formation.
In conclusion, an inverse relationship between potassium and kidney stone
formation tendencies is unsettled, but possible.

CRAMPS
As noted earlier, a common notion among the general public is that potassium
depletion, especially when combined with muscle exertion, causes muscle cramps.
A connection certainly holds for severe potassium depletion and muscle tetany,
which is a potentially dangerous form of cramps.30 However, this type of potassium
depletion is associated mostly with non-routine medical treatments, not the more
common cramping occurring in athletes or in everyday life. Surprisingly, in the last
35 years, very little study of this type of cramping and potassium is reported in the
biomedical literature. Among the few studies reported, there is more than one
suggesting that exercise-induced cramping often occurs independent of any role of
potassium depletion.31 Therefore, in this author’s opinion, the role of potassium
depletion and repletion in the most common types of cramps remains largely
unknown. It is possible that potassium intake could be a factor some of the time,
but adequate hydration and physical approaches (e.g., stretching or massage) may
be more helpful more often. Therefore, taking potassium supplements to prevent
common forms of cramps would seem to be unwarranted. On the other hand, if
people want to eat good amounts of potassium, just in case it may help prevent them
from cramping, this author recommends eating high-potassium foods. Even if the
foods don’t prevent cramps, they will still provide a good share of various nutrients,
and in many cases, a good deal of phytochemicals.
POTASSIUM AND EXERCISE PERFORMANCE

Besides the speculative influence on cramps, potassium has been tied to other aspects
of muscle performance and fatigue during exercise. However, this tying has been
from the metabolic perspective, not from the nutrition perspective. Numerous papers
suggest that the leakage of potassium from muscle to serum during exercise con-
tributes to fatigue.32,33 Despite this research, there is next to no research for actual
studies of potassium intake on exercise performance. In one exception, potassium
phosphate supplementation produces reduced effort perception during exercise, but
it is not clear how much the potassium, rather than the phosphate, contributes to the
effect.34 Therefore, in this author’s opinion, there is a need for new research on
exercise-induced fatigue in relation to potassium nutrition.
POTASSIUM AND STROKE RISK

In the popular press, the Internet, and a few scientific journal articles, potassium
supplements have been speculated to comprise a possible means of lowering stroke
risk. It is thought that this effect, if it really exists, includes, but is not limited to,
possible effects on hypertension. Still, there are no actual research studies of potas-
sium supplementation and stroke. On the other hand, there are epidemiology and
animal studies35,36,37 that raise the possibility that potassium intake can be linked
with stroke risk. However, the results in the human epidemiology studies are far
from clean. For example, in one study, which examined various types of people, an
association of dietary potassium intake with stroke mortality is detected only among
black men and hypertensive men.38 Furthermore, in other work, the possible effects

of potassium are difficult to tease out. The dietary potassium effect may require a
combination with other dietary factors, or may not really be occurring at all. If the
latter case is true, the seemingly protective action of potassium may simply be a
coincidental association with other diet and lifestyle patterns. Therefore, at this point,
in the author’s opinion, taking potassium supplements to lower stroke risk is still
extremely speculative. On the other hand, eating a diet high in potassium, whether
the potassium directly helps prevent strokes or not, is a good idea. Such diets are
often health promoting due to their high content of various micronutrients, phy-
tochemicals, and fiber.
POTASSIUM AND OSTEOPOROSIS

This possible relationship has been proposed primarily for protection against a
deleterious action of a high-sodium diet. According to this idea, a high-salt diet
alters calcium metabolism in a way that raises osteoporosis risk, but this action is
blocked by a high-potassium diet.39 Although a major contribution to osteoporosis
risk of a high-salt diet is still a long way from confirmed, there is a study showing
that four weeks of high salt intake increases the rate of bone resorption in postmeno-
pausal women.40 In this same study,40 the effect of the high-salt diet was inhibited
by potassium citrate supplementation. There is also an epidemiological study linking
salt intake and urinary calcium excretion.41 If these studies can be confirmed and
expanded, then in some people, an anti-osteoporosis value may be ascribed for high
potassium intake via diet or supplementation.
TOXICITY
There is no doubt that too much potassium can be very dangerous due to potential
cardiovascular effects and neuromuscular malfunctions.2 For most people, it would
not be easy to reach toxic levels via supplements for two reasons. One, healthy
kidneys can eliminate large excesses of orally ingested potassium.2 Two, due to the
low potassium dose per pill or capsule, many of these would have to be taken to
produce very high intakes. Not surprisingly, overdose of potassium is not frequently
encountered in clinical practice except due to excess retention during renal disease.2
One concern can be a rapid build-up of body potassium, which could create problems
before the kidney has a chance to eliminate the excess. A fairly recent report notes
two cases of poisoning in people ingesting enormously high, single doses of sus-
tained-release potassium preparations.42
In this author’s opinion, in people with normal renal function, potassium sup-
plement overload is not near as apt to occur as many other self-inflicted health
problems. Nonetheless, due to the serious dangers of potassium poisoning, this
possibility should not be taken lightly.

Potassium has tremendously important functions, but uncertainty exists about opti-
mal intake levels and exactly what benefits can be ascribed to such an intake.

TABLE 3.2
Potassium Supplements at a Glance
RDA: None set; optimal intake debatable
Typical dose in supplement studies: 900–2000 mg (minimal effective dose unknown)
Best supplement complex: a number seem to have good absorption
Applications: hypertension treatment possible, though not as a sole treatment; high-potassium foods
may work better; a few other applications promising, but under-researched
Safety issues: most people not apt to consume toxic levels
Prescription supplements are an important part of treatment for some medical con-
ditions. Over-the-counter uses are less clear, though interesting. Such supplements
are usually used safely and are not actually pushed all that much by most supplement
companies. The best-studied application is for blood pressure, where it may help
some people, though the benefit degree may vary with varying circumstances, and
may work best when combined with other measures.
REFERENCES
1. Preuss, H.G., Sodium, chloride, and potassium, in Present Knowledge in Nutrition,
8th ed., Bowman, B.A., and Russell, R.M., Eds., ILSI Press, Washington, 2001, chap.
29.
2. Peterson, L.N., Potassium in nutrition, in Handbook of Nutritionally Essential Mineral
Elements, O’Dell, B.L., and Sunde, R.A., Eds., Marcel Dekker, New York, 1997,
chap. 6.
3. Yang, B.C., Li, D.Y., Weng, Y.F., Lynch, J., Wingo, C.S., and Mehta, J.L., Increased
superoxide anion generation and altered vasoreactivity in rabbits on low-potassium
diet, Am. J. Physiol, 274, H1955, 1998.
5. Sweeney, G. and Klip, A., Regulation of the Na+/K+-ATPase by insulin: why and
how?, Mol. Cell Biochem., 182, 121, 1998.
6. Glitsch, H.G., Electrophysiology of the sodium-potassium-ATPase in cardiac cells,
Physiol Rev., 81, 1791, 2001.
7. Gennari, F.J., Hypokalemia, N. Engl. J. Med., 339, 451, 1998.
8. Halperin, M.L. and Kamel, K.S., Potassium, Lancet, 352, 135, 1998.
9. Delgado, M.C. and Delgado-Almeida, A., Red blood cell potassium and blood pres-
sure in adolescents: a mixture analysis, Nutr. Metab Cardiovasc. Dis., 12, 112, 2002.
10. Agarwal, R., Afzalpurkar, R., and Fordtran, J.S., Pathophysiology of potassium
absorption and secretion by the human intestine, Gastroenterology, 107, 548, 1994.
11. Caplain, H., Dahan, R., Pamphile, R., and Thebault, J.J., A single blind normal
volunteer bioavailability study of a new microencapsulated potassium chloride tablet
compared with two reference potassium formulations, Eur. J. Drug Metab Pharma-
cokinet., 16, 241, 1991.

12. Whiting, S.J., Gorecki, D.K., and Jones, D., In vitro and in vivo assessment of the
bioavailability of potassium from a potassium tartrate tablet, Biopharm. Drug Dispos.,
12, 207, 1991.
13. Koenig, K., Padalino, P., Alexandrides, G., and Pak, C.Y., Bioavailability of potassium
and magnesium, and citraturic response from potassium-magnesium citrate, J. Urol.,
145, 330, 1991.
14. Sinar, D.R., Bozymski, E.M., and Blackshear, J.L., Effects of oral potassium supple-
ments on upper gastrointestinal mucosa: multicenter clinical comparison of three
formulations and placebo, Clin. Ther., 8, 157, 1986.
16. Espeland, M.A., Kumanyika, S., Yunis, C., Zheng, B., Brown, W.M., Jackson, S.,
Wilson, A.C., and Bahnson, J., Electrolyte intake and nonpharmacologic blood pres-
sure control, Ann. Epidemiol., 12, 587, 2002.
17. Yamori, Y., Liu, L., Mu, L., Zhao, H., Pen, Y., Hu, Z., Kuga, S., Negishi, H., and
Ikeda, K., Diet-related factors, educational levels and blood pressure in a Chinese
population sample: findings from the Japan-China Cooperative Research Project,
Hypertens. Res, 25, 559, 2002.
18. Cutler, J.A., The effects of reducing sodium and increasing potassium intake for
control of hypertension and improving health, Clin. Exp. Hypertens., 21, 769, 1999.
19. Barri, Y.M. and Wingo, C.S., The effects of potassium depletion and supplementation
on blood pressure: a clinical review, Am. J. Med. Sci., 314, 37, 1997.
20. Whelton, P.K. and He, J., Potassium in preventing and treating high blood pressure,
Semin. Nephrol., 19, 494, 1999.
21. Naismith, D.J. and Braschi, A., The effect of low-dose potassium supplementation
on blood pressure in apparently healthy volunteers, Br. J. Nutr., 90, 53, 2003.
22. Geleijnse, J.M., Kok, F.J., and Grobbee, D.E., Blood pressure response to changes
in sodium and potassium intake: a metaregression analysis of randomised trials, J.
Hum. Hypertens., 17, 471, 2003.
23. Anonymous, The effects of nonpharmacologic interventions on blood pressure of
persons with high normal levels. Results of the Trials of Hypertension Prevention,
Phase I, JAMA, 267, 1213, 1992.
24. Miller, J.Z., Weinberger, M.H., and Christian, J.C., Blood pressure response to potas-
sium supplementation in normotensive adults and children, Hypertension, 10, 437,
1987.
25. Sacks, F.M., Willett, W.C., Smith, A., Brown, L.E., Rosner, B., and Moore, T.J., Effect
on blood pressure of potassium, calcium, and magnesium in women with low habitual
intake, Hypertension, 31, 131, 1998.
26. Gradman, A.H. and Acevedo, C., Evolving strategies for the use of combination
therapy in hypertension, Curr. Hypertens. Rep., 4, 343, 2002.
27. Appel, L.J., Lifestyle modification as a means to prevent and treat high blood pressure,
J. Am. Soc. Nephrol., 14, S99, 2003.
28. Klugman, V. and Favus, M.J., Diagnosis and treatment of calcium kidney stones, Adv.
Endocrinol. Metab, 6, 117, 1995.
29. Hall, W.D., Pettinger, M., Oberman, A., Watts, N.B., Johnson, K.C., Paskett, E.D.,
Limacher, M.C., and Hays, J., Risk factors for kidney stones in older women in the
southern U.S., Am. J. Med. Sci., 322, 12, 2001.
30. Ault, M.J. and Geiderman, J., Hypokalemia as a cause of tetany, West J. Med., 157,
65, 1992.

31. Maughan, R.J., Exercise-induced muscle cramp: a prospective biochemical study in

marathon runners, J. Sports Sci., 4, 31, 1986.
32. Fraser, S.F., Li, J.L., Carey, M.F., Wang, X.N., Sangkabutra, T., Sostaric, S., Selig,
S.E., Kjeldsen, K., and McKenna, M.J., Fatigue depresses maximal in vitro skeletal
muscle Na(+)-K(+)-ATPase activity in untrained and trained individuals, J. Appl.
Physiol, 93, 1650, 2002.
33. Lindinger, M.I. and Sjogaard, G., Potassium regulation during exercise and recovery,
Sports Med., 11, 382, 1991.
34. Goss, F., Robertson, R., Riechman, S., Zoeller, R., Dabayebeh, I.D., Moyna, N., Boer,
N., Peoples, J., and Metz, K., Effect of potassium phosphate supplementation on
perceptual and physiological responses to maximal graded exercise, Int. J. Sport Nutr.
Exerc. Metab, 11, 53, 2001.
35. Suter, P.M., The effects of potassium, magnesium, calcium, and fiber on risk of stroke,
Nutr. Rev., 57, 84, 1999.
36. Sica, D.A., Struthers, A.D., Cushman, W.C., Wood, M., Banas, J.S., Jr., and Epstein,
M., Importance of potassium in cardiovascular disease, J. Clin. Hypertens. (Green-
wich.), 4, 198, 2002.
37. Young, D.B., Lin, H., and McCabe, R.D., Potassium’s cardiovascular protective
mechanisms, Am. J. Physiol., 268, R825, 1995.
38. Fang, J., Madhavan, S., and Alderman, M.H., Dietary potassium intake and stroke
mortality, Stroke, 31, 1532, 2000.
39. Harrington, M. and Cashman, K.D., High salt intake appears to increase bone resorp-
tion in postmenopausal women but high potassium intake ameliorates this adverse
effect, Nutr. Rev., 61, 179, 2003.
40. Sellmeyer, D.E., Schloetter, M., and Sebastian, A., Potassium citrate prevents
increased urine calcium excretion and bone resorption induced by a high sodium
chloride diet, J. Clin. Endocrinol. Metab, 87, 2008, 2002.
41. Ho, S.C., Chen, Y.M., Woo, J.L., Leung, S.S., Lam, T.H., and Janus, E.D., Sodium
is the leading dietary factor associated with urinary calcium excretion in Hong Kong
Chinese adults, Osteoporos. Int., 12, 723, 2001.
42. Su, M., Stork, C., Ravuri, S., Lavoie, T., Anguish, D., Nelson, L.S., and Hoffman,
R.S., Sustained-release potassium chloride overdose, J. Toxicol. Clin. Toxicol., 39,
641, 2001.

4 Iron
Iron supplements have been studied since a time when many other minerals were
not even known to be essential nutrients. For that reason, we have some clear tools
for studying the outcomes of iron supplementation. Nevertheless, even with this
knowledge base, there is still much more research needed concerning both the
benefits and safety of iron supplements.
The best-known function of iron is to be part of the proteins hemoglobin and
myoglobin, which participate in oxygen transport.1 In these proteins, the iron is not
inserted directly into the amino acid structure of the proteins, but rather is inserted
into chemical structures known as heme rings, which are inserted into the protein’s
amino acid backbone.2 Iron also functions in enzymes that are iron–sulfur enzymes
(iron is chelated by sulfur amino acids). Iron also is part of structures known as
cytochromes, which are part of the electron transport chain of aerobic energy release,
and are part of a family of enzymes called cytochrome P-450 dependent enzymes.2
The P-450 enzymes are involved in processes such as drug metabolism and steroid
hormone synthesis.
Iron affects aerobic energy metabolism in at least three ways:2
1. Oxygen transport to cells (needed for the electron transport chain)

2. The iron enzyme aconitase in the Krebs Cycle
3. Cytochromes and iron–sulfur proteins in the electron transport chain
Iron enzymes participate in an assortment of other biological processes including

synthesis of neurotransmitters, peroxide conversions, purine metabolism, fatty acid
synthesis, DNA synthesis, and nitric oxide production.2,3 Iron function also impacts
the immune system. The exact molecular mechanisms for this last connection are
hard to identify, since many iron functions could theoretically affect immune func-
tion. For example, iron can affect DNA synthesis, which can affect cell multiplica-
tion, which can affect immune responses.4

Iron metabolism promotes iron function while inhibiting iron toxicity.2 Although
this system doesn’t work perfectly if total body iron is very low or very high, it still
works very well much of the time. Handling of iron is affected by a number of
factors, but the most influential is body iron stores. If stores are low, the intestine
becomes more efficient at iron absorption. If stores are high, iron absorption is
inhibited.
Intestinal cells make a high molecular weight, iron-binding protein called ferritin
in inverse proportion to body iron stores.2 A good deal of the regulation of ferritin
synthesis is at the level of ferritin mRNA translation. If iron stores are low, little
ferritin is made. This elevates iron absorption, since ferritin is a barrier to iron getting
to the bloodstream. If iron stores are high, a lot of ferritin is made, which binds iron
as it enters intestinal cells. A lot of this iron is kept from ever entering the bloodstream
because, after just a few days, intestinal cells are sloughed off and excreted. Once
iron is absorbed from the intestine, it can be stored in the liver. As with the intestine,
ferritin is the primary liver iron binder.
Iron can be transported out of the liver to other body sites using a transport
protein called transferrin.2 Attachment of iron to transferrin has been said to require
an oxidation step catalyzed by the serum copper enzyme ceruloplasmin, though there
has been some debate on this.5 Ceruloplasmin must have some relationship to iron
metabolism since rodents or humans with genetic ceruloplasmin deficiency can
become anemic.5 Less debatable is the idea that transferrin protein binds to receptors
on cells, which take up the whole transferrin protein by endocytosis (an engulfing
of the molecule by the membrane, which then forms a small capsule containing the
engulfed material).6 The engulfed molecule then finds its way to the lysosomes,
where acid releases the iron from transferrin. The released iron can then go to various
iron molecules such as iron-containing enzymes, hemoglobin (if a red blood cell is
being made), myoglobin (a protein that traps oxygen in tissues), and ferritin (which
stores iron and helps prevent toxicity). In states of iron overload, ferritin is degraded
to a water-insoluble iron-binding protein called hemosiderin. This helps reduce iron
toxicity but cannot always prevent it. The main defense against iron toxicity is the
ferritin in the intestine. If a lot of iron manages to get by this defense, then therapy
steps need to be taken (see the Toxicity section below).
A good deal of the body’s iron is inserted into hemoglobin, which transports
oxygen in red blood cells.2 These red blood cells eventually die but most of the iron
from hemoglobin is conserved by the body. The same is true for iron used for other
purposes. Nonetheless, some iron is lost each day via the GI tract, urine, and skin.
Women who are menstruating also lose iron as part of blood losses.

Iron deficiency anemia is traditionally detected by a blood measurement called
hematocrit, which is the percent of blood volume occupied by the red blood cells.7,8
Values below 34 to 37% are associated with iron deficiency anemia. Now, clinical
laboratories tend to measure whole blood hemoglobin to assess anemia. For both

measurements, there can be causes of anemia other than iron deficiency, though this
is a common cause.7,8 Generally, anemia testing is followed by more specific mea-
sures of iron status. These measures are also used to test for iron status in the absence
of anemia. One method is serum ferritin, which is proportional to iron stores.1,8 One
drawback to this evaluation is that ferritin values can be affected by factors other
than iron status such as inflammatory stress. Another drawback to ferritin measure-
ments is day-to-day variations within individuals.
Serum iron is also sometimes used for iron status assessment, but it has draw-
backs, including its wide diurnal variation and its depression as a regulatory response
to infection and inflammatory stress.1,8 In addition, values can fall after blood loss
and with pregnancy or cancer. Serum transferrin or transferrin saturation (the ratio
of serum iron to iron-binding capacity) can also be evaluated.1,8 The use of these
measurements for iron status assessment has some of the same drawbacks as serum
iron.
Another evaluation is erythrocyte protoporphyrin,1,3 a method requiring just a
few drops of blood and minimal technical experience. Values are less subject to
diurnal variations than some other iron assessment measurements. On the other hand,
values are increased by lead poisoning, inflammation, and some uncommon situa-
tions.3 Protoporphyrin is used in population surveys but not typically in clinical
applications.
The most recent addition to iron status assessment tools is serum transferrin
receptors.6 These receptors are found on cell membranes but make their way into
the serum. When iron supply falls, even to a mild degree, synthesis is increased for
transferrin receptors.6,9,10 A few situations other than iron deficiency can affect these
readings,10,11 but unlike values for serum ferritin or iron, serum transferrin receptor
values do not change with inflammation.10 This assessment method may be partic-
ularly useful for diagnosing iron deficiency when chronic disease is prevalent,
especially in elderly subjects. In the elderly, chronic diseases can cause anemia with
high ferritin levels, even during iron deficiency.12 In contrast, diagnosis of iron
deficiency has been reported to work well in the elderly using a TR-F index (the
ratio of serum transferrin receptor level to log ferritin level).12

As already mentioned, iron absorption is strongly influenced by the iron status of
the individual (iron-deficient individuals absorb a much higher percent of ingested
iron than iron-replete individuals). However, iron absorption is also affected by the
particular iron complex ingested, as well as by other dietary components, and by
physiological factors such as stomach acid production.2,3
Iron is consumed in two general classes: heme iron and non-heme iron.3 In meat
(in a broad sense to include poultry and fish), some iron is associated with the
proteins hemoglobin and myoglobin, which collectively are called heme iron. The
rest of the iron in meat, as well as all the iron in vegetables, grains, and supplements,
are non-heme iron. Heme iron is absorbed much better than non-heme iron. Another
selling point for meat as a source of iron is that the amount of iron in meat is higher
than the amount of iron occurring naturally in most other foods. Moreover, meat

contains a substance, termed meat protein factor, which actually improves absorption
of the non-heme iron from other foods eaten at the same time.3
Non-heme iron absorption can also be increased if the metal is in the +2 state
rather than +3.3 This can be accomplished by eating the reducing agent ascorbic
acid (vitamin C), which also may help iron by chelating it into a more absorbable
complex.2 The iron in most supplements is already in the +2 state, which means that
vitamin C will not have the same stimulating effect on absorption. Calcium supple-
ments can be inhibitory to iron absorption, though the extent to which this occurs
is controversial (see the chapter on calcium). Iron absorption can be reduced by a
variety of food components such as phytic acid and some polyphenols such as the
tannins in tea.3,13 However, one study gives evidence that promoters of iron absorp-
tion such as vitamin C and meat can more than compensate for any ill effects of tea
on iron absorption.13 Also, one evaluation of a cross section of studies concludes
that tea consumption does not influence iron status unless status is poor or border-
line.14 This concept should be tested more directly before a final conclusion can be
reached.
A substantial variation in absorption is reported for a series of multi-vita-
min–mineral supplements, presumably due to the other nutrients and additives
present, especially calcium and magnesium.15–19 Thus, such supplements may not
always be a reliable means of getting as much absorbable iron as consumers think
they are getting.
Supplemental iron is usually absorbed better when taken between meals.16 How-
ever, in some people, some iron complexes and doses taken between meals can
produce GI tract discomforts, such as upset stomach.20
Ferrous sulfate is the most common standalone iron supplement, partly because
it is less costly than most other iron supplements. One downside of ferrous sulfate
is that compared to other iron supplements, this complex is apt to produce gas-
trointestinal discomforts in some people.20,21 These discomforts can sometimes be
reduced by taking the supplements with meals20,22 (though this can reduce absorption
if the meal has absorption inhibitors), or keeping the doses low,3 or by splitting up
the daily dose (though this can affect compliance).3 Other iron supplements include
ferrous fumarate, which shows lower GI tract side effects than ferrous sulfate,23
ferrous citrate, ferrous succinate, ferrous gluconate, ferric pyrophosphate, ferric
trimaltol, and iron bis-glycine chelate (Ferrochel®). Under most circumstances the
first four ferrous compounds just named have similar oral absorptions to ferrous
sulfate, and ferrous sulfate and the other compounds named have much better
absorptions than ferric complexes.24–28 A number of these studies have compared
the different iron complexes for absorption when mixed with different foods. For
example, in a study of iron absorption from chocolate drink powder, the absorption
of ferrous fumarate is 5.27%, ferrous sulfate 2.62%, and ferric pyrophosphate
0.55%.29 In a different study, which assesses iron absorption from a test meal,
absorption of ferrous fumarate is 5.5 to 6.2%, while ferrous sulfate is 5.5%.26 In still
another study,30 where iron is mixed with infant cereal, though fed to adults, there
is no difference in absorption between ferrous fumarate and ferrous sulfate. In the
same study, values for ferrous succinate and ferric pyrophosphate are 92% and 39%
of the ferrous sulfate values, respectively.30

In contrast to the studies just mentioned, in two other studies, Ferrochel®

(ferrous bis-glycine chelate) is reported to have far better bioactivity than ferrous
sulfate.31,32 In addition, compared to other forms of iron, Ferrochel® is reported to
show low GI tract upset tendencies,33 shows some resistance to absorption inhibition
by phytate,31 and in rats, requires a relatively high dose to produce toxicity.33 Fer-
rochel® has been successfully used to fortify dairy products in Brazil34 and on a
smaller basis in Saudi Arabia,35 since this complex does not damage dairy products
as easily as do some other iron complexes.36 The one down side to Ferrochel® is
that it is more expensive than ferrous sulfate, though less Ferrochel® can be used
to give the same absorbable iron as some higher concentrations of ferrous sulfate.
Iron mixed with EDTA also has some possible uses for fortification of certain
foods.36,37,38 In some cases, the EDTA addition can also improve iron absorption
substantially, though this seems to depend on what iron complex is mixed with
EDTA.38,39
Another common iron form used in fortification is so-called reduced iron, which
is found in many breakfast cereal foods.40 The phrase “reduced iron” is a catch-all
term for several different types of finely powdered, elemental iron preparations.
These preparations can vary considerably in terms of particle size and other char-
acteristics. One type of reduced iron, know as electrolytic iron, has been recom-
mended as the best absorbed of the reduced iron family, though the absorption is
still not outstanding.40 Unfortunately, seeing the term “reduced iron” on a breakfast
cereal label does not guarantee that electrolytic iron is the form used; in fact, in
most cases, it probably isn’t the form used.41Moreover, the preparations of even
electrolytic iron are not uniform.41
Furthermore, according to one report, absorption of one of the better electrolytic
iron preparations is still only half that of ferrous sulfate.40 This means that in many
fortified cereal products, which use a reduced iron that is not electrolytic iron, the iron
absorption is considerably below 50% of ferrous sulfate. It also must be remembered
that the iron in cereal can be affected negatively by other components of the cereal
product, such as fiber and phytate.1 Besides all this, any form of iron in fortified cereal,
when expressed as a percent of the RDA, is actually a vastly inflated number. The
reason for this statement is that the RDA assumes that some iron is being consumed
as heme iron,1 whereas all the iron in fortified cereal is non-heme iron.
Despite all that was just said, iron-fortified infant cereal has been reported to
help prevent severe iron deficiency in the intended target group.42 However, the
amount of iron needed for this purpose is fairly small. On the other hand, for
menstruating adult women, it is not a good idea to rely on one serving per day of
fortified breakfast cereal as a main supply of iron.
Iron–carbohydrate preparations are also sometimes used for oral supplements.
Ferric trimaltol was mentioned above. This complex has less problem with GI tract
intolerance than ferrous sulfate.43 In one study, ferric trimaltol corrects anemia in
14 of 19 anemic individuals, most of which had inflammatory bowel disease (which
makes them very sensitive to GI track distress due to ferrous sulfate).43 This study
does not mean that ferric trimaltol is necessarily absorbed as well as ferrous sulfate,
only that the former compound, at certain doses, could correct anemia in some
individuals.

Another type of iron carbohydrate complex is iron bound to polysaccharides. For

example, polymaltose–iron has shown similar absorption to ferrous salts in multiple
circumstances.44 On the other hand, in some other studies using various end points
in humans and rats, polymaltose–iron complex is not as bioactive as ferrous sul-
fate,28,45,46 though by some measures, the differences are not that large. Another
polysaccharide that is attached to iron for human use is iron dextran. The main use
of iron dextran is for non-oral administration (i.e., injections and IV infusions).
Sodium ferric gluconate and iron–sucrose are also used for administration IV.
In conclusion, a number of different types of iron supplements can be absorbed
well enough to impact iron status. Considerations in choosing a supplement include
cost, GI reactions, and compliance when high doses are needed (e.g., a better
absorbed supplement could involve smaller capsules or pills or fewer capsules or
pills). Food fortification choices must consider the effects of the food components
on the iron, as well as the iron effects on the food. Finally, multi-vitamin–mineral
pills and iron-fortified cereals may not provide as much absorbable iron as implied
by the label contents.

The RDA for iron is based on iron balance (losses vs. gains) with the assumption
that 18% of the iron in the diet will be absorbed.1 Since a big source of iron loss
can be menstrual blood loss, the iron RDA varies a lot with age and gender. For
adult women, the RDA is 18 mg per day, while it is only 8 mg for adult men. The
RDA is not intended to cover women with high menstrual losses, who may need to
meet their extra needs with a supplement. The RDA for teenaged girls, 15 mg, is
slightly lower than adult women. The RDA for teenaged boys, 11 mg, is slightly
higher than adult men due to the need to support more lean body growth in the
teenagers.
Iron deficiency is still a major problem around the world47 and could be con-
sidered the most common micronutrient deficiency worldwide.3 Deficiency occurs
both in underdeveloped and industrialized countries. In fact, when describing people
groups prone to iron deficiency, it is easier to name groups that are not overly prone
than those who are. Probably every description of a group of people can be said to
have some vulnerability to iron deficiency except for full-term, normal-birth-weight
infants born to mothers of good iron status; healthy, male meat-eating teenagers;
and male, meat-eating young adults (meat used in the broad sense to include fish
and poultry). On the other hand, young adult women, as well as teenaged girls, are
often at risk for iron deficiency due to blood iron losses plus a lower average meat
consumption than their male counterparts.47 Women with heavy menstrual blood
losses are especially prone to iron deficiency.48 The iron needs for such women can
exceed the RDA. Supplements are considered helpful for at least some such women
to meet iron needs.47
Pregnant women don’t have to contend with menstrual blood losses, but iron is
still a big concern. During pregnancy, a lot of body iron goes to making a new
bloodstream and for other body changes.1,48

As a person reaches the elderly stage of life, iron can become a problem as iron
intake often falls, chronic diseases set in, and GI blood losses can occur.49–52 In some
settings, poor iron status seems to occur more often in women than in men.50,51
However, this may not be universally true, and even in the studies where it is
found,50,51 elderly men are not exempt from iron deficiency. On the other hand, not
all elderly male or female populations have high percentages of iron deficiency. For
example, one large group of non-institutionalized U.S. elderly subjects show a fairly
low incidence of low iron stores.53 At the opposite end of the age spectrum, premature
infants can have iron problems.54,55 During the early stages postbirth, iron stores are
supposed to meet a lot of a baby’s needs. Because these iron stores are built mostly
during the last trimester of pregnancy, a premature birth cuts iron storage short.
Two other groups of people particularly prone to iron deficiency are picky-eating,
young children who avoid iron-rich foods, and vegetarians.1,48 The latter group has
a challenge to get enough iron because as noted earlier, meat provides relatively
well-absorbed heme iron, plus meat promotes iron absorption from other foods.
Moreover, the high fiber or oxalic acid content of many vegetarian diets can further
depress iron absorption. On the other hand, most vegetarian diets contain a good
amount of vitamin C, which can promote iron absorption.1 Therefore, vegetarians
should consume vitamin C-rich foods simultaneously with the few non-animal foods
that contain respectable amounts of iron without oxalates (e.g., blackstrap molasses).
A food such as spinach has a good amount of iron but oxalates, which block iron
absorption, keep this food from being a good iron source.1 Consumption of an iron
supplement can be useful for vegetarians even though this iron is not as well absorbed
as meat iron. Adding milk to a vegetarian diet is not very helpful, since milk is not
a good iron source. Some vegetarians rely heavily on iron-fortified breakfast cereals
for this mineral. However, as noted earlier, such products may not provide as much
bioavailable iron as what the label implies.

GENERAL COMMENTS ON DOSES AND USES
The doses to use for iron supplementation are not always straightforward. Often,
doses as high as 200 to 300 mg/day, which are well above the RDA, are used to
correct problems because the goal is to make a big and quick impact on an iron-
deficient state. Also, it should be realized that the RDA is built around iron in foods,
with the assumption that some ingested iron will be heme iron. This heme iron can
be absorbed several-fold higher than the non-heme iron in supplements. Thus, a
supplement must greatly exceed the RDA to have the same impact as an RDA dose
of iron from a meat-containing diet. In light of the percent absorptions discussed in
preceding sections, it might seem reasonable to make mathematical comparisons
between the absorbable iron in a supplement vs. absorbable iron in certain diets.
For example, one could note that the RDA assumes 18% iron absorption,1 and that
ferrous sulfate is absorbed at about 3 to 6% in some studies.26,29 On that basis, one
could say that iron supplements must be given at three to six times the RDA to
provide an RDA-equivalent amount of absorbable iron. However, a flaw in this

thinking is that supplements are often given to iron-deficient subjects who can absorb
a higher percent of iron than normal. So, though it can be assumed that more iron
is needed with supplements than with a meat-containing diet, an exact quantitative
relationship cannot always be derived.
Since the ideal dose for iron supplementation may vary, iron supplements should
ideally be used under the supervision of a knowledgeable health care professional
team. In fact, a common theme in this section will be that iron supplementation
should be carried out under the monitoring and supervision of health professionals
such as physicians, dietitians, and, for community interventions, public health spe-
cialists. This may be the ideal approach for all mineral supplementation, but it is
especially important for iron for three reasons:
1. Maximal efficacy of iron supplements may require some trial and error
that needs to be monitored by tests that cannot generally be self-admin-
istered.
2. The margin for error for iron toxicity may be small and require monitoring.
3. For a number of health problems that can produce iron deficiency, the
handling of iron repletion can have major health consequences, even life
vs. death.
In many of the health problems associated with iron deficiency, the iron problem
requires a choice of how to deliver the iron (i.e., oral vs. parenteral), and what co-
treatments to use (e.g., other problems besides iron deficiency may co-exist).
Iron supplements are generally used for one of four general purposes (Table 4.1).
The first use in Table 4.1, treatment of iron deficiency anemia, is by far the most
common use of iron supplements when prescribed by health professionals. While
treating this anemic state, other effects can also occur. These effects could occur
because correcting anemia can also correct secondary symptoms due to the anemia.
In addition, the treatment of iron deficiency anemia can also treat symptoms of iron
deficiency that are not caused by anemia, but by coexisting impairments in iron
function.
The second use of iron supplements, prevention of anemia, is controversial and
is discussed below. The third use of iron supplements, treatment of marginal iron
deficiency, is also not settled, either in terms of what benefits can occur, or whether
diet changes are the better approach. The final use, therapy for problems that are
not solely a nutritional iron deficiency, have some basis, but are not all completely
confirmed.
TABLE 4.1
General Uses of Iron Supplements
Correction of iron deficiency anemia and coexisting deficiency symptoms
Prevention of iron deficiency anemia
Treatment of non-anemic iron depletion (marginal iron deficiency)
Therapy for problems not considered to be due solely to nutritional iron deficiency

TREATMENT AND PREVENTION OF ANEMIA IN INDIVIDUALS WITHOUT

OTHER DISCERNABLE HEALTH PROBLEMS
For a clinical setting, there is a fairly general consensus that oral iron supplements
are usually the appropriate corrective measure for iron deficiency anemia in the
absence of other major heath problems.56 The exact dose used can vary with cir-
cumstances, but doses as high as 300 mg can be found. In some cases, reversal of
anemia may require supplementation with other nutrients such as vitamin B12.57 In
all cases of anemia, outcomes should be monitored by a team of health professionals.
These professionals should also monitor general symptoms associated with anemia,
such as lethargy and poor work performance, since these symptoms may not be
entirely due to the anemia being treated.
Taking iron supplements to prevent anemia in susceptible individuals is more
controversial. There is evidence that moderate doses of iron supplementation can
reduce the frequency of anemia in certain populations of women.58–62 However, this
does not automatically mean that this approach is the best. One reason is that iron
supplementation, especially when self-prescribed, does not always prevent anemia
in every individual, or even in the majority of every group that has been stud-
ied.58,59,60,62 On the other hand, some would contend that in certain women, iron
supplementation is preferable to excess consumption of iron-rich meat products,
which may help promote obesity and cardiovascular disease. Others would dispute
this mind set. Along similar lines, some would contend that reliance on diet rather
than supplements for iron may improve intake of certain other nutrients. It could
also be argued that dietary approaches make iron toxicity less likely. Since the
dangers of even moderately high iron intake are getting considerable publicity, many
clinicians and public health specialists are leery of recommending widespread iron
supplementation in non-anemic people (for discussion of moderate iron toxicity, see
the Toxicity section below).
In this author’s opinion, iron supplementation may be the best option for pre-
venting anemia in some, but not all, people. This author feels that this decision
should be made by individuals in consultation with physicians and dietitians.
COMMUNITY INTERVENTIONS FOR ANEMIA TREATMENT AND

PREVENTION
Anemia on a large-scale level can not only affect an individual’s health, but also
impact a community’s productivity. Symptoms such as lethargy and reduced work
capacity in adults, and impaired cognitive development in children, can impact a
community’s economic growth.63 In addition, widespread anemia contributes to
health care burdens on a community. In communities in many parts of the world,
iron intake is clearly inadequate in a large percentage of people. In some cases,
encouraging and educating the people about a dietary approach to this problem may
make the best sense. This contention is supported by a study of Australian iron-
deficient, premenopausal women.64 In this study, although a high-iron diet produces
smaller increases in serum ferritin than iron supplementation, the former gives better
continued improvements in iron status during a six-month follow-up. This may mean

that individuals in Australia, when left to themselves, are more apt to sustain a
dietary philosophy than persist with iron supplementation. Still, this pattern may not
hold for all subjects in all circumstances.
In other cases, due to the economy, culture, or food supply, an iron deficiency
problem cannot easily be fixed just by admonishing people to eat more of the best
natural iron food sources. In these cases, it is more practical to consider community
interventions that increase iron intake via either supplements or fortified foods. In
some senses, food fortification is a form of supplementation, but the public health
strategy has some differences. Food fortification has been successful at reducing
iron deficiency rates in a number of places in the world.65 Whether food fortification
or supplements are used to combat iron deficiency, there may also be the need to
confront other dietary contributors to anemia, as well as non-dietary contributors
such as intestinal parasites like hookworm.47
If supplementation or food fortification is being considered for a community, be
it an entire country or a country subsection, many factors need to be considered.
These details are beyond the scope of this book, but it can be noted the details
include the economics and politics of supplying the supplement or food fortification.
Another consideration is whether specific subgroups within a community are being
targeted, such as pregnant women or certain aged children. Another concern is
whether the goal is correction of an existing problem or simply producing a modest
rise in iron intake. The former situation may require supplements, since food forti-
fication typically supplies far less iron per serving than a supplement. Another issue
is considering treatment of non-nutritional contributions to iron deficiency such as
hookworm.66
Another issue for large-scale iron supplementation programs is daily supple-
mentation versus once-a-week supplementation. This issue is not settled. The
best answer may depend on the specific circumstances involved, and in some
cases, both may work equally well. One concern had been the possibility that
the body may not absorb the large weekly doses as well as the smaller daily
doses. In reality, in the long run, though not always in the short run, the weekly
approach seems to affect iron status about the same or just slightly better than
the daily approach.60,67,68,69 GI tract side effects could be a concern in choosing
between the daily or weekly approaches, but the tendencies are not clear. For
example, in one study, GI tract upsets occur with both daily and weekly
approaches, but the incidence is higher with the weekly approach.70 In another
study, the pattern is the opposite.60 Despite the opposite observations on side
effects, both studies find that compliance is better with the weekly approach. A
possible explanation is that the weekly approach requires less effort by the
subjects. In fact, this better compliance may explain why, in some studies, the
weekly dose has a slightly better effect than the daily dose. At present, there is
no consensus on the best approach, but practical issues such as product distribu-
tion and economics may become prime concerns. In addition, there has been
some consideration of compromise approaches, such as twice weekly.

PREMATURE/LOW BIRTH WEIGHT INFANTS

Iron deficiency occurs commonly in early childhood following premature birth or
an otherwise extremely low weight birth.54,55 The prevalence of iron deficiency is
even higher if cerebral palsy is also present.54
The reasons for the iron deficiency could have to do with existing conditions in
the mother, such as severe iron deficiency or diabetes.55 However, iron deficiency
in these children can also have other causes.54,55 One has to do with limited storage
of iron, which normally is accelerated in the three months before birth. A premature
infant doesn’t have much, if any, of this storage period. Another problem can be due
to the large number of blood draws required during their hospitalizations. In addition,
in the months that follow birth, infants who were very low birth weight can have
an accelerated “catch up” growth period that increases iron needs.71,72 These factors
make iron deficiency a concern in these children, though sometimes over-treatment
with iron or blood transfusions can actually put the children at risk for iron over-
load.55 These children are very vulnerable to that problem because their capacities
for low iron-binding proteins and antioxidant systems are well below those of normal
adults.
Treatments for anemia in premature or low-birth-weight infants can vary at
different stages for the first year postbirth. Treatments can include blood cell trans-
fusions, human recombinant erythropoietin administration, iron fortification of
mother’s milk or formula, and parenteral iron (especially as iron dextran). The
optimal procedure is not yet universally agreed upon and may actually vary for
different individuals. For these reasons, treatment should be carried out by health
care providers with specialized experience in this area. This is still an area where
more research could be used.
One question that sometimes arises is whether non-anemic, marginally iron-
deficient low-birth-weight infants could benefit from increased iron intake. This area
has not been researched extensively. One study in Australia concludes that in
extremely low-birth-weight infants without cerebral palsy, non-anemia iron defi-
ciency does not impair development or affect behavior.54 However, since this issue
can be examined with many different design details, one study cannot be the final
word on the subject.
RENAL DIALYSIS PATIENTS

In end stage renal disease, where subjects are undergoing hemodialysis or peritoneal
dialysis, iron deficiency is often a problem.73 The causes include poor iron absorp-
tion, increased iron needs due to red blood cell production in response to erythro-
poietin administration, and various causes of blood losses.74,73 Clinical care typically
includes measures to prevent iron deficiency as well as monitoring for overt iron
deficiency, which is then promptly treated. Common treatments are erythropoietin
therapy and iron administration as either oral supplements or parenteral iron. The
decision on the latter choice is best left to specialists, who consider several factors.75
Among the considerations are the low expense and usual safety of most oral iron
supplementation plans. On the other hand, oral supplementation can be limited by

poor patient compliance (dialysis patients are notorious for not complying with self-
administered health interventions). In addition, low intestinal absorption of oral iron
by renal patients may limit oral supplement effectiveness.74 Intravenous iron
bypasses the absorption and compliance problems, but there can be a small risk of
allergic reactions.
Some concern has been expressed about the possibility that chronic iron may
increase infections in renal patients.76,77 Although iron can strengthen immune func-
tion, there is also the possibility that it can boost the growth of infectious organisms.
Indeed, in experimental animals, iron injections can lead to increased susceptibility
to bacterial infection.76 In addition, there are clinical studies in renal patients showing
an association between high serum ferritin levels and increased infectious risk,76,77
but this could be an effect of infection rather than a cause.76
Some physicians take the position that since we know that iron helps renal
patients in some ways, and can only speculate that iron could be problematic for
infections, priority should be given to what we know. A similar sentiment is
expressed in a review article that, after reviewing the background research, states:
“There is no reason to alter current iron treatment strategies based on this literature.”76
Another concern about iron administration, either by oral supplement or
parenteral administration, is increased oxidant stress, which in turn increases risk
for cardiovascular disease. The whole issue of iron intake, oxidant stress, and
cardiovascular disease risk is still controversial (see the Toxicity section). Thus, as
with the infection issue, the attitude could be that iron, which is known to be helpful
for renal dialysis patients, should not be withheld due to a risk that is speculative.
In fact, in dialysis patients, anemia itself can be a risk factor for cardiac disease.78,79
Nonetheless, this is an area that could certainly use more research.
CANCER PATIENTS
Anemia in cancer may be secondary to blood loss, displacement of normal bone
marrow cells by malignant cells, myelotoxic therapy, or the tumor itself.80 It can
also be speculated that poor iron status prior to cancer onset or initiation of cancer
therapy may be a factor in anemia incidence. A recent review article81 notes that
cancer-related anemia has detrimental effects on quality of life, adds the risk and
inconvenience of blood transfusions, and may be associated with decreased survival
or time to progression. Even so, this article also notes a high percentage of U.S.
cancer patients have anemia, but are not treated adequately for this condition. The
most common treatments for cancer-related anemia are iron supplementation, blood
transfusion, and recombinant human erythropoietin. In addition, another erythropoi-
etic agent, darbepoetin alfa (Aranesp), has been gaining attention for use in this
context.82 Future research would be useful to clarify the benefits vs. risks, if any, of
treating cancer-related anemia, and the best approach for various circumstances.
THE ELDERLY
The elderly can be at risk for iron deficiency due to low iron intake, blood loss,
chronic disease, and, occasionally, unknown reasons.49 In some cases, anemia can

be mild but, if untreated, can contribute to increased mortality, poor health, fatigue,
and functional dependence, as well as increased risk of cardiovascular or neurolog-
ical problems.49 As a first step, elderly patients with iron deficiency should undergo
endoscopic examination, because if the reason for the anemia is GI blood loss, then
that condition should be the first concern.50,52 In the opinion of some experts,83 the
endoscopic exam should be done not just when there are very low hemoglobin
values, but if there are any blood test signs of iron deficiency (even without a positive
result in a fecal occult blood test).
Once blood loss is ruled out, iron supplementation is often a prime treatment
for anemia in the elderly, just as it is for anemia at other ages. One study of U.S.
rural elderly home-delivered-meals recipients finds iron deficiency to be more com-
mon in elderly females than in elderly males.50 This finding occurs despite a similar
low dietary iron intake in both genders. The authors interpret this finding to result
from lifelong poorer iron status in the women compared to the men.
As with other age groups, there is concern about excess iron promoting increase
risk of cardiovascular disease. One study along these lines is mentioned below in
the Toxicity section.84 However, as already stated for other situations, it would seem
to make sense to treat anemia, when diagnosed, rather than withhold treatment for
speculative reasons. On the other hand, it would seem prudent to monitor iron status
in the elderly and not give more iron than is needed to restore and maintain good
iron status.
IRON DEFICIENCY WITHOUT ANEMIA

This is a topic that is still very unsettled. In this author’s opinion, there is evidence
for concern, but the exact range of consequences is far from clear. This issue badly
needs more large-scale studies. As consequences are clarified, the next questions is:
“Should supplements or diet be used to treat this state?” For research purposes,
supplement studies make for cleaner result interpretation. For human health purposes,
there may not be one right answer for everyone. The answer may depend on how
much iron intake has to be boosted to obtain adequate iron status. If the amount is not
too great, then diet may be the best course. If a person has very high iron needs, such
as a woman with very high menstrual blood losses, a supplement approach may be
better. That philosophy is already used widely for anemia prevention in women with
very high menstrual blood losses. In addition, in one study of non-anemic, iron-
deficient women, Ferrochel® supplementation makes a bigger impact on iron status
than does diet counseling to improve iron intake and absorption.85
For research purposes, iron deficiency without anemia, which can also be called
non-anemia iron deficiency or marginal iron deficiency, has sometimes been based
on a serum ferritin below 16 µg/L. This value is derived largely from a study of
over 200 women (mean age 38) with known iron status based on absence or presence
of stainable iron in bone marrow smears.86 In addition, marginal iron deficiency has
also been shown to be reflected by serum transferrin receptor concentrations. For
example, iron supplementation decreases these values in premenopausal female
subjects having iron depletion without anemia (hemoglobin > 120 g/L and serum
ferritin < 16 µg/L).87

From a biochemical standpoint, marginal iron deficiency without anemia could

conceivably affect iron’s non-hemoglobin-related functions in energy release, iron’s
non-anemia-related impacts on immune function, and iron antioxidant actions. The
latter would include iron’s role in the enzyme catalase, and possible iron protection
against inactivation of non-iron antioxidant enzymes. The energy-related biochem-
ical impairments could have general health consequences, such as impaired growth,
reduced aerobic exertion capacities, reduced energy for non-strenuous tasks, negative
effects on children’s cognitive development, and pregnancy outcome impacts.
Some of these possible consequences will be considered in this subsection, while
pregnancy, childhood cognitive development, immune function, and exercise per-
formance will be considered in their own subsections below. In the subsections,
these topics are discussed in view of both anemia and non-anemia iron deficiency.
In very limited study, antioxidant function has not seemed to be improved by
iron supplementation of marginally iron-deficient, college-aged females. In one
study,88 oxidative damage, as indicated by protein carbonyl and lipid hydroperoxide
concentrations, is not altered by eight weeks of iron supplementation despite
improved measures of iron status. In another study,89 selenium-related antioxidant
enzymes are not improved by iron supplementation of marginally iron-deficient
subjects. Iron deficiency anemia had been shown to alter erythrocyte activities of
non-iron metalloenzymes with antioxidant function, though the exact effect is incon-
sistent. There can be an increase, a decrease, or no change in different studies in
different circumstances.90,91,92 These effects may have to do with dietary factors other
than iron and anemia effects on blood cell life span and metabolism. More work
could be done in this area, especially with other types of assessments, as well as
with other types of subjects, including those prone to high degrees of oxidant stress.
Another issue for marginal iron deficiency is identifying what effects, if any, it
has on symptoms that might be called “general feelings” and “general performance.”
More severe iron deficiency, when accompanied by anemia, is known to be associated
with these types of symptoms including lethargy, low energy for daily non-strenuous
tasks, and reduced work capacity.3,93,94 Less is known about the same symptoms in
regard to iron deficiency without anemia. One review of a series of studies on such
topics concludes that what is termed “energetic efficiency” is affected at all levels
of iron deficiency, including that without anemia.93 The expression “energetic effi-
ciency” refers to the energy expended for a given work output. The expression can
be used in the context of exercise performance (e.g., on a treadmill), or in the context
of an occupational task or productivity. There have been studies tying both contexts
to iron status, including non-anemia iron deficiency.93 Even so, more research would
certainly be helpful.
There is also one study suggesting that non-anemic iron deficiency can impact
cognitive function, particularly in the area of attention retention, for dieting, obese
women.95 This contention is based on inverse correlations between evaluations of
cognitive function and values for iron status indicators. The values for iron status
indicators seem to indicate iron deficiency can occur in obese women despite iron
intakes that would normally be considered adequate. It would be interesting to see
follow-up studies assessing cognitive function after iron supplementation.

The subject of growth in children with non-anemia iron deficiency is another

under-investigated area. Some studies have found iron supplementation in the
absence of anemia to actually stunt growth.96 In contrast, a study of weekly iron
supplementation of non-anemic school-aged children shows no negative effect on
growth, while having a positive effect in preventing significant decreases in hemo-
globin concentration.97 Thus, this whole area needs more research.
PREGNANCY
There are four questions regarding iron supplementation and pregnancy:
1. Should iron supplements be given to women who are anemic at the onset
of pregnancy, as well as to those who become anemic during pregnancy?
2. Since iron needs rise during pregnancy, should iron supplements be given
to prevent anemia in women who are not anemic at pregnancy onset?
3. If a woman is iron deficient, but not anemic, is there any benefit to iron
supplementation besides possibly preventing later anemia development?
4. Is there any value to iron supplementation during pregnancy beyond
correcting or preventing any deficiency?
For the first question, supplements effectively treat anemia in supervised studies,
but are not always effective in clinical practices.62 Possible reasons for the latter
include insufficient dose and time of supplementation and poor adherence.62 There
has been debate as to the best dose, timing, and mode of administration. Another
area of uncertainty is the full range of consequences of not treating iron deficiency
anemia, especially in terms of maternal mortality, risk of preterm delivery, as well
as the impact on iron stores of full-term offspring.98,99 In regard to the last area,
recent data suggests that maternal iron status does influence iron status of the
offspring for the first year of life.100 In another research area, some, but not all, data
is consistent with anemia causing increased risks of maternal and child mortality,
premature labor, and low birth weight.98,101 However, the “gold standard” studies,
iron supplementation effects on these problems, have not consistently shown
improvements in birth weight or avoidance of preterm labor.101,102,103 Still, it should
be noted that the number of studies that clearly evaluate these issues for iron
supplementation are not especially numerous. Moreover, for iron supplement effects
on birth weight or the duration of gestation, one review claims that most studies
have a bias toward false-negative findings.101 Thus, this area is still not clear and is
difficult to evaluate due to ethical considerations.
The second question is even more controversial. Groups such as the World Health
Organization recommend iron supplementation for all pregnant women, while other
groups advocate iron supplements only with diagnosed anemia. A compromise
between the two is stated in one review article99 as follows:
“In industrialized countries, iron supplements should be prescribed for pregnant
women in the third trimester, when the need for iron is prominent. In developing
countries, supplementation should be initiated as soon as possible after conception

because of the high prevalence of iron deficiency at the onset of pregnancy.” Which,
if any, of these recommendations is the best option is still open to debate.
There are reasons to be wary of a general recommendation of iron supplemen-
tation for all pregnant women. Iron supplements during pregnancy can cause GI
tract problems such as nausea and constipation,70,104 though the latter can sometimes
be inhibited by stool softeners or high-fiber diets. In addition, iron supplementation,
if too high, can inhibit absorption of zinc (see the Toxicity section). This is a concern
because zinc is an important nutrient for pregnant women.105 Another concern for
extremely high-dose iron supplementation is that it can cause iron poisoning in the
child.106
One compromise approach to this issue is routine use of a low-dose iron sup-
plement. A trial in Australia of 20 mg iron/day (as ferrous sulfate) reduces the rate
of anemia in pregnant women, though it does not totally prevent it.107 The dose used
is too low to be expected to hinder zinc absorption or pose a toxicity threat to the
child.
The third and fourth questions, correction of non-anemia iron deficiency and
effects beyond correcting any deficiency, have received almost no real direct
research. There is one study that seems to mix the third question with the fourth
question.108 This work, which was done in the U.S., examines pregnant women who
are initially iron-replete and non-anemic. The work involves giving a daily iron
supplement (30 mg as ferrous sulfate) or placebo from early pregnancy to week 28
of gestation. At 28 and 38 weeks of gestation, women with a ferritin concentration
of 12 to 20 g/L or < 12 g/L receive 30 or 60 mg iron/day, respectively, regardless
of initial assignment. Compared with placebo, iron supplementation from enrollment
to 28 weeks of gestation does not affect the overall prevalence of anemia or the
incidence of preterm births, but leads to a significantly higher mean birth weight, a
significantly lower incidence of low-birth-weight infants, and a significantly lower
incidence of preterm low-birth-weight infants. One possible explanation is better
transfer of iron to the baby despite not necessarily improving the mother’s iron
status. The birth-weight effect was rather large compared to some other studies on
iron and birth weight.109 Part of this may be due to the early initiation of supple-
mentation in the recent study.108 In addition, this recent study may have been more
poised to see big effects due to the study population. This population may have had
a high inclusion rate of subjects who are not extremely malnourished, but who have
high risks for variations in birth weights. This study is very interesting, but does not
have a large subject number for a pregnancy outcome study. Follow-up studies would
prove to be very interesting.
In conclusion, details about the use of iron supplements in pregnancy are still
controversial, and the research that can be done has ethical limitations. In this author’s
opinion, until more information is gathered, a modest-dose iron supplement throughout
pregnancy, combined with good intake of other micronutrients, seems safe and possibly
helpful. In light of the above-mentioned questions about iron absorption from multi-
supplements, it may be helpful to combine a standalone iron supplement with a non-
iron-containing multi-supplement such as One-A-Day For Men. Taking these two
supplements at different times of day may also be helpful since, as noted in the toxicity

section, separating iron supplements from zinc ingestion may reduce the negative
interactions. Although the iron-free multi-supplement may not provide 100% of preg-
nancy RDAs for most micronutrients, it should help meet many of the pregnant
woman’s needs. Many clinicians would disagree with this approach to pregnancy
supplementation, but it is offered up to start discussions.
COGNITIVE AND BEHAVIORAL DEVELOPMENT

Anemia in children seems likely to be associated with impaired cognitive function,
but the picture is not completely clear. A review on this topic110 states that most
correlational studies find associations between iron deficiency anemia and poor
cognitive development, as well as motor development and behavioral problems. The
review further states that longitudinal studies consistently indicate that children
anemic in infancy continue to have poorer cognition and school achievement, and
more behavior problems into middle childhood. On the other hand, the review also
states that the results of some of these studies may be confounded by poor socio-
economic backgrounds, and further notes that in anemic children under 2 years old,
short-term trials of iron treatment have generally failed to benefit development. In
addition, most longer trials are said to lack randomized placebo groups and fail to
produce benefits.
In contrast to the concern about socioeconomic confounders in the survey stud-
ies, two recent studies in the U.S. seem to have less problem with that issue. In one
of the studies, a logistic regression analysis associates anemia with increased like-
lihood of mild to moderate mental retardation independent of birth weight, maternal
education, sex, race–ethnicity, the mother’s age, or the child’s age at entry into the
social program used for the study.111 In addition, analysis of data from the broad-
based National Health and Nutrition Examination Survey III shows lower standard-
ized math scores for iron-deficient school-aged children and adolescents, including
those with iron deficiency without anemia.112
Despite the above-mentioned, legitimate concerns about studies on iron status
effects on cognitive and behavioral development, there are definitely some studies
that show effects of iron supplementation. A number of the older studies are sum-
marized in a paper that dwells more on the common message of several studies than
on the design limitations.113 In addition, there are some newer studies that were
published after the above-mentioned review110 that noted many design limitations
in this research area. In one of these newer studies,114 iron supplements are tested
beginning at six months in full-term, anemia-free Chilean infants. The results suggest
that unsupplemented infants respond less positively to the physical and social envi-
ronment and process information more slowly. The benefits may not be limited
strictly to anemia prevention, though the study does not extensively explore this
issue. In another study,115 which was done in Indonesia, iron supplementation is
examined in children aged 6 to 60 months. No effect is seen for the whole group,
but when supplementation is started by 18 months of age (n = 73), the supplemented
children perform better than control children on the Sternberg test of working
memory.

This last study suggests that in at least some settings, iron depletion and repletion
has an effect on early development that can’t be duplicated later. However, there are
also studies that indicate that later iron supplementation could still have other effects
on cognitive and behavioral development. For example, in another study done in
Indonesia, an iron supplement study in 3- to 6–year-olds finds that iron deficiency
anemia alters cognitive processes related to visual attention and concept acquisi-
tion.116 In still another study in Indonesia, iron supplementation of iron-deficient
anemic children improves school achievement test scores.117 In addition, positive
results for cognition are reported by a review of four studies in India on iron
supplementation in anemic schoolchildren up to 15 years old.118
There are also a few studies in non-anemia iron deficiency that show benefits
of iron supplementation. In one such study in a U.S. urban population,119 iron
supplementation in adolescent girls improves verbal learning and memory. Another
study120 examines non-anemic infants, 9 to 12 months old, with varying degrees of
iron deficiency. In this study, iron supplementation impacts Mental Development
Index scores. No effect is seen for infants in good iron status. This is a rather old
study, which gets cited a lot. It would be good to see if the general results could be
confirmed by other studies.
There is also a non-placebo-controlled study of iron supplementation of non-
anemic children with attention deficit hyperactivity disorder.121 The supplementation
produces a significant decrease on the parents’ Connors Rating Scale scores. Some
people refer to this work as a study of non-anemic iron-deficient children, but the
mean ferritin values are higher than those typically used to define that state. Thus,
the iron could be having a pharmacological effect, possibly on dopaminergic activity,
rather than correcting a nutritional deficiency. Another explanation is that the parents’
evaluation reflects wishful thinking. This is possible since there is no placebo control,
and the iron does not affect blood parameters or teachers’ scores on the rating scale.
In conclusion, severe iron deficiency early in life likely has detrimental effects
on cognitive and behavioral development, though the benefits of iron intervention,
especially in terms of optimal starting age, are not fully clear. There may be cognitive
benefits of treating iron deficiency, with or without anemia, later in childhood and
adolescence, but there is hardly a wealth of studies in this area either. Still, it makes
sense to try to treat or prevent iron deficiency in all ages of all children.
INFECTIONS
It is beyond argument that iron affects immune function.122 However, there are
arguments concerning the particulars of the relationship of iron to infection occur-
rence. One of these issues is when to be concerned about too much iron intake
promoting infection. Part of this concern is based on the idea that microbes them-
selves have a strong need for iron.123 In fact, the depression in serum iron that occurs
with infections has long been speculated to give a host advantage by restricting
microbe access to iron.123 Thus, it is theoretically possible that high intakes of iron
could have negative effects on host defense.
Along these lines, there are human and animal studies associating parenteral
iron with increased infection risk,124 though in some cases, this may be due to

contaminated administration instruments, and not the iron. There have also been
studies reporting that iron supplementation increases the risk of malaria attack and
morbidity, though other studies do not confirm this.125 Statistical analysis across
these studies does not necessarily give a strong case for the idea that iron supple-
mentation promotes poor resistance to malaria.126 In addition, the assessments criteria
used in these studies has not always been precise. Even so, the studies raise the
possibility of some connection between high iron intake and high malaria risk. This
is problematic because malaria may cause anemia in some cases,127 which makes it
gray as to whether iron should be given during malaria. To complicate the matter
further, there are writings proposing that in some cases, iron supplementation can
actually help with malaria treatment by boosting immune function.128 However, some
review articles dispute this concept by saying that there are no clear demonstrations
that iron supplementation helps recovery from, or prevention of, malaria.125 The
whole area of iron and malaria could use more research.
Another approach to considering whether iron supplements can promote infections
is a recent systematic review of 28 past randomized controlled trials of children.126
These trials deal with infection rate responses to oral or parenteral iron supplementa-
tion, or to fortification of formula, milk, or cereals. The studies vary considerably in
terms of what types of children are studied (variations in age, degree of overall nutrition
intake quality, etc.). The studies also vary in terms of the types of infections (some
include malaria, some are not from areas of the world where malaria occurs). The
conclusion of the review is that iron supplementation has no apparent harmful effect
on the overall incidence of infectious illnesses in children. However, that conclusion
does not rule out that specific supplement regimens in specific circumstances could
have deleterious effects on resistance to certain infections.
On the opposite side of the issue, there are studies on iron deficiency and
increased risk of infections. For example, a recent study in Israel has examined the
association between iron deficiency anemia and the frequency of recurrent acute
otitis media (ear infections) in 680 children.129 The paper concludes that anemic
children have higher prevalence of episodes of acute otitis media in comparison to
healthy, non-anemic children, and shows that there is a direct relationship between
the degree of the anemia and the number of the episodes. However, not all studies
on iron supplementation and infection incidence are clear cut. For example, there
is not a clear protective effect of iron supplementation on overall infection rates in
the above-noted systematic review on the safety of iron supplements in regard to
infections.126 Thus, more research can be done to identify the circumstances where
iron deficiency affects infection risk.
Another area that could use more research is how iron depletion effects on
laboratory immune assessments relate to iron supplementation effects on resistance
to infections. This area is difficult to study because in many settings, iron deficiency
does not occur in isolation from other nutrient deficiencies that can affect immune
function. A recent review article125 states the case well in saying: “Iron deficiency
is associated with reversible abnormalities of immune function, but it is difficult to
demonstrate the severity and relevance of these in observational studies.” Another
review article declares that data on the relationship between iron deficiency and
infection is conflicting.42 There are some reports of food iron or supplements

reducing infections in children in developing countries, but there are also reports of
no effect.42,126 A recent study along these lines was done in western Kenya.130 Iron
supplementation has no effect on reinfection with intestinal helminths and Schisto-
soma mansoni reports in children or adults. However, one limitation of this study
is that the iron status of the subjects is not restricted to a narrow range.
Surprisingly, there are not a lot of recent human studies on iron supplementation
and immune function. In one exception, in a study done with children in Sri Lanka,
iron supplementation improves iron status and reduces morbidity from recurrent
respiratory tract infections.131 Only half the children in the study were anemic, which
raises the question of whether the iron supplements helped children with non-anemic
iron deficiency. In contrast, in a study in Bangladesh, iron supplements had no effect
on attack incidence or duration for diarrhea, dysentery, and acute respiratory tract
infections.132 Thus, there is no real strong basis for definitive statements on iron
supplementation and reduction of infection incidence.
In conclusion, based on cellular tests of iron status and immunity, iron deficiency
can impair immune capacity. This means that correcting iron deficiency should
impact resistance to infection, though demonstration of this concept has not been
as strong as would be hoped. On the other end of the spectrum, iron supplements
may sometimes increase the risk of problems with infections, but exactly when this
is and is not a problem has not been well clarified.
EXERCISE PERFORMANCE
This area of research has been applied to both trained athletes and non-athletes.
Athletes will be discussed here first. Trained athletes can often present with blood
readings for hemoglobin or hematocrit that are consistent with anemia. This may or
may not actually be indicative of anemia. In some cases, athletes involved in exten-
sive endurance training can adapt to their training with a blood hemodilution effect
(the blood accumulates a relatively high amount of water).1 This gives the appearance
of low hemoglobin in a blood test, but in reality, the total hemoglobin may not be
low. By analogy, one cup of orange juice can be diluted with one cup of water,
which would halve the concentration of vitamin C per cup. However, the total vitamin
C would not change.
This type of situation is sometimes called sports anemia, though others use this
term to connote actual anemia in athletes. Some types of athletes can be prone to
actual anemia for a number of reasons. One reason is simply that some athletes are
females who are adolescents or young adults. This population is prone to anemia
whether they are athletes or not. In addition, low body iron levels can develop in
either gender due to mechanical hemolysis, GI blood loss, hematuria (blood in the
urine), other causes of high urinary iron, sweating, low iron intake, or poor intestinal
absorption.133 The relative contribution of any of these factors to iron status can be
debated. For example, one article134 argues that the sweat and urine losses are
negligible, but that there could be effects of increased rates of red cell iron and
whole-body iron turnover. The latter could be due in part to increased GI blood loss,
which has been observed in male runners.135 In these subjects, iron supplementation
improves values for indicators of iron status.

A number of studies have shown that anemia and non-anemia iron deficiency can
occur with some frequency in endurance athletes.133 Although female athletes may be
more prone to iron deficiency than male athletes, males are not exempt, especially
adolescent boys. For example, one study136 reports that in boys, endurance training
brings about a significant decrease in serum ferritin and iron stores. Moreover, anemia
is found in 10 to 15% of the subjects studied. Another study,137 of adolescent Israel
gymnasts of both genders, shows results indicating that they are prone to non-anemia
iron deficiency. Although the problem is more prevalent in the girls, it is reported for
both genders. In another study, 138 non-anemia iron deficiency is reported as common
in a group of adolescent runners. In this study, iron deficiency is more common in
females, but 20% of the males show iron depletion by the close of their season. This
suggests that preseason screening alone is not adequate for detecting iron deficiency in
athletes.
The logical question to ask is: Does correcting iron deficiency improve exercise or
physical training performance in athletics? The use of training performance as an end
point is easier than using sports performance, which would involve skill issues. When
anemia is present, even if it is mild, iron supplementation seems to help performance.133
As far as correcting non-anemia iron deficiency, there have been some conflicting results
in studying athletes.133 However, it is not surprising that the results in this area are not
totally consistent. The results in studies of exercise performance in general, even if well
designed, can be different for the different circumstances. In addition, for some specific
studies of iron supplementation in non-anemia iron deficiency, design limitations may
have been a problem. For example, some studies showing negative results may have had
mixtures of marginally iron-deficient and non-deficient subjects. Moreover, one study139
uses a mixed mineral supplement, which, as noted above, may not always provide as
much bioavailable iron as anticipated. In this study of the mixed supplement, there is
no improvement of values for iron status indicators.
Another important consideration for these studies of iron supplementation is
what is actually measured. Several of the positive result studies, which are discussed
below, note that not all of their assessments give the positive results. Possibly, in
the studies that give negative results, different assessments would have given positive
results. In addition, as noted in a review article,133 not all studies have used one of
the best choices for type of iron supplement, some have used doses that are low
compared to the usual treatments for iron deficiency, some have not controlled for
supplement timing and co-ingestion of foods that reduce iron absorption, some
treatment periods are possibly too short, and the use of serum ferritin to monitor
changes in iron status could be affected by inflammation responses to training or
hemodilution. Another issue is that some studies with negative results did not use
many subjects (though the same criticism can be made for some of the positive result
studies). Finally, maximal iron improvement of exercise performance, since it
involves better energy release, likely requires sufficient intake of calories, which
may not always be a “given” in these studies. This point is supported by a study of
iron and calorie supplementation in women in India.140 In this study, combined
energy and iron deficits have a greater adverse effect on physical work capacity than
energy or iron deficits alone. Although this study involves anemic subjects, the
general idea could also apply to marginal iron deficiency.

TABLE 4.2
Positive Impact of Iron Supplements on Exercise Performance in Non-
Anemia Iron Deficiency
Subject Type Key Finding
Runners Treadmill endurance times improve141

Teenaged/young adult elite athletes Increased maximal aerobic capacity142
Postcollege-aged young adult women Improved muscle fatigability (resistance exercise)143
Untrained women Enhanced aerobic adaptation to training87
Young adult women Increased energetic efficiency144
A number of positive findings for iron supplementation and exercise performance

in marginal iron deficiency have come forth. These findings are summarized in Table
4.2. As mentioned above, many of these studies report that iron supplementation
effects do not occur for all the parameters considered in the study.
There are a few other studies that could be put in Table 4.2. Two are excluded
because the severity of iron deficiency of the subjects is unclear, and in another case,
the assessments are subjective and have no placebo control.
It is worth mentioning that in the first study of Table 4.2,141 though the subject
number is not large, all but one iron-supplemented subject show improvement, while
the placebo group shows loss of endurance.
This research area of iron supplementation and exercise performance in non-
anemia iron deficiency can still hardly be called clear. Even so, this author feels that
in light of some questions about the negative studies, and the existence of positive
findings, iron supplements likely enhance some aspects of exercise performance is
some people with non-anemia iron deficiency. More research is definitely needed,
especially for non-athletes, who have not been studied extensively in this area.
MISCELLANEOUS HEALTH PROBLEMS

Iron supplementation has been used with some apparent success for a number of
health problems listed below:
• Restless leg syndrome

• Plummer-Vinson syndrome
• Breath-holding spells in children
• Obesity
• Goiter treatment (iron co-administered with iodine)
The first condition, restless leg syndrome, is a description of a symptom that

can have a number of precipitating causes.54,145 Often, the best approach to treating
this problem is to deal with a primary health condition that causes this symptom.54
As far as iron and restless leg syndrome, it does appear that some, but not all, people
with the problem are iron deficient based on blood measurements.146,147,148 A simple
approach to iron supplementation for people with restless leg syndrome is to only

give iron to people with blood measurement signs of iron deficiency. There are
studies to support this approach. For example, there is a report that iron supplemen-
tation improves symptoms only in subjects with low ferritin.149 Similarly, another
study finds no iron supplement-induced improvement of symptoms in the whole
study group, but finds that responders show an increase in iron saturation values.150
However, there is some indication that iron metabolism can be abnormal during
restless leg syndrome. In one study, though serum values for iron status are not
abnormal, cerebral spinal fluid values are.147 In another study, autopsied brain tissue
from seven subjects who had restless leg syndrome shows low iron and tranferrin
receptors in certain types of brain cells.151 These two studies suggest the presence
of a defect in iron transport in certain neurological tissue. The next question is
whether high-dose iron could help some people by forcing iron into brain cells
despite the transport defect. This is not yet established. Moreover, safety issues mean
that such treatments may not be ideal, especially since there are other pharmaco-
logical and behavioral treatments available (though some have side effects).152 Per-
haps, new treatments can be developed to specifically overcome the iron transport
defect.
In this author’s opinion, at present, it seems prudent to try iron for this condition
if there is evidence of iron deficiency, since that should be corrected anyway. If iron
deficiency is not present, then low-dose iron supplements may not help and high-
dose supplementation carries risk, plus its efficacy is uncertain. In that case, a
decision should be made by individual subjects with their physician.
In the case of Plummer-Vinson syndrome, a condition where there is difficulty
swallowing and web-like tissue membranes in the lower throat, the primary lesion
may or may not involve iron deficiency. One review has contended that decreased
incidence of Plummer-Vinson disease has been related to iron dietary intake and
supplementation.153 However, not everyone in this medical area is convinced that
iron deficiency is a prime cause of this problem. Obviously, the vast majority of
people who are iron deficient do not develop this condition. Still, it is possible that
iron deficiency plus some other circumstances are the root causes. It is also possible
that the syndrome does not need iron deficiency to develop, but the lesion, especially
if there is blood loss, can cause iron deficiency anemia, which can then worsen the
symptoms.154 Whether or not iron deficiency is part of the prime cause, it does seem
that iron supplementation can correct the anemia that is often present, and in at least
some subjects, drastically reverse symptoms.154–157 However, if the lesion is far
advanced, physical interventions may be necessary.157
In some children, iron deficiency anemia can be associated with breath holding,
possibly due to a problem in regulating autonomic nervous system reflexes.158,159 A
number of studies find that giving iron supplements reduces the incidence of breath
holding in subjects with anemia.159–162 An interesting question is whether the iron
effect is due to eliminating anemia or eliminating another iron function impairment
that co-exists with the anemia. The latter idea is supported by a case study, though
it involves only one subject.163 In this subject, the breath-holding spells resolve before
the anemia is completely eliminated. To this author’s knowledge, there is no evidence
that iron supplements will help breath holding in subjects who are not iron deficient.

In fact, one study argues that the subjects most apt to be helped by iron supplemen-
tation are those with iron deficiency.160
A relationship of iron to weight loss in overweight people has a theoretical basis.
Iron status affects thyroid function,164 and thyroid function can affect weight loss.165
In fact, iron deficiency has been associated with impaired thermoregulation.166 There
is one study167 where obese women on a very-low-calorie diet maintain better
circulating thyroid hormone levels if supplemented with iron. The supplemented
women lose more weight on average, but the difference is not statistically significant.
Still, there is indication that the most weight was lost by women whose iron status
and thyroid hormone levels were maintained the best. In any case, this whole area
is still in the very speculative stage of research.
In terms of goiter, in some countries of Africa, many children are at high risk
for both iodine deficiency-induced goiter and iron deficiency anemia. Since iron
deficiency can impair thyroid metabolism,164 in theory, iron supplements can com-
plement iodine effects on thyroid function. This possibility is supported by a study
where goiter shrinkage by iodized salt is enhanced by also adding iron to the salt.168
TOXICITY
Ironically (no pun intended), alongside the big concern for iron deficiency, there is
also a big concern from the toxicity standpoint. There are a number of different
implications that come up in this regard (Table 4.3).
Prominent symptoms of iron toxicity, such as organ damage and death, can be
associated with the genetic condition hemochromatosis and repeated blood transfu-
sions.1 The latter occurs because iron bypasses the body’s best defense against iron
toxicity, namely using ferritin to block iron absorption from the GI tract. The former
becomes problematic due to high absorption of iron. The typical treatment for the
genetic condition is regular blood withdrawals.1 In other cases of iron overload, the
iron chelator deferroxamine (Desferal®) or other oral iron chelators have been
used.169 There is some speculation that a substantial number of people have mild
forms of hemochromatosis. Such people would include those who are heterozygous
carriers of a mutation commonly associated with hemochromatosis.20 However, this
concept is not confirmed.20
TABLE 4.3
Iron Toxicity Effects
Prominent symptoms due to non-nutritional toxicity or definite oral overdosing
Iron antagonism of copper and zinc absorption
GI tract irritation
Increased sensitivity to infections (covered above in the immune function section)
Increased risk of cardiovascular disease
Stimulation of oxidant stress (which may cause increased risk of various diseases)

Since the intestine has a good defense against oral iron toxicity, it is not easy
to produce severe iron toxicity due to oral iron consumption. However, it is possible
to get a chronic or acute oral overdose in adults and children.170
Iron supplements are definitely capable of impacting zinc status, largely via
competition for intestinal absorption.20 The exact doses of iron that cause zinc
problems is not fully clear, though a ratio of iron to zinc of 2.5:1 is too low to impair
zinc absorption in one study.171 The exact problematic dose of iron for impairing
zinc absorption may vary with different zinc intakes, timing of the supplementation,
iron status of the person, and other health aspects of the person. In one interesting
study,172 iron supplementation (100 mg iron/day as ferrous sulfate) at bedtime, is
studied in young women with non-anemia iron deficiency. Zinc absorption, studied
using zinc stable isotopes, does not change despite an improvement in iron status.
One explanation is that the iron supplement is separated from the majority of zinc
intake. Another aspect of timing has to do with taking both the zinc and iron with
meals. In at least some circumstances, consuming iron and zinc supplements with
a meal has little effect on the zinc absorbed.20 In summary, although iron supple-
mentation can adversely affect zinc absorption, it is not clear how often this is
actually a big concern.
Iron antagonism of copper, though not as publicized as iron effects on zinc, may
be a concern. In livestock and experimental animals, high iron intake can negatively
affect copper status.5,173 However, human studies on this subject are few, focus mostly
on just serum copper, and give mixed results.174–177 In fact, in one study,177 iron
supplementation of non-anemic iron-deficient subjects seems to improve copper
status, though other interpretations of the results are possible. For example, serum
copper is known to increase with inflammation (see the chapter on copper). Possibly,
the increase in serum copper due to iron supplementation is a response to inflam-
mation caused by the iron supplements.
In some people, a concern for high doses of iron complexes such as ferrous
sulfate is the production of GI tract discomforts, such as upset stomach and consti-
pation.20,21 In fact, this criterion has been used to set the Upper Levels (UL) for
iron.20 As a result, the iron UL for adults (45 mg) is well below the doses of iron
typically used to treat anemia. For people sensitive to iron-induced GI problems,
but for whom high doses of iron are prescribed, the following solutions can help at
least some of the time:
• Take the iron with meals.20,22

• Use a form of iron that is not as irritating, such as iron bis-glycine chelate
or ferrous fumarate.34,33
• Spread out the daily dose over the day.3
• Use a stool softener or eat a high-fiber diet (though the latter can cut down
on iron absorption if the fiber and iron are consumed together).
The issue of moderate iron over-consumption and cardiovascular disease has

been given a lot of attention by two epidemiological projects, one known as the
Rotterdam Study84,178 and one done in Finland.179,180 In the Rotterdam Study,84,178
high dietary heme iron intake, as well as high serum ferritin, are related to an

increased risk of myocardial infarction in an elderly population. For the dietary heme
iron, the relationship is more pronounced for the fatal cases of myocardial infarction.
The Finland epidemiology project179,180 also related serum ferritin to risk of myo-
cardial infarction. Although these studies are cited a lot, both in scientific literature
and in writings for the general public, the studies have major limitations. First, it is
often ignored that the Rotterdam Study finds no association of risk for myocardial
infarction with serum iron, serum transferrin, or total dietary iron. It is also often
ignored that in the Rotterdam Study, the association of myocardial infarction with
serum ferritin is strongest for people with various health problems such as smoking
and diabetes. Since ferritin is increased by physiological stress,181,182 the high ferritin
values in both the Rotterdam and Finland studies could simply be identifying people
with the most physiological stress. The last point can also be said of two studies
finding that high serum ferritin levels after a stroke are associated with high risk of
poor outcome.183,184 The Rotterdam Study does make some attempt to account for
this issue by reanalyzing data after excluding subjects over a certain value for C-
reactive protein, a marker of inflammation.84 However, the cutoff value is twice that
of the value used as a minimum to assess relationships between C-reactive protein
and metabolic syndrome.185
One other potential problem with relating ferritin to risk of cardiovascular
disease is that in at least some of the analysis, low ferritin could be associated with
regular exercise. Serum ferritin can be reduced in some circumstances by exercise,
including just moderate exercise in middle-aged or older people.186,187
One study in western Australia,178 as well as some other studies,20 give results
in conflict with the Rotterdam and Finland studies. For example, in the study in
Australia, ferritin values are compared to first coronary heart disease event and time
to first stroke event. There are some other studies that do show a relationship, but
within these studies, there are some inconsistencies among the results for different
indicators of iron status.20 Thus, the correlation study results for this subject are
mixed. Moreover, even the studies with positive results do not have clear-cut inter-
pretations. Thus, in this author’s opinion, the concept that dietary iron or iron stores
play a major role in cardiovascular disease risk is still unconfirmed by population-
based, correlation studies.
On the other hand, there are other lines of indirect evidence that iron can be
involved in cardiovascular diseases, and the vast number of other diseases that
involve oxidant stress. This involvement may not require overt iron toxicity to occur.
The indirect evidence is that iron is very capable of generating free radicals that
cause oxidant stress.188 This has mostly been demonstrated in vitro,188 but there is
some evidence that iron can be found in vivo in forms that could give rise to
radicals.189,190,191 There is also data in rats showing that injection of the iron chelator
desferrioxamine can slow chemically induced oxidant injuries.192,193,194 However,
these chelators could also work via mechanisms other than iron chelation.195 Another
issue here is that even if iron does generate radicals in vivo, the dietary iron con-
nection is not necessarily clarified. Dietary iron intake may not be a major determi-
nant of how much iron-catalyzed radical generation occurs. The major determinant
could be processes that put iron in a form that is free to generate radicals. By analogy,
if in a car, the carburetor floods with gasoline, the problem is not too much gasoline

in the car. Instead, faulty carburetor mechanisms are to blame. Using a more bio-
medical analogy, just because atherosclerotic plaques contain calcium, a low-calcium
diet is not advocated to prevent atherosclerosis.
Despite what was just said, there is one study supporting the idea that iron
supplements can induce oxidant stress in intact people.195 Co-supplementation of
relatively low doses of iron plus vitamin C increases oxidative DNA damage in
white blood cells. However, the results are hard to interpret because the damage was
found by one assay but not another. Also, the damage disappeared upon extending
the supplement time, and in one study subgroup, oxidative DNA damage decreases
with iron supplementation. It can also be noted that in another study196 with similar
design, iron has modest beneficial effects on LDL oxidation, an indicator of free
radical mediated oxidant stress. Although this study has a small subject number, the
results are consistent with an earlier study.197 In that study, iron supplementation in
subjects with high plasma vitamin C have no effect on oxidant-damaged DNA. In
other work, eight weeks of iron supplementation has no effect on oxidant stress, as
indicated by plasma protein carbonyl and lipid hydroperoxide concentrations.88 This
work is done in college-aged females with either adequate iron status or with non-
anemia iron deficiency.
In contrast to these last three studies, high-dose iron supplementation (100
mg/day) plus vitamin C supplementation in pregnant women lowers plasma vitamin
E and increases plasma values for lipid peroxides, a measure of oxidant damage to
lipids.198 One concern about this study is that the variances in values between
individuals is extremely low for the method used. Also, even if oxidant stress does
occur, this dose of iron may be outside the realm of moderately high iron intake.
However, nobody has yet defined what constitutes moderately high iron intake.
There is a report of high-dose ferrous fumarate producing some signs of oxidant
stress in Crohn’s disease patients.199 However, there is also an increase in GI tract
irritation, a prime symptom of this disease. This high sensitivity to GI distress may
have triggered the oxidant stress. Also, it should be noted that this study’s main
indicators of oxidant stress are based on plasma sulfur compound levels, which may
not always be indicative of oxidant stress changes.
In this author’s opinion, the studies with negative results on oxidant stress, and
interpretation problems for the studies with positive findings, mean that moderately
high iron supplements cannot be said to routinely produce oxidant stress. On the
other hand, this area could use much more research, especially for defining the
minimal intake of iron that is apt to cause oxidant stress.
In summary, there are certainly situations where iron toxicity is dangerous, but
it is still unsettled as to whether subtle toxicities occur with modestly high dietary
iron intakes.

There is no question that iron deficiency is still a major problem and that iron
supplements benefit some people. Nonetheless, many unresolved issues still remain
about iron supplements such as who should get them, how to give them (e.g., daily

TABLE 4.4,
Iron Supplements at a Glance
Adult RDA: 18 mg (male), 8 mg (female)
Typical dose in supplement studies: variable, but for correction of anemia, can be as high as 300
mg/day (RDA may not be the perfect guideline due to low absorption of supplements vs. meat
products; however, high doses for all uses may be unwarranted)
Best supplement complex: ferrous sulfate is the cheapest and is absorbed as well or better than most
iron supplements, but some doses cause GI tract irritations in some people; iron bis-glycine chelate
Ferrochel® is better absorbed, has low GI irritation, but is more expensive than ferrous sulfate
Applications: beneficial to treat anemia; possibly beneficial to prevent anemia; helpful in pregnancy,
though there are debatable issues such as the exact benefits, who should receive the supplements,
and what protocol to use; a number of other uses are somewhat supported, but not fully confirmed
Upper Level: 45 mg (based on GI tract irritations; this dose is very often exceeded in anemia therapy)
Safety issues: many possible problems, but only overdosing is confirmed (especially in children)
vs. weekly), how much should be given, what benefits should be expected, and at
what point safety issues become a concern.
REFERENCES
ed., McGraw-Hill Education, Madison, 2004, chap. 12.
2. Beard, J.L. and Dawson, H.D., Iron, in Handbook of Nutritionally Essential Mineral
Elements, O’Dell, B.L., and Sunde, R.A., Eds., Marcel Dekker, New York, 1997,
chap. 9.
3. Yip, R., Iron, in Present Knowledge in Nutrition, 8th ed., Bowman, B.A., and Russell,
R.M., Eds., ILSI Press, Washington, 2001, chap. 30.
4. Le, N.T. and Richardson, D.R., The role of iron in cell cycle progression and the
proliferation of neoplastic cells, Biochim. Biophys. Acta, 1603, 31, 2002.
5. Fox, P.L., The copper-iron chronicles: the story of an intimate relationship, Biometals,
16, 9, 2003.
6. Feelders, R.A., Kuiper-Kramer, E.P., and van Eijk, H.G., Structure, function and
clinical significance of transferrin receptors, Clin. Chem. Lab Med., 37, 1, 1999.
7. Braunwald, E., Fauci, A.S., Kapser, D.L., Hauser, S.L., Longo, D.L., and Jameson,
L.J., Harrison’s Principles of Internal Medicine, 15th ed., 2001.
8. Ross, E.M., Evaluation and treatment of iron deficiency in adults, Nutr. Clin. Care,
5, 220, McGraw-Hill Education, Madison, 2002.
9. Takala, T.I., Suominen, P., Lehtonen-Veromaa, M., Mottonen, T., Viikari, J., Raja-
maki, A., and Irjala, K., Increased serum soluble transferrin receptor concentration
detects subclinical iron deficiency in healthy adolescent girls, Clin. Chem. Lab Med.,
41, 203, 2003.
10. Beguin, Y., Soluble transferrin receptor for the evaluation of erythropoiesis and iron
status, Clin. Chim. Acta, 329, 9, 2003.

11. Matsuda, A., Bessho, M., Mori, S., Takeuchi, T., Abe, T., Yawata, Y., Mori, H., Omine,
M., Nakamura, Y., Furusawa, S., Maeda, T., Haginosita, S., Hirasawa, Y., Kinugasa,
E., Akizawa, T., Kawakami, N., Nagata, A., and Hirashima, K., Diagnostic signifi-
cance of serum soluble transferrin receptors in various anemic diseases: the first multi-
institutional joint study in Japan, Haematologia, 32, 225, 2002.
12. Rimon, E., Levy, S., Sapir, A., Gelzer, G., Peled, R., Ergas, D., and Sthoeger, Z.M.,
Diagnosis of iron deficiency anemia in the elderly by transferrin receptor-ferritin
index, Arch. Intern. Med., 162, 445, 2002.
13. Zijp, I.M., Korver, O., and Tijburg, L.B., Effect of tea and other dietary factors on
iron absorption, Crit. Rev. Food Sci. Nutr., 40, 371, 2000.
14. Temme, E.H. and Van Hoydonck, P.G., Tea consumption and iron status, Eur. J. Clin.
Nutr., 56, 379, 2002.
15. Babior, B.M., Peters, W.A., Briden, P.M., and Cetrulo, C.L., Pregnant women’s
absorption of iron from prenatal supplements, J. Reprod. Med., 30, 355, 1985.
16. Dawson, E.B. and McGanity, W.J., Bioavailability of iron in prenatal multivita-
min/multimineral supplements administered to pregnant teenagers, Clin. Ther., 10,
429, 1988.
17. Neufeld, L.M., Ramakrishnan, U., Rivera, J., and Villalpando, S., Prevalence of
anemia and iron deficiency during pregnancy of women supplemented with iron or
iron and multiple micronutrients, FASEB J., 15, abstract #505.2, 2001.
18. Reid, E.D., Lopez, P., Galaviz, I.A., and Isoard, F., Hematological and Biochemical
responses of rural Mexican preschoolers to iron alone or iron plus micronutrients,
FASEB J., 15, A731, 2001.
19. Seligman, P.A., Caskey, J.H., Frazier, J.L., Zucker, R.M., Podell, E.R., and Allen,
R.H., Measurements of iron absorption from prenatal multivitamin–mineral supple-
ments, Obstet. Gynecol., 61, 356, 1983.
20. Anonymous, Iron: tolerable upper intake levels, Nutr. Clin. Care, 5, 236, 2002.
21. Cook, J.D., Carriaga, M., Kahn, S.G., Schalch, W., and Skikne, B.S., Gastric delivery
system for iron supplementation, Lancet, 335, 1136, 1990.
22. Brock, C., Curry, H., Hanna, C., Knipfer, M., and Taylor, L., Adverse effects of iron
supplementation: a comparative trial of a wax-matrix iron preparation and conven-
tional ferrous sulfate tablets, Clin. Ther., 7, 568, 1985.
23. Glassman, E., Oral iron therapy with ferrous fumarate and polysaccharide iron com-
plex, ANNA J., 19, 277, 1992.
24. Arvas, A. and Gur, E., Are ferric compounds useful in treatment of iron deficiency
anemia?, Turk. J. Pediatr., 42, 352, 2000.
25. Davidsson, L., Kastenmayer, P., Szajewska, H., Hurrell, R.F., and Barclay, D., Iron
bioavailability in infants from an infant cereal fortified with ferric pyrophosphate or
ferrous fumarate, Am. J. Clin. Nutr., 71, 1597, 2000.
26. Davidsson, L., Dimitriou, T., Boy, E., Walczyk, T., and Hurrell, R.F., Iron bioavail-
ability from iron-fortified Guatemalan meals based on corn tortillas and black bean
paste, Am. J. Clin. Nutr., 75, 535, 2002.
27. Dietzfelbinger, H. and Kaboth, W., Investigations of the bioavailability of iron from
bi- and trivalent iron salts, Med. Klin., 72, 654, 1977.
28. Nielsen, P., Gabbe, E.E., Fischer, R., and Heinrich, H.C., Bioavailability of iron from
oral ferric polymaltose in humans, Arzneimittelforschung., 44, 743, 1994.
29. Hurrell, R.F., Reddy, M.B., Dassenko, S.A., and Cook, J.D., Ferrous fumarate forti-
fication of a chocolate drink powder, Br. J. Nutr., 65, 271, 1991.

30. Hurrell, R.F., Furniss, D.E., Burri, J., Whittaker, P., Lynch, S.R., and Cook, J.D., Iron
fortification of infant cereals: a proposal for the use of ferrous fumarate or ferrous
succinate, Am. J. Clin. Nutr., 49, 1274, 1989.
31. Layrisse, M., Garcia-Casal, M.N., Solano, L., Baron, M.A., Arguello, F., Llovera, D.,
Ramirez, J., Leets, I., and Tropper, E., Iron bioavailability in humans from breakfasts
enriched with iron bis-glycine chelate, phytates and polyphenols, J. Nutr., 130, 2195,
2000.
32. Szarfarc, S.C., de Cassana, L.M., Fujimori, E., Guerra-Shinohara, E.M., and de
Oliveira, I.M., Relative effectiveness of iron bis-glycinate chelate (Ferrochel) and
ferrous sulfate in the control of iron deficiency in pregnant women, Arch. Latinoam.
Nutr., 51, 42, 2001.
33. Jeppsen, R.B. and Borzelleca, J.F., Safety evaluation of ferrous bisglycinate chelate,
Food Chem. Toxicol., 37, 723, 1999.
34. Iost, C., Name, J.J., Jeppsen, R.B., and Ashmead, H.D., Repleting hemoglobin in
iron deficiency anemia in young children through liquid milk fortification with bio-
available iron amino acid chelate, J. Am. Coll. Nutr., 17, 187, 1998.
35. Osman, A.K. and al Othaimeen, A., Experience with ferrous bis-glycine chelate as
an iron fortificant in milk, Int. J. Vitam. Nutr. Res., 72, 257, 2002.
36. Umbelino, D.C., Cardello, H.M., and Rossi, E.A., Effect of iron salts addition on the
sensory characteristics of soy yogurt, Arch. Latinoam. Nutr., 51, 199, 2001.
37. Hurrell, R.F., Reddy, M.B., Burri, J., and Cook, J.D., An evaluation of EDTA com-
pounds for iron fortification of cereal-based foods, Br. J. Nutr., 84, 903, 2000.
38. Mendoza, C., Viteri, F.E., Lonnerdal, B., Raboy, V., Young, K.A., and Brown, K.H.,
Absorption of iron from unmodified maize and genetically altered, low-phytate maize
fortified with ferrous sulfate or sodium iron EDTA, Am. J. Clin. Nutr., 73, 80, 2001.
39. Fairweather-Tait, S.J., Wortley, G.M., Teucher, B., and Dainty, J., Iron absorption
from a breakfast cereal: effects of EDTA compounds and ascorbic acid, Int. J. Vitam.
Nutr. Res., 71, 117, 2001.
40. Hurrell, R., Bothwell, T., Cook, J.D., Dary, O., Davidsson, L., Fairweather-Tait, S.,
Hallberg, L., Lynch, S., Rosado, J., Walter, T., and Whittaker, P., The usefulness of
elemental iron for cereal flour fortification: a SUSTAIN Task Force report. Sharing
United States Technology to Aid in the Improvement of Nutrition, Nutr. Rev., 60,
391, 2002.
41. Hurrell, R.F., Fortification: overcoming technical and practical barriers, J. Nutr., 132,
806S, 2002.
42. Walter, T., Dallman, P.R., Pizarro, F., Velozo, L., Pena, G., Bartholmey, S.J., Her-
trampf, E., Olivares, M., Letelier, A., and Arredondo, M., Effectiveness of iron-
fortified infant cereal in prevention of iron deficiency anemia, Pediatrics, 91, 976,
1993.
43. Harvey, R.S., Reffitt, D.M., Doig, L.A., Meenan, J., Ellis, R.D., Thompson, R.P., and
Powell, J.J., Ferric trimaltol corrects iron deficiency anaemia in patients intolerant of
iron, Aliment. Pharmacol. Ther., 12, 845, 1998.
44. Jacobs, P., Equivalent bioavailability of iron from ferrous salts and a ferric polymal-
tose complex. Clinical and experimental studies, Arzneimittelforschung., 37, 113,
1987.
45. Jacobs, P., Fransman, D., and Coghlan, P., Comparative bioavailability of ferric
polymaltose and ferrous sulphate in iron-deficient blood donors, J. Clin. Apheresis.,
8, 89, 1993.
46. Schafer, S. and Forth, W., On the absorption of divalent and trivalent iron in living
rats, Arzneimittelforschung., 34, 1570, 1984.

47. Allen, L.H., Iron supplements: scientific issues concerning efficacy and implications
for research and programs, J. Nutr., 132, 813S, 2002.
48. Marx, J.J., Iron deficiency in developed countries: prevalence, influence of lifestyle
factors and hazards of prevention, Eur. J. Clin. Nutr., 51, 491, 1997.
49. Balducci, L., Epidemiology of anemia in the elderly: information on diagnostic
evaluation, J. Am. Geriatr. Soc., 51, S2, 2003.
50. Beard, J.L., Richards, R.E., Smiciklas-Wright, H., Bernardo, V., and Kordish, S., Iron
nutrition in rural home bound elderly persons, J. Nutr. Elder., 15, 3, 1996.
51. Bohmer, F., Fruhwald, T., and Lapin, A., Soluble transferrin receptor and iron status
in elderly patients, Wien. Med. Wochenschr., 153, 232, 2003.
52. Coban, E., Timuragaoglu, A., and Meric, M., Iron deficiency anemia in the elderly:
prevalence and endoscopic evaluation of the gastrointestinal tract in outpatients, Acta
Haematol., 110, 25, 2003.
53. Fleming, D.J., Jacques, P.F., Tucker, K.L., Massaro, J.M., D’Agostino, R.B., Sr.,
Wilson, P.W., and Wood, R.J., Iron status of the free-living, elderly Framingham
Heart Study cohort: an iron-replete population with a high prevalence of elevated
iron stores, Am. J. Clin. Nutr., 73, 638, 2001.
54. O’Keeffe, M.J., O’Callaghan, M.J., Cowley, D., Tudehope, D.I., Gray, P., Burns, Y.,
and Mohay, H., Non-anaemic iron deficiency identified by ZPP test in extremely
premature infants: prevalence, dietary risk factors, and association with neurodevel-
opmental problems, Early Hum. Dev., 70, 73, 2002.
55. Rao, R. and Georgieff, M.K., Perinatal aspects of iron metabolism, Acta Paediatr.
Suppl., 91, 124, 2002.
56. Massey, A.C., Microcytic anemia. Differential diagnosis and management of iron
deficiency anemia, Med. Clin. North Am., 76, 549, 1992.
57. Demiroglu, H. and Dundar, S., Pernicious anaemia patients should be screened for
iron deficiency during follow up, N. Z. Med. J., 110, 147, 1997.
58. Cogswell, M.E., Kettel-Khan, L., and Ramakrishnan, U., Iron supplement use among
women in the United States: science, policy and practice, J. Nutr., 133, 1974S, 2003.
59. Gordeuk, V.R., Brittenham, G.M., Bravo, J., Hughes, M.A., and Keating, L.J., Pre-
vention of iron deficiency with carbonyl iron in female blood donors, Transfusion,
30, 239, 1990.
60. Haidar, J., Omwega, A.M., Muroki, N.M., and Ayana, G., Daily vs. weekly iron
supplementation and prevention of iron deficiency anaemia in lactating women, East
Afr. Med. J., 80, 11, 2003.
61. Makola, D., Ash, D.M., Tatala, S.R., Latham, M.C., Ndossi, G., and Mehansho, H.,
A micronutrient-fortified beverage prevents iron deficiency, reduces anemia and
improves the hemoglobin concentration of pregnant Tanzanian women, J. Nutr., 133,
1339, 2003.
62. Viteri, F.E., Iron supplementation for the control of iron deficiency in populations at
risk, Nutr. Rev., 55, 195, 1997.
63. Hunt, J.M., Reversing productivity losses from iron deficiency: the economic case,
J. Nutr., 132, 794S, 2002.
64. Patterson, A.J., Brown, W.J., Roberts, D.C., and Seldon, M.R., Dietary treatment of
iron deficiency in women of childbearing age, Am. J. Clin. Nutr., 74, 650, 2001.
65. Mannar, V. and Gallego, E.B., Iron fortification: country level experiences and lessons
learned, J. Nutr., 132, 856S, 2002.
66. Stoltzfus, R.J., Dreyfuss, M.L., Chwaya, H.M., and Albonico, M., Hookworm control
as a strategy to prevent iron deficiency, Nutr. Rev., 55, 223, 1997.

67. Agarwal, K.N., Gomber, S., Bisht, H., and Som, M., Anemia prophylaxis in adolescent
school girls by weekly or daily iron-folate supplementation, Indian Pediatr., 40, 296,
2003.
68. Ekstrom, E.C., Hyder, S.M., Chowdhury, A.M., Chowdhury, S.A., Lonnerdal, B.,
Habicht, J.P., and Persson, L.A., Efficacy and trial effectiveness of weekly and daily
iron supplementation among pregnant women in rural Bangladesh: disentangling the
issues, Am. J. Clin. Nutr., 76, 1392, 2002.
69. Kianfar, H., Kimiagar, M., and Ghaffarpour, M., Effect of daily and intermittent iron
supplementation on iron status of high school girls, Int. J. Vitam. Nutr. Res., 70, 172,
2000.
70. Hyder, S.M., Persson, L.A., Chowdhury, A.M., and Ekstrom, E.C., Do side-effects
reduce compliance to iron supplementation? A study of daily- and weekly-dose
regimens in pregnancy, J. Health Popul. Nutr., 20, 175, 2002.
71. Trachtenbarg, D.E. and Golemon, T.B., Care of the premature infant: Part I. Moni-
toring growth and development, Am. Fam. Physician, 57, 2123, 1998.
72. Wasowska-Krolikowska, K. and Baranowski, W.J., The significance of iron in infant
development and nutrition. I. Metabolism of iron, Med. Wieku. Rozwoj., 4, 67, 2000.
73. Nissenson, A.R. and Strobos, J., Iron deficiency in patients with renal failure, Kidney
Int. Suppl., 69, S18, 1999.
74. Kooistra, M.P. and Marx, J.J., The absorption of iron is disturbed in recombinant
human erythroietin-treated peritoneal dialysis patients, Nephrol. Dial. Transplant.,
13, 2578, 1998.
75. Macdougall, I.C., Strategies for iron supplementation: oral versus intravenous, Kidney
Int. Suppl., 69, S61, 1999.
76. Fishbane, S., Review of issues relating to iron and infection, Am. J. Kidney Dis., 34,
S47, 1999.
77. Hoen, B., Iron and infection: clinical experience, Am. J. Kidney Dis., 34, S30, 1999.
78. Santoro, A., Anemia in renal insufficiency, Rev. Clin. Exp. Hematol., Suppl. 1, 12,
2002.
79. Silverberg, D.S., Wexler, D., Blum, B., and Iaina, A., Anemia in chronic kidney
disease and congestive heart failure, Blood Purif., 21, 124, 2003.
80. Gillespie, T.W., Anemia in cancer: therapeutic implications and interventions, Cancer
Nurs., 26, 119, 2003.
81. Gillespie, T.W., Effects of cancer-related anemia on clinical and quality-of-life out-
comes, Clin. J. Oncol. Nurs., 6, 206, 2002.
82. Kotasek, D., Steger, G., Faught, W., Underhill, C., Poulsen, E., Colowick, A.B., Rossi,
G., and Mackey, J., Darbepoetin alfa administered every 3 weeks alleviates anaemia
in patients with solid tumours receiving chemotherapy; results of a double-blind,
placebo-controlled, randomised study, Eur. J. Cancer, 39, 2026, 2003.
83. Joosten, E., Ghesquiere, B., Linthoudt, H., Krekelberghs, F., Dejaeger, E., Boonen,
S., Flamaing, J., Pelemans, W., Hiele, M., and Gevers, A.M., Upper and lower
gastrointestinal evaluation of elderly inpatients who are iron deficient, Am. J. Med.,
107, 24, 1999.
84. Klipstein-Grobusch, K., Koster, J.F., Grobbee, D.E., Lindemans, J., Boeing, H.,
Hofman, A., and Witteman, J.C., Serum ferritin and risk of myocardial infarction in
the elderly: the Rotterdam Study, Am. J. Clin. Nutr., 69, 1231, 1999.
85. Heath, A.L., Skeaff, C.M., O’Brien, S.M., Williams, S.M., and Gibson, R.S., Can
dietary treatment of non-anemic iron deficiency improve iron status?, J. Am. Coll.
Nutr., 20, 477, 2001.

86. Hallberg, L., Bengtsson, C., Lapidus, L., Lindstedt, G., Lundberg, P.A., and Hulten,
L., Screening for iron deficiency: an analysis based on bone-marrow examinations
and serum ferritin determinations in a population sample of women, Br. J. Haematol.,
85, 787, 1993.
87. Hinton, P.S., Giordano, C., Brownlie, T., and Haas, J.D., Iron supplementation
improves endurance after training in iron-depleted, nonanemic women, J. Appl. Phys-
iol., 88, 1103, 2000.
88. Gropper, S.S., Kerr, S., and Barksdale, J.M., Non-anemic iron deficiency, oral iron
supplementation, and oxidative damage in college-aged females, J. Nutr. Biochem.,
14, 409, 2003.
89. McAnulty, L.S., Gropper, S.S., McAnulty, S.R., and Keith, R.E., Iron depletion
without anemia is not associated with impaired selenium status in college-aged
women, Biol. Trace Elem. Res., 91, 125, 2003.
90. Acharya, J., Punchard, N.A., Taylor, J.A., Thompson, R.P., and Pearson, T.C., Red
cell lipid peroxidation and antioxidant enzymes in iron deficiency, Eur. J. Haematol.,
47, 287, 1991.
91. Isler, M., Delibas, N., Guclu, M., Gultekin, F., Sutcu, R., Bahceci, M., and Kosar,
A., Superoxide dismutase and glutathione peroxidase in erythrocytes of patients with
iron deficiency anemia: effects of different treatment modalities, Croat. Med. J., 43,
16, 2002.
92. Tekin, D., Yavuzer, S., Tekin, M., Akar, N., and Cin, S., Possible effects of antioxidant
status on increased platelet aggregation in childhood iron-deficiency anemia, Pediatr.
Int., 43, 74, 2001.
93. Haas, J.D. and Brownlie, T., Iron deficiency and reduced work capacity: a critical
review of the research to determine a causal relationship, J. Nutr., 131, 676S, 2001.
94. Higgins, C., Deficiency testing for iron, vitamin B12 and folate, Nurs. Times, 91, 38,
1995.
95. Kretsch, M.J., Fong, A.K., Green, M.W., and Johnson, H.L., Cognitive function, iron
status, and hemoglobin concentration in obese dieting women, Eur. J. Clin. Nutr., 52,
512, 1998.
96. Majumdar, I., Paul, P., Talib, V.H., and Ranga, S., The effect of iron therapy on the
growth of iron-replete and iron-deplete children, J. Trop. Pediatr., 49, 84, 2003.
97. Aguayo, V.M., School-administered weekly iron supplementation—effect on the
growth and hemoglobin status of non-anemic Bolivian school-age children. A ran-
domized placebo-controlled trial, Eur. J. Nutr., 39, 263, 2000.
98. Allen, L.H., Pregnancy and iron deficiency: unresolved issues, Nutr. Rev., 55, 91,
1997.
99. Blot, I., Diallo, D., and Tchernia, G., Iron deficiency in pregnancy: effects on the
newborn, Curr. Opin. Hematol., 6, 65, 1999.
100. Haram, K., Nilsen, S.T., and Ulvik, R.J., Iron supplementation in pregnancy—evi-
dence and controversies, Acta Obstet. Gynecol. Scand., 80, 683, 2001.
101. Rasmussen, K., Is there a causal relationship between iron deficiency or iron-defi-
ciency anemia and weight at birth, length of gestation and perinatal mortality?, J.
Nutr., 131, 590S, 2001.
102. Merialdi, M., Carroli, G., Villar, J., Abalos, E., Gulmezoglu, A.M., Kulier, R., and
de Onis, M., Nutritional interventions during pregnancy for the prevention or treat-
ment of impaired fetal growth: an overview of randomized controlled trials, J. Nutr.,
133, 1626S, 2003.

103. Villar, J., Merialdi, M., Gulmezoglu, A.M., Abalos, E., Carroli, G., Kulier, R., and
de Onis, M., Nutritional interventions during pregnancy for the prevention or treat-
ment of maternal morbidity and preterm delivery: an overview of randomized con-
trolled trials, J. Nutr., 133, 1606S, 2003.
104. Galloway, R. and McGuire, J., Determinants of compliance with iron supplementa-
tion: supplies, side effects, or psychology?, Soc. Sci. Med., 39, 381, 1994.
105. Caulfield, L.E., Zavaleta, N., Shankar, A.H., and Merialdi, M., Potential contribution
of maternal zinc supplementation during pregnancy to maternal and child survival,
Am. J. Clin. Nutr., 68, 499S, 1998.
106. Tran, T., Wax, J.R., Philput, C., Steinfeld, J.D., and Ingardia, C.J., Intentional iron
overdose in pregnancy—management and outcome, J. Emerg. Med., 18, 225, 2000.
107. Makrides, M., Crowther, C.A., Gibson, R.A., Gibson, R.S., and Skeaff, C.M., Efficacy
and tolerability of low-dose iron supplements during pregnancy: a randomized con-
trolled trial, Am. J. Clin. Nutr., 78, 145, 2003.
108. Cogswell, M.E., Parvanta, I., Ickes, L., Yip, R., and Brittenham, G.M., Iron supple-
mentation during pregnancy, anemia, and birth weight: a randomized controlled trial,
Am. J. Clin. Nutr., 78, 773, 2003.
109. Rasmussen, K.M. and Stoltzfus, R.J., New evidence that iron supplementation during
pregnancy improves birth weight: new scientific questions, Am. J. Clin. Nutr., 78,
673, 2003.
110. Grantham-McGregor, S. and Ani, C., A review of studies on the effect of iron
deficiency on cognitive development in children, J. Nutr., 131, 649S, 2001.
111. Hurtado, E.K., Claussen, A.H., and Scott, K.G., Early childhood anemia and mild or
moderate mental retardation, Am. J. Clin. Nutr., 69, 115, 1999.
112. Halterman, J.S., Kaczorowski, J.M., Aligne, C.A., Auinger, P., and Szilagyi, P.G.,
Iron deficiency and cognitive achievement among school-aged children and adoles-
cents in the United States, Pediatrics, 107, 1381, 2001.
113. Prasad, A.N. and Prasad, C., Iron deficiency; non-hematological manifestations, Prog.
Food Nutr. Sci., 15, 255, 1991.
114. Lozoff, B., De, A., I, Castillo, M., Smith, J.B., Walter, T., and Pino, P., Behavioral
and developmental effects of preventing iron-deficiency anemia in healthy full-term
infants, Pediatrics, 112, 846, 2003.
115. Pollitt, E., Watkins, W.E., and Husaini, M.A., Three-month nutritional supplementa-
tion in Indonesian infants and toddlers benefits memory function 8 y later, Am. J.
Clin. Nutr., 66, 1357, 1997.
116. Soewondo, S., The effect of iron deficiency and mental stimulation on Indonesian
children’s cognitive performance and development, Kobe J. Med. Sci., 41, 1, 1995.
117. Soemantri, A.G., Pollitt, E., and Kim, I., Iron deficiency anemia and educational
achievement, Am. J. Clin. Nutr., 42, 1221, 1985.
118. Seshadri, S. and Gopaldas, T., Impact of iron supplementation on cognitive functions
in preschool and school-aged children: the Indian experience, Am. J. Clin. Nutr., 50,
675, 1989.
119. Bruner, A.B., Joffe, A., Duggan, A.K., Casella, J.F., and Brandt, J., Randomised study
of cognitive effects of iron supplementation in non-anaemic iron-deficient adolescent
girls, Lancet, 348, 992, 1996.
120. Oski, F.A., Honig, A.S., Helu, B., and Howanitz, P., Effect of iron therapy on behavior
performance in nonanemic, iron-deficient infants, Pediatrics, 71, 877, 1983.
121. Sever, Y., Ashkenazi, A., Tyano, S., and Weizman, A., Iron treatment in children with
attention deficit hyperactivity disorder. A preliminary report, Neuropsychobiology,
35, 178, 1997.

122. Chandra, R.K., Nutrition and the immune system from birth to old age, Eur. J. Clin.
Nutr., 56 Suppl. 3, S73, 2002.
123. Marx, J.J., Iron and infection: competition between host and microbes for a precious
element, Best. Pract. Res. Clin. Haematol., 15, 411, 2002.
124. Patruta, S.I. and Horl, W.H., Iron and infection, Kidney Int. Suppl, 69, S125, 1999.
125. Oppenheimer, S.J., Iron and its relation to immunity and infectious disease, J. Nutr.,
131, 616S, 2001.
126. Gera, T. and Sachdev, H.P., Effect of iron supplementation on incidence of infectious
illness in children: systematic review, BMJ, 325, 1142, 2002.
127. Shulman, C.E., Graham, W.J., Jilo, H., Lowe, B.S., New, L., Obiero, J., Snow, R.W.,
and Marsh, K., Malaria is an important cause of anaemia in primigravidae: evidence
from a district hospital in coastal Kenya, Trans. R. Soc. Trop. Med. Hyg., 90, 535,
1996.
128. Carre, N., Eono, P., Kouakou, K., Duponchel, J.L., Marquis, M., and Zahui, K.H.,
[Iron supplementation associated with malaria prevention among pregnant women in
Abidjan], Rev. Epidemiol. Sante Publique, 51, 31, 2003.
129. Golz, A., Netzer, A., Goldenberg, D., Westerman, S.T., Westerman, L.M., and
Joachims, H.Z., The association between iron-deficiency anemia and recurrent acute
otitis media, Am. J. Otolaryngol., 22, 391, 2001.
130. Olsen, A., Nawiri, J., and Friis, H., The impact of iron supplementation on reinfection
with intestinal helminths and Schistosoma mansoni in western Kenya, Trans. R. Soc.
Trop. Med. Hyg., 94, 493, 2000.
131. de Silva, A., Atukorala, S., Weerasinghe, I., and Ahluwalia, N., Iron supplementation
improves iron status and reduces morbidity in children with or without upper respi-
ratory tract infections: a randomized controlled study in Colombo, Sri Lanka, Am. J.
Clin. Nutr., 77, 234, 2003.
132. Mitra, A.K., Akramuzzaman, S.M., Fuchs, G.J., Rahman, M.M., and Mahalanabis,
D., Long-term oral supplementation with iron is not harmful for young children in
a poor community of Bangladesh, J. Nutr., 127, 1451, 1997.
133. Nielsen, P. and Nachtigall, D., Iron supplementation in athletes. Current recommen-
dations, Sports Med., 26, 207, 1998.
134. Beard, J. and Tobin, B., Iron status and exercise, Am. J. Clin. Nutr., 72, 594S, 2000.
135. Nachtigall, D., Nielsen, P., Fischer, R., Engelhardt, R., and Gabbe, E.E., Iron defi-
ciency in distance runners. A reinvestigation using Fe-labelling and non-invasive liver
iron quantification, Int. J. Sports Med., 17, 473, 1996.
136. Spodaryk, K., Iron metabolism in boys involved in intensive physical training, Physiol
Behav., 75, 201, 2002.
137. Constantini, N.W., Eliakim, A., Zigel, L., Yaaron, M., and Falk, B., Iron status of
highly active adolescents: evidence of depleted iron stores in gymnasts, Int. J. Sport
Nutr. Exerc. Metab., 10, 62, 2000.
138. Rowland, T.W., Black, S.A., and Kelleher, J.F., Iron deficiency in adolescent endur-
ance athletes, J. Adolesc. Health Care, 8, 322, 1987.
139. Dressendorfer, R.H., Keen, C.L., Wade, C.E., Claybaugh, J.R., and Timmis, G.C.,
Development of runner’s anemia during a 20-day road race: effect of iron supple-
ments, Int. J. Sports Med., 12, 332, 1991.
140. Mann, S.K., Kaur, S., and Bains, K., Iron and energy supplementation improves the
physical work capacity of female college students, Food Nutr. Bull., 23, 57, 2002.
141. Rowland, T.W., Deisroth, M.B., Green, G.M., and Kelleher, J.F., The effect of iron
therapy on the exercise capacity of nonanemic iron-deficient adolescent runners, Am.
J. Dis. Child, 142, 165, 1988.

142. Friedmann, B., Weller, E., Mairbaurl, H., and Bartsch, P., Effects of iron repletion
on blood volume and performance capacity in young athletes, Med. Sci. Sports Exerc.,
33, 741, 2001.
143. Brutsaert, T.D., Hernandez-Cordero, S., Rivera, J., Viola, T., Hughes, G., and Haas,
J.D., Iron supplementation improves progressive fatigue resistance during dynamic
knee extensor exercise in iron-depleted, nonanemic women, Am. J. Clin. Nutr., 77,
441, 2003.
144. Zhu, Y.I. and Haas, J.D., Altered metabolic response of iron-depleted nonanemic
women during a 15-km time trial, J. Appl. Physiol., 84, 1768, 1998.
145. Paulson, G.W., Restless legs syndrome. How to provide symptom relief with drug
and nondrug therapies, Geriatrics, 55, 35, 2000.
146. Berger, K., von Eckardstein, A., Trenkwalder, C., Rothdach, A., Junker, R., and
Weiland, S.K., Iron metabolism and the risk of restless legs syndrome in an elderly
general population—the MEMO-Study, J. Neurol., 249, 1195, 2002.
147. Earley, C.J., Connor, J.R., Beard, J.L., Malecki, E.A., Epstein, D.K., and Allen, R.P.,
Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syn-
drome, Neurology, 54, 1698, 2000.
148. O’Keeffe, S.T., Noel, J., and Lavan, J.N., Restless legs syndrome in the elderly,
Postgrad. Med. J., 69, 701, 1993.
149. Milligan, S.A. and Chesson, A.L., Restless legs syndrome in the older adult: diagnosis
and management, Drugs Aging, 19, 741, 2002.
150. Davis, B.J., Rajput, A., Rajput, M.L., Aul, E.A., and Eichhorn, G.R., A randomized,
double-blind placebo-controlled trial of iron in restless legs syndrome, Eur. Neurol.,
43, 70, 2000.
151. Connor, J.R., Boyer, P.J., Menzies, S.L., Dellinger, B., Allen, R.P., Ondo, W.G., and
Earley, C.J., Neuropathological examination suggests impaired brain iron acquisition
in restless legs syndrome, Neurology, 61, 304, 2003.
152. Silber, M.H., Restless legs syndrome, Mayo Clin. Proc., 72, 261, 1997.
153. Chen, T.S. and Chen, P.S., Rise and fall of the Plummer-Vinson syndrome, J. Gas-
troenterol. Hepatol., 9, 654, 1994.
154. Maleki, D. and Cameron, A.J., Plummer-Vinson syndrome associated with chronic
blood loss anemia and large diaphragmatic hernia, Am. J. Gastroenterol., 97, 190,
2002.
155. Atmatzidis, K., Papaziogas, B., Pavlidis, T., Mirelis, C., and Papaziogas, T., Plummer-
Vinson syndrome, Dis. Esophagus., 16, 154, 2003.
156. Bredenkamp, J.K., Castro, D.J., and Mickel, R.A., Importance of iron repletion in
the management of Plummer-Vinson syndrome, Ann. Otol. Rhinol. Laryngol., 99, 51,
1990.
157. Hoffman, R.M. and Jaffe, P.E., Plummer-Vinson syndrome. A case report and liter-
ature review, Arch. Intern. Med., 155, 2008, 1995.
158. Orii, K.E., Kato, Z., Osamu, F., Funato, M., Kubodera, U., Inoue, R., Shimozawa,
N., and Kondo, N., Changes of autonomic nervous system function in patients with
breath-holding spells treated with iron, J. Child Neurol., 17, 337, 2002.
159. Mocan, H., Yildiran, A., Orhan, F., and Erduran, E., Breath-holding spells in 91
children and response to treatment with iron, Arch. Dis. Child, 81, 261, 1999.
160. Daoud, A.S., Batieha, A., al Sheyyab, M., Abuekteish, F., and Hijazi, S., Effectiveness
of iron therapy on breath-holding spells, J. Pediatr., 130, 547, 1997.
161. Colina, K.F. and Abelson, H.T., Resolution of breath-holding spells with treatment
of concomitant anemia, J. Pediatr., 126, 395, 1995.

162. Bhatia, M.S., Singhal, P.K., Dhar, N.K., Nigam, V.R., Malik, S.C., and Mullick, D.N.,
Breath holding spells: an analysis of 50 cases, Indian Pediatr., 27, 1073, 1990.
163. Tam, D.A. and Rash, F.C., Breath-holding spells in a patient with transient erythro-
blastopenia of childhood, J. Pediatr., 130, 651, 1997.
164. Zimmermann, M.B. and Kohrle, J., The impact of iron and selenium deficiencies on
iodine and thyroid metabolism: biochemistry and relevance to public health, Thyroid,
12, 867, 2002.
165. Astrup, A., Obesity and metabolic efficiency, Ciba Found. Symp., 201, 159, 1996.
166. Rosenzweig, P.H. and Volpe, S.L., Iron, thermoregulation, and metabolic rate, Crit
Rev. Food Sci. Nutr., 39, 131, 1999.
167. Beard, J., Borel, M., and Peterson, F.J., Changes in iron status during weight loss
with very-low-energy diets, Am. J. Clin. Nutr., 66, 104, 1997.
168. Zimmermann, M.B., Zeder, C., Chaouki, N., Torresani, T., Saad, A., and Hurrell,
R.F., Addition of microencapsulated iron to iodized salt improves the efficacy of
iodine in goitrous, iron-deficient children: a randomized, double-blind, controlled
trial, Eur. J. Endocrinol., 147, 747, 2002.
169. Chaston, T.B. and Richardson, D.R., Iron chelators for the treatment of iron overload
disease: relationship between structure, redox activity, and toxicity, Am. J. Hematol.,
73, 200, 2003.
170. Pestaner, J.P., Ishak, K.G., Mullick, F.G., and Centeno, J.A., Ferrous sulfate toxicity:
a review of autopsy findings, Biol. Trace Elem. Res., 69, 191, 1999.
171. Sandstrom, B., Davidsson, L., Cederblad, A., and Lonnerdal, B., Oral iron, dietary
ligands and zinc absorption, J. Nutr., 115, 411, 1985.
172. Donangelo, C.M., Woodhouse, L.R., King, S.M., Viteri, F.E., and King, J.C., Sup-
plemental zinc lowers measures of iron status in young women with low iron reserves,
J. Nutr., 132, 1860, 2002.
173. Abdel-Mageed, A.B. and Oehme, F.W., A review on biochemical roles, toxicity and
interactions of zinc, copper and iron: IV. Interactions, Vet. Hum. Toxicol., 32, 456,
1990.
174. Arnaud, J., Prual, A., Preziosi, P., Cherouvrier, F., Favier, A., Galan, P., and Hercberg,
S., Effect of iron supplementation during pregnancy on trace element (Cu, Se, Zn)
concentrations in serum and breast milk from Nigerian women, Ann. Nutr. Metab,
37, 262, 1993.
175. Newhouse, I.J., Clement, D.B., and Lai, C., Effects of iron supplementation and
discontinuation on serum copper, zinc, calcium, and magnesium levels in women,
Med. Sci. Sports Exerc., 25, 562, 1993.
176. Burns, J. and Paterson, C.R., Effect of iron-folate supplementation on serum copper
concentration in late pregnancy, Acta Obstet. Gynecol. Scand., 72, 616, 1993.
177. Gropper, S.S., Bader-Crowe, D.M., McAnulty, L.S., White, B.D., and Keith, R.E.,
Non-anemic iron depletion, oral iron supplementation and indices of copper status
in college-aged females, J. Am. Coll. Nutr., 21, 545, 2002.
178. Klipstein-Grobusch, K., Grobbee, D.E., den Breeijen, J.H., Boeing, H., Hofman, A.,
and Witteman, J.C., Dietary iron and risk of myocardial infarction in the Rotterdam
Study, Am. J. Epidemiol., 149, 421, 1999.
179. Salonen, J.T., Nyyssonen, K., Korpela, H., Tuomilehto, J., Seppanen, R., and Salonen,
R., High stored iron levels are associated with excess risk of myocardial infarction
in eastern Finnish men, Circulation, 86, 803, 1992.
180. Salonen, J.T., Nyyssonen, K., and Salonen, R., Body iron stores and the risk of
coronary heart disease, N. Engl. J. Med., 331, 1159, 1994.

181. Tomkins, A., Assessing micronutrient status in the presence of inflammation, J.

Nutr., 133, 1649S, 2003.
182. Mascotti, D.P., Rup, D., and Thach, R.E., Regulation of iron metabolism: translational
effects mediated by iron, heme, and cytokines, Annu. Rev. Nutr., 15, 239, 1995.
183. Davalos, A., Fernandez-Real, J.M., Ricart, W., Soler, S., Molins, A., Planas, E., and
Genis, D., Iron-related damage in acute ischemic stroke, Stroke, 25, 1543, 1994.
184. Erdemoglu, A.K. and Ozbakir, S., Serum ferritin levels and early prognosis of stroke,
Eur. J. Neurol., 9, 633, 2002.
185. Ford, E.S., The metabolic syndrome and C-reactive protein, fibrinogen, and leukocyte
count: findings from the Third National Health and Nutrition Examination Survey,
Atherosclerosis, 168, 351, 2003.
186. Wells, A.M., Haub, M.D., Fluckey, J., Williams, D.K., Chernoff, R., and Campbell,
W.W., Comparisons of vegetarian and beef-containing diets on hematological indexes
and iron stores during a period of resistive training in older men, J. Am. Diet. Assoc.,
103, 594, 2003.
187. Naimark, B.J., Ready, A.E., Sawatzky, J.A., Boreskie, S., Ducas, J., Drinkwater, D.T.,
and Oosterveen, S., Serum ferritin and heart disease: the effect of moderate exercise
on stored iron levels in postmenopausal women, Can. J. Cardiol., 12, 1253, 1996.
188. Kehrer, J.P., Free radicals as mediators of tissue injury and disease, Crit. Rev. Toxicol.,
23, 21, 1993.
189. Kooistra, M.P., Kersting, S., Gosriwatana, I., Lu, S., Nijhoff-Schutte, J., Hider, R.C.,
and Marx, J.J., Nontransferrin-bound iron in the plasma of haemodialysis patients
after intravenous iron saccharate infusion, Eur. J. Clin. Invest., 32 Suppl. 1, 36, 2002.
190. Lund, E.K., Wharf, S.G., Fairweather-Tait, S.J., and Johnson, I.T., Oral ferrous sulfate
supplements increase the free radical-generating capacity of feces from healthy vol-
unteers, Am. J. Clin. Nutr., 69, 250, 1999.
191. Gutteridge, J.M., Rowley, D.A., Halliwell, B., Cooper, D.F., and Heeley, D.M.,
Copper and iron complexes catalytic for oxygen radical reactions in sweat from
human athletes, Clin. Chim. Acta, 145, 267, 1985.
192. Chopra, K., Singh, M., Kaul, N., Andrabi, K.I., and Ganguly, N.K., Decrease of
myocardial infarct size with desferrioxamine: possible role of oxygen free radicals
in its ameliorative effect, Mol. Cell Biochem., 113, 71, 1992.
193. Tsokos-Kuhn, J.O., Smith, C.V., Hughes, H., and Mitchell, J.R., Liver membrane
calcium transport in diquat-induced oxidative stress in vivo, Mol. Pharmacol., 34,
209, 1988.
194. Blake, D.R., Hall, N.D., Bacon, P.A., Dieppe, P.A., Halliwell, B., and Gutteridge,
J.M., Effect of a specific iron chelating agent on animal models of inflammation,
Ann. Rheum. Dis., 42, 89, 1983.
195. Hartley, A., Davies, M., and Rice-Evans, C., Desferrioxamine as a lipid chain-
breaking antioxidant in sickle erythrocyte membranes, FEBS Lett., 264, 145, 1990.
196. Yang, M., Collis, C.S., Kelly, M., Diplock, A.T., and Rice-Evans, C., Do iron and
vitamin C co-supplementation influence platelet function or LDL oxidizability in
healthy volunteers?, Eur. J. Clin. Nutr., 53, 367, 1999.
197. Proteggente, A.R., England, T.G., Rice-Evans, C.A., and Halliwell, B., Iron supple-
mentation and oxidative damage to DNA in healthy individuals with high plasma
ascorbate, Biochem. Biophys. Res. Commun., 288, 245, 2001.
198. Lachili, B., Hininger, I., Faure, H., Arnaud, J., Richard, M.J., Favier, A., and Roussel,
A.M., Increased lipid peroxidation in pregnant women after iron and vitamin C
supplementation, Biol. Trace Elem. Res., 83, 103, 2001.

199. Erichsen, K., Hausken, T., Ulvik, R.J., Svardal, A., Berstad, A., and Berge, R.K.,
Ferrous fumarate deteriorated plasma antioxidant status in patients with Crohn dis-
ease, Scand. J. Gastroenterol., 38, 543, 2003.

5 Zinc
Hundreds of papers have been published on various biological aspects of zinc. Many
of these involve human supplementation studies. Yet, there is much that we still
don’t know about zinc. We do know that zinc can affect numerous biological
processes. In fact, it’s hard to think of a human body process where zinc is not
involved. For this reason, many claims have been made about zinc supplementation
and health. Some of these claims are supported by at least some research, but there
are still a lot of uncertainties. The majority of the claims focus on correcting marginal
deficiencies, though some claims involve getting “extra” zinc above the RDA.
Zinc is needed for the function of many enzymes. The exact number varies depending
on how one defines separate enzymes, but some estimates say over 200 enzymes
need zinc.1 Most of these enzymes are metalloenzymes where zinc is incorporated
tightly into the protein structure, where zinc acts as a catalyst or to stabilize protein
structure.2 For some other enzymes, zinc binds more transiently as an enzyme
activator rather than a more permanent part of a metalloenzyme.3 In addition to roles
with enzymes, zinc can also stabilize the structures of various other molecules,
including non-enzyme proteins, certain hormones, transcription factors (e.g., zinc
fingers), nucleic acids, and small regulatory molecules such as the peptide thymulin.3
This stabilizing function includes proteins in cell membranes, a function that seems
to greatly affect cell membrane structure. This cell membrane stabilization function
has wide implications because membrane stability affects receptors, which signal
many actions in cells. If cell membrane stability is diminished, then some receptors
may become less active while others become more active. So, some cellular functions
may become sluggish while others may become overactive. Among the overactive
processes seems to be secretion of superoxide and other reactive oxygen species by
immune cells.3,4,5 Zinc, by maintaining membrane stability, can restrict this secretion
and thus act as an indirect antioxidant. This and other indirect antioxidant actions
of zinc are noted in Table 5.1.
Not all zinc functions diminish equally during progressive degrees of zinc
deficiency. For example, in zinc-deficient rats, liver and erythrocyte activities for
cytosolic superoxide dismutase 1 are not low at all.15,16 In contrast, zinc status in
rats, humans, and a non-human primate does affect activities of extracellular super-
oxide dismutase,9,17,18 a protein distinct from superoxide dismutase 1.8 Among the
most sensitive of all zinc functions to mild zinc deficiency is membrane stabilization,

TABLE 5.1
Proposed Zinc Antioxidant Actions
Increase synthesis and likely inhibit degradation of the protein metallothionein, which can have
antioxidant actions6,7
Required for normal activity of superoxide dismutase antioxidant enzymes8,9
Inhibit inappropriate activation of pro-inflammatory cells (activation causes secretion of superoxide
radical and hydrogen peroxide, a radical precursor)3,4,5
Limit intracellular free radical production10
Block pro-oxidant reactions of redox-active transition metals11
Protect protein sulfhydryl groups against oxidant damage11
Protect against inflammatory cytokine-mediated activation of oxidative stress-responsive transcription
factors12
Promote absorption and reduce degradation of vitamin E13,14
which can affect multiple processes, probably including the third indirect antioxidant
function listed in Table 5.1.3 This effect of zinc deficiency is a hyper-responsiveness
of this aspect of the immune system, whereas other effects of zinc deficiency on
immune function produce under-responsiveness.3 These opposite effects of zinc
status on immune function may both be linked to membrane stabilization, though
zinc can also affect the immune system in other ways, such as activating the T-cell
regulator thymulin.3
Zinc movement within the body is less chaperoned than is iron or copper. In fact,
a lot of the zinc in serum just binds reversibly to albumin.2 Some other serum zinc
is tightly bound to a protein called alpha-2-macroglobulin, though the metabolic or
functional importance of that zinc is unknown.
Zinc movement in and out of cells is affected by cell concentrations of a protein
family called metallothionein. Metallothionein I and II are structurally similar, high
cysteine, low molecular weight proteins found in most cell types.6 The brain also
contains a brain-specific metallothionein III.19 Metallothionein proteins bind a vari-
ety of metals such as zinc, copper, and cadmium.6 In the liver and kidney, this binding
seems to play a role in inhibiting toxicity of these metals if they are present in high
concentrations. Also, in intestinal cells, metallothionein levels rise with high body
zinc, which appears to inhibit absorption of orally consumed zinc. In addition to
such detoxification actions, metallothionein in various tissues seems to be important
in drawing zinc into cells. This can be especially prominent during inflammatory
stress, where serum zinc falls and there is a rise in zinc bound to metallothionein
in the liver and kidney.20 Local inflammation in other body sites also brings about
a metallothionein–zinc build-up at those sites.21 Besides roles in zinc distribution,
metallothionein–zinc has other functions such as free radical scavenging.7 Synthesis
and possibly degradation of metallothionein are very sensitive to zinc nutritional
status as well as a number of other influences.6


Typically, serum or plasma zinc is used to assess zinc status.22 Very low values are
associated with severe zinc deficiency, and moderately low values can be associated
with marginal zinc deficiency.3,22,23 However, the use of serum or plasma zinc for
identifying marginal zinc deficiency has two major limitations. One, values are not
always sensitive to small changes in zinc status.24 Two, values are depressed by inflam-
mation and other physiological stress even without any degree of zinc deficiency.6,20,25
This has led to the need for additional methods of assessing marginal zinc deficiency,
though no ideal method has emerged. Even so, some methods seem to hold value
for this purpose. In this author’s opinion, for research purposes, a marginal zinc
deficiency can be declared if low values are seen for serum zinc plus one other
indicator of zinc status, particularly if values for both indicators are raised by zinc
supplementation. This author would also call a marginal zinc deficiency likely if
serum zinc is not low, but values are low for two other indicators of zinc status,
particularly if values for both are raised by zinc supplementation. Although these
approaches are not ideal for clinical health care assessments, they can be valuable
for clinical research. The methods for assessing zinc status, other than serum zinc,
are discussed below.
One method that receives occasional use is plasma alkaline phosphatase activ-
ity.26 Values for this measure are influenced by zinc status, since zinc is needed for
this enzyme activity.3 However, the activity values are also subject to so many other
influences that the use for zinc status is limited mainly to highly controlled inter-
vention studies (e.g., taking measures before and after a zinc supplementation
period). As an alternative, some laboratories now use erythrocyte membrane alkaline
phosphatase activities, since the activities are sensitive to small changes in zinc
status.27
Urinary zinc can also sometimes be a helpful measurement,22 but proper inter-
pretation of the results can be tricky. For example, a high urinary zinc value could
mean that zinc stores are high, or it could mean that excessive loss of zinc is adversely
affecting zinc status. Thus, the use of this measurement should be done in the context
of other measurements.
The zinc tolerance test is also sometimes used for zinc status evaluation.28,29 In
this test, a single dose of oral zinc is given and serum zinc changes are followed
over time. In principle, the faster the zinc is cleared, the less zinc is in the tissues.
This test has not been directly compared very much to other markers of zinc status
or to moderate dietary zinc depletion and repletion. One comparison to varying zinc
intake does not yield a strong support for this tool.30 Therefore, though the test’s
validity for assessing marginal zinc status may hold in some circumstances, there
are still some questions. On the other hand, the zinc tolerance test does seem useful
for studying acute, relative zinc absorption.31 An example of this use is the study of
an acute effect of calcium on zinc absorption.32
This author’s laboratory has assessed zinc status with plasma activities of the zinc
metalloenzyme 5′-nucleotidase.24,33 The author’s group has found that these activities
respond to moderate, relatively short-term changes in zinc intake in elderly subjects,
even in the absence of a change in plasma zinc.24 Activities of 5′-nucleotidase activities

are also low in mildly zinc-deficient rats (unpublished results), and extremely low in
type 2 diabetic women,33 a group prone to marginal zinc deficiency.34 In type 2 diabetic
women, 5′-nucleotidase activities are raised by zinc supplementation.33 The 5′-nucle-
otidase activity assay is a little quirky in that two long lag times must be monitored as
part of the method.35 Nonetheless, our laboratory has obtained very good reproducibility
(unpublished results). One limitation of this method of assessing zinc status is that
certain types of tissue injury can raise values.36 Still, this does not preclude the use of
this method in most types of studies. Blood cell membrane 5′-nucleotidase activities
have also been used to study marginal zinc deficiency,37,38 though the need for specific
blood sample processing can be a problem in some studies.3
Erythrocyte metallothionein protein contents, or monocyte metallothionein
mRNA, have also been shown to reflect zinc status.23,39 The protein values may
change a little slowly in response to elevated zinc intake, but this may actually be
helpful in studies where zinc intake varies a lot day to day. One limitation with
either type of metallothionein measurement is the methodology. The RNA measure-
ments require PCR, which is not routinely done by all research laboratories. The
protein measurements require an antibody to metallothionein that works well with
the assay employed. A number of antibodies from commercial sources and some
antibodies made by individual investigators don’t always work well for metallothio-
nein ELISA methods (based on this author’s own experience and conversations with
others). Another issue for these methods is the influence of factors other than zinc
status. Tissue metallothionein levels are affected by many regulators.6 It is not known
how many of these same regulators affect blood cell levels.
Plasma activities of the peptide thymulin, a T-cell immune regulator,3 are very
sensitive to marginal zinc deficiency in humans37,40 and in rats (DiSilvestro, R.A.,
unpublished data). Again, there are some factors other than zinc status that are known
to affect activities,41 but a correction for this can be done by running the assay with
and without added zinc. Adding zinc to the assay will increase activity in marginal
zinc status even if synthesis of the peptide portion of thymulin is high. A bigger
problem with the thymulin activity assay is that there are only two laboratories in
the world that have routinely done the activity bio-assay for zinc studies (Dardenne’s
group in France40 and Mocchegiani’s group in Italy42). There are commercially
available thymulin immunoassays, but they are not useful for zinc status assessments
since this status affects activity, not peptide levels.
Various white blood cell zinc contents can also be used to diagnose marginal
zinc status.3 The biggest issue here is that if the white cell subpopulations are not
constant, then subpopulations must be separated to get meaningful results. Erythro-
cyte zinc contents have changed in response to dietary zinc in some controlled
feeding studies, but this measure is not considered tremendously reliable for assess-
ing zinc status.22
One other assessment tool that is sometimes employed is hair zinc. This has
been used as an initial screening tool for marginal zinc deficiency in children.43 If
used for this purpose, care must be taken to minimize topical zinc contamination.
This is the only documented use of hair mineral analysis, and at that, it is a fragile
use in that it has many pitfalls.44,45 Nonetheless, some companies charge high fees
for unfounded uses of a range of hair mineral analysis.

In conclusion, evaluation of marginal zinc status may often require more than
one measurement and always requires attention to what else may be affecting values
for the measurements. For research purposes, the best approach is to take measures
before and after zinc supplementation.

Zinc seems to be absorbed best from animal products, though plant sources can
provide absorbable zinc.1,3 The best known inhibitor of zinc absorption is phytate,
a phosphate-containing compound that is particularly high in certain grain products
and some beans, including soybeans.1,3
A number of types of zinc supplements are sold. Most multi-vitamin–mineral
pills, as well as cereal fortifications, use zinc oxide. Most tests of this complex of
zinc, either in humans or other species, have found the absorption to be lower than
other zinc complexes.46 An exception has been for fortification of bread and other
wheat products where zinc oxide is reported to be equal to zinc sulfate.47 However,
in this study, both zinc complexes give a relatively low percent absorption.
Zinc sulfate is a standard form of zinc in experimental animal studies, and it
has been used in the past as a standalone zinc supplement. However, current human
use is limited mostly to just a few multi-vitamin–mineral supplements. Based on
animal studies, absorption of zinc sulfate appears to be superior to zinc oxide.48–51
There are reports of GI tract upset in some people who take zinc sulfate.52,53
Zinc gluconate is the most common standalone zinc supplement and is used in
zinc lozenges, which are discussed later. In one study, the use of a zinc tolerance
test shows zinc gluconate to be better absorbed than zinc sulfate.54 It can also be
noted that zinc gluconate has given positive results in a number of supplementation
studies, including some done for malnutrition situations.55,56 On the other hand, in
a small unpublished study from this author, zinc gluconate was very ineffective at
raising plasma zinc, while a zinc amino acid chelate raised plasma zinc in all subjects
tested (Figure 5.1). In addition, in a rat supplementation study, neither zinc gluconate
nor zinc sulfate was as effective as a zinc–amino acid chelate in protecting against
chemically induced oxidant damage.5 Thus, zinc gluconate seems to be a good source
of zinc for many purposes, though in some applications, it may not be the absolute
best source.
As just noted, zinc–amino acid chelates are also used as zinc supplements. At
present, there is not a lot of data comparing the stability and biological effectiveness
of such chelates from different suppliers. Thus, data on one zinc–amino acid chelate
may or may not be applicable to a zinc–amino acid chelate from a different source.
This author’s laboratory has completed two studies where zinc glycinate from Albion
Laboratories has produced positive results,33,57 but these studies did not make com-
parisons with other zinc preparations. On the other hand, the data in Figure 5.1
involves comparison of zinc glycinate with zinc gluconate, where the glycinate shows
better activity, though based only on plasma zinc readings. A number of animal
studies have shown good effects of one type of zinc–amino acid chelate or another,
which, in some cases, have been better than what is obtained from other forms of
zinc such as oxide or sulfate.46,58 However, in other studies, differences between

2
1.5
0.5
0
PRE POST PRE POST
GLUCONATE GLYCINATE
FIGURE 5.1 Plasma zinc response to zinc supplementation as gluconate (GLUC) or glycinate chelate (CHE). Young adult females were given 60 mg
zinc/day for six weeks. Post-treatment values for the glycinate but not the gluconate were significantly different from pretreatment (p < 0.001, paired t-test).

certain amino acid chelates and zinc sulfate have not been seen.58 Future research
should be done on various zinc–amino acid chelates from different suppliers in
regard to absorption and other bioactivities.
Another form of zinc supplement is zinc picolinate. Although zinc picolinate is
not used as much as chromium picolinate, this form of zinc has been shown to raise
serum zinc and improve taste abnormalities.59,60 In an old study, 50 mg of zinc as
zinc picolinate, but not as zinc gluconate or citrate, raises urine, erythrocyte, and
hair zinc in adult men.61 However, this study is a little hard to interpret, since none
of the three supplements raised plasma zinc, which normally would rise with 50 mg
zinc.
Zinc citrate is sometimes used in food fortifications and has been shown to be
reasonably well absorbed.62
In summary, zinc oxide appears to be the least desirable choice for a zinc
supplement. A number of other zinc complexes have been used effectively, though
some complexes may be more active in some applications. This last area could use
more research.

Severe zinc deficiency on a large scale in humans was first reported in areas of the
Middle East.3 Although multiple factors may have played a role, a major influence
was consumption of unleavened bread, which is high in phytate, which impairs zinc
absorption.3
Besides dietary causes of severe zinc deficiency, this state can also be produced
by a genetic condition where zinc absorption is impaired.3 This disease, acroderma-
titis enteropathica, is recognizable by a skin condition that develops at a very early
age. The condition can be treated with supplemental zinc.
Marginal zinc deficiency may occur in many people, though there are still many
questions here. One obvious theoretical reason why marginal zinc deficiency could
occur would be moderately low zinc intake. Many surveys have found moderately
low zinc in different groups. For example, in the U.S., analysis of the third National
Health and Nutrition Examination Studies indicates that a substantial number of
people in the U.S. do not eat the recommended amounts of zinc.63,64,65 At particular
risk are children aged 1 to 3 years, adolescents who eat a lot of low-nutrient-density
foods, adolescent females in general, and the elderly, especially but not exclusively
in low-income situations. There is also some doubt as to whether the zinc RDA is
even accurate (11 mg for adult men, 8 mg for adult women). The RDA has been
lowered over the years from the 15 mg that is used for the recommended intake on
food and supplement labels. The zinc RDA is based on balance studies (amount of
zinc needed to balance losses) rather than on functional indications. The balance
approach can be somewhat justified in that there is no clear choice for what to use
for zinc functional indicators. Even so, the balance approach to determining the zinc
RDA has drawn some questions for a long time.66
Besides zinc intake, other factors could also contribute to marginal zinc defi-
ciency. These include impaired zinc absorption, high zinc excretion, abnormal body
distribution of zinc (i.e., high levels of one zinc protein pool drains zinc from other

TABLE 5.2
Examples of People Groups Prone to Biochemical Signs
or Dietary Zinc Intake Patterns Consistent with Marginal
Zinc Deficiency
Crohn’s disease patients69,70 Sickle cell anemia patients71,72
Renal dialysis patients73 Children with Down’s syndrome74
Diabetic individuals33,75 Vegetarians76
Alcoholics77,78 People with hepatitis79
Rheumatoid arthritis patients80 Some types of young children81,82
Young adult females* Middle-aged adult females83
Adolescent/preadolescent girls84,85 The elderly (both genders)24,37,86
Some cancer patients87 People with AIDS88
This listing of people types is meant to provide examples and not be complete.
The same is true of references listed for each people type.
* DiSilvestro, R.A., unpublished results based on plasma zinc and 5′-nucle-

otidase activities in over 80 subjects
pools), and high needs for certain zinc functions. One or more of these factors are
suspected to produce marginal zinc deficiencies in a variety of types of people. Table
5.2 gives a list of some types of people where at least one study has shown this
group to be prone to marginal zinc deficiency based on dietary survey or biochemical
assessments. The listing of children with Down’s syndrome provides an example
where abnormal zinc pool distribution may be a key factor. In this case, such children
have an extra copy of a gene that codes for the enzyme copper–zinc superoxide
dismutase.67 Copper–zinc superoxide dismutase can account for a substantial portion
of a cell’s content of the metals contained in the enzyme.68 This is not typical for
most metalloenzymes in relation to a cell’s metal distribution, but it is true for
copper–zinc superoxide dismutase and these two minerals. The increase in this
enzyme in Down’s syndrome may draw zinc away from other functions unless extra
zinc is consumed. The same rationale could be applied to copper, but this has not
been tested.
Table 5.2 is not meant to be comprehensive but is meant to illustrate the range
of people who may be vulnerable. A complete list may grow in the future as more
people groups are studied for marginal zinc status.
Table 5.2 lists vegetarians since vegetarian diets are often lower in zinc than
are diets that contain meat.89,90 In addition, vegetarian diets can be high in factors
that reduce zinc absorption.1,3 There are also studies showing lower serum zinc
values in subjects consuming vegetarian diets.90,91 In contrast, there have been some
propositions that vegetarians can adapt to the low zinc intake and low zinc bio-
availability of some vegetarian diets by reducing zinc excretion and increasing zinc
absorption.1 This could turn a negative zinc balance (zinc losses exceed zinc gains)
into a zero balance (losses equal gains). There is evidence that this type of balancing
can go on to some extent with variations in zinc intake,92 but there is not extensive

characterization of how well it works for different types of vegetarian diets. Even
if overall zinc balance can be maintained in terms of zinc in vs. zinc out, it can be
asked: Are zinc functions maintained adequately during this process of balancing?
Since this question has not yet been answered, it seems wise to this author that
vegetarians should strive to eat the best non-meat sources of zinc (e.g., legumes
and certain grain products) or consider zinc supplementation.
In almost every one of the situations listed in Table 5.2, there is still uncertainty
about how frequently marginal deficiency really occurs. This uncertainty arises
mainly because large groups of people have not been tested thoroughly. There is
also uncertainty about what symptoms, if any, result from marginal zinc deficiency.
The symptoms may vary depending on what else is happening simultaneously. For
example, in someone with diabetes plus marginal zinc deficiency, there may be
increased risk of developing side complications, whereas in children with marginal
zinc deficiency, the most pronounced symptom may be poor growth. The whole area
of marginal zinc deficiency occurrence and consequences sorely needs more
research.

This section is among the longest in the book because so many different uses have
been considered for zinc supplements. In general, these applications have been given
research attention, though some applications have been given much more than others.
There is still a lot of question as to who should get zinc supplements and what
benefits they would have. Another issue is the dose to use. The doses have varied
considerably in different studies, and dose response curves are virtually non-existent.
OVERT DEFICIENCY CORRECTION IN CHILDREN

This book emphasizes supplement uses other than correcting overt deficiencies.
Nonetheless, it can be stated here that in certain parts of the world, where economics
limit food choices, the effects of zinc deficiency can be clearly seen in children.3
Zinc supplementation has been used successfully to treat zinc deficiency in a number
of settings. One example is protection against diarrhea in children.56 The possible
uses of zinc supplements for treating severe zinc deficiency requires more research
as to where supplementation is most needed, identification of the full range of
benefits of zinc supplementation, as well as the pros and cons of supplementation
vs. diet changes or food fortification.
CORRECTION OF MARGINAL ZINC DEFICIENCY IN YOUNG CHILDREN

Some classic examples of documented marginal zinc deficiency involve studies done
some time ago by Krebs and Hambidge on children in Colorado, U.S. These studies
are summarized below:
• Children are identified who have low values for hair zinc who also have
anorexia, poor growth, and poor taste sensitivity.93

• In young children with evidence of mild zinc deficiency, zinc supplemen-

tation improves food intake.81
• In children with low growth percentiles, zinc supplementation improves
growth.82
• Intake of a zinc-fortified food product increases plasma and hair zinc
values.94
• In children with pica, a rapid improvement follows zinc supplementa-
tion.95
There have also been studies by other investigators suggesting that zinc supple-
mentation can improve growth in short children with marginal zinc deficiency.96,97,98
In one of these studies, the effect is most pronounced when treatment includes iron
supplementation.96
Other work concerning marginal zinc deficiency and zinc supplementation in
children has concerned possible connections to physical activity maturation, motor
development, and cognitive function development, particularly in the area of neu-
ropsychological processes. These studies have not been extremely extensive yet, and
the results have been conflicting.99,100 This inconsistency is not terribly surprising
considering all the potential nutritional and non-nutritional variables that can influ-
ence these health effects. In addition, in these studies, there can be variations in
assessment methodology, the choice of zinc complex and dose, subject age range,
and other variations. In this author’s opinion, it is safe to say that some children
would probably be helped in these areas by increasing their zinc intake via diet or
supplementation. However, there is just no good clinical practice yardstick to say
who these children are and how much zinc they should get. Even so, this author
feels that clinicians and community public health specialists should be more aware
of the possibility of marginal zinc deficiency in children. This author recommends
the use of hair and serum zinc monitoring in individual patients or in populations
that show poor growth. Despite the limitations of these methods in diagnosing
marginal zinc deficiency, more often than not, low values would likely be informative
about children who have no other severe health problems.
SELECTED BREAST-FED INFANTS

Some infants who are exclusively breast fed can develop symptomatic zinc defi-
ciency. In these situations, the deficiency seems to result due to a defect in transfer
of zinc from maternal serum to breast milk.101,102 Supplementation with zinc is a
practical means for addressing this problem. In addition, an appropriate solid food
introduction strategy should be adopted.
PREMATURE INFANTS
Premature infants can show biochemical signs of zinc deficiency such as low serum
zinc values both right after birth and during growth spurts in the first year post-
birth.103–107 The cause may be similar to that which may occur for premature infants
with iron and copper deficiencies. Specifically, premature birth cuts out the latter

stages of pregnancy where the inborn baby stores substantial amounts of zinc.
These stores are supposed to meet much of the zinc need for the first six months
or more past birth. If a child is born prematurely, the time to build these stores is
eliminated or minimized, which can result in some degree of zinc deficiency.
Although signs of some degree of zinc deficiency are found in premature infants,
there are two major questions connected with this issue. One, what percent of
premature-born children actually have substantial problems with zinc deficiency?
Two, what physiological consequences are associated with this deficiency? Unfor-
tunately, not enough research has been directed toward these questions. One excep-
tion is a recent study reporting a zinc-induced increase in linear growth at six
months corrected postnatal age, along with higher serum zinc and serum alkaline
phosphatase activities.108
IMMUNE FUNCTION
Immune function can affect resistance to classical infectious diseases as well as
resistance to other problems such as cancer and stroke.109,110 In rats and mice, immune
function seems to be especially sensitive to marginal zinc deficiency.3 Therefore, one
could expect that indices of immune function would be among the easiest measures
to change with zinc supplementation. Consistent with this idea, a number of studies
of zinc supplementation have shown improvements in one aspect or another of
laboratory assessments of immune function. These are summarized in Table 5.3. It
should be noted that many of the measurements in these studies are biochemical or
cellular, such as changes in readings for immune regulatory molecules, cell popu-
lations, antibody titers, short-term vaccine responses, and blood cell secretion rates
of specific molecules ex vivo (rates assessed after blood removal from the zinc-
supplemented subjects). These measurements, though very important, cannot always
be translated into a quantitative assessment of how zinc supplements would affect
more practical outcomes such as infection incidence, protection against cancer onset
or reoccurrence, impact on stroke risk, and so on.
TABLE 5.3
Subject Types where Zinc Supplementation has
Improved Measures of Immune Function
Down’s syndrome children114,115 Renal dialysis patients116,117
Burn patients112 The elderly86,118
Cancer patients87,119 Sickle cell patients71,111
People with AIDS42 Rheumatoid arthritis patients120
Preschool children55 Low birth weight infants113
Alcoholics121
Men with experimentally induced
marginal zinc deficiency122
People groups listed and references used are representative and not
exhaustive.

However, there are a number of studies that do look at practical consequences.

In one such study, which involved sickle cell anemia patients, zinc supplementation
has practical impacts on immune health including decreased incidence of docu-
mented bacteriologically positive infections.111 Although the number of subjects was
not tremendously large, these results merit follow-up. In another study, zinc supple-
mentation of burn patients produced a significant decrease in the number of bron-
chopneumonia infections.112 In still another study, low-birth-weight infants in Brazil
showed a reduction in the prevalence of cough in response to zinc supplementation.113
In yet another case, zinc supplementation of people with AIDS lowered the rate of
opportunistic infectious episodes.42 Finally, in a group of children with Down’s
syndrome, zinc administration reduced the incidence of infections.114 More on zinc
and Down’s syndrome is presented in the Down’s Syndrome subsection.
Thus, these studies suggest that zinc supplements can have good effects on
immune function in a variety of people. Nonetheless, research in an area like this
normally has to become very extensive before a general consensus is reached that
a given intervention should be a standard procedure. It should also be noted that not
all studies of zinc supplementation have shown effects on immune function, even
in subjects that seem to overlap those of Table 5.3.123,124,125
Three reasons for the inconsistency could be the starting zinc status of the
subjects, the dose used (high doses of zinc can be immunosuppressive; see the
Toxicity section), and the type of immune parameter measured. In the latter regard,
some aspects of immune response should be more apt to respond to zinc than others.
As far as starting zinc status goes, it is noteworthy that the subject types listed in
Table 5.3 are generally also listed in Table 5.2 as groups prone to marginal zinc
deficiency. Therefore, it would be simple to conclude that zinc supplements tend to
help with immunity when there is a degree of zinc deficiency, and do not help when
there is not any deficiency.
However, there are two problems with this simple conclusion. One, not all studies
of zinc supplements and immunity have monitored overall zinc nutritional status.
Therefore, to state that starting zinc status affects response to zinc supplements is
an assumption, not a confirmed conclusion. Moreover, there is at least one study
reporting that zinc-replete subjects can respond to zinc supplementation with boosted
immunity based on vaccine response.126 However, this study must be interpreted
cautiously in terms of “zinc replete,” since the study makes that assertion based
solely on normal range serum zinc values. Serum zinc is not always an infallible
indicator of marginal zinc deficiency.22
The studies showing zinc supplementation and improved immune function in
cancer patients are still extremely limited in scope. One study was done in China
on a group of subjects87 whose zinc status is very uncertain in comparison to other
parts of the world. Another study involves a small group of lung cancer patients,
which may or may not have applicability to a broader cancer patient population.119
Whether or not zinc supplements can safely improve immunocompetence in a large
percentage of cancer patients, undergoing various types of treatments, is still a very
underdeveloped research area.
The benefits of zinc supplementation on immune function, or on other aspects
of health in alcoholics, has not been studied extensively. An old, small study does

report an improvement in one parameter of immune function with high-dose zinc

supplementation.121 One problem with studying alcoholics and zinc is that cytokine
metabolism can be abnormal in alcoholics,127 which can alter serum zinc values.6
This could explain why low serum zinc values do not always respond to zinc
supplementation.
DOWN’S SYNDROME
As noted above, Down’s syndrome is associated with an extra copy of a gene that
codes for a protein that can account for a good deal of a cell’s zinc.67 This could
rob other zinc pools of this metal unless moderately high zinc levels are consumed.
There may be other zinc metabolism abnormalities as well in this population.
Quite a few studies report a beneficial effect of zinc supplementation in people
with Down’s syndrome.74,114,115,128–132 These benefits are not a cure of the disease,
but include the above-noted improved immune function, as well as enhanced DNA
repair, and desirable hormonal changes, especially for thyroid hormones. It can be
pointed out that trials with larger numbers of subjects would be useful. However,
some would argue that there is already enough data to justify clinical use of low-
dose, long-term zinc supplements in Down’s syndrome. On the other hand, there
has been a letter to the editor in one journal cautioning that zinc supplements in
Down’s syndrome could increase the risk of later Alzheimer’s disease.133 However,
the link between zinc and this problem is still very debatable from a physiology
standpoint, and not studied at all from a nutrition standpoint (see the Toxicity
section). In addition, the above-mentioned letter drew a response letter that argues
that zinc may help people with Down’s syndrome lower Alzheimer’s disease risk.134
One drawback of routine use of zinc supplements in Down’s syndrome could
be an antagonism of copper absorption.6 Although low doses of zinc should not
bother copper function in copper-adequate people, much less is known about the
effects in people with marginal copper deficiency. Down’s syndrome patients prob-
ably fall into this category, though this has not been checked by research. However,
the theoretical reason to expect copper deficiency is strong. The zinc protein that is
over-expressed in Down’s syndrome is superoxide dismutase 1, which also contains
a high percent of a cell’s copper content.68 One objection to the Down’s syn-
drome–copper deficiency hypothesis is that serum copper values are high in some
studies of Down’s syndrome.135 However, it should be noted that under some cir-
cumstances, serum copper can be high despite some degree of copper defi-
ciency.136,137 Thus, the best mineral treatment for Down’s syndrome may be a modest
dose of zinc plus a modest dose of copper, with both minerals given as well-absorbed
complexes. However, before this can be recommended, the copper status and metab-
olism of Down’s syndrome patients needs to be evaluated to determine that copper
supplements would do no harm.
MACULAR DEGENERATION
A number of years back, a pilot study was presented suggesting that zinc supple-
mentation could slow macular degeneration, the leading cause of blindness in the

elderly.138 Although the study design may have had some limitations, as pilot studies
often do, the study drew considerable attention to the possible relationship of zinc
and eyesight loss. One difficulty in studying macular degeneration is the slow
progression of eyesight loss. A lengthy research project, known as the AREDS study
(Age-Related Eye Disease Study), finished recently.139 In this work, subjects were
given either placebo, zinc plus copper, an antioxidant vitamin cocktail, or zinc/copper
+ the cocktail for five years. Modest effects on eyesight protection are reported for
either the zinc or antioxidant treatments in a study subpopulation, with a little better
response with the combination treatment.139 Possibly, the effect would have been
better with an even longer study, but obviously, the length previously used already
required a large commitment of funds and professional time. Another concern about
the AREDS study is the use of a high dose of zinc oxide rather than a lower dose
of a better absorbed form of zinc. In addition, the antioxidant cocktail used in
conjunction with zinc may not have been the optimal preparation. It would be
interesting to see the results of an upgraded study, but due to the time and money
needed, we may not ever see such a study.
ACNE
Zinc has been tried both orally and topically for treatment of acne. One might assume
that the oral zinc would treat acne by correcting a marginal zinc deficiency. This
assumption would derive from the fact that the genetic zinc deficiency noted earlier
is characterized by a dermatitis-like condition.3 However, there is not a lot of direct
evidence that more moderate forms of zinc deficiency can produce skin problems
such as acne. In one study, subjects with the most advanced acne in the study group
had lower mean serum zinc than other subjects in the study.140 However, this could
be as much a marker of inflammation as of zinc status.6 Thus, any effectiveness of
zinc against acne may or may not be limited to correction of a deficiency. An
alternative basis for zinc in acne treatment could be an anti-inflammatory effect due
to an above-adequate zinc intake.
A number of studies have found that zinc supplements can reduce acne, partic-
ularly inflammatory acne.141–144 In most cases, the zinc doses are high, which is
consistent with an anti-inflammatory effect. This approach has drawn some concern
because high-dose zinc can cause copper deficiency.1 Indeed, a number of the case
studies of high-dose zinc supplements causing copper deficiency involve people who
were trying to treat acne.145,146,147 However, the idea that zinc doses must be extremely
high to treat acne may be flawed. At least one study reports effectiveness with just
a moderately high zinc gluconate dose (30 mg zinc/day).142
Despite some observations suggesting that zinc can treat acne, it is still debatable
as to whether the effect is better than, or even equal to, alternative treatments. In
addition, since many of the studies with positive results for zinc tend to emphasize
inflammatory acne, zinc’s effectiveness on acne may not be as good with other types
of acne.
Besides oral zinc use for acne, topical use has been considered. This use, since
it is not a supplement issue, is not covered here.

WOUND HEALING
There is no question that severe zinc deficiency impairs wound healing, possibly
via multiple mechanisms.3 However, it is less clear if oral zinc supplements can help
wound healing by correcting marginal zinc deficiency, or if zinc can have benefits
beyond correcting deficiency. Much of the support for recommending zinc supple-
ments for wound healing have come from topical zinc applications,148 which may
not be relevant to oral supplementation. Some other support has been derived from
an old study on young men with wounds caused by excision of pilonidal sinuses.149
This study reports that zinc helps subjects who have low serum zinc. In addition,
there are some studies on zinc and certain types of ulcerations. A meta-analysis
concludes that while oral zinc sulfate does not appear to aid healing of leg ulcers,
it might be beneficial in those with venous leg ulcers and low serum zinc.150 These
two considerations have led to the attitude that zinc supplements help with wound
healing, but only in people with some degree of zinc deficiency. Unfortunately, this
conclusion has been built on relatively little data. For one thing, the venous ulcer
data may not be relevant to other types of wound healing. Moreover, the older
study149 has not had confirmation. Furthermore, even if zinc is effective for wound
healing when there is low serum zinc, this could reflect that effectiveness is tied not
to poor zinc status, but rather the presence of inflammation, which can also depress
serum zinc.3
In this author’s opinion, we still know very little about any of the following:
• The degree of zinc deficiency necessary to impair wound healing

• Whether zinc supplements can help with wound healing in the absence
of any deficiency
• What range of wound types might be helped by zinc supplements
This sort of uncertainty is echoed in an opinion article that appeared awhile ago
in the journal Lancet.151 Although a number of years have passed since that article
appeared, not much new research has occurred in this area.
In this author’s opinion, since low-dose zinc supplementation probably won’t
hurt healing, such supplementation is reasonable in people recovering from wounds.
On the other hand, high-dose zinc supplements would not be a good idea because
of possible antagonism of the absorption of copper, which is also needed for wound
healing.152
ZINC–CARNOSINE AND ULCERS

This particular zinc complex has been proposed for use in the healing of gastric
ulcers. The strategy is that complexing zinc with carnosine delays exit of zinc from
the stomach and also sticks zinc to the ulcer.153 This retained zinc, being anti-
inflammatory, can promote healing of the ulcer (the carnosine itself may also have
anti-inflammatory effects). The anti-ulcer activity has been tested in experimental
animals154 and in a whole series of clinical trials in Japan, though finding the
publications can be challenging. Some of the results are mentioned in a review

article.155 This author has read reports of these studies. In his opinion, the design of
these studies for zinc–carnosine and ulcers is not always spelled out well in the
reports, and some have questionable aspects of design. Nonetheless, the sheer num-
ber of subjects, the impressiveness of the reported efficacies, and the multi-site nature
of the studies all suggest that the potential anti-ulcer efficacy of zinc–carnosine
should be taken very seriously. Even so, a new, well-controlled clinical study would
be useful to see if the anti-ulcer use of zinc–carnosine can be confirmed.
RHEUMATOID ARTHRITIS/CROHN’S DISEASE

Although zinc can stimulate immune function, it can also suppress some aspects of
the immune system relevant to oxidant stress and inflammation.4,5 In addition, zinc
could conceivably help with inflammation via the other indirect antioxidant effects
of zinc (Table 5.1). This leads to the logical question: Are zinc anti-inflammatory
actions of any value in arthritis or Crohn’s disease, either for correction of marginal
zinc deficiencies or for pharmacological purposes? The answer is that we don’t
know. As far as correction of a marginal deficiency in arthritis, there is some limited
evidence that marginal zinc deficiency may be common in people with rheumatoid
arthritis. First, low-serum zinc has been reported for people with rheumatoid arthri-
tis,156,157 though this could just be due to cytokine release, which can lower plasma
zinc via regulatory mechanisms.158 In fact, in one study of human arthritis,156 serum
zinc correlates inversely with serum values for two cytokines.
On the other hand, there is a study that, based on a zinc tolerance test and urinary
zinc, implies that rheumatoid arthritis patients may be prone to marginal zinc defi-
ciency.80 However, as noted above, these methods are not overly confirmed means
of assessing zinc status. On the other hand, based on zinc metabolism and inflam-
mation in rats, one could make a theoretical argument that inflammation, as occurs
in arthritis, raises dietary zinc requirements. In rats, inflammation greatly increases
the amount of the zinc-binding protein metallothionein in the liver and other tis-
sues.6,20,158,159 It can be reasoned that since this increased metallothionein becomes
the largest zinc pool in tissues, zinc will be pulled from other pools unless dietary
zinc is moderately high. Although this idea makes sense, it has not been confirmed
directly, even in rats.
If zinc needs are raised by arthritis, this could be especially problematic if zinc
intake is also moderately low. Indeed, one paper finds that rheumatoid arthritis
patients in New Zealand tend not to eat even the amount of zinc recommended for
healthy people.160 The same is true for a study of similar subjects in the U.S.161
If marginal zinc deficiency is common in people with rheumatoid arthritis, then
what would be the benefits of correcting it? One possibility is that the primary
symptoms of arthritis may diminish, particularly if combined with other therapy.
Another possibility is that other aspects of health would be improved. Unfortunately,
neither of these possibilities has been tested very much. For the second possibility,
two studies have been done. In a very small study (five subjects), which is not
placebo controlled, supplementation with beta-alanyl-L-histidinato zinc improves
some, but not other, parameters of bone health.162 In another study, zinc supplemen-
tation improves one measure of cellular immune function, though in the authors’

own words, the clinical importance of this effect is unknown.120 Therefore, in people
with rheumatoid arthritis, the possibility that zinc supplementation correction of
marginal zinc deficiency helps with primary or secondary symptoms is interesting,
but very much untested.
In addition to correcting marginal zinc deficiency, zinc supplements may also
have a benefit for arthritis from a pharmacological perspective. This case could be
made by noting the following:
• High doses of zinc can certainly be anti-inflammatory in animals.10,14

• Topical zinc has been anti-inflammatory for ulcers in humans.148
• Oral zinc–carnosine appears to have anti-ulcer activity,155 which is a type
of anti-inflammatory effect.
• An old pilot study reports that very high-dose zinc supplementation can
cause some clinical improvement in rheumatoid arthritis patients.163
The last study is counter-balanced by a small study with zinc sulfate, which
does not show long-term improvement in rheumatoid arthritis patients.52 Thus, at
present, despite some background rationale, the following question still remains:
Can high-dose zinc supplementation provide a safe treatment that can exceed or
extend what is already accomplished by current therapies? This question has simply
not been answered yet.
The same questions about zinc supplementation and arthritis can also be asked
about Crohn’s disease. However, compared to the situation with rheumatoid arthritis,
marginal zinc deficiency seems to be a little more established for Crohn’s dis-
ease.164–167 In Crohn’s disease, zinc status would not only be influenced by inflam-
mation effects on body zinc distribution, but in some subjects, there is also impaired
zinc absorption.168,169 Even so, not all reports on zinc status in Crohn’s disease
consistently find evidence of marginal zinc deficiency in all patients.170,172,173 Studies
on zinc supplementation in people with Crohn’s disease are limited. One study shows
a supplementation-induced rise in two markers of zinc status.171,175 In addition, a
project is nearing completion in this author’s laboratory on zinc supplementation in
Crohn’s disease.
In conclusion, there is a basis to suspect that marginal zinc deficiency occurs in
some people with rheumatoid arthritis or Crohn’s disease. The possible benefits of
correcting these marginal deficiencies is not yet well tested, nor is the possible value
of zinc pharmacological treatments.
CANCER PREVENTION
Two zinc actions, antioxidant effects and immunostimulation, are consistent with
cancer risk reduction. Furthermore, epidemiologic studies and some experimental
animal work suggest that some degrees of zinc deficiency may be associated with
increased risk of some types of cancer.172 Of particular interest are two epidemiology
studies showing an inverse relationship between zinc intake and skin cancer.173,174
What makes these studies particularly interesting is that they cover two different
countries, do not involve overt malnutrition, and do not show a relationship for most

other nutrients tested. However, these results are somewhat confusing in light of a
paper reporting high serum zinc values in melanoma patients.175
Unfortunately, further consideration of zinc–cancer risk via supplement studies
has not yet developed. The few zinc supplement intervention studies in this area
have used zinc in combination with other micronutrients, which makes the results
difficult to interpret.
EXERCISE
Strenuous exercise alters zinc metabolism,176 but this does not necessarily mean that
strenuous exercise raises zinc nutritional needs. For example, serum zinc can be
depressed by strenuous endurance exercise, but such depressions can simply be an
inflammatory response.6 There are various reports saying that zinc nutritional status
may or may not be compromised in a number of types of endurance athletes or other
people who engage in strenuous exercise.176 However, most of these studies are
based on serum, sweat, or urine zinc, which are not always a reliable means of
assessing zinc nutritional status. Also, some of the studies176 focus on very specific
types of people, where the results may or may not apply to other circumstances.
Thus, at present, it is hard to say whether exercise influences zinc needs.
There are a lot of functional reasons why good zinc status or extra zinc might
influence exercise performance. These include antioxidant and anti-inflammatory
actions (which can enhance muscle recovery), hormonal effects, energy substrate
utilization, cell signaling, and others. There has also been speculation that poor zinc
status combined with habitual strenuous exercise has particularly negative effects
on immune function and bone health. However, at present, we simply don’t know
whether zinc supplements can actually be of major help for exercise performance,
or help with immune function or bone health in exercisers. There is one study of
acute supplementation with zinc before exhaustive running.177 There is no effect
noted for some metabolic and endocrine responses. In contrast, short-term zinc
supplementation does show some effects on blood flow properties and exercise
tolerance in submaximal evidence in 10 men.178 In another small study (five subjects),
zinc plus copper supplementation lowers postexercise activation of phagocytes, a
process that leads to oxidant stress.179 Even so, a lot more subjects, types of settings,
and measures need to be done before making any big conclusions on zinc supple-
ments and exercise.
A current popular supplement for exercise is “ZMA,” which contains zinc,
magnesium, and vitamin B6. A meeting abstract reports some benefits for ZMA in
exercise performance,180 but more detailed reports will be needed to evaluate these
findings. Some Internet sites claim that other research backs up this product, but the
research cited is not specific to ZMA. Rather, the research deals with zinc function
in general or zinc supplements in contexts that may not be relevant to the people
most apt to use ZMA.

HEPATITIS
Mild zinc deficiency makes rats highly vulnerable to chemically induced liver
injury,159,181 while pharmacological zinc injections have the opposite effect.182 The
relevance of the latter to human hepatitis situations has never been tested. As far as
marginal zinc deficiency, there is evidence that it may occur frequently in at least
some forms of hepatitis. This evidence for marginal zinc deficiency is low serum
zinc in hepatitis patients,183,184 low serum 5′-nucleotidase activities in subjects with
fulminant hepatitis,185 low values for zinc tolerance test in one category of liver
damage (though not in another),186 elimination of a skin lesion with zinc supple-
mentation in a few patients with hepatitis C (not a controlled study),187 hepatic liver
content that decreases as severity of hepatitis increases,188 and low polymorphonu-
clear cell zinc contents in certain hepatitis patients.189
Although this seems like an impressive list, the evidence is not all that tight.
Many of the studies use small subject numbers, the serum zinc results can be
explained by regulatory factors unrelated to zinc nutritional status, and the designs
are not always ideal. Nonetheless, the range of the studies noted in the previous
paragraph at least raise the possibility that many people with some forms of hepatitis
have a degree of zinc deficiency. This idea is reinforced by a very interesting study
in hepatitis C patients.190 A group of responders and non-responders to interferon
therapy are examined for serum zinc and liver metallothionein. The responders have
higher serum zinc and most show therapy-induced increases in liver immunoreactive
staining for metallothionein (non-responders show a decrease). Since in rats, met-
allothionein induction by several agents can be inhibited by even moderate zinc
deficiency,159,181 the work in humans on interferon therapy190 suggests that responders
have better zinc status than non-responders. In fact, interferon induction of metal-
lothionein could possibly be a mechanism by which this therapy works. If that is
the case, then adequate zinc status would be needed for the therapy to be effective.
This idea is supported by a study in which zinc supplementation enhances the
response to interferon therapy in certain patients with intractable chronic hepatitis
C.191 The effect of zinc supplementation by itself is not reported.
In summary, zinc status may be compromised in many people with hepatitis
(though the data is not airtight), zinc supplementation helps some hepatitis C patients
respond to interferon therapy (at least based on limited study), and mild zinc defi-
ciency and pharmacological zinc affect hepatitis in rat models (but similar studies
have not been done in humans).
OSTEOPOROSIS PREVENTION
In principle, zinc can affect bone via multiple mechanisms, which include:
• Enzymatic roles in bone matrix structure192

• Regulatory stimulation of bone formation and inhibition of bone
resorption3
• Cofactor role in alkaline phosphatase, a key enzyme in bone synthesis3

• Stimulation of the production of hormones like IGF, which influence bone

health193
• Antioxidant actions (Table 5.1) (bone resorption is stimulated by certain
oxidant stress194)
Although this is an interesting area for future research, there are just a few
studies as to how much variations in zinc intake or zinc supplementation affect
osteoporosis risk. In one such study,193 dietary zinc supplementation correlates with
IGF values in postmenopausal women, and IGF increases with zinc supplementation.
In other work, in healthy adult males in Belgium, zinc supplementation increases
blood activities of alkaline phosphatase as well as bone-specific alkaline phos-
phatase, which is involved in bone synthesis.195 However, this study is hard to
interpret for the following reasons:
• Values for a urine marker of bone resorption are unaffected.

• Young adult men in meat-eating communities tend to be in good zinc
status.
• Bone metabolism tends to be problematic in fewer young adult men than
women.
• The changes in blood readings for bone-specific alkaline phosphatase are
hard to interpret because blood activities should go up with better zinc
activation but down with better bone synthesis (less release into the blood).
There are a couple of other positive studies for zinc on bone-related measures,
but neither presents a totally clear picture.162,196 In one case, as noted earlier, a
particular zinc complex, usually used for ulcers, had beneficial effects on some but
not other measures of bone health in a group of arthritis patients.162 However, the
subject number is very small, there is no placebo control, and the zinc complex used
may have specific pharmacological actions beyond zinc status impact. In the other
study, bone loss in healthy older postmenopausal women is reduced by calcium plus
a zinc-inclusive trace element cocktail.196 Although this is interesting, it is hard to
know what role is played by any of the individual minerals.
There is also at least one study with a negative finding for zinc supplementation
and bone health.84 In pubertal girls, supplementation with 15 mg of zinc as citrate
has no effect on serum IGF nor on a urinary measure of bone resorption.
Therefore, at present, although zinc has a possible theoretical role in preventing
osteoporosis, practical research in this area has barely begun.
RENAL DIALYSIS PATIENTS

Renal dialysis patients seem prone to some degree of deficiency for a number of
nutrients due to low intakes or high needs.79 Low serum zinc values have been reported
for dialysis patients in a number of studies.117,197 This could indicate a tendency toward
marginal zinc deficiency, but it could also just indicate inflammation, which can lower
serum zinc independently of zinc nutritional status.6 The former explanation is sup-
ported by the results of zinc tolerance tests in renal dialysis patients.73

There have been papers reporting an inverse correlation between serum zinc and
some other factor such as antibody response to immunization.198 The papers typically
interpret this to mean that zinc status is a major factor in determining health in
dialysis patients. However, subjects with the lowest serum zinc may simply be those
with the most inflammation, which could mean those with the worst overall health.
Thus, at this point it is hard to say if zinc status has a major impact on health in
dialysis patients. Nonetheless, there are some supplementation studies that lend
credibility to the idea that zinc status is a problem in many dialysis patients.
In one such study, zinc is administered to a small group of patients in the lowest
30th percentile for serum zinc among a group of dialysis patients.199 The adminis-
tered zinc raises serum alkaline phosphatase, which can be an indicator of zinc status
in some situations.22 In other work with hemodialysis patients, zinc supplementation
decreases osmotic fragility and lipid peroxidation,200 which are two symptoms of
zinc deficiency in rats.3 In still another study of renal dialysis patients, zinc supple-
mentation increases the protein catabolic rate.201 There are also studies in this same
type of subjects showing that zinc supplementation can increase serum thyroid
hormone levels and have various positive effects on immune function.117,202,203 For
example, zinc administration improves lymphocyte function in a way that seems to
be mediated by increased intracellular ATP.116 In addition, an old study finds that
zinc supplementation can improve gonadal function in dialysis patients.204 Further-
more, zinc supplementation in dialysis patients improves food intake and serum
cholesterol readings.205
In light of the above studies, zinc supplementation would appear to be beneficial
for at least some dialysis patients, but that conclusion is not totally clear. Some of
the above-mentioned studies do not have a large number of subjects, and there are
other studies where zinc supplementation does not show an intended benefit.206,207,208
In some of the negative studies, questions can be raised about design. For example,
one study looks for an increase of zinc in the leukocytes and an enhanced response
to a vaccination.206 However, leukocyte zinc in people with health problems is not
always very informative since there are frequent variations in leukocyte subpopula-
tions, which vary greatly in their zinc concentrations.3 In addition, the subject number
is low in this study.206 Furthermore, the zinc administration protocol consists of
adding zinc chloride to the dialysate. Zinc chloride may not be an ideal complex
for this means of zinc delivery. In fact, in this study, serum zinc is not elevated,
which would be expected if the administered zinc was retained well. Nonetheless,
one cannot simply dismiss the negative findings of this or some other studies without
further new studies.
In this author’s opinion, there needs to be a study that evaluates different types
of dialysis patients (varying ages, dialysis treatment type, medications, other com-
plications, dietary practices, etc.). This study should include various indicators of
zinc status before and after zinc supplementation. If such a study demonstrates
marginal zinc deficiency in a high percentage of the patients, then various doses of
zinc supplementation should be tested for effects on health parameters such as
immune function and hormonal make-up. This examination should be done in both
the subjects that appear to be zinc deficient and in subjects with the best zinc status.

This will determine what benefits are associated with correcting zinc deficiency, and
if zinc can have any benefits apart from such correction.
In the meantime, in the absence of such a study, it seems that a low-dose zinc
supplement may help some people on dialysis without posing a risk. The one red
flag here is that one study finds high erythrocyte zinc in dialysis patients.209 If this
is some sort of toxic reaction, then zinc supplementation may be problematic. On
the other hand, the high erythrocyte zinc may just reflect abnormal blood cell
metabolism. There could be a high number of erythrocytes at a cell age where they
accumulate more zinc. Alternatively, some abnormal physiology in dialysis patients
may elevate erythrocyte levels of a zinc-accumulating protein such as metallothio-
nein. In that case, increasing zinc intake may help fill non-erythrocyte zinc pools
depleted by zinc movement into the erythrocyte. Based on general trends in zinc
metabolism, this author feels that the high erythrocyte zinc contents in dialysis
patients is not a good reason to avoid low-dose zinc supplementation. Even so, this
author would like to see some study of erythrocyte zinc metabolism in dialysis
patients.
CARDIOVASCULAR DISEASE
In terms of the two most common evaluators of cardiovascular disease risk, blood
pressure and blood lipid profiles, zinc has not been given much attention as a cause
of problems. On the other hand, there is a little bit of work suggesting that some
drugs given for hypertension may tend to compromise zinc status.210 However, this
is not the same as saying low dietary zinc can cause or aggravate hypertension
(though there is one recent study in rats along these lines).211 If zinc does affect risk
of cardiovascular disease, most of the effect is likely to be due to actions other than
lowering blood pressure or serum lipid values. Alternative actions could include the
indirect antioxidant actions of zinc (Table 5.1), which can restrict inflammation,
which is thought to contribute to atherosclerosis.212 Certain immunosuppressive
actions, such as restricting cytokine actions, could also work against cardiovascular-
relevant inflammation. These anti-inflammatory actions may be especially useful for
protecting against endothelial integrity12 and for inhibiting lipoprotein oxidation, an
initiator of atherosclerosis. A zinc effect on the former has been demonstrated in
cell culture work,12 which the latter has been shown to be dramatically affected by
mild zinc deficiency in rats.213 Zinc function may also be important to maintaining
cardiac muscle integrity. Along these lines, one study suggests that zinc status is
poor in subjects with dilated or hypertrophic cardiomyopathies.214 Unfortunately,
the subject number in this study is small and bases zinc status on zinc in the urine,
plasma, and erythrocytes, none of which are among the best ways to identify
marginal zinc deficiency (see Nutritional Status Assessment). Nonetheless, the study
is interesting and merits follow-up.
There have been two studies on zinc supplementation and lipoprotein oxidation,
neither of which finds any effect.33,215 However, neither study holds the last word
on the subject. In one study,33 which is from this author’s laboratory, the zinc
supplementation period (three weeks) may have been too short to see an effect. The
subjects are type 2 diabetic women in poor glucose control, which show very bad

zinc status based on plasma zinc and 5′-nucleotidase activities. The supplementation
treatment does not fully restore adequate zinc status based on the latter parameter
(which increases but does not normalize) in the subjects. Thus, the lack of effect on
lipoprotein oxidation may require a better improvement in zinc status. In the other
study,215 young healthy men are examined, which may mean that zinc status was
already good before supplementation.
In summary, zinc status may affect risk of cardiovascular disease primarily via
mechanisms that don’t involve lowering blood pressure or serum lipid values. How-
ever, the extent to which zinc status typically affects risk is still very uncertain.
DIABETES
Type 1 and type 2 diabetes increase urinary zinc losses.76 In addition, based on a
rat study, diabetes pushes relatively large amounts of zinc into certain pools,216 which
may increase the amount of zinc needed to fill other pools. These effects of diabetes
would be expected to make people very vulnerable to some degree of zinc deficiency.
Indeed, there are signs of marginal zinc deficiency in diabetic subjects.33,75,217 How-
ever, the work in this area cannot be called exhaustive nor 100% consistent. Some
questions that are not completely answered are:
• What percentage of people with diabetes have some degree of zinc

deficiency?
• Does glucose control affect the tendency toward zinc deficiency?
• Do factors such as gender and disease treatment affect the tendency toward
zinc deficiency?
• What health consequences accompany marginal zinc deficiency in
diabetes?
One way of answering the last question is to see what happens when marginal
zinc deficiency is reversed by zinc supplementation. As noted earlier, this author’s
laboratory has done one such study.33 Three weeks supplementation with 30 mg of
zinc as glycinate, but not placebo, raises plasma zinc and plasma activities of the
zinc enzyme 5′-nucleotidase in 20 type 2 diabetic, postmenopausal women. However,
the latter increase, though substantial, does not bring activities back to normal. As
noted earlier, the zinc supplementation in these subjects does not affect lipoprotein
oxidation, but this could be due to the short supplementation duration, which may
not have normalized zinc status. An interesting effect is noted for insulin-like growth
factor values, which are compressed by zinc treatment (low values increase and high
values decrease).
In another study, short-term zinc administration IV decreases cortisol levels in
type 1 diabetic subjects, but does not change blood glucose readings.218 In a different
study of type 1 diabetic subjects, zinc supplementation decreases lipid peroxidation
readings, an indicator of oxidant stress.219 A similar effect is noted for zinc supple-
mentation in type 2 diabetic subjects in Tunisia.220 In that study, zinc does not change
glucose homeostasis.

Obviously, these studies are just the start of what could be done in the way of
trials of zinc supplementation in diabetes. The very early work suggests that zinc
supplementation does improve zinc status, does not affect the primary glucose defect,
has antioxidant effects, and may normalize some hormone abnormalities. Much more
research can be used in this area.
PREGNANCY
In experimental animals, adequate zinc is known to be essential for the normal growth
and development of the fetus.3 On the other hand, studies of zinc supplementation in
women living in industrialized countries have yielded mixed results. For example, a
pair of studies by Tamura’s group hr 221,222 examines supplementation with 25 mg zinc
in the second half of pregnancy in women of low socioeconomic status with low plasma
zinc concentrations. In the offspring, supplementation increases birth weight and head
circumference, but not neurologic development at age 5. In another study, in urban poor
women in the U.S., low intake of dietary zinc in early pregnancy is associated with over
a threefold increase in the risk of very preterm delivery.223
In less-developed countries, the degree of marginal zinc deficiency may be
greater on average than that seen in more industrialized countries. A recent review224
discusses preliminary findings of eight randomized, controlled intervention trials
performed in less-developed countries. These studies indicate maternal zinc supple-
mentation has a beneficial effect on neonatal immune status, early neonatal morbid-
ity, and infant infections. The results are more conflicting for labor and delivery
complications, gestational age at birth, and fetal neurobehavioral development. In
another study, prenatal supplementation with zinc in poor women from Bangladesh
does not confer benefits on infants’ mental development.225 In contrast, in a study
of Nepalese pregnant women with low serum zinc, zinc supplementation enhances
the effect of vitamin A in reducing night blindness.226 However, the presence of
night blindness suggests that there is more than marginal problems with zinc defi-
ciency and nutrition in general. There has also been a study in India showing a
beneficial effect of zinc supplementation on hematological indexes in pregnant
women.227 Again, these studies may involve women with fairly substantial zinc
deficiencies.
Unfortunately, these studies do not present a clear picture of which pregnant
women would benefit from zinc supplementation and the potential benefits.
Another issue is that in some situations, zinc supplements might only produce
benefits in conjunction with increased intake of other nutrients. Thus, clinicians
and public health professionals are not left with a clear mission in terms of zinc
supplementation and pregnancy. In countries like the U.S., a clinician can prescribe
a prenatal supplement that includes zinc, but the zinc is usually the poorly absorbed
zinc oxide.
ZINC LOZENGES AND COLDS

Exactly why a zinc lozenge should be effective for treating or preventing colds is
not clear. At first glance, the rationale for zinc and colds may seem to be an

improvement of immune function by correction of marginal zinc deficiency. How-

ever, in that case, a lozenge would not be an improvement over a zinc pill. Alter-
natively, a lozenge might seem to be good at generating a high local concentration
of zinc at the site of potential nasal infection. However, this does not seem to actually
happen with currently used zinc lozenges.228 Other explanations for how the lozenges
might work also have problems.228 Thus, there is not yet a known reason why the
zinc lozenges should work. Nonetheless, it can still be asked: Do the lozenges work,
even if we don’t know how they work? The answer here seems to be that we don’t
know.
Two types of studies have been done concerning zinc lozenges and the common
cold. In one type, a cold is induced experimentally. In the other type, “naturally
occurring” colds are monitored. In the former design, zinc lozenges have generally
not been shown to be effective.228 For the “naturally occurring” colds, a revised
meta-analysis has been applied.228 The analysis only examined cold duration, which
means it may not be applicable to other assessments such as symptom severity or
number of colds. In this meta-analysis, the zinc lozenge effect is not statistically
significant. There has also been the concern that some studies showing a positive
result may not have been blinded well (e.g., the participants could taste the difference
between the zinc and the placebo).228,229 On the other hand, there have been comments
made that the studies giving negative results have not given the lozenges with the
most effective timing nor used the best lozenge composition.228 However, the rele-
vance of the latter has been disputed, though some make-ups may be better than
others at releasing zinc from the lozenge and binding it to the mouth.230,231
After the revised meta-analysis was done, three new studies have appeared. In
one, zinc acetate is used rather than the zinc gluconate used more often in these
studies.232 Benefits are reported as superior to placebo. The number of subjects that
completed the study, though large for some types of studies, is not large for this
type of a study. Nonetheless, the strong separation of values between zinc and
placebo for some of the parameters is attention catching. Even so, it should be
noticed that cold severity and durations, though reduced, are still very detectable in
the zinc group. Thus, at best, this study suggests that zinc cuts down on cold severity
and duration, but does not do this instantly, or at 100% symptom elimination. In
contrast to the positive results of this study, mostly negative results are obtained in
another recent study comparing zinc gluconate, zinc acetate, and placebo.233 Both
naturally occurring and experimentally induced colds are considered. The number
of subjects is substantial. The only positive result is a small change in cold duration
for the induced colds. All other results are negative. The study makes an attempt to
eliminate blinding problems.
In the third more recent study, there is an examination of children enrolled at a
school where zinc lozenges were introduced.234 Medical chart review is done for
periods before and after lozenge introduction for students who did or did not take
the lozenges. Statistically significant decreases are reported for three parameters:
cold duration (though the mean difference is small), the median number of colds
per year (also a small mean difference), and concomitant antibiotic use to manage
colds (a substantial mean difference). One issue with this study is that there is no
placebo control. Also, the number of colds per year is reported as 0 for the treatment

group, and 1.3 for the non-treatment group. These low mean numbers make quan-
titative interpretations of the benefits of zinc lozenges difficult.
At present, it is hard to say if zinc lozenges are very effective, a little bit effective,
or not effective for preventing and treating common colds. Also, when used for long-
term prevention, there are unresolved safety issues. The doses used are typically
well above the zinc Upper Levels, which could conceivably produce problems with
copper status, cholesterol profiles, and suppression of some aspects of immunity
(see the next section).
TOXICITY
COPPER DEFICIENCY
Historically, the single biggest concern about high-dose zinc supplementation has
been the possibility of inducing copper deficiency. Indeed, there are case histories
of copper deficiency, characterized by anemia and low neutrophil counts, due to
high-dose zinc supplementation (usually over 100 mg/day).235,236 In addition, mod-
erately high-dose zinc supplementation has been seen to lower HDL cholesterol,
possibly via compromised copper status.237
The lowest supplement dose at which problems occur for copper status is not
actually known and may vary depending on the person’s dietary zinc and copper
intake. One study reports no adverse effects of 30 mg zinc/day on certain white
blood cell counts or on indicators of copper status.124 Another study finds that 50
mg per day of zinc for just 12 days can produce a 20% decrease in erythrocyte
activities of the copper enzyme superoxide dismutase.238 A similar effect is seen for
60 mg/day of zinc as gluconate.239 In contrast, in college-aged women, this author’s
laboratory does not find any effect of that same zinc dose as either gluconate or
glycinate on that same copper enzyme activity (unpublished data).
At this point, there has not been a zinc supplement vs. copper status dose
response curve done. This would be useful, especially for different dietary copper
and zinc background intakes. For present, the Upper Level has been set at 40 mg,
with the assumption that this dose won’t bother copper status in most people.1 This
seems to be a good safety cap for adults, though this author is not convinced that
higher doses will always affect copper status, or that lower doses always will not.
IMMUNOSUPRESSION
This effect of zinc can occur due to copper deficiency, but there may be other causes
as well.3,240 The exact zinc dose at which this becomes a problem has not been well
defined. In some situations, this effect may be helpful (e.g., in arthritis), though
long-term consequences could often be detrimental. Again, the dose at which this
becomes problematic is unknown.
PROSTATE CANCER
This concern derives in part from an epidemiological study showing increased risk
in men taking over 100 mg of supplemental zinc,241 which is about nine times the

adult male RDA. This risk increase is not seen for lower doses. The increased risk
associated with the high-dose supplements could be coincidental and not actually
involve the zinc supplements themselves. However, even if the zinc relationship is
cause and effect, the risk can be avoided simply by not taking such a high zinc dose.
On the other hand, poor zinc intake may increase prostate cancer risk based on the
following:
• Prostate contains the highest zinc concentration of any tissue in the body,
but these concentrations fall with prostate cancer.242
• Zinc function affects citrate levels, which are thought to affect prostate
cancer risk.243
• Zinc can inhibit growth of cultured prostate cancer cells.244
• Some epidemiological studies show an inverse relationship between zinc
and prostate cancer risk.242,250
ALZHEIMER’S DISEASE
The evidence for detrimental effects of zinc is as follows:
A. Zinc interacts with amyloid proteins in vitro in a way that induces changes
resembling those that occur during Alzheimer’s disease.246
B. There is a news report, which is not published as a journal article, that
zinc supplements can adversely affect Alzheimer’s disease patients.
C. Some studies show high accumulations of zinc, or metallothionein, a
protein induced by high levels of zinc, in certain sites in Alzheimer’s
disease patients.246
D. An antibiotic with metal chelating properties (clioquinol) has positive
effects on transgenic mice with some Alzheimer’s disease traits;247 also,
a short-term clinical trial of clioquinol in Alzheimer’s disease shows
modest cognitive function improvement.248
Each of these evidences is thought provoking but none is conclusive. An objec-

tion to evidence A is that in these studies, the other brain molecules that would bind
zinc are not typically included. Thus, there is no competition for zinc binding with
the amyloid proteins. Also, the zinc concentrations used are very high. This statement
is made based not on total zinc in a tissue or fluid, but based on the concentrations
of this mineral in vivo, which might be free to bind to amyloid proteins. It can also
be mentioned that zinc can have actions in vitro that may be protective against
Alzheimer’s disease development.249 For evidence B, two major objections are that
the subject number is low and technical details are not available. For example, the
zinc dose is not given (which could be toxic), nor is the zinc complex identified (the
metal binder, rather than the zinc, could have produced the adverse effects). In
addition, according to a newspaper report and comments made at a zinc meeting
(National Institute of Health conference: “Zinc and Health: Current Status–Future
Directions, ” November 1998), there is lack of Alzheimer’s disease specificity for
the negative effects that the zinc produced (i.e., stomach discomfort and mental

stress). Such effects could have been triggered by something as simple as an upset
stomach, a symptom that can result from some zinc supplements.
A problem with evidence C is that local elevations in zinc may be a response
to Alzheimer’s disease inflammation rather than a cause. An objection to the human
subjects trial in evidence D is that it is not a well-controlled trial. In addition, for
both this study and the related one in mice,247 it cannot be said that the benefits were
due to lowering the negative effects of zinc. The chelator given has a range of
biological effects.250,251
In contrast to the assertions that zinc promotes Alzheimer’s disease, there are
evidences for beneficial effects of zinc:
A. In the so-called “Nun study” of Alzheimer’s disease, serum zinc values

in nuns are inversely correlated with progression time of dementia symp-
toms.252
B. Low concentrations of zinc can interact with amyloid proteins in vitro in
a way that could restrict Alzheimer’s disease symptoms.249
C. A modest improvement in Alzheimer’s disease symptoms has been noted
for a few Alzheimer’s disease patients treated with zinc supplements.253
D. In this author’s laboratory, eight Alzheimer’s disease patients show lower
values for zinc status indicators than their spouses (unpublished data).
As with the detriment scenario, each evidence of benefit is interesting but

inconclusive. An objection to A could be that serum zinc values are just being
depressed by inflammation.6 A problem with B is that there are papers showing the
opposite effect.246 A limitation of C and D is the low subject number.
In summary, there are reasons to suspect that zinc could aggravate or inhibit
Alzheimer’s disease symptom progression. However, at present, there are no clear
indications of whether either is true. It should also be noted that even if zinc–amyloid
protein binding is a problem in Alzheimer’s disease, there is no real evidence that
TABLE 5.4
Zinc Supplements at a Glance
Adult RDA: 11 mg (male), 8 mg (female) (based on balance studies, not function indexes)
Typical dose in supplement studies: very variable (dose response curves not available)
Best supplement complex: oxide least desirable; a number of others are well absorbed, though some
complexes may have advantages in certain applications (not well studied)
Applications: correction of overt deficiency seems well established; use in Down’s syndrome and
renal dialysis is likely helpful, but not fully confirmed; use in diabetes or small-for-age children is
possibly useful for some subjects; several other uses (e.g., osteoporosis prevention) are interesting
but not fully confirmed; lozenge use for the common cold (still under debate); some other uses
questionable (e.g., acne treatment)
Upper Level: 40 mg (not well established)
Safety issues: copper deficiency risk is well established but minimum safe dose is not; other toxicity
issues are unresolved

dietary zinc has any effect on the problem. By analogy, although calcification occurs
in atherosclerotic plaques, low calcium intake is not being recommended to protect
against atherosclerosis. Therefore, in this author’s opinion, fear of Alzheimer’s
disease is not currently a known reason for avoiding zinc supplements.

A large volume of research has been done in relation to zinc and various health
concerns. Despite all this research, there are few practical guidelines for who would
benefit from zinc supplements, and how much should be given. Nonetheless, it is
very likely that some people will benefit from zinc supplements, especially where
health problems make adequate intake of zinc difficult due to high needs or low
food intake. Toxicity issues for zinc supplementation have not been fully clarified.
REFERENCES
2. Chesters, J.K., Zinc, in Handbook of Nutritionally Essential Mineral Elements,
3. Prasad, A.S., Biochemistry of Zinc, Kluwer Academic Publishers, Hingham, 1993.
4. Yatsuyanagi, J. and Ogiso, T., Zinc inhibition of respiratory burst in zymosan-stim-
ulated neutrophils: a possible membrane action of zinc, Chem. Pharm. Bull. (Tokyo),
36, 1035, 1988.
5. Bagchi, D., Vuchetich, P.J., Bagchi, M., Tran, M.X., Krohn, R.L., Ray, S.D., and
Stohs, S.J., Protective effects of zinc salts on TPA-induced hepatic and brain lipid
peroxidation, glutathione depletion, DNA damage and peritoneal macrophage acti-
vation in mice, Gen. Pharmacol., 30, 43, 1998.
6. Cousins, R.J., Absorption, transport, and hepatic metabolism of copper and zinc:
special reference to metallothionein and ceruloplasmin, Physiol Rev., 65, 238, 1985.
7. Sato, M. and Bremner, I., Oxygen free radicals and metallothionein, Free Radic. Biol.
Med., 14, 325, 1993.
8. Zelko, I.N., Mariani, T.J., and Folz, R.J., Superoxide dismutase multigene family: a
comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3)
gene structures, evolution, and expression, Free Radic. Biol. Med., 33, 337, 2002.
9. Paik, H.Y., Joung, H., Lee, J.Y., Lee, H.K., King, J.C., and Keen, C.L., Serum
extracellular superoxide dismutase activity as an indicator of zinc status in humans,
Biol. Trace Elem. Res., 69, 45, 1999.
10. Bray, T.M. and Bettger, W.J., The physiological role of zinc as an antioxidant, Free
Radic. Biol. Med., 8, 281, 1990.
11. Powell, S.R., The antioxidant properties of zinc, J. Nutr., 130, 1447S, 2000.
12. Hennig, B., Toborek, M., and McClain, C.J., Antiatherogenic properties of zinc:
implications in endothelial cell metabolism, Nutrition, 12, 711, 1996.
13. Kim, E.S., Noh, S.K., and Koo, S.I., Marginal zinc deficiency lowers the lymphatic
absorption of alpha-tocopherol in rats, J. Nutr., 128, 265, 1998.

14. Taylor, C.G., McCutchon, T.L., Boermans, H.J., DiSilvestro, R.A., and Bray, T.M.,
Comparison of Zn and vitamin E for protection against hyperoxia-induced lung
damage, Free Radic. Biol. Med., 22, 543, 1997.
15. Bettger, W.J., Fish, T.J., and O’dell, B.L., Effects of copper and zinc status of rats
on erythrocyte stability and superoxide dismutase activity, Proc. Soc. Exp. Biol. Med.,
158, 279, 1978.
16. Taylor, C.G., Bettger, W.J., and Bray, T.M., Effect of dietary zinc or copper deficiency
on the primary free radical defense system in rats, J. Nutr., 118, 613, 1988.
17. Davis, C.D., Milne, D.B., and Nielsen, F.H., Changes in dietary zinc and copper
affect zinc-status indicators of postmenopausal women, notably, extracellular super-
oxide dismutase and amyloid precursor proteins, Am. J. Clin. Nutr., 71, 781, 2000.
18. Olin, K.L., Golub, M.S., Gershwin, M.E., Hendrickx, A.G., Lonnerdal, B., and Keen,
C.L., Extracellular superoxide dismutase activity is affected by dietary zinc intake in
nonhuman primate and rodent models, Am. J. Clin. Nutr., 61, 1263, 1995.
19. Zheng, J., [Research progress in brain-specific metallothionein-III], Sheng Li Ke. Xue.
Jin. Zhan., 29, 325, 1998.
20. DiSilvestro, R.A. and Cousins, R.J., Mediation of endotoxin-induced changes in zinc
metabolism in rats, Am. J. Physiol, 247, E436, 1984.
21. Perkowski, S., Sun, J., Singhal, S., Santiago, J., Leikauf, G.D., and Albelda, S.M.,
Gene expression profiling of the early pulmonary response to hyperoxia in mice, Am.
J. Respir. Cell Mol. Biol., 28, 682, 2003.
22. Thompson, R.P., Assessment of zinc status, Proc. Nutr. Soc., 50, 19, 1991.
23. Thomas, E.A., Bailey, L.B., Kauwell, G.A., Lee, D.Y., and Cousins, R.J., Erythrocyte
metallothionein response to dietary zinc in humans, J. Nutr., 122, 2408, 1992.
24. Bales, C.W., DiSilvestro, R.A., Currie, K.L., Plaisted, C.S., Joung, H., Galanos, A.N.,
and Lin, P.H., Marginal zinc deficiency in older adults: responsiveness of zinc status
indicators, J. Am. Coll. Nutr., 13, 455, 1994.
25. Naber, T.H., van den Hamer, C.J., van den Broek, W. J., and van Tongeren, J. H.,
Zinc uptake by blood cells of rats in zinc deficiency and inflammation, Biol. Trace
Elem. Res. 35, 137, 1992.
26. Roth, H.P. and Kirchgessner, M., Diagnosis of zinc deficiency, Z. Gerontol. Geriatr.,
32 Suppl. 1, I55, 1999.
27. Ruz, M., Cavan, K.R., Bettger, W.J., and Gibson, R.S., Erythrocytes, erythrocyte
membranes, neutrophils and platelets as biopsy materials for the assessment of zinc
status in humans, Br. J. Nutr., 68, 515, 1992.
28. Capel, I.D., Spencer, E.P., Daivies, A.E., and Levitt, H.N., The assessment of zinc
status by the zinc tolerance test in various groups of patients, Clin. Biochem., 15,
257, 1982.
29. Sullivan, J.F., Jetton, M.M., and Burch, R.E., A zinc tolerance test, J. Lab Clin. Med.,
93, 485, 1979.
30. Fickel, J.J., Freeland-Graves, J.H., and Roby, M.J., Zinc tolerance tests in zinc
deficient and zinc supplemented diets, Am. J. Clin. Nutr., 43, 47, 1986.
31. Valberg, L.S., Flanagan, P.R., Brennan, J., and Chamberlain, M.J., Does the oral zinc
tolerance test measure zinc absorption?, Am. J. Clin. Nutr., 41, 37, 1985.
32. Argiratos, V. and Samman, S., The effect of calcium carbonate and calcium citrate
on the absorption of zinc in healthy female subjects, Eur. J. Clin. Nutr., 48, 198, 1994.
33. Blostein-Fujii, A., DiSilvestro, R.A., Frid, D., Katz, C., and Malarkey, W., Short-term
zinc supplementation in women with non-insulin-dependent diabetes mellitus: effects
on plasma 5′-nucleotidase activities, insulin-like growth factor I concentrations, and
lipoprotein oxidation rates in vitro, Am. J. Clin. Nutr., 66, 639, 1997.

34. DiSilvestro, R.A., Zinc in relation to diabetes and oxidative disease, J. Nutr., 130,
1509S, 2000.
35. Bertrand, A. and Buret, J., A one-step determination of serum 5′-nucleotidase using
a centrifugal analyzer, Clin. Chim. Acta, 119, 275, 1982.
36. Stojanovic, T., Clinical significance of 5′-nucleotidase, Srp. Arh. Celok. Lek., 120,
110, 1992.
37. Prasad, A.S., Fitzgerald, J.T., Hess, J.W., Kaplan, J., Pelen, F., and Dardenne, M.,
Zinc deficiency in elderly patients, Nutrition, 9, 218, 1993.
38. Meftah, S., Prasad, A.S., Lee, D.Y., and Brewer, G.J., Ecto 5′ nucleotidase (5′NT) as
a sensitive indicator of human zinc deficiency. J. Lab. Clin. Med., 118, 309, 1991.
39. Sullivan, V.K., Burnett, F.R., and Cousins, R.J., Metallothionein expression is
increased in monocytes and erythrocytes of young men during zinc supplementation,
J. Nutr., 128, 707, 1998.
40. Prasad, A.S., Meftah, S., Abdallah, J., Kaplan, J., Brewer, G.J., Bach, J.F., and
Dardenne, M., Serum thymulin in human zinc deficiency, J. Clin. Invest., 82, 1202,
1988.
41. Savino, W., Smaniotto, S., Binart, N., Postel-Vinay, M.C., and Dardenne, M., In vivo
effects of growth hormone on thymic cells, Ann. N.Y. Acad. Sci., 992, 179, 2003.
42. Mocchegiani, E., Veccia, S., Ancarani, F., Scalise, G., and Fabris, N., Benefit of oral
zinc supplementation as an adjunct to zidovudine (AZT) therapy against opportunistic
infections in AIDS, Int. J. Immunopharmacol., 17, 719, 1995.
43. Ghavami-Maibodi, S.Z., Collipp, P.J., Castro-Magana, M., Stewart, C., and Chen,
S.Y., Effect of oral zinc supplements on growth, hormonal levels, and zinc in healthy
short children, Ann. Nutr. Metab., 27, 214, 1983.
44. Van Wouwe, J.P., de Wolff, F.A., and van Gelderen, H.H., Zinc in hair and urine of
paediatric patients, Clin. Chim. Acta, 155, 77, 1986.
45. Bradfield, R.B. and Hambidge, K.M., Problems with hair zinc as an indicator of body
zinc status, Lancet, 1, 363, 1980.
46. Spears, J.W. and Kegley, E.B., Effect of zinc source (zinc oxide vs. zinc proteinate)
and level on performance, carcass characteristics, and immune response of growing
and finishing steers, J. Anim. Sci., 80, 2747, 2002.
47. Lopez, d.R., Lonnerdal, B., and Brown, K.H., Absorption of zinc from wheat products
fortified with iron and either zinc sulfate or zinc oxide, Am. J. Clin. Nutr., 78, 279,
2003.
48. Sandoval, M., Henry, P.R., Ammerman, C.B., Miles, R.D., and Littell, R.C., Relative
bioavailability of supplemental inorganic zinc sources for chicks, J. Anim. Sci., 75,
3195, 1997.
49. Schell, T.C. and Kornegay, E.T., Zinc concentration in tissues and performance of
weanling pigs fed pharmacological levels of zinc from ZnO, Zn-methionine, Zn-
lysine, or ZnSO4, J. Anim. Sci., 74, 1584, 1996.
50. Wedekind, K.J., Lewis, A.J., Giesemann, M.A., and Miller, P.S., Bioavailability of
zinc from inorganic and organic sources for pigs fed corn-soybean meal diets, J.
Anim. Sci., 72, 2681, 1994.
51. Wedekind, K.J., Hortin, A.E., and Baker, D.H., Methodology for assessing zinc
bioavailability: efficacy estimates for zinc-methionine, zinc sulfate, and zinc oxide,
J. Anim. Sci., 70, 178, 1992.
52. Rasker, J.J. and Kardaun, S.H., Lack of beneficial effect of zinc sulphate in rheumatoid
arthritis, Scand. J. Rheumatol., 11, 168, 1982.

53. Samman, S. and Roberts, D.C., The effect of zinc supplements on plasma zinc and
copper levels and the reported symptoms in healthy volunteers, Med. J. Aust., 146,
246, 1987.
54. Neve, J., Hanocq, M., Peretz, A., Abi, K.F., and Pelen, F., Some factors influencing
the bioavailability of zinc in oral pharmaceutical dosage forms, J. Pharm. Belg., 48,
5, 1993.
55. Sazawal, S., Jalla, S., Mazumder, S., Sinha, A., Black, R.E., and Bhan, M.K., Effect
of zinc supplementation on cell-mediated immunity and lymphocyte subsets in pre-
school children, Indian Pediatr., 34, 589, 1997.
56. Sazawal, S., Black, R.E., Bhan, M.K., Jalla, S., Sinha, A., and Bhandari, N., Efficacy
of zinc supplementation in reducing the incidence and prevalence of acute diarrhea—
a community-based, double-blind, controlled trial, Am. J. Clin. Nutr., 66, 413, 1997.
57. Best, K., McCoy, K., Gemma, S., and DiSilvestro, R.A., Copper enzyme activities
in cystic fibrosis before and after copper supplementation plus or minus zinc, Metab-
olism, 53, 37, 2004.
58. Kincaid, R.L., Chew, B.P., and Cronrath, J.D., Zinc oxide and amino acids as sources
of dietary zinc for calves: effects on uptake and immunity, J. Dairy Sci., 80, 1381,
1997.
59. Sakai, F., Yoshida, S., Endo, S., and Tomita, H., Therapeutic efficacy of zinc picolinate
in patients with taste disorders, Nippon Jibiinkoka Gakkai Kaiho, 98, 1135, 1995.
60. Sakai, F., Yoshida, S., Endo, S., and Tomita, H., Double-blind, placebo-controlled
trial of zinc picolinate for taste disorders, Acta Otolaryngol. Suppl., 129, 2002.
61. Barrie, S.A., Wright, J.V., Pizzorno, J.E., Kutter, E., and Barron, P.C., Comparative
absorption of zinc picolinate, zinc citrate and zinc gluconate in humans, Agents
Actions, 21, 223, 1987.
62. Lonnerdal, B., Dietary factors influencing zinc absorption, J. Nutr., 130, 1378S, 2000.
63. Briefel, R.R., Bialostosky, K., Kennedy-Stephenson, J., McDowell, M.A., Ervin, R.B.,
and Wright, J.D., Zinc intake of the U.S. population: findings from the third National
Health and Nutrition Examination Survey, 1988-1994, J. Nutr., 130, 1367S, 2000.
64. Ervin, R.B. and Kennedy-Stephenson, J., Mineral intakes of elderly adult supplement
and non-supplement users in the third national health and nutrition examination
survey, J. Nutr., 132, 3422, 2002.
65. Kant, A.K., Reported consumption of low-nutrient-density foods by American chil-
dren and adolescents: nutritional and health correlates, NHANES III, 1988 to 1994,
Arch. Pediatr. Adolesc. Med., 157, 789, 2003.
66. Sandstead, H.H. and Smith, J.C., Jr., Deliberations and evaluations of approaches,
endpoints and paradigms for determining zinc dietary recommendations, J. Nutr.,
126, 2410S, 1996.
67. De La, T.R., Casado, A., Lopez-Fernandez, E., Carrascosa, D., Ramirez, V., and Saez,
J., Overexpression of copper-zinc superoxide dismutase in trisomy 21, Experientia,
52, 871, 1996.
68. DiSilvestro, R.A., Copper activation of superoxide dismutase in rat erythrocytes,
Arch. Biochem. Biophys., 274, 298, 1989.
69. Goh, J. and O’Morain, C.A., Review article: nutrition and adult inflammatory bowel
disease, Aliment. Pharmacol. Ther., 17, 307, 2003.
70. Brignola, C., Belloli, C., De Simone, G., Evangelisti, A., Parente, R., Mancini, R.,
Iannone, P., Mocheggiani, E., Fabris, N., and Morini, M.C., Zinc supplementation
restores plasma concentrations of zinc and thymulin in patients with Crohn’s disease,
Aliment. Pharmacol. Ther., 7, 275, 1993.

71. Beck, F.W., Kaplan, J., Fine, N., Handschu, W., and Prasad, A.S., Decreased expres-
sion of CD73 (ecto-5’-nucleotidase) in the CD8+ subset is associated with zinc
deficiency in human patients, J. Lab Clin. Med., 130, 147, 1997.
72. Prasad, A.S., Kaplan, J., Brewer, G.J., and Dardenne, M., Immunological effects of
zinc deficiency in sickle cell anemia (SCA), Prog. Clin. Biol. Res., 319, 629, 1989.
73. Abu-Hamdan, D.K., Mahajan, S.K., Migdal, S.D., Prasad, A.S., and McDonald, F.D.,
Zinc tolerance test in uremia. Effect of ferrous sulfate and aluminum hydroxide, Ann.
Intern. Med., 104, 50, 1986.
74. Stabile, A., Pesaresi, M.A., Stabile, A.M., Pastore, M., Sopo, S.M., Ricci, R., Celes-
tini, E., and Segni, G., Immunodeficiency and plasma zinc levels in children with
Down’s syndrome: a long-term follow-up of oral zinc supplementation, Clin. Immu-
nol. Immunopathol., 58, 207, 1991.
75. Chausmer, A.B., Zinc, insulin and diabetes, J. Am. Coll. Nutr., 17, 109, 1998.
76. Lowik, M.R., Schrijver, J., Odink, J., van den, B.H., and Wedel, M., Long-term effects
of a vegetarian diet on the nutritional status of elderly people (Dutch Nutrition
Surveillance System), J. Am. Coll. Nutr., 9, 600, 1990.
77. Dinsmore, W., Callender, M.E., McMaster, D., Todd, S.J., and Love, A.H., Zinc
absorption in alcoholics using zinc-65, Digestion, 32, 238, 1985.
78. McClain, C.J. and Su, L.C., Zinc deficiency in the alcoholic: a review, Alcohol Clin.
Exp. Res., 7, 5, 1983.
79. Zima, T., Tesar, V., Mestek, O., and Nemecek, K., Trace elements in end-stage renal
disease. 2. Clinical implication of trace elements, Blood Purif., 17, 187, 1999.
80. Naveh, Y., Schapira, D., Ravel, Y., Geller, E., and Scharf, Y., Zinc metabolism in
rheumatoid arthritis: plasma and urinary zinc and relationship to disease activity, J.
Rheumatol., 24, 643, 1997.
81. Krebs, N.F., Hambidge, K.M., and Walravens, P.A., Increased food intake of young
children receiving a zinc supplement, Am. J. Dis. Child, 138, 270, 1984.
82. Walravens, P.A., Krebs, N.F., and Hambidge, K.M., Linear growth of low income
preschool children receiving a zinc supplement, Am. J. Clin. Nutr., 38, 195, 1983.
83. Samman, S., Is zinc an important nutrient for women aged 40 and over?, Med. J.
Aust., 173 Suppl. S98, 2000.
84. Clark, P.J., Eastell, R., and Barker, M.E., Zinc supplementation and bone growth in
pubertal girls, Lancet, 354, 485, 1999.
85. Gibson, R.S., Heath, A.L., and Ferguson, E.L., Risk of suboptimal iron and zinc
nutriture among adolescent girls in Australia and New Zealand: causes, consequences,
and solutions, Asia Pac. J. Clin. Nutr., 11 Suppl. 3, S543, 2002.
86. Cossack, Z.T., T-lymphocyte dysfunction in the elderly associated with zinc defi-
ciency and subnormal nucleoside phosphorylase activity: effect of zinc supplemen-
tation, Eur. J. Cancer Clin. Oncol., 25, 973, 1989.
87. Mei, W., Dong, Z.M., Liao, B.L., and Xu, H.B., Study of immune function of cancer
patients influenced by supplemental zinc or selenium-zinc combination, Biol. Trace
Elem. Res., 28, 11, 1991.
88. Baum, M.K., Shor-Posner, G., Lu, Y., Rosner, B., Sauberlich, H.E., Fletcher, M.A.,
Szapocznik, J., Eisdorfer, C., Buring, J.E., and Hennekens, C.H., Micronutrients and
HIV-1 disease progression, AIDS, 9, 1051, 1995.
89. Donovan, U.M. and Gibson, R.S., Dietary intakes of adolescent females consuming
vegetarian, semi-vegetarian, and omnivorous diets, J. Adolesc. Health, 18, 292, 1996.
90. Hunt, J.R., Matthys, L.A., and Johnson, L.K., Zinc absorption, mineral balance, and
blood lipids in women consuming controlled lactoovovegetarian and omnivorous diets
for 8 wk, Am. J. Clin. Nutr., 67, 421, 1998.

91. Donovan, U.M. and Gibson, R.S., Iron and zinc status of young women aged 14 to
19 years consuming vegetarian and omnivorous diets, J. Am. Coll. Nutr., 14, 463,
1995.
92. Hambidge, M., Underwood Memorial Lecture: human zinc homeostasis: good but
not perfect, J. Nutr., 133, 1438S, 2003.
93. Hambidge, K.M., Hambidge, C., Jacobs, M., and Baum, J.D., Low levels of zinc in
hair, anorexia, poor growth, and hypogeusia in children, Pediatr. Res., 6, 868, 1972.
94. Hambidge, K.M., Chavez, M.N., Brown, R.M., and Walravens, P.A., Zinc nutritional
status of young middle-income children and effects of consuming zinc-fortified break-
fast cereals, Am. J. Clin. Nutr., 32, 2532, 1979.
95. Hambidge, K.M. and Silverman, A., Pica with rapid improvement after dietary zinc
supplementation, Arch. Dis. Child, 48, 567, 1973.
96. Perrone, L., Salerno, M., Gialanella, G., Feng, S.L., Moro, R., Di Lascio, R., Boccia,
E., and Di Toro, R., Long-term zinc and iron supplementation in children of short
stature: effect of growth and on trace element content in tissues, J. Trace Elem. Med.
Biol., 13, 51, 1999.
97. Kaji, M., Gotoh, M., Takagi, Y., Masuda, H., Kimura, Y., and Uenoyama, Y., Studies
to determine the usefulness of the zinc clearance test to diagnose marginal zinc
deficiency and the effects of oral zinc supplementation for short children, J. Am. Coll.
Nutr., 17, 388, 1998.
98. Nakamura, T., Nishiyama, S., Futagoishi-Suginohara, Y., Matsuda, I., and Higashi,
A., Mild to moderate zinc deficiency in short children: effect of zinc supplementation
on linear growth velocity, J. Pediatr., 123, 65, 1993.
99. Black, M.M., Micronutrient deficiencies and cognitive functioning, J. Nutr., 133,
3927S, 2003.
100. Black, M.M., The evidence linking zinc deficiency with children’s cognitive and
motor functioning, J. Nutr., 133, 1473S, 2003.
101. Stevens, J. and Lubitz, L., Symptomatic zinc deficiency in breast-fed term and
premature infants, J. Paediatr. Child Health, 34, 97, 1998.
102. Roberts, L.J., Shadwick, C.F., and Bergstresser, P.R., Zinc deficiency in two full-term
breast-fed infants, J. Am. Acad. Dermatol., 16, 301, 1987.
103. Friel, J.K., Gibson, R.S., Balassa, R., and Watts, J.L., A comparison of the zinc,
copper and manganese status of very low birth weight pre-term and full-term infants
during the first twelve months, Acta Paediatr. Scand., 73, 596, 1984.
104. Friel, J.K. and Andrews, W.L., Zinc requirement of premature infants, Nutrition, 10,
63, 1994.
105. Koo, W.W., Succop, P., and Hambidge, K.M., Serum alkaline phosphatase and serum
zinc concentrations in preterm infants with rickets and fractures, Am. J. Dis. Child,
143, 1342, 1989.
106. Kuramoto, Y., Igarashi, Y., and Tagami, H., Acquired zinc deficiency in breast-fed
infants, Semin. Dermatol., 10, 309, 1991.
107. Prasad, A.S., Zinc deficiency in women, infants and children, J. Am. Coll. Nutr., 15,
113, 1996.
108. Diaz-Gomez, N.M., Domenech, E., Barroso, F., Castells, S., Cortabarria, C., and
Jimenez, A., The effect of zinc supplementation on linear growth, body composition,
and growth factors in preterm infants, Pediatrics, 111, 1002, 2003.
109. Emsley, H.C. and Tyrrell, P.J., Inflammation and infection in clinical stroke, J. Cereb.
Blood Flow Metab., 22, 1399, 2002.
110. Furberg, A.H. and Ambrosone, C.B., Molecular epidemiology, biomarkers and cancer
prevention, Trends Mol. Med., 7, 517, 2001.

111. Prasad, A.S., Beck, F.W., Kaplan, J., Chandrasekar, P.H., Ortega, J., Fitzgerald, J.T.,
and Swerdlow, P., Effect of zinc supplementation on incidence of infections and
hospital admissions in sickle cell disease (SCD), Am. J. Hematol., 61, 194, 1999.
112. Berger, M.M., Spertini, F., Shenkin, A., Wardle, C., Wiesner, L., Schindler, C., and
Chiolero, R.L., Trace element supplementation modulates pulmonary infection rates
after major burns: a double-blind, placebo-controlled trial, Am. J. Clin. Nutr., 68, 365,
1998.
113. Lira, P.I., Ashworth, A., and Morris, S.S., Effect of zinc supplementation on the
morbidity, immune function, and growth of low-birth-weight, full-term infants in
northeast Brazil, Am. J. Clin. Nutr., 68, 418S, 1998.
114. Licastro, F., Chiricolo, M., Mocchegiani, E., Fabris, N., Zannoti, M., Beltrandi, E.,
Mancini, R., Parente, R., Arena, G., and Masi, M., Oral zinc supplementation in
Down’s syndrome subjects decreased infections and normalized some humoral and
cellular immune parameters, J. Intellect. Disabil. Res., 38, 149, 1994.
115. Licastro, F., Mocchegiani, E., Masi, M., and Fabris, N., Modulation of the neuroen-
docrine system and immune functions by zinc supplementation in children with
Down’s syndrome, J. Trace Elem. Electrolytes Health Dis., 7, 237, 1993.
116. Bonomini, M., Palmieri, P.F., Evangelista, M., Manfrini, V., and Albertazzi, A., Zinc-
mediated lymphocyte energy charge modification in dialysis patients, ASAIO Trans.,
37, M387, 1991.
117. Holtkamp, W., Brodersen, H.P., Stollberg, T., Thiery, J., and Falkner, C., Zinc sup-
plementation stimulates tetanus antibody formation and soluble interleukin-2 receptor
levels in chronic hemodialysis patients, Clin. Investig., 71, 537, 1993.
118. Fortes, C., Forastiere, F., Agabiti, N., Fano, V., Pacifici, R., Virgili, F., Piras, G., Guidi,
L., Bartoloni, C., Tricerri, A., Zuccaro, P., Ebrahim, S., and Perucci, C.A., The effect
of zinc and vitamin A supplementation on immune response in an older population,
J. Am. Geriatr. Soc., 46, 19, 1998.
119. Allen, J.I., Bell, E., Boosalis, M.G., Oken, M.M., McClain, C.J., Levine, A.S., and
Morley, J.E., Association between urinary zinc excretion and lymphocyte dysfunction
in patients with lung cancer, Am. J. Med., 79, 209, 1985.
120. Peretz, A., Cantinieaux, B., Neve, J., Siderova, V., and Fondu, P., Effects of zinc
supplementation on the phagocytic functions of polymorphonuclears in patients with
inflammatory rheumatic diseases, J. Trace Elem. Electrolytes Health Dis., 8, 189,
1994.
121. Labadie, H., Verneau, A., Trinchet, J.C., and Beaugrand, M., Does oral zinc improve
the cellular immunity of patients with alcoholic cirrhosis?, Gastroenterol. Clin. Biol.,
10, 799, 1986.
122. Baer, M.T., King, J.C., Tamura, T., Margen, S., Bradfield, R.B., Weston, W.L., and
Daugherty, N.A., Nitrogen utilization, enzyme activity, glucose intolerance and leu-
kocyte chemotaxis in human experimental zinc depletion, Am. J. Clin. Nutr., 41, 1220,
1985.
123. Bogden, J.D., Oleske, J.M., Lavenhar, M.A., Munves, E.M., Kemp, F.W., Bruening,
K.S., Holding, K.J., Denny, T.N., Guarino, M.A., and Krieger, L.M., Zinc and immu-
nocompetence in elderly people: effects of zinc supplementation for 3 months, Am.
J. Clin. Nutr., 48, 655, 1988.
124. Bonham, M., O’Connor, J.M., Alexander, H.D., Coulter, J., Walsh, P.M., McAnena,
L.B., Downes, C.S., Hannigan, B.M., and Strain, J.J., Zinc supplementation has no
effect on circulating levels of peripheral blood leucocytes and lymphocyte subsets in
healthy adult men, Br. J. Nutr., 89, 695, 2003.

125. Provinciali, M., Montenovo, A., Di Stefano, G., Colombo, M., Daghetta, L., Cairati,
M., Veroni, C., Cassino, R., Della, T.F., and Fabris, N., Effect of zinc or zinc plus
arginine supplementation on antibody titre and lymphocyte subsets after influenza
vaccination in elderly subjects: a randomized controlled trial, Age Ageing, 27, 715,
1998.
126. Karlsen, T.H., Sommerfelt, H., Klomstad, S., Andersen, P.K., Strand, T.A., Ulvik,
R.J., Ahren, C., and Grewal, H.M., Intestinal and systemic immune responses to an
oral cholera toxoid B subunit whole-cell vaccine administered during zinc supple-
mentation, Infect. Immun., 71, 3909, 2003.
127. McClain, C.J., Hill, D.B., Song, Z., Deaciuc, I., and Barve, S., Monocyte activation
in alcoholic liver disease, Alcohol, 27, 53, 2002.
128. Bucci, I., Napolitano, G., Giuliani, C., Lio, S., Minnucci, A., Di Giacomo, F., Cala-
brese, G., Sabatino, G., Palka, G., and Monaco, F., Zinc sulfate supplementation
improves thyroid function in hypozincemic Down children, Biol. Trace Elem. Res.,
67, 257, 1999.
129. Chiricolo, M., Musa, A.R., Monti, D., Zannotti, M., and Franceschi, C., Enhanced
DNA repair in lymphocytes of Down syndrome patients: the influence of zinc nutri-
tional supplementation, Mutat. Res., 295, 105, 1993.
130. Franceschi, C., Chiricolo, M., Licastro, F., Zannotti, M., Masi, M., Mocchegiani,
E., and Fabris, N., Oral zinc supplementation in Down’s syndrome: restoration of
thymic endocrine activity and of some immune defects, J. Ment. Defic. Res., 32,
169, 1988.
131. Licastro, F., Mocchegiani, E., Zannotti, M., Arena, G., Masi, M., and Fabris, N., Zinc
affects the metabolism of thyroid hormones in children with Down’s syndrome:
normalization of thyroid stimulating hormone and of reversal triiodothyronine plas-
mic levels by dietary zinc supplementation, Int. J. Neurosci., 65, 259, 1992.
132. Sustrova, M. and Strbak, V., Thyroid function and plasma immunoglobulins in sub-
jects with Down’s syndrome (DS) during ontogenesis and zinc therapy, J. Endocrinol.
Invest., 17, 385, 1994.
133. Zatta, P., Zinc may be a double-faced Janus to Down’s syndrome patients, Biol. Trace
Elem. Res., 73, 93, 2000.
134. Bucci, I., Napolitano, G., Giuliani, C., Lio, S., Minnucci, A., Monaco, F., Di Giacomo,
F., Calabrese, G., Palka, G., and Sabatino, G., Concerns about using Zn supplemen-
tation in Down’s syndrome (DS) children, Biol. Trace Elem. Res., 82, 273, 2001.
135. Kadrabova, J., Madaric, A., Sustrova, M., and Ginter, E., Changed serum trace
element profile in Down’s syndrome, Biol. Trace Elem. Res., 54, 201, 1996.
136. DiSilvestro, R.A. and Marten, J.T., Effects of inflammation and copper intake on rat
liver and erythrocyte Cu-Zn superoxide dismutase activity levels, J. Nutr., 120, 1223,
1990.
137. DiSilvestro, R.A., Marten, J., and Skehan, M., Effects of copper supplementation on
ceruloplasmin and copper-zinc superoxide dismutase in free-living rheumatoid arthri-
tis patients, J. Am. Coll. Nutr., 11, 177, 1992.
138. Newsome, D.A., Swartz, M., Leone, N.C., Elston, R.C., and Miller, E., Oral zinc in
macular degeneration, Arch. Ophthalmol., 106, 192, 1988.
139. Anonymous, A randomized, placebo-controlled, clinical trial of high-dose supple-
mentation with vitamins C and E, beta carotene, and zinc for age-related macular
degeneration and vision loss: AREDS report no. 8, Arch. Ophthalmol., 119, 1417,
2001.
140. Amer, M., Bahgat, M.R., Tosson, Z., Abdel Mowla, M.Y., and Amer, K., Serum zinc
in acne vulgaris, Int. J. Dermatol., 21, 481, 1982.

141. Cunliffe, W.J., Burke, B., Dodman, B., and Gould, D.J., A double-blind trial of a zinc
sulphate/citrate complex and tetracycline in the treatment of acne vulgaris, Br. J.
Dermatol., 101, 321, 1979.
142. Dreno, B., Amblard, P., Agache, P., Sirot, S., and Litoux, P., Low doses of zinc
gluconate for inflammatory acne, Acta Derm. Venereol., 69, 541, 1989.
143. Meynadier, J., Efficacy and safety study of two zinc gluconate regimens in the
treatment of inflammatory acne, Eur. J. Dermatol., 10, 269, 2000.
144. Verma, K.C., Saini, A.S., and Dhamija, S.K., Oral zinc sulphate therapy in acne
vulgaris: a double-blind trial, Acta Derm. Venereol., 60, 337, 1980.
145. Igic, P.G., Lee, E., Harper, W., and Roach, K.W., Toxic effects associated with
consumption of zinc, Mayo Clin. Proc., 77, 713, 2002.
146. Porea, T.J., Belmont, J.W., and Mahoney, D.H., Jr., Zinc-induced anemia and neu-
tropenia in an adolescent, J. Pediatr., 136, 688, 2000.
147. Salzman, M.B., Smith, E.M., and Koo, C., Excessive oral zinc supplementation, J.
Pediatr. Hematol. Oncol., 24, 582, 2002.
148. Agren, M.S., Studies on zinc in wound healing, Acta Derm. Venereol. Suppl. (Stockh),
154, 1, 1990.
149. Pories, W.J., Henzel, J.H., Rob, C.G., and Strain, W.H., Acceleration of wound healing
in man with zinc sulphate given by mouth, Lancet, 1, 121, 1967.
150. Wilkinson, E.A. and Hawke, C.I., Oral zinc for arterial and venous leg ulcers,
Cochrane Database Syst. Rev., CD001273, 2000.
151. Lansdown, A.B., Zinc in the healing wound, Lancet, 347, 706, 1996.
152. Pollack, S.V., Wound healing: a review. III. Nutritional factors affecting wound
healing, J. Dermatol. Surg. Oncol., 5, 615, 1979.
153. Furuta, S., Toyama, S., Miwa, M., Itabashi, T., Sano, H., and Yoneta, T., Residence
time of polaprezinc (zinc L-carnosine complex) in the rat stomach and adhesiveness
to ulcerous sites, Jpn. J. Pharmacol., 67, 271, 1995.
154. Nishiwaki, H., Kato, S., Sugamoto, S., Umeda, M., Morita, H., Yoneta, T., and
Takeuchi, K., Ulcerogenic and healing impairing actions of monochloramine in rat
stomachs: effects of zinc L-carnosine, polaprezinc, J. Physiol Pharmacol., 50, 183,
1999.
155. Matsukura, T. and Tanaka, H., Applicability of zinc complex of L-carnosine for
medical use, Biochemistry (Moscow), 65, 817, 2000.
156. Zoli, A., Altomonte, L., Caricchio, R., Galossi, A., Mirone, L., Ruffini, M.P., and
Magaro, M., Serum zinc and copper in active rheumatoid arthritis: correlation with
interleukin 1 beta and tumour necrosis factor alpha, Clin. Rheumatol., 17, 378, 1998.
157. Honkanen, V., Konttinen, Y.T., Sorsa, T., Hukkanen, M., Kemppinen, P., Santavirta,
S., Saari, H., and Westermarck, T., Serum zinc, copper and selenium in rheumatoid
arthritis, J. Trace Elem. Electrolytes Health Dis., 5, 261, 1991.
158. DiSilvestro, R.A. and Cousins, R.J., Glucocorticoid independent mediation of inter-
leukin-1 induced changes in serum zinc and liver metallothionein levels, Life Sci.,
35, 2113, 1984.
159. Parsons, S.E. and DiSilvestro, R.A., Effects of mild zinc deficiency, plus or minus
an acute-phase response, on galactosamine-induced hepatitis in rats, Br. J. Nutr., 72,
611, 1994.
160. Stone, J., Doube, A., Dudson, D., and Wallace, J., Inadequate calcium, folic acid,
vitamin E, zinc, and selenium intake in rheumatoid arthritis patients: results of a
dietary survey, Semin. Arthritis Rheum., 27, 180, 1997.
161. Kremer, J.M. and Bigaouette, J., Nutrient intake of patients with rheumatoid arthritis
is deficient in pyridoxine, zinc, copper, and magnesium, J. Rheumatol., 23, 990, 1996.

162. Sugiyama, T., Tanaka, H., and Kawai, S., Improvement of periarticular osteoporosis
in postmenopausal women with rheumatoid arthritis by beta-alanyl-L-histidinato zinc:
a pilot study, J. Bone Miner. Metab, 18, 335, 2000.
163. Simkin, P.A., Oral zinc sulphate in rheumatoid arthritis, Lancet, 2, 539, 1976.
165. Mocchegiani, E., Brignola, C., Iannone, P., Campieri, M., Pasquali, M., Lanfranchi,
G.A., Barbara, L., Fabris, N., and Licastro, F., Levels of zinc and thymulin in plasma
from patients with Crohn’s disease, J. Clin. Lab. Immunol., 32, 79, 1990.
166. Nakamura, T., Higashi, A., Takano, S., Akagi, M., and Matsuda, I., Zinc clearance
correlates with clinical severity of Crohn’s disease. A kinetic study, Dig. Dis. Sci.,
33, 1520, 1988.
167. Sjogren, A., Floren, C.H., and Nilsson, A., Evaluation of zinc status in subjects with
Crohn’s disease, J. Am. Coll. Nutr., 7, 57, 1988.
169. Stoll, R., Schmidt, H., Stern, H., Ruppin, H., and Domschke, W., Functional defect
of zinc transport in patients with Crohn’s disease, Hepatogastroenterology, 34, 178,
1987.
170. Ainley, C., Cason, J., Slavin, B.M., Wolstencroft, R.A., and Thompson, R.P., The
influence of zinc status and malnutrition on immunological function in Crohn’s
disease, Gastroenterology, 100, 1616, 1991.
171. Brignola, C., Belloli, C., De Simone, G., Evangelisti, A., Parente, R., Mancini, R.,
Iannone, P., Mocheggiani, E., Fabris, N., and Morini, M.C., Zinc supplementation
restores plasma concentrations of zinc and thymulin in patients with Crohn’s disease,
Aliment. Pharmacol. Ther., 7, 275, 1993.
172. Prasad, A.S. and Kucuk, O., Zinc in cancer prevention, Cancer Metastasis Rev., 21,
291, 2002.
173. Bain, C., Green, A., Siskind, V., Alexander, J., and Harvey, P., Diet and melanoma.
An exploratory case-control study, Ann. Epidemiol., 3, 235, 1993.
174. Kirkpatrick, C.S., White, E., and Lee, J.A., Case-control study of malignant melanoma
in Washington State. II. Diet, alcohol, and obesity, Am. J. Epidemiol., 139, 869, 1994.
175. Ros-Bullon, M.R., Sanchez-Pedreno, P., and Martinez-Liarte, J.H., Serum zinc levels
are increased in melanoma patients, Melanoma Res., 8, 273, 1998.
176. Ganapathy, S. and Volpe, S.L., Zinc, exercise, and thyroid hormone function, Crit.
Rev. Food Sci. Nutr., 39, 369, 1999.
177. Singh, A., Papanicolaou, D.A., Lawrence, L.L., Howell, E.A., Chrousos, G.P., and
Deuster, P.A., Neuroendocrine responses to running in women after zinc and vitamin
E supplementation, Med. Sci. Sports Exerc., 31, 536, 1999.
178. Khaled, S., Brun, J.F., Cassanas, G., Bardet, L., and Orsetti, A., Effects of zinc
supplementation on blood rheology during exercise, Clin. Hemorheol. Microcirc., 20,
1, 1999.
179. Singh, A., Failla, M.L., and Deuster, P.A., Exercise-induced changes in immune
function: effects of zinc supplementation, J. Appl. Physiol., 76, 2298, 1994.
180. Brilla, L.R. and Conte, V., Effects of zinc-magnesium formulation increases anabolic
hormones and strength in athletes, Med. Sci. Sports Exer., 31, 483, 1999.
181. DiSilvestro, R.A. and Carlson, G.P., Effects of mild zinc deficiency, plus or minus
acute phase response, on CCl4 hepatotoxicity, Free Radic. Biol. Med., 16, 57, 1994.
182. Cagen, S.Z. and Klaassen, C.D., Protection of carbon tetrachloride-induced hepato-
toxicity by zinc: role of metallothionein, Toxicol. Appl. Pharmacol., 51, 107, 1979.

183. Bro, S., Stokholm, M., and Jorgensen, P.J., Zinc in mononuclear leucocytes in alco-
holics with liver cirrhosis or chronic pancreatitis and in patients with Crohn’s disease
before and after zinc supplementation, J. Trace Elem. Electrolytes Health Dis., 3,
243, 1989.
184. Solis-Herruzo, J., De Cuenca, B., and Munoz-Rivero, M.C., Intestinal zinc absorption
in cirrhotic patients, Z. Gastroenterol., 27, 335, 1989.
185. Blostein, A., DiSilvestro, R.A., Sanders, S., Demetriou, A., and Horgan N., Plasma zinc
& 5′-nucleotidase activities in subjects with Type 2 diabetes or fulminant hepatitis,
FASEB J., 10, A550, 1996.
186. Arakawa, Y., Suzuki, K., Oyama, R., and Moriyama, M., Methods and clinical
significance of an oral tolerance test of essential trace element, especially an oral
zinc tolerance test, Nippon Rinsho, 54, 162, 1996.
187. Khanna, V.J., Shieh, S., Benjamin, J., Somach, S., Zaim, M.T., Dorner, W., Jr., Shill,
M., and Wood, G.S., Necrolytic acral erythema associated with hepatitis C: effective
treatment with interferon alfa and zinc, Arch. Dermatol., 136, 755, 2000.
188. Gur, G., Bayraktar, Y., Ozer, D., Ozdogan, M., and Kayhan, B., Determination of
hepatic zinc content in chronic liver disease due to hepatitis B virus, Hepatogastro-
enterology, 45, 472, 1998.
189. Keeling, P.W., Jones, R.B., Hilton, P.J., and Thompson, R.P., Reduced leucocyte zinc
in liver disease, Gut, 21, 561, 1980.
190. Nagamine, T., Takagi, H., Hashimoto, Y., Takayama, H., Shimoda, R., Nomura, N.,
Suzuki, K., Mori, M., and Nakajima, K., The possible role of zinc and metallothionein
in the liver on the therapeutic effect of IFN-alpha to hepatitis C patients, Biol. Trace
Elem. Res., 58, 65, 1997.
191. Takagi, H., Nagamine, T., Abe, T., Takayama, H., Sato, K., Otsuka, T., Kakizaki, S.,
Hashimoto, Y., Matsumoto, T., Kojima, A., Takezawa, J., Suzuki, K., Sato, S., and
Mori, M., Zinc supplementation enhances the response to interferon therapy in
patients with chronic hepatitis C, J. Viral Hepat., 8, 367, 2001.
192. Lowe, N.M., Lowe, N.M., Fraser, W.D., and Jackson, M.J., Is there a potential
therapeutic value of copper and zinc for osteoporosis?, Proc. Nutr. Soc., 61, 181, 2002.
193. Devine, A., Rosen, C., Mohan, S., Baylink, D., and Prince, R.L., Effects of zinc and
other nutritional factors on insulin-like growth factor I and insulin-like growth factor
binding proteins in postmenopausal women, Am. J. Clin. Nutr., 68, 200, 1998.
194. Darden, A.G., Ries, W.L., Wolf, W.C., Rodriguiz, R.M., and Key, L.L., Jr., Osteo-
clastic superoxide production and bone resorption: stimulation and inhibition by
modulators of NADPH oxidase, J. Bone Miner. Res., 11, 671, 1996.
195. Peretz, A., Papadopoulos, T., Willems, D., Hotimsky, A., Michiels, N., Siderova, V.,
Bergmann, P., and Neve, J., Zinc supplementation increases bone alkaline phosphatase
in healthy men, J. Trace Elem. Med. Biol., 15, 175, 2001.
196. Strause, L., Saltman, P., Smith, K.T., Bracker, M., and Andon, M.B., Spinal bone
loss in postmenopausal women supplemented with calcium and trace minerals, J.
Nutr., 124, 1060, 1994.
197. Beerbower, K.S. and Raess, B.U., Erythrocyte, plasma, urine and dialysate zinc levels
in patients on continuous ambulatory peritoneal dialysis, Am. J. Clin. Nutr., 41, 697,
1985.
198. Kreft, B., Fischer, A., Kruger, S., Sack, K., Kirchner, H., and Rink, L., The impaired
immune response to diphtheria vaccination in elderly chronic hemodialysis patients
is related to zinc deficiency, Biogerontology, 1, 61, 2000.

199. Stammler, G., Klooker, P., Bommer, J., Ziegler, T., Fiehn, W., Manthey, J., and Ritz,
E., Response of alkaline phosphatase to zinc repletion in hypozincemic hemodialysis
patients, Blood Purif., 3, 192, 1985.
200. Candan, F., Gultekin, F., and Candan, F., Effect of vitamin C and zinc on osmotic
fragility and lipid peroxidation in zinc-deficient haemodialysis patients, Cell Biochem.
Funct., 20, 95, 2002.
201. Jern, N.A., VanBeber, A.D., Gorman, M.A., Weber, C.G., Liepa, G.U., and Cochran,
C.C., The effects of zinc supplementation on serum zinc concentration and protein
catabolic rate in hemodialysis patients, J. Ren. Nutr., 10, 148, 2000.
202. Arreola, F., Paniagua, R., Perez, A., Diaz-Bensussen, S., Junco, E., Villalpando, S.,
and Exaire, E., Effect of zinc treatment on serum thyroid hormones in uremic patients
under peritoneal dialysis, Horm. Metab. Res., 25, 539, 1993.
203. Grekas, D., Tsakalos, N., Giannopoulos, Z., and Tourkantonis, A., Effect of zinc
treatment on cell mediated immunity of chronic renal failure patients, Proc. Eur. Dial.
Transplant. Assoc. Eur. Ren. Assoc., 21, 825, 1985.
204. Mahajan, S.K., Abbasi, A.A., Prasad, A.S., Rabbani, P., Briggs, W.A., and McDonald,
F.D., Effect of oral zinc therapy on gonadal function in hemodialysis patients. A
double-blind study, Ann. Intern. Med., 97, 357, 1982.
205. Chevalier, C.A., Liepa, G., Murphy, M.D., Suneson, J., Vanbeber, A.D., Gorman,
M.A., and Cochran, C., The effects of zinc supplementation on serum zinc and
cholesterol concentrations in hemodialysis patients, J. Ren. Nutr., 12, 183, 2002.
206. Brodersen, H.P., Holtkamp, W., Larbig, D., Beckers, B., Thiery, J., Lautenschlager,
J., Probst, H.J., Ropertz, S., and Yavari, A., Zinc supplementation and hepatitis B
vaccination in chronic haemodialysis patients: a multicentre study, Nephrol. Dial.
Transplant., 10, 1780, 1995.
207. Kouw, P.M., Konings, C.H., de Vries, P.M., van der Meulen, J., and Oe, P.L., Effects
of zinc supplementation on zinc status and immunity in haemodialysis patients, J.
Trace Elem. Electrolytes Health Dis., 5, 115, 1991.
208. Turk, S., Bozfakioglu, S., Ecder, S.T., Kahraman, T., Gurel, N., Erkoc, R., Aysuna,
N., Turkmen, A., Bekiroglu, N., and Ark, E., Effects of zinc supplementation on the
immune system and on antibody response to multivalent influenza vaccine in hemo-
dialysis patients, Int. J. Artif. Organs, 21, 274, 1998.
209. Beerbower, K.S. and Raess, B.U., Erythrocyte, plasma, urine and dialysate zinc levels
in patients on continuous ambulatory peritoneal dialysis, Am. J. Clin. Nutr., 41, 697,
1985.
210. Golik, A., Zaidenstein, R., Dishi, V., Blatt, A., Cohen, N., Cotter, G., Berman, S.,
and Weissgarten, J., Effects of captopril and enalapril on zinc metabolism in hyper-
tensive patients, J. Am. Coll. Nutr., 17, 75, 1998.
211. Sato, M., Yanagisawa, H., Nojima, Y., Tamura, J., and Wada, O., Zn deficiency
aggravates hypertension in spontaneously hypertensive rats: possible role of Cu/Zn-
superoxide dismutase, Clin. Exp. Hypertens., 24, 355, 2002.
212. Tousoulis, D., Davies, G., Stefanadis, C., Toutouzas, P., and Ambrose, J.A., Inflam-
matory and thrombotic mechanisms in coronary atherosclerosis, Heart, 89, 993, 2003.
213. DiSilvestro, R.A. and Blostein-Fujii, A., Moderate zinc deficiency in rats enhances
lipoprotein oxidation in vitro, Free Radic. Biol. Med., 22, 739, 1997.
214. Ripa, S., Ripa, R., and Giustiniani, S., Are failured cardiomyopathies a zinc-deficit
related disease? A study on Zn and Cu in patients with chronic failured dilated and
hypertrophic cardiomyopathies, Minerva Med., 89, 397, 1998.

215. Gatto, L.M. and Samman, S., The effect of zinc supplementation on plasma lipids
and low-density lipoprotein oxidation in males, Free Radic. Biol. Med., 19, 517, 1995.
216. Failla, M.L. and Kiser, R.A., Altered tissue content and cytosol distribution of trace
metals in experimental diabetes, J. Nutr., 111, 1900, 1981.
217. Salgueiro, M.J., Krebs, N., Zubillaga, M.B., Weill, R., Postaire, E., Lysionek, A.E.,
Caro, R.A., De Paoli, T., Hager, A., and Boccio, J., Zinc and diabetes mellitus: is
there a need of zinc supplementation in diabetes mellitus patients?, Biol. Trace Elem.
Res., 81, 215, 2001.
218. Brandao-Neto, J., da Silva, C.A., Figueiredo, N.B., Shuhama, T., da Cunha, N.F.,
Dourado, F.B., and Naves, L.A., Lack of acute zinc effects in glucose metabolism in
healthy and insulin-dependent diabetes mellitus patients, Biometals, 12, 161, 1999.
219. Faure, P., Benhamou, P.Y., Perard, A., Halimi, S. and Roussel, A.M., Lipid peroxi-
dation in insulin-dependent diabetic patients with early retina degenerative lesions:
effects of an oral zinc supplementation, Eur. J. Clin. Nutr., 49, 282, 1995.
220. Anderson, R.A., Roussel, A.M., Zouari, N., Mahjoub, S., Matheau, J.M., and Kerkeni,
A., Potential antioxidant effects of zinc and chromium supplementation in people
with type 2 diabetes mellitus, J. Am. Coll. Nutr., 20, 212, 2001.
221. Goldenberg, R.L., Tamura, T., Neggers, Y., Copper, R.L., Johnston, K.E., Dubard,
M.B., and Hauth, J.C., The effect of zinc supplementation on pregnancy outcome,
JAMA, 274, 463, 1995.
222. Tamura, T., Goldenberg, R.L., Ramey, S.L., Nelson, K.G., and Chapman, V.R., Effect
of zinc supplementation of pregnant women on the mental and psychomotor devel-
opment of their children at 5 y of age, Am. J. Clin. Nutr., 77, 1512, 2003.
223. Scholl, T.O., Hediger, M.L., Schall, J.I., Fischer, R.L., and Khoo, C.S., Low zinc
intake during pregnancy: its association with preterm and very preterm delivery, Am.
J. Epidemiol., 137, 1115, 1993.
224. Osendarp, S.J., West, C.E., and Black, R.E., The need for maternal zinc supplemen-
tation in developing countries: an unresolved issue, J. Nutr., 133, 817S, 2003.
225. Hamadani, J.D., Fuchs, G.J., Osendarp, S.J., Huda, S.N., and Grantham-McGregor,
S.M., Zinc supplementation during pregnancy and effects on mental development
and behaviour of infants: a follow-up study, Lancet, 360, 290, 2002.
226. Christian, P., Khatry, S.K., Yamini, S., Stallings, R., LeClerq, S.C., Shrestha, S.R.,
Pradhan, E.K., and West, K.P.J., Zinc supplementation might potentiate the effect of
vitamin A in restoring night vision in pregnant Nepalese women, Am. J. Clin. Nutr.,
73, 1045, 2001.
227. Garg, H.K., Singhal, K.C., and Arshad, Z., Effect of oral zinc supplementation on
copper and haemoglobin levels in pregnant women, Indian J. Physiol Pharmacol.,
38, 272, 1994.
228. Jackson, J.L., Lesho, E., and Peterson, C., Zinc and the common cold: a meta-analysis
revisited, J. Nutr., 130, 1512S, 2000.
229. Farr, B.M. and Gwaltney, J.M., Jr., The problems of taste in placebo matching: an
evaluation of zinc gluconate for the common cold, J. Chronic. Dis., 40, 875, 1987.
230. Zarembo, J.E., Godfrey, J.C., and Godfrey, N.J., Zinc(II) in saliva: determination of
concentrations produced by different formulations of zinc gluconate lozenges con-
taining common excipients, J. Pharm. Sci., 81, 128, 1992.
231. Marshall, S., Zinc gluconate and the common cold. Review of randomized controlled
trials, Can. Fam. Physician, 44, 1037, 1998.

232. Prasad, A.S., Fitzgerald, J.T., Bao, B., Beck, F.W., and Chandrasekar, P.H., Duration
of symptoms and plasma cytokine levels in patients with the common cold treated
with zinc acetate. A randomized, double-blind, placebo-controlled trial, Ann. Intern.
Med., 133, 245, 2000.
233. Turner, R.B. and Cetnarowski, W.E., Effect of treatment with zinc gluconate or zinc
acetate on experimental and natural colds, Clin. Infect. Dis., 31, 1202, 2000.
234. McElroy, B.H. and Miller, S.P., Effectiveness of zinc gluconate glycine lozenges
(Cold-Eeze) against the common cold in school-aged subjects: a retrospective chart
review, Am. J. Ther., 9, 472, 2002.
235. Fosmire, G.J., Zinc toxicity, Am. J. Clin. Nutr., 51, 225, 1990.
236. Irving, J.A., Mattman, A., Lockitch, G., Farrell, K., and Wadsworth, L.D., Element
of caution: a case of reversible cytopenias associated with excessive zinc supplemen-
tation, CMAJ, 169, 129, 2003.
237. Black, M.R., Medeiros, D.M., Brunett, E., and Welke, R., Zinc supplements and
serum lipids in young adult white males, Am. J. Clin. Nutr., 47, 970, 1988.
238. Abdallah, S.M. and Samman, S., The effect of increasing dietary zinc on the activity
of superoxide dismutase and zinc concentration in erythrocytes of healthy female
subjects, Eur. J. Clin. Nutr., 47, 327, 1993.
239. Fischer, P.W., Giroux, A., and L’Abbe, M.R., Effect of zinc supplementation on copper
status in adult men, Am. J. Clin. Nutr., 40, 743, 1984.
240. Chandra, R.K., Excessive intake of zinc impairs immune responses, JAMA, 252, 1443,
1984.
241. Leitzmann, M.F., Stampfer, M.J., Wu, K., Colditz, G.A., Willett, W.C., and Giovan-
nucci, E.L., Zinc supplement use and risk of prostate cancer, J. Natl. Cancer Inst.,
95, 1004, 2003.
242. Platz, E.A. and Helzlsouer, K.J., Selenium, zinc, and prostate cancer, Epidemiol. Rev.,
23, 93, 2001.
243. Costello, L.C. and Franklin, R.B., Novel role of zinc in the regulation of prostate
citrate metabolism and its implications in prostate cancer, Prostate, 35, 285, 1998.
244. Liang, J.Y., Liu, Y.Y., Zou, J., Franklin, R.B., Costello, L.C., and Feng, P., Inhibitory
effect of zinc on human prostatic carcinoma cell growth, Prostate, 40, 200, 1999.
245. Boyle, P., Severi, G., and Giles, G.G., The epidemiology of prostate cancer, Urol.
Clin. North Am., 30, 209, 2003.
246. Finefrock, A.E., Bush, A.I., and Doraiswamy, P.M., Current status of metals as
therapeutic targets in Alzheimer’s disease, J. Am. Geriatr. Soc., 51, 1143, 2003.
247. Cherny, R.A., Atwood, C.S., Xilinas, M.E., Gray, D.N., Jones, W.D., McLean, C.A.,
Barnham, K.J., Volitakis, I., Fraser, F.W., Kim, Y., Huang, X., Goldstein, L.E., Moir,
R.D., Lim, J.T., Beyreuther, K., Zheng, H., Tanzi, R.E., Masters, C.L., and Bush,
A.I., Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-
amyloid accumulation in Alzheimer’s disease transgenic mice, Neuron, 30, 665, 2001.
248. Regland, B., Lehmann, W., Abedini, I., Blennow, K., Jonsson, M., Karlsson, I.,
Sjogren, M., Wallin, A., Xilinas, M., and Gottfries, C.G., Treatment of Alzheimer’s
disease with clioquinol, Dement. Geriatr. Cogn. Disord., 12, 408, 2001.
249. Cuajungco, M.P. and Faget, K.Y., Zinc takes the center stage: its paradoxical role in
Alzheimer’s disease, Brain Res. Rev., 41, 44, 2003.
250. Anonymous, Clioquinol and related drugs, Br. Med. J., 2, 607, 1979.
251. Yassin, M.S., Ekblom, J., Lofberg, C., and Oreland, L., Transmethylation reactions
and autoradiographic distribution of vitamin B12: effects of clioquinol treatment in
mice, Jpn. J. Pharmacol., 78, 55, 1998.

252. Tully, C.L., Snowdon, D.A., and Markesbery, W.R., Serum zinc, senile plaques, and
neurofibrillary tangles: findings from the Nun Study, Neuroreport, 6, 2105, 1995.
253. Potocnik, F.C., van Rensburg, S.J., Park, C., Taljaard, J.J., and Emsley, R.A., Zinc
and platelet membrane microviscosity in Alzheimer’s disease. The in vivo effect of
zinc on platelet membranes and cognition, S. Afr. Med. J., 87, 1116, 1997.

6 Copper
For the last 25 years or so, a number of copper researchers have pointed to marginal
copper deficiency as a possible problem in many people. However, this message has
not spread extensively to most of the nutrition field, nor to the rest of the biomedical
community. Although the message is supported by some research, the copper nutri-
tion field needs a blockbuster, large-scale, broad-scope, copper supplementation
intervention study to either spread the alarm or calm down the alarm sounders.
Copper functions in certain metalloenzymes by cycling between +2 and +1 charges
to donate electrons to a substrate.1 Some of the known copper enzymes and their
functions are listed in Table 6.1. Ceruloplasmin is unusual in that it is thought to
both possess enzyme function and contribute to serum copper transport.2 There are
some symptoms of copper deficiency that have not yet been matched to depressed
activity of a specific copper metalloenzyme. Examples of such symptoms include
impairments of immune function3 and abnormal cholesterol metabolism. In the latter
case, part of the story could be superoxide dismutase 1, which eliminates superox-
ide.1 Superoxide is known to alter activity of an enzyme involved in cholesterol
synthesis.4
Copper is absorbed mostly in the upper intestine.5 The main interference with this
process is high intake of oral zinc. In the past, the mechanism for zinc antagonism
of copper absorption was assumed to involve the protein metallothionein.1 Recent
work with metallothionein knock out mice have shown that this is not the main
mechanism.6
Once copper is absorbed, its metabolism seems to be geared toward restricting
free movement of copper. This would seem beneficial because the redox properties
of free copper, like those of iron, can cause damaging oxidant reactions.7 Based on
laboratory animal work, when copper enters the body, via diet or injection, it is
cleared rapidly from the blood and enters the liver and kidney, the two main copper
storage sites.1 The liver can place copper into metalloenzymes, eliminate copper via
the bile, store this mineral bound to the protein metallothionein (which also occurs
in the kidney and, to some extent, in other tissues), or secrete copper back into the

TABLE 6.1
Copper Enzymes
Name Function
Ceruloplasmin Iron transport, antioxidant actions (e.g., restrict iron

catalyzed radical creation)
Superoxide dismutase 1 Eliminate superoxide radicals in cells
Extracellar superoxide dismutase Eliminate superoxide radicals outside cells
Cytochrome c oxidase Aerobic energy release in electron transport chain
Dopamine–hydroxylase Make norepinephrine (hormone and neurotransmitter)
Diamine oxidase Degradation of polyphenols
Lysyl Oxidase Crosslink collagen and elastin in connective tissue
Tyrosinase Melanin formation
Peptidylglycine alpha-amidating Neuropeptide activation
Monooxygenase
Others Copper is likely part of some other enzymes
Adapted from References 1 and 5.
blood.1 In the latter case, the copper is tightly incorporated into the protein cerulo-
plasmin.1 The protein ceruloplasmin has enzymatic activity plus it transports copper
to other tissues.2,8 Receptors for ceruloplasmin have been found on tissue samples
and cultured cells.8,9 These receptors release copper from ceruloplasmin, which is
reminiscent of iron uptake from transferrin, but the copper uptake process has some
differences from iron.8 Despite these findings on ceruloplasmin receptors, copper
transport independent of ceruloplasmin can also be demonstrated.9 Thus, ceruloplas-
min may not be essential for copper transport, though it may be the primary means
in most circumstances. Once inside extra-hepatic cells, copper binds to chaperone
proteins via a process that is garnering substantial research attention.10

Severe copper deficiency can be spotted by low values for serum copper or enzyme
activity of ceruloplasmin,11 which contains most of the copper in serum.9 Cerulo-
plasmin protein levels can also be affected by copper status, since copper-poor
ceruloplasmin degrades faster than normal.12 However, during deficiency, cerulo-
plasmin protein values decline a little less than does ceruloplasmin activity.12 One
problem with identifying severe copper deficiency using serum copper or cerulo-
plasmin values is that Wilson’s disease, a genetic disorder of copper toxicity, also
causes low values for serum copper and ceruloplasmin.5 The two states can be
distinguished by other evaluations. For example, in severe copper deficiency, anemia
and low neutrophil counts often occur.1
A method for identification of marginal copper deficiency has not been given any
consensus among copper researchers, though a number of candidates have some support.
This lack of consensus has restricted efforts to identify the frequency and consequences
of marginal copper deficiency. The use of serum copper or ceruloplasmin values is not

TABLE 6.2
Parameters Proposed for
Assessment of Moderate Copper
Deficiency
White blood cell copper19
Erythrocyte superoxide dismutase activity17,20
Platelet cytochrome c oxidase activity21
Plasma or serum diamine oxidase activity17,18
Ceruloplasmin activity to protein ratios22
ideal because values do not always fall quickly or consistently with marginal copper
deficiency.13 Moreover, values can be influenced by other factors such as inflammation,
other physiological stress, oral contraceptive use, menstrual state, and pregnancy.1,14 A
number of other measurements have been proposed as alternates for assessing marginal
copper deficiency (Table 6.2). Each has some data to support its use, but none has the
full support of the copper research community.
Part of the problem is that each of these parameters seem to “work” in some
studies but not others. Another issue is that not one of these measures seems
impervious to all influences other than copper status. Despite these problems, in this
author’s opinion, these measures can be used right now to study marginal copper
deficiency if two criteria are met. One, the studies involve measures taken before
and after copper supplementation. In these circumstances, even if there is some
variation in baseline values, if copper is a limiting factor in values, copper supple-
mentation should affect the values. The other criterion is that the measure or mea-
sures used should be chosen with the study population in mind. For example, diamine
oxidase activities should not be used during pregnancy nor in subjects with renal
problems, because both situations greatly affect serum diamine oxidase activity
values.15,16 On the other hand, these values can work well for healthy, non-pregnant
subjects given copper supplements.17,18

Copper absorption from foods has not been studied as extensively as has iron or
zinc. Copper absorption from foods does not seem to be as inhibited by phytate as
are some other minerals.23 Animal proteins may promote copper absorption even
though foods like beef and dairy products don’t provide real high percents of the
copper RDA.24,25 In the U.S., vegetarian diets often contain more copper than meat-
inclusive diets, but the absorption of the copper appears to be lower in the meatless
diets.26,27 An exception to this pattern may be diets that are very high in soy products.
Soy protein contains a good amount of copper that seems to be well absorbed, but
substantial amounts must be eaten to have a major impact on daily copper intake.28
In this author’s work, subjects eating 40 g of soy protein per day for three to four
weeks showed an increase in activities for the copper enzyme diamine oxidase
(unpublished results).

High-dose vitamin C is often claimed to reduce copper absorption. This does

seem to be true in experimental animals given very high vitamin C doses,29,30,31 but
these doses greatly exceed what people typically take, even as so-called megadoses.
In human studies, vitamin C supplements can reduce ceruloplasmin activity.31,32,33
However, in at least some of these cases, this may be a direct effect of vitamin C
on ceruloplasmin enzyme activity, rather than reduced copper absorption.33,34 Thus,
whether vitamin C supplements typically pose a major threat to copper absorption
is still debatable. We also don’t know if vitamin C ever directly inhibits ceruloplasmin
activity in vivo enough to cause problems. One paper contends that the inhibition
effect, though it may take place during an assay, does not occur for normal situations
in vivo.34 In contrast, there has been speculation that this inhibition does take place
in some premature infants.35
The biggest known influence on copper absorption from foods is zinc supple-
mentation. High-dose zinc supplements have been known to cause severe copper
deficiency.36,37 High-dose iron supplements could also be a problem,38 though this
has not been given as much study as zinc. To complicate matters, some doses of
iron, in some circumstances, may promote good copper status.39
The copper in most multi-vitamin–mineral pills and food fortifications is oxide,
though sulfate is sometimes used. The latter is a common copper complex in animal
feeds. Copper is not typically added to cereal products intended for human con-
sumption because of negative effects on the product during storage. The most
common form of copper in standalone human supplements is copper gluconate.
Copper chelated to amino acids or hydrolyzed protein has been used in some human
and livestock research studies. These copper chelates can also be applied to food
fortification and supplement capsules or pills, though this has not been done as often
as with copper oxide or gluconate. Comparisons of these different types of copper
complexes in human studies are pretty much non-existent. However, some inferences
can be drawn from animal studies. One inference is that copper oxide is generally
poorly absorbed. In a number of studies in experimental animals and farm animals,
copper oxide has shown very low bioavailability.40,41,42
In contrast, in these same studies, copper sulfate has shown considerably better
bioavailability than copper oxide.40,41,42 In a few studies, an amino acid–copper
complex shows better bioavailability by various indices than does copper sulfate.43
On the other hand, in a cattle study, a copper–amino acid chelate and copper sulfate
give the same results.40 The last study is difficult to evaluate for two reasons. One,
the evaluation method is limited (plasma copper response by initially copper-defi-
cient animals). Two, little is known about the copper chelate complex used. Although
many mineral–amino acid mixtures are called chelates, different preparations may
have different chemical interactions and stability. Interestingly, copper gluconate,
the most common standalone human copper supplement, has not been tested to any
great extent for bioavailability.

The best sources of copper are not typically eaten often, or are eaten in small
amounts.44 These sources include liver, shellfish, nuts, seeds, soy protein products,

and cocoa. In regard to the last food, cocoa, foods concentrated in cocoa, such as
dark chocolate candy, are high in copper.45 On the other hand, products that contain
less cocoa, such as milk chocolate candy, are not as high, though they can make a
contribution to copper intake.45 For many people, much of the copper intake is a
cumulative effect from different fair sources, as well as from a substantial intake of
one given fair source. For the latter situation, a case in point is beef. Beef will not
provide as high a percent of the copper RDA per serving as it would for iron or
zinc.44 Even so, if beef is eaten in substantial quantities, it can provide some of a
day’s copper needs.44 In addition, as discussed above, meat may help promote copper
absorption from other foods.
Copper intakes have been reported many times as often falling below former
recommendations.11,46,47 However, the recent RDAs are more in line with lower
copper intakes. There are no obvious symptoms associated with such lower intakes,
though this does not rule out unrecognized symptoms. Along these lines, a section
heading in a past Annual Review of Nutrition11 asked: “Is mild chronic copper
deficiency a significant health problem in humans?” The first sentence in this section
stated: “This is the important practical question for the future.” It is now many years
later, and the question still remains. Controlled human feeding trials in USDA
laboratories have highlighted potential issues, but there is little work with “naturally
occurring” marginal copper deficiency in free-living subjects. One reason for this
lack of work has been the lack of consensus noted above about how to identify who
has marginal copper deficiency.
Another issue in this area is the effect of various health problems on needs. In
rats and humans, copper needs are increased by inflammatory stress, at least based
on copper enzyme activities.20,48 If this translates into impact on various aspects of
health, then inflammation, and possibly other physiological stress, could make peo-
ple especially prone to problems related to marginal copper deficiency. However,
this issue requires considerably more research.
One argument that many people eat insufficient copper is that submaximal values
for copper-related parameters can be found in both apparently healthy people and
in subjects with some health problems. Examples include:
• Diamine oxidase activities in normal adults18 and in some men with

moderately high cholesterol15,17
• Erythrocyte superoxide dismutase 1 activities in rheumatoid arthritis
patients, apparently healthy adults, and young adult women17,20,49
• White blood cell copper in people with atherosclerosis19
• Superoxide dismutase 1 activities (and low activity to immunoreactive
protein ratios) in aortic samples removed during surgery for aneurysms
or coronary bypass50
• Serum copper in certain women who subsequently developed breast
cancer51
• Ceruloplasmin and superoxide dismutase 1 activities in premature
infants52,53

• Three blood copper enzymes, including blood cell cytochrome c oxidase,

in a large number of cystic fibrosis patients54,55,56
• Ceruloplasmin activity to immunoreactive protein ratios in a large number
of renal dialysis patients22 and DiSilvestro, R.A., unpublished results
One problem in interpreting these studies is that it is not certain whether factors
other than copper status are causing the abnormalities in copper-related parameters.
For instance, ceruloplasmin and superoxide dismutase could be inactivated by cop-
per-independent mechanisms. Nonetheless, copper status would seem to be the most
likely explanation in studies where multiple copper parameters are measured. Even
so, in these and other studies, further clarification would be helpful. For example,
determining the copper content of the enzymes being studied would be helpful. This
would say whether there is a low amount of copper per enzyme molecule. However,
this is rarely done due to time concerns and technical requirements.
If human copper intake often fails to maximize values for copper-related param-
eters, then what are the practical health consequences, if any? One consideration is
that in experimental animals, copper deficiency, sometimes including marginal defi-
ciency, can produce negative effects relevant to human health problems.1,57–65 These
effects include compromised immune function, poor resistance to chemically
induced acute tissue injury, high vulnerability to chemical carcinogenesis, various
negative effects on cardiovascular-related parameters including elevated serum cho-
lesterol, and some hormonal abnormalities. Some of these same effects can also
occur in studies where small numbers of healthy human volunteers are fed low
copper levels.11,13,21,66–69 Nonetheless, an important question remains largely unan-
swered: Does “naturally” occurring marginal copper deficiency in free-living people
cause any real problems? This question can be subdivided into three questions:
1. Does moderate copper deficiency cause undetected health defects in

apparently healthy people (i.e., compromised immune function)?
2. Can moderate copper deficiency increase the risk of developing health
problems that are not strictly copper deficiency diseases (e.g., cancer)?
3. Will moderate copper deficiency aggravate primary or secondary symp-
toms of existing diseases (e.g., rheumatoid arthritis)?
One way to answer any of these questions is intervention studies where moderate
copper deficiency is diagnosed and is then treated with increased copper intake. For
example, subjects at risk for certain diseases can be screened for moderate copper
deficiency, then given copper or placebo supplements, and then evaluated for either
disease onset or measures that assess risk for the disease. This has not yet been done
to any great extent. One reason has been the lack of consensus about diagnosing
marginal copper deficiency. However, as noted above, this author feels that the
currently available diagnostic tools can be used if the right tool is selected for the
people being studied.


Despite the various studies claiming that copper intake is often below optimal levels,
and despite the speculations that such moderate deficiencies could have negative
health effects, there are just a few copper supplementation studies. The main existing
studies are summarized in Table 6.3. It should be noted that many of these studies
have focused just on effects on copper metalloenzyme activities, rather than on
parameters directly related to specific health problems. This is because most copper
supplement studies are trying to justify that marginal copper deficiency occurs in a
given situation, or verify that a given copper enzyme is a good indicator of marginal
deficiency. Both goals are supported by finding submaximal values for copper
metalloenzyme activities, which increase in response to copper supplementation.
A number of the studies cited in Table 6.3 show that copper supplementation
can raise copper enzyme activities. This supports the view that marginal copper
deficiency does occur in some people, at least based on copper enzyme activities.
An alternative interpretation is that copper enzymes can keep increasing as copper
intake increases beyond adequate levels. This latter contention is weakened by one
study where split analysis is done by dividing subjects into two groups based on a
median split in copper enzyme activities.17 In that case, copper supplementation
produces an increase in copper enzyme activities when starting values are below the
median split, but not when values are above the split.
TABLE 6.3
Copper (Cu) Supplementation Trials
Subjects Complex Outcomea
Young adult women Glycinate 2 Cu enzymes up, oxidant stress markers down49
Normal adults Glycinate Various Cu enzymes up18
Normal adults Glycinate Erythrocyte superoxide dismutase up20
Rheumatoid arthritis adults Glycinate Erythrocyte superoxide dismutase up20
Cystic fibrosis patients Glycinate No effect: 3 Cu enzymes54
Adults (high cholesterol) Not stated Reduce serum cholesterol70
Males (high cholesterol) Glycinate No effect: cholesterol; varied effect with split
analysisb on 2 Cu enzymes, lipoprotein
oxidation17,71
Young adult men Sulfate No depression in total serum cholesterol71
Young adult women Glycinate Erythrocyte superoxide dismutase up; no effect:
on sulfate bone markers72
Young adult women Glycinate Erythrocyte superoxide dismutase up; bone
markers ratio up (Figure 6.1)
Postmenopause women Gluconate Bone loss down73
a Enzyme effects refer to changes in activities
b See text for details on split analysis

The next logical question is whether an improvement in copper enzyme activities

translates to any practical health improvements. The median split study gives one
indication along those lines. In subjects below the median split, copper supplementation
depresses lipoprotein oxidation,17 a measure related to atherosclerosis development.74
In experimental animals, a large number of studies find high serum cholesterol
readings with copper deficiency.75 That observation is duplicated in a few humans
intentionally fed a low-copper diet.67,68 Unfortunately, little is known about how well
copper supplementation can affect cholesterol readings in free-living people. None
of the three cholesterol studies noted in Table 6.3 is ideal, including the one by this
author.17 One study shows no copper-induced decrease in cholesterol parameters,
but this study shows high variability in the placebo groups.71 In addition, the study
examines young adult men with low starting cholesterol. Thus, this group may not
easily show improvement in cholesterol readings. The study by this author,17 which
showed no effect on plasma total cholesterol, does examine subjects with moderately
high cholesterol. However, this study uses only a four-week supplementation period,
which may be too short to lower cholesterol by copper supplementation. The one
study that does show copper depression of serum cholesterol examines a very small
subject number who are not screened for starting copper status.70 Despite these
limitations, the area of copper and cholesterol should be given more study in human
subjects, especially since correction of marginal copper deficiency in livestock can
reduce cholesterol values.64
The practical consequences of copper supplementation for bone health in women
is still very unsettled. A review article76 provides a good theoretical basis for copper’s
importance for bone. In theory, copper status influences bone structure via lysyl
oxidase, which affects the collagen in bone.77 Copper also is needed for antioxidant
superoxide dismutase enzymes,1 which eliminate superoxide, which can stimulate
bone resorption.78 Still, these functional considerations do not necessarily mean that
typical variations in copper intake affect bone health. This can only be determined
via human intervention trials. One such study has shown that copper slows bone
loss in postmenopausal women,73 but the results are difficult to interpret. For one
thing, copper is given with a group of minerals. This means that we don’t know
how much the copper contributed to the results. In addition, there is a lot of overlap
in results between study groups, and a lot of variation within groups. Along these
lines, a group getting just calcium has a slightly better mean value than a group
getting calcium plus trace minerals. Yet, only the latter differs statistically from the
placebo group.
For young adult women, two studies each give negative results for copper
supplementation effects on blood and urine markers for bone metabolism.72,79 How-
ever, a meeting abstract by this author shows that if the bone marker results are
expressed a certain way, then a statistically significant effect can be observed.49 In
this study, copper has no effect on two urinary markers of collagen degradation:
deoxypyridinoline (DPD), a crosslink in collagen, and type I collagen helical peptide.
However, if a ratio of DPD to type I collagen helical peptide is examined, copper
increases this ratio (Figure 6.1). This ratio may be a more accurate reflection of
copper effects on bone health than either of the two parameters individually. The
reasoning is as follows. Marginal copper deficiency could restrict lysyl oxidase

activity, which can limit DPD crosslink formation in collagen.77 This could cause
low values for the DPD crosslinks in urine. At the same time, this low crosslinking
can cause collagen degradation to increase, which will increase urinary DPD values.
Collagen degradation could also be increased by marginal copper deficiency due to
high superoxide stimulation of bone resorption. Thus, marginal copper deficiency
could simultaneously produce opposite effects on urinary DPD values, which could
essentially cancel each other out. However, a ratio of DPD crosslinks to another
marker of collagen, such as that used in Figure 6.1, should reflect how well the
crosslinking process is occurring. These results merit follow up research.
The lack of copper effect in cystic fibrosis54 is disappointing. These people seem
to be prone to a more severe marginal copper deficiency than is typical.54,55,56 One
reason for the negative results may be that cellular copper uptake processes are
impaired in these subjects. Possibly, a novel copper complex could be designed to
remedy this situation.
Clearly, there is a need for more copper supplementation studies where starting
copper status is considered, and where effects on copper enzyme activities are
examined in concert with other health-related effects. This should be done both for
healthy people and for people with health problems that might raise copper needs.
One of the biggest barriers to such studies has simply been a lack of funding for
such work.
All of the discussion of copper supplementation thus far has revolved around
correcting marginal deficiency. Could there be benefits to copper intake beyond that
needed to prevent or correct deficiencies? At present, the idea of health benefits for
an above-adequate copper intake has not been studied to any great degree in humans.
However, there is one study that raises the possibility. Administration of copper
sulfate or glycinate increases erythrocyte resistance to lysis in vitro.80 Since there is
no accompanying increase in erythrocyte superoxide dismutase activities, this action
may not work via correction of a deficiency. Another justification of copper benefits
beyond correcting deficiencies could be found in a series of studies in copper-
adequate rats and mice.81 In this work, specific copper complexes have anti-inflam-
matory and other protective actions. However, these effects may be limited to just
these complexes acting as drugs.
TOXICITY
According to present knowledge, copper supplementation at doses typically used by
the public seem to be safe unless they cause GI tract upsets. The current adult Upper
Level for copper is 10 mg,44 which is well beyond what is found in any typical
copper supplement. Even this dose may not be terribly dangerous except for GI
problems. In a 12-week study, a 10 mg daily dose of copper produces no obvious
physical or clinical chemistry symptoms.82 Nonetheless, there is the possibility that
some copper toxicity effects are not recognized yet. Along these lines, in hypercho-
lesterolemic postmenopausal women, 12 weeks of supplementation of 3 mg cop-
per/day suppresses lymphocyte proliferation when the cells are removed from the
body (the type of copper complex used is not stated).83 The general applicability of
this study is not yet known since the population studied is not a generic population.

FIGURE 6.1 Ratios of deoxypyridinoline (DPD), a crosslink in collagen, and type I collagen helical peptide (a measure of excreted total collagen
protein) in response to copper glycinate (Cu) or placebo. Young adult females (N = 8 per group) were given copper glycinate (2 mg copper/day) or
placebo for six weeks. Values are means ± SD for arbitrary ratio units. Copper, but not placebo, produced a statistically significant effect (p < 0.05,
paired t-test).

Also, the practical health implications of the effect on lymphocytes are also not
known yet.
Nausea or other GI tract discomforts can be an early symptom in many people
with copper poisoning.1 In fact, this author has noted from his own experience that
some people get nauseated even from a 2 or 3 mg copper dose if taken on an empty
stomach. Thus, there is some built-in protection against oral copper supplementation
toxicity. Even so, this is not necessarily a foolproof protection, since the study of
10 mg copper/day as gluconate reports no more GI problems than placebo.82
Most medical reports on copper toxicity involve environmental and occupational
exposures, or the genetic condition Wilson’s disease, rather than dietary copper
intake or high-dose supplementation.1 There has been some speculation at mineral
meetings that some mild, undiagnosed forms of Wilson’s disease may exist, and that
some people may have other genetic sensitivities to copper toxicity. However, at
present, there is little documentation for these ideas, though they can’t be ruled out.
There has also been some speculation that moderately high copper intake can
promote breast cancer and cardiovascular disease. One argument for the latter arises
from an epidemiological linking of high serum copper with cardiovascular disease in
Finland.84 However, these high serum copper values likely just mark physiologic stress.
Serum levels of ceruloplasmin, which contains nearly all serum copper, tend to rise
with most any stress.14 This author has shown that in rats, stress produces high serum
copper or ceruloplasmin levels even with marginal copper deficiency.48,85 Another reason
that copper is sometimes thought to promote cardiovascular disease is that copper ions,
and the copper protein ceruloplasmin, can oxidize lipoproteins in vitro.74,86 Oxidized
lipoproteins are thought to promote atherosclerosis.74 However, catalytically active, low
molecular weight copper ion is generally absent from serum.87 Moreover, this author
notes that elevation of ceruloplasmin levels in rats does not increase lipoprotein vul-
nerability to oxidation.88 Also, ceruloplasmin promotion of LDL oxidation in vitro
requires a loosely bound copper.86 This author and others note that such loose copper
is not considered part of native ceruloplasmin and can be easily removed by serum
albumin.86,88,89 This removal should occur readily in the blood during real-life situa-
tions.89 It should also be noted that in humans, a fairly high dose of copper (6 mg/day)
does not increase lipoprotein oxidation.90 Plus, in one study, copper supplementation
at lower levels actually reduces lipoprotein oxidation in some people.17
The breast cancer issue is similar to the cardiovascular issue in that there is an
epidemiological linking of high serum copper with high risk of breast cancer.51 Once
again, this likely has more to do with stress elevation of serum ceruloplasmin levels
than with high copper intake. Interestingly, the same epidemiological study51 also
found that low serum copper readings are associated with a high breast cancer risk.
Thus, low copper intake could be a problem in this regard.
In this author’s opinion, the most common copper supplement doses (1 to 3
mg/day) do not pose any known dangers. Nonetheless, research should be done to
see if there are unidentified dangers of moderately high copper doses, and to identify
who, if anyone, is overly sensitive to copper toxicity.

TABLE 6.4
Copper Supplements at a Glance
Adult RDA: 0.9 mg (controversial; may be too low)
Typical dose in supplement studies: 2–5 mg (2 mg is probably effective in most cases)
Best supplement complex: glycinate or sulfate is used in most research; gluconate may be good,
though largely untested; oxide is commonly used, but has very low bioavailability in animal studies
Applications: increases copper enzyme activities in some people; several health promotion effects
possible, but not well confirmed
Upper Level: 10 mg
Safety issues: supplement uses have been well below the Upper Limit

There are reasons to believe that marginal copper deficiency is a problem in many
people and that correction, including that by supplementation, can have various
health benefits. However, this concept is still missing too many pieces of the research
puzzle to make definitive conclusions. Copper toxicity of supplements requires more
research, though at present no major dangers have been clearly identified for typical
doses.
REFERENCES
1. Howell, J.M.C. and Gawthorne, J.M., Copper in Animals and Man, CRC Press, Boca
Raton, 1987.
2. Bielli, P. and Calabrese, L., Structure to function relationships in ceruloplasmin: a
‘moonlighting’ protein, Cell Mol. Life Sci., 59, 1413, 2002.
3. Percival, S.S., Copper and immunity, Am. J. Clin. Nutr., 67, 1064S, 1998.
4. Thakur, N.K., Hayashi, T., Sumi, D., Kano, H., Tsunekawa, T., and Iguchi, A., HMG-
CoA reductase inhibitor stabilizes rabbit atheroma by increasing basal NO and
decreasing superoxide, Am. J. Physiol. Heart Circ. Physiol., 281, H75, 2001.
5. Harris, E.D., Copper, in Handbook of Nutritionally Essential Mineral Elements,
6. Reeves, P.G., Copper metabolism in metallothionein-null mice fed a high-zinc diet,
J. Nutr. Biochem., 9, 598, 1998.
7. Buettner, G.R. and Jurkiewicz, B.A., Catalytic metals, ascorbate and free radicals:
combinations to avoid, Radiat. Res.,145, 532, 1996.
8. Harris, E.D. and Percival, S.S., Copper transport: insights into a ceruloplasmin-based
delivery system, Adv. Exp. Med. Biol., 258, 95, 1989.
9. Hellman, N.E. and Gitlin, J.D., Ceruloplasmin metabolism and function, Annu. Rev.
Nutr., 22, 439, 2002.
10. Huffman, D.L. and O’Halloran, T.V., Function, structure, and mechanism of intra-
cellular copper trafficking proteins, Annu. Rev. Biochem., 70, 677, 2001.
11. Danks, D.M., Copper deficiency in humans, Ann. Rev. Nutr., 8, 235, 1988.
12. Holtzman, N.A. and Gaumnitz, B.M., Identification of an apoceruloplasmin-like
substance in the plasma of copper-deficient rats, J. Biol. Chem., 245, 2350, 1970.

13. Reiser, S., Smith, J.C., Jr., Mertz, W., Holbrook, J.T., Scholfield, D.J., Powell, A.S.,
Canfield, W.K., and Canary, J.J., Indices of copper status in humans consuming a
typical American diet containing either fructose or starch, Am. J. Clin. Nutr., 42, 242,
1985.
14. Cousins, R.J., Absorption, transport, and hepatic metabolism of copper and zinc:
special reference to metallothionein and ceruloplasmin, Physiol. Rev., 65, 238, 1985.
15. DiSilvestro, R.A., Jones, A.A., Smith, D., and Wildman, R., Plasma diamine oxidase
activities in renal dialysis patients, a human with spontaneous copper deficiency and
marginally copper deficient rats, Clin. Biochem., 30, 559, 1997.
16. Wolvekamp, M.C. and de Bruin, R.W., Diamine oxidase: an overview of historical,
biochemical and functional aspects, Dig. Dis., 12, 2, 1994.
17. Jones, A.A., DiSilvestro, R.A., Coleman, M., and Wagner, T.L., Copper supplemen-
tation of adult men: effects on blood copper enzyme activities and indicators of
cardiovascular disease risk, Metabolism, 46, 1380, 1997.
18. Kehoe, C.A., Turley, E., Bonham, M.P., O’Connor, J.M., McKeown, A., Faughnan,
M.S., Coulter, J.S., Gilmore, W.S., Howard, A.N., and Strain, J.J., Response of
putative indices of copper status to copper supplementation in human subjects, Br. J.
Nutr., 84, 151, 2000.
19. Kinsman, G.D., Howard, A.N., Stone, D.L., and Mullins, P.A., Studies in copper
status and atherosclerosis, Biochem. Soc. Trans., 18, 1186, 1990.
20. DiSilvestro, R.A., Marten, J., and Skehan, M., Effects of copper supplementation on
ceruloplasmin and copper-zinc superoxide dismutase in free-living rheumatoid arthri-
tis patients, J. Am. Coll. Nutr., 11, 177, 1992.
21. Milne, D.B. and Nielsen, F.H., Effects of a diet low in copper on copper-status
indicators in postmenopausal women, Am. J. Clin. Nutr., 63, 358, 1996.
22. Emenaker, N.J., DiSilvestro, R.A., Nahman, N.S., Jr., and Percival, S., Copper-related
blood indexes in kidney dialysis patients, Am. J. Clin. Nutr., 64, 757, 1996.
23. Lonnerdal, B., Jayawickrama, L., and Lien, E.L., Effect of reducing the phytate
content and of partially hydrolyzing the protein in soy formula on zinc and copper
absorption and status in infant rhesus monkeys and rat pups, Am. J. Clin. Nutr., 69,
490, 1999.
24. Brewer, G.W., Yuzbasiyan-Gurkan, V., Dick, R., Wang, Y., and Johnson, V., Does a
vegetarian diet control Wilson’s disease?, J. Amer. Coll. Nutr., 12, 527, 1993.
25. Konig, J.S. and Elmadfa, I., Plasma copper concentration as marker of copper intake
from food, Ann. Nutr. Metab., 44, 129, 2000.
26. Hunt, J.R. and Vanderpool, R.A., Apparent copper absorption from a vegetarian diet,
Am. J. Clin. Nutr., 74, 803, 2001.
27. Srikumar, T.S., Johansson, G.K., Ockerman, P.A., Gustafsson, J.A., and Akesson, B.,
Trace element status in healthy subjects switching from a mixed to a lactovegetarian
diet for 12 mo, Am. J. Clin. Nutr., 55, 885, 1992.
28. Lowy, S.L., Fisler, J.S., Drenick, E.J., Hunt, I.F., and Swendseid, M.E., Zinc and
copper nutriture in obese men receiving very low calorie diets of soy or collagen
protein, Am. J. Clin. Nutr., 43, 272, 1986.
29. Milne, D.B. and Omaye, S.T., Effect of vitamin C on copper and iron metabolism in
the guinea pig, Int. J. Vitam. Nutr. Res., 50, 301, 1980.
30. Milne, D.B., Omaye, S.T., and Amos, W.H., Jr., Effect of ascorbic acid on copper
and cholesterol in adult cynomolgus monkeys fed a diet marginal in copper, Am. J.
Clin. Nutr., 34, 2389, 1981.
31. Pekiner, B. and Nebioglu, S., Effect of vitamin C on copper and iron status in men
and guinea pigs, J. Nutr. Sci. Vitaminol. (Tokyo), 40, 401, 1994.

32. Finley, E.B. and Cerklewski, F.L., Influence of ascorbic acid supplementation on
copper status in young adult men, Am. J. Clin. Nutr., 37, 553, 1983.
33. Jacob, R.A., Skala, J.H., Omaye, S.T., and Turnlund, J.R., Effect of varying ascorbic
acid intakes on copper absorption and ceruloplasmin levels of young men, J. Nutr.,
117, 2109, 1987.
34. Lovstad, R.A., A study on ascorbate inhibition of ceruloplasmin ferroxidase activity,
Biometals, 10, 123, 1997.
35. Powers, H.J., Loban, A., Silvers, K., and Gibson, A.T., Vitamin C at concentrations
observed in premature babies inhibits the ferroxidase activity of ceruloplasmin, Free
Radic. Res., 22, 57, 1995.
36. Abdallah, S.M. and Samman, S., The effect of increasing dietary zinc on the activity
of superoxide dismutase and zinc concentration in erythrocytes of healthy female
subjects, Eur. J. Clin. Nutr., 47, 327, 1993.
37. Fosmire, G.J., Zinc toxicity, Am. J. Clin. Nutr., 51, 225, 1990.
38. Johnson, M.A. and Murphy, C.L., Adverse effects of high dietary iron and ascorbic
acid on copper status in copper-deficient and copper-adequate rats, Am. J. Clin. Nutr.,
47, 96, 1988.
39. Gropper, S.S., Bader-Crowe, D.M., McAnulty, L.S., White, B.D., and Keith, R.E.,
Non-anemic iron depletion, oral iron supplementation and indices of copper status
in college-aged females, J. Am. Coll. Nutr., 21, 545, 2002.
40. Kegley, E.B. and Spears, J.W., Bioavailability of feed-grade copper sources (oxide,
sulfate, or lysine) in growing cattle, J. Anim. Sci., 72, 2728, 1994.
41. Rojas, L.X., McDowell, L.R., Cousins, R.J., Martin, F.G., Wilkinson, N.S., Johnson,
A.B., and Velasquez, J.B., Interaction of different organic and inorganic zinc and
copper sources fed to rats, J. Trace Elem. Med. Biol., 10, 139, 1996.
42. Xin, Z., Waterman, D.F., Hemken, R.W., Harmon, R.J., and Jackson, J.A., Effects of
copper sources and dietary cation-anion balance on copper availability and acid-base
status in dairy calves, J. Dairy Sci., 74, 3167, 1991.
43. Guo, R., Henry, P.R., Holwerda, R.A., Cao, J., Littell, R.C., Miles, R.D., and Ammer-
man, C.B., Chemical characteristics and relative bioavailability of supplemental
organic copper sources for poultry, J. Anim. Sci., 79, 1132, 2001.
45. Joo. S. and Betts, N., Copper intakes and consumption patterns of chocolate foods
as sources of copper for individuals in the 1987–88 nationwide food consumption
survey, Nutr. Res., 16, 41, 1996.
46. Klevay, L.M., Reck, S.J., and Barcome, D.F., Evidence of dietary copper and zinc
deficiencies, JAMA, 241, 1916, 1979.
47. Turnlund, J.R., Copper nutriture, bioavailability, and the influence of dietary factors,
J. Am. Diet. Assoc., 88, 303, 1988.
48. DiSilvestro, R.A. and Marten, J.T., Effects of inflammation and copper intake on rat
liver and erythrocyte Cu-Zn superoxide dismutase activity levels, J. Nutr., 120, 1223,
1990.
49. DiSilvestro, R.A., Copper supplementation effects on oxidant stress and bone turnover
markers in young adult women, FASEB J., 17, A1129, 2003.
50. Dubick, M.A., Keen, C.L., DiSilvestro, R.A., Eskelson, C.D., Ireton, J., and Hunter,
G.C., Antioxidant enzyme activity in human abdominal aortic aneurysmal and occlu-
sive disease, Proc. Soc. Exp. Biol. Med., 220, 39, 1999.

51. Overvad, K., Wang, D.Y., Olsen, J., Allen, D.S., Thorling, E.B., Bulbrook, R.D., and
Hayward, J.L., Copper in human mammary carcinogenesis: a case-cohort study, Am.
J. Epidemiol., 137, 409, 1993.
52. L’Abbe, M.R. and Friel, J.K., Copper status of very low birth weight infants during
the first 12 months of infancy, Pediatr. Res., 32, 183, 1992.
53. Phylactos, A.C., Leaf, A.A., Costeloe, K., and Crawford, M.A., Erythrocyte
cupric/zinc superoxide dismutase exhibits reduced activity in preterm and low-birth-
weight infants at birth, Acta Paediatr., 84, 1421, 1995.
54. Best, K., McCoy, K., Gemma, S., and DiSilvestro, R.A., Copper enzyme activities
in cystic fibrosis before and after copper supplementation plus or minus zinc, Metab-
olism, 53, 37, 2004.
55. Percival, S.S., Bowser, E., and Wagner, M., Reduced copper enzyme activities in
blood cells of children with cystic fibrosis, Am. J. Clin. Nutr., 62, 633, 1995.
56. Percival, S.S., Kauwell, G.P., Bowser, E., and Wagner, M., Altered copper status in
adult men with cystic fibrosis, J. Am. Coll. Nutr., 18, 614, 1999.
57. Hunsaker, H.A., Morita, M., and Allen, K.G., Marginal copper deficiency in rats.
Aortal morphology of elastin and cholesterol values in first-generation adult males,
Atherosclerosis, 51, 1, 1984.
58. Medeiros, D.M. and Wildman, R.E., Newer findings on a unified perspective of copper
restriction and cardiomyopathy, Proc. Soc. Exp. Biol. Med., 215, 299, 1997.
59. Nelson, S.K., Huang, C.J., Mathias, M.M., and Allen, K.G., Copper-marginal and
copper-deficient diets decrease aortic prostacyclin production and copper-dependent
superoxide dismutase activity, and increase aortic lipid peroxidation in rats, J. Nutr.,
122, 2101, 1992.
60. Rayssiguier, Y., Gueux, E., Bussiere, L., and Mazur, A., Copper deficiency increases
the susceptibility of lipoproteins and tissues to peroxidation in rats, J. Nutr., 123,
1343, 1993.
61. Wildman, R.E., Hopkins, R., Failla, M.L., and Medeiros, D.M., Marginal copper-
restricted diets produce altered cardiac ultrastructure in the rat, Proc. Soc. Exp. Biol.
Med., 210, 43, 1995.
62. DiSilvestro, R.A. and Carlson, G.P., Effects of moderate copper deficiency on carbon
tetrachloride-induced hepatotoxicity in rats, Proc. Soc. Exp. Biol. Med., 197, 32, 1991.
63. DiSilvestro, R.A., Greenson, J.K., and Liao, Z., Effects of low copper intake on
dimethylhydrazine-induced colon cancer in rats, Proc. Soc. Exp. Biol. Med., 201, 94,
1992.
64. Engle, T.E., Spears, J.W., Xi, L., and Edens, F.W., Dietary copper effects on lipid
metabolism and circulating catecholamine concentrations in finishing steers, J. Anim.
Sci., 78, 2737, 2000.
65. Babu, U. and Failla, M.L., Copper status and function of neutrophils are reversibly
depressed in marginally and severely copper-deficient rats, J. Nutr., 120, 1700, 1990.
66. Bhathena, S.J., Recant, L., Voyles, N.R., Timmers, K.I., Reiser, S., Smith, J.C., Jr.,
and Powell, A.S., Decreased plasma enkephalins in copper deficiency in man, Am.
J. Clin. Nutr., 43, 42, 1986.
67. Klevay, L.M., Inman, L., Johnson, L.K., Lawler, M., Mahalko, J.R., Milne, D.B.,
Lukaski, H.C., Bolonchuk, W., and Sandstead, H.H., Increased cholesterol in plasma
in a young man during experimental copper depletion, Metabolism, 33, 1112, 1984.
68. Reiser, S., Powell, A., Yang, C.Y., and Canary, J.J., Effect of copper intake on blood
cholesterol and its lipoprotein distribution in man, Nutr. Rep. Int., 36, 641, 1987.
69. Lukaski, H.C., Klevay, L.M., and Milne, D.B., Effects of dietary copper on human
autonomic cardiovascular function, Eur. J. Appl. Physiol., 58,74, 1988.

70. Hermann, J., Chung, H., and Burns, M., Effects of chromium or copper supplemen-
tation on plasma lipids, glucose and serum insulin in adults over age 50, FASEB J.,
9, A577, 1995.
71. Medeiros, D.M., Milton, A., Brunett, E., and Stacy, L., Copper supplementation
effects on indicators of copper status and serum cholesterol in adult males, Biol. Trace
Elem. Res., 30, 19, 1991.
72. Cashman, K.D., Baker, A., Ginty, F., Flynn, A., Strain, J.J., Bonham, M.P., O’Connor,
J.M., Bugel, S., and Sandstrom, B., No effect of copper supplementation on biochem-
ical markers of bone metabolism in healthy young adult females despite apparently
improved copper status, Eur. J. Clin. Nutr., 55, 525, 2001.
Nutr., 124, 1060, 1994.
74. Heller, F.R., Descamps, O., and Hondekijn, J.C., LDL oxidation: therapeutic perspec-
tives, Atherosclerosis, 137 Suppl., S25, 1998.
75. Olivares, M. and Uauy, R., Copper as an essential nutrient, Am. J. Clin. Nutr., 63,
791S, 1996.
76. Lowe, N.M., Lowe, N.M., Fraser, W.D., and Jackson, M.J., Is there a potential
therapeutic value of copper and zinc for osteoporosis?, Proc. Nutr. Soc., 61, 181,
2002.
77. Rucker, R.B., Kosonen, T., Clegg, M.S., Mitchell, A.E., Rucker, B.R., Uriu-Hare,
J.Y., and Keen, C.L., Copper, lysyl oxidase, and extracellular matrix protein cross-
linking, Am. J. Clin. Nutr., 67, 996S, 1998.
79. Baker, A., Turley, E., Bonham, M.P., O’Connor, J.M., Strain, J.J., Flynn, A., and
Cashman, K.D., No effect of copper supplementation on biochemical markers of bone
metabolism in healthy adults, Br. J. Nutr., 82, 283, 1999.
80. Rock, E., Mazur, A., O’Connor, J.M., Bonham, M.P., Rayssiguier, Y., and Strain, J.J.,
The effect of copper supplementation on red blood cell oxidizability and plasma
antioxidants in middle-aged healthy volunteers, Free Radic. Biol. Med., 28, 324, 2000.
81. Sorenson, J.R., Antiinflammatory, analgesic, and antiulcer activities of copper com-
plexes suggest their use in a physiologic approach to treatment of arthritic diseases,
Basic Life Sci., 49, 591, 1988.
82. Pratt, W.B., Omdahl, J.L., and Sorenson, J.R., Lack of effects of copper gluconate
supplementation, Am. J. Clin. Nutr., 42, 681, 1985.
83. Rhee, Y.S., Hermann, J.R., Burnham, K., Arquitt, A.B., and Stoecker, B.J., The effects
of chromium and copper supplementation on mitogen-stimulated T cell proliferation
in hypercholesterolaemic postmenopausal women, Clin. Exp. Immunol., 127, 463,
2002.
84. Salonen, J.T., Salonen, R., Korpela, H., Suntioinen, S., and Tuomilehto, J., Serum
copper and the risk of acute myocardial infarction: a prospective population study in
men in eastern Finland, Am. J. Epidemiol., 134, 268, 1991.
85. DiSilvestro, R.A., Effects of copper intake, inflammation and copper injection on rat
serum ceruloplasmin activity levels, Nutr. Res., 10, 355, 1990.
86. Fox, P.L., Mukhopadhyay, C., and Ehrenwald, E., Structure, oxidant activity, and
cardiovascular mechanisms of human ceruloplasmin, Life Sci., 56, 1749, 1995.

87. Evans, P.J., Bomford, A., and Halliwell, B., Non-ceruloplasmin copper and ferroxi-
dase activity in mammalian serum. Ferroxidase activity and phenanthroline-detectable
copper in human serum in Wilson’s disease, Free Radic. Res. Commun., 7, 55, 1989.
88. DiSilvestro, R.A. and Jones, A.A., High ceruloplasmin levels in rats without high
lipoprotein oxidation rates, Biochim. Biophys. Acta, 1317, 81, 1996.
89. Zgirski, A. and Frieden, E., Binding of Cu(II) to non-prosthetic sites in ceruloplasmin
and bovine serum albumin, J. Inorg. Biochem., 39, 137, 1990.
90. O’Connor, J.M., Bonham, M.P., Turley, E., McKeown, A., McKelvey-Martin, V.J.,
Gilmore, W.S., and Strain, J.J., Copper supplementation has no effect on markers of
DNA damage and liver function in healthy adults (FOODCUE project), Ann. Nutr.
Metab., 47, 201, 2003.

7 Selenium
Selenium functions in certain enzymes, but the way selenium is incorporated into
these enzymes is quite different from the processes for other minerals. Selenium has
drawn interest for its roles in antioxidant defense and thyroid hormone production,
as well as for possible applications in cancer prevention. The latter may be inde-
pendent of selenium’s enzyme functions and may require intake well beyond the
levels needed to prevent deÞciency. This last area will be a prominent research
interest for selenium for quite some time. Some other applications of selenium
supplements also have some data to support usefulness. In contrast, for still other
claims, despite some Internet sites making very deÞnitive claims, the current evi-
dence is not very deÞnitive.
Selenium is a component of a number of proteins. Selenium can exist as an anion
at biological pH, which makes it able to both give and accept electrons.1 The best
understood physiological functions of selenium are two enzyme functions.1 One of
these functions is done as part of a family of proteins named glutathione peroxidase
(one is found inside of cells, another is outside cells in places like the plasma).
Glutathione peroxidase is part of the body’s antioxidant defense network by elimi-
nating peroxides, including hydrogen peroxide, which can be both precursors and
products of free radicals.2 Selenium also functions in an enzyme that is part thyroid
hormone synthesis.1
A more recently discovered selenium enzyme is known as thioredoxin reductase,
which seems to have a number of regulatory roles within cells, and seems to affect
antioxidant defense by inßuencing electron ßow in some reactions.3,4 One interesting
point about this enzyme is that in rats, the enzyme activities can be increased by
elevating selenium intake above those normally considered adequate.5
Selenoproteins can also have non-enzymatic functions. Sperm capsule seleno-
protein is a structural protein found in the midpiece region of the sperm tail.3 In
selenium deÞciency, morphological anomalies in this region give rise to spermatozoa
with impaired motility.6 There are also several other selenoproteins in the male
gonads that may contribute to male reproductive function.7 In addition, selenium is
needed for normal testosterone metabolism and testicular morphology.8
A protein called selenoprotein P has been studied from a regulatory perspective,
but the functional importance of this protein is still not fully understood.3

There are other proteins in the body that have been found to contain selenium,
but their function is not yet known.3 Selenium may also exert some enzyme-inde-
pendent actions relevant to cancer prevention (see Cancer subsection), but it is gray
as to whether to call these actions selenium functions or selenium pharmacological
effects. The latter would be based on processes that can be affected by selenium,
but that are not essential roles for this element.
Selenium deÞciency can also affect immune function, though the mechanisms
are not completely clear.9 Both the antioxidant and thyroid modulating actions of
selenium could be involved, though there may be other mechanisms as well. One
unusual interaction between selenium status and immune function is the impact on
viral virulence.10 This is discussed further in the Human ImmunodeÞciency Virus
(HIV) subsection. Selenium interactions with viral virulence also extend to other
virus classes. For example, in mice, selenium deÞciency increases the pathology of
an inßuenza virus infection.10
Selenium from foods is absorbed well by mechanisms that overlap amino acid
absorption.11 Selenium absorption is not controlled by homeostatic mechanisms such
as those that exist for minerals like iron and calcium.
Most minerals that exist in metalloproteins are inserted into the protein by
attaching to selected amino acids, or in the case of some iron proteins, by insertion
into a heme or ctyochrome structure, which can be inserted into a protein. Selenium
is different in that it is substituted for a sulfur in amino acids, typically cysteine.
This selenocysteine amino acid becomes a part of certain proteins during protein
synthesis. Selenocysteine has its own codon and speciÞc biosynthetic and insertion
machinery.3 In the presence of a downstream stem-loop structure, the UGA codon
in mRNA, instead of behaving as a stop codon, speciÞes the insertion of a seleno-
cysteine into an expanding peptide chain.

Unlike the case for a lot of minerals, selenium has some well-established methods
for status assessment. Plasma selenium is proportional to selenium intake at both
high and low levels.12 Whole blood or red blood cell selenium can also be useful
for marking long-term selenium status.12 Plasma glutathione peroxidase activities
are proportional to selenium intake, but do plateau at certain intakes.11,12 In fact,
these plateaus are used to establish the selenium RDAs.11 For this application, one
under-addressed issue is how well the plasma value plateaus compare to tissue
plateaus for glutathione peroxidase activites.
Erythrocyte glutathione peroxidase activity is also sometimes used to assess
selenium status, though the values may be affected to a small degree by some
inßuences other than selenium status.13 The combination of glutathione peroxidase
activities and plasma selenium can provide information on the response to selenium
supplementation in subjects who are barely deÞcient, or in adequate status, before
treatment. For example, if the supplementation raises plasma selenium but not

glutathione peroxdidase, the subjects are likely in adequate status but the selenium
supplement did add to body selenium. This type of analysis is important in cancer
prevention studies (see Cancer subsection) where the goal is not always just to
correct deÞciency, but to provide an above-adequate intake.
A number of large-scale studies use toenail selenium for status assessment. There
is data showing higher values with long-term selenium supplementation, and a small
degree of association with dietary selenium intake.14,15,16 Values seem to rise very
slowly with increased selenium intake, which means the main use of this parameter
would be for long-term assessments.

Selenium in foods is generally part of selenocyteine and selenomethionine.1 Since
these compounds are absorbed similarly to the common amino acids, the percent
absorptions for selenium are very high compared to other trace minerals. One
exception, at least based on a rat study,17 is the selenium in tuna. The bioavailability,
though not terrible, is not as high as most other types of foods or even other seafoods.
One other food with low selenium bioavailability, based on a study in Finnish
women,18 is mushrooms.
There are four main selenium supplements: sodium selenate, sodium selenite,
L-selenomethionine, and high selenium yeast, which contains protein-bound L-
selenomethionine, which is liberated during digestion.19 Selenium supplements are
absorbed relatively well.20 However, in some, but not all, comparisons between
supplement types, there are differences found for various bioactivities. The “winner”
in these comparisons varies for different end points, and sometimes for the same
end points in different circumstances. L-selenomethionine, in yeast or in the free
form, is the “winner” more often than the inorganic forms (though there are also a
number of “ties”). Examples of those studies where L-selenomethionine shows an
advantage are summarized in Table 7.1. However, it should be noted that in some
TABLE 7.1
Examples of Better Activity of L-Selenomethionine (Free or in Yeast)
vs. Selenite
Subject Type Key Finding
Dairy cows Higher blood and milk Se*, blood GPx**22

Humans, low-Se area of China Better increases in plasma and erythrocyte Se23
Young adult women in New Zealand Higher blood Se21
Cattle Higher Se in milk and some tissues22
Lactating women Higher Se absorption24
Pigs Higher muscle Se25
Rats Higher Se in some tissues26
* Se = selenium; **GPx = glutathione peroxidase

of the studies cited, L-selenomethionine is not better at some parameters that are
not noted in the table. Moreover, for certain circumstances in some of the studies,
L-selenomethionine is not better at even the parameters listed. In fact, for some
measures in some circumstances, sodium selenite or selenate works better. For
example, in one study, the yeast works better for blood selenium, but selenate has
a bigger effect on glutathione peroxidase activities in the platelets.21
To make matters more complicated, in rats given a chemical that induces colon
cancer, supplemental selenite or selenate, but not L-selenomethionine, reduces values
for precancer indicators.27 The protective effect of selenite and selenate is not due
to better elevation of tissue selenium contents or glutathione peroxidase activity. In
fact, selenomethionine gives better results in those regards. The mechanisms respon-
sible for the protective effects on the inorganic selenium are unclear. They may
involve breakdown and elimination of the cancer-producing chemicals given to the
rats. Such an action may or may not be relevant to human cancer situations that are
not necessarily initiated by the same chemicals used in rat experiments. Thus, we
don’t know if selenite and selenate would have an advantage over L-selenomethone
in preventing human cancers. It is noteworthy that in the most publicized study of
human cancer prevention by selenium, selenomethionine in yeast is used.28
Selenate and selenite seem to have both similarities and differences in terms of
bioactivity. For example, when relatively low doses are given to human subjects,
selenate absorption and urinary excretion are faster than that of selenite, though
retention is about the same.29
One disturbing result is found in a study in selenium-replete humans.30 In this
work, one commercial yeast selenium supplement is far superior to another com-
mercial yeast selenium supplement. This study is from a number of years ago. It
would be interesting to see if today’s high-yeast selenium supplement products show
differences in bioavailability.
In conclusion, all of the major selenium supplement forms are capable of impact-
ing selenium function, but for certain effects, differences have been seen between
supplement forms. Unfortunately, the differences do not present a clear picture of
the advantages of one form over another.

Selenium intake is very much tied to the soil selenium content or bioavailability
where plants are grown or livestock is grazed.11 Among commonly eaten foods, two
of the best sources are wheat products, especially whole grains, and meat, in the
broad sense to include poultry and Þsh.31 For the latter category, though all meat
products are respectable selenium sources, some products are better than others. As
far as wheat products, the selenium content can vary greatly depending on the soil
where the wheat was grown. In the U.S., pasta is an especially good selenium source
because it is made from durum wheat that comes from the Dakotas, where soil
selenium is high.31 Another food, Brazil nuts, can be extremely high in selenium,
though the content may vary depending on the origin of the product.32
There are a substantial number of records of selenium deÞciency in livestock in
areas where there is low soil selenium or low selenium bioavailability to the plants.11

In some of these same areas, marked selenium deÞciency can also be seen in humans
(see Geographical Populations with Severe Selenium DeÞciency). On the other hand,
in some of these areas, there are not many cases of severe human selenium deÞ-
ciencies. Possibly, the selenium in the soil may be good enough to prevent severe
human deÞciency. In addition, not all human food in these areas is derived from
local sources. Furthermore, as discussed immediately below, the worst cases of
human selenium deÞciency seem to involve not just low selenium intake, but also
additional factors that worsen the consequences of low selenium intake.
The Þrst report of a large-scale selenium deÞciency was for a section of China
where a condition called Keshan disease was observed.11 The disease appears to
result from a combination of low selenium intake plus a susceptibility to a strain of
virus known as the coxsackievirus. The cause of the low selenium intake appears to
be that the selenium in the soil is largely unavailable to the plants grown in the
region. Keshan disease has a number of symptoms including cardiomyopathy.11 Once
the disease is established, selenium administration is unable to cure it. On the other
hand, increased oral intake of selenium is very protective against Keshan disease.
Another seemingly selenium-related disease, known as Kaschin-Beck disease,
has been detected in children in parts of Asia.11 The most prominent symptoms are
joint necrosis related. As with Keshan disease, Kaschin-Beck disease also occurs in
areas where the availability of soil selenium for plant growth is low. Kaschin-Beck
disease is thought to be caused by a combination of selenium deÞciency plus other
factors such as mycotoxins in grains grown in the region.
There are some other areas, such as Turkey, where iodine deÞciency plus some
degree of selenium deÞciency combine to disrupt thyroid function.33 Supplementation
with both iodine and selenium help with thyroid function.
Somewhat low soil selenium has been identiÞed in other areas of the world,
such as in parts of Australia, Finland, and New Zealand.34–39 In Australia, selenium
intake is considered moderately low, but no obvious symptoms of widespread, overt
selenium deÞciency have been noted.34 In Finland, there has been a conscious effort
to keep selenium intake adequate by measures such as adding selenium to fertilizers
for agricultural crops.35 In New Zealand, there are reports of moderately low intake,
low blood selenium values, and low blood glutathione peroxidase activities.36,37,39
However, what, if any, health symptoms are associated with these Þndings are not
well characterized. Several attempts at elucidating the symptoms have not produced
clear examples. For example, selenium supplementation has no obvious effects on
outcome in low-birth-weight infants.38 In other work, since degeneration of the
cardiac and skeletal muscle is associated with selenium deÞciency in livestock and
experimental animals, a study was done to see if similar problems occurred in New
Zealand.40 In subjects who complained of muscle problems like pain and tenderness,
both selenium supplementation and placebo improved subjective symptoms in about
half the subjects tested. In still other work, an analysis of whole blood selenium in
a small number of people with dilated cardiomyopathy is similar to controls (lower
values in the patients but not statistically signiÞcant).41
Selenium deÞciency also occurs with some medical states such as total
parenteral nutrition (though this is usually treated or prevented now).42 Another
example is GI tract problems such as Crohn’s disease and surgical intestinal

removal, which can impair selenium absorption.43,44 There may also be some
degree of selenium deÞciency in other types of inßammation, though this issue
is not settled. Serum selenium falls with inßammation,45,46 though how this affects
overall body selenium functional status is still unclear. For example, in rats,
endotoxin injection drastically lowers serum and liver selenium, but produces
small increases of selenium in some other tissues.46 It is not clear if the inßam-
mation-induced fall in serum and liver selenium produces a degree of selenium
deÞciency, though that seems to be the assumption that many researchers are
making. More research is needed to conÞrm or refute this idea, though some has
started (see the Arthritis and HIV subsections).
The consequences of marginal selenium deÞciency in otherwise healthy people
are poorly characterized. There are indications that this research area will be given
more attention in the next few years. One reason is that concern has been expressed
about falling selenium intake in the U.K.48 Among the causes for this trend is the
decline in import of high selenium wheat products. There has also been some
speculation that bioavailability of selenium may have fallen in certain areas due to
acid rain or excessive artiÞcial fertilization of soils, both of which reduce plant
selenium absorption. The average selenium intakes in the U.K. are now below
recommendations of both the U.K. and U.S.48 A pilot study of low-dose selenium
supplements in U.K. residents show improved selenium enzyme activities, though
the effect varied a lot between subjects.49
Selenium intake in the U.S. and some other industrialized countries generally
exceeds the RDA,50 but there are reasons why selenium intake may still be a concern
there:
1. The RDA is based on blood glutathione peroxidase activities, but it is

unclear how well these activities relate to tissue activities.
2. There may a substantial number of people who are the exception to the
rule that selenium intake exceeds the RDA, though this has not been
checked extensively.
3. Based on blood selenium values, certain health conditions, such as critical
illnesses, premature birth, alcoholism, and HIV infection, produce some
degree of deÞciency in some people (see the next section).
4. Optimal selenium intake for cancer prevention may be considerably
greater than the RDA (see the Cancer subsection).

GEOGRAPHICAL POPULATIONS WITH SEVERE SELENIUM DEFICIENCY
Applications of selenium supplementation to geographical pockets of severe sele-
nium deÞciency, or suspected severe selenium deÞciency, can be efÞcacious.11 These
applications, in some cases, can include treatment of the combination of selenium
and iodine deÞciencies.33

CANCER
The idea that selenium intake and cancer could be connected is not new. The Þrst
big impetus for this connection was a series of epidemiological observations and
rodent carcinogenesis studies.11 The rodent studies show differences between high
and low selenium intake in terms of resistance to chemically induced carcinogenesis.
The main problem with many of the early studies is that the high selenium intake
levels are too high to have practical human applications.
Some of the emphasis on research examining the relationship of selenium to
cancer has focused on deÞciency, severe or marginal. In principle, selenium deÞ-
ciency could compromise immune function, which could also affect cancer risk.9 In
addition, selenium deÞciency could produce low glutathione peroxidase activities,
which could produce high oxidant stress, which is a factor in cancer onset.2 Despite
this rationale, a lot of the work on selenium and cancer has considered selenium
supplementation for purposes other than correcting a deÞciency. The supplementa-
tion levels (usually 200 g/day) are generally well above the RDA. At those intakes,
glutathione peroxidase activities would not be expected to increase beyond those
produced by RDA level intakes. Possible anti-cancer mechanisms for the high
selenium intakes include immunostimulation, which selenium could conceivably do
even when intake is increased from RDA levels to above-adequate levels. Another
possibility is that thioredoxin reductase activity is involved.51 More dietary selenium
may be needed to saturate this enzyme activity compared to glutathione peroxidase.5
Other proposed mechanisms involve moderately high concentration of selenium
compound metabolites, such as methyl selenol, causing apoptosis of cancer cells
(programmed cell death) and having other regulatory effects.51 It may be relevant
to these latter mechanisms that oral selenium supplementation increases prostate
selenium levels in non-selenium-deÞcient men.52
This author also proposes another possible anti-cancer mechanism for a moder-
ately high selenium intake. This mechanism involves glutathione peroxidase.
Although erythrocyte glutathione peroxidase activities normally plateau at RDA
intake levels, this enzyme activity may not plateau as easily at some potential cancer
sites, particularly if precancer processes affect selenium distribution. Thus, high
selenium intake may be needed to maximize glutathione activities at certain sites in
certain circumstances.
A number of lines of evidence have been used to link selenium and cancer.
Examples are summarized in Table 7.2. Note that a prospective study is where some
type of reading is taken (e.g., serum selenium) for samples obtained before testing
for an outcome (in this case, a cancer-related measure). For example, serum selenium
readings are done for cancer-free subjects who are then monitored for cancer onset.
It is noteworthy that the prospective studies listed in Table 7.2 are just a few
examples of many studies. These studies have surveyed literally tens of thousands
of people. For example, in a study of Taiwanese men with chronic hepatitis–virus
infection, a noted risk factor for liver cancer, over 7000 men are studied.57 In this
study, an inverse association is seen between selenium levels in stored plasma and
later development of hepatocellular carcinoma. One question about the serum or
toenail selenium studies is whether they are suggestive of a detrimental effect of

TABLE 7.2
Examples of Evidences Linking Selenium to Cancer Risk
Prospective studies: serum or toenail selenium predict risk of cancer incidence or mortality53–57
Chinese hepatitis carriers: liver cancer cases, selenium supplement vs. placebo, 7 vs 058
Selenium in salt in China: 35% reduction in liver cancer incidence vs. control towns59
Selenium supplements (3 and 9 months) gives a small but signiÞcant decrease in PSA* 60
Supplementation with selenium plus other factors lowers cancer mortality, especially for stomach
cancer, in a high-cancer section of China61
Long-term selenium supplementation in U.S. in subjects with a history of non-melanoma skin cancer:
lower cancer mortality and lower total cancer incidence; lower prostate, lung, and colorectal cancer
incidence62,63
* Prostate-speciÞc antigen levels, which are correlated with prostate cancer risk64
some degree of selenium deÞciency, or whether they are suggesting a protective

effect of high selenium intake.
The observations of Table 7.2 that have gotten the biggest recent attention are
those of the last listing. Some of the results that have garnered the most attention
are not the original primary focus of the project, which had to do with skin cancer.
The most attention-catching results include a lower prostate cancer risk in the
selenium supplement users. Unfortunately, some of the initial excitement has been
tempered by new analysis of the subjects for the years following the initial published
report.28,65,66 Although some positive effects still remain, some became less general,
some others were eliminated, plus some detrimental results appeared. These negative
observations, plus examples of other observations not supporting a selenium-cancer
prevention relationship, are summarized in Table 7.3.
Many speculations can be made about the supportive and non-supportive studies
for selenium intake and cancer prevention. The bottom line seems to be that the
picture is not yet clear. One point that can be made for the positive results is that
the prospective studies (predictive studies) with positive results cover many more
people than those of prospective studies with negative results. Also, the negative
TABLE 7.3
Examples of Negative Results for Studies on Selenium and Cancer Risk
Lack of association of toenail selenium and some cancers67
No association is seen for serum selenium and later lung cancer in Chinese tin miners68
Serum selenium shows no predictive value for later colon cancer incidence69
Update of the study on long-term selenium supplementation in the U.S. in subjects with a history
of non-melanoma skin cancer: total cancer incidence effect now found to be signiÞcant just for
men, biggest change for prostate cancer seen only in certain subgroups, former report of reduced
risk of colon and lung cancer are not seen in longer time frame; higher rates seen for some forms
of skin cancer and some other body site cancers, all-site cancer higher in men with the highest
serum selenium values 28,65,66

study with Chinese miners68 may not have wide-range applicability since the envi-
ronmental stress is very high, and the selenium supplement levels may have been
too low.
Some of the concerns brought out in the reevaluation of the large U.S. selenium
supplementation study (last line, Table 7.3) may not be all that serious. For example,
the increase in cancer risk seen for skin cancer may not indicate a real increased
risk. As noted in one of the papers,66 for certain skin cancers, if one eliminates
cancers diagnosed in the Þrst year of supplementation or placebo, then the increase
is no longer statistically signiÞcant. This elimination may be justiÞed under the
grounds that the cancer process may have already begun before the selenium sup-
plementation started. In addition, it is often forgotten that the increases seen for
some other body sites in the supplemented group, such as breast cancer, are not
statistically signiÞcant.28 The same is true for the increase in all site cancer in men
with the highest serum selenium values.28 In addition, for many body sites, the total
number of cases is not overly large, especially considering the size of the total study
population, and considering that this population is a high cancer risk group. There-
fore, this work raises the possibility, but does not prove, that selenium supplemen-
tation can raise the rate of some cancers.
Another issue that is perhaps overrated is that overall cancer incidence effects
are statistically signiÞcant only for men.28 This is not that surprising considering
two facts. One, there are about three times more men in the study than women. Two,
the biggest effect is on prostate cancer, which is limited to men.
It also needs to be remembered that this study is done on only one type of
subject: people with a past history of certain types of skin cancer. Thus, any results
found here may or may not be applicable to other populations. Along similar lines,
it should be recalled that certain subgroups of men in this project show better
responses than others (e.g., PSA levels and starting serum selenium levels). Although
some people view this as a negative Þnding, this should not be overly unexpected.
For many supplementation therapies, some people are more apt to be helped than
others. Thus, selenium has not yet been ruled out for value in some types of cancer
prevention.
On the other hand, it should be noted that for the positive results obtained in
the large supplementation project,28,63,65,66 the selenium supplementation does not
eliminate cancer. Thus, at best, selenium supplementation should only be part of a
cancer prevention plan. That should be obvious, given that cancer is a complex
disease. Even so, this idea is often forgotten when discussing one speciÞc interven-
tion. Similarly, the fact that selenium does not lower cancer rates in all sites should
be expected. Many preventive agents may be better at certain site cancers than others.
In conclusion, there is data on both sides of the issue as to whether selenium
supplementation can reduce cancer risk, but there are still many research directions
left to explore. There is the possibility that selenium supplementation can sometimes
increase cancer risk, but this is very uncertain. Ultimately, we may Þnd that selenium
supplementation is more appropriate for some people than others, but that may be
the case for many applications of mineral supplements.

CARDIOVASCULAR DISEASE
Severe selenium deÞciency, particularly when combined with viral infection, can
cause cardiovascular problems including cardiomyopathy.11 However, much of the
current interest in selenium and cardiovascular health centers around two different
questions. One, can marginal selenium deÞciency raise the risk of common cardio-
vascular disease? Two, can above-adequate selenium intake lower the risk of com-
mon cardiovascular disease?
There is some theoretical reason to think that selenium may help prevent com-
mon cardiovascular disease. One idea is that selenium has antioxidant roles1 and
oxidant stress contributes to cardiovascular disease.2 However, there may also be
other possible mechanisms such as inhibition of platelet aggregation, which is an
action of selenium.70
Although this issue has drawn some attention, there is not much recently pub-
lished new research on the subject. Older epidemiological studies have provided
some evidence for a possible role of selenium intake in cardiovascular disease.70,71
On the other hand, studies on serum selenium patterns within populations are
conßicting (some show a relationship, others do not).70,71 An interesting perspective
can be found in a recent review article.71 Although this article centers on the possible
need for many people to increase selenium intake, the cardiovascular disease con-
nection is not presented as a strong argument. Instead, the review presents this area
mostly in light of the conßicting epidemiological evidence. The review also states
that even if low serum selenium is associated with some cases of cardiovascular
disease, it may just be a regulatory reaction to inßammation.
There is a need for supplementation studies to settle the issue. Many studies of
nutrient supplements and cardiovascular disease use markers of risk such as cholesterol
or LDL oxidation. However, in the case of selenium, the main mechanisms of protection
against cardiovascular disease may not affect these measurements.70 Therefore, studies
on selenium supplementation may have to use actual cardiovascular disease events as
the end points. This would be quite lengthy and require a lot of research subjects. This
may explain why there has not been a lot of recent research in this area.
In summary, despite the hype in the popular press and on the Internet about
selenium supplements and cardiovascular disease, there are no direct demonstrations
of this concept, and indirect evidence is not clear.
ARTHRITIS
As noted earlier, serum selenium values drop in humans with inßammation such as
arthritis,45,46 but it is not known whether or not this is a sign of selenium deÞciency.
One argument for marginal selenium deÞciency contributing to arthritis risk is a
large case-control study in Finland.72 This study examines serum selenium in people
who initially do not have arthritis. Although no relationship is seen for development
of rheumatoid factor-positive arthritis, the group with the lowest serum selenium
values has the highest incidence rate for rheumatoid factor-negative rheumatoid
arthritis. Since these results assess serum selenium prior to arthritis onset, the results
argue against the idea that low serum selenium in arthritis is only due to disease-

induced regulatory responses. On the other hand, the study does not completely rule
out the possibility that low serum selenium is just a coincidental marker of other
factors that predispose to arthritis.
One German study supports the idea that selenium status may often be marginal
in arthritis patients.73 This study reports a substantial difference between controls
and arthritis patients in erythrocyte selenium contents. Selenium supplementation
does not normalize these values, but does improve certain indices of disease severity.
The results for glutathione peroxidase activities in rheumatoid arthritis patients
are mixed (reports range from low values to high values).74 There is also some
diversity in reports on selenium supplementation effect on glutathione peroxidase
activities in rheumatoid arthritis. For example, selenium supplementation can
increase activities in erythrocytes without fully normalizing activity in a white blood
cell population.74
Clinical trials of selenium supplementation in rheumatoid arthritis have not been
exhaustive. One study in Germany was mentioned earlier.73 The other few that exist
have not been as encouraging as hoped. The most positive result came in a double-
blind, randomized controlled trial in a very small group of people. Supplementation
with 200 g selenium as selenium-enriched yeast for three months shows a signiÞcant
reduction in pain and joint involvement.75 However, a later similar study by the same
group was not as positive.76 Both the placebo group and the selenium group show
the same degree of reduction in a number of symptoms of discomfort. The authors
themselves state that the placebo effect is strong in the results. The selenium group
does show some improvement in arm movements and health perception. However,
this may be related to selenium effects on mood, which though still tentative, are
possibly true (see the Mood subsection).
Another study examines six months of selenium supplementation versus placebo
in 40 rheumatoid arthritis patients.77 The patients in the selenium group are given
daily supplements of 256 g selenium as selenium-enriched yeast. Although concen-
trations of selenium in serum and erythrocytes increase considerably, no signiÞcant
anti-rheumatic effects of selenium are demonstrated.
Although most of the work on selenium and arthritis has focused on the rheu-
matoid variety, one supplementation study has considered osteoarthritis.78 In this
work, a commercial supplement of selenium plus three vitamins fails to demonstrate
signiÞcant efÞcacy versus placebo at three or six months.
In conclusion, rheumatoid arthritis might make people prone to marginal sele-
nium deÞciency, which might worsen the arthritis. In addition, marginal selenium
deÞciency in non-arthritic subjects may increase the risk of later arthritis. However,
none of these statements has been conÞrmed satisfactorily. Selenium supplement
studies, though not extensive, have not given a clear indication of efÞcacy. Possibly,
future work with different study designs might show beneÞts in at least some people
with arthritis, but this is still speculative.
PANCREATITIS
Another disease of inßammation is pancreatitis. Selenium supplementation has been
considered as part of the therapy and prevention of this problem, but usually, this

consideration has come as part of a combination antioxidant therapy, not selenium

administration alone. A recent review79 concludes that there is evidence that patients
with chronic pancreatitis have enhanced levels of free radical production and anti-
oxidant deÞciencies, especially for selenium. The review further concludes that
limited published research suggests that dietary antioxidant supplementation may
ameliorate the pain associated with chronic pancreatitis, diminish the frequency of
acute exacerbations, and reduce the requirement for pancreatic surgery.
Exactly why there would be deÞciencies of selenium and other antioxidant
nutrients during chronic pancreatitis is not totally settled. Various reasons have been
proposed, though not all data supports these propositions.
The best-known study of selenium and chronic pancreatitis is from the Manches-
ter Royal InÞrmary, Manchester, U.K.80 In fact, the connection between chronic
pancreatitis and antioxidant therapy is sometimes called the Manchester Oxidant
Stress Hypothesis.80 The treatment of the combination of selenium (600 µg/day)
plus other antioxidants, in patients with chronic and recurrent pancreatitis, signiÞ-
cantly reduces pain and number of days spent in the hospital. The treatment also
seems to greatly reduce the need for surgery. If this success can be duplicated in
other settings, then this therapy could become a standard treatment.
In contrast to the work on chronic pancreatitis, the work on acute pancreatitis
in relation to selenium and other antioxidants has not been as encouraging. On the
positive side, in animal models for severe acute pancreatitis, a seleno-compound,
which has a glutathione peroxidase-like activity, has protective action.81 In contrast,
a review82 notes that human clinical trials of selenium therapy have not been suc-
cessful for acute pancreatitis. One reason for the difference in human and animal
work could be in the form of selenium given. The selenium supplements used in
the human trials can only increase glutathione peroxidase activity within the limits
of synthesis of the proteins. On the other hand, the animal studies use a speciÞc
compound that could have glutathione peroxidase-like activity independently of the
glutathione peroxidase enzymes. Whether this same compound, or one like it, could
be used for human therapies remains to be seen.
In contrast to these results, there is a small study in Germany where intra-
venous selenium, in patients suffering from acute necrotising pancreatitis, shows
a mortality of 89% in controls vs. 0% in treated.83 This observation should be
given follow-up.
In summary, there are indications that chronic pancreatitis can be helped by
supplementation with selenium plus other antioxidants, though a large-scale dem-
onstration is needed for conÞrmation. The case for selenium with acute pancreatitis
has been less promising, though there may be some selenium-related approaches
that can be tested more.
HUMAN IMMUNODEFICIENCY VIRUS (HIV)

There is a precedent for tying selenium status to progression of a viral disease. As
noted earlier, the classic selenium deÞciency known as Keshan disease involves
enhanced virulence of a virus.11 Thus, progression of another viral problem, HIV
infection, could be affected by selenium status. This would be especially true if the

viral infection predisposes a person to selenium deÞciency. This may happen even
in the early stages of HIV infection, as evidenced by a decline in plasma selenium.84
During the development of acquired immune deÞciency syndrome (AIDS), selenium
deÞciency can be substantial, though a degree of malnutrition can exist for a number
of nutrients.84 However, the decline in selenium status has predictive value for the
rate of AIDS progression and mortality,84,85,86 though this may be coincidental to
macronutrient depletion.84 In a mouse model for AIDS, selenium supplementation
produces higher glutathione peroxidase activities and lower lipid peroxide values,
an indication of decreased oxidant stress.87 Some immunological effects are also
noted.
There have been a few studies of selenium supplementation in HIV positive
people, though none has shown a major, large-scale physiological effect. One study
has reported improvements in mood-related parameters.88 Another study reports
inconsistent results.89 An additional study of selenium supplementation has been
carried out in 186 HIV positive men and women.90 A signiÞcant decrease is seen in
hospitalization parameters (e.g., number of hospitalizations). There are two limita-
tions to the study. First, a substantial effect is seen in the placebo group. Second,
the placebo and selenium groups are not identical in regard to conventional HIV
therapy drug use. Nonetheless, this study, along with the other considerations noted
above, justiÞes further research on selenium supplementation in HIV positive people.
On the other hand, to say that selenium supplementation is a major beneÞt for AIDS
patients, as is claimed on some Internet sites, is premature.
MALE INFERTILITY
As noted above in the Overview of Function section, selenium has speciÞc roles in
male reproduction. In addition, there is a form of glutathione peroxidase that seems
to be especially involved in protecting the fertility of spermatozoa.88 In one study
of infertile men, the sperm protein activity of this enzyme in infertile men is just
half that of fertile men.91 It would be interesting to see if selenium supplementation
can raise these activities in infertile men, or if the low activities are just a regulatory
reaction or a metabolic defect that cannot be overcome with high selenium intake.
If supplementation could raise activities, then this could mean that some infertile
men do not consume an RDA level of selenium. On the other hand, it could also
mean that some infertile men need moderately high amounts of selenium to get
normal activation of this form of glutathione peroxidase. However, all of this is
speculative at this time.
Another argument for a selenium–infertility connection is that in animals con-
suming selenium-deÞcient diets, structural abnormalities in the sperm midpiece
occur that are linked to poor motility and frequent tail breakage.92,93 Therefore,
selenium nutritional status could be a factor in human male infertility. Even so, this
does not automatically mean that selenium deÞciency is a usual contributor to this
problem in humans. One reason is that in the animal studies, the degree of selenium
deÞciency likely greatly exceeds what would be seen in most infertile males (many
of which may not even be selenium deÞcient at all).

One argument for a selenium–human infertility connection is that seminal ßuid

selenium concentrations correlate positively with sperm count, as well as with total
sperm concentration, in a group of subfertile Norwegian men.94 However, it should
be noted that high sperm selenium concentrations are also reported to have a negative
inßuence on the number of spermatozoa, sperm motility, partner abortion rate, and
signs of partner ovarian dysfunction.95 Thus, too much or too little selenium in semen
could be detrimental. It should also be considered that in another study, selenium
concentration in 211 semen samples from normozoospermic, oligozoospermic,
asthenozoospermic, and azoospermic men Þnds no correlation with sperm count or
motility.96
A few studies have been done on selenium supplementation and fertility-related
parameters. For example, supplementation of subfertile men with 100 g selenium/day
for three months signiÞcantly increases sperm motility.97 This study is done with
subjects from the U.K., where mean selenium intake has become marginal in recent
years.48 Of the men receiving the selenium, 11% (Þve men) achieve paternity com-
pared to none in the placebo group. On the other hand, it should be noted that for
sperm motility, the study had a high number of non-responders. In fact, a statistically
signiÞcant effect is only achieved if the selenium group is pooled with a selenium-
plus-vitamins group. It is also noteworthy that in a study of subfertile Polish men,
administration of 200 g selenium/day shows no beneÞt for sperm motility.98 In
another study,99 nine oligoasthenoteratozoospermic men are supplemented for a
period of four months with both selenium and vitamin E. Statistically signiÞcant
increases are observed for selenium and vitamin E levels, sperm motility, and percent
live or percent normal spermatozoa. All of the parameters return to baseline values
during the posttreatment period. Even so, none of the couples report a pregnancy
during the supplementation period. Furthermore, this study is not placebo controlled.
Finally, in a recent study, vitamin E plus selenium supplementation produces a
signiÞcant decrease in a measure of lipid oxidant stress and an improvement of
sperm motility.100 However, the study seems to suffer from poor compliance, as less
than half the original subjects completed the study.
In conclusion, there is only weak or inconsistent evidence that selenium
supplementation could help many men with infertility. One possible need for
future studies is to look for subpopulations of infertile men who may be selenium
responsive. There may also be an optimal level of selenium supplementation that
has not been identiÞed. Too much as well as too little seminal selenium could
be detrimental.
PREGNANCY MISCARRIAGES
This issue in relation to selenium gets some strong endorsements on the Internet.
One line of reasoning is that selenium supplementation has sometimes been used to
prevent miscarriages in veterinary practice.71 Despite these endorsements, the current
data linking selenium supplementation to human risk for miscarriage is weak. First
of all, there are no direct studies of the subject. Moreover, the evidence for marginal
selenium deÞciency associated with miscarriage is not very strong because the
number of studies is low, most of the studies focus on just serum selenium, and the

studies give mixed results (some studies Þnd depressed serum selenium in women
with recurring miscarriage, while others do not).101,102,103 One of the studies with a
negative Þnding has been criticized for including women who have had one miscar-
riage,103 but there are other studies with negative Þndings where that is not the case.102
One study in India has evaluated selenium content of red blood cells and found the
values low in women with recurring miscarriage.104 However, the mean value is not
that low (80% of normal). In addition, the values are taken after the miscarriages,
when the women are not pregnant. This means that any selenium depletion could
be due to a practice or body reaction that has resulted from the women’s response
to the miscarriages.
Even if serum or blood cell selenium is low in women with recurring miscarriage,
it does not necessarily mean that marginal selenium deÞciency contributes heavily
to miscarriage. Possibly, the low blood selenium level is a reaction to the processes
behind the miscarriage, rather than a cause of the processes. Also, poor selenium
status, if it is really occurring, could just be a marker of some aspects of poor
nutrition, or some physiological tendency, either of which could be the real contrib-
utor to the miscarriages.
Conspicuously absent from most studies on selenium and miscarriage is mea-
surement of glutathione peroxidase. In one exception, red blood cell and plasma
glutathione peroxidase activities of women who had a miscarriage are signiÞcantly
lower than in normal pregnancies.105 However, the measurements are taken right
after pregnancy termination. This lowering of glutathione peroxidase could be a
recovery reaction rather than a cause of what happened. Also, it is unclear that the
lower enzyme activities are due to a selenium problem. In support of this concept,
plasma selenium contents are normal in these women.
Despite all the concerns just expressed about existing data, it is still possible
that selenium status does play a major role in a substantial number of miscarriages.
The existing data do not rule that out. However, the data also do not rule it in, given
the small amount of ambiguous data currently available.
MOOD
During selenium deÞciency, the brain retains this mineral better than other tissues.106
This suggests that some selenium functions in the brain are of high priority. One
possible function is mood maintenance. The mechanisms that could be involved are
unknown, though speculations include the involvement of thyroid hormone.107 Sev-
eral studies have reported that a low selenium intake is associated with poorer
mood.71 One example is a study where 11 healthy men are given diets to deplete,
then replete, selenium.108 The men are tested by a criterion known as the ProÞle of
Mood States–Bipolar Form. No signiÞcant effects are reported for selenium intake,
but the lower the starting selenium, the lower the scores fall with selenium depletion.
Thus, this study does not in itself provide a direct link between mood and selenium
intake, but does offer the possibility that other study designs might provide the link.
In a study of selenium supplementation, 50 subjects are given either a placebo
or selenium, plus they have their background diet analyzed for dietary selenium.109
On three occasions, these subjects Þll out the ProÞle of Moods States form. Selenium

intake is reported as associated with a general elevation of mood, and in particular,

a decrease in anxiety when taking selenium. In addition, the lower the level of
selenium in the diet, the more reports of anxiety, depression, and tiredness, which
also decrease following Þve weeks of selenium therapy. The strength of this study
is that it is a double-blind crossover design. There is variation in the background
diet, though the study tries to examine diet and supplementation simultaneously.
If selenium does affect mood, it is not known whether the connection concerns
detriments of marginal deÞciency, beneÞts of above-adequate intake, or both. One
argument against the marginal deÞciency is that if the brain resists depletion of
selenium, then marginal selenium deÞciency should not impact brain function
(including mood regulation). On the other hand, a marginal selenium defect that
does not occur directly in the brain may still affect the brain. For example, an effect
on thyroid hormone metabolism could affect brain functioning.
This area is far from settled, but in this author’s opinion, there is enough pilot
data to consider the matter with further research.
IMMUNE FUNCTION
In addition to effects on viral virulence (see the HIV subsection), selenium can have
other effects on immune function. This can be seen in selenium-deÞcient animals,
though as noted earlier, the mechanisms are not completely clear.9 A number of
human studies have been done with selenium supplementation and immune function.
However, many are hard to interpret in terms of practical consequences. Some studies
give multiple nutrients, not just selenium.110 In another study, although just selenium
is tested, and improvement is shown for some of the parameters, the subject size is
very small.111 This is especially true for the population studied, which is renal dialysis
patients. In such subjects, there can be tremendous variations in secondary health
problems, drug prescriptions, compliance tendencies, and dietary practices. In some
other studies, the starting selenium status of the subjects is not well characterized,
or only high selenium doses are tested. In some of the high-dose studies,110,112 certain
laboratory parameters of immune function, such as natural killer cell activity, do
increase. In one of these studies,110 the subjects are declared to be selenium replete,
which raises the possibility of a stimulating effect on immune function of above-
adequate selenium intakes. Even so, this concept would require considerably more
veriÞcation before it would be accepted.
Despite these issues, there are enough positive results that it would seem worth-
while to expand studies on selenium supplementation and immune function.
ASTHMA
Some Internet sites and alternative medicine writings are declaring that selenium
prevents and treats asthma. There may be some truth in this claim, but at this point,
the claim is still speculative. Several studies show that values for some selenium
status assessment tools are low in asthmatics vs. controls, and low for atopic vs.
non-atopic subjects.113,114,115 However, these differences are generally not very large.
Conceivably, the differences in selenium function could be bigger in certain tissues,

such as the lung, but that is pure speculation. It is also possible that the small
differences in selenium-related blood measures are just a relatively benign effect of
asthma or the drugs given to treat this problem.
A few small selenium supplementation studies have been tried with asthmatic
subjects. In one, anti-inßammatory regulatory actions are seen when cells are chal-
lenged outside the body.116 This work is interesting, but it needs follow-up in other
study designs. A different study, which examines 17 corticodependent asthmatics in
Slovakia, reports the selenium brings about reduced consumption of inhaled corti-
costeroids.117 However, the study is small, plus, it is not placebo controlled despite
involving a patient-controlled end point. In an additional study, a signiÞcant improve-
ment is reported for assembled clinical evaluations in 12 selenium-supplemented
Swedish asthmatics compared to a placebo group.118 However, this improvement did
not translate to signiÞcant changes in the separate clinical parameters of lung func-
tion and airway hyperresponsiveness.
In conclusion, there is some data connecting selenium status with asthma pre-
vention or treatment, but the case is not compelling yet.
KETOGENIC DIET IN EPILEPSY PATIENTS

The so-called ketogenic diet is often applied to intractable epilepsy, even though the
diet is deÞcient in a number of nutrients. A very recent study reports a patient on
this diet who had no detectable whole blood selenium plus cardiomyopathy,119 the
classic symptom of Keshan disease.11 In further work in this same study,119 10 of
39 children show low blood selenium values, which improves upon selenium sup-
plementation. This study is interesting and potentially important for children on the
ketogenic diet. Follow-up studies should include other measures of selenium status
(e.g., glutathione peroxidase) and more parameters indicative of potential health
consequences of selenium deÞciency.
MISCELLANEOUS HEALTH PROBLEMS

There are a number of other health problems where some type of blood selenium
measures are reported as low. At present, there is not a tremendous amount of
information on the beneÞts of selenium supplementation in these states. In this
author’s opinion, if low serum selenium combined with low erythrocyte glutathione
peroxidase values appear in the literature for a condition, then low-dose supplemen-
tation of selenium shouldn’t hurt and may help. In some extreme cases, more
aggressive supplementation may be warranted, but that can’t be said until more
information is gathered.
An example where more study is needed is for critical care patients. In one study
of some types of these patients, low serum selenium remains low despite some
degree of selenium supplementation.120 In other work, a study in Germany considers
high-dose selenium supplementation in critical care patients at risk for septic
shock.121 The supplementation improves serum selenium readings, as well as a few
measures of oxidant stress and thyroid hormone metabolism. It would be good to

know if, in critical care settings, high selenium doses actually confer any beneÞts
or pose any risks.
GENERAL ANTIOXIDANT EFFECTS

In this author’s opinion, there is a need for a general characterization of various
markers of antioxidant function and oxidant stress in people with differing starting
selenium status and health states. This has been done only to a minimal degree with
varying results, and in some of the studies selenium is given only as part of an
antioxidant mixture. At present, we don’t know enough about how much variations
in selenium status actually affect antioxidant capacities and in whom. Unfortunately,
a comprehensive version of such a study is unlikely to get funded by U.S. government
grant agencies because it would be labeled as a “loser descriptive study.”
TOXICITY
The biggest known case of selenium toxicity from foods or supplements occurred
in certain areas of China,20 the same country that has shown the biggest population
group for selenium deÞciency.20 The toxicity cause was eating food grown in high-
selenium soil, the exact opposite of the case for Keshan disease in another part of
China.
TABLE 7.4
Selenium Supplements at a Glance
Adult RDA: 55 g (may cover basic function without maximizing protective actions against health
problems that are not strictly selenium deÞciencies)
Typical dose in supplement studies: RDA levels for selenium deÞciency prevention, 200 g for health
problem treatment or prevention
Best supplement complex: selenite, selenate, L-selenomethionine (free or in yeast) all have high
absorption compared to most trace mineral supplements; in comparison studies for various
bioactivities, the different forms have shown the same activity in some cases, but differences in
others (all three forms have been “winners” in comparisons, but L-selenomethionine has more “wins”
than the others)
Applications: there is supportive, but not conclusive, data for prevention of some cancers, for chronic
pancreatitis treatment, and for nutritional support for epileptic children on the ketogenic diet; for
other applications, there is less supporting data, but more research is justiÞed; these applications
include miscellaneous immune and antioxidant effects, as well as nutritional support for people with
HIV; for many other applications, there is a theoretical basis, but just a little supporting data (e.g.,
treatment/prevention of arthritis and therapy for reproductive problems)
Upper Level: 400 g (below an intake that will cause early physical signs of toxicity)
Safety issues: supplements usually not a concern since most doses are well below 400 g; the idea
that supplements raise the risk of certain cancers is very speculative

The adult Upper Level is based on the intake from food plus supplements that
should stay below the total intake that cause an early toxic reaction observed in
China.11 This reaction is marked by hair loss and nail sloughing.
Selenium toxicity due to supplements has not been commonly reported, probably
because the doses being considered for cancer prevention, though higher than the
RDA, are still below the Upper Level for adults. There has been one prominent
report of severe selenium supplement toxicity, but this was due to a manufacturing
error that produced toxic levels of selenium in the supplements.11

For parts of the world with low soil selenium, or low bioavailability of the soil
selenium, it seems useful to promote either selenium supplementation, selenium
food fortiÞcation, high-selenium fertilizers for food plant growing, or the importing
of grain foods from high-selenium soil regions. Selenium supplementation for the
prevention of cancer, as part of the treatment of chronic pancreatitis, and as a
nutritional support for epileptic children on the ketogenic diet all may have some
merit, though these applications are not conÞrmed. The use of selenium supplements
to treat or prevent other health problems have various degrees of support, but all
still remain fairly speculative. Toxicity risks from common selenium supplement
doses are low.
REFERENCES
1. Sunde, R.A., Selenium, in Handbook of Nutritionally Essential Mineral Elements,
2. Kehrer, J.P., Free radicals as mediators of tissue injury and disease, Crit Rev. Toxicol.,
23, 21, 1993.
3. Brown, K.M. and Arthur, J.R., Selenium, selenoproteins and human health: a review,
Public Health Nutr., 4, 593, 2001.
4. Schallreuter, K.U. and Wood, J.M., Thioredoxin reductase — its role in epidermal
redox status, J. Photochem. Photobiol., B, 64, 179, 2001.
5. Berggren, M.M., Mangin, J.F., Gasdaka, J.R., and Powis, G., Effect of selenium on
rat thioredoxin reductase activity: increase by supranutritional selenium and decrease
by selenium deÞciency, Biochem. Pharmacol., 57, 187, 1999.
6. Hansen, J.C. and Deguchi, Y., Selenium and fertility in animals and man — a review,
Acta Vet. Scand., 37, 19, 1996.
7. Behne, D., Duk, M., and Elger, W., Selenium content and glutathione peroxidase
activity in the testis of the maturing rat, J. Nutr., 116, 1442, 1986.
8. Behne, D., Weiler, H., and Kyriakopoulos, A., Effects of selenium deÞciency on
testicular morphology and function in rats, J. Reprod. Fertil., 106, 291, 1996.
9. Arthur, J.R., McKenzie, R.C., and Beckett, G.J., Selenium in the immune system, J.
Nutr., 133, 1457S, 2003.
10. Beck, M.A., Levander, O.A., and Handy, J., Selenium deÞciency and viral infection,
J. Nutr., 133, 1463S, 2003.
11. Sunde, R.A., Selenium, in Present Knowledge in Nutrition, 8th ed., Bowman, B.A.,
and Russell, R.M., Eds., ILSI Press, Washington, 2001, chap. 33.

12. Hambidge, M., Biomarkers of trace mineral intake and status, J. Nutr., 133 Suppl. 3,
948S, 2003.
13. L’abbe, M.R., Collins, M.W., Trick, K.D., and Laffey, P.J., Glutathione peroxidase
activity in a healthy Canadian population. Effects of age, smoking and drinking habits,
exercise and oral contraceptive use, Trace Elem. Med., 9, 45, 1992.
14. van den Brandt, P.A., Goldbohm, R.A., van’t Veer, P., Bode, P., Hermus, R.J., and
Sturmans, F., Predictors of toenail selenium levels in men and women, Cancer
Epidemiol. Biomarkers Prev., 2, 107, 1993.
15. Hunter, D.J., Morris, J.S., Chute, C.G., Kushner, E., Colditz, G.A., Stampfer, M.J.,
Speizer, F.E., and Willett, W.C., Predictors of selenium concentration in human
toenails, Am. J. Epidemiol., 132, 114, 1990.
16. Longnecker, M.P., Stampfer, M.J., Morris, J.S., Spate, V., Baskett, C., Mason, M.,
and Willett, W.C., A 1-y trial of the effect of high-selenium bread on selenium
concentrations in blood and toenails, Am. J. Clin. Nutr., 57, 408, 1993.
17. Alexander, A.R., Whanger, P.D., and Miller, L.T., Bioavailability to rats of selenium
in various tuna and wheat products, J. Nutr., 113, 196, 1983.
18. Mutanen, M., Bioavailability of selenium in mushrooms, Boletus edulis, to young
women, Int. J. Vitam. Nutr. Res., 56, 297, 1986.
19. Yoshida, M., Sugihara, S., Suenaga, T., Naito, C., Fukunaga, K., and Tsuchita, H.,
Digestibility and chemical species of selenium contained in high-selenium yeast, J.
Nutr. Sci. Vitaminol. (Tokyo), 48, 401, 2002.
20. Barceloux, D.G., Selenium, J. Toxicol. Clin. Toxicol., 37, 145, 1999.
21. Thomson, C.D., Robinson, M.F., Butler, J.A., and Whanger, P.D., Long-term supple-
mentation with selenate and selenomethionine: selenium and glutathione peroxidase
(EC 1.11.1.9) in blood components of New Zealand women, Br. J. Nutr., 69, 577,
1993.
22. Spears, J.W., Trace mineral bioavailability in ruminants, J. Nutr., 133, 1506S, 2003.
23. Luo, X.M., Wei, H.J., Yang, C.L., Xing, J., Liu, X., Qiao, C.H., Feng, Y.M., Liu, J.,
Liu, Y.X., and Wu, Q., Bioavailability of selenium to residents in a low-selenium area
of China, Am. J. Clin. Nutr., 42, 439, 1985.
24. Moser-Veillon, P.B., Mangels, A.R., Patterson, K.Y. and Veillon, C., Utilization of
two different chemical forms of selenium during lactation using stable isotope tracers:
an example of speciation in nutrition, Analyst, 117, 559, 1992.
25. Mahan, D.C. and Parrett, N.A., Evaluating the efÞcacy of selenium-enriched yeast
and sodium selenite on tissue selenium retention and serum glutathione peroxidase
activity in grower and Þnisher swine, J. Anim. Sci., 74, 2967, 1996.
26. Whanger, P.D. and Butler, J.A., Effects of various dietary levels of selenium as selenite
or selenomethionine on tissue selenium levels and glutathione peroxidase activity in
rats, J. Nutr., 118, 846, 1988.
27. Feng, Y., Finley, J.W., Davis, C.D., Becker, W.K., Fretland, A.J., and Hein, D.W.,
Dietary selenium reduces the formation of aberrant crypts in rats administered 3,2¢-
dimethyl-4-aminobiphenyl, Toxicol. Appl. Pharmacol., 157, 36, 1999.
28. DufÞeld-Lillico, A.J., Reid, M.E., Turnbull, B.W., Combs, G.F., Jr., Slate, E.H.,
Fischbach, L.A., Marshall, J.R., and Clark, L.C., Baseline characteristics and the
effect of selenium supplementation on cancer incidence in a randomized clinical trial:
a summary report of the Nutritional Prevention of Cancer Trial, Cancer Epidemiol.
Biomarkers Prev., 11, 630, 2002.
29. Van Dael, P., Davidsson, L., Munoz-Box, R., Fay, L.B., and Barclay, D., Selenium
absorption and retention from a selenite- or selenate-fortiÞed milk-based formula in
men measured by a stable-isotope technique, Br. J. Nutr., 85, 157, 2001.

30. Meltzer, H.M., Norheim, G., Bibow, K., Myhre, K., and Holm, H., The form of
selenium determines the response to supplementation in a selenium replete popula-
tion, Eur. J. Clin. Nutr., 44, 435, 1990.
32. Chang, J.C., Gutenmann, W.H., Reid, C.M., and Lisk, D.J., Selenium content of
Brazil nuts from two geographic locations in Brazil, Chemosphere, 30, 801, 1995.
33. Aydin, K., Kendirci, M., Kurtoglu, S., Karakucuk, E.I., and Kiris, A., Iodine and
selenium deÞciency in school-children in an endemic goiter area in Turkey, J. Pediatr.
Endocrinol. Metab., 15, 1027, 2002.
34. Tinggi, U., Essentiality and toxicity of selenium and its status in Australia: a review,
Toxicol. Lett., 137, 103, 2003.
35. Wang, W.C., Makela, A.L., Nanto, V., Makela, P., and Lagstrom, H., The serum
selenium concentrations in children and young adults: a long-term study during the
Finnish selenium fertilization programme, Eur. J. Clin. Nutr., 52, 529, 1998.
36. de Jong, N., Gibson, R.S., Thomson, C.D., Ferguson, E.L., McKenzie, J.E., Green,
T.J., and Horwath, C.C., Selenium and zinc status are suboptimal in a sample of older
New Zealand women in a community-based study, J. Nutr., 131, 2677, 2001.
37. DufÞeld, A.J. and Thomson, C.D., A comparison of methods of assessment of dietary
selenium intakes in Otago, New Zealand, Br. J. Nutr., 82, 131, 1999.
38. Darlow, B.A., Winterbourn, C.C., Inder, T.E., Graham, P.J., Harding, J.E., Weston,
P.J., Austin, N.C., Elder, D.E., Mogridge, N., Buss, I.H., and Sluis, K.B., The effect
of selenium supplementation on outcome in very low birth weight infants: a random-
ized controlled trial. The New Zealand Neonatal Study Group, J. Pediatr., 136, 473,
2000.
39. DufÞeld, A.J., Thomson, C.D., Hill, K.E., and Williams, S., An estimation of selenium
requirements for New Zealanders, Am. J. Clin. Nutr., 70, 896, 1999.
40. Robinson, M.F., Campbell, D.R., Stewart, R.D., Rea, H.M., Thomson, C.D., Snow,
P.G., and Squires, I.H., Effect of daily supplements of selenium on patients with
muscular complaints in Otago and Canterbury, N.Z., Med. J., 93, 289, 1981.
41. Ikram, H., Crozier, I.G., Webster, M., and Low, C.J., The role of selenium deÞciency
in occidental dilated cardiomyopathy, N.Z. Med. J., 102, 100, 1989.
42. Gramm, H.J., Kopf, A., and Bratter, P., [Importance and physiologic nutritional
requirement of the selenium trace element within the scope of parenteral nutrition
(TPN)], Med. Klin. (Munich), 92 Suppl. 3, 20, 1997.
43. Rannem, T., Ladefoged, K., Hylander, E., Hegnhoj, J., and Staun, M., Selenium
depletion in patients with gastrointestinal diseases: are there any predictive factors?,
Scand. J. Gastroenterol., 33, 1057, 1998.
44. Rannem, T., Ladefoged, K., Hylander, E., Hegnhoj, J., and Jarnum, S., Selenium
status in patients with Crohn’s disease, Am. J. Clin. Nutr., 56, 933, 1992.
45. Kose, K., Dogan, P., Kardas, Y. and Saraymen, R., Plasma selenium levels in rheu-
matoid arthritis, Biol. Trace Elem. Res., 53, 51, 1996.
46. Maehira, F., Luyo, G.A., Miyagi, I., Oshiro, M., Yamane, N., Kuba, M., and Nakazato,
Y., Alterations of serum selenium concentrations in the acute phase of pathological
conditions, Clin. Chim. Acta, 316, 137, 2002.
47. Maehira, F., Luyo, G.A., Miyagi, I., Oshiro, M., Yamane, N., Kuba, M., and Nakazato,
Y., Alterations of serum selenium concentrations in the acute phase of pathological
conditions, Clin. Chim. Acta, 316, 137, 2002.
48. Jackson, M.J., Broome, C.S., and McArdle, F., Marginal dietary selenium intakes in
the U.K.: are there functional consequences?, J. Nutr., 133, 1557S, 2003.

49. Brown, K.M., Pickard, K., Nicol, F., Beckett, G.J., Duthie, G.G., and Arthur, J.R.,
Effects of organic and inorganic selenium supplementation on selenoenzyme activity
in blood lymphoctyes, granulocytes, platelets and erythrocytes, Clin. Sci. (Lond.), 98,
593, 2000.
50. Burk, R.F., Selenium, an antioxidant nutrient, Nutr. Clin. Care, 5, 75, 2002.
51. Ganther, H.E., Selenium metabolism, selenoproteins and mechanisms of cancer pre-
vention: complexities with thioredoxin reductase, Carcinogenesis, 20, 1657, 1999.
52. Gianduzzo, T.R., Holmes, e.g., Tinggi, U., Shahin, M., Mactaggart, P., and Nicol, D.,
Prostatic and peripheral blood selenium levels after oral supplementation, J. Urol.,
170, 870, 2003.
53. Zeegers, M.P., Goldbohm, R.A., Bode, P., and van den Brandt, P.A., Prediagnostic
toenail selenium and risk of bladder cancer, Cancer Epidemiol. Biomarkers Prev.,
11, 1292, 2002.
54. Yoshizawa, K., Willett, W.C., Morris, S.J., Stampfer, M.J., Spiegelman, D., Rimm,
E.B., and Giovannucci, E., Study of prediagnostic selenium level in toenails and the
risk of advanced prostate cancer, J. Natl. Cancer Inst., 90, 1219, 1998.
55. Helzlsouer, K.J., Alberg, A.J., Norkus, E.P., Morris, J.S., Hoffman, S.C., and Com-
stock, G.W., Prospective study of serum micronutrients and ovarian cancer, J. Natl.
Cancer Inst., 88, 32, 1996.
56. Mark, S.D., Qiao, Y.L., Dawsey, S.M., Wu, Y.P., Katki, H., Gunter, E.W., Fraumeni,
J.F., Jr., Blot, W.J., Dong, Z.W., and Taylor, P.R., Prospective study of serum selenium
levels and incident esophageal and gastric cancers, J. Natl. Cancer Inst., 92, 1753,
2000.
57. Yu, M.W., Horng, I.S., Hsu, K.H., Chiang, Y.C., Liaw, Y.F., and Chen, C.J., Plasma
selenium levels and risk of hepatocellular carcinoma among men with chronic hep-
atitis virus infection, Am. J. Epidemiol., 150, 367, 1999.
58. Yu, S.Y., Zhu, Y.J., and Li, W.G., Protective role of selenium against hepatitis B virus
and primary liver cancer in Qidong, Biol. Trace Elem. Res., 56, 117, 1997.
59. Yu, S.Y., Zhu, Y.J., Li, W.G., Huang, Q.S., Huang, C.Z., Zhang, Q.N., and Hou, C.,
A preliminary report on the intervention trials of primary liver cancer in high-risk
populations with nutritional supplementation of selenium in China, Biol. Trace Elem.
Res., 29, 289, 1991.
60. El Bayoumy, K., Richie, J.P., Jr., Boyiri, T., Komninou, D., Prokopczyk, B., Trushin,
N., Kleinman, W., Cox, J., Pittman, B., and Colosimo, S., Inßuence of selenium-
enriched yeast supplementation on biomarkers of oxidative damage and hormone
status in healthy adult males: a clinical pilot study, Cancer Epidemiol. Biomarkers
Prev., 11, 1459, 2002.
61. Blot, W.J., Li, J.Y., Taylor, P.R., Guo, W., Dawsey, S., Wang, G.Q., Yang, C.S.,
Zheng, S.F., Gail, M., and Li, G.Y., Nutrition intervention trials in Linxian, China:
supplementation with speciÞc vitamin/mineral combinations, cancer incidence,
and disease-speciÞc mortality in the general population, J. Natl. Cancer Inst., 85,
1483, 1993.
62. Clark, L.C., Dalkin, B., Krongrad, A., Combs, G.F., Jr., Turnbull, B.W., Slate,
E.H., Witherington, R., Herlong, J.H., Janosko, E., Carpenter, D., Borosso, C.,
Falk, S., and Rounder, J., Decreased incidence of prostate cancer with selenium
supplementation: results of a double-blind cancer prevention trial, Br. J. Urol.,
81, 730, 1998.

63. Clark, L.C., Combs, G.F., Jr., Turnbull, B.W., Slate, E.H., Chalker, D.K., Chow, J.,
Davis, L.S., Glover, R.A., Graham, G.F., Gross, E.G., Krongrad, A., Lesher, J.L., Jr.,
Park, H.K., Sanders, B.B., Jr., Smith, C.L., and Taylor, J.R., Effects of selenium
supplementation for cancer prevention in patients with carcinoma of the skin. A
randomized controlled trial, Nutritional Prevention of Cancer Study Group, JAMA,
276, 1957, 1996.
64. Boyle, P., Severi, G., and Giles, G.G., The epidemiology of prostate cancer, Urol.
Clin. North Am., 30, 209, 2003.
65. DufÞeld-Lillico, A.J., Dalkin, B.L., Reid, M.E., Turnbull, B.W., Slate, E.H., Jacobs,
E.T., Marshall, J.R., and Clark, L.C., Selenium supplementation, baseline plasma
selenium status and incidence of prostate cancer: an analysis of the complete treatment
period of the Nutritional Prevention of Cancer Trial, BJU Int., 91, 608, 2003.
66. DufÞeld-Lillico, A.J., Slate, E.H., Reid, M.E., Turnbull, B.W., Wilkins, P.A., Combs,
G.F., Jr., Park, H.K., Gross, E.G., Graham, G.F., Stratton, M.S., Marshall, J.R., and
Clark, L.C., Selenium supplementation and secondary prevention of nonmelanoma
skin cancer in a randomized trial, J. Natl. Cancer Inst., 95, 1477, 2003.
67. Michaud, D.S., Hartman, T.J., Taylor, P.R., Pietinen, P., Alfthan, G., Virtamo, J., and
Albanes, D., No association between toenail selenium levels and bladder cancer risk,
Cancer Epidemiol. Biomarkers Prev., 11, 1505, 2002.
68. Ratnasinghe, D., Tangrea, J.A., Forman, M.R., Hartman, T., Gunter, E.W., Qiao, Y.L.,
Yao, S.X., Barett, M.J., Giffen, C.A., Erozan, Y., Tockman, M.S., and Taylor, P.R.,
Serum tocopherols, selenium and lung cancer risk among tin miners in China, Cancer
Causes Control, 11, 129, 2000.
69. Schober, S.E., Comstock, G.W., Helsing, K.J., Salkeld, R.M., Morris, J.S., Rider,
A.A., and Brookmeyer, R., Serologic precursors of cancer. I. Prediagnostic serum
nutrients and colon cancer risk, Am. J. Epidemiol., 126, 1033, 1987.
70. Neve, J., Selenium as a risk factor for cardiovascular diseases, J. Cardiovasc. Risk,
3, 42, 1996.
71. Rayman, M.P. and Rayman, M.P., The argument for increasing selenium intake, Proc.
Nutr. Soc., 61, 203, 2002.
72. Knekt, P., Heliovaara, M., Aho, K., Alfthan, G., Marniemi, J., and Aromaa, A., Serum
selenium, serum alpha-tocopherol, and the risk of rheumatoid arthritis, Epidemiology,
11, 402, 2000.
73. Heinle, K., Adam, A., Gradl, M., Wiseman, M., and Adam, O., [Selenium concen-
tration in erythrocytes of patients with rheumatoid arthritis. Clinical and laboratory
chemistry infection markers during administration of selenium], Med. Klin. (Munich),
92 Suppl. 3, 29, 1997.
74. Tarp, U., Selenium and the selenium-dependent glutathione peroxidase in rheumatoid
arthritis, Dan. Med. Bull., 41, 264, 1994.
75. Peretz, A., Neve, J., Duchateau, J., and Famaey, J.P., Adjuvant treatment of recent
onset rheumatoid arthritis by selenium supplementation: preliminary observations,
Br. J. Rheumatol., 31, 281, 1992.
76. Peretz, A., Siderova, V., and Neve, J., Selenium supplementation in rheumatoid
arthritis investigated in a double blind, placebo-controlled trial, Scand. J. Rheumatol.,
30, 208, 2001.
77. Tarp, U., Overvad, K., Thorling, E.B., Graudal, H., and Hansen, J.C., Selenium
treatment in rheumatoid arthritis, Scand. J. Rheumatol., 14, 364, 1985.
78. Hill, J., and Bird, H.A., Failure of selenium-ace to improve osteoarthritis, Br. J.
Rheumatol., 29, 211, 1990.

79. Bowrey, D.J., Morris-Stiff, G.J., and Puntis, M.C., Selenium deÞciency and chronic
pancreatitis: disease mechanism and potential for therapy, HPB Surg., 11, 207, 1999.
80. McCloy, R., Chronic pancreatitis at Manchester, UK. Focus on antioxidant therapy,
Digestion, 59 Suppl. 4, 36, 1998.
81. Niederau, C., Ude, K., Niederau, M., Luthen, R., Strohmeyer, G., Ferrell, L.D., and
Grendell, J.H., Effects of the seleno-organic substance Ebselen in two different
models of acute pancreatitis, Pancreas, 6, 282, 1991.
82. Schulz, H.U., Niederau, C., Klonowski-Stumpe, H., Halangk, W., Luthen, R., and
Lippert, H., Oxidative stress in acute pancreatitis, Hepatogastroenterology, 46, 2736,
1999.
83. Kuklinski, B., Buchner, M., Schweder, R., and Nagel, R., [Acute pancreatitis—a free
radical disease. Decrease in fatality with sodium selenite (Na2SeO3) therapy], Z.
Gesamte Inn. Med., 46, 145, 1991.
84. Constans, J., Conri, C., and Sergeant, C., Selenium and HIV infection, Nutrition, 15,
719, 1999.
85. Baum, M.K., Shor-Posner, G., Lai, S., Zhang, G., Lai, H., Fletcher, M.A., Sauberlich,
H., and Page, J.B., High risk of HIV-related mortality is associated with selenium
deÞciency, J. Acquir. Immune DeÞc. Syndr. Hum. Retrovirol., 15, 370, 1997.
86. Campa, A., Shor-Posner, G., Indacochea, F., Zhang, G., Lai, H., Asthana, D., Scott,
G.B., and Baum, M.K., Mortality risk in selenium-deÞcient HIV-positive children, J.
Acquir. Immune DeÞc. Syndr. Hum. Retrovirol., 20, 508, 1999.
87. Chen, C., Zhou, J., Xu, H., Jiang, Y., and Zhu, G., Effect of selenium supplementation
on mice infected with LP-BM5 MuLV, a murine AIDS model, Biol. Trace Elem. Res.,
59, 187, 1997.
88. Shor-Posner, G., Lecusay, R., Miguez, M.J., Moreno-Black, G., Zhang, G., Rodriguez,
N., Burbano, X., Baum, M., and Wilkie, F., Psychological burden in the era of
HAART: impact of selenium therapy, Int. J. Psychiatry Med., 33, 55, 2003.
89. Look, M.P., Rockstroh, J.K., Rao, G.S., Barton, S., Lemoch, H., Kaiser, R., Kupfer,
B., Sudhop, T., Spengler, U., and Sauerbruch, T., Sodium selenite and N-acetylcys-
teine in antiretroviral-naive HIV-1-infected patients: a randomized, controlled pilot
study, Eur. J. Clin. Invest., 28, 389, 1998.
90. Burbano, X., Miguez-Burbano, M.J., McCollister, K., Zhang, G., Rodriguez, A., Ruiz,
P., Lecusay, R., and Shor-Posner, G., Impact of a selenium chemoprevention clinical
trial on hospital admissions of HIV-infected participants, HIV. Clin. Trials, 3, 483,
2002.
91. Foresta, C., Flohe, L., Garolla, A., Roveri, A., Ursini, F., and Maiorino, M., Male
fertility is linked to the selenoprotein phospholipid hydroperoxide glutathione per-
oxidase, Biol. Reprod., 67, 967, 2002.
92. Marin-Guzman, J., Mahan, D.C., and Whitmoyer, R., Effect of dietary selenium and
vitamin E on the ultrastructure and ATP concentration of boar spermatozoa, and the
efÞcacy of added sodium selenite in extended semen on sperm motility, J. Anim. Sci.,
78, 1544, 2000.
93. Kaur, R. and Parshad, V.R., Effects of dietary selenium on differentiation, morphology
and functions of spermatozoa of the house rat, Rattus rattus L, Mutat. Res., 309, 29,
1994.
94. Oldereid, N.B., Thomassen, Y., and Purvis, K., Selenium in human male reproductive
organs, Hum. Reprod., 13, 2172, 1998.
95. Bleau, G., Lemarbre, J., Faucher, G., Roberts, K.D., and Chapdelaine, A., Semen
selenium and human fertility, Fertil. Steril., 42, 890, 1984.

96. Roy, A.C., Karunanithy, R., and Ratnam, S.S., Lack of correlation of selenium level
in human semen with sperm count/motility, Arch. Androl, 25, 59, 1990.
97. Scott, R., MacPherson, A., Yates, R.W., Hussain, B., and Dixon, J., The effect of oral
selenium supplementation on human sperm motility, Br. J. Urol., 82, 76, 1998.
98. Iwanier, K. and Zachara, B.A., Selenium supplementation enhances the element
concentration in blood and seminal ßuid but does not change the spermatozoal quality
characteristics in subfertile men, J. Androl., 16, 441, 1995.
99. Vezina, D., Mauffette, F., Roberts, K.D., and Bleau, G., Selenium-vitamin E supple-
mentation in infertile men. Effects on semen parameters and micronutrient levels and
distribution, Biol. Trace Elem. Res., 53, 65, 1996.
100. Keskes-Ammar, L., Feki-Chakroun, N., Rebai, T., Sahnoun, Z., Ghozzi, H., Ham-
mami, S., Zghal, K., Fki, H., Damak, J., and Bahloul, A., Sperm oxidative stress and
the effect of an oral vitamin E and selenium supplement on semen quality in infertile
men, Arch. Androl., 49, 83, 2003.
101. Barrington, J.W., Lindsay, P., James, D., Smith, S., and Roberts, A., Selenium deÞ-
ciency and miscarriage: a possible link?, Br. J. Obstet. Gynaecol., 103, 130, 1996.
102. Al Kunani, A.S., Knight, R., Haswell, S.J., Thompson, J.W., and Lindow, S.W., The
selenium status of women with a history of recurrent miscarriage, BJOG, 108, 1094,
2001.
103. Nicoll, A.E., Norman, J., Macpherson, A., and Acharya, U., Association of reduced
selenium status in the aetiology of recurrent miscarriage, Br. J. Obstet. Gynaecol.,
106, 1188, 1999.
104. Kumar, K.S., Kumar, A., Prakash, S., Swamy, K., Jagadeesan, V., and Jyothy, A.,
Role of red cell selenium in recurrent pregnancy loss, J. Obstet. Gynaecol., 22, 181,
2002.
105. Zachara, B.A., Dobrzynski, W., TraÞkowska, U., and Szymanski, W., Blood selenium
and glutathione peroxidases in miscarriage, BJOG, 108, 244, 2001.
106. Chen, J. and Berry, M.J., Selenium and selenoproteins in the brain and brain diseases,
J. Neurochem., 86, 1, 2003.
107. Sher, L., Selenium, thyroid hormones, mood, and behaviour, Can. J. Psychiatry, 47,
284, 2002.
108. Hawkes, W.C. and Hornbostel, L., Effects of dietary selenium on mood in healthy
men living in a metabolic research unit, Biol. Psychiatry, 39, 121, 1996.
109. Benton, D. and Cook, R., The impact of selenium supplementation on mood, Biol.
Psychiatry, 29, 1092, 1991.
110. Kiremidjian-Schumacher, L., Roy, M., Wishe, H.I., Cohen, M.W., and Stotzky, G.,
Supplementation with selenium and human immune cell functions. II. Effect on
cytotoxic lymphocytes and natural killer cells, Biol. Trace Elem. Res., 41, 115, 1994.
111. Bonomini, M., Forster, S., De Risio, F., Rychly, J., Nebe, B., Manfrini, V., Klinkmann,
H., and Albertazzi, A., Effects of selenium supplementation on immune parameters
in chronic uraemic patients on haemodialysis, Nephrol. Dial. Transplant., 10, 1654,
1995.
112. Kiremidjian-Schumacher, L. and Roy, M., Selenium and immune function, Z. Ernahr-
ungswiss., 37 Suppl. 1, 50, 1998.
113. Omland, O., Deguchi, Y., Sigsgaard, T., and Hansen, J.C., Selenium serum and urine
is associated to mild asthma and atopy. The SUS study, J. Trace Elem. Med. Biol.,
16, 123, 2002.
114. Misso, N.L., Powers, K.A., Gillon, R.L., Stewart, G.A., and Thompson, P.J., Reduced
platelet glutathione peroxidase activity and serum selenium concentration in atopic
asthmatic patients, Clin. Exp. Allergy, 26, 838, 1996.

115. Pearson, D.J., Suarez-Mendez, V.J., Day, J.P., and Miller, P.F., Selenium status in
relation to reduced glutathione peroxidase activity in aspirin-sensitive asthma, Clin.
Exp. Allergy, 21, 203, 1991.
116. Horvathova, M., Jahnova, E., and Gazdik, F., Effect of selenium supplementation in
asthmatic subjects on the expression of endothelial cell adhesion molecules in culture,
117. Gazdik, F., Horvathova, M., Gazdikova, K., and Jahnova, E., The inßuence of sele-
nium supplementation on the immunity of corticoid-dependent asthmatics, Bratisl.
Lek. Listy, 103, 17, 2002.
118. Hasselmark, L., Malmgren, R., Zetterstrom, O., and Unge, G., Selenium supplemen-
tation in intrinsic asthma, Allergy, 48, 30, 1993.
119. Bergqvist, A.G., Chee, C.M., Lutchka, L., Rychik, J., and Stallings, V.A., Selenium
deÞciency associated with cardiomyopathy: a complication of the ketogenic diet,
Epilepsia, 44, 618, 2003.
120. Forceville, X., Vitoux, D., Gauzit, R., Combes, A., Lahilaire, P., and Chappuis, P.,
Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill
patients, Crit. Care Med., 26, 1536, 1998.
121. Lehmann, C., Egerer, K., Weber, M., Krausch, D., Wauer, H., Newie, T., and Kox,
W.J., [Effect of selenium administration on various laboratory parameters of patients
at risk for sepsis syndrome], Med. Klin. (Munich), 92 Suppl. 3, 14, 1997.

8 Manganese
Manganese could be poised to garner major attention from both researchers and the
public, or it could continue to generate limited attention. The potential interest burst
would likely involve this element as a contributor to antioxidant function, as a builder
of bone structure, or as a regulator of blood sugar. On the other hand, the relative
obscurity of manganese could continue due to limited information in three areas:
1. Typical intakes vs. needs

2. Bioavailability from different food and supplement sources
3. Sensitivity of various functions to small changes in nutritional status
In other words, we still don’t know if moderate changes in manganese intake

from various sources really impacts health in many people. If we can gain more
insight on these issues, manganese could prove to be a very interesting mineral in
human nutrition.
Manganese has two general categories of biochemical function.1,2 One, which is like
magnesium, is that manganese is needed to activate certain enzymes that utilize ATP.
It appears that the number of enzymes with an absolute requirement for manganese
over magnesium is far less than those that work better with magnesium. Nonetheless,
the manganese enzymes are very important. Among these enzymes are phosphoe-
nolpyruvate carboxykinase, a component of gluconeogenesis, and an enzyme family
known as the glycosyl transferases. The latter enzymes are involved in producing
connective tissue structural carbohydrate, which are especially important in bone
formation and maintenance. These carbohydrates, including chondroitin sulfate, are
also involved in other connective tissue aspects, most notably joint health.
The other major biochemical function of manganese is to be a component of
some metalloenzymes.1,2 The best known of these is manganese superoxide dismu-
tase (Mn SOD), which eliminates superoxide radicals in the mitochondria. This
enzyme has been the topic of literally hundreds of research papers, though a relatively
low percentage of these papers have a nutrition focus. Instead, most of these papers
consider biochemical or physiological aspects of Mn SOD. Other manganese met-
alloenzymes include arginase, the terminal enzyme in the urea cycle, and pyruvate
carboxylase, an important enzyme in liver synthesis of glucose.

A substantial amount of a cell’s manganese is found in the nucleus, which has

led to speculation that manganese can play enzymatic and non-enzymatic roles in
gene expression.1,2 More study is needed to sort out this issue.
There are many knowledge gaps concerning the metabolic biochemistry of manga-
nese. However, there are assorted observations and speculations. For instance, little
is known about manganese absorption into intestinal cells, but there are hints that
regulation occurs to work against excess uptake.3,4 Manganese absorption appears
to have some overlap with iron mechanisms.2 After manganese is absorbed from the
intestine, much of it binds to albumin and rapidly enters the liver.1,2 From there it
can be excreted in the bile, go into liver enzymes, or be transported to other tissues.
Manganese excretion via the bile seems to be regulated by body manganese content.3
Manganese transport from the liver to other tissues seems to involve transferrin, the
protein that transports iron, but some manganese also binds to alpha-2-macroglob-
ulin, a protein that contains tightly bound zinc.1,2 The metabolic importance of the
latter is unknown. It is not certain how manganese enters extrahepatic tissue cells.1,2
There is the thought that this mineral rides in with transferrin in a process that
overlaps iron absorption.1 Manganese does not seem to have a specific storage protein
as does iron or zinc, but quite a bit passively accumulates in bone.1

There has not been a lot of work in this area simply because there has not been a
lot of demand for it. Serum or plasma total manganese is the most commonly used
tool, but urinary manganese as well as activities of serum arginase or lymphocyte
manganese SOD have also been used.3

This area sorely needs more research. Among the foods with the most manganese
are nuts, tea, and whole grains.5 The bioavailability from these foods is largely
unknown, though a rat study suggests that manganese absorption from tea is good.6
Indirect evidence suggests that manganese absorption, at least in some circum-
stances, is inhibited by iron supplements.2,7
Supplement forms include sulfate, gluconate, ascorbate (found in one prominent
joint health product), and amino acid chelates. As with food sources of manganese,
little is known about the absorption properties of different manganese supplements.
The Internet has various sites warning that calcium supplements will impair absorp-
tion of manganese supplements. This claim has some support, but the importance
is far from clear cut. In a human study, acute absorption of manganese is lowered
by adding calcium to human milk but not to other test meals.8 In a rat study with a
perfusion in vivo, calcium inhibits manganese absorption in one section of the
intestine, but increases it in another section.9 In a study in chickens, feeding high

calcium levels does not affect manganese absorption.10 Thus, the practical impor-
tance of the calcium–manganese interaction remains unknown. Unresolved questions
include:
• How high does the calcium-to-manganese ratio have to be to produce a

major impairment in manganese absorption?
• Will different calcium complexes have more, less, or the same tendencies
to inhibit manganese absorption?
• How is the inhibition enhanced or restricted by foods eaten at the same
time as the supplements?
Some Internet sites state that manganese supplements should be taken on an

empty stomach. The rationale for this recommendation is unclear. As with most
minerals, there are some dietary components known to increase, decrease, or have
no effect on manganese absorption.11,12,13

Severe manganese deficiency in humans is considered rare or nonexistent short of
overall malnutrition.1,2 The idea of more marginal deficiencies has received little
attention, partly because there is not a good handle on what constitutes adequate
manganese intake. In fact, no RDA has been established for manganese. Some
consideration of the occurrence of marginal manganese deficiency may eventually
be motivated by four considerations:
1. In a balance study, university students do no not show particularly high

stores of manganese.14
2. One supplement study suggests that lymphocyte Mn SOD activities are
not maximized by typical intakes by a group of male university students7
(though this interpretation of this study is controversial; see below).
3. There may be some situations that raise manganese requirements to the
point where needs are not easily met by most diets;15 the data for the
practical importance of this concern is not yet compelling, but may
become that way with more research; situations that could raise manga-
nese requirements include epilepsy, rheumatoid arthritis, hemodialysis,
and states associated with fat malabsorption.
4. Scattered observations8,9 say that calcium can interfere with manganese
absorption.
The practical consequences of this interference is poorly characterized, but in

light of the increasing popularity of calcium supplementation, this issue merits
attention.
These considerations indicate that there is the possibility that marginal manga-
nese deficiency may occur in various types of people. However, this issue remains
unsettled and is often met with indifference by both researchers and the general
public.


There are relatively few supplementation studies on manganese compared to a
number of other minerals. The main studies are summarized in Table 8.1. The study
that has drawn the most attention is number 1, a study where manganese chelate
supplements increase lymphocyte Mn SOD activities in a group of university male
students. There are four possible interpretations of this result:
1. Typical intakes in such subjects are insufficient to saturate Mn SOD

protein, which indicates a moderate manganese deficiency is common in
these subjects.
2. Typical intakes in such subjects is insufficient to saturate Mn SOD protein,
but this and other manganese functions are still good enough to maintain
good health.
3. Lymphocyte Mn SOD activity does not max out easily with increasing
manganese intake, possibly because Mn SOD gene expression is regulated
by dietary manganese.
4. Manganese supplementation at 12 mg/day, which is above the Upper Level
(UL), induces a toxic reaction; this elevates Mn SOD gene expression,
which is known to be increased by physiological stress.16,17
At present, it is hard to distinguish between these possible interpretations of this

very interesting study. Some would argue against the last of the interpretations by
saying that there is no direct evidence that the study’s manganese dose and duration
can cause a toxic reaction. Although the dose exceeds the Upper Level, the basis
for the Upper Level value is somewhat vague (see the Toxicity section).
The casual observer might assume that multiple follow-up studies would imme-
diately follow Study number 1 of Table 8.1. Yet, that has not been the case. Possibly,
the reason is simply that manganese is not a big funding priority of nutrition agencies.
Study number 2 of Table 8.1 may give the impression that supplementation with
manganese gluconate plus calcium carbonate may aid body weight management.
However, the percent increase in fecal fat loss is very small. Moreover, this percent
is per total fecal fat, not percent of total ingested fat. The latter would represent a
bigger impact on fat balance. Therefore, the impact on absorbed calories is very
small.
Studies number 3 and 4 from Table 8.1 are interesting, but manganese supple-
mentation was not tested by itself, only in combination with other products. Thus,
it is hard to determine to what extent, if any, the manganese promotes bone and
joint health in these studies. Possibly, the non-manganese portion of the products
accounted for the full effect. Moreover, if the manganese did play a role, it is not
known if the role was correction of some degree of deficiency, or an effect of
elevating manganese intake beyond that needed for maintenance of basic functions
(an above-adequate intake effect).
There is a rationale for manganese to affect bone and joint health. Manganese
function, via the glycosyl transferases, affects production of structural carbohydrates
needed for the connective tissue found in bones and joints.1 This function is

TABLE 8.1
Human Manganese (Mn) Supplementation Studies
Subjects Effect
1. College-aged males Increases lymphocyte Mn SOD activity7,17

2. Adults When given + Ca Carbonate, increases fecal fat, decreases fecal
nitrogen18
3. Postmenopausal women When given + copper/zinc, slows bone turnover19
4. Osteoarthritis adults When given + chondroitin sulfate/glucosamine, reduces symptoms20
5. Adults ± type 2 diabetes No consistent effects21
apparently important for both growth and maintenance.1 In addition, it is within the
realm of possibility that Mn SOD also affects bone health. Superoxide is thought
to stimulate bone and joint degeneration.22,23
These connections between manganese and bone or joint health are based heavily
on data from severe manganese deficiency in animals. Since severe deficiency is
considered very rare in humans,1,15 three questions arise concerning manganese and
bone or joint health:
1. Can a marginal manganese deficiency affect bone or joint health?

2. If so, how often does this marginal deficiency occur?
3. Would bone health be promoted by eating manganese at levels beyond
the minimum needed to prevent marginal deficiency?
At present, each of these questions remains largely unanswered.

Study number 5 from Table 8.1 was likely motivated by three observations. One,
severe manganese deficiency in rats produces poor glucose tolerance.24 Two, some
diabetic subjects show high urinary manganese values, which could mean that such
subjects lose a lot of manganese.25 Three, there is an anecdotal report of manganese
supplementation helping blood sugar control in a diabetic subject. Despite this
background, Study number 5 did not produce a consistent lowering of blood sugar
in subjects with or without type 1 diabetes. This may not be extremely surprising
upon closer inspection of the blood sugar abnormality in manganese-deficient rats.
The effect appears to be due to low concentrations of insulin mRNA.26 This condition
is not considered a typical cause of high blood sugar in type 2 diabetes or in most
human high blood sugar states. Type 1 diabetes is characterized by impaired insulin
secretion, but the cause is likely completely independent of manganese function.
Therefore, unless a new connection is established between manganese deficiency
and high blood sugar, manganese supplementation would seem inappropriate for
depressing blood sugar in most human situations.
Ironically, it might be interesting to consider an opposite manganese effect,
restriction of blood sugar depression. As noted above, two enzymes that need
manganese for function are components of gluconeogenesis.1
Conspicuously absent from manganese research is work on interactions between
dietary manganese and agents that can elevate Mn SOD gene expression. Mn SOD

gene expression appears to be heavily regulated by a variety of factors.16,17,27 In many

situations, increasing Mn SOD gene expression could be beneficial as evidenced by
work in transgenic mice that over- or under-express Mn SOD. These mice show
resistance to a variety of induced maladies.16,28,29 Thus, induction of high gene
expression of Mn SOD in some human situations may produce above-normal resis-
tance to some health problems. However, this effect may require that manganese
intake is sufficient to fully activate the enzyme being produced. This may not be the
case where a marginal deficiency exists. Moreover, in some cases, “extra” intake of
manganese may be needed to fully saturate Mn SOD when “extra” Mn SOD protein
is being produced. However, we currently know next to nothing about interactions
between manganese intake and states that elevate Mn SOD gene expression.
This author has done an unpublished study along these lines in rats. A marginal
manganese deficiency produces low Mn SOD activities in liver and lungs, plus it
prevents cytokine-induced increases in Mn SOD activities (lung data shown in Figure
8.1). In addition, marginally manganese-deficient rats die from a normally sublethal
dose of injected endotoxin (unpublished results), a model for septic shock.30 One
problem with this unpublished study is that we don’t know if the degree of manga-
nese deficiency induced in the rats is common in humans.
MANGANESE AND EPILEPSY

There have been rumblings on the Internet that people with epilepsy may benefit
from manganese supplementation. Manganese-deficient rats show vulnerability to
seizures, and rats that are genetically prone to epilepsy have low brain and blood
manganese levels.2,31 Patients with some types of epilepsy show low values for whole
blood manganese. However, the relationship of whole blood manganese to overall
manganese functional status is poorly defined. Even if there is a strong relationship,
it is not known if the low manganese values are a cause or effect of the neurological
problems. In addition, there are no established human trials demonstrating the utility
of manganese supplementation in epilepsy.
TOXICITY
Manganese toxicity is known to occur due to occupational or environmental expo-
sure.1,2,3 Symptoms include neurological problems, some of which can show a
resemblance to Parkinson’s disease. The manganese toxicity in itself should not
actually cause Parkinson’s disease, because the manganese toxicity affects a different
aspect of neurochemistry than does the primary defect of Parkinson’s disease. In
any case, an association of Parkinson’s-like symptoms with typical oral manganese
supplement doses is not well established. On the other hand, in rats with a pre-
Parkinson’s disease-like state, symptoms can be accelerated by high-dose manganese
toxicity.32 Thus, at least in theory, manganese overexposure, in a person with a
tendency toward Parkinson’s disease, may impact time of onset and severity of
neurological symptoms. The logical question is: How much manganese exposure is
necessary to enhance Parkinson’s disease symptoms? This question is not yet

2000
1500
1000
500
0
+ CYTO +CYTO
Adequate Marginal
FIGURE 8.1 Cytokine treatment (Cyto) effect on lung manganese superoxide dismutase activities in growing rats fed adequate or marginal manganese
levels. Values are means ± SD for enzyme activity units/g lung tissue. Cytokine treatment and manganese intake had significant effects (ANOVA, p <
0.01), with all groups significantly different from each other except that marginal versus marginal/cytokine (p < 0.01, LSD).

answered, especially for oral exposure, which could require higher doses for toxicity
than with skin or inhalation exposure. However, some experts have opted for the
safety-first approach and urged caution for manganese supplementation.
This caution can be seen in the setting of the adult Upper Level for manganese
at 10 mg/day. There are some diets that can give that type of intake even without
supplements.33 In addition, two supplement studies have given manganese at well
above the UL without observing any adverse effects.7,34 It is not known yet whether
this UL is excessively cautious or realistic.
Two special areas of concern for manganese toxicity are for people with blocked
bile flow and for fortification of soy-based infant formulas. In the former case, since
manganese excretion is largely via the bile, in principle, a blockage there could make
one prone to manganese toxicity. Direct human studies of this issue have not yet
occurred. In the case of soy and infant formula, since manganese is so well absorbed
when mixed with soy protein,13 manganese toxicity may occur at unusually low
intakes. Although there is not yet data showing that infants have been manganese
poisoned from soy-based infant formulas, caution here would seem prudent.

Manganese research will not move forward until we firm up a basis for an RDA for
manganese, more fully characterize what situations raise manganese requirements,
know more about typical dietary levels of manganese, and characterize how well
different food sources and supplements of manganese are absorbed. We also need
to know if there is any value to eating manganese at levels above those needed to
maintain basic function, particularly for bone and joint health. In addition, nothing
has been done on interactions between manganese intake and factors that can elevate
Mn SOD gene expression. In contrast to these research needs, it is currently hard
to justify further research on manganese supplements as a means of lowering blood
sugar. If manganese supplementation does increase in popularity, then toxicity issues
need to be better defined. At present, some concerns about toxicity may be an
overreaction, but others may be justified, especially as more research comes forward.
TABLE 8.2
Manganese Supplements at a Glance
RDA: none
Typical dose in supplement studies: 5–15 mg (minimal effective dose unknown)
Best supplement complex: not enough studies to classify a best complex
Applications: bone and joint applications are possible, but only slightly researched; various
antioxidant uses are possible, but not researched directly yet
Upper Level: 10 mg (controversial; may be low for most people)
Safety issues: dose needed to produce neurological problems in sensitive individuals is not yet well
defined

REFERENCES
1. Leach, R.M. and Harris, E.D., Manganese, in Handbook of Nutritionally Essential
Mineral Elements, O’Dell, B.L., and Sunde, R.A., Eds., Marcel Dekker, New York,
1997, chap. 10.
2. Keen, C.L. and Zidenberg-Cherr, S., Manganese, in Present Knowledge in Nutrition.
6th edition, Brown, M.L., Ed., ILSI, Washington, 1990, chap. 32.
3. Greger, J.L., Nutrition versus toxicology of manganese in humans: evaluation of
potential biomarkers, Neurotoxicology, 20, 205, 1999.
4. Davis, C.D., Wolf, T.L., and Greger, J.L., Varying levels of manganese and iron affect
absorption and gut endogenous losses of manganese by rats, J. Nutr., 122, 1300, 1992.
6. Zeyuan, D., Bingying, T., Xiaolin, L., Jinming, H., and Yifeng, C., Effect of green
tea and black tea on the metabolisms of mineral elements in old rats, Biol. Trace
Elem. Res., 65, 75, 1998.
7. Davis, C.D. and Greger, J.L., Longitudinal changes of manganese-dependent super-
oxide dismutase and other indexes of manganese and iron status in women, Am. J.
Clin. Nutr., 55, 747, 1992.
8. Davidsson, L., Cederblad, A., Lonnerdal, B., and Sandstrom, B., The effect of indi-
vidual dietary components on manganese absorption in humans, Am. J. Clin. Nutr.,
54, 1065, 1991.
9. Lutz, T.A., Schroff, A., and Scharrer, E., An in vivo luminal perfusion technique.
Effects of calcium and sugars on intestinal manganese absorption, Biol. Trace Elem.
Res., 39, 221, 1993.
10. Wedekind, K.J., Titgemeyer, E.C., Twardock, A.R., and Baker, D.H., Phosphorus, but
not calcium, affects manganese absorption and turnover in chicks, J. Nutr., 121, 1776,
1991.
11. Greger, J.L., Nondigestible carbohydrates and mineral bioavailability, J. Nutr., 129,
1434S, 1999.
12. Lutz, T.A., Schroff, A., and Scharrer, E., Effects of calcium and sugars on intestinal
manganese absorption, Biol. Trace Elem. Res., 39, 221, 1993.
13. Lonnerdal, B., Trace element absorption in infants as a foundation to setting upper
limits for trace elements in infant formulas, J. Nutr., 119, 1839, 1989.
14. Freeland-Graves, J.H., Behmardi, F., Bales, C.W., Dougherty, V., Lin, P.H., Crosby,
J.B., and Trickett, P.C., Metabolic balance of manganese in young men consuming
diets containing five levels of dietary manganese, J. Nutr., 118, 764, 1988.
15. Klimis-Tavantzis, D.J, Manganese in Health and Disease, CRC Press, Boca Raton,
FL, 1994
16. Hoshida, S., Yamashita, N., Otsu, K., and Hori, M., The importance of manganese
superoxide dismutase in delayed preconditioning: involvement of reactive oxygen
species and cytokines, Cardiovasc. Res., 55, 495, 2002.
17. Wong, G.H., Kaspar, R.L., and Vehar, G., Tumor necrosis factor and lymphotoxin:
protection against oxidative stress through induction of MnSOD, EXS, 77, 321, 1996.
18. Potter, S.M., Kies, C.V., and Rojhani, A., Protein and fat utilization by humans as
affected by calcium phosphate, calcium carbonate, and manganese gluconate supple-
ments, Nutrition, 6, 309, 1990.
Nutr., 124, 1060, 1994.

20. Leffler, C.T., Philippi, A.F., Leffler, S.G., Mosure, J.C., and Kim, P.D., Glucosamine,
chondroitin, and manganese ascorbate for degenerative joint disease of the knee or
low back: a randomized, double-blind, placebo-controlled pilot study, Mil. Med., 164,
85, 1999.
21. Walter, R.M., Aoki, T.T., and Keen, C.L., Acute oral manganese does not consistently
affect glucose tolerance in non-diabetic and type II diabetic humans, J. Trace Elem.
Exp. Med., 4, 73, 1991.
23. Ghosh, P., The pathobiology of osteoarthritis and the rationale for the use of pentosan
polysulfate for its treatment, Semin. Arthritis Rheum., 28, 211, 1999.
24. Baly, D.L., Curry, D.L., Keen, C.L., and Hurley, L.S., Effect of manganese deficiency
on insulin secretion and carbohydrate homeostasis in rats, J. Nutr., 114, 1438, 1984.
25. Walter, R.M., Jr., Uriu-Hare, J.Y., Olin, K.L., Oster, M.H., Anawalt, B.D., Critchfield,
J.W., and Keen, C.L., Copper, zinc, manganese, and magnesium status and compli-
cations of diabetes mellitus, Diabetes Care, 14, 1050, 1991.
26. Baly, D.L., Lee, I., and Doshi, R., Mechanism of decreased insulinogenesis in man-
ganese-deficient rats. Decreased insulin mRNA levels, FEBS Lett., 239, 55, 1988.
27. Zelko, I.N., Mariani, T.J., and Folz, R.J., Superoxide dismutase multigene family: a
comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3)
gene structures, evolution, and expression, Free Radic. Biol. Med., 33, 337, 2002.
28. Ho, Y.S., Vincent, R., Dey, M.S., Slot, J.W., and Crapo, J.D., Transgenic models for
the study of lung antioxidant defense: enhanced manganese-containing superoxide
dismutase activity gives partial protection to B6C3 hybrid mice exposed to hyperoxia,
Am. J. Respir. Cell Mol. Biol., 18, 538, 1998.
29. Murakami, K., Kondo, T., Kawase, M., Li, Y., Sato, S., Chen, S.F., and Chan, P.H.,
Mitochondrial susceptibility to oxidative stress exacerbates cerebral infarction that
follows permanent focal cerebral ischemia in mutant mice with manganese superoxide
dismutase deficiency, J. Neurosci., 18, 205, 1998.
30. Wise, W.C., Cook, J.A., Tempel, G.E., Reines, H.D., and Halushka, P.V., The rat in
sepsis and endotoxic shock, Prog. Clin. Biol. Res., 299, 243, 1989.
31. Carl, G.F., Keen, C.L., Gallagher, B.B., Clegg, M.S., Littleton, W.H., Flannery, D.B.,
and Hurley, L.S., Association of low blood manganese concentrations with epilepsy,
Neurology, 36, 1584, 1986.
32. Witholt, R., Gwiazda, R.H., and Smith, D.R., The neurobehavioral effects of sub-
chronic manganese exposure in the presence and absence of pre-parkinsonism, Neu-
rotoxicol. Teratol., 22, 851, 2000.
33. Gibson, R.S., Content and bioavailability of trace elements in vegetarian diets, Am.
J. Clin. Nutr., 59, 1223S, 1994.
34. Finley, J.W., Manganese absorption and retention by young women is associated with
serum ferritin concentration, Am. J. Clin. Nutr., 70, 37, 1999.

9 Chromium
In terms of nutrition, chromium received little attention prior to the last 40 years.
In contrast, in the last 25 years, chromium supplements have grabbed considerable
public attention for various perceived health benefits. Nutrition researchers and the
medical community, though accepting that chromium is an essential nutrient, have
been hesitant to accept the validity of supplement claims. Some of the hesitancy has
been justified by gaps in available research data. One reason for the gaps has been
the technical problems in studying this mineral. Nonetheless, research is slowly
clarifying what chromium supplements can and can’t do.
Much of the impetus to declare chromium as an essential nutrient arose when type
2 diabetes-like symptoms were reversed in subjects on total parenteral nutrition.1
Subsequently, chromium deficiency in experimental animals was found to cause
high blood sugar due to poor insulin utilization.2 Upon further study, it was decided
that chromium plays a role in cellular utilization of insulin.2 The mechanism for this
chromium function is still not settled. At one time, it was thought that a serum
chromium-containing glucose tolerance factor aids insulin utilization. At times, it
looked like this factor had been identified via isolation techniques. Instead, many
isolation attempts produced chromium complex “artifacts” (complexes that formed
during the isolation procedure). It is now thought that chromium mediation of insulin
utilization may involve, at least in part, a low molecular weight-binding molecule
in cell membranes.3
Some other functions have been ascribed to chromium, including effects on lipid
metabolism and indirect antioxidant actions.2,4 These actions may result in whole or
in part from chromium’s actions on insulin utilization. There are also some poorly
defined interactions of chromium with nucleic acids.2 These interactions may include
regulating a gene that affects certain cells’ response to insulin, which may be one
of the ways that chromium affects insulin utilization.
Chromium metabolism has not been studied extensively. One thing that is known is
that absorption is very low (under 2.5% in some studies).2 It is also known that
chromium in the serum can bind to a number of molecules, but much of it locates

in transferrin, the protein that transports iron.2 In theory, chromium binding to

transferrin can compete with iron, but this has little impact on iron metabolism. The
reason is that serum contains much more iron than chromium.2

The lack of a routine means of assessing marginal chromium deficiency has been a
major stumbling block to chromium research. Chromium in blood and urine are
very low. Until recently, the instrumentation needed to measure these levels was not
available to most nutrition researchers. Now, instrumentation has been developed
that allows more researchers to make such measures. However, these measures still
require specialized equipment and considerable effort to deal with problems such
as chromium contamination of samples. Even if the measures are made, serum or
plasma chromium values are not considered ideal means of assessing moderate
chromium deficiency. Although values can rise with chromium supplementation,
values do not reflect tissue levels all that well.5
Another approach is to consider the effects of a chromium supplement interven-
tion on glucose tolerance, but obviously, this strategy is not an easy approach to this
task. In addition, glucose tolerance response to chromium supplementation may be
overshadowed in some individuals by other factors that affect glucose tolerance.
Thus, many studies on chromium supplementation simply don’t test for chromium
status. Others just use urinary chromium as an assumed indicator that some of the
administered chromium is absorbed from the intestine.
These considerations have greatly limited the amount of research on human
chromium status. As a result, there is still need for more development of means to
assess moderate deficiencies of chromium.

Chromium absorption from foods has been given little research. In terms of supple-
ments, inorganic chromium shows a very low percent absorption.2 As a result,
chromium picolinate and chromium nicotinate have been advertised as better means
of obtaining supplemental chromium, a claim backed by some research on radioac-
tive chromium absorption by rats.6 A high chromium yeast product has also been
used as a chromium supplement, though this use has declined.
There have been some claims that chromium nicotinate is superior to chromium
picolinate. In contrast, both chromium picolinate and chromium nicotinate are effec-
tive at restricting blood pressure in spontaneously hypertensive rats.7 Some of the
claim that nicotinate is the better chromium source is based on a rat study examining
radiolabeled chromium.6 By one type of assessment, chromium nicotinate shows
better tissue retention than chromium picolinate. Even so, this study, though inter-
esting, should be interpreted carefully. For example, it should be noted that the
results varied with tissue and time point, that the total chromium intake was not
overly high (which may influence relative absorption), and that the retentions were
based on fractional absorptions, not absolute labeling. Although this approach has

certain advantages for error corrections, there are also limits to how the data can be
applied. For example, total chromium retention in a tissue for one type complex
could exceed the other, but still have a lower fractional retention.

There are claims that chromium intake in the U.S. is often inadequate enough to
produce a marginal deficiency. It has been difficult to verify this contention due to
the above-noted technical barriers to identifying marginal deficiency. In addition, it
has often been hard to figure out chromium contents of various diets. This is because
development of a broad data base for food chromium has been hampered by the
need for specialized equipment and problems with chromium contamination of
samples. Based on present knowledge, the best food sources of chromium include
whole grain products, some animal products, and a few vegetable products, such as
mushrooms.1
Despite the difficulties in evaluating chromium intake and status, there is work
that raises the possibility that typical U.S. chromium intakes fall well below adequate
levels.8
Despite these lines of evidence, there is not a wide range of studies demonstrating
that poor chromium status is a major health concern for a majority of people in the
U.S.. However, in fairness, it has to be said that this lack of demonstration may
simply result from there just not being enough data. Data have been slow in coming
due to technical difficulties, limitations in the funds made available to study chro-
mium, and the low number of researchers committed to studying chromium.

Claims for chromium supplements mainly fall into the categories noted in Table 9.1.
Each of these may have considerable overlap. For example, if the first two effects
occur (fat loss, lean body mass gain), then this could promote total body weight loss
(since lean body mass stimulates basal metabolic rate more than does fat mass). Two
other potentially overlapping areas are improved glucose tolerance and altered blood
lipid profiles. In principle, the former can produce the latter. Possibly, all of the possible
claims of Table 9.1 could derive from chromium’s function of enhancing insulin
sensitivity, which in turn can reduce the amount of insulin released over time.
TABLE 9.1
Claims for Chromium Supplementation
Promotion of fat loss
Promotion of lean body mass gain
Stimulation of body weight loss
Improved glucose tolerance
Beneficial alterations in blood lipid profiles
Indirect antioxidant actions

Are any of the claims of Table 9.1 true? At times, the majority of the biomedical
research community has considered some of these claims dead and buried, but then
they have resurfaced again for another look. Each claim is considered in more detail
below.
BODY WEIGHT AND COMPOSITION ALTERATIONS

Research on the claim for an effect on total weight loss and on fat loss is currently
in the dormant stage. Most studies on chromium supplementation have not shown
a large impact on body weight or fat loss.9 However, it should be noted that many
of the studies that report a negative finding were not designed with total body weight
loss as the main focus. Another issue here is that any pronounced effect of chromium
on body weight loss may take a very long time to see. This long time exceeds the
time used by most studies done so far. The reason for the need for a long-time
intervention has to do with a proposed mechanism by which chromium would affect
weight loss. Under this mechanism, chromium plus exercise would follow the fol-
lowing sequence:
1. Lean body mass increases and body fat decreases.

2. This change elevates basal metabolic rate (BMR).
3. This increase in BMR is sustained for a long enough period to affect body
weight.
The last step would take considerable time. Increases in BMR due to altered
body composition are usually not big enough to have a large short-term effect, though
they may have a substantial effect over a long period. Most, if not all, studies on
chromium and weight loss have not considered long time periods such as one year
or more. This limitation in research arises for very practical reasons. A weight loss
study where the intervention lasts one to two years is expensive and consumes a lot
of effort on the part of both the researchers and subjects.
This author concludes, at least for now, that if chromium can affect weight loss
(and fat loss), it will be a small, and often undetectable, effect over short periods of
time. Even so, the effect might be noticeable over a long period of time. Note that
the words “if” and “might” are used to describe an effect of chromium on weight
loss. The first step to strengthening this very speculative conclusion is to demonstrate
that chromium can impact lean body mass (essentially the same as saying impact
muscle mass). This effect could be useful not only where total body weight loss is
an issue, but also for other considerations. For example, athletes often desire to add
muscle weight while maintaining or increasing total body weight. Another case
where muscle gain would be desirable is in elderly subjects, where muscle weight
loss can contribute to a decline in quality of life. So, for considerations of both
weight loss and other concerns, it has to be asked: Can chromium supplementation,
particularly when combined with exercise, increase lean body mass? Unfortunately,
the answer is: It depends on what study is cited.
There has been great inconsistency as to whether chromium does or does not
enhance exercise-induced increases in lean body mass. Part of the problem may be

that there are a large number of variables that can affect whether or not a given
nutritional–exercise intervention can affect lean body mass gain. These variables
include the type of subjects, the type of exercise, background diet, study duration,
and other considerations.
A number of years ago, Richard Anderson of the USDA wrote a review trying
to make sense of diverse results for studies on chromium supplementation and lean
body mass.10 Anderson cites 13 human studies that examine effects on lean body
mass of chromium supplementation, mostly in conjunction with exercise. Some
studies show an effect, while others do not. He also notes a number of studies in
pigs that support a role for chromium in promoting lean body mass gain. For the
human studies, Anderson proposes that the negative results are caused by one or
more of the following factors:
1. The subjects had adequate chromium intake without supplementation.

2. The study’s exercise plan, in the time frame used, could not promote lean
body mass gain for the given subjects’ fitness level.
3. The amount of chromium administered was insufficient to have the desired
effect.
The explanations offered could explain some of the diversity of the results, and
in this author’s opinion, present excellent starting points for examining the diversity
of results. Even so, these explanations may not cover all the differences in results.
For example, the first proposition assumes that chromium administration will only
help with lean body mass gain if the subjects have some degree of chromium
deficiency. This is not an automatic assumption. Theoretically, chromium supple-
mentation could increase lean body mass by increasing chromium intake beyond
that needed for basic function. Unfortunately, some speculation is involved in this
area because, for reasons discussed earlier, chromium status has not been checked
in most studies on chromium supplementation.
Another issue is the chromium dose. If chromium will only produce an effect
where there is a pre-existing moderate deficiency, it can be asked: Why would the
chromium dose for any of these studies be insufficient to correct this deficiency?
Each of the studies cited use at least 200 µg chromium, which is much higher than
what is currently considered an adequate intake. It could be said that current rec-
ommendations are wrong, but such a contention would be highly speculative. If
current recommendations are correct, it can be asked: Shouldn’t 200 µg chromium
be enough to correct a moderate deficiency? The answer could be no, but there is
no direct evidence yet for such an answer. Moreover, some studies cited show positive
results with 200 µg. Therefore, it can be asked why would this dose work in some
studies but not others? Therefore, there is still gray as to the role of initial chromium
status or chromium dose in determining the outcome of chromium supplement
studies.
Since the time of Dr. Anderson’s review article, four more studies have appeared
on chromium supplementation and lean body mass.10–14 All four produce negative
results (no effect of chromium). Two of the studies examine moderately overweight
older subjects, one examines elite athletes, and one considers moderately obese

women participating in an exercise program. In two studies, the chromium dose is

over 900 µg, but in the athletes, 500 µg is employed. In one of the studies in the
older subjects, the subjects did not appear to be chromium deficient based on
chromium supplement effects on insulin sensitivity.13 In the other studies, chromium
status is uncertain. Therefore, these studies add to the list of negative results, but
don’t clarify the reason for conflict with the studies showing positive results.
There are two other considerations that can be offered as to why conflicting
results have been obtained. First, in some of the positive results studies, some of
the methodology, especially for lean body mass assessment, has been criticized.
Even so, methodology concerns don’t explain all the conflicting results. Alterna-
tively, another source of variability could be background diet. Perhaps chromium
works best in conjunction with good intake of some other nutrients or phytochem-
icals. Possibly, in some of the chromium studies showing positive results, the sub-
jects’ diets were superior in some unidentified way to the diets in the studies showing
negative results. In support of this concept, one study reports that chromium in
combination with other supplements promotes desirable changes in body composi-
tion.15 Unfortunately, in this study, chromium was not examined by itself. Even so,
this study at least raises the possibility that perhaps chromium works best when
combined with good intake of other dietary factors.
In light of these conflicting reports, it is still uncertain as to whether chromium
supplementation can consistently affect lean body mass gain. If it does affect lean
body mass gain in some circumstances, the exact definitions of those circumstances
have not been identified yet.
IMPROVED GLUCOSE TOLERANCE

The following sequence of reasoning has taken place in some people’s minds:
1. Chromium deficiency impairs glucose tolerance via poor insulin utiliza-

tion.
2. Type 2 diabetes as well as other conditions, such as obesity without
diabetes, impairs glucose tolerance via poor insulin utilization.
3. Therefore, chromium supplementation will help glucose tolerance in peo-
ple with poor insulin utilization (insulin resistance).
However, this line of reasoning is not necessarily valid because the cause of
poor insulin utilization in type 2 diabetes and certain other situations is not
chromium deficiency. Therefore, claims that chromium supplements can eliminate
the root cause of type 2 diabetes and some other problems of blood sugar regulation
are clearly wrong. Nonetheless, one or more of the following possibilities could
be true:
1. If some degree of diet-induced chromium deficiency is superimposed over

other causes of insulin resistance, then blood sugar problems will be
heightened; correcting the deficiency will help with glucose tolerance.

2. Type 2 diabetes, and perhaps other conditions, produce very high chro-
mium needs that cannot typically be met by dietary chromium intake;
high-dose chromium supplementation can meet the high needs and help
with glucose tolerance.
3. Even if a person with type 2 diabetes or a related problem has no chro-
mium deficiency, high-dose chromium supplementation can have an
“above-adequate intake effect” or a drug-like effect, which helps with
glucose tolerance.
Unfortunately most studies of chromium supplementation have not directly

addressed these different possibilities, but have just looked at the overall effects of
the supplementation. One reason for this more general approach is that, as noted
earlier, it has not been easy to determine chromium nutritional status.
Compared to a lot of other mineral supplement issues, the issue of chromium
supplementation and glucose tolerance has been the subject of quite a few studies.
However, as is often true of nutrient supplement studies, there is a mixture of positive
or negative results. One recent critical review of the various studies16 concludes that
chromium supplementation does not appear to reduce glucose levels in people with
normal blood glucose, but that chromium supplementation may reduce glucose levels
in people with high blood sugar. Another recent paper17 applies meta-analysis to
randomized controlled studies of chromium supplementation studies in regard to
blood sugar control. This study also finds no effect in non-diabetic studies but, unlike
the other paper, this study concludes that the data for diabetic subjects is inconclu-
sive. This paper drew three letters to the editor that questioned the criteria for
inclusion and exclusion of various studies for analysis.
From this author’s perspective, the meta-analysis17 follows the principles that
statisticians should follow for inclusion and exclusion. On the other hand, this author
can also see the critics’ points about the meta-analysis not accounting for the
following:
1. A large study in China shows a beneficial effect of chromium18 (excluded

from the meta-analysis because the population is different from those of
the other studies).
2. A number of studies with a beneficial effect are excluded (a reasonable
decision in terms of randomized design standards, but these excluded
studies collectively do make some case for chromium).
3. Some negative results included in the meta-analysis use chromium doses
or chromium supplement forms that may not be ideal.
4. Some people with diabetes may respond to chromium better than others;
the meta-analysis cannot account for this because there is no established
criteria for screening who is most apt to respond.
Therefore, in this author’s opinion, the proposition that chromium supplemen-

tation can improve glucose tolerance in people with type 2 diabetes or other insulin
resistance has support, but the support is not airtight. Furthermore, we may not yet

know the ideal conditions where chromium might be maximally effective (e.g., dose,
adjuvant therapy, types of subjects, etc.). An ideal study, which would also be very
expensive and time consuming, should consider variations in supplement forms,
time frames, co-existing therapies, initial chromium status, doses, and stages of
diabetes or insulin resistance. The last few variables may be related, as the dose
may need to be adjusted to the degree of glucose tolerance impairment.
So far, most of the studies done on chromium have used large doses relative to
the normal chromium requirement. This suggests that if chromium helps those with
type 2 diabetes, either the help is a non-nutritional pharmacological effect, or these
subjects have a very abnormally high chromium requirement. However, one could
also argue that until lower doses are thoroughly studied, we cannot reach any
conclusions about dose.
BENEFICIAL ALTERATIONS IN BLOOD LIPID PROFILES

If chromium improves glucose tolerance, then that action can produce beneficial
actions on blood lipid profiles. However, there have also been human studies, though
some are small, plus studies in experimental animals, where chromium supplemen-
tation alters some serum lipid parameters in the absence of diabetes.8 It is possible
that a subtle effect of chromium on insulin metabolism could be responsible for an
effect.
Pretty much everything that was just said about chromium and glucose tolerance
could also be said about chromium and blood lipids, except that there are not as
many studies for the latter. Thus, in this author’s opinion, there is some reason to
believe that chromium supplementation can alter blood lipids in some people, though
it is still debatable as to how often, how much, and in whom the effect can occur.
It is also up for debate as to whether the effect, if and when it occurs, is due to
correction of a deficiency or a pharmacological effect (or both could occur).
INDIRECT ANTIOXIDANT ACTIONS

This claim is based primarily on a study in Tunisian subjects with type 2 diabetes.4
Supplementation with chromium, plus or minus zinc, lowers values for a marker of
oxidant stress. The mechanism is speculated to involve an indirect hormonal effect.
TOXICITY
The movie Erin Brockovich made many people aware of the toxicity of hexavalent
chromium. The chromium in nutritional supplements is trivalent, which is much less
toxic, though as with any metal, toxicity can occur. Even so, there is no Upper Level
(UL) set for chromium because trivalent chromium has not shown obvious toxicity
in the many studies in which supplements have been studied. Thus, we are not yet
sure at what dose and duration trivalent chromium becomes toxic. There is one case
study where a woman shows renal impairment after consuming chromium picolinate
at 1200 to 2400 g/day for four to five months.19 The impairment reverses with therapy,
which includes eliminating chromium supplements. It is not known if this subject

was overly sensitive to chromium. It is also not known if the chromium actually
caused the problems, since therapy was not limited to discontinuing chromium
supplementation.
There has been a suggestion that chromium picolinate can exert toxicity beyond
that of other chromium complexes. This toxicity includes generation of hydroxyl
radicals, which can damage DNA and other biological molecules. Much of this
contention is based on cell culture work where non-physiologically large concen-
trations of chromium picolinate are studied.20 There is also a study where chromium
picolinate produces deleterious effects in fruit flies, but this effect may have been
due more to the picolinate than the chromium.21 In addition, the relevance of this
study to humans taking chromium picolinate is not known.
In contrast to the negative cell culture studies on chromium picolinate, no toxic
effects are reported for rats fed chromium picolinate at doses many times higher
than typically used in human supplementation.22 However, the rat toxicology assess-
ments do not directly check for signs of hydroxyl radical-induced damage. In
contrast, a study in humans does report a lack of DNA damage due to chromium
picolinate supplementation.23 Unfortunately, the dose (400 µg chromium) and dosing
time (four or eight weeks) are less than those used in many chromium studies. In
addition, the method used to assess DNA damage, antibody titers to 5-hydroxymethyl
uracil, is not heavily used, especially for the time frame of this study. Therefore, in
this author’s opinion, doubts remain about the practical importance of chromium
picolinate as a stimulator of DNA damage due to hydroxyl radicals, though this area
certainly could use more study.

Chromium supplementation continues to be interesting, though consensus about
applications has not been forthcoming. Part of the reason for the uncertainty seems
to be the current difficulties in studying chromium, plus the difficulties in studying
the health applications being considered. A big unanswered question is whether
chromium supplementation is effective only for correcting deficiencies, or if there
are pharmacological benefits.
TABLE 9.2
Chromium Supplements at a Glance
Adult RDA: none; adequate intake is 35 µg (male), 25 µg (female)
Typical dose in supplement studies: 200–1000 µg (effective dose debatable, could sometimes be
< 200 µg)
Best supplement complex: picolinate or nicotinate (controversial between the two)
Applications: none settled; blood sugar and lipids best current candidates for utility
Safety issues: debatable accusations against picolinate form

REFERENCES
2. Offenbacher, E.G., Pi-Sunyer, F.X., and Stoecker, B.J., Chromium, in Handbook of
Nutritionally Essential Mineral Elements, O’Dell, B.L., and Sunde, R.A., Eds., Mar-
cel Dekker, New York, 1997, chap. 12.
3. Vincent, J.B., Mechanisms of chromium action: low-molecular-weight chromium-
binding substance, J. Am. Coll. Nutr., 18, 6, 1999.
4. Anderson, R.A., Roussel, A.M., Zouari, N., Mahjoub, S., Matheau, J.M., and Kerkeni,
A., Potential antioxidant effects of zinc and chromium supplementation in people
with type 2 diabetes mellitus, J. Am. Coll. Nutr., 20, 212, 2001.
5. Jain, R., Verch, R.L., Wallach, S., and Peabody, R.A., Tissue chromium exchange in
the rat, Am. J. Clin. Nutr., 34, 2199, 1981.
6. Olin, K.L., Stearns, D.M., Armstrong, W.H., and Keen, C.L., Comparative reten-
tion/Absorption of 51chromium (51Cr) from 51Cr chloride, 51Cr nicotinate and 51Cr
picolinate in a rat model, Trace Elem. Electrolytes, 11, 182, 1994.
7. Preuss, H.G., Grojec, P.L., Lieberman, S., and Anderson, R.A., Effects of different
chromium compounds on blood pressure and lipid peroxidation in spontaneously
hypertensive rats, Clin. Nephrol., 47, 325, 1997.
8. Anderson, R.A., Chromium as an essential nutrient for humans, Regul. Toxicol.
Pharmacol., 26, S35, 1997.
9. Pittler, M.H., Stevinson, C., and Ernst, E., Chromium picolinate for reducing body
weight: meta-analysis of randomized trials, Int. J. Obes. Relat. Metab. Disord., 27,
522, 2003.
10. Anderson, R.A., Effects of chromium on body composition and weight loss, Nutr.
Rev., 56, 266, 1998.
11. Livolsi, J.M., Adams, G.M., and Laguna, P.L., The effect of chromium picolinate on
muscular strength and body composition in women athletes, J. Strength. Cond. Res.,
15, 161, 2001.
12. Campbell, W.W., Joseph, L.J., Davey, S.L., Cyr-Campbell, D., Anderson, R.A., and
Evans, W.J., Effects of resistance training and chromium picolinate on body compo-
sition and skeletal muscle in older men, J. Appl. Physiol., 86, 29, 1999.
13. Amato, P., Morales, A.J., and Yen, S.S., Effects of chromium picolinate supplemen-
tation on insulin sensitivity, serum lipids, and body composition in healthy, nonobese,
older men and women, J. Gerontol. A. Biol. Sci. Med. Sci., 55, M260, 2000.
14. Volpe, S.L., Huang, H.W., Larpadisorn, K., and Lesser, I.I., Effect of chromium
supplementation and exercise on body composition, resting metabolic rate and
selected biochemical parameters in moderately obese women following an exercise
program, J. Am. Coll. Nutr., 20, 293, 2001.
15. Hoeger, W.W., Harris, C., Long, E.M., and Hopkins, D.R., Four-week supplementa-
tion with a natural dietary compound produces favorable changes in body composi-
tion, Adv. Ther., 15, 305, 1998.
16. Ryan, G.J., Wanko, N.S., Redman, A.R., and Cook, C.B., Chromium as adjunctive
treatment for type 2 diabetes, Ann. Pharmacother., 37, 876, 2003.
17. Althuis, M.D., Jordan, N.E., Ludington, E.A., and Wittes, J.T., Glucose and insulin
responses to dietary chromium supplements: a meta-analysis, Am. J. Clin. Nutr., 76,
148, 2002.
18. Anderson, R.A., Chromium, glucose intolerance and diabetes, J. Am. Coll. Nutr., 17,
548, 1998.

19. Cerulli, J., Grabe, D.W., Gauthier, I., Malone, M., and McGoldrick, M.D., Chromium
picolinate toxicity, Ann. Pharmacother., 32, 428, 1998.
20. Bagchi, D., Bagchi, M., Balmoori, J., Ye, X., and Stohs, S.J., Comparative induction
of oxidative stress in cultured J774A.1 macrophage cells by chromium picolinate and
chromium nicotinate, Res. Commun. Mol. Pathol. Pharmacol., 97, 335, 1997.
21. Hepburn, D.D., Xiao, J., Bindom, S., Vincent, J.B., and O’Donnell, J., Nutritional
supplement chromium picolinate causes sterility and lethal mutations in Drosophila
melanogaster, Proc. Natl. Acad. Sci. U.S.A., 100, 3766, 2003.
22. Anderson, R.A., Bryden, N.A., and Polansky, M.M., Lack of toxicity of chromium
chloride and chromium picolinate in rats, J. Am. Coll. Nutr., 16, 273, 1997.
23. Kato, I., Vogelman, J.H., Dilman, V., Karkoszka, J., Frenkel, K., Durr, N.P., Orentre-
ich, N., and Toniolo, P., Effect of supplementation with chromium picolinate on
antibody titers to 5-hydroxymethyl uracil, Eur. J. Epidemiol., 14, 621, 1998.

10 Other Minerals
Most of the current interest in mineral supplements revolves around the minerals
that have been given their own chapter in this book. Even so, there is some interest
in certain other minerals. These are covered below.
PHOSPHORUS
Unlike most nutritionally essential minerals, phosphorus is not a metal. Rather,
phosphorus exists in the body primarily bound to oxygen as a negatively charged
phosphate ion.1 Phosphorus intake is usually adequate in most people without mal-
nutrition because good food sources are found in almost any diet.2 Compared to
most other essential minerals, there are not a lot of cases of documented phosphorus
deficiency, though a few causes do exist in unusual circumstances.1,3 Supplement
suppliers have not done much advertising for standalone phosphorus supplements,
though there can be a fair amount of phosphorus in some protein and creatine
supplement powders. Similarly, calcium supplements, when in the form of calcium
phosphate, also can supply a good amount of phosphorus. One paper has proposed
that the phosphate portion of this type of supplement is important.4 The reasoning
is that high calcium intake decreases phosphorus absorption, which can be offset by
a calcium supplement being at least partly phosphate. A counter-argument is that
most diets are so high in phosphorus that calcium effects on absorption are not
overly important. Thus, ensuring the inclusion of some calcium phosphate in calcium
supplement regimens is not overly important. So far, the first view has not drawn
too much attention.
One other area of attention for phosphorus supplementation is for a procedure
known as phosphate loading.5 For a period such as three days, high doses of phos-
phate are ingested to improve competitive performance in sports of high exertion,
especially cycling. A number of possible mechanisms can be evoked for a perfor-
mance-enhancing effect of high-dose phosphate. These include a buffering effect,
enhanced synthesis of a molecule that affects oxygen transport dynamics, and
increased ATP production.5 Actual studies of phosphate loading do not show unan-
imous results,3,5 but there are a number of studies that show apparent benefits on
factors such as perceived exertion, VO2 max (a measure relevant to aerobic exercise
capacity), acute recovery of peak power, and anaerobic threshold.5,6,7 No obvious
safety problems have emerged yet with infrequent use of phosphate loading, other
than GI tract irritations in some people.3 However, it should be noted that more safety
studies could be done. Repeated use of phosphate loading could be problematic

since the loading plus diet could produce a very high total phosphorus intake.
However, the exact risks of excess phosphorus intake in most types of people other
than renal dialysis patients are poorly characterized.
IODINE
In a sense, iodine is the most heavily used mineral supplement in the world because
so many people use iodized salt. However, in a more narrow definition of supplement
(i.e., in a pill or capsule), iodine is not widely used.
Iodine is another mineral that is not a metal. Rather, in the body, this element
exists as iodide, a negatively charged ion. Iodide is an essential component of thyroid
hormones T3 and T4.8 Iodine deficiency impairs the functions of these thyroid
hormones, which has deleterious effects on various body processes. In severe cases,
this deficiency can produce a goiter, which is an enlarged thyroid gland.
Iodine intake can be tied to the soil levels.2 As a result, iodine deficiency has
often occurred in geographical areas where soil iodine is low, especially if combined
with low intake of saltwater fish, a good iodine source.2 In many countries, iodine
deficiency has been largely eliminated by adding iodine to salt, or in some cases,
to vegetable oils.8 In the U.S., salt is typically iodized, including much of the salt
that finds its way into processed foods. Many multi-vitamin–mineral supplements
also contain iodine. Even so, iodine deficiency is still a major problem in some parts
of the world where iodine-fortified products are not widely available or are not
consumed.2,8,9
In contrast to the parts of the world where iodine deficiency abounds, in other
parts of the world, including the U.S., iodine nutriture gets little attention com-
pared to other nutritional issues. Even so, a few people in industrialized countries
like the U.S. and Australia still become iodine deficient.10,11 There is also some
question as to whether mild forms of iodine deficiency occur with some regularity
in a number of industrialized countries. Although this issue hasn’t drawn large
amounts of attention yet, this may change.12,13 A mild deficiency would be a
problem, since it could produce serious effects, such as impairment of mental
and physical development in children pre- and postbirth.14 If this mild deficiency
does occur with some regularity, then in some of these cases iodine supplemen-
tation may prove to be a viable response. Nonetheless, it does not seem that the
nutrition community thinks that mild iodine deficiency represents a major threat
in countries such as the U.S.
For the most part, few claims for iodine supplementation have appeared in
popular nutrition advertising. Occasionally, there have been scattered claims that
iodine supplementation could help obese people lose weight. The rationale is that
there can be a connection between poor thyroid function and obesity, and that iodine
deficiency can cause poor thyroid function. Although at face value these ideas are
true, there is no evidence that most obesity is caused by poor thyroid function due
to iodine deficiency. In fact, in one study of a large number of obese German children
with abnormal serum thyroid hormone profiles, iodine nutritional status appeared to
be normal.15

There has also been some attention given to the idea that iodine supplementation
could help women with fibrocystic breast disease. The Internet contains many sites
reporting this use, and often the claim is made that the purpose of the iodine
supplements is the correction of an iodine deficiency. However, such sites neglect
to point out that the work that examines this effect of iodine uses doses that are
huge compared to the iodine RDA.16 This means that iodine is being used as a drug,
not as a means to correct a deficiency. The adult RDA for iodine is 150 µg but 80
µg/kg body weight is a typical dose tested for treatment of fibrocystic breast disease.
The main rationale for this use of iodine is a paper published in 1993,16 which
evaluates three previous studies. It is noteworthy that different forms of iodine are
used among the studies and even within the studies. Each of the three reviewed
studies report subjective or objective improvement in some but not all of the women.
In one trial, there are reports of side effects with sodium iodide. The review16
concludes that molecular iodine works better than sodium iodide or protein-bound
iodide. Whether or not these studies constitute enough data to say that relevant
women can be safely and effectively treated with molecular iodine is debatable.
ULTRATRACE MINERALS
Very small amounts of a number of minerals find their way into the human body.
These are sometimes termed “ultratrace minerals. ” It is not known if these minerals
are required for normal body function, or if they are just body “contaminants” from
the environment. Most likely, some of these ultratrace minerals will ultimately be
recognized as essential nutrients, and some already seem to be on their way. Besides
the possible roles as essential nutrients, some of these ultratrace minerals may have
drug applications. In fact, one could say that this has already happened with the use
of lithium to treat depression.
Some supplement companies are including certain ultratrace minerals in their
products. One possible motivation could be just to say that their products contain
something lacking in a competitor’s product. On the other hand, some of the inclu-
sions may have some more noble motivations. The three ultratrace elements that
have gotten the most attention are vanadium, boron, and silicon.
Vanadium could be essential in humans, but that is based mainly on some
properties in vitro, a vanadium requirement for some enzymes in lower life forms,
and a few studies of supplementation in experimental animals.17 There have also
been some studies attempting to demonstrate that a vanadium deficiency can occur
in animals, though interpretation of those studies has been gray.17
The vanadium action that has drawn the most attention may be more of a drug
effect than a reflection of an essential function. This effect is to lower blood sugar.
This effect has been shown in diabetic rats,18 plus in a small number of humans with
or without diabetes.19,20 The typical vanadium complex used for this purpose has
been vanadyl sulfate. However, other complexes are being considered for better
qualities in terms of oral absorption, safety, and anti-diabetes properties.21 The
mechanism behind the blood sugar-lowering effects of vanadium complexes is still
not known, though some ideas exist.18

This author is classifying the anti-diabetic effects as a drug action rather than a
nutrient effect because of the doses involved. The tests of vanadium complexes in
humans have given 100 mg or more per day.19,20 Even at this dose, the effect on
blood glucose is not enormous, and in one small, short-term study of non-diabetic
subjects, there is no effect.22 In rats, the doses giving strong anti-diabetic actions of
vanadium complexes, if scaled up to human body weights, would be even much
higher than what has been tried in the human studies. On the other hand, from a
nutritional standpoint, if animal growth studies are extrapolated to humans, the
vanadium requirement, if any, could be as low as 10 µg.17
The long-term safety of vanadium doses for treating diabetic humans raises
concerns. There is evidence that vanadium toxicity can begin at under 20 mg/day.23
As noted above, some research groups are trying to cope with this issue by searching
for a particular vanadium complex that, in a safe dose, can substantially lower blood
sugar in people with diabetes.21 If this occurs, then vanadium complexes may become
a means of treating diabetes. However, at present, given the possible risks of taking
vanadium at thousands times higher than what may be considered nutritional, this
author cannot recommend that diabetic people treat themselves with vanadium
complexes.
Vanadium has also been touted for improving exercise performance but this has
no real research rationale at present.
Silicon appears to stimulate connective tissue health in experimental animals,
especially in regard to extracellular matrix glycoprotein metabolism.17 This has led
to consideration of silicon as a promoter of bone health in humans, and possibly as
a promoter of cartilage maintenance. In regard to the bone issue, there is a small
study reporting that silicon can improve femoral bone density in women with
osteoporosis.24 It has also been speculated that silicon effects on connective tissue
promote cardiovascular health. Some of this speculation arises because silicon sup-
plementation can inhibit atherosclerosis in rabbits.25 In humans, an old study notes
that silicon in blood vessel declines with age as cardiovascular disease incidence
increases.26 Silicon supplements are appearing on the market, but human research
on the effectiveness of such supplements is nonexistent. Eventually, such research
may prove interesting.
Boron is gaining increasing interest as a possibly essential nutrient. This mineral
influences the activities of a variety of enzymes, impacts plasma steroid hormone
metabolism, and affects the metabolism of other micronutrients including calcium,
magnesium, copper, and vitamin D.17 A lot of this information comes from animal
studies, but there has also been some human work concerning boron interactions
with other minerals. For example, effects on the status of other minerals has been
shown in small controlled feeding studies in humans.27,28 In this work, boron-
restricted diets are fed followed by boron repletion. In addition, in two small human
studies of postmenopausal women, boron supplementation has influenced calcium,
vitamin D, and magnesium measures.29,30
Since the nutrients proposed to be influenced by boron intake are all involved
in bone health, boron has a potential tie with bone health. Along these lines, manip-
ulation of dietary boron in experimental animals affects bone health.17 In contrast,
in an initial study of young adult females, boron supplementation did not influence

TABLE 10.1.
Other Mineral Supplements at a Glance
RDA: phosphorus, 700 mg; iodine, 150 g; rest, none set
Typical dose in supplement studies: variable
Best supplement complex: not enough studies to classify a best complex
Applications:
Phosphorus: athletic applications (debatable but possible)
Iodine: treat severe and marginal deficiencies (latter occurrence rates unknown); drug use for
fibrocystic breast disease (may help, but data is limited)
Vanadium: treat diabetes (the degree of benefits possible may be limited; both safety and efficacy
might be improved by finding an ideal vanadium compound to use)
Silicon: promote connective tissue health, which could promote bone and cardiovascular health
(interesting possibilities, but not much human data)
Boron: enhancement of other mineral functions, especially for bone health (interesting controlled
human feeding studies, early attempts at supplementation studies do not give dramatic results, but
the designs may be have been limited by lack of background knowledge)
Upper Level: phosphorus, 4 g; iodine, 1100 g; vanadium, 1.8 mg, rest, none set
Safety issues: the safety of phosphorus loading by athletes needs more research; with vanadium, the
doses needed to strongly affect diabetic symptoms may be too high to be safe in other regards
bone mineral density, though dietary intake of other minerals may have been a factor
in this study.31 Additional studies may be needed to see if boron intake can play a
major role in bone health.
A number of other possible beneficial actions have been proposed for boron,
including enhancement of lean body mass gain, beneficial effects on plasma lipid
profiles, stimulation of brain cognitive functions, and improvement in the somatic
and psychological symptoms of menopause.17,31,32 These propositions are based on
possible boron functions derived from animal studies, plus anecdotal reports. A few
small pilot human studies have not given dramatic support to these claims, though
there has been some interesting data.17,31,32 However, these studies may not be
optimally designed because we do not yet know the best circumstances to see any
possible benefits of increased boron intake.
In summary, boron is an interesting mineral, may be essential, and supplements
may have benefits in certain circumstances, but these circumstances have not been
clarified greatly in initial human supplement studies.
REFERENCES
1. Berner, Y.N., Phosphorous, in Handbook of Nutritionally Essential Mineral Elements,
3. Hendler, S.S. and Rorvik, D., PDR for Nutritional Supplements, Medical Economics
Thompson Healthcare, Montvale, NJ, 2001, 356.

4. Heaney, R.P. and Nordin, B.E., Calcium effects on phosphorus absorption: implica-
tions for the prevention and co-therapy of osteoporosis, J. Am. Coll. Nutr., 21, 239,
2002.
5. Menore, M. and Thompson, J., Sport Nutrition for Health and Performance, Human
Kinetics, Champaign, IL, 2000, chap 13.
6. Kreider, R.B., Miller, G.W., Schenck, D., Cortes, C.W., Miriel, V., Somma, C.T.,
Rowland, P., Turner, C., and Hill, D., Effects of phosphate loading on metabolic and
myocardial responses to maximal and endurance exercise, Int. J. Sport Nutr., 2, 20,
1992.
7. Stewart, I., McNaughton, L., Davies, P., and Tristram, S., Phosphate loading and the
effects on VO2max in trained cyclists, Res. Q. Exerc. Sport, 61, 80, 1990.
8. Hetzel, B.S. and Wellby, M.L. Iodine, in Handbook of Nutritionally Essential Mineral
Elements, O’Dell, B.L. and Sunde, R.A., Eds., Marcel Dekker, New York, 1997, chap.
19.
9. Zimmermann, M.B., Bridson, J., Bozo, M., Grimci, L., Selimaj, V., and Tanner, M.S.,
Severe iodine deficiency in southern Albania, Int. J. Vitam. Nutr. Res., 73, 347, 2003.
10. Glinoer, D., Feto-maternal repercussions of iodine deficiency during pregnancy. An
update, Ann. Endocrinol., 64, 37, 2003.
11. Li, M., Ma, G., Boyages, S.C., and Eastman, C.J., Re-emergence of iodine deficiency
in Australia, Asia Pac. J. Clin. Nutr., 10, 200, 2001.
12. Skeaff, S.A., Thomson, C.D., and Gibson, R.S., Mild iodine deficiency in a sample
of New Zealand schoolchildren, Eur. J. Clin. Nutr., 56, 1169, 2002.
13. Pedersen, I.B., Knudsen, N., Jorgensen, T., Perrild, H., Ovesen, L., and Laurberg, P.,
Thyroid peroxidase and thyroglobulin autoantibodies in a large survey of populations
with mild and moderate iodine deficiency, Clin. Endocrinol., 58, 36, 2003.
14. Pinchera, A., Rago, T., and Vitti, P., Physiopathology of iodine deficiency, Ann. Ist.
Super. Sanita, 34, 301, 1998.
15. Stichel, H., l’Allemand, D., and Gruters, A., Thyroid function and obesity in children
and adolescents, Horm. Res., 54, 14, 2000.
16. Ghent, W.R., Eskin, B.A., Low, D.A., and Hill, L.P., Iodine replacement in fibrocystic
disease of the breast, Can. J. Surg., 36, 453, 1993.
17. Nielsen, F.H., Boron, manganese, molybdenum, and other trace elements, in Present
Knowledge in Nutrition, 8th ed., Bowman, B.A. and Russell, R.M., Eds., ILSI Press,
Washington, 2001, chap. 36.
18. Poucheret, P., Verma, S., Grynpas, M.D., and McNeill, J.H., Vanadium and diabetes,
Mol. Cell Biochem., 188, 73, 1998.
19. Boden, G., Chen, X., Ruiz, J., van Rossum, G.D., and Turco, S., Effects of vanadyl
sulfate on carbohydrate and lipid metabolism in patients with non-insulin-dependent
diabetes mellitus, Metabolism, 45, 1130, 1996.
20. Cohen, N., Halberstam, M., Shlimovich, P., Chang, C.J., Shamoon, H., and Rossetti,
L., Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients
with non-insulin-dependent diabetes mellitus, J. Clin. Invest., 95, 2501, 1995.
21. Reul, B.A., Amin, S.S., Buchet, J.P., Ongemba, L.N., Crans, D.C., and Brichard,
S.M., Effects of vanadium complexes with organic ligands on glucose metabolism:
a comparison study in diabetic rats, Br. J. Pharmacol., 126, 467, 1999.
22. Jentjens, R.L. and Jeukendrup, A.E., Effect of acute and short-term administration
of vanadyl sulphate on insulin sensitivity in healthy active humans, Int. J. Sport Nutr.
Exerc. Metab., 12, 470, 2002.
23. Nielsen, F.H., Vanadium, in Handbook of Nutritionally Essential Mineral Elements,
O’Dell, B.L. and Sunde, R.A., Eds., Marcel Dekker, New York, 1997, chap. 22.

24. Eisinger, J. and Clairet, D., Effects of silicon, fluoride, etidronate and magnesium on
bone mineral density: a retrospective study, Magnes. Res., 6, 247, 1993.
25. Loeper, J., Goy-Loeper, J., Rozensztajn, L., and Fragny, M., The antiatheromatous
action of silicon, Atherosclerosis, 33, 397, 1979.
26. Loeper, J. and Lemaire, A., Study of silicon in human atherosclerosis, G. Clin. Med.,
47, 595, 1966.
27. Hunt, C.D., Herbel, J.L., and Nielsen, F.H., Metabolic responses of postmenopausal
women to supplemental dietary boron and aluminum during usual and low magnesium
intake: boron, calcium, and magnesium absorption and retention and blood mineral
concentrations, Am. J. Clin. Nutr., 65, 803, 1997.
28. Nielsen, F.H., Biochemical and physiologic consequences of boron deprivation in
humans, Environ. Health Perspect., 102 Suppl. 7, 59, 1994.
29. Meacham, S.L., Taper, L.J., and Volpe, S.L., Effect of boron supplementation on
blood and urinary calcium, magnesium, and phosphorus, and urinary boron in athletic
and sedentary women, Am. J. Clin. Nutr., 61, 341, 1995.
30. Nielsen, F.H., Hunt, C.D., Mullen, L.M., and Hunt, J.R., Effect of dietary boron on
mineral, estrogen, and testosterone metabolism in postmenopausal women, FASEB
J., 1, 394, 1987.
31. Devirian, T.A. and Volpe, S.L., The physiological effects of dietary boron, Crit. Rev.
Food Sci. Nutr., 43, 219, 2003.
32. Penland, J.G., The importance of boron nutrition for brain and psychological function,

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