Zinc and Health: Current Status and Future Directions

Assessment of Marginal Zinc Status in Humans1,2

Richard J. Wood
Mineral Bioavailability Laboratory, U.S. Department of Agriculture Human Nutrition Research Center
on Aging at Tufts University, Boston, MA 02111

KEY WORDS: zinc status

yeast genetics

metallothionein

zinc-dependent enzymes

The interested reader is referred to several recent publications that have provided important overviews of zinc metabolism and function (DiSilvestro and Cousins, 1983, King and
Keen, 1994, Mills 1989, Prasad 1991, Sandstead 1995, Solomons and Cousins, 1984, Walsh et al. 1994, Williams 1989),
as well as the narrower issue of the assessment of zinc status
(Aggett 1991, King 1990, Thompson 1991). In brief, zinc is an
essential mineral that plays an important functional role in a
wide range of zinc-containing proteins, including a large number of zinc-dependent enzymes. Zinc is needed for growth,

differential mRNA display

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ABSTRACT The assessment of marginal zinc status is problematic. Currently, there is no universally accepted
single measure to assess zinc status in humans. The development of a reliable measure of marginal or moderate
zinc status would be useful for a variety of purposes. For example, a simple, yet sensitive and accurate measure
of zinc nutritional status is critically needed to further our limited understanding of the possible associations
between zinc status and the risk of developing various chronic diseases and in predicting favorable health
outcomes in patient populations. A convenient and reliable zinc assessment tool is needed to identify subpopulations who are at a risk of zinc deficiency and as an objective guidepost to determine the need for initiation of zinc
supplementation or zinc fortification of the food supply, as well in the refinement of recommendations of dietary
zinc allowances. In frank zinc deficiency, clinical signs and static measures of zinc concentrations in a variety of
readily available tissues, such as plasma, various blood cell types and hair, may uniformly confirm the presence of
depleted body zinc stores. However, in general, the relative insensitivity or imprecision of these measurements has
resulted in general disappointment in their use to assess marginal zinc status. Therefore, the search continues to
find a useful and reliable marker of marginal zinc deficiency. In an attempt to speculate on possible future
developments in the zinc status assessment field, a number of new and potentially promising approaches to this
problem are highlighted. J. Nutr. 130: 1350S1354S, 2000.

normal development, DNA synthesis, immunity, neurosensory

function and other important cellular processes. Zinc deficiency can be precipitated quite rapidly in young experimental
animals by feeding a zinc-deficient diet. In contrast, zinc
deficiency is not easily achieved in adult humans under experimental conditions where very low dietary zinc levels are fed.
The characteristics of zinc deficiency in several animal species
are well described (Underwood 1977). Moreover, frank zinc
deficiency in humans does occur under various circumstances.
Acrodermatitis enteropathica is a congenital genetic disorder
in humans that causes zinc deficiency (Moynahan 1974).
Human nutritional zinc deficiency was originally described in
1961 in young men living in Egypt and coincided with the
consumption of diets with very low zinc bioavailability due to
high phytic acid content (Prasad et al. 1961). Zinc deficiency
in these individuals was characterized by stunted growth and
delayed sexual maturation that were reversible with zinc supplementation. Frank zinc deficiency, due to congenital disorders or severe dietary zinc restriction, may be signaled by
clinical sequelae such as a prominent skin rash or growthstunting endocrine dysfunction and can be confirmed by low
zinc concentrations in blood and various other tissues. The
problem of marginal zinc nutriture and status may be widespread because many studies have reported positive growth
response in young children who were administered zinc supplements (Brown et al. 1998, Walravens et al. 1983, 1989).
Poor zinc status may also be quite prevalent in clinical populations secondary to various disease states, such as sickle cell

1
Presented at the international workshop Zinc and Health: Current Status
and Future Directions, held at the National Institutes of Health in Bethesda, MD,
on November 4 5, 1998. This workshop was organized by the Office of Dietary
Supplements, NIH and cosponsored with the American Dietetic Association, the
American Society for Clinical Nutrition, the Centers for Disease Control and
Prevention, Department of Defense, Food and Drug Administration/Center for
Food Safety and Applied Nutrition and seven Institutes, Centers and Offices of the
NIH (Fogarty International Center, National Institute on Aging, National Institute of
Dental and Craniofacial Research, National Institute of Diabetes and Digestive
and Kidney Diseases, National Institute on Drug Abuse, National Institute of
General Medical Sciences and the Office of Research on Womens Health).
Published as a supplement to The Journal of Nutrition. Guest editors for this
publication were Michael Hambidge, University of Colorado Health Sciences
Center, Denver; Robert Cousins, University of Florida, Gainesville; Rebecca
Costello, Office of Dietary Supplements, NIH, Bethesda, MD; and session chair,
Nancy Krebs, University of Colorado School of Medicine, Denver.
2
Supported in part by the U.S. Department of Agriculture, Agricultural Research Service (contract number 53-3K06-5-10). The contents of this publication
do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products or organizations
imply endorsement by the U.S. government.

0022-3166/00 $3.00 2000 American Society for Nutritional Sciences.

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ASSESSING ZINC STATUS

anemia (Prasad 1984). Among more healthy populations, elderly persons are a potentially vulnerable subpopulation
(Sandstead 1995) due to low dietary zinc intakes (MaresPerlman et al. 1995) and age-associated decreases in intestinal
zinc absorption efficiency (Turnlund et al. 1986).
Assessment of marginal zinc status

possible zinc-dependent biomarkers. In a subsequent study by

Baer and King (1984), six young men were fed a semipurified,
egg albumen based diet supplying 0.3 mg Zn/d for 4 6 wk,
until their serum zinc concentrations were 70 g/dL, and
then they were repleted for 25 wk with zinc. In this study, no
effect of zinc was apparent on serum lactic dehydrogenase,
alkaline phosphatase, ribonuclease or red blood cell (RBC)3aminolevulinic acid dehydrogenase. Ruz et al. (1991) fed 15
young men 0.6 mg Zn/d for 1 wk and then 4 mg Zn/d for 4 wk,
followed by a 2-wk zinc-repletion period; the authors reported
the lack of an effect of dietary zinc depletion on putative
zinc-responsive enzymes such as plasma angiotensin 1 converting enzyme, purine 5-nucleotidase, -D-mannosidase and
alkaline phosphatase. Thus, for whatever reason, human dietary zinc depletion studies have not identified a reliable
zinc-dependent enzyme marker of zinc deficiency.
Metallothionein. Intriguing findings concerning the effects of dietary zinc depletion on metallothionein (MT) have
been reported. Grider et al. (1990) studied seven subjects after
a short-term, 8-d dietary zinc-depletion (0.46 mg Zn/d) period
and found that RBC lysate MT concentrations decreased
significantly by 50% (from 34 to 20 g/g protein). In a
separate group of subjects, RBC MT increased by 10 d of zinc
supplementation with 50 mg Zn/d. In a subsequent study by
this group, Thomas et al. (1992) showed that RBC MT was
responsive to a 12-d zinc-depletion period when 15 young men
were fed 0.55 mg Zn/d followed by a 30-d zinc-repletion period
with 50 mg Zn/d. Parenthetically, it should be noted that
despite the changes found in RBC MT concentration in response to zinc, no changes were observed in plasma zinc levels.
This may have been due to tissue breakdown and release of
intracellular zinc into plasma. It is interesting that changes in
RBC MT were observed in both of the studies (Grider et al.
1990, Thomas et al. 1992) that involved the use of severe, but
very short-duration (712 d), zinc-depletion periods that presumably would not result in major changes in total body zinc
stores. Thus, RBC MT may be responsive to a very labile
functional zinc pool and could prove to be a useful marker of
zinc deficiency. The rapidity of response of the MT-sensitive
intracellular zinc pool is further attested to by the rapid
changes reported by this group (Sullivan et al. 1998) in monocyte MT mRNA levels in response to short-term zinc supplementation. Additional study of the potential usefulness of this
measure of zinc status under more chronic conditions of zinc
depletion appears to be warranted at this time.

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Despite the potential widespread public health importance

of poor zinc nutriture and the possible high prevalence of
marginal zinc deficiency (Sandstead 1995), there is still considerable debate and frustration concerning our current methods of assessing zinc status (King 1990). There is no universally
accepted single measure suitable to accurately assess the zinc
status of an individual. The most often used approach to
assessment of zinc status, particularly in large population studies, is the measurement of serum zinc levels. Although relatively convenient, especially for epidemiological investigations, plasma zinc content is generally considered a poor
measure of marginal zinc deficiency (King 1990). Thus, it
remains an important scientific challenge to develop a reliable
and sensitive measure of marginal zinc status. Such a zinc
status assessment tool should be of great use in obtaining an
accurate picture of the zinc status of both various population
groups and the individual patient or subject.
Experimental zinc deficiency in humans. A relatively
small number of human zinc depletion-repletion studies have
been reported since the initial report of human zinc deficiency
in the 1960s. The number of subjects studied in these investigations has been quite limited. Moreover, several zinc depletion-repletion study designs have been used that could differentially influence study outcomes. In general, these studies
have revealed that it is difficult to deplete adult humans of a
significant amount of body zinc, even when the dietary zinc
intake is quite low. This has led many investigators to also feed
their subjects various inhibitory substances, such as phytate,
which is found in soy-based diets or added directly as sodium
phytate, to help minimize zinc absorption. The remarkable
homeostatic ability of the body allows it to severely limit
obligatory zinc losses from the body. Normally, the quantity of
zinc lost in urine is minimal, only 0.5 mg/d, and in zinc
depletion, urinary losses can be even less. The major change in
obligatory zinc losses in response to various dietary zinc loads
is achieved by altering endogenous fecal zinc losses (King and
Keen, 1994). Endogenous fecal zinc is a major regulatory focal
point of whole body zinc homeostasis in both animals and
humans. These findings from experimental studies are in general in accord with the recent report that endogenous zinc
excretion is only 12 mg/d in apparently healthy young
Chinese women who typically consume 5 mg zinc/d (Sian et
al. 1996). Thus, assuming there are no other significant zinc
losses from the body, obligatory zinc losses apparently can be
maintained for long periods of time at 2 mg/d. This may
explain why it has been difficult in human zinc depletion
studies to demonstrate significant effects of feeding low dietary
zinc intakes on several outcome parameters.
Zinc-dependent enzymes. Because zinc has an important
role in many enzymes, human zinc depletion-repletion studies
have investigated whether changes in some of these enzyme
activities might be a marker of zinc status. For example, Prasad
et al. (1978) fed four adult male subjects a soy-based, semipurified, zinc-depletion diet containing 3 mg zinc/d for 6 12 mo
and then repleted them for 23 mo with 30 mg zinc/d. Measurements of plasma lactic dehydrogenase, plasma ribonuclease
and plasma alkaline phosphatase appeared to show promise as

1351S

Zinc status as a selection criterion in zinc supplementation

studies
Zinc nutritionists are fundamentally interested in the influence of zinc status on various bodily functions. In particular,
it is very important to define the limits of physiological adaptation to dietary zinc depletion and to investigate the extent of
functional accommodation that occurs in the organism when
normal physiological adaptations are no longer sufficient to
maintain zinc homeostasis. Moreover, identification of the
nature and regulation of important functional pools of zinc in
the body that are altered in response to zinc intake is a high
research priority. One experimental approach to this question
is to measure an appropriate biochemical or functional end
point that is a reasonable biomarker of zinc status and to
explore the effect of altering zinc intake on that putative
3
Abbreviations: IRE, iron-responsive element; IRP, iron-responsive protein;
RBC, red blood cell; MT, metallothionein.

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SUPPLEMENT

Possible new approaches to zinc status assessment

An overall assessment of the current methods available to
assess marginal zinc status suggests that new assessment tools
are needed. A review of MEDLINE publications concerning
zinc status assessment in various populations during the past
10 y indicates that the most common zinc status assessment
measure is plasma zinc. In the body, zinc is primarily found
intracellularly. However, a small and important portion of
body zinc is found in the circulation, mainly bound to plasma
protein. Plasma levels of zinc are homeostatically regulated,
although the signals and processes involved in this regulation
are poorly understood. Plasma zinc levels are also affected by
other factors, such as diurnal rhythm, stress, infection, starvation and plasma protein levels. As a consequence of its regulation and other common factors that can influence its distribution, plasma zinc levels are not considered an accurate
reflection of dietary zinc intake or status. Given this problem,
increased effort has been directed toward evaluating the potential benefit of intracellular zinc concentrations in other
tissues and various cell types. However, the added usefulness of
these cellular approaches is still under active investigation and
can be of limited use in large-scale epidemiological studies.
Thus, the search continues for a simple and reliable measure of
zinc status.
Ferritin model of iron status assessment. A potentially
instructive paradigm concerning the assessment of mineral
status that could act as a goal for work in the area of zinc status
assessment is the measurement of serum ferritin and serum
transferrin receptor concentrations to assess the full range of
iron status. Serum ferritin concentration provides a reliable
measure of body iron stores in most circumstances, although it
can be confounded by inflammatory conditions or during episodes of acute infection (Cook and Finch, 1979). Serum
transferrin receptor has been shown to be useful as a biomarker
of tissue iron deficiency (Flowers et al. 1989) that is independent of inflammation or the acute phase response (Skikne et
al. 1990).
Ferritin is a multichain, ubiquitous cellular iron-storage
protein that is translationally regulated according to cellular
iron status via the action of cellular iron-responsive proteins
(IRP1 and IRP2) that bind to a 5 iron-responsive element
(IRE) on the ferritin mRNA (Theil 1998). Under conditions
of cellular iron surfeit, the iron-loaded IRP dissociates from the
mRNA IRE, thus allowing translation of the protein subunits
to occur. Some of the ferritin protein can be immunologically
detected in the serum and has been shown to reflect body iron
stores over a considerable range. Very low serum ferritin concentrations have been shown to correspond to the absence of
stainable iron in bone marrow and thereby are useful to identify individuals with low iron stores. The measurement of
serum ferritin concentration has been confirmed to be a good
measure of a wide range of body iron stores, and low serum
ferritin can be used as a marker of depletion of body iron
reserves, which precedes the development of frank iron deficiency, characterized by reduced hemoglobin synthesis and the
development of a microcytic, hypochromic anemia.
Metallothionein as a measure of zinc status. MT is an
ubiquitous cellular zinc storage protein that may prove to be a
useful measure of zinc status. Grider et al. (1990) first reported
in 1990 that RBC concentrations of MT could be shown to
decrease in young men fed a zinc-deficient diet for several days
and to be rapidly increased after supplementation with 50 mg
zinc/d. Thus, RBC MT concentrations appeared to be a promising measure of zinc status. Recently, Sullivan et al. (1998)
extended these earlier observations by examining the expres-

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biomarker. The important underlying assumption in these

studies is that many of the individuals in the selected group of
subjects have less-than-optimal zinc status that has resulted in
a zinc-dependent change in the level of the biomarker or the
adequacy of the functional response. Thus, the provision of
increased dietary zinc alone as a zinc supplement should be
able to restore optimal physiological function or normal levels
of the biomarker. The selection of study participants for such
an experiment could be approached in different ways. For
example, a pool of potential subjects could be screened using
a measure of zinc status, and representative subjects with poor
zinc status could be chosen to be randomly assigned to a
placebo treatment or zinc supplement. The assumption is that
zinc treatment will have a high chance of success in changing
the putative zinc-dependent biomarker because the supplement will demonstrably replenish the poor zinc stores of the
zinc-deficient subjects. Moreover, a second group of subjects,
representative of those with good zinc status, could also be
chosen to participate to demonstrate the specificity of the zinc
supplement to cause a positive (nutritional) response only in
the zinc-deficient group. However, because we do not currently possess an accurate and specific biomarker of zinc status,
the ideal approach to demonstrating the functional consequences of zinc supplementation in the population is obviously
problematic. In addition, dietary zinc intake information may
be of little additional help, even if accurate and available for
the population of interest, because of the ability of the body to
adapt to a wide range of zinc intakes, including low intakes of
zinc, as may be found in the general populace. Indeed, a review
of MEDLINE publications on zinc supplementation trials during the past 10 y confirms the lack of the use of any zinc status
assessment measure as a selection criterion in many zinc supplement studies.
An alternative approach to the question of zinc-dependent
function could be to select a subject population with suboptimal levels of the biomarker (e.g., growth rate or immune
status) of interest and then hypothesize that poor zinc status is
responsible for a significant portion of the poor biomarker
status and thus will likely change in response to zinc supplementation. This approach has been used extensively in trying
to define the role of zinc in the immune response of elderly
persons and in growth in children. However, there are several
potentially important drawbacks to this approach to the definition of zinc-dependent functions in human populations. For
example, the depressed immunity or growth function may
have a multifactorial pathogenesis that will obscure the role of
zinc in the dysfunction of interest. From the strictly nutritional
point of view, it is likely that a population with poor zinc
nutriture may also have several other unknown nutritional
deficiencies, some of which could significantly limit the responsiveness of the measured biomarker. Another important
limitation is that it can be expected that even where zinc does
have an important functional role, only those individuals
within the study population with suboptimal zinc status will
respond to treatment. Because the prevalence of poor zinc
status is unknown, the overall effect of zinc treatment can vary
considerably from study to study due to a variable number of
subjects who are in fact zinc deficient. This results in a highly
conflicting body of evidence when all of the studies are examined as a whole. This state of affairs seems to be generally true
if one looks at all of the studies that have been published
concerning the effects of zinc supplementation on various
functional outcomes.

ASSESSING ZINC STATUS

Novel insights from genetic studies

Yeast studies. As a possible future investigational strategy,
it is important to consider that many functional proteins have
been well conserved during the evolution of higher multicellular organisms. In this regard, useful insights into mammalian
mineral metabolism, especially for iron and copper, have already been gained from a better understanding of metal metabolism in simple eukaryotic organisms, such as the yeast
Saccharomyces cerevisiae (Wood and Han 1999). Additional
research insights into the regulation of metal homeostasis in

these more simple organisms will undoubtedly have a significant payoff of a greater understanding of metal regulation in
mammals. In the case of zinc, there are an increasing number
of genes that are being identified that are involved with zinc
metabolism (Eide 1998). In my opinion, two interesting yeast
genes, -zap1 and zrt1, that might have mammalian counterparts deserve particular scrutiny as possible biomarkers of zinc
status. zrt1 is a yeast gene that codes for a high affinity zinc
transporter (Zhao and Eide 1996). Presuming a mammalian
counterpart exists, does dietary zinc depletion result in an
up-regulation of the expression of this gene? If so, could a
human zrt homologue be a useful and convenient biomarker of
zinc deficiency? The second yeast gene of interest is zap1 (Zhao
et al. 1998, Zhao and Eide 1997), which codes for a transcriptional activator of the zinc transporter gene zrt. An interesting
aspect of zap, at least in yeast, is that it is positively autoregulated, i.e., increasing expression of zap results in further upregulation of its own expression. Thus, zap might be a sensitive
cellular zinc sensor, wherein small changes in cellular zinc
status may result in significant changes in zap expression that
could be used to monitor cellular zinc status.
Differential mRNA display. Increasing knowledge of
metal homeostasis in simple organisms will certainly augment
our understanding of metal metabolism in higher organisms
and hopefully lead to important insights that will help to
identify useful markers of zinc status. An additional approach
to this problem is the use of differential mRNA display from
mammalian tissues. This technique has the potential of identifying mRNAs in various tissues that are preferentially up- or
down-regulated by zinc deficiency. Some of these genes may
already be known to be regulated by zinc, but some may
represent novel zinc-regulated genes. For example, Blanchard
and Cousins (1996) recently used this approach in intestinal
tissue from zinc-deficient and zinc-replete rats to identify a
variety of genes that are differentially regulated by zinc status.
Extension of this novel mRNA expression discovery technique
to additional tissues may be fruitful in identifying potential
protein markers of zinc status.
Despite its obvious potential role in the discovery process,
gene-based approaches to identifying potential candidate
markers of marginal zinc deficiency will likely need to be
complemented by more traditional protein-based discovery
approaches. Increasing technical advances in both genomic
and proteomic (Celis et al. 1998, Humphery-Smith and
Blackstock 1997) investigations will hopefully advance our
knowledge of cellular zinc homeostasis and result in the refinement of zinc status assessment markers. These novel findings will eventually have to be examined in the context of zinc
depletion-repletion studies in humans. The pathway to better
zinc assessment tools will likely continue to be tortuous. However, the payoff from this effort can be considerable. The
development of better zinc assessment tools will help to define
the important role of zinc status in a variety of important
health outcomes and lead to a more precise definition of the
optimal levels of zinc nutrition for individuals throughout the
life cycle.

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sion of MT mRNA in circulating monocytes from humans.

Monocyte MT mRNA measured by a competitive reverse
transcription-polymerase chain reaction assay responds rapidly
to zinc supplementation, resulting in a severalfold induction of
mRNA within 2 d of consumption of a 50 mg/d zinc supplement. Thus, this novel measure of zinc-induced transcriptional
activity is a sensitive indicator of changes in zinc status caused
by zinc supplementation. However, an important question that
remains is whether RBC MT or monocyte MT mRNA levels
are useful in the detection of marginal zinc deficiency. Because
MT is primarily an intracellular zinc storage protein, the
measurement of MT mRNA or MT protein is likely to not be
an ideal measure of marginal zinc deficiency. On the other
hand, it may have significant use as a selection criterion to
eliminate from zinc supplementation studies subjects who have
robust zinc stores. Similarly, the usefulness of serum ferritin as
an index of iron stores becomes limited in the phase of iron
depletion immediately preceding the onset of frank deficiency.
Under these conditions, the expression of this iron storage
protein is quite low, but no obvious iron-responsive functional
deficit may be present. Nevertheless, a high prevalence of truly
iron-deficient (anemic) subjects will be found among subjects
with low serum ferritin. Thus, by analogy, subjects with very
low RBC MT concentrations may be at an increased risk of
zinc deficiency.
Serum transferrin receptor and tissue iron deficiency.
The period of early tissue iron depletion in the absence of
anemia can be estimated by the measurement of serum transferrin receptor concentrations (Skikne et al. 1990). The synthesis of ferritin and transferrin receptor reflects cellular iron
status but in reciprocal directions. Like ferritin mRNA, the
transferrin receptor mRNA also contains an IRE that can bind
IRP. However, in the case of the transferrin receptor mRNA,
the IRE is 3. High cellular iron stores result in a disassociation
of the IRP from the 3 IRE in transferrin receptor mRNA, but
in this case the dissociation of IRP from the IRE results in
increased degradation of the transferrin receptor mRNA, leading in turn to lower levels of transferrin receptor protein. In
contrast, when intracellular iron concentrations are low, the
levels of transferrin receptor mRNA are increased due to
increased stabilization of the mRNA, and more transferrin
receptor is synthesized and sent to the cell surface. More
transferrin receptor results in an increased ability to take up
iron-bound transferrin from the circulation and replenish the
depleted cellular iron stores. The increased concentration of
transferrin receptor protein during iron deficiency is reflected
in increased plasma levels of a truncated form of the cell
surface transferrin receptor that can be detected in an antibody-based assay as a measure of tissue iron depletion (Skikne
et al. 1990). The search for a functionally parallel protein
involved in regulating cellular zinc homeostasis, such as a
putative cell surface zinc transporter, may be a fruitful approach to the identification of a potential specific candidate
measure of zinc status.

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