Review

Relevance, essentiality and toxicity

of trace elements in human health
Cesar G. Fraga
*
Department of Nutrition, University of California, Davis, CA 95616, USA
Physical Chemistry-PRALIB, University of Buenos Aires-CONICET, Buenos Aires, Argentina
Abstract
The metals Mn, Fe, Cu, and Zn, and the non-metal Se are considered trace elements
(TE) because of their essentiality and very limited quantity in humans. The biological activities
of Cu, Fe, Mn, and Se are strongly associated with the presence of unpaired electrons that
allow their participation in redox reactions. In biological systems these metals are mostly
bound to proteins, forming metalloproteins. Many of the metals in metalloproteins are part
of enzymatic systems, have structural and storage functions, or use the protein to be trans-
ported to their target site in the organism. In humans Mn, Fe, Cu, Zn, and Se accomplish deci-
sive functions to maintain human health. Deciency in any of these TE leads to undesirable
pathological conditions that can be prevented or reversed by adequate supplementation. In
suciently nourished persons, supplementation should be carefully controlled, given the toxic
eects ascribed to TE when present in quantities exceeding those required for accomplishing
their biological functions. The dietary reference intakes provided by national regulatory agen-
cies are guides to dene intake, supplementation and toxicity of Mn, Fe, Cu, Zn, and Se, as
well other elements considered micronutrients for humans.
2005 Elsevier Ltd. All rights reserved.
Abbreviations: TE, Trace elements; DRI, Dietary reference intakes
Keywords: Micronutrients; Manganese; Iron; Copper; Zinc; Selenium; Oxidative stress
0098-2997/$ - see front matter 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mam.2005.07.013
*
Tel.: +1 530 7546667; fax: +1 530 7528966.
E-mail address: cgfraga@ucdavis.edu
www.elsevier.com/locate/mam
Molecular Aspects of Medicine 26 (2005) 235244
Contents
1. Elements, trace elements and micronutrients . . . . . . . . . . . . . . . . . . . . . . . . . . 236
2. Metals as trace elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
3. Manganese, iron, copper, zinc, and selenium in humans . . . . . . . . . . . . . . . . . . 238
4. Beyond metal deficiency but before toxicity: limits for supplementation . . . . . . . 242
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
1. Elements, trace elements and micronutrients
Four elements (oxygen, carbon, hydrogen, and nitrogen) account for 96% of liv-
ing matter. About 50 of the known elements occur in measurable concentrations in
the living systems. In humans and other mammals, 23 elements have known physi-
ological activities. From these elements, 11 can be classied as trace elements (TE)
because of their essentiality and very limited quantity in humans. Out of these 11 TE,
eight are in the period 4 of the Periodic Table (Fig. 1), suggesting an optimal rela-
tionship of nuclei size/electron availability of the elements in this period to interact
with organic molecules present in biological systems. TE include, at least, the tran-
sition metals vanadium, chromium, manganese (Mn), iron (Fe), cobalt, copper (Cu),
zinc (Zn), and molybdenum; and the non-metals selenium (Se), uorine, and iodine.
All of these belong to the category of micronutrients, which are needed by the human
body in very small quantities (generally less than 100 mg/day), as opposed to ele-
ments considered macronutrients, such as sodium, calcium, magnesium, potassium,
chlorine, etc., which are required in larger quantities.
TE are essential components of biological structures, but at the same time they
can be toxic at concentrations beyond those necessary for their biological functions.
H
Li
Na Mg
K
Rb
Cs Ba
Fr
Be
Ra
Sr
Ca Sc
N
P
O
S
V
Nb Mo
Ta W
Cr Mn
Y
L
A
Hf
Zr
Ti Co
Rh Pd
Ir Pt
Ni
Tc
Re Os
Ru
Fe Cu Zn
Ag
Au Hg
Cd
Br
I
At Rn
Xe
Kr Ga
In
Tl Pb
Sn Sb
Ge As
Bi Po
Te
Se
F
Cl
Ne
Ar
He
B
Al
C
Si
1
2
3
4
5
6
7
1 Group 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 2
Period
Fig. 1. Periodic Table indicating elements essential for humans (white background) and the trace elements
(black characters).
236 C.G. Fraga / Molecular Aspects of Medicine 26 (2005) 235244
In addition, the toxicity can be extended to other non-essential elements of very sim-
ilar atomic characteristics that can mimic the reactivity of a TE. To deal with this
essentiality/toxicity duality, biological systems have developed the ability to recog-
nize a metal, and deliver it to the target without allowing the metal to participate
in toxic reactions (Luk et al., 2003). Proteins are primarily responsible for such rec-
ognition and transport, and most of the associations of TE with other biomolecules
lead to undesirable chemical modications of these molecules.
2. Metals as trace elements
Metals are generally solids at room temperature, they have high electrical conduc-
tivity, luster, and malleability, and they can lose electrons and form positive ions.
According to their position in the Periodic Table, metals include alkali metals, alka-
line earth metals, transition metals, and rare earth metals. Non-metals, exist primar-
ily in the gaseous state at room temperature (selenium and sulfur are solids), they
have poor electrical conductivity, and they tend to win electrons and form negative
ions. In this review the focus will be on four transition metals (Mn, Fe, Cu, Zn) and
one non-metal (Se).
Cations of Cu, Fe, Mn, and anions of Se have unpaired electrons that allow their
participation in redox reactions involving mostly one electron loss (oxidation) or
gain (reduction). The unpaired electrons also allow the chemical classication of
most metals as free radicals (Halliwell and Gutteridge, 1999). Several of the biolog-
ical eects, mostly toxic, of these elements can be explained by their capacity to
catalyze the initiation of free radical reactions or the decomposition of peroxides
and other unstable molecules, allowing the propagation of deleterious free radical
reactions. Following the recognition of the participation of free radicals (reactive
oxygen species, oxygen radicals, oxidants) in a number of biological processes and
patholo-gical states, metals (free or bound to chelators or proteins) were identied
as participants in most of the free radical reactions, acting as pro-oxidant or antiox-
idant entities (Fraga and Oteiza, 2002). The role the metal plays depends on its
chemical structure (iron can act as pro-oxidant and antioxidant; selenium is usually
an antioxidant), as well as on the molecule that is chelating the metal (Halliwell and
Gutteridge, 1999). Zn, as with other group 12 elements, has no unpaired electrons
when in the state Zn
2+
, preventing its participation in redox reactions. Nevertheless,
Zn has been recognized to act as an antioxidant by replacing metals that are active in
catalyzing free radical reactions, such as Fe (Oteiza et al., 2004; Zago and Oteiza,
2001).
Other transition metals that are TE of signicance for human physiology
are: (1) cobalt, a component of cobalamine, or vitamin B12 (Kobayashi and Shi-
mizu, 1999); (2) molybdenum, an electron transfer agent in enzymes such as xan-
thine oxidase and sulphite reductase (Rajagopalan, 1988); and (3) chromium and
vanadium, which are biochemically related to glucose and lipid metabolism, but
specic functions for which are uncertain (Coderre and Srivastava, 2004; Vincent,
2004).
C.G. Fraga / Molecular Aspects of Medicine 26 (2005) 235244 237
In biological systems, metal TE are mostly conjugated or bound to proteins
forming metalloproteins, or to smaller molecules, such as phosphates, phytates,
polyphenols and other chelating compounds. Most of the metals in metalloproteins
are part of enzymatic systems, have structural functions, or use the protein to be
transported to their target site in the organism. In enzymes, the metals partici-
pate in catalytic processes as: (1) constituents of enzyme active sites; (2) stabilizers
of enzyme tertiary or quaternary structure; or (3) associates in forming weak-
bonding complexes with the substrate that can contribute to orienting the substrate
for reactions, or stabilizing charged transition states. As constituents of active
sites, metal cations with unpaired electrons mediate oxidationreduction (redox)
processes by reversible changes in their oxidation state, transferring or receiving
electrons to or from the substrate and co-factor. For example, human superox-
ide dismutases reduce one superoxide anion to hydrogen peroxide, and oxidize a
second superoxide anion to generate molecular oxygen by means of either Cu or
Mn present in the active site of the cytosolic or mitochondrial enzyme,
respectively. The presence of metals bound to lipids, nucleic acids, and carbohy-
drates is well documented, but the biochemical functions of the metals present
in these molecules is unclear, beyond their deleterious actions through oxidant
reactions.
3. Manganese, iron, copper, zinc, and selenium in humans
In Table 1, the main functions, dietary sources, presence, and potential for toxic-
ity are summarized for Cu, Zn, Fe, Se, and Mn. Based on the functions for these TE,
on their dietary origin, and on the diseases and pathological situations developed be-
cause of TE deciency or toxicity, an appropriate intake of TE is a relevant aspect of
a healthy diet. The presence of TE in foods is often determined by the availability of
metals in the soil. Thus, within a geographical region with soils deprived of a TE, its
population is at risk and TE supplementation becomes necessary. Such supplemen-
tation has been implemented or is being evaluated in several places around the world
by adding the appropriate TE to basic foods (milk, our, etc.) (de Romana et al.,
2005; Hurrell et al., 2004). Also, supplementation becomes necessary in several dis-
ease treatments, e.g. anemic conditions in kidney dialysis (Locatelli et al., 2004), and
physiological conditions, e.g. extensive blood loss during menstruation (Munro,
2000). Unfortunately, in recent years the avalanche of uncontrolled supplementation
with TE has put some TE on the border of toxicity in several populations. Thus, it is
a crucial priority to dene the requirements for TE, based on essentiality and health
promotion, and the limits for toxicity.
Many countries and regions have dened the requirements and limits of supple-
mentation for TE, e.g. Japan (www.dietitian.or.jp/english/jp_health_nutrition/sixth-
revision.html); UK (archive.food.gov.uk/ma/archive/food/infsheet); Australia and
New Zealand (www.moh.govt.nz/moh.nsf/0/CC515A13536B3CB4CC256F6D000-
ABDE0). Although these requirements and toxicity reference values can slightly
dier for some micronutrients, in general the values are rather homogeneous. In
238 C.G. Fraga / Molecular Aspects of Medicine 26 (2005) 235244
Table 1
Functions, dietary sources, presence, and potential of toxicity for manganese, iron, copper, zinc, and selenium
Manganese Mn is associated with bone development, and with amino acid, lipid, and carbohydrate metabolism. Mn is found in dierent enzymes,
e.g. mitocondrial Mn superoxide dismutase, glutamine synthetase, arginase, and activates several hydrolases, transferases and carboxylases.
Mn is transported in the body by transferrin and by macroglobulins and albumin (Davis and Greger, 1992; Rabin et al., 1993). Sources of
dietary Mn include grain, rice, tea, and nuts. Mn is toxic in excess; in brain it can cause a Parkinson-type syndrome (Aschner, 2000)
Iron Found in four classes of proteins: Fe-heme proteins (e.g. hemoglobin (2/3 body iron), myoglobin, catalase, cytochromes); Fesulfur
enzymes (e.g. aconitase, fumarate reductase); proteins for Fe storage and transport (transferrin, lactoferrin, ferritin, hemosiderin), and
other Fe-containing or Fe-activated enzymes (e.g. NADH dehydrogenase, succinate dehydrogenase, alcohol dehydrogenase,
cyclooxygenases). Total iron intake ranges from 14.4 to 20.2 mg/day (Chanarin, 1999). Serum Fe is about 1.3 mg/L, mostly bound
to transferrin. Iron content in an adult man is about 4 g, decreasing to about 3 g in menstruating women. Fe deciency causes anemia.
Sources of heme Fe (15% of consumption) are hemoglobin and myoglobin from animals. Sources of non-heme Fe are cereals, seeds
of leguminous plants, fruits, vegetables, and dairy products. One of the most serious forms of Fe overload is acute Fe poisoning.
Chronic Fe intoxication occurs frequently associated to genetic and metabolic diseases, repeated blood transfusions, or excessive
intake (Fraga and Oteiza, 2002)
Copper In humans Cu is necessary for the development of connective tissue, nerve coverings, and bone. Cu also participates in both Fe and
energy metabolism. Cu acts as a reductant in the enzymes superoxide dismutase, cytochrome oxidase, lysil oxidase, dopamine hydroxylase,
and several other oxidases that reduce molecular oxygen. It is transported in the organism by the protein ceruloplasmin. There is about
80 mg of Cu in the adult body (highest concentrations in liver and brain) and median intake of Cu ranges between 1.0 and 1.6 mg/day
in adults (US data). Good sources of dietary Cu are liver and other organ meats, oysters, nuts, seeds, dark chocolate, and whole grains.
Cu deciency in humans is rare, but when it occurs leads to normocytic, hypochromic anemia, leucopenia and neuropenia, and inclusive
osteoporosis in children (Kanumakala et al., 2002). Excessive dietary Zn can cause Cu deciency. Chronic Cu toxicity is rare in humans,
and mostly associated with liver damage. Acute Cu intoxication leads to gastrointestinal eects characterized by abdominal pain,
cramps, nausea, diarrhea, and vomiting
Zinc Zn is involved in the activity of about 100 enzymes, e.g. RNA polymerase, carbonic anhydrase, CuZn superoxide dismutase,
angiotensin I converting enzyme. Also it is present in Zn-ngers associated with DNA. Zn is mainly transported by ceruloplasmin.
There are 23 g of Zn present in the human body (second to Fe in body content) and about 1 mg/L in plasma. Zn deciency is
common in underdeveloped countries and is mainly associated with malnutrition, aecting the immune system, wound healing, the
senses of taste and smell, and impairing DNA synthesis. Zn seems to support normal growth and development in pregnancy, childhood,
and adolescence. Zn is found in red meat and poultry, beans, nuts, seafood (oysters are extremely rich in Zn), whole grains, fortied
breakfast cereals, and dairy products. Zn toxicity has been seen in both acute and chronic forms. Intakes of 150450 mg of Zn per day
have been associated with low Cu status, altered Fe function, reduced immune function, and reduced levels of HDL (Hamilton et al., 2000)
(continued on next page)
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Table 1 (continued)
Selenium Se is incorporated into proteins to make selenoproteins, which are important antioxidant enzymes. Se is found in glutathione peroxidase,
thioredoxins, and selenoprotein P. Se is obtained from grains, cereals, red meats and seafood. Some nuts are also sources of selenium
(Brazil nuts may contain as much as 20 mg of Se per g). Human Se deciency is rare in the US but is seen in other countries, most notably
China, where soil concentration of selenium is low. There is evidence that Se deciency may contribute to a form of heart disease,
hypothyroidism, and a weakened immune system (Combs, 2000; Zimmermann and Kohrle, 2002). There is also evidence that Se deciency
does not usually cause illness by itself. Rather, it can make the body more susceptible to illnesses caused by other nutritional, biochemical or
infectious stresses (Levander and Beck, 1997). High blood levels of Se (>1 mg/L) can result in selenosis. Symptoms of selenosis include
gastrointestinal upsets, hair loss, white blotchy nails, garlic breath odor, fatigue, irritability, and mild nerve damage. Se toxicity is
rare in the US, being the few reported cases being associated with accidental exposure
2
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the USA the Institute of Medicine has dened four kinds of dietary reference intakes
(DRI) (Food and Nutrition Board, 2000; Food and Nutrition Board, 2001) which
are explained in the footnote to Table 2. This table shows the DRI values for Fe,
Cu, Zn, Mn, and Se. It is important to note that although the published reference
values are based on scientic data, these data are often scanty or drawn from studies
that had limitations in addressing a specic question (Food and Nutrition Board,
2000). Furthermore, to dene a value for a determined nutrient, it is necessary to
consider dierent aspects in the metabolism of this nutrient. For example, the
requirements for Fe are calculated from a factorial model that includes basal Fe
losses, menstrual losses, fetal requirement in pregnancy, increased requirement dur-
ing growth, and/or increased tissue and storage of Fe (Kennedy and Meyers, 2005).
As a consequence the Fe requirement for women varies signicantly depending on
the age and condition of the woman.
In terms of nutrition, databases for food content of TE are rather well established
(www.fao.org/infoods/directory_en.stm; www.nal.usda.gov/fnic/foodcomp). How-
ever, as previously indicated, the TE content in most foods will vary signicantly
depending on the TE availability in the soil in which the fruit, vegetable or animal
is grown.
There are other factors to consider that can dene the requirements for essential
elements beyond their presence in foods: (1) interaction among nutrients, e.g. inter-
actions between iron and other metals (Aschner, 2000); (2) the presence in the diet of
certain compounds, that can impair metal absorption, e.g. phytates bind Zn, pre-
venting absorption (Greger, 1999; Lestienne et al., 2005); (3) genetic defects, e.g.
Zn absorption is decreased in acrodermatitis enteropathica (Wang et al., 2004); (4)
drugnutrient interactions, e.g. penicillamine used in the treatment of Wilsons dis-
ease causes Zn deciency (Schilsky, 2001).
Table 2
Dietary reference intakes (DRI) for manganese, iron, copper, zinc, and selenium
a
EAR
b
RDA
b
AI
b
UL
b
Mn (mg/day) 2.3/1.8 11
Fe (mg/day) 6/8.1 8/18 45
Cu (mg/day) 0.7 0.9 10
Zn (mg/day) 9.4/6.8 11/8 40
Se (lg/day) 45 55 400
a
Values for this table were taken from dietary reference intakes (Food and Nutrition Board, 2000; Food
and Nutrition Board, 2001).
b
Estimated average requirement (EAR), a nutrient intake value that is estimated to meet the requirement
of half of the healthy individuals in a life stage and gender group; recommended dietary allowance (RDA),
the dietary intake level that is sucient to meet the nutrient requirements of nearly all healthy individuals
in a life stage and gender group; adequate intake (AI): a recommended intake value based on observed or
experimentally determined approximations or estimates of nutrient intake by a group (or groups) of
healthy people that are assumed to be adequate (used when an RDA cannot be determined); tolerable
upper intake level (UL), the highest level of nutrient intake that is likely to pose no risk of adverse health
eects for almost all individuals in the general population. As intakes increase above the UL, the risk of
adverse eects increases. Figures separated by a bar indicate values for men/women.
C.G. Fraga / Molecular Aspects of Medicine 26 (2005) 235244 241
4. Beyond metal deciency but before toxicity: limits for supplementation
For many years foods were accepted as the source of all the nutrients required to
accomplish the physiological functions needed for development, growth, health, and
reproduction. During that time, little or no attention was directed on the eects of
nutrients on the development of diseases dierent than those caused by the nutrient
deciency. Based on the increased knowledge of the biological mechanisms ruling
life, as well as the increase in life expectancy and the resultant increased incidence
of chronic and degenerative diseases, the concept that increasing the intake of certain
nutrients may inuence the onset and development of the disease becomes a public
concern. It has been claimed that poor diet and physical inactivity were responsible
for about 1/6 of the deaths in the USA in 2000 (Mokdad et al., 2004). Associations
for cancer, diabetes and cardiovascular disease with diet have prompted the con-
sumption of ber, fatty acids, phytochemicals, and trace elements (Willett, 2002).
As a result of this gain in knowledge, in the last 20 years there has been a not al-
ways desirable explosion in the availability and consumption of supplements aimed
to prevent the onset of disease. Furthermore, the passive acceptation of the concept
that more is better . . . has led to unjustied high supplementation with many TE
(Harper, 1999). For TE, given the absence of metabolization of the metal or non-
metal atoms, it is possible to establish clear separations among essentially, health
benets and toxicity. The DRI, as the shown in Table 2, should guide any intention
of supplementation beyond normal food consumption to prevent toxicity.
Other important variables that should be considered when the levels of TE are in-
creased in the body are the eects genetic and individual dierences in the targeted
population, life-style, nutra-genetic interactions, and other individual factors that
can determine the eects of the nutrient on the disease.
5. Conclusion
Mn, Fe, Cu, Zn, and Se accomplish functions essential to maintaining human
health. Deciency in any of these TE leads to undesirable pathological conditions
that can be prevented or reversed by adequate supplementation. In suciently nour-
ished persons, supplementation should be carefully controlled, given the toxic eects
ascribed to TE when present at levels that exceed those required for accomplishing
their biological functions.
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