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TRACE ELEMENTS
Trace mineral elements are metals, except for selenium and the halogens,
fluoride, and iodine. Individually, they are in tissue concentrations of less than 1 μg/g of
wet tissue and constitute less than 0.01% of dry body weight. They are referred to as
“trace elements” because quantitation was not possible with the analytical methods
available at that time.

The various essential trace elements were discovered by several different means.
Deficiencies of some of these elements were found in areas where the soil, water, or
plants were inadequate in a specific element, such as iodine, fluorine, cobalt, or copper.
Deficiencies were also identified when essential elements became biologically
unavailable because of interference by other dietary ingestants.

Ten trace mineral elements have been generally recognized as essential in

humans. The roles of the trace mineral elements include structural, signal transduction,
and especially catalytic properties. Some of the trace mineral elements are components
of metalloenzymes, function as enzyme cofactors, provide electron and oxygen
transport, and are active in the maintenance of macromolecule conformation or vitamin
and hormonal activity.

CHROMIUM (Cr)
Came from the Greek word chroma (“color”), makes rubies red and emeralds
green. Known to enhance the action of insulin. Chromium is the 21st most abundant
element in the earth’s crust and is used in the manufacturing of stainless steel.
Occupational exposure to chromium occurs in wood treatment, stainless steel welding,
chrome plating, the leather tanning industry, and the use of lead chromate or strontium
chromate paints. Chromium exists in two main valency states: trivalent and hexavalent.
Increased chromium in urine is confirmation of recent occupational or environmental
exposure to excess chromium.

Absorption of chromium from the intestine is low. Chromium sources include

meats, whole grains, green beans, broccoli, and some spices. After absorption,
chromium binds to plasma transferrin and then concentrates in the liver, spleen, other
soft tissues, and bone. Clinical signs of chromium deficiency were first described in
patients receiving parenteral nutrition. Chromium depletion is thought to be associated
with increased cardiovascular risk, and supplementation has demonstrated increased
HDL cholesterol and decreased insulin. Hexavalent chromium is a recognized
carcinogen. Industrial exposure to metal fumes and dust is associated with lung cancer,
renal failure, dermatitis, and skin ulcers.

Chromium may be determined by GFAAS, NAA, or ICP-MS. Plasma, serum, and

urine do not indicate the total body status of the individual, whereas urine levels may
be useful for metabolic studies. In the setting of suspected failure of MoM hip implants
that use a cobalt chrome alloy femoral head, serum is the preferred specimen type for
both chromium and cobalt analysis.

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COBALT (Co)
Essential for humans only as an integral part of vitamin B12 (cobalamin). Cobalt
has no other known function in humans. Diet has to supply the human vitamin B12
needs. Microflora of the human intestine are not able to use cobalt to synthesize
cobalmine; free cobalt does not impact with the body’s vitamin B12 pool.

COPPER (Cu)
The third most abundant trace element in the human body, following zinc and
iron. It is a very effective cation in reactions that involve electron transfer and binding
to organic molecules. Relatively soft yet tough metal with excellent electrical and heat
conducting properties. Copper is widely distributed in nature both in its elemental form
and in compounds. Copper is an important cofactor for several metalloenzymes and is
critical for the reduction of iron in heme synthesis. Copper is present in all living cells.

The copper content in the normal human adult is 50 to 120 mg. Copper is
distributed through the body with the highest concentrations found in liver, brain,
heart, and kidneys. Hepatic copper accounts for about 10%. Copper is also found in the
cornea, spleen, intestine, and lungs. The amount of copper absorbed from the intestine
is 50% to 80% of ingested copper. The average daily intake is approximately 10 mg or
more of copper.

Copper is transported to the liver and bounds to albumin, transcuprein, and low-
molecular-weight components in the portal system. In a normal physiological state,
98% of copper excretion is through the bile, with copper losses in the urine and sweat
comprising approximately 2% of dietary intake. Menstrual losses of copper are minor.

Copper deficiency is observed in premature infants and copper absorption is

impaired in severe diffuse diseases of small bowel, lymphosarcoma, and scleroderma.
Deficiency is related to malnutrition, malabsorption, chronic diarrhea,
hyperalimentation, and prolonged feeding with low copper, total-milk diets.

Menkes’ syndrome, a rare X-linked recessive congenital defect of copper

absorption with symptoms usually appear at the age of 3 months and death usually
occurring by the age of 5. This invariably fatal, progressive brain disease is characterized
by peculiar hair, called kinky or steely, and retardation of growth. Clinical signs include
progressive mental deterioration, coarse feces, and disturbance of muscle tone, seizures,
and episodes of severe hypothermia.

Wilson’s disease is a genetically determined copper accumulation disease that

usually presents between the ages of 6 and 40 years. Clinical findings include neurologic
disorders, liver dysfunction, and Kayser-Fleischer rings (green-brown discoloration) in
the cornea caused by copper deposition.

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FLUORIDE (Fl)
Used to prevent dental caries. Fluoridation of drinking water now reduces the
incidence of tooth decay for more than 60% of the U.S. population and reduces the
incidence of tooth decay by more than 60%. Dental fluorosis is the unsightly mottling
of dental enamel and is seen in erupting teeth of children due to excessive fluoride,
possibly from ingestion of fluoride-containing toothpastes.

Occupational exposure to inhaled fluoride dust during aluminum refining causes

severe bone abnormalities; safety equipment now limits such exposure. No cases are
attributable to the controlled fluoridation of water supplies. Fluoride-specific electrode
is used for water and urine analysis.

IODINE (I)
The basic element for the synthesis of thyroid hormones. It is transported to the
thyroid follicles, where it is trapped and concentrated. The gland is stimulated by the
pituitary hormone, thyroid-stimulating hormone (TSH), to incorporate iodide into
tyrosine to form thyronines within the thyroglobulin in the follicular lumen. Proteolytic
cleavage of the thyroglobulin releases the iodothyronine hormones into the circulation.
With blockade of iodine uptake by antithyroid drugs such as propylthiouracil, the
glandular iodide concentration can reach 800 times the plasma iodide concentration. A
tightly controlled feedback system among the thyroid, the hypothalamus, and the
pituitary maintains the thyroid hormone concentration within physiologic limits.

Deficiency results in inadequate thyroid hormone and hypothyroidism.

Depending on the patient’s age, congenital hypothyroidism causes mental retardation
and cretinism. Adults with myxedema hypothyroidism have mental status changes and
hypotension. Patients often develop a goiter.

IRON (Fe)
The fourth most abundant element in the earth’s crust and the most abundant
transition metal. Although highly abundant in the earth’s crust, iron is classified as a
trace element in the body. Iron ions are able to participate in redox chemistry in both
the ferrous and ferric states, allowing iron to fill numerous biochemical roles as a carrier
of other biochemically active substances and as an agent in redox and electron transfer
reactions.

Body iron is present in hemoglobin, myoglobin, storage iron, and tissue iron.
Iron is stored as ferritin and hemosiderin. Normally, very small amounts of iron are
present in most cells and in body fluids. There is no excretory system for excess iron.
Rather, rigorous conservation of iron occurs. Ferritin is present in nearly all cells in the
body. In hepatocytes and macrophages of the marrow, ferritin provides a reserve of iron
for the formation of hemoglobin and other heme proteins. Hemosiderin is formed when
ferritin is broken down. Iron is transported from one organ to another by the transport
protein apotransferrin.

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Iron deficiency affects about 15% of the worldwide population. Those with a
higher than average risk of iron deficiency anemia include pregnant women, young
children, adolescents, and women of reproductive age. Primary Fe overload is most
frequently associated with hereditary hemochromatosis (HH). HH is a single-gene
homozygous recessive disorder leading to abnormally high Fe absorption, culminating
in Fe overload. HH causes tissue accumulation of iron, affects liver function, and often
leads to hyperpigmentation of the skin. Secondary Fe overload may result from
excessive dietary, medicinal, or transfusional Fe intake or due to metabolic dysfunction.
Hemosiderosis has been used to specifically designate a condition of iron overload as
demonstrated by an increased serum iron and total ironbinding capacity (TIBC) or
transferrin, in the absence of demonstrable tissue damage.

Disorders of iron metabolism are evaluated primarily by packed cell volume,

hemoglobin, red cell count and indices, total iron and TIBC, percent saturation,
transferrin, and ferritin. Measurement of serum iron concentration refers specifically to
the Fe(3+) bound to transferrin and not to the iron circulating as free hemoglobin in
serum. Early morning sampling is preferred because of the diurnal variation in iron
concentration. Specimens with visible hemolysis should be rejected. TIBC refers to the
theoretical amount of iron that could be bound if transferrin and other minor iron-
binding proteins present in the serum or plasma sample were saturated. Typically, only
one-third of the iron-binding sites on transferrin are saturated. Percent saturation, also
called the transferrin saturation, is the ratio of serum iron to TIBC. The normal range
for this is approximately 20% to 50%, but it varies with age and sex. Transferrin is
measured by immunochemical methods such as nephelometry. Transferrin is increased
in iron deficiency and decreased in iron overload and hemochromatosis. Ferritin is
measured in serum by various immunochemical methods. Ferritin is decreased in iron
deficiency anemia and increased in iron overload and hemochromatosis.

MANGANESE (Mn)
It is the12th most abundant element in the earth’s crust, found in over 250
minerals, of which 15 have commercial importance. Associated with the formation of
connective and bony tissue and carbohydrate and lipid metabolism. Food sources
include wholegrain foods, nuts, leafy vegetables, soy, and teas.

Roughly, 2% to 15% of dietary manganese is absorbed in the small intestine and

transported to the liver, bound to albumin. Excretion occurs via bile into feces.
Manganese is a constituent of many important metalloenzymes, including superoxide
dismutase, pyruvate carboxylase, arginase, and glycosyl transferases. On a normal diet,
deficiency has not been documented. Diet deficiency results in low plasma cholesterol,
impaired glucose tolerance, skeletal abnormalities, dermatitis, color changes in hair,
and reduced blood-clotting function not responsive to vitamin K.

Manganese toxicity causes nausea, vomiting, headache, disorientation, memory

loss, anxiety, and compulsive laughing or crying. Chronic manganese toxicity resembles
Parkinson’s disease with akinesia, rigidity, tremors, and mask-like faces. A clinical

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condition named locura manganica (manganese madness) was described in Chilean

manganese miners with acute manganese aerosol intoxication.

Manganese is measured by ICP-MS and GFAAS. Urine manganese is used in

conjunction with serum manganese to evaluate possible toxicity or deficiency.

MOLYBDENUM (Mo)
Is a hard, silvery white metal occurring naturally as molybdenite, wulfenite, and
powelite. Molybdenum is an essential trace element with the importance of
molybdenum-containing organic compounds in biological systems identified over 80
years ago. Is incorporated into metalloenzymes and several important enzymes,
including sulfite oxidase and xanthine dehydrogenase.

Between 25% and 80% of ingested molybdenum isabsorbed predominately in the

stomach and small intestine, with the majority of absorbed molybdenum retained in the
liver, skeleton, and kidney. Molybdenum can cross the placental barrier, and increased
intake of molybdenum in the diet of the mother can increase its level in the liver of the
neonate.

Deficiency has not been observed in healthy people on a normal diet. Dietary
molybdenum deficiency is rare with a single case reported because of total parenteral
nutrition in a man with Crohn’s disease. Molybdenum toxicity is rarely reported, as
there are few known cases of human exposure to excess molybdenum. High dietary and
occupational exposures to molybdenum have been linked to elevated uric acid in blood
and an increased incidence of gout.

Diagnosis of molybdenum deficiency is based on demonstration of excess sulfite

in the urine. Molybdenum compounds have low toxicity in humans. Excess intake
induces copper deficiency, blocking copper absorption. Molybdenum levels are
measured by ICP-MS and GFAAS. Blood levels are less than 60 μg/L.

SELENIUM (Se)
A naturally occurring metalloid with many chemical and physical properties
similar to those of sulfur. Selenium is an essential trace element and a major constituent
of 40 minerals and a minor constituent of 37 others. Selenium is a constituent of
glutathione peroxidase that is associated with vitamin E in its functions. It is a nonmetal
and is important in defense against oxidative stress and regulation of thyroid hormone
action.

Selenium is well absorbed from the gastrointestinal tract (50%). Selenium

homeostasis is largely achieved by excretion via urine and feces. Other routes of
elimination include sweat and, at very high intakes, exhalation of volatile forms of
selenium.

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In the 1930s, selenium was considered a toxic element, in the 1940s, a carcinogen,
in the 1950s, it was declared as an essential element, and since the 1960s and especially
the 1970s, and it has been viewed as an anticarcinogen. Glutathione peroxidase (in the
form of selenocysteine) is part of the cellular antioxidant defense system against free
radicals and selenium is also involved in the metabolism of thyroid hormones.

Selenium deficiency has been associated with cardiomyopathy, skeletal muscle

weakness, and osteoarthritis. A significant negative correlation was observed between
selenium intakes and the rate of cancer of the large intestine, rectum, prostate, breast,
ovary, and lungs and leukemia. Keshan disease, an endemic cardiomyopathy that affects
mostly children and women in childbearing age in certain areas in China, has been
associated with selenium deficiency with low soil selenium levels, as well as skeletal
muscle disorders with prosimal weakness and serum creatinine elevation. Kashin-Beck
disease, an endemic osteoarthritis that occurs during adolescent and preadolescent
years, is another disease linked to low selenium status in northern China, North Korea,
and eastern Siberia.

Acute oral exposure to extremely high levels of selenium may produce

gastrointestinal symptoms (nausea, vomiting, and diarrhea) and cardiovascular
symptoms such as tachycardia. Chronic exposure to very high levels can cause dermal
effects, including diseased nails and skin and hair loss, as well as neurologic problems
such as unsteady gait or paralysis. Toxicity from selenium includes hair loss, garlic
breath, irritability, and mild nerve and nail damage.

Selenium is most often determined by ICP-MS or GFAAS. The determination of

urinary and blood selenium is a useful measure of selenium status.

ZINC (Zn)
Second to iron as the most abundant trace element in the body. It is the most
common catalytic metal ion in the cytoplasm of cells. A bluish white, lustrous metal
that is stable in dry air and becomes covered with a white coating when exposed to
moisture. Zinc is an essential trace element and deficiency is common throughout life,
especially in individuals that do not ingest meat.

Total body stores of zinc are 1.5 g in adult women and 2.5 g in men, which are
distributed in all tissues. It is almost entirely intracellular. Most zinc is in skeletal muscle
(~60%) and bone (~30%). It is a cofactor for almost 300 enzymes and is involved in
almost all aspects of metabolism. Zinc is important in protein and nucleic acid synthesis
and essential for gene activation. It is also essential for the synthesis and action of
insulin. Zinc is only in the divalent state in biological systems, and oxidationreduction
functions are not possible. Important zinc-containing metalloenzymes include carbonic
anhydrase, alkaline phosphatase, RNA and DNA polymerases, reverse transcriptase,
thymidine kinase, carboxypeptidases, alcohol dehydrogenase, and superoxide
dismutase.

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The main biochemical role of zinc is seen in its influence on the activity of more
than 300 enzymes in classes such as oxidoreductases, transferases, hydrolases, leases,
isomerases, and lipases. Zinc deficiency causes growth retardation, slows skeletal
maturation, causes testicular atrophy, and reduces taste perception. Zinc is relatively
nontoxic. Nevertheless, high doses (1 g) or repetitive doses of 100 mg/d for several
months may lead to gastrointestinal tract symptoms, decrease in heme synthesis due to
an induced copper deficiency, and hyperglycemia. Exposure to ZnO fumes and dust may
cause “zinc fume fever,” with symptoms including chemically induced pneumonia,
severe pulmonary inflammation, fever, hyperpnea, coughing, pains in legs and chest,
and vomiting.

Zinc deficiency is common in patients with diabetes mellitus, alcohol abuse,

malabsorption syndromes, and liver and kidney diseases. Symptoms are general because
of the many enzymes and tissues affected. In severe deficiencies there is hypogonadism,
dwarfism, deformed bones, poor wound healing, abnormal hair and nails, loss of taste,
gastrointestinal disturbances, poor chylomicron formation, CNS abnormalities,
immunodeficiencies, and malabsorption. Nutritional zinc deficiency is fairly prevalent
despite the wide availability of zinc in foods. Zinc deficiency produces a syndrome of
growth retardation, male hypogonadism, skin changes, mental lethargy,
hepatosplenomegaly, iron-deficiency anemia, and geophagia (eating clay). Zinc
deficiency has also been reported in old age, pregnancy, lactation, steatorrhea, extensive
burns, and renal disease, and diuretic and antimetabolite therapies. Zinc deficiency in
alcoholics and in cirrhosis shows low serum zinc concentrations and demonstrates
increased urinary excretion. Acrodermatitis enteropathica is a rare autosomal recessive
disorder with impaired intestinal absorption and transport of zinc.

There is no single test that is definitive for the status of zinc stores. The two
groups of tests include analysis of zinc in a body tissue or body fluid, such as plasma,
serum, blood cells, or urine, and testing a zinc-dependent function, such as taste acuity
or the measurement of the activity of zinccontaining enzymes. Zinc is measured by
FAAS, ICP-AES, and ICP-MS. Low urine zinc levels in the presence of low serum zinc
levels usually confirm zinc deficiency. The estimated average requirement to maintain
adequate stores is 8 mg/day for women eating a mixed diet and 11 mg/day for men.

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