/. C/J/-0/7. £>is. 1965, Vol. 18, pp. 217-228. Pergamon Press Ltd.

Printed in Great Britain

Editorial
i

THE BIOLOGICAL TRACE ELEMENTS

OR

PERIPATETICS THROUGH THE PERIODIC TABLE*

(Received 30 -4^w.tf 1964)

THE essential trace elements are more important in the nutrition of living things than
are their organic micronutrient counterparts, the vitamins. They cannot be synthe-
sized, as can the \itamins, but must be present in the environment within a relatively
narrow rar.se of concentration. Both deficiencies and excesses kill. They cannot be
metabolized, although they can, and often do, change their valences. Their only
sources are the earth's crust and sea water, and without them life would cease to exist.
A trace element can be defined as one comprising less than 0.01 per cent of the
organism, s. definition not always applicable when high concentrations occur in special
cases. An essential element has been strictly denned as one without which the organism
cannot exist. This definition requires broadening to include those elements without
which the organism cannot maintain optimum growth, health and longevity, which
perform physiological functions desirable for normal metabolism, and without which
disease occurs.
It is no accident that more than 99 per cent of the structure of living things is com-
posed of 12 bulk elements from the first 20 in the Periodic Table. Life depends upon
availability in the environment, and there is an inverse relationship between atomic
number and abundance of an element in the universe and on the earth's crust. There-
fore, it appears to be no accident that the trace elements which have known favorable
biological activities are found in the first half of the Periodic Table, among those with
atomic numbers 22 to 42, the one exception being iodine, No. 53.
Although our interest lies primarily in mammals and especially in man, we must
remember that the major sources of all trace and bulk elements for terrestrial animals,
except for the gases, are plants or marine animals. The latter live in a relatively con-
stant environment, ihe former do not. Variations in concentration of many minor and
some major elements occur from one area to another of the earth's crust, some result-
ing from natural causes and some induced by living organisms, including man.
•This work was supponed by Grant HE-05076 from the National Institutes of Health, United States
Public Health Service, Bethesda, Maryland; the Vermont Heart Association and Ciba Pharmaceuti-
cal Products, L-c.
Requests for reprints should be addressed to Dr. Henry A. Schroeder, 75 Linden Street, Brattleboro,
Vermont, U.S.A.
217
218 HENRY A. SCHROEDER

TABLE 1. BIOLOGICALLY IMPORTANT ELEMENTS IN SEA WATER, ON THE EARTH'S CRUST AND IN MAN
(by weight)

Human body
Sea water 1Earth's crust
o/
/o /o /o g 70 kg

MAJOR ELEMENTS
Chlorine 1.9 0.02 0.15 105
Sodium 1.05 2.83 0.15 105
Magnesium 0.135 2.09 0.05 35
Sulfur 0.0885 0.52 0.25 175
Calcium 0.04 3.63 1.5 1050
Potassium 0.038 2.59 0.2 140
Bromine 0.0065 0.0003 P P
Strontium 0.0008 0.045 0.0002 0.140
Boron 0.00046 0.0016 <0. 000014 <0.01
Phosphorus 0.000007 0.118 1.0 700

Total 3.26* 11.84: 3.301 23101

p.p.b. p.p.m. p.p.m. mg'70kg

MINOR ELEMENTS
Fluorine 1300 700 P P
Silicon 10-4000 277,200 P P
Aluminum 3-2400 81,300 1.4 100
Rubidium 120 120 17 1200
Lithium 100 30 P P
Iodine 50 0.3 0.43 30
Molybdenum 12-16 1 <0.07 5
Zinc 9-21 65 33 2300
Barium 6 400 0.23 16
Lead 4-5 15 1.1 80
Selenium 4 0.09 P P
Iron 3.4 50,000 57 4100
Tin 3 3 0.43 30
Uranium 3^3 2 0.0003 0.02
Vanadium 2.4-7 110 0.3 20
Cesium 2 1 <0. 00014 <0.01
Arsenic 1.6-5 2 < 1 .4 <100
Nickel 1.5-6 SO <0.14 <10
Titanium 1-9 4400 <0.21 <15
Copper 1-25 45 1.4 100
Chromium 1-2.5 200 <0.09 <6
Manganese 0.7-1 1000 0.3 20
Antimony 0.2 0.2 <1.3 <90
Cobalt 0.1 23 <0.04 ~3
Silver 0.15 0.1 <0.01 <1
Cadmium 0.03 0.2 0.43 30
Mercury 0.03 0.5 P P
Gold 0.004 0.005 <0.01 <1
Thorium 0.001 10 7 ?
0.3X10- 10 1 xlO- 1 1 1.4xlO- 13 10 -io
Radium

Elements in italics are essential or probably essential for mammals.

Data on sea water and earth's crust from MASOX [1], on rnan from 1CRP Committee Report [2].
p=Present, but amounts not estimated because of insumcient data.
*With sulfate, borate and bicarbonate the total is 99.99 per cent of the solids.
tOxygen makes up 86.60 of the earth's crust, and with major elements, the total is 98.60 per cent.
JOxygen, nitrogen, carbon and hydrogen make up 96 per cent of the human body. With the major
elements, the total is 99.3 per cent and 69.51 kg in a 70 kg man.
 Editorial 219

Paleobiological speculation may be rewarding at this point. At some Jurassic time

when the first terrestrial vertebrate, our ancestor, left the littoral, the problems he met
were enormous. The new environment, as it does now, contained an abundance of
sodium, potassium, magnesium, calcium, and a super-abundance of silicon, aluminum,
iron, titanium, cobalt, manganese, chromium, fluorine, rubidium and barium. It was
partly or relatively deficient in chlorine, bromine, iodine, selenium, molybdenum and
boron; a paucity of water was obvious (Table 1). Sodium was not evenly distributed;
the vertebrate's chordate predecessors, however, had learned to handle it well during
their evolution in fresh water beginning in Silurian times, and his new impervious skin
prevented death from dessication. It apparently took him about 250 million years to
make this move from water to land.
In respect of certain trace elements there was also uneven distribution. Whereas
strontium, vanadium, chromium, manganese, iron, copper and zinc were fairly
ubiquitous, they varied in crustal and vegetal concentrations from place to place,
depending upon solubility and leaching by rainfall. Cobalt, boron and molybdenum
were not distributed uniformly. Therefore, in order to survive, this land-based
animal had to learn to conserve essential elements in the face of deficiencies and to
reject excesses which could be toxic. When his descendants became mammals,
specialized homeostatic mechanisms were highly developed; out of a large body pool
of iron, for example, only about 0.025 per cent is absorbed and excreted daily by man.*
We do not know when the use of trace elements as cofactors became evolutionarily
fixed. The bulk elements undoubtedly were incorporated into living things during the
most primitive stage of life: potassium and sodium from the beginning, calcium and
silicon when structure became necessary, magnesium with motility, all four cations and
phosphorus with the appearance of irritability. Metabolic processes dependent on
iron and copper, and promoting oxidation, must have appeared very early in evolution,
long antedating their specialized functions of carrying oxygen in a circulating medium.
With increasing cellular specialization, however, came the need for more sophisticated
enzymatic reactions, and a variety of transitional elements were available to act in
many anabolic and catabolic processes. When the motile invertebrate with the
primitive gut evolved, in Infra-Cambrian times, the hepatopancreatic anlage became
the principal metabolic organ. Excretory ducts not only fulfilled an exocrine function
but also served for excretion of absorbed minerals. Excretion was mandatory, for all
trace metals have affinities for proteins and in varying amounts can be toxic.
Bertrand's Law of optimum nutritive concentration of essential elements states
that a plant cannot Jive with a deficiency whereas an excess is toxic. This Law applies
to all types of living cells, and to those whole animals which have poorly developed
homeostatic mechanisms, such as fresh and salt water invertebrates, fish and amphi-
bians, and are susceptible to toxic exposures. This Law applies to mammals, toxicity
being readily induced by injection of cationic elements, although they are less suscep-
tible to oral exposures. There were no deficiencies in the primitive sea, but
cellular excesses occurred whenever a tissue concentrated an element above
that in the environment. COTZIAS and PAPAVASILIOU [3] have recently demonstrated
The efficiency of this homeostatic mechanism becomes clear when one considers the enormous
volume of fluid excreted into and absorbed from the human gastrointestinal tract daily, and the
ready absorption therefrom of molecules much larger than those of iron salts.
 220 HENRY A. SCHROEDER

that manganese is excreted in bile and pancreatic juice, and propose the idea that
because the hepatopancreatic anlage long antedates the kidney, manganese had
significant biological functions in the earlier forms of invertebrate life and required a
homeostatic mechanism based on this primitive method of excretion.
The kidney is obviously a more efficient vehicle for excretion than are the liver and
pancreas. Not until Silurian times did primitive pre-chordates invade the fresh water
of rivers. By that time, the electrolytic composition of extracellular fluids had become
fixed by the composition of major salts in the sea. That new environment, in our
frame of reference, contained all of the elements found in sea water, but in very dilute
amounts. Principally because of the relative lack of sodium and potassium in river
water, the kidney became necessary in order to excrete excess water and retain the
small amount of sodium contained in it. Upon the kidney was also placed the burden
of excreting or retaining calcium and magnesium, as well as the halogens. Perhaps this
organ's equivocally active role toward potassium can be laid to the relative abundance
of this alkali metal in fresh water and in plants, as much as to its fairly constant
intracellular content.
It is hard to conceive that entirely new metabolic systems based on such fundamental
reactions as those exhibited by trace metals have evolved recently. A metal is a metal
and has always been so; its reactivity is predictable and cannot change. It has always
been present in the living environment. Although an almost infinite variety of proteins
are possible, and new enzyme systems can evolve in response to metabolic needs, the
reactions in which metals can take part are relatively limited and very basic. There-
fore, metabolically active trace metals and other elements may have been fixed in the
first Eocene primate and other mammals with virtually little change during the past
many million years. Furthermore, the types of reactions which they catalyze (oxi-
dation, reduction, hydrogenation, dehydrogenation. deamination. cyclization, hydroxy-
lation) were used by living matter since the beginning of life or when the need for the
reactions evolved.
In this light, when we examine the known major routes of excretion of the various
elements present in man and taken in foods and fluids, we find (Table 2) that alkali
metals, alkaline earths and anions are excreted by the kidney whereas cationic trace
metals are excreted by the gut. The sparse but toxic metal cadmium is also excreted
by a later evolutionary organ, the kidney, whereas the only non-metal excreted
principally into the gut is tellurium.* Furthermore, the relative toxicities of non-
essential cations and anions excreted by the kidney, except cadmiumf, are low
(lithium, rubidium, cesium, borate, fluoride, silicate, arsenate, bromide, germanate and
niobate), as might be expected when all body cells are directly exposed.
A second law concerning absorption is discernible, although in places somewhat
dimly. This Law states: Absorption of trace metals by living things from (he environ-
/I
*In this recitation we do not include the excretory routes of injected metals, which usually appear in
the urine to greater or less extent, as well as in the gut. Normal excretory mechanisms were developed
before the invention of the hollow needle, which has allowed extensive testing of Bertrand's Law as
applied to mammals, and indicates that all metals can be toxic when in contact with cells.
fThe idea that metallothionein, a zinc- and cadmium-binding protein in mammalian liver and kidney
[5], may have evolved fairly recently as a protective mechanism against cellular toxicity, has been
proposed by PISCATOR [6].
 Editorial 221

ntent is inversely related to the concentration of environmental calcium. This Law

applies to plants, lower animals, fish, and in so far as is known, to mammals.

TABLE 2. PRINCIPAL ROUTE OF EXCRETION OF SOME ELEMENTS OF BIOLOGICAL SIGNIFICANCE AFTER ORAL
INGESTION BY MAMMALS INCLUDING MAN

Intestine Kidney

Metals Metals Non-metals

4 Beryllium 31 Gallium 3 Lithium 5 B orate

13 Aluminum* 40 Zirconium* 11 Sodium 9 Fluoride
22 Titanium 46 Palladium 12 Magnesium 14 Silicate
23 Vanadium 47 Silver 19 Potassium 15 Phosphate
24 Chromium 49 Indium 20 Calcium 16 Sulphate
25 Manganese 50 Tin* 32 Germanate 17 Chloride
26 Iron 51 Antimony 37 Rubidium 33 Arsenate
27 Cobalt 56 Barium 38 Strontium 34 Sclenite
28 Nickel 57 Lanthanum* 41 Niobate 35 Bromide
29 Copper SO Mercury 42 Molybdate 53 Iodide
30 Zinc 82 Lead 48 Cadmium
Non-metals 55 Cesium
52 Tellurium

Atomic numbers of the elements are shown.

Excretion by intestine includes that fraction presumably excreted in bile and intestinal secretions, as
\vell as that fraction which is unabsorbed from intestine. Elements with poor absorption are indicated
by an asterisk. Excretion by kidney indicates good absorption from intestine. These considerations
are based on 'usual" amounts ingested in food and fluids and do not include toxic doses. Elements
considered essential for mammals are in italics.
Data largely from BROWNING [4].

1. Plants. In Table 3 are summarized the metals affected by calcium, lime, orpH
of the soil. Agronomists recognize metal deficiencies in crops caused by over-liming,
especially of manganese, iron and zinc. LOUNAMAA [7] sho\ved clearly that vegetation
growing wild on calcareous soils (containing much calcium) contained less of nine
elements than did vegetation growing on silicic and ultra-basic soils low or deficient in
calcium. Metal to.xicity to plants, notably from chromium and nickel, has been
observed in serpentine soils high in magnesium and deficient in calcium, or in other
soils allowed to become acid and calcium-depleted.
2. Lower animals. Copper is more toxic in soft water than in hard (calcium-
containing) water to Crustacea, molluscs, insects and zoo-plankton. Zinc is four times
as toxic to snails in soft as in hard water [9].
3. Fish. Many studies have shown that metal ions are less toxic to fish in hard
water than in soft (Table 4). Calcium is the principal component making up hardness
of water, with magnesium filling a lesser role; whereas it is possible that magnesium
maybe the active protectanr, the ratio Ca: Mg is high in all waters and the two are
biologically antagonistic.
4. Higher animals. The most clear-cut experiments concern the production of
zinc deficiency in swine by high calcium intakes. The requirements of sheep for copper,
of chicks for manganese and zinc, and of rats for zinc are increased by calciumin the diet
[10]. Whether or not absorption of other trace metals is affected by calcium in the
222 HENRY A. SCHROEDER

TABLE 3. ABSORPTION OF TRACE ELEMENTS BY PLANTS ACCORDING TO AMOUNT OF CALCIUM is SOIL

No calcium Low calcium Highcal ciurn

Source Decreased
Increased Decreased Increased Decreased Increased

LOUNAMAA (by Boron

analysis) [7] Boron Gallium Manganese Chromium
Chromium Copper Cobalt Chromium
Cobalt Zinc Nickel Manganese
Nickel Zirconium Molybdenum Cobalr
Copper Silver Xickel
Molybdenum Cadmium Copper
Lead Lead Zinc
Zirconium
Lead

CARLISLE and Aluminum

CLEVELAND [8] Aluminum
Iron Calcium
Manganese Magnesium
Copper Sodium
Zinc Potassium
Boron Molybdenum
Tungsten
Selenium
Silicon
Barium

Soils analyzed by LOUNAMAA t / j wcic^ia^m^u..^^,.^..^.^ v

silicic (granite, gneiss, feldspar, pegmatite, quartz) low in calcium, and ultrabasic (serc-emine, talc)
with little or no calcium, but high in magnesium. There were 819 specimens of plants, 134 soils and
268 rocks analyzed. Uptakes of chromium, cobalt, nickel and molybdenum were especially sensitive
to calcium. Elements in italics represent highest or lowest values. CARLISLE and CLEVELAND [s] list
uptakes from acid and basic soils; aluminum is absorbed in two ranges of pH.

intestine remains to be determined, although iron appears not to be so influenced in

rats [11]. Aqueous permeability of the rat intestine is depressed by calcium and
magnesium [12]. Table 5 shows these effects.
There has been little or no need for efficient repulsive mechanisms towards essential
trace metals in fresh-water and marine animals, because toxic amounts have appeared
locally in river and sea water only during the past few hundred years. Calcium in these
media acts, therefore, as an external mediator of absorption.
There are diverse opinions on the mechanism by which calcium decreases the uptake
of trace elements. Formation of insoluble salts, binding by soil, alkalinity, lessened
'availability,' increased excretion, have been proposed as explanations, none of them
completely tenable. Because of this apparently universal effect upon cations (boron in
plants appears to be the only anion so affected), there may be a cellular transport
mechanism common to living things which is saturated by calcium ion, regulating
exchange of other cations from the immediate environment. Such a basic mechanism
remains to be investigated.*
"If this mechanism functions in man, and if abnormal trace metals aie implicated in cardiovascular
diseases [13], the curious inverse association of hardness of municipal water supplies and cardio-
vascular mortality, demonstrated in Japan, England, South Africa, the Canary Islands, Australia and
the United States [9] may be partly explained.

wjra" it.
.•!?**•*%•>•
"*'" "
 Editorial 223

TABLE 4. TOXICTTY OF METALLIC AND NON-METALLIC IONS TO FISH IN SOFT AND HARD WATER

Metal Atomic Ratio, toxic concentration Approximate toxicity in

No. in hard: soft water soft water (p.p. m. water)

Beryllium* 4 10-100 <0.2

Borate 5 1.0 19,000
Fluoride 9 10 100
Magnesium 12 <1 5000
Aluminum 13 2 500
Titanium* 22 14.6 8
Vanadium* 23 4.2-9.2 5
Chromium 24 15 5
Manganese 25 — 2400
Iron 26 77 1.3
Cobalt 27 100 10
Nickel* 28 24 4
Copper* 29 15-500 <0.1
Zinc 30 3-67 2
Selenite 34 0.1 100
Zirconium* 40 8.2 14
Molybdenum* 42 5,3 70
Cadmium* 48 5.5 <0.1
Tin 50 ±4 1
Antimony 51 0.6 20
Lead* 82 33 2
Uranium* 92 48 3

Data from Water Quality Criteria [9].

*Studies of TARZE\\TLL and HENDERSON, reported in Ref. [9], on 2 species of fish, are strictly
comparable; soft water had 20 p.p.m. hardness and hard water had 400 p.p.m.

Various other interactions of essential trace elements have been described [14],
usually involving large doses and marginal deficiencies. Furthermore, there are
several examples of displacement of an essential element by a non-essential one, either
in the same or a contiguous periodic group, in cells and tissues. The result could
produce a conditioned deficiency.
One significant phenomenon appears in mammals. The body alters the valence of a
soluble metal to that required, during or after absorption from the intestine. This

TABLE 5. EFFECT OF CALCIUM ON ABSORPTION OR UTILIZATION OF TRACE ELEMENTS BY HIGHER ANIMALS

Species Element High calcium intake

Chick Manganese Decreased

»» Zinc H
Mouse Iron Decreased
Rat Iron Decreased
••
Zinc ii
»> Iodine ,,
Pig Manganese Decreased
»> Zinc »»
Rabbit Manganese Decreased
Sheep Copper Decreased

From DAVIS [14] and UNDERWOOD [10].

Animals on a marginal intake of the element became deficient when dietary calcium was elevated.
Deficiency was overcome by feeding the element.
224 HENRY A. SCHROEDER

phenomenon has been demonstrated for manganese, iron, cobalt, and copper and
partly for chromium.
Man is not excepted from the need for inorganic micronutrients. But modern man,
in his hubristic wisdom, has changed his exposures to them in several ways. Pastures
are over-grazed, resulting in depletions which are only partly restored by fertilization,
and giving rise to a number of deficiency diseases in cattle and sheep. Soils are over-
cropped, removing micronutrients, some of which are restored by fertilizers and others
of which are unrecognized, being not necessary for the growth of plants. Foods are
processed, and major sources of carbohydrates, the grains, are refined by removing the
germ in which micronutrients are concentrated; inorganic ones are not restored.*
Furthermore, a series of non-essential elements in larger than normal concentrations
have been mined from mineral deposits and introduced into the environment, into food,
water and air. Industry has released them into rivers and seas and into the air; foods
are exposed and absorb them or they are deliberately added; they are ingested from
potable waters and from marine and fresh-water foods which concentrate them from
contaminated waters near the mouths of rivers. These exposures began with the
Bronze Age, have become widespread only in the past few hundred years and have
increased enormously during the past hundred. Urban air in this country contains 6
essential and 7 non-essential or toxic metals.t Many of these elements accumulate in
man with age, especially in lung, kidney, liver and aorta.
If trace elements are related to human disorders, they can be considered in two
categories: (a) as micronutrients. and (b) as accumulating environmental contamin-
ants. Homeostatic mechanisms undoubtedly exist for essential micronutrients as
requisites for terrestrial existence, just as they do for bulk elements, conserving in the
face of inadequate intakes and excreting or rejecting excesses in food and water; they
may be overcome by large exposures. Poorly developed mechanisms exist for anions,
although in certain cases accuirudation in specialized structures can occur (bone, skin,
hair, nails, for fluorine, selenium and arsenic are examples).
In the spectrum of toxicity of accumulating trace elements, there is a wide band
which is largely unexplored. Overt toxicities have been reasonably well studied, both
experimentally and clinically from occupational exposures [4]. Sub-clinical toxicities,
however, from 'usual' exposures and possibly influencing a variety of chronic diseases
of older persons, have been little studied. It is in this band that we are interested.
In theory, three general types of naturally occurring disease can be expected.!
Type I. Deficiencies of essential elements
(a) Simple deficiencies. In man inadequate intakes of iron, iodine, and possibly
copper, are recognized, but deficiencies of molybdenum, zinc and cobalt, which occur
in other mammals, are not. Essential elements not now considered so may initiate
deficiency diseases. For example, chromium deficiency produces latent diabetes
*At least one imbalance could occur from this practice. The germ contains most of the zinc; the
kernel and germ contain similar concentrations of cadmium. Continual ingestion of refined flours
and polished rice might cause a disturbed Cd: Zn ratio in tissues, especially kidney.
tin urban air samples in the United States have been found chromium, copper, iron, manganese,
zinc and molybdenum, as well as lead, nickel, tin, titanium, antimony, bismuth and cadmium [15].
JThe problem is not as simple as this, but must be approached simply at present. A confusing variety
of altered metal patterns in various organs have been found, in cancer, rheumatoid arthritis and
sarcoidosis, for example, indicating many interactions of metals in diseased states. Normal standards
however, are just beginning to be found. Methodological differences are often apparent and the
need for uniform techniques is real.
 •'••Ti.rT= "5T!?;-:
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Editorial 225

mellitus in rats. Chromium decreases in all tissues but lung with age and deficiencies
in man may be expected [16]; early adult diabetes mellitus has been influenced by
feeding small amounts [17J.
(b) Secondary to other disorders: Malabsorption, depletion through excessive
excretion or decreases in carriers of the blood may result in a variety of deficiencies
which may or may not contribute to the primary disorder. Zinc is depleted in protein-
uria and Laennec's cirrhosis of the liver. Copper deficiency occurs in chronic hypo-
proteinemia [18].

Type II. Excesses of the essential elements

(a) Accumulating because of inborn errors of transport systems. Failure of
homeostatic mechanisms to reject intestinal excesses are probably responsible for iron
accumulation leading to hemochromatosis and copper accumulation leading to
hepatolenticular degeneration.* Similar hereditary or congenital diseases dependent
upon anions are unlikely, because of urinary excretion. Disorders of these mechan-
isms for chromium, vanadium, and perhaps cobalt and zinc, are possible. Similarity of
manganese toxicity by inhalation of dust in mines and Parkinsonism has been noticed
[19], but evidence of accumulation in the latter condition is not known.
(b) Accumulating because of large dietary intakes and increased absorption or
decreased excretion resulting from other disorders: Bilary obstruction can prevent
excretion. Renal insufficiency may lead to accumulation of anions, such as arsenic,
selenium, bromine, iodine and molybdenum. In local disorders of the intestinal tract
or in the presence of low dietary calcium, iron and copper may be excessively absorbed,
»v^&
and perhaps others.
(c) During the aging process, internal shifts in essential metallic content of organs
may occur. Calcium accumulates in aorta, kidney, prostate, thyroid and trachea with
age. Copper decreases in aorta, whereas iron increases in brain, kidney, lung, larynx,
pancreas, spleen and testes. Zinc accumulates in prostate and is depleted in uterus [20].
The meaning of these changes is obscure.

Type III. Disorders caused by metals for which there are poor homeostatic mechanisms
and which accumulate in man with age
Cadmium in kidney has been linked to hypertension [21,22]. Lead causes excessive
mortality in small mammals at human tissue concentrations [14, 23, 24]. Lead and
cadmium increase aortic Jipids in rats; chromium appears to act contrariwise [25].
Fluoride accumulates at every level of intake and produces abnormalities of bone when
intakes are high. Tin accumulates with age in the heart, lung, prostate, trachea and
uterus of Americans, but is inconsistently found in Africans [26].
In addition, the lung, a portal of entry from the gaseous environment, is especially
prone to accumulate metals [27] found in air, either naturally or from industrial
sources. These include aluminum, chromium, iron, lead, nickel, strontium, tin,
titanium and vanadium. Aluminum, titanium and vanadium probably are deposited
•It is not beyond the bounds of possibility that a deficient transport system may allow accumulation of
several trace metals, the principal one causing toxicity being that with the highest environmental
exposure. Specificities of transport mechanisms have not been investigated thoroughly, except for
iron; there may be only a few such systems, each transporting several transitional elements with
similar ionic radii. The basic laws of chelation, which show that no ligand is specific for one metal,
lend support to this idea.
226 HENRY A. SCHROEDER

as insoluble contaminants, whereas lead and tin are probably absorbed. There are no
known effects of these metals on lung.
Awareness of the possibility that certain metals may be linked to certain diseases is a
sine qua non of discovery. A metal accumulating with age in man is suspect of causing
Type III disorders, especially when it is non-essential, relatively toxic in larger
amounts, reactive chemically, capable of competing for binding sites on proteins, and
has appeared in the environment in greater than usual quantities within the last five
thousand years. Such age-linked disorders as adult diabetes mellitus, atherosclerosis,
hypertension, rheumatoid arthritis, certain malignant conditions and diseases of
nervous origin need be investigated from this viewpoint. Changes common to civilized,
but not to uncivilized man, such as the rise of blood pressure and circulating cholesterol
with age are also suspect.*
The elements deserving consideration at present are lead, tin, cadmium, barium,
arsenic, antimony, fluorine, niobium, nickel and lanthanum. The elements which need
testing for essentiality are vanadium, nickel, gallium, germanium, zirconium, bromine,
arsenic and niobium. It is unrealistic to spend time and effort on elements which, (a)
are not detected in the body of man; (b) are detected in such minute amounts that it is
difficult to conceive of their causing abnormalities (such as silver and gold), or, (c)
are known to be relatively inert biologically and chemically. These considerations
narrow the Periodic Table to a reasonable number of elements for investigation in
terms of micronutrients or disease-causing agents.
One is sometimes exposed to the superficial attitude that we are dealing in micro-
gram quantities of metal which can hardly be considered seriously. Three examples
can be offered to dispel such illusions: (a) As little as 1 ug of cobalt per day can control
pernicious anemia; (b) Retention of 3 ug of cadmium per day, of the 25 ug in the
usual American diet, can produce 10 mg in the kidneys after 30 years, a common
occurrence in American adults [28], whereas 5 ug provides an amount exceeding
normal renal zinc; (c) Partial chromium deficiency occurs in rats receiving 1 ug daily
in their diets, but not in those receiving 3 ug. Very little of an abnormal metal competing
with the binding sites of cobalt or chromium in a tissue, as cadmium does for zinc,
would be required to alter the normal catalytic action of the essential metal.
The problem may be briefly stated (Table 6). There are 9 essential inorganic micro-
nutrients for mammals; 7 are metals and 2 are non-metals. Four have been or are
being considered as causing deficiency diseases, and only 3 as causing diseases of
accumulation. There are 10 trace elements with requisite capacities to act as essential
micronutrients for mammals, but which have not been investigated as such, either
because of ubiquity in foods or because of lack of interest; 7 are metals. There are 4
alkali metals or alkaline earths which may exert biological activities, either beneficial or
antagonistic. There are 13 heavier elements to which modern man is exposed; his

*Somehow present concepts of causes of several prevalent chronic diseases fail to satisfy strict
criteria. Ingestion of fats may influence atherosclerosis, but the mechanism or agents promoting
deposition of fats in arterial walls are more important than the fats themselves. Alteration of a tissue
to anerobic glycolysis might explain the onset of metaplasia, but an agent (or lack of one) suppressing
oxidative mechanisms should be sought. There is no normal process of aging resulting in increased
reactivity, such as is found in a rising diastolic pressure. Trace metals logically fulfill these require-
ments. Disorders involving specific degeneration of a tissue and those with strong hereditary aspects
and slow onsets need examination from this viewpoint.
 ^a^ir"
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afe^^^^liffg^lggjy

Editorial
227
ancestors had minimal exposures to at least 7 of these All
or less toxic;
4 are known to accumulate in tissues with age and 6
man s present environment than on the earth' crust 'ncentraled in
influence a disease. so are considered to

TABLE 6.
OUTLINE OF THE PROBLEM—IMPORTANT ELEMENTS IN MODERN MAN REQUIRING INVESTIGATION
r>o;i..
Daily <" ' —
%of Amount Accumu-
Element intake body Chrome Systems or tissue
retained lation disease, affected
frs) pool (Kg) with age
• •—• . type
fiery Ik unit 7 7
•• — ' — _
Boron 7 7 — _
10,000 100 HI Sarcoidosis
Fluorine 0 No n
1000 7 9
Aluminum 36,400 Bone II, III Bone
Silicon 36 6.9 Lung (A)
3500 0.16 4 II, III
Titanium 300 Lung (A) II
2 0.4 Lung (A) Integument
Vanadium 2000 II, III Pigment, ?
Chromium 10 0-0.2 Lung (A)
60 1 I Lipids
Manganese 0-0.3 Lung (A) I, II
5000 25 0 Glucose, lipids
L-on* No I, II
15,000 0.4 0 Brain, several
Cobalt* 75 Lung (A) I, II Blood, storage
Nickel 0.25 0 No
450 4.5 I, II Blood
Copper* No I, II Pigment, ?
2000 2 0 No I, II Storage, liver,
Zinc 12,000 brain, blood
Gallium 0.5 0 No
7 7 7 7 I, II Skin, many
Germanium 7 ? 7
*?
Arsenic 7 7
3500 17.5 7
Selenium 7 No II, III
? 7 XT
No Integument
Bromine 7500 I Muscle
Rubidium 6.3 0 No *?
10,000 0.8 7
Strontium 2000
Kn
i>U *?

Zirconium 1.4 1
Bone
7 7 7 I, II Bone
Niobium *?
600 17 ?
Molybdenum 0 No
i>(_* II
Silverf
1000 25 n\j No
7 ? ty I Purines
Cadmiumf Yes None
25 0.08 3
Indium 7 7 Kidney III
7 7 Hypertension
Tint 4000
Antimony 13 5 Several
7 7 7 III Coagulation ?
Tellurium 7 7 O
7
Iodine* 150 0.5
7
Liver Ilir
Cesium 7 7 r\
No I Goitre
Barium No 7
16,000 100
Lanthanum 7 9
Bone II Bone?
Mercuryf 7 No? 7
5 7 Coagulation
260 Kidney? ?
Leadf 0.3 6 -Several-.
———____ HI Lipids, brain
-,»~_i' i *•
i —~ i
• __
Elements in italics are essential for one or more living organisms.
•Elements reasonably well studied for human disorders.
fEJements probably without physiological function. Information lacking on remainder.
(a) cadmium,
Daily intake
tin measured
and lead. in our laboratory for titanium, vanadium, chromium, nickel, niobium,
Otters estimated from literature, mainly UNDERWOOD [10].
(A) Per cent of body pool calculated from ICRP Report [2].
(c) Amount retained calculated from American values of TIPTON and COOK [27].
(ef) Accumulation with age: (A) == Airborne metal probable.
(e) Type of disease possible, see text.
(f) Systems or tissues affected are those on which some experimental evidence for effect exists; they
do not include overt toxicity in man.
228 HENRY A. SCHROEDER

Possibilities for chronic diseases of older ages resulting from these basic com-
ponents of the earth are therefore multiple. Each deserves investigation in this light,
beginning with life-term studies in small mammals.
HENRY A. SCHROEDER, M.D.
Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire
and Brattleboro Retreat, Brattleboro, Vermont
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