SPECIAL ARTICLE
Cadmium, Chromium, and Cardiovascular
Disease
By HENRY A. SCHROEDER, M.D.
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SUMMARY
Observations made in the last 15 years by the author and others concerning the effect
of trace metals, particularly cadmium and chromium, on animals and man are reviewed
with special reference to hypertension and atherosclerosis. These trace metals come
from the soil or sea. Among the topics covered are cadmium hypertension in rats,
diabetes mellitus and chromium deficiency, deficiency sources, and possible losses of
chromium, and the influence of drinking water on death rates from atherosclerosis. The
conclusions are that one common form of hypertension is probably an example of accumulation of cadmium in the kidney and that deficiency of chromium may influence
glucose and lipid metabolism and affect atherosclerosis. Other trace elements may contribute also.
ADDITIONAL INDEXING WORDS:
Hypertension
Drinking water
Chromium in sugars and fat
Atherosclerosis
Zinc
THIS PRESENTATION, the twenty-seventh lecture of a series honoring the
memory of George E. Brown, gives me the
opportunity to assemble a number of observations made during the past 15 years on
certain elemental factors which I believe are
involved in the pathogenesis of two common
vascular disorders. Dr. Brown was interested
in peripheral vascular diseases. In their broadest terms, both arterial hypertension and
Diabetes mellitus
Trace metals in wheat and flour
Renal cadmium and zinc
atherosclerosis can be considered diseases of
the peripheral blood vessels. My discussion
will be confined to these two conditions, and
to the relation of two trace metals to their
presence in animals and man.
Progress in science is often the result of
chance observations. In 1949, Reubi1 found
that 1-hydrazinophthalazine (hydralazine)
had the unique property of increasing renal
blood flow of human hypertensive patients
in the face of a lowered blood pressure. This
compound, which had a prolonged hypotensive effect in renal hypertensive dogs, was
stored in metal-capped bottles. Perry noticed
that the solution was corroding the caps, despite a neutral pH. He tested the compound
against various metal ions and found that it
chelated a number of them.2 Five other drugs
more or less effective in human hypertension
also had the property of binding some of the
From the Department of Physiology, Dartmouth
Medical School, Hanover, New Hampshire, and the
Brattleboro Memorial Hospital, Brattleboro, Vermont.
This investigation was supported by grants-in-aid
from the National Heart Institute, U. S. Public
Health Service (HE-05076), United States Army
Contract DA 2595, and CIBA Pharmaceutical Products, Inc.
The George E. Brown Memorial Lecture presented
at the Thirty-ninth Scientific Sessions of the American
Heart Association, New York, October 22, 1966.
570
Circulation, Volume XXXV, March 1967
CADMIUM AND CHROMIUM
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trace metals present in the human body: thiocyanate, nitroprusside, azide, 2-3 dimercaptopropanol (BAL), and ethylene diamine tetraacetic acid (EDTA).3 None of these agents
appeared to act on the sympathetic nervous
system. Hydralazine binds zinc, iron, and cobalt4 as well as vanadium, chromium, manganese, and copper.2
Small doses of known chelating agents
with nitrogen, sulfur, oxygen, and carbon ligands, or donor atoms, which bound metals
the most strongly, lowered blood pressure
acutely in hypertensive but not in normotensive rats, especially compounds containing
sulfhydryl and nitrogen ligands.5 Other compounds were either depressor in both types
of animals or inactive. Salts of some transitional metals were active; among the pressor metals were vanadyl, manganous, nickelic, and cadmium ions. Iron, cobalt, copper,
zinc, and chromium ions were depressors, but
only zinc had a differential action, affecting
hypertensive but not normotensive levels of
blood pressure.6
Tipton and her colleagues7' 8while analyzing
human autopsy tissues for 29 stable isotopes
by emission spectrography as a guide to determining maximal permissible doses of radionuclides, found large amounts of cadmium in
the American human kidney. In order to ascertain whether or not all human kidneys
have such large amounts of cadmium, tissues
from still-born and newborn infants, tissues
from African natives relatively unexposed to
modern civilization, and tissues from subjects
in the Orient and Middle East exposed to
differing civilizations, were collected. Some
180,000 analyses on more than 400 subjects
were made.7-9
The following results appeared: (1) infants
had no detectable cadmium in their kidneys
or other tissues10; (2) Orientals generally had
more renal cadmium than did Americans9 11;
(3) Africans generally had considerably less
renal cadmium than did Americans, especially
those from the Eastern Highlands; (4) levels
of cadmium increased in human kidneys with
age but declined in old age (fig. 1). Lead
also increased with age in most tissues, later
Circulation, Volume XXXV, March 1967
571
declining12; chromium declined precipitously
from birth to the second or third decade of
life and thereafter, except in the lung, where
it rose, probably from airborne chromium'3;
tin increased in the heart with age.'4 The
essential trace metals manganese, copper, and
zinc were concentrated in the infant, declined
somewhat in concentration and then remained
remarkably constant in tissues throughout
life15-17 except for renal zinc which followed
the curve of cadmium.
Basic data on the physiological roles of
most of the trace elements found by Tipton
and her colleagues in human tissues were
lacking. The essentiality of manganese, iron,
cobalt, copper, and zinc as micronutrients had
been established, but the functions of such
elements as titanium, vanadium, chromium,
nickel, gallium, germanium, arsenic, zirconium, niobium, molybdenum, cadmium, tin, antimony, tellurium, and lead were largely
unexplored. Was one or more of them essential to optimal mammalian health? Were
homeostatic mechanisms operative for some
or all of these elements or did one or more
accumulate in human tissues with age? If a
metal accumulated with age, could it influence
or cause a chronic disease or a metabolic
abnormality leading to a chronic disease?
Could accumulation of an abnormal metal
be related to the mean rise of blood pressure
with age, the mean rise of circulating cholesterol with age, the increase in the incidence
of diabetes mellitus with age, the increase
in the severity of atherosclerosis with age, and
the appearance of metaplasia?
Environmental
Control of Trace Metals
To obtain basic data, an attempt was made
to duplicate in small mammals for their lifetimes the experiment civilized man has inadvertently performed on himself, to observe
the results in terms of chronic diseases, if any,
and to analyze their tissues for metals and
their accumulation with age. On a mountain
top in Vermont was built an animal laboratory
of wood, as metal-free as possible.'8 Build-
ing materials were analyzed for lead and
SCHROEDER
572
ZINC and CADMIUM
in KIDNEY
Cd:Zn ppm
ratio ash
0.7 r 7000
x
.
x
0.6 [ 6000
0.5
.-X - --.
/
/
50001
I,
-
-,
J
- . -X
'.
N.,
.
I
.
0.3 1 3000 \
/
' /
..
p.
/
I/
0
\ /
..
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0.2k 2000
[
0.0l
.1
o*.O
x. Zn
..
k
0.1
_
.0.~~~..
0.4 [ 4000
Zn
/
/
.
.
Cd
0
IA
1000
°]
0-
Io--
i
-'
St.11-
0-10
born
mos.
b
'
1-9
10-19
20-29 30-39 40-49 50-59
Age in Years
Figure
60-69
70-79
80-p
1
Mean concentrations of cadmium and zinc and the ratios of cadmium to zinc by weight, in the
kidneys of 221 subjects from the United States according to age. Ranges were wide about
each mean. After age 30, 18.4% of 136 persons had ratios below 0.50, whereas 22.0% of persons
had ratios of 0.80 or greater and 5.9% greater than 1.0. A ratio of 0.80 or greater was usually
associated with death from the consequences of hypertension.25 The declines in renal cadmium
and the Cd:Zn ratios after age 60 are compatible with the theory that a high ratio or excess
renal cadmium decreases longevity. There is no evidence that the kidneys of older persons
lose cadmium; none was detected in infants. The correlation coefficient (r) of relnal cadmium
and zinc was 0.70 (P<O.001), and of renal cadmium with age was 0.35 (P<0.001). Reproduced
by permission of the publisher of Journal of Chronic Disease.'7
cadmium. Spring water was doubly deionized;
was electrostatically filtered to remove
airborne contaminants from motor vehicle
exhausts. Polyethylene and acrylic plastic were
used throughout. Precautions to avoid metallic contamination were extensive. Rats and
mice were fed, from weaning until death,
a diet low in most trace metals, composed
of seed rye, powdered skim milk, and corn
oil; groups of 100 or more were given traces
of single metals in drinking water until they
died.18 Under these environmental conditions,
two major chronic diseases, arterial hypertension and diabetes mellitus, have appeared in our laboratory.
air
Cadmium Hypertension in Rats
We have raised several thousand rats and
mice with little or no detectable cadmium in
their tissues, indicating that cadmium is probably not an essential micronutrient for these
mammals.'8-21 When rats were given traces
of cadmium in drinking water (5 ,ug/ml) from
the time of weaning, hypertension began to
appear after about a year and increased in
incidence with age. Once hypertensive, the
rats remained so until death.22' 23 This disorder was similar to its human counterpart,
in that the incidence in females was greater
than in males, the mortality among males
with hypertension was greater than that
among the females, both sexes had decreased
Circulation, Volume XXXV, March 1967
CADMIUM AND CHROMIUM
573
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median life spans compared to cadmium-free
controls,21 of 156 and 140 days, respectively
(P < 0.005), aortic lipids were increased, and
the incidence of spontaneous aortic plaques
were sizeable,24 although less than in the human disease. Hearts were enlarged, renal arteriolar sclerosis was found frequently, considerable cadmium was present in kidneys,
and some of the systolic blood pressures were
over 260 mm Hg.23 Incidences of hypertension
in the controls and in rats given chromium
or lead were low and accompanied pyelonephritis or hydronephrosis, which was unusual in our strain of rats. Normotensive rats
given cadmium had higher levels of blood
pressure than did their "cadmium-free" controls (table 1). Mice showed similar changes
in mortality and life-span.20
This study was repeated: half of 40 rats
being also supplied with "hard" or calciumcontaining water and the other half, with
"soft" water. Eighty per cent of the animals
receiving "soft" water were hypertensive by
500 days of age, whereas only 17.7% of those
receiving "hard" water exhibited the disease.
Analyses of their kidneys showed that the
hypertensive rats had mean cadmium-zinc
ratios of 1.02 0.11 and the normotensive
Table
1
Effect of Ingestion of Cadmium (5 pxg/ml) in
Drinking Water on Systemic Blood Pressure of
Normotensive Rats
Males
Control
Cadmium
Control
Cadmium
Females
No. of
rats
Age
(mo)
Blood
pressure
(mm Hg)
12
10
11
6
17
17
24
24
94 ± 3.8
107 ±2.6*
70 ± 3.5
94 3.4*
14
84 ±5.7
10
98 5.2t
14
13
Cadmium
100 ± 5.8t
18
8
Cadmium
*Differs from control group, P < 0.005.
tDiffers from control group, P < 0.05.
Note: Hypertensive rats, that is, those with systolic pressures > 142 mm Hg, were excluded from
these data. Rats were fed cadmium from the time of
weaning. No controls were hypertensive.
Control
Circulation, Volume XXXV, March 1967
rats had ratios of 0.35
0.18 (SEM), by
weight.
In a third study, nine of 22 female rats
given cadmium in water from the time of
weaning became hypertensive at 400 days of
age, an expected number.* An attempt was
made to displace the cadmium accumulated
in their kidneys by zinc, using a chelating
agent with 5.7 times the affinity for cadmium
as for zinc, and chelated to zinc. One week
after a single injection of this agent, 2diaminocyclohexane disodium zinc tetra-acetate (di Na-Zn-CDTA), all hypertensive rats
were normotensive, mean blood pressure
falling from 169 13.4 mm Hg to 82.8 5.6
mm Hg (SEM ) .25 This agent was not toxic,
and the rats remained normotensive and
healthy for 6 weeks, despite being fed
cadmium. Five months later, hypertension
(B.P., 189 + 26.2 mm Hg) had recurred in
four animals, whereas the remainder were
still normotensive (B.P., 75 + 4.4 mm Hg).
A fourth study involved direct intraperitoneal injection of cadmium acetate into rats,
in doses below the LD50.26 The dose exceeded
the total body cadmium of rats absorbing it
slowly by mouth for 3 years and resulted in
a high mortality rate during the next
2 months. All of 24 survivors showed hypertension, and deaths were largely caused by
internal hemorrhage. Mean blood pressures
were higher than in rats with partial constriction of one renal artery. Blood pressure,
measured in five rats, rose a mean value of
47 mm Hg within a half hour of the injection.
When the cadmium hypertensive rats were
given the zinc chelate 5 weeks later, blood
pressures declined to normal levels, but more
slowly than in the cases of the rats receiving
cadmium by mouth.25 Analyses of their kidneys and livers showed that expected concentrations of cadmium were not found after
injection of the chelate, and that the cadmium-zinc ratios were lower than in those given
the cadmium alone (table 2). Smaller doses
of cadmium appeared to elevate the blood
*At 540 days of age, five additional rats had
become hypertensive.
SCHROEDER
574
the animal was sometimes hypertensive. When
it was 0.80 or more (0.46 on a molar basis),
the animal was always hypertensive.26 Hepatic
levels and ratios were not significant in
this respect. Rats fed a commercial diet which
contained cadmium had a mean renal ratio
of 0.52 by weight. It appeared that more than
two atoms of renal cadmium to five atoms of
zinc were necessary to induce hypertension.
Therefore, we have established that rats
fed or given by injection small doses of cadmium become hypertensive, that removal of
some of the cadmium results in a return to
pressure to higher, but still "normotensive"
levels (table 3).
From analyses for cadmium and zinc in
the kidneys and livers of 90 hypertensive and
normotensive rats, one could predict with
reasonable accuracy whether or not hypertension had been present in an animal. Neither
the concentration of cadmium nor that of
zinc were good indices, but the renal ratios
of the two metals correlated reasonably well
with the level of blood pressure. When the
ratio of cadmium to zinc by weight was more
than 0.64, or more than 0.37 on a molar basis,
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Table 2
in
Zinc
the
and
Kidneys of Cadmium Hypertensive and Normotensive
Mean Molar Ratios of Cadmium
Female Rats, Treated with CDTA-Zinc*
No. of
rats
Dose of Cd
(mgikg)
Controls
Treated, CDTA-Zn
10
9
0
Injected, Cd
Treated, CDTA-Zn
10
10
10
9
5
2
4
1.5
1.5
B.P.*
(mm Hg)
98
118
+
4.2
+
8.5
140 +
96 ±
84+
156 +
107 +
166 +
87 +
7.2
7.4
5.7
8.6
6.1
14.2
8.8
Ratio
Cd: Znt
Remarks
Obtained from supplier
Zn, 40 mg/kg; no cadmium given
Obtained from supplier
Zn, 40 mg/kg
Bred in laboratory
Bred in laboratory
Zn, 40 mg/kg
Obtained from supplier
Zn, 80 mg/kg
0.30
0.14
0.52
0.27
<0.01
0.44
0.29
0
"cadmium free"
2.0
Cd
2.0
CDTA-Zn
3.0
0.55
Cd
3.0
0.24
CDTA-Zn
*Data computed from reference 25.
tCoefficient of correlation (r) of mean systolic blood pressure and renal ratio of cadmium to zinc, 0.78, P<
Controls,
Injected,
Treated,
Injected,
Treated,
0.01.
Table 3
Effect of Injection of Cadmium on Systolic Blood Pressure of Female Rats*
No. of
rats
B.P.
(mm Hg)
Experiment 1
Controls
Controls
Cadmium, 2 mg/kg
Cadmium, 3 mg/kg
8
12
29
16
124
204
Experiment 2
Controls
Cadmium, 1 mg/kg
Cadmium, 2 mg/kg
20
10
9
87 + 4.5
117 ± 6.54
156 + 8.6*§
79
+
3.4
84± 5.7
+
+
7.4:
12.4t§
% Elevatedt
0
0
31
100
0
20
78
Reniarks
130 days old
180 days old
1 injection
2 injections,
2 weeks apart
300 days old
1 injection
2 injections,
1 week apart
*Rats were anesthetized (Pentobarbital sodium) and warmed. Blood pressure measured
by sensitive microphone on tail 1 to 3 weeks after injection of cadmium acetate. Data from
reference 26.
tElevated > 3 standard deviations above control.
t:Differs from control value, P < 0.005.
§Differs from level after I injection, P < 0.001.
Circulation,
Volumne
XXXV, March 1967
575
CADMIUM AND CHROMIUM
normotension, and that a high ratio of renal
cadmium to zinc is usually associated with
hypertension.
Perry and Yunice27 have recently shown
that cadmium is an intense vasoconstrictor
agent when injected intra-arterially into rats
in doses of 10 to 40 pAg/ 100 g body weight,
whereas larger doses (80 to 320 ,ug/100 g)
were depressor. Pahizek28 has produced toxemia of pregnancy in rats by injecting
cadmium in doses similar to ours. Under
many conditions, cadmium acts as an antimetabolite for zinc. Cook and Lee29 have
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demonstrated that cadmium ion inhibits the
activity of angiotensinase found in blood.
Among the 400 human subjects analyzed
by Tipton and associates8' 9 were 34 who had
hypertensive deaths, mainly from cerebral
hemorrhage. When the data on their kidneys were subjected to statistical analysis,
a high cadmium level or a high ratio of
cadmium to zinc appeared in most of
them,30' 31 comparable to the values in hypertensive rats given cadmium.* Subjects dying of a variety of other conditions, including
accidents, had lower renal ratios of cadmium
to zinc. Of subjects dying of malignant hypertension with renal failure, five of seven
had low values of both cadmium and zinc,
presumably due to loss of renal tissue. Several years prior to this study Perry and 132
found that the urine of hypertensive patients contained some 40 times as much
cadmium as did urine of normotensive subjects. Cadmium levels in human blood follow
a two-population curve.33 However, most
human beings absorbing large quantities of
cadmium from industrial dusts into lungs do
not exhibit excessive incidences of hyperten*Median molar ratios of cadmium to zinc in the
kidneys of 187 American and 119 foreign subjects,
according to major cause of death were: hypertension,
U. S. 0.45, foreign, 0.58; accidents, U. S. 0.36,
foreign, 0.38; arteriosclerotic heart disease, U. S.
0.36, foreign, 0.28; miscellaneous, U. S. 0.32, foreign,
0.32; malignant disease, foreign, 0.29; chronic infections, foreign, 0.28. The differences between hypertensive and other values were significant (P < 0.01
to < 0.05).
Circulation,
Volume
XXXV, March 1967
sion (personal communication from M. Pis-
cator) probably because the dose response
curve is parabolic, that is, a small amount
has one effect, whereas more has the opposite
effect, a phenomenon common to all the trace
metals studied.34
As these data fulfill Koch's postulates modified for a chronic disease,35 it appears that
cadmium may be the unknown factor responsible for cases of hypertension in the human
which are not dependent upon hypersecretion of the adrenal cortex or medulla,
partial obstruction of renal or carotid arteries, organic renal disease, or other obvious
conditions with which elevated blood pressure is associated; in other words, for socalled "essential hypertension."t It is also possible that renal cadmium may raise normal
blood pressure levels, as it does in rats.
Sources of Environmental Cadmium
Cadmium is present in varying quantities
in foods, water, beverages, and air.10 17, 36
Most of it occurs as a contaminant; man is
the only mammal known accumulating cadmium in the kidneys to this extent, and
uncivilized man accumulates little (the domestic horse may be an exception). Cadmium occurs in commercial zinc and alloyed
copper.
has been measured
per day, with wide
variations depending upon types of foods and
waters.'7 Tea and coffee contain 10 to 50 ,ug
per liter. The use of phosphate fertilizers
which contain 5 to 10 parts per million
(ppm) of cadmium has induced some growing vegetables and grains to take up cadmium
from soil.37 Most oysters are excellent sources,
as are other mollusks and crustaceans; oysters
may concentrate the metal 10,000 to 100,000
times from sea water. Soft lake water in our
area accumulated cadmium from mains and
copper or galvanized pipes to the extent that
The daily intake of
man
at 200 to 400 ,ug cadmium
tCadmium may be the unknown factor that converts a temporary vasoconstrictive reaction to stress
into a permanent one. Partial constriction of a renal
artery and organic renal diseases may also act in
this way.
SCHROEDER
576
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half of the tap waters we have analyzed exceeded the allowable Public Health Service
standards of 10 ppb.'7 Water, however, contributes but 5 to 10% of the total intake and
that only after standing in pipes.
The practice of refining wheat and polishing rice may alter the relative amounts of
cadmium and zinc contained in the finished
grain (table 4). Cadmium is distributed
throughout the endosperm and germ; zinc
is concentrated in the germ and bran. Refined
white flour contained only 28% of the zinc
in the whole grain, all of it bound to gluten,
but cadmium was not removed by refining.'7
In rice, cadmium was found firmly bound
to glutelin,38 and the concentration in ash
rose sharply with polishing.39
Refined wheat flour has a ratio of cadmium
to zinc of 1:17 to 1:23, compared to 1:120
in whole wheat. Persons from areas of the
world where the major source of calories
comes from refined grains are apt to show
high levels of renal cadmium.9 10,31
The urinary output of cadmium approximates 30 to 40 ,ug per day17 or about 10%
of the intake. About 3 ug per day is retained
in the body, of which 1 p,g daily is bound to
the kidney, making up 10 mg at 30 years of
age.'0, 17 The relative absorption of ionic
cadmium in water as compared to cadmium
bound to glutelin in grains, bound to protein
in seafood, or contained in other foods is
unknown.
There is good correlation with deaths from
hypertensive heart disease and the softness
Table 4
Zinc, Cadmium, and Chromium in Wheat and
Various Grades of Flour (,g/g Dry Weight)*
Grades
Zinc
Wheat
31.5
0.26
8.9
15.9
33.6
3.6
106.0
100.2
133.4
0.38
0.26
0.26
0.28
0.92
0.88
1.11
Patent flour, 61%
First clear flour, 11%
Low grade flour, 2.5%t
Red Dogt
Shortst
Bran, 15%t
Germ
*Data from reference 17.
fUsed as feed for animals.
Cadmium Chromium
0.97
0.58
0.92
0.53
0.29
1.20
1.24
1.36
of municipal water supplies in this country,
hard water areas having considerably lower
rates.40' 41 Death rates are also higher in states
having a seacoast than in states without;
proximity to the sea generally produces
more rainfall and allows the municipal use
of surface water, which is characteristically
soft. A good correlation has been found by
Carroll36 with cardiovascular death rates and
with the amount of cadmium in the air as
an industrial pollutant. Although air can be
calculated to be a relatively small source, it
probably contributes to cadmium in rainwater. The cadmium in tap water coming
from pipes, according to our analyses, provides an additional source.
Diabetes Mellitus from Chromium
Deficiency
Partial dietary deficiency of chromium in
rats has resulted in a moderate diabetic state
characterized by elevated fasting serum glucose levels and glycosuria.42'4 Schwarz and
Mertz,45 and Mertz and associates46 have
shown that the low tolerance to glucose of
rats on certain diets was the result of partial
chromium deficiency, a defect restored by
traces of trivalent chromium. With the environmental exclusion of chromium in our rat
laboratory, a more severe deficiency was produced,42 resulting in retarded growth and
diabetes mellitus,43, 44 that was rapidly relieved by traces (1 to 2 ,ug/ml) of chromium
(III) acetate in drinking water. Furthermore,
by taking advantage of the demands of the
rat fetus for chromium (pregnancy depleting
the mother'3), we have raised five generations
of rats which showed increasing incidence
of diabetes. This strain would be considered
to have an hereditary disorder were it not
known to be dietary and reversed by chromium (III).
Relation of Chromium
Deficiency to Atherosclerosis
Chromium deficient rats showed at death
a fairly high percentage of plaques in their
aortas, especially when old. Rats given chromium for their lifetimes demonstrated three
interesting findings: a significant prolongation
Possible
Circulation, Volume XXXV, March 1967
CADMIUM AND CHROMIUM
of life span, as did mice (one rat lived 4
years), almost complete absence of spontaneous aortic plaques, and abolition of the
usual rise of serum cholesterol levels with
age.24 These observations are being continued
with a second series of rats, but to obtain
the answer requires 4 years. Chromium is
an essential micronutrient for rats and mice,
both for optimal growth'9 and for longevity.
Chromium Deficiency in Man
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The possible influence of chromium deficiency in abnormal lipid metabolism and
atherosclerosis in man is less evident than
that of cadmium and hypertension, but there
are a number of indirect observations which
should stimulate study.
1. Tissue levels of chromium in Americans, high at birth, declined precipitously
with age, and a sizeable number were deficient'3 (figs. 2 and 3). Pulmonary chromium,
however, rose with age, probably from airborne metal, and this rise was not reflected
in increased deposits in other tissues.'3 These
low tissue levels of chromium were not duplicated in other mammals nor in subjects
from the Orient, Africa, and the Middle
East, who had 2.5 to 8 times as much in
aorta, 3 to 13 times as much in brain, 2.5 to
4 times as much in heart, 2.5 to 7 times as
much in kidney, twice as much in liver,
2 to 4 times as much in pancreas, 3 to 6
times as much in spleen, and 2.5 to 5 times
as much in testes as did Americans.9 Furthermore, only 15 of 949 foreign tissues were
devoid of chromium (1.57%), whereas 181 of
1,029 of the same tissues of Americans had
no detectable chromium (17.6%, P<0.0005).
In kidney, liver, spleen, and brain 23.3% of
American samples lacked chromium (<0.001
,g/g, wet weight), compared with 1.6%
of foreigners (P < 0.0001 ). Therefore, adult
Americans, according to 200 or more subjects
from 10 cities, are low in tissue chromium
compared to a similar number of human
beings from other areas of the world.
2. There is some evidence that excessive
ingestion of sugar may alter the lipids in
human serum in a manner considered to
Circulation, Volume XXXV, March 1967
577
predispose to atherosclerosis.47 48 There is
likewise indirect evidence that excessive ingestion of sugar may influence the development of maturity-onset diabetes mellitus.49
The predisposition of atherosclerotic complications to develop in diabetic subjects has
been known for 50 years. Many patients suffering from atherosclerotic disorders or elevated serum triglycerides have low tolerance
to glucose meals.47 50 Some 87% of older persons examined have exhibited abnormal glucose tolerance.5" 52 Consumption of sugar in
the United States has been calculated at
50 kg/person/year.49
3. Evidence is accumulating that some older diabetic subjects respond to small doses
of chromium (III) chloride by an amelioration of the diabetic state. Although to date
only small series of patients have been
treated, improvement has been noted in 40%
of patients in Syracuse,52 67% of patients in
Washington,53 33% of patients in Brattleboro,
Vermont, and no patients in Hanover, New
Hampshire (in a short-term study). Difficulties with dose, absorption, and form of
salt or complex are apparent and require
further study. Oral chromic chloride is poorly
absorbed.54
4. Chromium may act on lipid metabolism.55 In aged persons, oral chromic acetate was relatively ineffective in altering
serum cholesterol levels, only 9% reduction
being observed.56 The oxidation of C'4-palmitate by aortas of chromium-deficient rats,
however, was stimulated.57 If this work is
confirmed, it should have wide implications.
The aortas of male foreign subjects contained
in ash 5.5 to 15 ppm chromium and of American subjects, 1.9 ppm, 13% of whom were
devoid of chromium (fig. 2). Atherosclerosis
is believed to be less severe in areas where
tissue chromium was high.9
Sources and Possible Losses of Chromium
There is adequate chromium in soil,
although little is available to plants,'3 from
which come our essential mineral micronutrients. Chromium (III) in solution has the
capacity to "olate," that is, to form long
SCHROEDER
578
chains with water molecules. In an alkaline
medium, and when heated to 120 C, olation
is enhanced. It is possible that chromium
in foods becomes unavailable when superheated. Although less chromium was found
in refined flour than in wheat (table 4), the
decrement was not large enough to account
for dietary deficiencies.
An explanation for the depletion of bodily
chromium in Americans may lie in the experiments of Glinsmann and associates,58 who
demonstrated that circulating chromium rises
after a glucose load by a factor of 2 to 3 in
normal but not in diabetic subjects. We have
found increases in urinary chromium after
oral glucose loads up to 400 ug/L, the normal
CHROMIUM
IN
LIVER and AORTA
ppm
ash
25
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20 (0)
15 \
\
*'0(8)
Numbers in parentheses
indicate"/,
not detected
10
0(2 2)
5
*(0)
X%
*(33
,
(17)
~
ol-
(9
0(5))
0
oiert
-
0-45
days
/ c
c
4 5 -lo
10-20 20-30 30-40 40-50 50-60 60-70 70-80
Age in Years
Figure 2
Mean concentrations of chromium, a trace metal essential for normal glucose metabolism, in
186 livers and 103 aortas of American subjects according to age, when present in tissues.
Mean values of all adults were 0.7 and 2.0 ppm, respectively. The numbers in parentheses
indicate the percentage of samples in each age group in which chromium was not detected
(<0.1 ,ug/g ash) and not included in the mean values. Note the maintenance of hepatic
birth levels up to 10 years of age and the rapid decline thereafter. Tissues of foreigners had significantly higher levels. Livers of 45 African adults had 1.3 ppm (two were deficient); of 33
Near Eastern adults 2.4 ppm (P<0.001); of 67 Far Eastern adults, 4.6 ppm (P<0.001);
of nine Swiss adults, 5.8 ppm (P<0.001) (one from Near East was deficient). Aortic concentrations were as follows: 15 Africans, 6.6 ppm (none deficient); 15 Near Eastern subjects, 11 ppm
(P<0.001) (two deficient); 65 Orientals, 15 ppm (P<0.001) (two deficient); five Swiss, 8.8 ppm
(P<0.001) (none deficient). It is apparent not only that a large percentage of these tissues from
Americans were deficient in chromium, but that tissues from foreigners contained more than
did those from Americans. (American data from Tipton and Cook8; foreign data from Tipton
and associates.9)
C7rculation, Volurne
XXXV, March 1967
CADMIUM AND CHROMIUM
579
amount being 4 ,ug/L. Hopkins59 has shown
in the rat that the kidney clears 30% of injected 51Cr (III) in 2 hours. As the American
adult contains an estimated 5 mg of chromium
in his body,13 depletion of body stores could
theoretically result from repeated insults with
glucose or refined sugars having little or no
chromium. Analysis of raw sugars showed
appreciable amounts of chromium, whereas
refined sugar had little (table 5). Most fats
were good sources.
We have measured and calculated that
about 200 pg of chromium/day are contained
in a normal adult diet, or about 3 ,ug/kg of
body weight. Rats and mice became deficient
of 10 ,ug/kg of body weight/day.20' 21
ppm
ash
60.
* (4 )
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. -.
CHROMIUM
IN
SPLEEN and KIDNEY
I\
50
(o)
20 \Spleen
I Kidney
I
1a
Numbers in parentheses
indicate '/. not detected
\
I
I\
I
b0o
I ~
~~
o 0i F .
0~(21)
031,
(22)
0(F
(9)(3
(1)()
27
(3
°3
(25)
21)= :(SO)
da0s das -10 10-20 20-30 30-40 40-50 50-60 60-70 70410
Age in Years
Figure 3
Mean concentrations of chromium, when present, in 135 spleens and 176 kidneys of American
subjects according to age. Mean values of all adults were 0.5 and 1.0 ppm, respectively. Note
the maintenance of the renal birth level up to age 10 years and the sharp decline thereafter.
The numbers in parentheses indicate the percentage of samples in each age group deficient
(< 0.1 Ag/g ash) in chromium and not included in the mean values. Adult foreign concentrations were significantly higher as follows: Spleen, 40 Africans, 2.2 ppm; 34 Near Eastern
subjects, 5.5 ppm (P<0.001); 62 Orientals, 3.1 ppm (P<0.001); eight Swiss, 4.5 ppm
(P<0.001) (two Orientals deficient). Kidney, 48 Africans, 3.3 ppm; 31 Near Eastern subjects,
13 ppm (P<0.001); 66 Orientals, 24 ppm (P<0.001); nine Swiss, 17 ppm (P<0.001)
(none deficient). In the tissues of a large percentage of American subjects, chromium deficiency existed and most foreigners had larger amounts. (American data from Tipton and Cook8;
foreign data from Tipton and associates.9)
Circalation, VolTue XXXV, Marcb 1967
SCHROEDER
580
Table 5
Chromium in Various Types of Sugars and Fats
(Wet Weight)*
AgIg
Sugars
Refined, granulated no. 1
Same, no. 2
Raw, Columbian
Filipino
Brown
Molasses, household
Refinery
Black-strap
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Corn syrup
Maple syrup
Honey, refined
Grape juice
Orange juice
Fats and oils
Lard, raw
Butter
Lecithin, egg
Corn oil
Cottonseed oil
Sunflower seed oil
Lecithin, soy
Gluten, wheat
N.D.0.09
1.58
1.59
1.19
0.25
0.35
0.43
3.42
3.07
0.41
0.34
0.25
2.06
0.70
0.83
0.58
1.64
correlations were found with cardiovascular
death rates and chromium in municipal
water,60 nor with chromium in water and
deaths from diabetes mellitus. The most significant associations were between the two
types of heart disease and the degree of
softness of water, which may reflect the uptake of cadmium from pipes.00 Atherosclerotic heart disease often has a hypertensive
component, which may explain this association.
Conclusions
-
-
2.58
1.56
2.31
1.11
4.17
2.40
*Analyses by atomic absorption spectrophotometry
made by Jeffrey Buckman, M. S.
tN.D. =not detected.
Possible Influence of Drinking Water
on Death Rates from Atherosclerosis
The correlation of death rates from hypertensive and atherosclerotic heart disease with
some factor associated with the degree of
softness of muncipal water supplies in the
United States, using 1949-51 rates and water
analyses,40'4' was confirmed for 1960 rates
and waters,60 and in the interval, was demonstrated in Great Britain6' and Sweden.62
A similar correlation of death rates from
cerebral hemorrhage and acidity of river
water has been found in Japan.63 64 Correlalations of the type of water with rates from
vascular lesions of the central nervous system,
however, were poor.60 62 In reviewing the data,
we have come to the conclusion, tentatively,
that deaths from cerebral thrombosis, and perhaps other peripheral atherosclerotic complications, are not associated with the type
of potable water. Furthermore, no significant
Trace elements are important catalysts for
many biological processes, most of them still
unknown. They all come from soil or sea.
Implications for microbiology, nutrition, pharmacology, biochemistry, and even molecular
biology are becoming apparent.
Man's use of metals has exposed him to
a number of extraneous elements by introducing them into food, water, and air, and
to which he and other mammals have little
or no ability to adapt. Chronic diseases may
result from these lifetime exposures, diseases
which are not prevalent in more primitive
societies. They may arise especially from
those abnormal elements which accumulate
with age from excessive exposures, or from
those essential elements which decline because of conditioned dietary deficiencies.
One common form of hypertension is probably an example of accumulation of cadmium
in the kidney; deficiency of chromium may
influence glucose and lipid metabolism and
affect atherosclerosis. These observations do
not exclude the involvement of other elements
in both diseases.
References
1. REUBI, F. C.: Renal hyperemia induced in man
by a new phthalazine derivative. Proc Soc
Exp Biol Med 73: 102, 1950.
2. PERRY, H. M., JR., AND SCHROEDER, H. A.:
Studies on the control of hypertension by
Hyphex: III. Pharmacological and chemical
observations on 1-hydrazinophthalazine. Amer
J Med Sci 228: 396, 1954.
3. ScHROEDoR, H. A.: Mechanisms of Hypertension.
Springfield, Illinois, Charles C Thomas, Publisher, 1957, 379 pp.
Circulation, Volume XXXV, March 1967
CADMIUM AND CHROMIUM
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
4. Stability Constants of Metal-Ion Complexes. London, The Chemical Society, 1964.
5. SCHROEDER, H. A., MEHIARD, E. M., AND PERRY,
H. M., JR.: The antihypertensive properties
of some mercaptans and other sulfur containing compounds. J Lab Clin Med 45:
431, 1955.
6. SCHROEDER, H. A., AND PERRY, H. M., JR.: The
antihypertensive effects of metal binding
agents. J Lab Clin Med 46: 416, 1955.
7. TIPrON, I. H., COOK, M. J., STEINER, R. L.,
BOYE, C. A., PERRY, H. M., JR., AND SCHROEDER, H. A.: Trace elements in human tissue:
I. Methods. Health Phys 9: 89, 1963.
8. TIPTON, I. H., AND COOK, M. J.: Trace elements
in human tissue: II. Adult subjects from the
United States. Health Phys 9: 103, 1963.
9. TIPTON, I. H., SCHROEDER, H. A., PERRY, H. M.,
JR., AND COOK, M. J.: Trace elements in
human tissue: III. Subjects from Africa, the
Near and Far East and Europe. Health
Phys 11: 403, 1965.
10. SCHROEDER, H. A., AND BALASSA, J. J.: Abnormal trace metals in man: Cadmium. J Chronic Dis 14: 236, 1961.
11. PERRY, H. M., JR., TIPrON, I. H., SCHROEDER,
H. A., STEINER, R. L., AND COOK, M. J.:
Variation in the concentration of cadmium
in human kidney as a function of age and
geographic origin. J Chronic Dis 14: 259,
1961.
12. SCHROEDER, H. A., AND BALASSA, J. J.: Abnormal trace metals in man: Lead. J Chronic
Dis 14: 408, 1961.
13. SCHROEDER, H. A., BALASSA, J. J., AND TIPTON,
I. H.: Abnormal trace metals in man: Chromium. J Chronic Dis 15: 941, 1962.
14. SCHROEDER, H. A., BALASSA, J. J., AND TIPTON,
I. H.: Abnormal trace metals in man: Tin.
J Chronic Dis 17: 483, 1964.
15. SCHROEDER, H. A., BALASSA, J. J., AND TIPTON,
I. H.: Essential trace metals in man: Manganese: A study in homeostasis. J Chronic
Dis 19: 573, 1966.
16. SCHROEDER, H. A., NASON, A. P., TIPTON, I. H.,
AND BALASSA, J. J.: Essential trace metals
in man: Copper. J Chronic Dis 19: 1007, 1966.
17. SCHROEDER, H. A., NASON, A. P., TIPTON, I. H.,
AND BALASSA, J. J.: Essential trace metals
in man: Zinc: Relation to environmental cadmium. Submitted for publication.
18. SCHROEDER, H. A., VINTON, W. H., JR., AND
BALASSA, J. J.: Effects of chromium, cadmium
and other trace metals on the growth and
survival of mice. J Nutr 80: 39, 1963.
19. SCHROEDER, H. A., VINTON, W. H., JR., AND
BALASSA, J. J.: Effects of chromium, cadmium
and lead on the growth and survival of
rats. J. Nutr 80: 48, 1963.
Circulation, Volume XXXV, March 1967
581
20. SCHROEDER, H. A., BALASSA, J. J., AND VINTON,
W. H., JR.: Chromium, lead, cadmium, nickel
and titanium in mice: Effect on mortality,
tumors and tissue levels. J. Nutr 83: 239,
1964.
21. SCHROEDER, H. A., BALASSA, J. J., AND VINTON,
W. H., JR.: Chromium, cadmium and lead
in rats: Effects on life span, tumors and
tissue levels. J Nutr 86: 51, 1965.
22. SCHROEDER, H. A., AND VINTON, W. H., JR.:
Hypertension induced in rats by small doses
of cadmium. Amer J Physiol 202: 515, 1962.
23. SCHROEDER, H. A.: Cadmium hypertension in
rats. Amer J Physiol 207: 62, 1964.
24. SCHROEDER, H. A., AND BALASSA, J. J.: Influence
of chromium, cadmium and lead on rat aortic
lipids and circulating cholesterol. Amer J
Physiol 209: 433, 1965.
25. SCHROEDER, H. A., AND BUCKMAN, J.: Reversal of
cadmium hypertension in rats by a zinc chelate.
Arch Environ Health (Chicago). In press.
26. SCHROEDER, H. A., KROLL, S. S., LITTLE, J. W.,
LIVINGSTON, P. O., AND MYERS, M. A. G.:
Hypertension in rats from injection of cadmium. Arch Environ Health (Chicago) 13:
788, 1966.
27. PERRY, H. M., JR., AND YUNICE, A.: Acute
pressor effects of intra-arterial cadmium and
mercuric ions in anaesthetized rats. Proc Soc
Exp Biol Med 120: 805, 1965.
28. PARIZEK, J.: The peculiar toxicity of cadmium
during pregnancy-an experimental "Toxaemia
of Pregnancy" induced by cadmium salts. J
Reprod Fertil 9: 111, 1965.
29. COOK, W. F., AND LEE, M. R.: The preparation of rabbit renin-substrate for the assay
of minute amounts of renin. Biochem J 96:
413, 1965.
30. SCHROEDER, H. A.: Renal cadmium and essential hypertension: Preliminary communication. JAMA 187: 358, 1964.
31. SCHROEDER, H. A.: Cadmium as a factor in
hypertension. J Chronic Dis 18: 647, 1965.
32. PERRY, H. M., JR., AND SCHROEDER, H. A.:
Concentration of trace metals in urine of
treated and untreated hypertensive patients.
J Lab Clin Med 46: 936, 1955.
33. RUSTAGI, J. S.: Stochastic behavior of trace
substances. Arch Environ Health (Chicago)
8: 68, 1964.
34. SCHROEDER, H. A.: The biological trace elements
or peripatetics through the Periodic Table. J
Chronic Dis 18: 217, 1965.
35. YERUSHALMY, J., AND PALMER, C. E.: Methodology of investigations of etiologic factors
in chronic diseases. J Chronic Dis 10: 27,
1959.
582
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
36. CARROLL, R. E.: The relationship of cadmium
in the air to cardiovascular disease death
rates. JAMA 198: 177, 1966.
37. SCHROEDER, H. A., AND BALASSA, J. J.: Cadmium:
Uptake by vegetables from superphosphate
in soil. Science 140: 819, 1963.
38. MORITSUGU, M.: A study on combination of
glutelin with cadmium in rice grain. Ber
6hara Inst Landw Biol 12: 251, 1964
39. MORrrsuGu, M., AND KOBAYASHI, J.: Study on
trace metals in biomaterial: II. Cadmium content of polished rice. Ber O5hara Inst Landw
Biol 12: 145, 1964.
40. SCHROEDER, H. A.: Relation between mortality
from cardiovascular disease and treated water
supplies: Variations in states and 163 largest
municipalities in the United States. JAMA
172: 1902, 1960.
41. SCHROEDER, H. A.: Relations between hardness
of water and death rates from certain chronic
and degenerative diseases in the U. S. J Chronic Dis 12: 586, 1960.
42. MERTZ, W., ROGINSKI, E. E., AND SCHROEDER,
H. A.: Some aspects of glucose metabolism
of chromium-deficient rats raised in a strictly
controlled environment. J Nutr 86: 107, 1965.
43. SCHROEDER, H. A.: Diabetic-like serum glucose
levels in chromium-deficient rats. Life Sci
4: 2057, 1965.
44. SCHROEDER, H. A.: Chromium deficiency in rats:
A syndrome simulating diabetes mellitus with
retarded growth. J Nutr 88: 439, 1966.
45. SCHWARZ, K., AND MERTZ, W.: Chromium
(III) and the glucose tolerance factor. Arch
Biochem 85: 292, 1959.
46. MERIZ, W., ROGINSKI, E. E., AND SCHWARZ,
K.: Effect of trivalent chromium complexes
on glucose uptake by epididymal fat tissue
of rats. J Biol Chem 236: 318, 1961.
47. YUDKIN, J.: Dietary fat and dietary sugar in
relation to ischaemic heart disease and diabetes. Lancet 2: 4, 1964.
48. GROEN, J. J., BALOGH, M., YARON, E., AND
COHEN, A. M.: Effect of interchanging bread
and sucrose as main source of carbohydrate
in a low fat diet on the serum cholesterol
levels of healthy volunteer subjects. Amer
J Clin Nutr 19: 46, 1966.
49. LEVIN, M. E., AND RECANT, L.: Diabetes and
the environment. Arch Environ Health (Chicago) 12: 621, 1966.
SCHROEDER
50. ALBIUNK, M. J.,
AND
DAVIDSON,
P.
C.: Impaired
glucose tolerance in patients with hypertriglyceridemia. J Lab Clin Med 67: 573, 1966.
51. STREETEN, D. H. P., GERSTEIN, M. M., MARMOR,
B. M., AND DoisY, R. J.: Reduced glucose
tolerance in elderly human subjects. Diabetes
14: 579, 1965.
52. LEVINE, R. A., STREETEN, D. H. P., AND
DoisY, R. J.: Correction of the abnormal
glucose tolerance of some elderly humans by
dietary chromium supplementation. Submitted
for publication.
53. GLINSMANN, W. H., AND MERTZ, W.: Effect
of trivalent chromium on glucose utilization in diabetes mellitus. Metabolism 15: 510,
1966.
54. DONALDSON, R. M., JR., AND BARRIERAS, R. F.:
Intestinal absorption of trace quantities of
chromium. J Lab Clin Med 68: 484, 1966.
55. CURRAN, G. L.: Effect of certain transition group
elements on hepatic synthesis of cholesterol
in the rat. J Biol Chem 210: 765, 1954.
56. SCHROEDER, H. A., BALASSA, J. J., AND TIPTON,
I. H.: Abnormal trace metals in man:
Vanadium. J Chronic Dis 16: 1047, 1963.
57. ROGINSia, E. E., AND MERTZ, W.: Effect of
insulin and chromium (III) on palmitate oxidation. Fed Proc 24: 510, 1965.
58. GLINSMANN, W. H., FELDMAN, F. J., AND
MERTZ, W.: Plasma chromium after glucose
administration. Science 152: 1243, 1966.
59. HoPKINS, L. L.: Distribution in the rat of physiological amounts of injected Cr5l (III) with
time. Amer J Physiol 209: 731, 1965.
60. SCHROEDER, H. A.: Municipal drinking water
and cardiovascular death rates. JAMA 195:
81, 1966.
61. MoRRis, J. N., CRAWFORD, M. D., AND HEADY,
J. A.: Hardness of local water supplies and
mortality from cardiovascular disease. Lancet
1: 860, 1961.
62. BIORCK, G., BOSTR6M, H., AND WIDSTR6M, A.: On
the relationship between water hardness and
death rates in cardiovascular diseases. Acta
Med Scand 178: 239, 1965.
63. KOBAYASHI, J.: Geographical relationship between
the chemical nature of river water and deathrate from apoplexy. Ber Ohara Inst Landw
Biol 11: 12, 1957.
64. SCHROEDER, H. A.: Degenerative cardiovascular
disease in the Orient: II. Hypertension. J
Chronic Dis 8: 312, 1958.
KVE
Circulation, Volume XXXV, March 1967
SPECIAL ARTICLE: Cadmium, Chromium, and Cardiovascular Disease
HENRY A. SCHROEDER
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Circulation. 1967;35:570-582
doi: 10.1161/01.CIR.35.3.570
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