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OAR Box 1126 

Prepped by Ollie Stewart 

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J71) 11-1-285 

Docket Number: 

A-83-22 

Printed 4/18/2008 9:58:24 AM Sheet 71 of 182 
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Environmental Health Perspectives 

Vol. 28. pp. 251-260.1979 

Increase in the Systolic Pressure of Rats 

Chronically Fed Cadmium 

by H. Mitchell Perry,* Margaret Erlanger,* and 

Elizabeth F. Perry* 

In oar laboratory, chronically bed tag cadmium to groups of rats has been reproducftty 1 

average Increases of 15 to 20 nun Hg In systolic pressure. A total of 497 female Long-Evan* rats were 

continuously provided with drinking water fortified wtth five essential dements aad containing from 0.01 

to SO ppm cadmium, as tbe acetate, from weaning for as long as 30 months. These rats, pins 311 matched 

control animals which received fortified water without added cadmium, were fed a apodal low cadmium 

diet. AU 808 rau were weighed at least monthly as a screen for cadmium toxicity, aad their systolic 

pressures were measured every 3 or 6 months. The two lowest concentrations of cadmium tested (0.01 and 

0.03 ppm) were not pressor; the three highest concentrations (10,25, and 50 ppm) sltlindrty proved to he 

toxic. 

All indirect systolic pressures (each measured In triplicate) of aB rats which rsedved 0.1 to 5 ppm 

cadmium (i.e., nontoxic pressor doses) averaged 15.0 mm Hg more than stmuhancously aiissiuiJ pressures of control rats. This average increase over the control pressure is extremely dgnificant statistically, 

even though it seems relatively small in absolute terms. Occasionally, however, some rats had much larger 

than average Increases in pressure; thus, 10 of M rats receiving from 0.1 to 04 ppm cadmiam fcr 18 

months had systolic pressures that were more than 50 mm Hg above thr average pressure of the central 

rats. Cadmium-Induced hypertension is not limited to females or to a particular strata. Although wc have 

asually used ooe strata of female Long-Evans rat from a single source, male* of the same strain aad female 

Sprague-Dawley rats have also developed comparable hypertension. 

All subgroup II elements can apparently Induce similar Increases In systolic puiiuu awaftag IS to 20 

mm Hg, but cadmium Is pressor la much smaller amounts than mercury or shx. Tans, to todace a 

dcnxmtraUe tacrcase in pressure requires more than tm times at much divalent mercnr 

and more than 1000 times as much sine as cadmium. Exposure to another metal along with < 

markedly alter the ability of cadmium to Induce hypertension. Selenium protects against the hy 

Induced by twice as much cadmium. Large excesses of both sine and copper have also Inyhhrd the 

Induction of hypertension by cadmium. In contrast, lead, which Ilk* cadmium, can also bdace hyper-tendon, augments rather than Inhibits cadmium-Induced hypertension; thus, lead and cadmium together can 

Induce an average Increase in systolic pressure la excess of 40 mm Hg, at least twice as large as Is asnaUy 

Induced by either metal alone. 

Introduction 

In 1962, Schroeder et al. first reported that 

chronic cadmium feeding could induce hypertension in rats; their report indicated that the induced 

hypertension was marked (/). They extended these 

observations in 1964 (2). In 1967, however, this 

group of investigators revised the magnitude of the 

induced hypertension sharply downward by considering the average change in pressure for the entire 

exposed rat population rather than just for those 

* Medical Service, Veterans Administration Hospital, and the 

Hypertension Division, Department of Internal Medicine, 

Washington University School of Medicine. St. Louis, Missouri. 

February 1979 

animals which developed hypertension, i.e., the 

"responders" (?). Throughout, these investigators 

used standard conditions, including a standard dose 

of 5 ppm cadmium in drinking water (/). 

My purpose here is to summarize the extensive 

observations which our group has made on the 

blood pressures of rats chronically fed cadmium. 

We were able to confirm that long-term cadmium 

ingestion can induce hypertension, but the magnitude of the effect was less than expected from 

Schroeder's reports. It therefore seemed prudent to 

repeat our observations to demonstrate their reproducibility before starting to investigate 

mechanisms. Thus, much of our work to date has 

been designed to demonstrate the pressor effect and 

251 

cr 
to define its magnitude and the amount of exposure 

necessary to evoke it. Two general types of data are 

presented below. The first deals with the 

cadmium-induced effects on blood pressure and the 

second with the changes in these effects brought 

about by other metals. 

We have studied eight populations of animals, involving a total of 808 Long-Evans female rats, 

which were handled under standard conditions and 

exposed to cadmium alone in one of 10 concentrations, ranging from 0.01 to 50 ppm, or used as 

litter-mate controls for such animals. The average 

systolic pressures cited were obtained from groups 

which initially contained at least IS rats; in determining these averages all animals in the group were 

included. Six groups of rats totaling 144 animals 

were exposed to 5 ppm cadmium, duplicating 

Schroeder's standard conditions; the average 

cadmium-induced increases in systolic pressures for 

the groups ranged from 6 to 23 mm Hg. 

Since the 5 ppm cadmium dose is considerably 

above the intake of the average adult American (on 

the basis of milligrams cadmium ingested per kilogram body weight), a range of cadmium exposures 

was tested. Essentially the same pressor effect was 

found with exposures ranging from 0.1 to 5 ppm 

cadmium. Exposures below 0.1 ppm had little pressor 

effect, and exposures above 5 ppm were eventually 

toxic. Although separate subpopulations of blood 

pressure "responders" and nonresponders could 

not be recognized in most of our rat populations, at 

least one unusually responsive subpopulation developed marked hypertension following exposures 

to less than 1 ppm cadmium. Having confirmed 

cadmium-induced hypertension in female LongEvans rats, the effect was shown to occur in males 

and in another strain of rats; thus 5 ppm cadmium 

was pressor for male Long-Evans and female 

Sprague-Dawley rats. 

* Our initial cadmium-feeding studies in 1970 adhered as rigorously as practical to the standard experimental conditions established by Schroeder's group (/); we obtained our rats, and even 

our rye, from the same suppliers. We argued that failure to induce hypertension would not be definitive if the conditions were 

altered. However, because the plastic cages with stainless steel 

lids, which Schroeder used, placed severe constraints on the 

number of animals we could follow at any one time, our original 

experiment tested both the plastic cages with stainless steel lids 

and all stainless steel cages. The same degree of hypertension, 

i.e., difference between the pressures of the cadmium-exposed 

and control rats, was apparently induced in both types of cages, 

although the average systolic pressure of both the control and 

cadmium exposed populations were higher by almost 10 mm Hg 

in the stainless steel cages (4). In order to use large numbers of 

rets, we opted to work with the much more convenient stainless 

steel cages and accept the higher control pressures. Except for 

this single experiment where we tested the plastic cages, we have 

used the stainless steel cages throughout. 

Because of the modest size ofthe average pressor 

effect associated with cadmium, conditions were 

sought whjch might increase its magnitude. It was 

observed that all subgroup II metalst.can induce 

similar hypertension, although cadmium is effective 

at much lower concentrations than either nonessential mercury or essential zinc. Moreover, 

when exhibited with cadmium, at least three metals 

inhibit the pressor response to cadmium: selenium, 

zinc, and copper. In contrast, at least one metal, 

lead, can significantly augment the pressor response 

to cadmium. 

Methods 

Groups of at least IS weanling female LongEvans rats from Blue Spruce Farms in Altamont, 

New York, were treated as described by Schroeder 

(/) and modified slightly in our laboratory (4. 5).* 

On arrival, the rats were placed in a low contamination environment; they were all fed the same ryebased low-cadmium diet ad libitum and given free 

access to fortified drinking water containing any 

metals which were to be exhibited. Like the diet, 

the drinking water was made as described by 

Schroeder. It consisted of deionized water with a 

resistance of 5 megohms "fortified" by the addition 

of cobalt (1 ppm), molybdenum (I ppm), copper (5 

ppm), manganese (10 ppm), and zinc (50 ppm) (/, 5). 

Random batches of the diet were assayed regularly 

and found to contain an average of 0.0137 ± 0.0019 

(SD) ng cadmium/g food. For the other trace metals 

that were assayed, the following average amounts 

(in fig/g) were found: zinc, 35; mercury, < 0.005; 

selenium, 0.37; iron, 42; manganese, 23; copper, 

3.3; nickel, 0.29; and chromium, < 0.05. In addition, the following average amounts (in mg/g) of 

other metals were present: sodium, 5.9; calcium, 

3.8; potassium, 7.6; and magnesium, 1.4. Food intake throughout the life of the rat averaged approximately 20 g/rat/day. 

The metals to be tested were administered in 

drinking water made by dissolving cadmium, zinc, 

or lead acetate, mercuric or cupric chloride, or 

sodium selenite in the "fortified" deionized water. 

(Studies with radioactive tracers indicated that 

there was no significant precipitation and that all 

metals remained in solution. The only exception to 

this was in some experiments with hard water, not 

considered here.) Although there was variability 

between both individual and group means, the average intake of water for a single rat approximated 15 

ml daily at the start ofthe experiment and rose in a 

roughly linear fashion to about 25 ml by 12 months 

after which it remained relatively constant. 

Systolic pressure was determined in triplicate in 

4 

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J 

1 

5 

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lightly 

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252 Environmental Health Perspectives 
lightly anesthetized (0.2S mg intraperitoneal 

pentobarbital/kg body weight) animals by the tail 

cuff method, as previously described (5). [Although 

only systolic pressure is reported here, consistently 

parallel changes in systolic and diastolic pressures 

have been regularly observed and previously reported (4). Direct determination of diastolic pressure requires canulation of the artery which is a 

major procedure and results in sacrifice of the vessel. It cannot therefore be routinely used for serial 

blood pressure determinations. The directly determined systolic pressure averaged 6 mm Hg lower 

than the indirectly measured pressure.] During their 

entire stay in our laboratory, animals were removed 

from their cages for only two purposes: (a) determination of systolic pressure at intervals of three to six 

months and (b) weekly cage cleaning and group 

weighing. Measuring pressure was done at long 

intervals to ensure that the animals were uninfluenced by the anesthetic or its after effects for the 

very large majority of their lives. Weighing was 

used as an index of group well-being. Except as 

specifically indicated below, the average weights of 

the experimental groups did not differ significantly 

from those of the control animals. 

Results 

Standard 5 ppm Cadmium Exposure 

We have measured the effect ofthe standard exposure to drinking water containing 5 ppm cadmium 

in six separate populations of female Long-Evans 

rats. The average cadmium-induced increases in 

systolic pressure are shown at four different times 

in Figure 1. After six months of cadmium exposure, 

the average difference in systolic pressure between 

the cadmium-fed groups, which totalled 144 animals, and their 267 control animals was 12.4 mm 

Hg, with a standard deviation of 13.9 mm Hg. This 

difference was statistically significant with ap value 

of < 0.001 (t = 8.88). The average difference rose to 

16.6 mm Hg after 12 months (/ = 6.55) and became 

maxima] at 21.5 mm Hg after 18 months (t «= 8.38). 

The six separate populations of rats exposed to 5 

ppm cadmium all had similar pressor responses 

(Table 1). After six months, all six had mean increases in systolic pressure, which ranged from 6 to 

20 mm Hg and averaged 12.4 mm Hg. After 12 

months, the mean increases ranged from 9 to 22 mm 

Hg and averaged 16.6 mm Hg. 

Range of Cadmium Exposures 

In Figure 2, the average cadmium-induced increase in systolic pressure is examined as functions 

of two aspects of exposure, its length and the dosage used. Increases with successively doubled exposure periods from 3 to 24 months and a 

hundred-fold range of cadmium concentrations 

from 0.1 to 10 ppm are presented. The lowest cadmium concentration and the shortest exposure induced only a small increase in pressure, averaging 5 

mm Hg. The same concentration and doubled exposure induced an increase of 10 mm Hg. The remaining bars from left to right in the graph generally 

trended slightly upward from the 10 mm Hg increase toward an increase of 15 mm Hg. 

-\&-r.. 

•j-tf. 

. ; *«a«i » 

T-afV* : 

Table 1. 

DateCd 

feeding 

began 

Increase In systolic pnasit in six separate experiments alter 6 and 12 months exposure to standard 5 ppm cadmhun.* 

6 months cadmium feeding „ t|i# r . „ miii m f ^ ifl f 

Comrol ippmC d u>nmm r „ ntm , , ppil l rA Inr „ w 

No. of Mean * SD, No. of Mean * SD mean, mean * SD mean * SD, mean, 

rats mm Hg tats (mm Hg) mm Hg mm Hg mm Hg mm Hg 

Oct. 21 '70» 

Aug. 7 '74 

Mar. 26 '75 

Aug. 18 '76 

Dec. 1 '76 

Sept. 1 '77 

Total 

(64) 

(60) 

(40) 

(43) 

(15) 

(45) 

(IffJf 

112 * 1? 

9 9 * 13 

106 ± 8 

103 * 12 

103 ± 12 

99 a 11 

164.1 * lJ.S 

(32) 

(20) 

(20) 

(42) 

(15) 

(15) 

<W 

125 £ 17 

112 * 11 

112 * 12 

115 * 12 

113 * 12 

119 ± 11 

lid J * 13.9 

13 

13 

6 

12 

10 

20 

ITT 

110 * 1 * 

102* 9 

103 ± 13 

9 8 * 18 

107 ± 9 

127*2 0 

111 * 

119* 

117* 

129* 

10 

13 

18 

10 

16 

9 

16 

19 

22 

163.3 * l3.l 119.9 * ld.8 "RT 

• Average systolic pressures * standard deviations (SD) at 6 and 12 months are tabulated for all rats exposed to the standard 5 ppm 

cadmium under standard conditions. In addition, the numbers of rats included at 6 months are tabulated (in parenthesis); the numbers 

were essentiaUy the same at 12 months. Finally, the average cadmium-induced increases in systolic pressure at 6 and 12 months are also 

tabulated. 

• The October *70 experiment included a second population of control rats housed in plastic cages designed to decrease contamination, as described by Schroeder (/). These rats had an average control pressure of 103 mm Hg (<); they have not been included here 

because they were not handled in our standard manner. The small numbers (5 per group) of "Population II" rau from the October '70 

experiment have not been included here; their pressures have been reported previously (5). 

' The control pressures in our first experiment averaged almost 10 mm Hg higher than in subsequent experiments, possibly because 

our technique for excluding environmental cadmium was less well developed. 

February 1979 253 

..fusn^iv^sitts.. 
M -

10-

18-

w5-

0-

144 

13.9 

.001 

126 

16.8 

.001 

76 

17.5 

.001 

15 

21.7 

.05 

12 I I 24 

• 

S.D. 

f 

Mos. 

FIGURE 1. Pressor effect from varying exposure to standard 5 

ppm cadmium. Average increases in systolic pressure of six 

rat populations exposed to 5 ppm cadmium for 6, 12, 18, and 

24 months. The numbers of rats involved in each average, the 

standard deviation, and the statistical significance ip value) 

are indicated by the numbers in the columns. All increases 

have been corrected for any change in the average systolic 

pressure of litter-mate control rats handled similarly but 

without cadmium (see Table 1). 

-= 24-i 

= 16-

£ 8 

- 0 

S 

• -4 

• » 

1 

0.\„mU 1.0 ppn U 10M-1 

FIOURE 2. Pressor effect as fkinction of length and intensity of 

cadmium exposure. Average changes in systolic pressure induced by three dosage levels of cadmium after successively 

doubled exposure intervals. Initially there were 15-60 rets in 

each cadmium-fed group, and 45-75 control rats against which 

increases in pressure were measured. 

With groups of the size used here, there is some 

uncertainty regarding any specific difference cited 

in the graph. For example, although the effect of 0.1 

ppm cadmium during the first year of exposure was 

somewhat smaller than the effect of 1.0 or 10 ppm, 

at subsequent times not shown on the graph, the 

increases were relatively large (i.e., at 15,18. and 21 

months, they averaged 16, 18, and 15 mm Hg, respectively). There is some confirmation for the unusually large increase of 25 mm Hg after 24 months 

exposure to 1 ppm cadmium, since 2.5 ppm cadmium induced a comparable increase of 24 mm Hg 

at 24 months. These large increases involved relatively small numbers of rats; the two groups included only 9 and 12 two year survivors, respectively. There was little uncertainty, however, about 

the decrease in pressure after 24 months of exposure to 10 ppm cadmium; this change was typical of 

a consistent pattern of toxicity following prolonged 

exposure to high concentrations. Incipient toxicity 

was already evident at 18 months when the induced 

change in pressure, although still positive, averaged 

only 7 mm Hg, as shown in Figure 3. 

Table 2 summarizes our average systolic pressure 

data for groups of rats exposed to cadmium alone 

under our standard conditions. At one extreme, we 

never observed an average increase in pressure of 

as much as 10 mmHg with exposures of 0.01 or 0.03 

ppm cadmium, although the increase after 12 

months was of borderline significance (p < O.OS). 

raising the question of whether some rats may have 

a pressor response to even these low concentrations 

(6). At the other extreme, there was an early increase in pressure for the 50 ppm group (p < 0.025 

after 6 months exposure), but thereafter that exposure was depressor; this concentration was overtly 

toxic and markedly inhibited growth in weanlings 

from the very first. Similarly, 25 ppm cadmium induced an increase in pressure for a year ip < 0.005 

at 6 months andp < 0.025 at 12 months), but it then 

became depressor; it too inhibited growth, albeit 

minimally. A level of 10 ppm cadmium was significantly pressor for a year, but from 18 to 30 months 

there was stepwise conversion of its pressor effect 

to a depressor effect; it never inhibited growth significantly. [Additional data for high cadmium exposures are available (5)]. 

For the intermediate concentrations from 0.1 to 5 

ppm cadmium, the average increases in pressure 

ranged from 5 mm Hg for the former after three 

months of exposure to 33 mm Hg for the latter after 

30 months of exposure. Three quarters of the 38 

tabulated averages for this intermediate range of 

concentrations represent increases of 10 to 20 mm 

Hg, suggesting that this is the usual response to a 

wide range of cadmium exposures under our standard co 

exposui 

pf 15 to 

trations 

Subpo 

Alth> 

pressu 

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v \ 

£ e 

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3 

6 

9 

12 

15 

18 

21 

24 

30 

Tc 

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254 Environmental Health Perspectives 
dard conditions. From the data for 18 months of 

exposure, the relatively constant average increase 

of 15 to 20 mm Hg to a range of cadmium concentrations is well shown in Figure 3. 

Subpopulation of Cadmium Responders 

Although the distribution pattern of individual 

pressures following cadmium exposure was difficult 

I 

-17 

0.01 0.10 0.1S 0.50 1X1 tS 5.0 10 \ 25 

part* fn ailliM CWaiMi 

FICUR£ 3. Exposure to average changes in systolic pressure induced by nine exposure levels of cadmium (0.01 to 25 ppm 

Cd) for 18 months. At this time, there were still at least 13 rats 

in all groups, and the groups exposed to 0.1,5, and 10 ppm Cd 

each contained more than 30 rats. 

to define precisely because of relatively small sample size, distribution usually appeared to be relatively normal (4). Occasionally, however, there 

seemed to be a subpopulation of responders in 

which cadmium induced marked hypertension. This 

phenomenon was most obvious for our August 7, 

1974, experiment involving 140 rats. After 18 

months, one-sixth ofthe rats exposed to 0.1, 0.25, 

and 0.5 ppm cadmium had systolic pressures which 

exceeded the control mean by four standard deviations, i.e., by 50 mm Hg. In contrast, none of the 

litter-mate controls or 5 ppm cadmium rats had this 

degree of hypertension (Table 3) (7). 

Pressor Response of Male and SpragueDawley Rats to Cadmium 

Since our early work was limited to female 

Long-Evans rats, it seemed important to demonstrate that the effect was not limited to one sex or 

one strain of rats. We, therefore, tested the standard 5 ppm cadmium in male Long-Evans rats and 

in female Sprague-Dawley rats. After a year of exposure, cadmium had induced a typical increase of 

17 mm Hg in the males, although both control and 

cadmium-exposed males had higher pressures than 

females (8). The data for the female SpragueDawley rats were more limited because the colony 

Table 2. Mean Increase la systolic pressure after varying cadmium exposure.' 

Months of 

Cd feeding 

3 

6 

9 

12 

15 

18 

21 

24 

30 

Totals' 

Means' 

No. of 

control 

rats 

tested 

175 

311 

58 

238 

166 

191 

32 

85 

21 

TiT 

105.0 

No. of 

Cdfed 

rats 

(total) 

165 

463 

56 

341 

211 

263 

30 

118 

39 

457" 

0.01 

ppm 

-I 

9 

2 

0 

Jo" 

0.03 

ppm 

0 

8 

3 

1 

25 

105.7 106.3 

Increase in systolic pressure at various levels of 

cadmium in drinking water from time of 

0.10 

ppm 

5 

10" 

9» 

12* 

18* 

15 

(I2f 

S T113.1 

0.25 

ppm 

22 

12 

12 

19 

(7) 

55" 

115.5 

0.50 

ppm 

11 

11 

10 

14 

(15) 

55" 

112.6 

1.0 

ppm 

14 

9». 

I3» 

17 

(14) 

(25f 

&r~ 117.5 

2.5 

ppm 

6 

10" 

15 

16 

(24) 

(17/» 

44 

125.1 

weaning 

5.0 

ppm 

12 

12" 

16" 

17" 

I2» 

2 2" 

(ID 

17 

(33)« 

144 

120.0 

mm Hg* 

10 

ppm 

12 

15** 

13* 

7* 

- 4 

(-12)" 

~W 117.8 

25 

ppm 

12 

9 

-17 

(-20) 

(-14)' 

16 

113.6 

50 

ppm 

II 

-13 

(-12) 

(-27) 

(-30f 

16 

108.1 

* Average increases in systolic pressure of cadmium-fed rats (corrected for any change in average control pressure) are tabulated for 

totals of 311 control rats and 497 cadmium-fed rats. Eight separate experiments with eight different populations of rats are included (one 

begun in May and another in September of 1973, which involved no rats exposed to 5 ppm cadmium, plus the six listed in Table I). This 

comprises all of our systolic pressure data on groups of 10 or more rats fed cadmium alone under standard conditions. 

* All entries which include data from more than 30 rats are marked with one asterisk, and those with data from more than 50 rats are 

marked with two asterisks. No group contained less than 15 rets at the outset of the experiment; any subsequent averages which 

included data from fewer than 15 rats have been placed in parentheses; and a superscript indicates the actual number when fewer than 

10 rats were included, The standard deviations ofthe tabulated averages ranged from 9 to 39 mm Hg, with 9/10 pf them being less than 

20 mm Hg and K less than 15 mm Hg. Using Student's / test, a change of 8-9 mm Hg usually hadp < 0.05, and one of 12 or more mm 

Hg had p < 0.001 mm Hg. 

' The totals row of the table indicates the number of rats which began a given exposure. The values in columns 2 and 3 are not 

obtained by summing the nine entries in the column, since each ret had its blood pressure measured more than once. 

' Means were obtained by averaging each pressure obtained from each rat. The values are lowered by the relatively low values after 

short exposures, and they are also moderated by the decreasing number of rets which survived long exposures. 

February 1979 255 

A&&$MiMj£-
developed a respiratory infection after nine months 

of cadmium exposure, but at six months there was a 

significant pressor effect in the cadmium-fed animals as compared to the controls (5). 

SimUar Pressor Responses to All Subgroup 

II Metals 

Chronic feeding of an appropriate concentration 

of any subgroup II metal is pressor in female 

Long-Evans rats. Although our data on zinc and 

mercury are not extensive and therefore have considerable uncertainty, all three subgroup II metals 

appear to induce average increases of 15 to 20 mm 

Hg in the systolic pressure, but the inducing doses 

differed by more than a thousand-fold (Table 4). 

Moreover, there is no pressor response when the 

challenging dose is increased to overtly toxic doses 

of nonessential cadmium or mercury. 

The pressor response to chronically ingested 

cadmium has been described above. Exposure to 5 

or 10 ppm mercuric ion for 12 months was pressor, 

whereas neither 2.5 nor 25 ppm was pressor, with 

the latter concentration being toxic (4). The situation was more complicated in the case of zinc which 

is essential and present to the extent of 35 ppm in 

our standard diet and to the extent of 50 ppm in the 

"fortified" water eaten and drunk by all of our rats. 

No effect on pressure was observed if the zinc in the 

water was decreased from 50 ppm to zero; however 

if it was increased from 50 to 75 ppm, the typical 

pressor response to cadmium and mercury was observed (9). Both 100 and 200 ppm zinc were pressor, 

and no search was made for a larger toxic but nonpressor concentration of zinc. 

Inhibition of Cadmium Effect by 

a Second Metal 

A second metal can either inhibit or enhance 

cadmium-induced hypertension. The three essential 

metals: selenium, zinc, and copper have each been 

shown to inhibit the pressor effect of cadmium; inhibition has ranged from 60 to 100%. Table 5 presents our copper data and the data for one of three 

similar experiments involving selenium and zinc. 

The inhibition studies were among our early experiments and were carried out while we were still 

using relatively large cadmium exposures. In brief, 

the pressor effects of both 2.5 and 10 ppm cadmium 

were inhibited by half as much (i.e., by half the 

molarity of) selenium (10). The pressor effects of 2.5 

and 10 ppm cadmium were also inhibited by 100 and 

200 ppm (i.e., by 70 and 35 times the molarity of) 

zinc. The pressor effect of 5 ppm cadmium was also 

inhibited by 20 ppm (i.e., by 8 times the molarity of) 

— . I 

Inhibitor 

expos"* 

level. | 

ppmj. 

Se (0») 

Se 0-3) 

zndpor 

Zn(W»y 

Cuj^__ _ 

• tteconct 

inhibiting"*' 

provide the" 

cadmium alo 

• The»eefl 

zinc were sn 

»;Since tnexie»sesof 

copper £)• 

copper. / 

pressor; 

signifies 

fir selcr, 

Table 3. Dtstrflmttoa of systolic (SP) fcr ew rat population' 

Cadmium 

dose, 

ppm 

Mean SP ± SD 

after 18 months. 

mm Hg 

Rau with SP more than 

2 SD above control mean, 

% > 125 mm Hg 

Rats with SP more than 

4 SD above control mean, 

* > 150 mm Hg 

0 

0.1 

0.25 

0.5 

S.O 

100.5 * 12.4 

124.3 * 15.1 

119.6 ± 19.8 

114.5 £ 16.9 

114.0 ± 15.0 

4 

33 

44 

20 

13 

0 

17 

19 

13 

0 

* There were initially 60 control rats and 20 rats per experimental group. One-sixth of the rats exposed to 0.1,0.25, and 0.5 ppm 

cadmium for 18 months had systolic pressures which exceeded the mean pressure of the control rats by more than four standard 

deviations (SD). No control ret and no rat exposed to the standard 5 ppm cadmium had this great a pressor response. Tne data 

presented here constitute a single complete experiment, i.e.. a single complete population. 

Table 4. Pressor effects of chronically hading subgroup II 

Response to minimum pressor dose 

Ion 

Minimum 

toxic 

dose. 

fiM* 

Minimum 

pressor 

dose, 

M W 

Number of 

rats 

tested 

Exposure 

Dose, 

ppmLength, mos 

Mean 

SPiS D 

increase, 

mm Hg Reference 

Zn** 

Cd»* 

Hg" 

89 

125 

1100 

0.89 

25.0 

14 

55 

16 

75 

0.1 

5 

15 

6 

12 

2 0 * 18 

10 £ II 

16 i 12 

(«) 

This report 

V) 

• Minimum pressor and toxic metal concentrations in drinking water are presented in micromoles per liter to allow comparison 

between metals while the doses in cited experiments are given in parts per million to conform with the rest ofthe manuscript. Thus the 

concentrations of the third and fifth columns are tbe same. Toxic doses were not pressor. 

256 Environmental Health Perspectives 

•s-" 

f^^-^-^^^^MiA'A 
P.8 

he 

al Inhibitor 

exposure 

level. 

ppm 

Se (0.9) 

Se(35) 

ZadOOf 

Zn(200f 

Cu(20X 

Tabic S. Inh&kta of cadmium-Induced kypertcBstoa by a seen 

Cadmium 

exposure 

level, 

ppm 

CS) 

(10) 

a.5) 

(10) 

(50) 

Pressor effect of inhibitor alone, 

% of Cd effect 

6 Mos 

133 

39 

None 

30 

None 

12 Mos 

40 

35 

167 

MP 

32 

id metal.* 

Inhibitory action of 

inhibitor + cadmium, 

% decrease in Cd effect 

6 Mos 

Complete 

72* 

Complete* 

67» 

92* 

12 Mos 

93 

Complete* 

60 

6<P 

89* 

* The concentrations of inhibiting metals and of cadmium are presented in the first two columns, and the pressor effects of the 

inhibiting metals alone and their inhibition of the cadmium pressor effects are presented in the next four columns. Four groups of rau 

provide the dau for each of the five rows of figures in the table; there was a group with neither cadmium nor inhibitor, a group with 

cadmium alone, a group with inhibitor alone, and a group with both cadmium and inhibitor. 

* These effecu were statistically significant with p < 0.01. The size of the groups of animals receiving 0.9 ppm selenium and 100 ppm 

zinc were small, and these dau are included primarily to indicate trends. 

' Since the "fortified" drinking water contained 50 ppm zinc and 5 ppm copper, the zinc concentrations used here represented 

excesses of SO and ISO ppm zinc above that given to the control rats, and the copper concentration represented an excess of 15 ppm 

copper (8). 

copper. As indicated previously, zinc itself can be 

pressor; moreover, a possible, but not statistically 

significant, pressor effect has also been observed 

for selenium, but not for copper (Table 5). 

Augmentation of Cadmium Effect by Lead 

Unlike the metals mentioned above, lead augmented the pressor effect of cadmium. By itself lead 

produced a pressor effect comparable to that produced by cadmium. In two separate experiments, 

when lead and cadmium were administered together, their effects were at least additive. The first 

experiment involved only one concentration of each 

metal but has now continued for 18 months; the 

second involved three concentrations but began 

only six months ago. Figure 4 presents the largest 

average increase in systolic pressure we have yet 

observed. This increase occurred after three 

months exposure to 1 ppm of both metals; it averaged 43 mm Hg -'—""J\\r i—TT*—rl —fan """* was 

more than three^imffThe average increase 

either cadrnjtffhor lead alone. In the same experi: 

ment, tariidditive pressor effect was also seen with 

a smaller concentration (0.1 ppm) after a longer exposure (6 months). Thus, the average systolic pressure for 45 control rats was 99 mm Hg. The average 

increase in the systolic pressure for 15 rats exposed 

0.1 ppm cadmium for six months was 13 mm Hg. 

e average increase for 15 rats exposed to 0.1 ppm 

idad was 10 mm Hg, and the average increase for 15 

rakexposed to 0.1 ppm of both cadmium and lead, 

wasiTmm Hg(//). 

DISCUJ 

Description of Findings by Others and Possible Explanation of Seeming Discrepancies 

The data presented here indicate that, with slight 

modifications of Schroeder's standard conditions. 

Environmental Health Perspectives 

we were able to confirm his observations that 

long-term, low-dose cadmium feeding can induce 

hypertension. There are some other published confirmatory data, but they are sparse. Sorenson et al. 

have reported a pressor effect in male rats following 

chronic cadmium feeding (12), and Ohanion has reported a cadmium-induced pressor response in 

"Dahl hypertension-sensitive" rats (13). These few 

confirmatory observations must be coupled with 

equally sparse reports of failure to induce hypertension with cadmium feeding (14-16). 

The paucity of positive reports could be related in 

part to the long lag period inherent in such experiments, and there may be various partial explanations for the several reported failures to induce 

hypertension by chronic cadmium feeding. 

Schroeder made the original observation in 1962 (/) 

and was able to repeat it many times (2, 3, 17). Our 

initial confirmation by abstract was in 1971 (18); our 

preliminary paper was in 1974 (4), and a complete 

report was not made until 1977 (5). In attempting to 

confirm Schroeder's observations, we opted to 

yadhere as closely to his conditions as possible, obining our rats and initially even our rye from his 

jppliers, feeling that we would have to repeat his 

iperiment with no deviations, if we altered his 

tmditions and failed to induce hypertension. Since 

lopting his conditions, we have observed 

Cadmium-induced hypertension in each of eight exr

periments carried out in our laboratory. Minor 

changes in the experimental conditions, which have 

been consistently used in both Schroeder's laboratory and in our laboratory, may well be very important. We have already found it possible both to 

inhibit the effect completely and to augment it 

markedly. Perhaps the rye-based diet is particularly 

well suited for such experiments since Schroeder's 

group and our group have both used it exclusively 

as the major dietary ingredient. 

257 
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^jia^»a^^.'u.-.-^Yfiiii,i1|- i * •-•' ^ . 

Because ofthe large range of cadmium exposures 

which can produce a near maximal pressor response, minima] unrecognized exposure could lead 

to hypertension in the control group which would 

then mask any hypertension in the experimental 

group. As little as 0.1 ppm cadmium in drinking 

water, amounting to an intake of about 2 fig of cadmium per day, induces hypertension, and there is 

frequent failure to realize the potential for unrecognized cadmium exposure in the usual animal facility. Likewise there has been frequent failure to 

realize that toxicity, which seems to be incompatible with hypertension, may be induced by what is 

often considered as moderate cadmium exposure. 

Facilities which can minimize extraneous cadmium 

exposure and still maintain healthy animals for 

years are rare, yet both conditions seem to be important. Anything which renders the animals 

overtly sick or even prevents them from gaining 

weight and growing in an optimum manner seems 

liable to inhibit cadmium-induced hypertension. 

Intercurrent pneumonia proved to be by far the 

most common such problem in our rat colonies 

during the 1960's. 

Cadmium-induced hypertension may also have 

been overlooked because it was not as marked as 

indicated in Schroeder's original descriptions (/, 2). 

j 150-i 

.5 140 -

«/» 

«/» 

130-

120-

110-

100

 J 

FIGURE 4. Augmentation of cadmium-induced hypertension by 

lead. Average systolic pressures ± standard deviations are 

presented for 45 control rats and for groups of 15 rats fed I 

ppm cadmium and/or lead for three months. 

258 

There is frequent failure to realize that his subsequent reports indicated much lesser degrees of 

cadmium-induced hypertension (3) and that the 

large average increase in pressure which was initially reported was limited to a group of "responders." As indicated in Table 3, we have observed 

subpopulations of responders (7), but they are the 

exception rather than the rule. 

Possible Mechanisms and Significance of 

Cadmium-Induced Hypertension 

The mechanism of the hypertension induced in 

rats by chronically feeding them low doses of cadmium has not been defined, although the following 

effects of injected cadmium suggest several possible 

mechanisms: (a) increased sodium retention (15, 

(19); (b) direct vasoconstriction (20); (c) hyperreninemia (2/); and (d) increased cardiac output 

(20). Although hyperreninemia has been observed 

following fed as well as injected cadmium (2/), the 

acute hypertensive effect of injected cadmium is not 

dependent on renin (22). On the other hand, although increased cardiac output has only been observed immediately after intraarterially injected 

cadmium, the standard 5 ppm dose of cadmium can 

produce significant cardiac effects; thus, Kopp, 

working with animals exposed to 5 ppm cadmium 

for 18 months in our laboratory, has observed depressed myocardial excitability, decreased high 

energy phosphate in the heart, and morphologic 

changes in cardiac muscle (25). Finally, without 

elucidating mechanism, "hypertension-sensitive 

Dahl rats" show a greater pressor response to intraarterial cadmium than do "hypertensionresistant Dahl rats" Q4). 

There is considerable variability in human exposure to environmental cadmium, and many of the 

details involving accumulation of the metals in man 

remain to be worked out. In the United States, the 

average cadmium intake is estimated to be 50 /ig/ 

day or just below 1 pg/kg-day (.25). After 40 or 50 

years, this results in an average renal cadmium concentration of 30/xg/g of kidney or 3 mg/g of renal ash 

(26). Rats ingesting the lowest pressor dose of cadmium (0.1 ppm) have an intake of about 5 fig/kgday; after 18 months of this intake, their kidneys 

contain 1 /tg/g (6). Thus, they ingest about five 

times as much cadmium (per unit body weight) as 

the average American, but their renal cadmium 

concentration is only one-thirtieth as high. Rats exposed to 5 ppm have renal cadmium concentrations 

of about 40 /ig/g (5), which is similar to the average 

for adults in this country. 

Cadmium-induced hypertension in rats, although 

reproducible, is usually relatively small in magEnvironmental Health Perspectives 

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nitude and thus frequently considered of little consequence; however, most human hypertension is 

.mild. Of the 60 miUion Americans who are now estimated to have hypertension (27), more than 80% 

have diastolic pressures which are usually below 

105 mm Hg. Nonetheless, in man at least, even such 

mUd elevations in blood pressure double the risk of 

heart attack and stroke, the major cardiovascular 

causes of disability and death (28). Moreover, like 

cadmium-induced hypertension in rats, mild essential hypertension in man has no obvious associated 

findings. In rats, the small amounts of cadmium that 

induce hypertension produce none of the usual 

toxic manifestations of more extensive exposure to 

cadmium, while, in man, the absence of symptoms 

is a major part of the problem in identifying mild 

hypertension and convincing the involved individuals of its ominous prognostic significance. 

It must be emphasized that heavy, and certainly 

toxic, cadmium exposure is not associated with 

hypertension in rat or man. In rats 0.1 to 5 ppm 

cadmium induces hypertension but 10 to 50 ppm 

cadmium does not or only does so during the early 

portion of the exposure before toxicity becomes 

evident. In man, itai-itai disease and chronic cadmium poisoning are not characterized by hypertension Q9); moreover, individuals with malignant 

hypertension and shrunken kidneys, consisting almost entirely of scar tissue with little parenchyma, 

have no excess renal cadmium (30). If cadmium 

plays any part in human hypertension, it is early in 

the course of the disease. By the time severe 

hypertension and compromised renal function have 

occurred, most of the accumulated renal cadmium 

has presumably been excreted in the urine in association with urinary protein. 

Although the evidence that feeding cadmium can 

induce hypertension in rats seems convincing, there 

is no comparable evidence that cadmium is responsible for any part of human essential hypertension. 

The cause of essential hypertension remains unknown, however. For the moment, it can only be 

said that cadmium is a ubiquitous environmental 

contaminant which is frequently present in concentrations which can induce hypertension in rats and 

which, in animals at least, can have other cardiovascular effects Q3). For the present it would 

certainly seem prudent to minimize cadmium exposure as much as economically practical while seeking answers as to whether cadmium has any effect 

on human blood pressure, or whether it produces 

any other undesirable effects. 

Conclusions 

Under the conditions originally reported by 

Schroeder and slightly modified in our laboratory. 

chronic ingestion of low doses of cadmium by rats 

reproducibly induces an increase in systolic pressure averaging 15 to 20 mm Hg. Occasionally the 

response is considerably larger, and the simultaneous exhibition of other metals can markedly influence it, with lead having the potential to at least 

double it. The extent, if any, to which these observations can be extrapolated from rat to man remains 

to be demonstrated. It is tempting to speculate 

whether these currently largely descriptive findings 

can be related to epidemiologic data of the type 

which associate cardiovascular mortality in man to 

the hardness of his water supply (31). The subject of 

the possible relationship between environmental 

cadmium and human hypertension certainly warrants further investigation. 

This research was supported by the Veterans Administration. 

REFERENCES 

1. Schroeder, H. A., and Vinton, W. H.. Jr. Hypertension in 

rats induced by small doses of cadmium. Am. J. Physiol. 

202: 515 (1962). 

2. Schroeder, H. A. Cadmium hypertension in rats. Am. J. 

Physiol. 207: 62 (1964). 

3. Schroeder, H. A., and Buclunan, J. Cadmium hypertension. 

Its reversal by a zinc chelate. Arch. Environ. Health 14:693 

(1967). 

4. Perry, H. M., Jr.. and Erlanger, M. VV. Metal-induced 

hypertension foUowing chronic feeding of low doses of cadmium and mercury. J. Lab. Clin. Med. 83: 541 (1974). 

5. Perry, H. M.. Jr., Erlanger, M. VV.. and Perry, E. F. Elevated systolic pressure following chronic low-level cadmium 

feeding. Am. J. Physiol. 232: HI 14 (1977). 

6. Perry, H. M.. Jr., Erlanger, M. W., and Perry, E. F. Hypertension following chronic very low dose cadmium feeding. 

Proc. Soc. Exptl. Biol. Med. 156: 173 (1977). 

7. Perry, H. M., Jr., and Erlanger, M. W. Marked increases in 

rat systolic pressure following very low but prolonged cadmium feeding. Fed. Proc. 27 (3): 294 (1978). 

8. Perry, H. M., Jr., Erlanger, M. W., and Perry, E. F. Limiting conditions for the induction of hypertension in rats by 

cadmium. Trace Substances in Environmental Health, D. D. 

Hemphill, Ed., University of Missouri, Columbia, Mo., Vol. 

10. 1976. p. 459. 

9. Perry, H. M., Jr., and Erlanger, M. W. Effect of a second 

metal on cadmium-induced hypertension. In: Trace Substances in Environmental Health, D. D. Hemphill, Ed., University of Missouri, Columbia, Mo. Vol. II, 1977, p. 280. 

Perry, H. M., Jr., Perry, E. F„ and Erlanger, M. W. Reversal of cadmium-induced hypertension by selenium or hard 

water. In: Trace Substances in Environmental Health, D. D. 

Hemphill, Ed., University of Missouri, Columbia, Mo.. Vol. 

8, 1974, p. SI. 

Perry, H. M., Jr., and Erlanger, M. W. Hypertensive effect 

of chronically feeding very low concentrations of lead and 

cadmium together. In: Trace Substances in Environmental 

Health, D. D. Hemphill, Ed., University of Missouri, Columbia, Mo., Vol. 12,1978, in press. 

Sorenson, J. R., Jr., et al. Cadmium-induced hypertension in 

male Sprague-Dawley rats. Ann. Rept.. of Center for Study 

10 

II 

12 

February 1979 259 
of Human Environment, Department of Environmental 

Health, College of Medicine, University of Cincinnati, Ohio, 

1973, p. 93. 

13. Ohanion, E. V. Genetic influence on hypertension induced 

by chronic cadmium feeding. Am. J. Physiol. 158, in press. 

14. Friberg, L., et al. Cadmium in the Environment, 2nd ed. 

CRC Press. Cleveland, 1974, p. 118. 

15. Doyle, J. J., Benihoft, It. A., and ftnstead. H. H. The effects of low dietary cadmium on blood pressure.

 MNa, UK, 

and Water Retention in Growing Rats. J. Lab. Clin. Med. 86: 

57 (1975). 

16. Letter, J., and Bibr, R. Cadmium content in some food stuffs 

in respect of its biological effects. Vital Zivilisation 14:125 

(1970). 

17. Schroeder, H. A., et al. Vascular reactivity of rats altered by 

cadmium and a zinc chelate. Arch. Environ. Health 21:609 

(1970). 

18. Perry, H. M., Jr., and Erlanger, M. W. Hypertension in rats 

induced by long-term low-level cadmium ingestion. Circulation 44: 130 (1971). 

19. Perry, H. M., Jr., Perry, E. F.. and Purifoy, J. W. Antinatriuretic effect of intramuscular cadmium in rats. Proc. Soc. 

Exptl. Biol. Med. 136: 1240 (1971). 

20. Perry, H. M., Jr., et al. Mechanisms ofthe acute hypertensive effect of intre-arterial cadmium and mercury in anesthetized rets. J. Lab. Clin. Med. 70: 963 (1967). 

21. Perry, H. M., Jr., and Erlanger, M. W. Elevated circulating 

renin activity in rets following doses of cadmium known to 

induce hypertension. J. Lab. Clin. Med. 82: 399 (1973). 

22. Perry, H. M., Jr., and Erlanger, M. W. Mechanism of 

cadmium-induced hypertension, ln: Trace Substances in 

Environmental Heahh, D. D. Hemphill, Ed., University of 

Missouri, Columbia, Mo., Vol. 9,1975, p. 339. 

23. Kopp, S. J., et al. Altered myocardial excitability, morphology and metabolism induced by long-term, low level cadmium feeding, ln: Trace Substances in Environmenul 

Health, D. D. Hemphill, Ed.. University of Missouri, Columbia, Mo., Vol. 12, in press. 

24. Ohanian, E. V., Dahl, L. K.. and Iwai, J. Oeaetic influence 

on hypertension induced by cadmium in Dahl hypertensionresistant and hypertension-sensitive rats. In: Trace Substances in Environmental Health, D. D. Hemphill. Ed., University of Missouri, Columbia, Mo., Vol. 10,1976, p. 4SI. 

25. Friberg, L., et al. Cadmium in the Environment. 2nd ed., 

CRC Press, Cleveland, 1974, p. 19. 

26. Tipton, 1. H. The distribution of trace metals in the body, ln: 

Metal-Binding in Medicine, M. J. Seven, Ed., J. B. Lippincott, Philadelphia, 1960, p. 27. 

27. National Center for Health Statistics. Blood preuure of persons 6-74 years of age in the United States. Advance Data. 

No. 1,1976. 

28. Paul, O. Complications of mild hypertension. Ann. N.Y. 

Acad. Sci. 304: 59 (1978). 

29. Nogawa, K., and Kawano, S. A survey ofthe blood pressure 

of woman suspected of itai-hai disease. J. Juzen Med. Soc. 

77: 357 (1969). 

30. Schroeder, H. A. Cadmium, chronium, and cardiovascular 

disease. Circulation 35: 570 (1967). 

31. Shaper, A. C , Clayton, D. O., and Stanley, F. Water hardness and hypertension, ln: Epidemiology and Control of 

Hypertension. O. Paul, Ed., Stratum, New York, 1975, 

p. 163. 

I ' 

260 Environmental Health Perspectives 

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