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## Document

Number: 

# J71 ) 11-1-28

5

Docket Number: 

# A-83-2 2

Printed 4/18/2008 9:58:24

AM Sheet 71 of 182P. 2

!

_IUJL

_ 

### u.cc § _JI- < 

## <o S f ZU J O **$ * Environmental

Health Perspectives Vol. 28. pp. 251-260.1979 

# Increas e i n th e Systoli c Pressur e o f Rat s Chronicall y Fe d Cadmiu m b y H . Mitchel l Perry, * Margaret Erlanger, * an d Elizabet h F . Perry *

I n oa r laboratory , chronicall y be d tag cadmiu

m to group s o f

rat s ha s bee n reproducftt

y 1 averag e Increase s o f 1 5 to 20 nu

n H g I n systolic pressure . A tota l o f 49 7 female Long-Evan* rat

s wer e continuousl

y provide d wit h drinkin g wate r fortifie d wtt h fiv e essentia l dement s aa d containin

g from 0.0 1 to S O pp m cadmium , a s tb e acetate , from weanin g fo r a s lon g a s 3 0 months . These rats , pin s 31 1 matche

d contro l animals whic

h receive d fortifie d wate r withou tadde d cadmium , wer

e fed a apoda

l lo w cadmiu m diet . A U 80 8 ra u wer

e weighe d a tleas tmonthl y a s a scree

n fo r cadmiu m toxicity , aa

d their systolic pressure s wer e measure d ever y 3 o r 6 months . Th

e tw o lowes tconcentration

s o f cadmiu m teste d (0.0 1 an d 0.0 3 ppm ) wer e no tpressor ; the thre

e highes tconcentration

s (10,25 , an

d 5 0 ppm ) sltlindrty prove

d to h e toxic. Al l indirec tsystolic pressure

s (eac h measure

d I n triplicate) o f

a B rat s whic h rsedve d 0. 1 to 5 pp

m cadmiu m (i.e. , nontoxi

c presso r doses ) average

d 15. 0 m m H g mor e tha n stmuhancousl

y aiissiui J pres sures o f contro l rats . This averag

e increas e ove r the contro

l pressur e i s extremel

y dgnifican

tstatistically , eve n thoug h i tseem s relativel y smal l i n absolut e terms . Occasionally , however, som e rat s ha d muc h larger tha n averag e Increase s in pressure ; thus , 1 0 o

f M rat s receivin g from 0. 1 to 0 4 pp

m cadmia m fcr 1 8 month s ha d systolic pressure

s tha twer e mor e tha n 5 0 m m H g abov e thr averag

e pressur e o f the centra

l rats . Cadmium-Induce

d hypertensio

n i s no tlimite d t o females or to a particula

r strata . Althoug

h w c hav e asuall y use d oo e strat

a o f femal e Long-Evan

s ra tfrom a singl

e source , male* o

f th e sam e strain aa

d female Sprague-Dawle

y rat s hav e als o develope

d comparabl

e hypertension . Al l subgrou p I I element s ca n apparentl

y Induc e simila r Increase s I n systolic puiiu u awafta g IS t o 20 m m Hg , bu tcadmiu m I s presso r l a muc h smalle r amount s tha n mercur y o r shx . Tans , to todace a dcnxmtraU e tacrcase i

n pressur e require s mor e tha n t m time s a tmuc h divalen tmercn r an d mor e tha n 100 0 time s a s muc h sine a s cadmium . Exposur

e to anothe

r meta l alon g wit h < markedl y alte r the abilit

y o f cadmiu m t o Induc e hypertension . Seleniu

m protect s agains tth e h y Induce d b y twic e a s muc h cadmium . Larg

e excesses o

f bot h sine an d coppe r hav e als o Inyhhrd th e Inductio n o f hypertensio

n b y cadmium . I

n contrast, lead , whic

h Ilk * cadmium , ca

n als o bdac e hyper-ten

don , augment

s rathe r tha n Inhibit s cadmium-Induce

d hypertension ; thus , lea

d an d cadmiu m together ca

n Induc e a n average Increas

e i n systolic pressur

e l a exces s o f

4 0 m m Hg , a tleas ttwic

e a s larg e a s I s asnaU y Induce d b y either meta

l alone . 

## Introductio n I n 1962 , Schroede r

e t al

. firs t reporte d tha t chroni c cadmiu

mfeedin g could induc e hyperten

sion i n rats ; thei r

report indicate d tha

t th e induce d hypertensio n wa s marked (/)

. The y extende d thes e observation s i

n 196 4 (2)

. I n 1967 , however , thi s grou p o f investigator s revised th e magnitud e o f th e induced hypertensio n sharpl y downwar

d b y consid

erin g th e averag e chang e i

n pressur e fo r th e entire expose d ra

t populatio n rather

tha n jus t fo r thos e

* Medica l Service , Veteran s Administratio n Hospital , an

d th e Hypertensio n Division , Departmen to f Internal Medicine , Washingto

n Universit

y Schoo l o f

Medicine . St . Louis , Missouri . 

### Februar y 197 9 animal s which develope d hypertension , i.e. , th e "responders " (?)

. Throughout , thes e investigator s use d standar

d conditions , includin

g astandar d dos e of 5 pp mcadmiu mi n drinking wate

r (/)

. M y purpos e her

e i s t o summariz e th e extensiv e observation s whic

h our group ha s mad

e o n th e bloo d pressure s of

rat s chronicall

y fe d cadmium

. W e wer e abl e t o confir

mtha t long-ter mcadmiu m ingestio n ca

n induc e hypertension , bu t th e mag nitude of th e effec t wa s les s tha

n expecte d from Schroeder' s reports. It

therefor e seeme d pruden t t o repeat ou r observation s to demonstrat e theirreproducibilit y befor e startin g t o investigat e mechanisms

. Thus , muc

h of ou r wor k t o dat e ha s been designed to demonstrat e th e presso r

effec t an d 25 1 

# c rt o defin

e it s magnitud

e an d th e amoun

to f exposur e necessar y t o evok e it . Tw o genera l type s o f dat a ar e presente d below . Th e firs tdeal s wit h th e cadmium-induce

d effect s o n bloo d pressur e an d th e secon d wit

h the change s i

n thes e effect s brough

t aboutb y othe r metals . W e hav e studied eigh tpopulation s o f animals , in volvin g a tota l o f

80 8 Long-Evan s femal e rats , whic h wer e handle d unde r standar d condition s an

d expose d t o cadmiu

m alon e i n on e o f 10 concentra tions , rangin

g fro m 0.0 1 t o 5 0 ppm , o r use d a s litter-mat e control s for suc

h animals . Th e averag e systoli c pressure s cite d were obtaine d from group s which initially containe d atleas tI S rats ; i n deter minin g thes e average s al

l animal s i

n th e grou

p were included . Si x group s o f

rat s totalin g 14

4 animal s wer e expose d t o 5 ppm cadmium , duplicatin g Schroeder' s standar d conditions ; th e averag e cadmium-induce

d increase s i

n systoli c pressure s for the group s range

d fro m 6 t o 2 3 m m Hg . Sinc e th e 5 pp

m cadmiu

m dos e i s considerabl y abov e the intak

e o f th e averag e adul

tAmerica n (o n the basi s o f

milligram

s cadmiu m ingeste d per kilo gra m bod y weight) , a rang

e o f cadmiu m exposure s was tested . Essentiall y th e same presso r effec twa s foun d wit h exposure s rangin

g fro m 0. 1 t o 5 pp

m cadmium. Exposures belo w 0. 1 pp m ha d little presso r effect , an d exposure s abov e 5 pp

m wer e eventuall y toxic . Althoug

h separat e subpopulation s o f

bloo d pressur e "responders " an

d nonresponder s coul d notb e recognize d i

n mos to f ou r ra tpopulations , a

t leas ton e unusuall

y responsive subpopulatio n de velope d marke

d hypertensio n followin g exposure s t o les s tha

n 1 pp m cadmium . Havin g confirme d cadmium-induce d hypertensio n in femal e Long Evan s rats , th e effec twa s show n t o occu r i n male s an d i n anothe r strain o f

rats ; thu s 5 pp

m cadmiu m wa s presso r fo r mal e Long-Evan s an d femal e Sprague-Dawle

y rats .

* Ou r initia l cadmium-feedin

g studie s i

n 197 0 adhere d a s rigorousl y a s practica l t o th e standar

d experimenta

l condition s estab lishe d b y Schroeder' s grou

p (/) ; we obtained our rats , an d eve n ou r rye , fro m the sam

e suppliers . W

e argue d tha tfailur e t o in duc e hypertension woul

d no tb e definitive if

the condition s wer

e altered . However , becaus e th e plasti c cage s wit h stainles s stee l lids , whic h Schroeder used , placed sever e constraint s o n th e numbe r o f animal s we coul d follo w a

tan y on e time , our origina

l experimen

tteste d bot

h the plasti c cage s wit

h stainles s stee l lid s an d al l stainles s steel cages . Th e same degree o f

hypertension , i.e. , differenc

e betwee n th e pressure s o f the cadmium-expose d an d contro l rats , was apparentl

y induced i

n bot h type s o f cages , althoug h th e averag e systoli c pressur

e o f bot h the control an

d cadmiu m expose d populations wer e highe r b y almos t10 m

m H g i n the stainles s steel cage s (4). I n orde r t o us e larg

e number s o f rets, w e opte d to wor

k wit h the muc h mor e convenien tstainles s stee l cage s an

d accep tthe highe

r control pressures . Excep tfo r thi s singl e experimen

twher e w e teste d the plasti c cages , we have used the stainles s steel cage s throughout . Becaus e o f th e modes tsiz e ofth e averag e presso r effec tassociate d wit

h cadmium , condition s wer e sough twhjc

h migh tincreas e its magnitude . I twa s observe d tha

tall subgroup I

I metals t .ca n induc

e similar hypertension , althoug h cadmiu m i s effectiv

e a tmuch lowe r concentration s than eithe r nonessentia l mercur

y o r essentia l zinc . Moreover , whe n exhibite d wit

h cadmium , a

tleas tthree metal

s inhibitth e presso r response t o cadmium : selenium , zinc , an d copper . I

n contrast , a

tleas ton e metal , lead , can significantly augmen tth e presso r response t o cadmium . 

## Method s Group s o f

a tleas tI S weanlin g femal e Long Evan s rat

s from Blu e Spruce Farm s i n Altamont, Ne w York , were treate d a s describe d b y Schroede r (/ ) an d modified slightl y in ou r laborator y (4. 5). * O n arrival , th e rat

s wer e place d i n a lo w contamina tio n environment ; the y were all fe d th e same rye base d low-cadmiu

m die tad libitum an

d give n fre

e acces s t o fortified drinkin g wate r containin g an

y metal s which were t o b e exhibited . Lik e th e diet , th e drinkin g wate r wa s mad e a s describe d b y Schroeder . I

tconsiste d o f

deionize d wate r wit

h a resistance o f

5 megohm s "fortified " b y th e additio n o f cobal t( 1 ppm) , molybdenu m ( I ppm) , coppe r ( 5 ppm) , manganes e (1 0 ppm) , an d zin c (5 0 ppm

) (/ , 5) . Rando m batche s o f

th e die twere assaye d regularl y an d foun d t o contai n a

n averag e o f

0.013 7 ± 0.001 9 (SD ) ng cadmium/

g food . Fo r th e othe r trace metal s tha twere assayed , th e followin g averag e amount s (in fig/g) were found : zinc , 35 ; mercury , < 0.005 ; selenium , 0.37 ; iron , 42 ; manganese , 23 ; copper , 3.3 ; nickel , 0.29 ; an

d chromium , < 0.05 . I

n addi tion , th e followin g averag e amount s (i n mg/g ) o f othe r metal s were present : sodium , 5.9 ; calcium , 3.8 ; potassium , 7.6 ; an

d magnesium , 1.4 . Foo d in take throughoutth e lif

e o f th e ra taverage d ap proximately 2 0 g/rat/day . Th e metal s t o b e teste d wer e administere d in drinkin g wate r mad

e b y dissolvin g cadmium , zinc , o r lea d acetate , mercuri c o r cupri c chloride , o r sodium selenite i

n th e "fortified " deionize d water . (Studie s wit

h radioactiv e tracer s indicate d that there wa s n o significan

tprecipitatio n an

d tha tall metal s remaine

d i n solution . Th e onl y exceptio n t o thi s wa s i n som e experiment

s wit h har d water , no t considere d here. ) Although there wa s variabilit y betwee n bot

h individua

l an d grou p means , th e aver ag e intak e o f wate r fo r a singl e ra

tapproximated 1

5 m l daily a tth e star tofth e experimentan

d rose i n a roughl y linear fashio n t o abou

t2 5 m l b y 1 2 month s after which i

tremained relatively constant . Systoli c pressur

e wa s determine

d i n triplicat e i n 4

t J 1 5 i lightl y pentob a cuf f me t only sy > paralle l have b < ported sur e r e nuyor i sel . U bloo d mine d thant l entir e fro m t natio r ; mont l i weig t inte r ence « very use d spe c th e t fro n 

## R e St a 

### v po $ ! i n ra t



### 25 2 Environmenta l Healt h Perspectives

### lightl

y anesthetize d (0.2 S m

g intraperitonea l pentobarbital/k

g bod y weight ) animal s b

y th e tai l cuf f method , a s previousl

y describe d (5)

. [Althoug

h onl y systoli c pressur

e i s reported here , consistently paralle l change s i

n systoli c an

d diastoli c pressure s hav e bee n regularly observe d an

d previousl

y reporte d (4). Direc t

determinatio n of

diastoli c pres sur e requires canulatio n of

th e arter y whic h i s a majo r procedur e an d results i n sacrific e o

f th e ves sel

. I t canno t therefor e b e routinely use d fo

r seria l bloo d pressur e determinations

. The directly deter

mine d systoli c pressur

e average d 6 m

mH g lowe r tha n the indirectl

y measured pressure. ] Durin g their entir e sta y i n ou r laboratory , animal s wer

e removed fro mthei r cage s fo r onl y tw o purposes : (a

) determi

nation o f systoli c pressur

e a t interval s o

f thre e t o si x month s an d (b ) weekl

y cag e cleanin g an

d grou p weighing

. Measurin g pressur e wa s don e at long interval s t o ensur

e tha t th e animal s wer

e uninflu

enced b y th e anestheti c o r

it s afte r effects fo r th e ver y larg e majorit

y o f thei r lives

. Weighin

g wa s use d a s a n inde x o f grou p well-being

. Except

a s specificall y indicate d below , th e averag e weights o f th e experimenta

l group s di

d not diffe r significantl

y fromthos e o

f th e contro l animals

. 

## Result s Standar d 5 pp m Cadmiu m Exposur e W e hav e measure d th e effec

t ofth e standar

d ex posur e t o drinking wate

r containin g 5 pp

mcadmiu m i n si x separat e population s o

f femal e Long-Evan s rats

. The averag e cadmium-induced increase s i n systoli c pressur

e ar e show n at fou r differen t time s i n Figur e 1

. Afte r si x month s of

cadmiu mexposure , th e averag e difference i

n systoli c pressur

e betwee n th e cadmium-fe

d groups , whic

h totalle d 14

4 ani

mals , an d their 26 7 contro l animal s wa s 12. 4 m m Hg , wit h astandar

d deviatio n o

f 13. 9 m mHg

. Thi s differenc e was statistically significan t wit h ap valu e of < 0.00 1 (t = 8.88)

. The averag e differenc e ros e t o 16. 6 m mH g afte r 12 month s (

/ = 6.55 ) an

d becam e maxima ] a t 21. 5 m mH g afte r 1 8 month s (t

« = 8.38)

. The si x separat e population s o

f rat s expose d t o 5 pp mcadmiu mall ha d simila r presso r response s (Table 1)

. Afte

r si x months , al

l si x ha d mea n in

crease s i n systoli c pressure , whic

h range d from6 t o 2 0 m mH g an d average d 12. 4 m

mHg

. Afte

r 1 2 months , th e mea

n increase s ranged from9 t o 2 2 m m H g an d average d 16. 6 m

mHg

. Rang e o f Cadmiu m Exposure s I n Figur e 2 , th e averag e cadmium-induced in

creas e i n systoli c pressur

e i s examined a s function s o f tw o aspect s o

f exposure , it s lengt

h an d th e dos

ag e used

. Increase s wit

h successively doubled ex posur e period s fro m3 t o 2 4 month s an d a hundred-fol d rang e o f

cadmiumconcentration s fro m0. 1 t o 1 0 pp

mar e presented

. Th

e lowes t cad

miu mconcentratio n an

d th e shortes t

exposur e in

duce d onl y asmal l increas e i n pressure , averaging 5 m mHg

. The sam

e concentratio n an

d double d expo sur e induced a

n increas e o

f 1 0 m mHg

. The remainin g bar s fro mlef t t o right i n th e graph generall

y trende d slightl

y upwar d fromth e 1 0 m

mH g in

creas e towar

d a n increas e o

f 1 5 m mHg

. -\&-r.. •j-tf.

. ; *«a«i » T-afV * :

Table 1 .

DateC d feedin g bega n Increase I

n systoli c pnasi ti n si

x separat e experiment

s alte r 6 an

d 1 2 month

s exposur e to standar

d 5 pp m cadmhun. * 6 months cadmiu

m feeding „ t|i #r . „ miii m f ^ ifl f Comro l ippmC d u>nmm r „ ntm , , ppil l rA Inr „ w No . o f Mea n * SD , No . o f

Mea n * S D mean , mea n * S D mea

n * SD , mean , rat s m

m H g tat s (m

m Hg) m

m H g m m Hg m

m H g m m H g Oct

. 2 1 '70 » Aug . 7 '7 4 Mar

. 2 6 '7 5 Aug . 1 8 '7 6 Dec

. 1 '7 6 Sept . 1 '7 7 Tota l (64 ) (60 ) (40 ) (43 ) (15 ) (45 ) (IffJ f 11 2 * 1 ?

9 9 * 1 3 10 6 ± 8 10 3 * 1 2 10 3 ± 1 2 9 9 a 1 1 164. 1 * lJ. S (32 )

(20 ) (20 ) (42 ) (15 ) (15 ) 

### < W 12

5 £ 1 7 11 2 * 1 1 11 2 * 1 2 11 5 * 1 2 11 3 * 1 2 11 9 ±1 1 li d J * 13. 9 1 3 1 3 6 1 2 1 0 2 0 

### ITT 11 0 * 1 *

102 * 9 10 3 ±1 3 9 8 * 1 8 107 ±9 127*2 0

11 1 * 119 * 117 * 129 * 1 0 1 3 1 8 1 0 1 6

9 16 1 9 22 163. 3 * l3. l 119. 9 * ld. 8 "R T

• Average systoli c pressure s * standar d deviation s (SD ) a

t6 an d 1 2 months ar

e tabulate d for al l rats expose d t o th e standar d 5 pp m cadmiu m unde r standar d conditions . I

n addition , th e number

s o f rat s included a

t6 months ar

e tabulate d (i n parenthesis) ; th e number s wer e essentiaU

y the same a

t1 2 months . Finally , th e average cadmium-induce d increase s i

n systoli c pressur

e a t6 an d 1 2 months ar

e als o tabulated . • The Octobe r *7

0 experimentincluded a secon d population o f control rat

s house d i n plasti c cage s designe d t o decreas e contamina tion , a s describe d b

y Schroede r (/) . Thes e rat s ha d a n average control pressur e o f 10 3 m m H g (<) ; the y have notbee n included her e becaus e the

y wer e no thandle d i n our standar

d manner. Th

e smal l number s ( 5 pe r group ) o f

"Populatio n II " ra u fro

m th e Octobe r '7 0 experimen

thav e no tbee n included here ; thei r pressure s have bee n reported previousl y (5) . ' The control pressure s in ou r firstexperimen

taverage d almos t10 m

m H g highe r tha n in subsequentexperiments , possibl y becaus e ou r techniqu e fo

r excludin g environmenta l cadmiu m wa s les s wel l developed . 

### Februar y 197 9 25 3

..fusn^iv^sitts..M -

10 -

18 -



## w 5 -

0 - 

## 14 4 

## 13.9 .00 1 12 6 

## 16. 8 .00 1 

## 7 6 17.5 .00 1 

## 1 5 21. 7 .05

1 2 I I 2

4 

### • S.D . 

### f

Mos . FIGUR E 1 . Presso r effectfro

m varyin g exposure t o standar

d 5 pp m cadmium . Averag

e increase s i

n systoli c pressur

e o f si x ra tpopulations expose d to 5 pp m cadmiu m fo r 6 , 12 , 18 , an

d 24 months . The number

s o f rats involve d i

n eac h average , the standar d deviation , an

d the statistica

l significance ip value ) ar e indicated b

y the number

s i n the columns . Al

l increase s hav e bee n correcte d fo

r an y chang e i n the averag

e systoli c pressur e o f litter-mat

e contro l rats handle

d similarl y bu t withou tcadmiu m (se e Table 1) .

- = 24- i

= 16 -

£ 8

- 0 S • - 4 

# • »

1 0.\„mU 1. 0 pp n U 10 M - 1

FIOUR E 2 . Presso r effecta s fkinctio n o f lengt h an d intensit y o f cadmiu m exposure . Average change s i n systoli c pressur

e in duce d b y thre e dosag e level s o f

cadmiu m afte r successivel y doubled exposure intervals . Initiall y ther e wer e 15-6 0 rets i n eac h cadmium-fe

d group , an

d 45-7 5 control rat

s againstwhic

h increase s i

n pressur e wer e measured . Wit h group s o f

th e siz e use d here , ther

e i s som e uncertaint

y regarding an

y specifi c differenc

e cite d i n th e graph . For example , althoug h the effec to f 0. 1 pp m cadmiu m durin g th e firs tyear o f exposur e wa s somewhatsmalle r tha

n th e effec to f

1. 0 or 1 0 ppm , a tsubsequen ttime s no tshow n o n the graph , th e increase s wer

e relatively larg

e (i.e. , a t15,18 . an d 2 1 months , the y average d 16 , 18 , an d 1 5 m m Hg , respectively) . Ther

e i s som e confirmation fo r th e unusually larg

e increas e o f

2 5 m m H g afte r 2 4 month s exposur e t o 1 pp

m cadmium , sinc e 2. 5 pp m cadmiu m induced a comparabl e increas e o f 2 4 m m H g a t2 4 months . Thes e larg

e increase s involve d rela

tivel y smal

l number s o f rats ; th e tw o groups include d onl y 9 an

d 1 2 tw o yea r survivors , respectively . Ther

e wa s littl e uncertainty , however , abou t th e decreas e i

n pressur e after 2 4 months o f

expo sur e t o 1 0 pp m cadmium ; thi s chang e wa s typica l o f a consisten tpatter

n o f toxicit y followin g prolonge

d exposur e t o hig

h concentrations . Incipien ttoxicit y wa s alread

y eviden ta

t1 8 month s when th

e induce d chang e i n pressure , althoug

h stil l positive , average

d onl y 7 m m Hg , a s show n i

n Figur e 3 . Tabl e 2 summarize s ou r averag e systoli c pressur e dat a fo r group s o f

rat s expose d t o cadmiu

m alon e unde r our standar

d conditions . A

ton e extreme , w

e neve r observe d a

n averag e increas e i

n pressur e o f a s muc h a s 1 0 mmH g wit

h exposure s o f

0.0 1 or 0.0

3 pp m cadmium , althoug h th e increas e afte r 1 2 month s wa s o f

borderline significanc e ( p < O.OS) . raising th e questio n o f

whethe r som e rat

s ma y hav e a presso r respons e t o eve n thes e lo w concentration s (6) . A tth e othe r extreme , there was a n early increas e i n pressur e for th e 5 0 pp

m grou p (p < 0.02

5 after 6 month s exposure) , bu tthereafter tha

texpo sur e was depressor ; thi s concentratio n wa s overtly toxi c an d markedl

y inhibited growt

h i n weanling s from the ver

y first. Similarly , 2

5 pp m cadmiu m induce d a n increas e i

n pressur e for a yea r ip < 0.00

5 a t6 month s and p < 0.02 5 a t1 2 months) , bu

ti tthe n becam e depressor ; i

tto o inhibited growth , albei t minimally . A leve l o f

1 0 pp m cadmiu m wa s signifi cantl y presso r fo r a year , bu tfrom 1 8 t o 3 0 months there wa s stepwis e conversio n o f its presso r effec

t t o a depresso r effect ; i

tneve r inhibited growt

h sig nificantly . [Additiona

l dat a fo r hig h cadmiu m expo sure s ar e availabl e (5)] . For th e intermediat

e concentration s fro

m 0. 1 t o 5 pp m cadmium , th e averag e increase s i n pressur e range d from 5 m

m H g for th e forme

r after thre

e month s o f

exposur e t o 33 m

m H g fo r the latter afte

r 3 0 month s o f

exposure . Three quarter s o f the 3 8 tabulate d average s for thi s intermediat e rang e o f concentration s representincrease s o f 1 0 t o 20 m m Hg , suggestin g tha

tthi s i s th e usua

l respons e t

o a wid e rang

e o f cadmiu m exposure s under ou r stan dar d c o exposu i p f 1 5 t o trations 

### Subp o Alth > press u •_» l \ \

v \ £ e

. 8 

# ! l 

# I f 1 4 - 0 -

-1 7 FlGU I d i C i n e ;

3 6 9 1 2 1 5 1 8 2 1 2 4 30 T c M

25 4 Environmenta l Healt h Perspective

s

### dar

d conditions

. Fro

mth e dat afo

r 1 8 month s of exposure , th e relativel

y constan t averag e increas e o f 1 5 t o 2 0 m mH g t o arang e of

cadmiu mconcen tration s i s wel

l show n i n Figur e 3

. Subpopulatio n o f

Cadmiu mResponder s Althoug h th e distributio n patter

n o f individua l pressure s followin

g cadmiu mexposur e wa s difficul

t



# I

-1 7 0.0

1 0.1 0 0.1 S 0.5 0 1X 1 tS 5.

0 1 0 \ 2 5 part * fn ailli M CWaiM i

FICUR £ 3 . Exposur

e to averag

e change s i

n systoli c pressur

e in duce d b y nin

e exposure level s o f

cadmiu m (0.0 1 t o 25 pp

m Cd) fo r 1 8 months . A

tthi s time , ther

e wer e still a tleas t1 3 rats i n al l groups , an

d the group s expose d to 0.1,5 , an d 1 0 pp m C d each containe d mor

e tha n 3 0 rats . 

### t o defin e precisel y becaus e o

f relatively smal

l sampl e size , distributio n usuall

y appeare d t o b e relativel y norma

l (4)

. Occasionally , however , ther e seeme d t o b e asubpopulatio n of responder s i

n whic h cadmiu minduce d marked hypertension

. Thi s phenomenon wa s mos t

obviou s fo

r our Augus t 7 , 1974 , experimen t

involvin g 14

0 rats

. Afte

r 1 8 months , one-sixt

h ofth e rat s expose d t o 0.1 , 0.25 , an d 0. 5 pp mcadmiu mha d systoli c pressure s whic

h exceede d th e contro l mea

n b y fou r standar d devia

tions , i.e. , b

y 5 0 m mHg

. I n contrast , non

e o f th e litter-mat e control s o r

5 pp mcadmiu mrat s ha d thi s degre e o f hypertensio n (Table 3 ) (7)

. Presso r Respons e o f

Mal e an d Sprague

Dawle y Rat s t o Cadmiu m Sinc e ou r earl y wor

k wa s limite d t o femal e Long-Evan s rats , i

t seeme d importan

t to demon

strate tha t th e effec t was no t limite d t o one se

x o r on e strai n of

rats

. We , therefore , teste d th e stan

dar d 5 pp mcadmiu mi n mal e Long-Evan s rat s an

d i n femal e Sprague-Dawle

y rats

. Afte

r ayea r o f ex posure , cadmiu

mha d induced atypica

l increas e of 1 7 m mH g i n the males , althoug

h bot h contro l an

d cadmium-exposed male s ha d highe r pressure s tha

n female s (8). Th e dat afor th e femal e Sprague

Dawle y rat s wer e mor e limite d becaus e th e colon

y Table 2 . Mea

n Increas e l a systolic pressur

e afte r varyin g cadmiu m exposure. '

Months o f C d feeding 3 6 9 1 2 1 5 18 2 1 2 4 3 0 Totals ' Means ' No . o f

control rat s teste d 17 5 31 1 5 8 23 8 16 6 19 1 32 8 5 2 1 

### Ti T 105. 0 No . o f

Cdfe d rats (total ) 16 5 463 5 6 34 1 21 1 263 3 0 118 3 9 457 " 0.0 1

pp m

- I 9 2 0



### Jo " 0.0 3 pp m 0 8 3 1



### 2 5 105. 7 106. 3 Increas e i n systoli c pressur

e a tvarious level s o f cadmiu m i n drinkin g wate r fro m tim e o f 0.1 0 pp m 5 10 " 9 » 12* 18 * 1 5 (I2 f 

### S T 113. 1 0.25 pp m 2 2 1 2 1 2 19 (7 ) 

### 55 " 115.5 0.5 0 pp m 1 1 1 1 10 1 4 (15 ) 

### 55 " 112. 6 1.

0 pp m 1 4 9» . I3 » 1 7 (14 ) (25 f 

## &r~ 117.5 2. 5 pp m 6 10 " 1 5 1 6 (24 ) (17/ » 44 125. 1 weaning 5. 0 pp m 1 2 12 " 16 " 17 " I2 » 2 2 " (I D 1 7 (33) « 14 4 120. 0 m

m Hg * 1 0 pp m 1 2 15* * 13 * 7 *

- 4 (-12) " 

## ~W 117. 8 2 5 pp m 1 2 9 -1 7 (-20 ) (-14) ' 1 6 113. 6 5 0 pp m I I -1 3 (-12 ) (-27 ) (-30 f 16 108. 1 * Averag e increase s i

n systoli c pressur

e o f cadmium-fe

d rats (corrected for an

y chang e i n averag e control pressure ) ar

e tabulate d for total s o f 31 1 control rat

s an d 49 7 cadmium-fe

d rats. Eigh

tseparat e experiment

s wit h eightdifferen

tpopulations o f

rats ar e included (on e begu n in Ma y an d anothe r i

n Septembe r o f

1973 , whic

h involve d n o rat

s expose d t o 5 pp

m cadmium , plu s th e si x liste d i n Tabl e I) . Thi s comprise s all o f

ou r systoli c pressur

e dat a o n group s o f

10 o r mor

e rat s fe d cadmiu m alon e unde

r standar d conditions . * Al l entrie s whic

h includ e dat

a from mor

e tha n 3 0 rats ar

e marke d wit h on e asterisk , an

d thos e wit

h dat a from mor

e tha n 5 0 rats ar

e marke d wit h tw o asterisks . N o grou p contained les s tha

n 1 5 rets a tth e outse to f

th e experiment ; an

y subsequentaverage s whic h include d dat

a from fewe r tha

n 1 5 rats have bee

n placed i n parentheses ; an

d a superscrip tindicate s th e actua l numbe r whe n fewe r tha

n 10 rats wer

e included , Th

e standar d deviation s ofth e tabulate d average s range

d fro m 9 to 3 9 m

m Hg , wit h 9/1 0 p f the m bein g les s tha n 2 0 m m H g an d K les s tha

n 1 5 m m Hg . Usin g Student' s /

test , a change o f

8- 9 m m H g usuall y had p < 0.05 , an

d on e o f 1 2 o r mor e m m H g ha d p < 0.00 1 m

m Hg . ' Th e total s ro

w o f the tabl e indicate s th

e numbe r o f rat s whic h bega n a give n exposure . Th

e value s i n column s 2 an

d 3 ar e not obtaine d b y summin

g th e nin e entrie s i n th e column , sinc e eac h retha d it s bloo d pressur

e measure

d mor e tha n once . ' Mean s wer e obtained b

y averagin

g each pressur

e obtained from each rat

. The value s ar

e lowered b

y the relatively low value s afte r shor texposures , an

d the y ar e als o moderate

d b y th e decreasin g numbe r o f rets whic h survived lon g exposures . 

### Februar y 197 9 25 5

A&&$MiMj£-develope d a respiratory infectio n after nine month s

o f cadmiu m exposure , bu

ta tsi x month s there wa s a significan tpresso r effec tin th e cadmium-fed ani mal s a s compared t o th e control s (5) . 

### SimUa r Presso r Response s to Al l Subgrou p I I Metal s Chronic feedin g o f

a n appropriat

e concentratio n o f an y subgrou p I

I meta l i s presso r i n femal e Long-Evan s rats . Althoug h ou r dat

a o n zin c an

d mercur y ar e notextensiv e an

d therefor e hav e con siderabl e uncertainty , all three subgrou p I I metal s appear t o induc e average increase s o f 1 5 t o 2 0 m m H g i n th e systoli c pressure , bu tthe inducin g dose s differe d b y mor

e tha n a thousand-fol d (Tabl e 4) . Moreover , there i s n o presso r response when th e challengin g dos e i s increase d t o overtl y toxi c dose s o f nonessential cadmiu

m o r mercury . Th e presso r respons e t o chronicall y ingeste d cadmiu m has bee n describe d above . Exposure t o 5 o r 10 pp m mercuric io n fo r 12 month s wa s pressor , whereas neithe r 2. 5 no r 2 5 pp m wa s pressor , wit

h th e latte r concentratio n bein g toxi c (4). Th e situa tio n wa s mor

e complicate d in th e cas e o f zin c which i s essentia l an

d presentt o th e exten to f 3 5 pp m in ou r standar

d die tan d t o th e exten to f

5 0 pp m in th e "fortified " wate r eate n an d drun k b y all o f ou r rats . N o effec to n pressure wa s observe d if th e zin c i n th e wate r wa s decrease d from 5 0 pp m t o zero ; howeve

r i f itwa s increase d from 5 0 t o 75 ppm , th e typica l presso r response t o cadmiu m an d mercur y wa s ob serve d (9) . Bot

h 10 0 an d 20 0 pp m zin c wer

e pressor, an d n o searc

h wa s mad

e fo r a large r toxi c bu tnonpresso r concentratio n o f

zinc . 

### Inhibitio n o f

Cadmiu m Effec tb y a Secon d Meta l A secon d meta

l ca n eithe r inhibito r enhanc e cadmium-induced hypertension . Th e thre e essentia l metals : selenium , zinc , an d coppe r hav

e eac h bee n show n t o inhibi

tth e presso r effecto f

cadmium ; in hibitio n has range

d from 6 0 t o 100% . Table 5 present s our coppe r dat

a an d the dat a fo r on e o f thre e similar experiments involvin g selenium an d zinc . Th e inhibitio n studie s were amon g ou r earl

y ex periment s an d were carrie

d ou twhil e we wer

e still usin g relatively larg

e cadmiu m exposures . I

n brief , th e presso r effect s o f

bot h 2. 5 an d 10 pp m cadmiu m wer e inhibited b y hal

f a s muc h (i.e. , b y hal f th e molarit y of ) selenium (10). Th e presso r effects o f 2. 5 an d 10 pp m cadmiu m wer e als o inhibite d b y 10 0 an d 20 0 pp m (i.e. , b y 7 0 an

d 3 5 time s th e molarit

y of ) zinc . Th e presso r effec to f 5 pp m cadmiu m was als o inhibite d b y 2 0 pp

m (i.e. , b y 8 time s th e molarit y of ) — . I

Inhibito r expos" * level . | ppmj . S e (0» ) S e 0-3 ) 

### zndpo r Zn(W» y Cuj^__

_ • tteconc t inhibiting"* ' provid e the " cadmiu m al o • The»e ef l zin c were s

n »;Sinc e tnex ie»seso f coppe r £) • copper . / pressor ; signifie s fi r selcr ,

Tabl e 3 . Dtstrflmtto a o f systoli c (SP ) fcr e w ra

tpopulation ' Cadmiu m dose , pp m Mea n S P ± S D afte r 1 8 months . m m H g Ra u wit h S P mor e tha n 2 S D abov e control mean , % > 12 5 m m Hg Rat

s wit h S P mor e tha n 4 S D abov

e contro l mean , * > 15 0 m m H g 0 0. 1 0.2 5 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 3 3 4 4 2 0 1 3 0 1 7 1 9 1 3 0 * Ther e wer e initially 6 0 control rats an d 20 rats pe

r experimenta

l group . One-sixt

h o f the rat s expose d t o 0.1,0.25 , an d 0. 5 pp m cadmiu m fo r 18 months ha

d systoli c pressures whic h exceede d th

e mea n pressur e o f the control rat

s b y mor e tha n fou r standar d deviation s (SD) . N o contro l retan d n o ratexpose d t o th e standar d 5 pp m cadmiu m ha d thi s grea

ta presso r response . Tn e dat a presente d her

e constitut

e a singl e complet

e experiment , i.e. . a singl e complet e population . Table 4 . Presso

r effect s o f chronicall y hadin g subgrou

p I I Respons e t o minimu

m presso r dos e

Io n Minimu m toxi c dose . fiM* Minimu m

presso r dose , M W Numbe r o f

rat s teste d Exposur e Dose , ppm Length ,

mo s Mea

n SPiS D increase , m m H g Referenc

e Zn* * Cd» * Hg " 8 9 12 5 110

0 0.8 9 25. 0 1

4 5 5 1 6 7

5 0. 1 5 1 5

6 1 2 2 0 * 1 8

1 0 £ I I 1 6 i 1 2 (« )

Thi s report V)

• Minimu m presso r an

d toxi c meta

l concentration s i

n drinkin g water ar

e presented in micromole s pe r lite r t o allo w comparison betwee n metal s whil e th e dose s i n cite d experiment

s ar e give n i n part s pe r million to confor

m wit h the restofth e manuscript . Thu s the concentration s o f

th e thir d an d fifth column s ar

e tb e same . Toxi c dose s were notpressor . 

### 256 Environmenta l Healt h Perspective

s

•s-" 

### f^^-^-^^^^MiA'AP. 8



### h e a l Inhibito r exposure level . pp m S e (0.9 ) Se(35 ) ZadOO f Zn(200 f Cu(20 X Tabic S . Inh&kt a o f cadmium-Induce

d kypertcBsto

a b y a see n Cadmiu m exposur e level , pp m CS ) (10 ) a.5 ) (10 ) (50 ) Presso r effec to f inhibito r alone , % o f C d effect 6 Mo s 13 3 3 9 Non e 30 Non e 1 2 Mo s

4 0 3 5 16 7 M P 3 2 i d metal. * Inhibitor y actio n o f inhibitor + cadmium , % decreas e i n Cd effec t 6 Mo s Complet e 72* Complete * 67 » 92 * 1

2 Mo s 9 3 Complete * 6 0 6< P 89 * * Th e concentration s o f

inhibiting metal s an

d o f cadmiu m ar e presented i n th e firsttw o columns , an d th e presso r effect s o f

th e inhibiting metal s alone an

d thei r inhibitio

n o f th e cadmiu

m presso r effects ar

e presented i

n the nex tfou

r columns . Fou

r group s o f

ra u provid e th e da u for eac h o f th e five rows o f

figure s i n th e table ; ther

e wa s a grou

p wit h neither cadmiu

m no r inhibitor , a grou

p wit h cadmiu m alone , a grou

p wit h inhibito r alone , an

d a grou p wit h bot h cadmiu m an d inhibitor . * Thes e effec u wer

e statistically significan

twit h p < 0.01 . Th

e siz e o f th e group s o f

animals receiving 0. 9 pp

m seleniu m an d 10 0 pp m zin c wer e small , an

d thes e da u ar

e included primaril

y t o indicat

e trends . ' Sinc e th e "fortified " drinkin g wate r containe d 5 0 pp

m zin c an d 5 pp m copper , th e zin c concentration s use d her e represented excesse s o f

S O an d IS O pp m zinc abov e tha

tgive n t o th e control rats , an d th e coppe r concentratio n represented a n exces s o f

1 5 pp m coppe r (8) . 

### copper . A s indicate d previously , zinc itself ca n b e pressor ; moreover , a possible , bu t no t statistically significant , presso r

effec t ha s als o been observe d fo r selenium , bu t

no t fo r copper (Tabl e 5)

. Augmentatio n o f

Cadmiu m Effec tb y Lea d Unlik e th e metal s mentione d above , lea d aug mente d th e presso r

effec t of cadmium

. B y itself

lea d produce d apresso r

effec t comparabl e t o that

pro duce d b y cadmium

. I n tw o separate experiments , whe n lead and cadmiumwer e administere d to

gether , their

effects wer

e a t leas t additive

. The firs t experimen t involved onl

y one concentratio n o

f eac h meta l bu t ha s no w continue d fo

r 1 8 months ; th e secon d involve d thre e concentration s bu t bega n onl y si x month s ago . Figur

e 4 present s th e larges t averag e increas e i

n systoli c pressure w

e hav e yet observed

. Thi s increas e occurre d afte r thre e month s exposur

e t o 1 pp mof bot h metals ; i

t aver aged 4 3 m mH g -'— ""J\\ r

i—TT*—r l —fa n """* wa s mor e tha n three^imffTh e averag e increas e either cadrnjtffho

r lea d alone

. In th e sam

e experi : 

### ment , tariidditive presso r

effec t wa s als o seen wit

h asmalle r concentratio n (0. 1 ppm

) afte r alonge r ex posur e ( 6 months)

. Thus , th e averag e systoli c pres sur e fo r 45 contro l rat s wa s 9 9 m

mHg

. The averag e increas e i n th e systoli c pressure fo

r 1 5 rat s expose d 0. 1 pp mcadmiu mfo r si x month s wa s 1 3 m

mHg

. e averag e increas e fo

r 1 5 rat s expose d t o 0. 1 ppm ida d wa s 1 0 m mHg , an d th e averag e increas e fo

r 1 5 rakexpose d t o 0. 1 pp

mo f bot h cadmiu man d lead , wasiTm mHg (//)

. DISCU J 

### Descriptio n o f

Finding s b y Other s an d Pos sibl e Explanatio n o f

Seemin g Discrepancie s Th e dat apresente d her

e indicat e that , wit h sligh t modification s o

f Schroeder' s standar

d conditions

. Environmenta

l Healt h Perspective

s w

e wer e abl e t o confir

mhi s observation s tha t long-term , low-dos e cadmiu mfeedin g ca n induc e hypertension

. Ther

e are som e othe r publishe d con firmator y data , bu t

they ar e sparse . Sorenso n e t

al

. hav e reported apresso r

effec t i n mal e rat s followin

g chroni c cadmiu

mfeedin g (12), an d Ohanion ha s reporte d acadmium-induce d presso r respons e i

n "Dah l hypertension-sensitive " rat s (13). Thes e fe w confirmator

y observation s mus t

b e couple d wit

h equall y spars e reports of

failur e t o induc e hyperten

sion wit h cadmiu mfeedin g (14-16). The paucit y o f positiv e reports could b e related i n par t t o th e lon g la g perio d inheren

t i n such experi

ments , and there ma

y b e variou s partia

l explana

tion s fo r th e several reporte d failure s t o induc e hypertensio n b y chroni c cadmiu mfeeding

. Schroede r mad e th e origina

l observatio n i

n 196 2 (/ ) an d wa s abl e to repeat

i t man y time s (2 , 3, 17). Ou

r initia l confirmatio

n b y abstract wa s i n 197 1 (18); ou

r preliminar y pape r wa s i n 197 4 (4), an d acomplet

e report wa s no t mad e unti l 197 7 (5)

. I n attemptin g t o confir mSchroeder' s observations , we opte d t o yadher e a s closel y t o hi s condition s a s possible , ob

inin g ou r rat s and initiall

y even our

ry e fromhi s jppliers , feelin

g tha t w e woul d hav e t o repeat

hi s iperimen t wit h n o deviations , i

f w e altere d hi s tmdition s and faile

d t o induc e hypertension

. Sinc e loptin g hi s conditions , w e hav e observe d Cadmium-induce

d hypertensio n i

n eac h o f eigh t ex r 

### periment s carrie d ou t

in ou r laboratory

. Mino r change s i n th e experimenta

l conditions , whic

h hav e bee n consistentl y used i

n bot h Schroeder' s labora

tor y an d i n ou r laboratory , ma

y wel l b e ver y im

portant

. W

e have alread

y foun d i t possibl e bot

h t o inhibi t th e effect

completel y an d t o augmen t i t markedly

. Perhap s th e rye-base d die t i s particularly wel l suite d fo r such experiment s sinc e Schroeder' s grou p an d ou r grou p hav e bot h used i t exclusivel y a s th e majo

r dietar y ingredient

. 25 7P. 9

^-tJte .-.-

• .;• . | ^-.. | a-, . ..... . .••\a 1 - a...^4_ . - r . | --^-.^...'.-^^^ , ^jia^» a ^^.'u.-.-^Yfiiii,i 1 | - i * •-• ' ^ .



### Becaus e ofth e larg e rang e o f cadmiu mexposure s which ca n produc e anea

r maxima l presso r re sponse , minima

] unrecognized exposur

e could lea

d t o hypertensio n i

n the contro l grou

p whic h woul d the n mas k an y hypertensio n i

n th e experimenta

l group . A s littl e a s 0. 1 pp

mcadmiu mi n drinking water , amounting to a

n intak e o f abou t 2 fig o f cad

miu mpe r day , induce s hypertension , and there i s frequen t failur e to realize th e potentia

l fo r unrecog nized cadmiu

mexposur

e i n th e usua l anima l facil

ity

. Likewis e there ha s bee n frequen t failur e t o realize tha

t toxicity , whic

h seem s t o b e incompati

ble wit h hypertension , ma

y b e induced b

y wha t i s ofte n considere d a s moderat

e cadmiu mexposure . Facilitie s whic

h ca n minimiz e extraneou s cadmiu

m exposur e an

d stil l maintain healthy animal s fo r year s ar e rare , ye t bot h condition s see

mt o b e im

portant

. Anythin g whic h render s th e animal s overtly sic

k o r even prevent s the

mfromgainin

g weigh t an d growin g i n a n optimu mmanne r seem s liabl e to inhibit

cadmium-induce d hypertension

. Intercurrent

pneumoni aprove d t o b e b y fa r th e mos t common suc h proble

mi n ou r ra t colonie s durin g th e 1960's

. Cadmium-induce

d hypertensio n ma

y als o hav e been overlooke d becaus e i t was not a s marked a s indicate d i n Schroeder' s origina

l description s (/ , 2). 

## j 150- i



## . 5 14 0 

## - «/ »

«/ » 

## 130 - 

## 120 - 110 - 10 0 J

FIGURE 4 . Augmentatio

n o f cadmium-induce

d hypertension b y lead . Averag

e systoli c pressure s ± standar d deviation s ar

e presented fo

r 45 control rat

s an d for group s o f

1 5 rat s fed I pp m cadmiu m and/o r lead fo r thre e months . 

### 25 8 Ther e i s frequen

t failur e t o realiz e tha

t hi s sub

sequen t reports indicated muc

h lesse r degree s o f cadmium-induce d hypertensio n (3) and tha t th e larg e averag e increas e i

n pressur e whic h was ini

tiall y reported was limite

d to agrou

p o f "respond

ers. " A s indicated i

n Tabl e 3 , w

e hav e observe d subpopulation s o

f responders (7) , bu

t they ar e th e exceptio n rather

tha n th e rule

. Possibl e Mechanism s an d Significanc e o f Cadmium-Induce d Hypertensio n Th e mechanis mo

f th e hypertensio n induced i n rat s b y chronicall

y feedin g the mlo w dose s o f cad

miu mha s not bee n defined , althoug

h the followin

g effects o f injecte d cadmiu msugges t severa l possible mechanisms : (a

) increase d sodiu

mretentio n (15, (19); (b ) direc t

vasoconstrictio n (20) ; (c ) hyper

reninemi a(2/) ; an

d (d) increase d cardia

c output (20)

. Althoug

h hyperreninemi aha s bee

n observed followin g fe d a s wel l a s injecte d cadmiu m(2/) , th e acut e hypertensiv e effec

t of injecte d cadmiu mi s no t dependen t o n renin (22)

. O

n th e other

hand , al

thoug h increase d cardia

c output ha s onl y bee n ob

serve d immediatel

y afte r intraarteriall y injecte d cadmium , th e standar

d 5 pp mdos e o f cadmiu mca n produc e significan

t cardia c effects ; thus , Kopp , workin g wit h animal s expose d to 5 pp mcadmiu m fo r 1 8 month s i

n ou r laboratory , ha s observe d de

presse d myocardia

l excitability , decrease d hig h energ y phosphat

e i n th e heart , an

d morphologic change s i n cardiac muscl e (25)

. Finally , withou t elucidatin g mechanism , "hypertension-sensitiv e Dah l rats " show agreate

r presso r response t o in

traarteria l cadmiu mtha n d o "hypertension

resistant Dah l rats " Q4). Ther e i s considerabl e variabilit

y i n huma n expo sur e t o environmenta

l cadmium , an

d man y o f th e detail s involvin

g accumulatio n o

f the metal s i

n ma n remain t o b e worked out

. I n th e United States , th e averag e cadmiu

mintak e i s estimate d t o b e 5 0 /ig/ da y o r jus t belo w 1 pg/kg-da

y (.25). Afte

r 4 0 o r 5 0 years , thi s results i

n a n averag e renal cadmiu

mcon centratio n of

30/xg/ g of kidne y o r 3 mg/ g o f renal as h (26). Rat s ingestin

g th e lowes t

presso r dos e o f cad

miu m(0. 1 ppm

) hav e a n intak e of about 5 fig/kgday ; afte r 1 8 month s of

thi s intake , their

kidney s contai n 1 /tg/

g (6)

. Thus , the y inges t

about fiv e time s a s muc

h cadmiu m(pe r unit bod y weight ) a s th e averag e American , bu t thei r rena l cadmiu m concentratio n i s onl

y one-thirtiet

h a s high

. Rat s ex pose d t o 5 pp

mhav e renal cadmiu

mconcentration s o f about 4 0 /ig/ g (5) , whic h i s simila r t o th e averag e fo r adult s i n thi s country

. Cadmium-induce

d hypertensio n i

n rats , althoug

h reproducible , i s usuall y relatively small in mag Environmenta

l Healt h Perspective s >

1 

# i

f

•

T i

- « i )

-



### i t * 

### S t hitud

e a sequen c mild . O timate d have d i ,10 5 m m mil d el t hear ta cause s cadmi u tia l hy i findin g induc e toxi c r cadmi i i s a t n hype n ; al s o f 1 It n toxic , hype r cadm i

. cad m i port k evid e miui r j sio n hyp e ; mos t 1 hav e play s ; th e < : hyp e occ u ha s soci ; A i ind u ts m

"Tf'V W*pmmir*mm*p~*mrmai^*fm *J!W*P.1 0

nitud e an d thu s frequently considere d o f littl e con sequence ; however , mos thuma n hypertensio n i s .mild . O f th e 6 0 miUio

n American s wh o ar

e no w es timate d t o hav e hypertensio n (27) , mor e tha n 80 % have diastoli c pressure s whic h ar e usuall y belo w 10 5 m m Hg . Nonetheless , in ma n a tleast , eve n suc h mU d elevation s i n bloo d pressure doubl e th e ris k o f hear tattac k an d stroke , th e majo

r cardiovascula r cause s o f disabilit y an d deat h (28). Moreover , lik e cadmium-induced hypertensio n in rats , mild essen tia l hypertensio n in ma

n ha s n o obviou s associate d findings . I

n rats , th e smal

l amount s o f cadmiu m tha t induc e hypertensio n produc e non e o f th e usual toxi c manifestation s o f

mor e extensiv e exposur e t o cadmium , while , in man , th e absenc e o f symptom s i s a majo r par to f th e proble

m i n identifyin g mil

d hypertensio n an

d convincin g th e involve d individu al s o f its ominou s prognosti c significance . I tmus tb e emphasize d tha theavy , an

d certainl y toxic , cadmium exposur e i s no tassociate d wit h hypertensio n in ra

to r man . I

n rat s 0. 1 t o 5 pp

m cadmiu m induce s hypertensio n bu t10 t o 5 0 pp

m cadmiu m doe s no to r onl y doe s s o durin g th e earl y portio n o f

th e exposur e befor e toxicity become s evident . I

n man , itai-ita

i diseas e an

d chroni c cad miu m poisonin g ar

e no tcharacterize d b y hyperten sio n Q9); moreover , individual s with malignan t hypertensio n an

d shrunken kidneys , consistin g al mos tentirel y o f

sca r tissu e wit

h littl e parenchyma , hav e n o exces s renal cadmium (30). If cadmiu m play s an y par ti n huma n hypertension , i ti s early in th e cours e o f

th e disease . B y th e tim e sever e hypertensio n an

d compromise d renal functio n hav e occurred , mos to f

th e accumulate d renal cadmiu m ha s presumabl

y bee n excrete d in th e urine i n as sociatio n wit

h urinar y protein . Although th e evidenc e tha tfeedin g cadmiu

m ca n induc e hypertensio n i

n rat s seem s convincing , there i s n o comparabl e evidenc e tha tcadmiu m i s responsibl e for an

y par to f huma n essentia l hypertension . Th e caus e o f

essentia l hypertensio n remains un known , however . Fo r th e moment , itca n onl y b e sai d tha tcadmiu m i s a ubiquitou s environmenta l contaminantwhich i s frequently presen tin concen tration s which ca n induc e hypertensio n in rat s an d which , i n animal s atleast , ca n hav e othe r car diovascula r effects Q3). Fo r th e presentitwoul d certainly see m pruden

tt o minimize cadmiu

m expo sur e a s muc

h a s economicall y practica l whil e seek in g answer s a s t o whethe r cadmiu m ha s an y effec t o n huma n bloo d pressure , o r whethe r itproduce s any othe r undesirabl e effects . 

# Conclusion

s Unde r th e condition s originally reporte d b y Schroede r an

d slightl y modified i

n ou r laboratory . chroni c ingestio n o f lo w dose s o f

cadmiu m b y rat s reproducibly induce s a

n increas e i n systoli c pres sure averagin g 1

5 t o 2 0 m

m Hg . Occasionall y th e respons e i s considerabl y larger , an d th e simultane ou s exhibitio n o f

othe r metal s ca n markedl y influ enc e it , wit

h lead havin g th e potentia l t o atleas t doubl e it . Th e extent , if

any , t o which thes e obser vation s ca n b e extrapolate d from ra tt o ma n remains t o b e demonstrated . I

ti s temptin g t o speculat e whethe r thes e currently largely descriptiv e findings ca n b e relate d to epidemiologi c dat a o f th e typ e which associat e cardiovascula r mortalit y in ma n t o th e hardnes s o f

hi s wate r supply (31). Th e subjec to f th e possibl e relationship betwee n environmental cadmiu m an d huma n hypertensio n certainl y war rant s furthe r investigation .

Thi s research wa s supporte d b y th e Veterans Administration .

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S 1 . Schroeder , H . A. , and Vinton , W . H. . Jr. Hypertensio n in rats induced b y smal

l dose s o f

cadmium . Am . J . Physiol . 202 : 51 5 (1962) . 2 . Schroeder , H . A . Cadmiu m hypertensio n i

n rats . Am . J . Physiol . 207 : 6 2 (1964) . 3 . Schroeder , H . A. , an

d Buclunan , J . Cadmiu

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e followin g chronic low-leve l cadmiu m feeding . Am . J . Physiol . 232 : H I 1 4 (1977) . 6 . Perry , H . M. . Jr. , Erlanger, M . W. , an d Perry , E . F . Hypertensio n followin g chroni c ver y lo w dos e cadmiu

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d Erlanger, M . W

. Marke d increase s in ra tsystoli c pressur

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y lo w bu tprolonge

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l Health , D . D . Hemphill , Ed. , Universit

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d Erlanger, M . W . Effec

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l Health , D . D . Hemphill , Ed. , Uni versit y o f Missouri , Columbia , Mo . Vol . II , 1977 , p . 280 . Perry , H . M. , Jr. , Perry , E . F „ an d Erlanger, M

. W. Rever sal o f cadmium-induce

d hypertensio n b y selenium o r har d water . In : Trac

e Substance s in Environmenta l Health , D . D . Hemphill , Ed. , Universit

y o f Missouri , Columbia , Mo. . Vol . 8 , 1974 , p . SI . Perry , H . M. , Jr. , and Erlanger, M . W. Hypertensiv e effec t o f chronically feeding ver

y lo w concentration s o f

lea d an d cadmiu m together . In : Trac

e Substance s i

n Environmenta

l Health , D . D . Hemphill , Ed. , Universit y o f Missouri , Co lumbia , Mo. , Vol . 12,1978 , i n press . Sorenson , J . R. , Jr. , e tal . Cadmium-induce d hypertensio n i

n male Sprague-Dawle

y rats . Ann . Rept. . o f

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y 1 0

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1 2 Februar y 197 9 

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Medicine , Universit

y o f Cincinnati , Ohio , 1973 , p . 93 . 13 . Ohanion , E . V . Geneti c influence o n hypertensio n induced b y chronic cadmiu

m feeding . Am . J . Physiol . 158 , i n press . 14 . Friberg , L. , e tal . Cadmiu m i n th e Environment, 2nd ed . CRC Press . Cleveland , 1974 , p . 118 . 15 . Doyle , J . J. , Benihoft , It . A. , an d ftnstead. H . H . Th e effect s o f lo w dietar

y cadmiu m o n bloo d pressure . M Na , U K , an d Wate r Retentio n in Growing Rats . J . Lab . Clin . Med . 86 : 5 7 (1975) . 16 . Letter , J. , an

d Bibr , R . Cadmiu m conten tin som e foo d stuff s i n respecto f

it s biologica

l effects . Vita

l Zivilisatio n 14:12 5 (1970) . 17 . Schroeder , H . A. , e tal . Vascula r reactivity o f rat s altere d b y cadmiu m an d a zin c chelate . Arch . Environ . Healt h 21:60 9 (1970) . 18 . Perry , H . M. , Jr. , an

d Erlanger, M . W . Hypertensio n i n rat s induced b y long-ter

m low-leve l cadmiu

m ingestion . Circulatio n 44 : 13

0 (1971) . 19 . Perry , H . M. , Jr. , Perry , E . F. . an d Purifoy , J . W . Antinatriuretic effecto f

intramuscula

r cadmiu m i n rats . Proc . Soc . Exptl . Biol . Med . 136 : 124 0 (1971) . 20 . Perry , H . M. , Jr. , e tal . Mechanism s ofth e acut e hyperten siv e effecto f

intre-arteria

l cadmiu m an d mercur y i n anes thetize d rets. J . Lab . Clin . Med . 70 : 96 3 (1967) . 21 . Perry , H . M. , Jr. , an

d Erlanger, M . W . Elevate d circulating renin activit

y i n rets followin g dose s o f cadmiu m know n t o induce hypertension . J . Lab . Clin . Med . 82 : 39 9 (1973) . 22 . Perry , H . M. , Jr. , and Erlanger , M . W . Mechanis m o f cadmium-induced hypertension , ln : Trace Substance s i n Environmenta l Heahh , D . D . Hemphill , Ed. , Universit y o f Missouri , Columbia , Mo. , Vol . 9,1975 , p . 339 . 23 . Kopp , S . J. , e tal . Altered myocardia l excitability , morphol og y an d metabolism induced b y long-term , lo w leve l cad miu m feeding , ln : Trac e Substance s i n Environmenu l Health , D . D . Hemphill , Ed. . Universit y o f Missouri , Co lumbia , Mo. , Vol . 12 , i n press . 24 . Ohanian , E . V. , Dahl , L . K. . and Iwai , J . Oeaeti c influence o n hypertensio n induce d b y cadmiu m i n Dah l hypertension resistan tan

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l Health , D . D . Hemphill . Ed. , Uni versit y o f Missouri , Columbia , Mo. , Vol . 10,1976 , p . 4SI . 25 . Friberg , L. , e tal . Cadmiu m i n th e Environment. 2nd ed. , CR C Press , Cleveland , 1974 , p . 19 . 26 . Tipton , 1 . H . Th e distribution o f trace metal s in th e body , ln : Metal-Bindin

g i n Medicine , M . J . Seven , Ed. , J . B . Lippin cott , Philadelphia , 1960 , p . 27 . 27 . Nationa

l Cente r for Healt

h Statistics . Bloo d preuur e o f person s 6-7 4 year s o f ag e in th e Unite d States . Advance Data . No . 1,1976 . 28 . Paul , O . Complication s o f mild hypertension . Ann . N.Y . Acad . Sci . 304 : 5 9 (1978) . 29 . Nogawa , K. , an

d Kawano , S . A surve y ofth e bloo d pressur e o f woma n suspecte d o f

itai-ha i disease . J . Juzen Med . Soc . 77 : 35 7 (1969) . 30 . Schroeder , H . A . Cadmium , chronium , and cardiovascular disease . Circulation 35 : 57 0 (1967) . 31 . Shaper , A . C , Clayton , D . O. , an d Stanley , F . Wate

r hardnes s an d hypertension , ln : Epidemiolog y an d Contro l o f Hypertension . O . Paul , Ed. , Stratum , Ne w York , 1975 , p . 163 .

I '

26 0 Environmenta l Healt h Perspective s

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