P. 1 

# OAR Box 1126 Prepped by Ollie Stewart



## Document

Number: 

# 124)11-1-33 8 Docket Number: 

# A-83-2 2

Printed 4/18/2008 9:58:26

AM Sheet 124 of 182

# J 

# fh&~* 7ZHS1339 P. 2

Environmental

H Vol. 78, pp. 15-2.

alth. 198 mpectives 

# Th e Relationshi p Betwee n Bloo d Lea d an d Bloo d Pressure i n th e NHANE S I I Survey b y Joe l Schwartz *

A larg e bod y o f

experimenta l dat a ha s show n tha tlea d raise s bloo d pressur e an d increase s responsivenes s t o a-adrenergi c agonist s i n rat s an d pigeons . Thes e studie s sugges tth e nee d to loo k fo r a simila r relationshi p i n humans . Thi s pape r examine s th e robustnes s o f th e previousl y reporte d associatio n betwee n bloo d lea d an d bloo d pressur e i n adul tmales . Th e associatio n remain s stron g an d i s essentiall y unchange d i n test s tha tinclud e nutritiona l factor s an d demographi c factors , alon e o r together , o r i n test s tha tinclud e insignifican tterms . Th e relationshi p wa s no tconfounde d b y age ; i thel d fo r al l adul tme n i n di e 20-4 5 ag e group , th e 40-5 9 ag e group , an d th e 46-7 4 ag e group . Interactio n term s fo r 2 5 30-yea r ag e group s (20-49 , 21-50 , . . . , 45-74 ) wer e al l insignificant , indicatin g n o differenc e i n th e relationshi p b y age . Th e relationshi p i s als o robus tt o th e inclusio n o f a tim e tren d t o accoun tfo r possibl e omitte d time-varyin g factors , an d i thel d i n a mode l tha tcontrolle d fo r possibl e sit e effects . Give n th e stron g experimenta l evidence , di e relationshi p i s likel y causal . 

## Introductio n Recen t experimental evidenc e ha s demonstrate dtha t moderate level s o

f lea dcaus e elevation s i n bloo d pressure i n animal s (1-6). Thes e finding s sho w effect s a t varying dose s an dacros s specie s an dindicat e pos sibl e mode s o

f actio n fo r

lea dtha t

involv e genera l mechanism s operan t

acros s all animal species . Fo r instance , bot h Iannoconn e e t al . (1) an dCar

mignan i e t al . (2) hav e reporte din vivo studie s show

ing tha t lead-expose drat s ha dincrease drespons e t o a adrenergi c stimulation . Thes e result s hav e bee n reporte din vitro b y Web b e t al . (4), usin g arterie s from rat s tha t ha dbee n expose din vivo. Suc h activit y woul db e expecte dt o lea

dt o increase s i

n bloo dpressure . Skoczynsk ae t al . (7) als o reporte dtha t

lead-treate drat s ha daugmente dan dprolonge dpresso r response s t o epinephrin e an dnorepinephrine , les s pronounce d depressio n o

f arteria l pressur e i n respons e t o isopro

terenol , an dmor e pronounce dtachycardi ai n respons e t o isoproterenol . Skoczynsk ae t al . als o foun di n perfu

sio n studie s o

f isolate darterie s tha t

lea dcause dmor e pronounce dvasoconstrictio n i n respons e t o norepi

nephrine . O f particular

interest , Piccinin i an dFavall i (8) have reporte dtha t

th e additio n o

f lea dt o th e medi ao f perfuse disolate dra t

tai l arterie s le dt o contractio n an d t o hyperreactivity i n respons e t o stimulation . Th e exposedarterie s ha dhighe r level s o f cytosoli c calciu m •Departmento

f Biostatistics , Schoo

l o f Publi c Health , Harvar

d University , Boston , M A 02115 . tha n th e contro l group , consisten t wit h othe r finding s o f lea dcausin g acalciu mleak int o cell s (9) . Lea

dha s bee n foun dt o contribut e t o increase dintracellula r concentration s o

f calciu mi n brai n capillarie s (10), neuron s (11), osteoclasts (12), an dhepatocyte s (13). A s increase dintracellula r

calciu mi s th e trigge r fo r smooth muscl e contraction , thes e result s agai n sugges t abiologica l mechanis mfo r a n effec t o f low-leve l lea d exposur e o n bloo dpressure . I n addition , Goldstei n an dA r (14) hav e reporte d tha t lea dactivate s calmoduli n in it s rol e o f activatin g phosphodiesterase , th e enzym e tha t convert s cycli c AM P int o AMP . Cycli c AM P i s involve d i n stimu

latin g th e calciu mpum p tha t remove s calciu mfro m th e cytoso l int o th e endoplasmi c reticulu man dals o lead s t o th e phosphorylatio n o f myosi n light-chai n kinase , reducin g it s sensitivit y t o activatio n b y cal

cium . Thes e ar e action s tha t woul db e expecte dt o reduc e reactivit y an dtone , an dalea deffec t o n cycli c AM P represent s apotentia l advers e disturbanc e o f thes e processes . Finally , th e experimenta l literatur e suggest s a nonlinea r relationship , wit

h effect s o n bloo dpressur e primaril y at

th e lowe r

bloo dlea dlevels . Pound s (13) reporte dtha t

low-leve l exposur e t o lea d cause din

crease daccumulatio n o f calciu mi n al l o

f th e com partment s o

f th e cell , wherea s a t

highe r lea dexposure , th e tw o shallowe r

compartments , includin g th e cyto sol , saturate dout , an dcalciu maccumulatio n con tinue donl y i

n th e deepes t

compartment , though t

t o b e th e mitochondria . Thus , th e hypothesi s tha t lea d increase s bloo dpressur e b y disturbin g cytosoli c cal

-P. 3

16 . S J. SCHWARTZ

. ciu mmetabolism s appear s consisten t wit h thi s non linearit y in response . I n ligh t o f thi s findin g o

f a n effec t an dpossibl e mechanism , w e examine dalarg e representativ e sur ve y o f th e U.S . populatio n fo

r arelationshi p betwee n bloo dlea dan dbloo dpressure . Som e o f thes e analyse s hav e previousl y bee n reporte d(15,16). Th e Secon dNationa l Healt h an dNutritio n Exam

inatio n Surve y (NHANE S II ) wa s conducte dbetwee n Februar y 197 6 an dFebruar y 198 0 o n asampl e chose n t o b e representativ e o

f th e civilian , noninstitution

alize dU.S . populatio n age d6 month s t o 7 4 years . A tota l o f 20,32 2 person s wer e examined , an dbloo dlea ddeter

mination s wer e obtaine dfor arepresentativ e sub

sampl e o f 9932 . Th e medica l evaluation s include d medica l history , physica l examination , anthropo

metri c measurements , dietar y informatio n (24-h r recal l an dfoo dfrequency) , laborator y tests , ECGs , an d radiographs . Specia l intervie w an dexaminatio n pro tocol s an dspecificall y traine dinterviewer s an dexam iner s wer e use dt o ensur e standardize dconduc t o f th e surve y at eac h site . Th e nutrien t

intak e fromth e 24-h

r recal l wa s quantifie dfo r eac h individua l usin g a curren t nutrien t dat abank . Bloo dsample s wer e analyze db y th e Clinical Chem

istr y Division , Center s for Diseas e Control . Bloo dlea d concentration s wer e determine db y atomi c absorptio n spectrophotometr y usin g amodifie dDelve s Cu p mi

crometho d(17). Bot

h benc h an dblin dquality control s were used . Th e analysi s o

f th e relationshi p betwee n bloo dlea d an dbloo dpressur e i s confounde db y age . Bot h leadan d bloo dpressur e increas e wit h age . Moreover , studie s o f population s no t

expose dt o th e environmen t o f wester n civilization , bot h in Afric aan dth e Pacifi c Islands , a s wel l a s in isolate dcommunitie s in Wales , sho w tha t bloo dpressur e doe s no t increas e wit

h age . Thus , ag e mus t b e treate dno t

a s representin g amarke r for th e agin g process , bu t

rathe r a s representin g unknow n stresses , an dth e cumulativ e effec t o f element s o

f th e wester n environment . Leadi s on e o f thes e elements , an dthu s th e confoundin g i s real . T o minimiz e tha t confoundin g w e hav e adopte dsevera l approaches . First , w e performe danalyse s in th e 40

- t o 59-year-ol d ag e group , th e ag e grou p wit h th e lowes t

correlatio n betwee n bloo dpressur e an dage . Second , w e hav e repeate dth e analyse s fo

r al l me n age d2 0 t o 74 , wit h th e expectatio n tha t

th e larg e sampl e siz e wil l partl y mitigat e th e confounding . Finally , w e hav e repeate d ou r analyse s wit

h interactio n term s for

differen t ag e groups , t o tes t

fo r th e uniformit

y o f th e effec t acros s age s withou t payin g th e sampl e siz e penalt y tha t sub

samplin g entails . 

## Initia l Analysi s 40

- t o 59-Year-Ol d Cohor t Th e establishe dcorrelate s o f bloo dpressur e ar e age , sex , race , an dobesity . W e use dQuetelet s bod y mas s inde x (BMI ) (weight/height 2 ) a s th e principa l obesit y measur e i

n thi s analysis . Fo r

th e 40

- t o 59-year-ol dag e grou p w e onl y considere dwhit e males . W e force d ag e int o th e model s i n orde r t o avoi dan y upwar dbia s i n th e leadcoefficients . Th e natura l lo g o

f bloo dlea dwa s mor e normall y distributed , mor e significant , an dgav e ahighe r R 2 tha n untransforme dbloo dlead , bloo dlea dsquared , bloo dlea d+ bloo dlea dsquared , th e squar e roo t o f bloo d lead , o r bloo dlea dt o othe r

fractiona l power s (w e examine d0.15 , 0.2 , 0.3 , an d0.4) . Al l o f th e result s reporte dher e ar e for

th e natura l lo g o

f bloo dlead , bu t regression s for

untransforme dlea dgav e ver y similar results . Th e initia l regression s analyze dsystoli c an d dias

toli c bloo dpressur e for

whit e males , 4 0 t o 5 9 year s old , wit h amode l consistin g o

f age , ag e squared , BMI , an d bloo dlead . Thes e regression s wer e don e t o determin e whethe r bloo dlea dlevel s wer e significantl y associate d wit h systoli c an ddiastoli c bloo dpressur e afte r controllin g fo

r th e well-documente dcorrelate s o f bloo d pressure . Lea

dwa s statisticall y significan t (p < 0.01 ) fo

r bot h systoli c an ddiastoli c bloo dpressure s in al l OL S (ordinar y leas t

squares ) regressions , i n weighte dre gressions , an di n weighte dregression s wit h th e desig n effect s o

f th e survey . 

### Test s o f Robustnes s Th e regressio n model s wer e the n expande dt o incor

porat e additiona l variables , wit h particula r

attentio n directe dt o th e stabilit y an dsignificanc e o f th e lea d coefficien t

i n th e presenc e o

f nutritiona l factor s an

d bloo dbiochemistries . A larg e se t

o f nutritiona l an dbiochemica l variable s fro mNHANE S I I wa s include di n stepwis e regres sions . Th e larg e se t

wa s use dbecaus e bloo dpressur e i s suc h amultifactorial outcom e an dbecaus e w e desire d t o tes t th e robustnes s o

f th e lea drelationshi p t o the inclusio n o

f othe r variables , an dth e reportin g o f sig

nificanc e fo

r an y o f the mi n thes e analyse s shoul dno t b e take n a s a

n endorsemen t

o f arelationship . In addi

tion , alarg e se t

o f demographi c an dpersona l histor y variable s wa s als o considere di n stepwis e regressions . 

## Nutritiona l an dBiochemica l Variable s T o provid e a

n unusuall y rigorou s tes t o f th e inde

penden t significanc e o

f bloo dlead , almos t

al l o f th e nutritiona l an dbiochemica l variable s in th e NHANES I I wer e include di

n stepwis e regressions . In addition , t o accoun t

fo r possibl e curvilinea r

relationships , square dan dnatura l logarithmi c transformation s o f thes e variable s wer e als o included . Th e variable s ar e liste di n Tabl e 1 . Th e objectiv e wa s no t t o evaluat e th

e possibl e associatio n o

f nutritiona l o r

biochemical measurement s wit

h bloo dpressure , bu t

rathe r t o conservativel y estimat e th e strengt h an dindependenc e o f th e relationshi p betwee n bloo dleadan dbloo d pressure . Pn . k . n < i t f c r e Vf. ( u St , gi \ ab : th e m< p n ch. . se l ani ' th e m o co r an c we i nif i in c an d wei i T < whir piec

SAS ' tW O : thre

Th eP. 4

obesity -ol d ag e ce dag e

. bia s i n normall y irhe r R 2 squared , o f bloo d sr s (w e result s ead , bu t ••• • simila r aid dias

ear s old ,

. MI , and .•r'termin e -sociate d a e afte r ; o f bloo d < 0.01 ) fo r .i i al l OL S thte d re nit h th e BLOOD LEAD AND BLOOD PRESSURE 1 7

t o mcorittentio n j th e lea d ior s an d i variable s regres - , essur e i s e desire d • • p t o th e •g o f sig

- ,oul d no t .- . I n addi

- ., 1 histor y rssions . 

## :able s ih e inde

- :> f th e n u •HANE S

. addition , jnships , I ation s of

^ cable s are , iluat e the ' chemical ,j r t o con-

f idenc e of , pressure . Tabl e 1 . Variable s include d i n th e stepwis e regressio n analysis .

Age * Age 2 3 Bod y mas s inde x Dietar y sodium b Salt-shake r

sodiu m Dietary sodiu mx salt-shake r

sodiu m Dietary potassium b Dietary sodium

potassiu mrati o Dietary calcium b Dietary phosphorus b Dietary protein b Dietary fat

b Dietary carbohydrate 1 5 Dietary cholesterol b Dietary saturate d fatt y acids b Dietary olei c acid b Dietary linolei c acid b Dietar y iron b Dietar y vitami n A b Dietar y vitami n C b Dietar y thiamine b Dietar y riboflavin b Dietar y niacin b Seru mcholesterol 1 1 Seru mvitami n C b Seru miron b Seru mtransferri n saturatio n Seru mzinc b Seru mcopper b Seru malbumin b Hemoglobin b Re dbloo dcel l coun t Ethano l consumption/week b Cigarette s smoked/da y Tota l dietar y grams b Tota l dietar y calories b Ciga r o r pip e smokin g "Force d int o eac h regressio n t o remov e an y possibl e ag e effect s o n bloo dpressure . b Th e natura l lo g an dsquare dtransformatio n o f thes e variable s wer e als o include di

n th e stepwis e regression . Includin g thes e additiona l 8 7 variable s increase s th e probabilit y o f variable s bein g foun dstatisticall y sig

nifican t du e t o chanc e alone . Thi s complicate s th e in

terpretatio n o

f nutritiona l an dbiochemica l factors , bu t no t th e interpretatio n o

f th e lea dvariable ; i t

onl y make s i t mor e difficul t for lea dt o maintai n it s significance . Th e genera

l procedur e for

variabl e selectio n wa s a s follows : First , weighted , stepwis e multipl e linea r regressio n wa s use dt o determin e whic h variable s wer e significantl

y relate d(p < 0.05 ) t o bloo dpressur e (usin g th e MAX

Roption s of

th e SA S procedur e Stepwise) . Th e MAX

Rprocedur e determine s fo r an y give n model siz e (i.e. , numbe r of independen t

vari

ables ) th e variable s tha t

explai n th e greates t

amoun t o f th e varianc e o

f bloo dpressure . W e chos e th e larges t mode l wit h al l variable s significantl y relate dt o bloo d pressur e (p < 0.05) . Fro mth e 8 7 nutritiona l an dbio

chemica l variables , th e weighted , stepwis e regressio n selecte d5 additiona l variable s fo r diastoli c pressur e an d6 additiona

l variable s fo r

systoli c pressure , usin g th e 5 % significanc e test . Thes e wer e use da s th e startin g model fo r th e SA S procedur e SURREGR , whic h in

corporate s th e surve y desig n effects . Fo r both systoli c anddiastoli c bloo dpressures , on e variabl e fromth e weighte dstepwis e regressio n faile dt o maintai n sig

nificanc e a

t th e 5 % leve l afte r

th e desig n effect s wer e incorporated . Th e fina

l regressio n result s fo r

systoli c anddiastoli c pressures , afte r accountin g fo r

th e weighting an

ddesig n effects , ar e give n in Tabl e 2 . T o investigat e whethe r

athreshol dlevel , belo w whic h n o effec t o f bloo dlea do n bloo dpressur e existed , piecewis e linea

r regression s wer e performe dusin g th e SA S procedure NLIN . Thes e segmente dregression s fit tw o line s to th e data . One , belo w th e putativ e bloo dlea d threshol dT, depend s o n al l th e variable s excep t lead . Th e other , for

bloo dlea dlevel s abov e T, include s lead . Tabl e 2 . Regressio n o f diastoli c an d systoli c bloo d pressure s i n whit e male s ag e 4 0 t o 59 . Variabl e Diastoli c Ag e Age 2 Bod y mas s inde x Lo g (bloo dlead ) Dietar y potassiu m Hemoglobi n Albumi n Log(dietar y vitami n C ) Systoli c Age Age 2 Bod y mas s inde x Lo g (bloo dlead ) Albumi n Lo g (dietar y vitami n C ) Log(dietar y riboflavin) Log(dietar y olei c acid ) Log(seru mvitami n C ) Coefficien t 0.276 8 -0.001 4 1.13 1 3.95 4 -0.001 8 1.54 8 3.58 7 1.83 8 1.31 1 -0.006 8 1.73 6 8.43 6 7.08 8 2.41 1 -5.50 9 3.99 2 -3.47 2 /-Statisti c

0.1 7 0.1 0 8.5 5 2.8 5 4.9 2 3.9 0 2.5 0 4.6 5 0.5 7 0.3 0 9.4 2 3.2 4 2.5 0 3.8 4 3.0 7 2.4 9 2.4 7 Probabilit y

0.863 6 0.932 1 0.000 1 0.008 0 0.000 1 0.000 5 0.017 9 0.000 1 0.572 0 0.770 6 0.000 1 0.002 8 0.017 8 0.000 5 0.004 4 0.018 3 0.018 4

W e use da n iterativ e algorith mtha t choose s th e threshol dpoin t

tha t minimize s th e su mo

f th e square s o f th e error s ove r

th e ful l rang e o f bloo dleadlevels . Afte r includin g th e nutritiona l variables , th e bloo d analytes , an dthei r

curvilinea r

transforms , bloo dlea d remaine dsignificantl y associate d(p < 0.05 ) wit h both systoli c an ddiastoli c bloo dpressures . Th e coefficien t o f lea di n th e regression s wa s withi n 10 % o f th e origina l value . Further , th e segmente dregressio n analysi s indicate dtha t

ther e wa s n o threshol dbloo dlea d leve l i n th e relationship . 

## Interactio n Term s I n multipl e regressio n analysis , anothe r considera

tio n i s th e possibilit y o

f significan t

interactio n terms . T o evaluat e thi s possibility , an additiona l weighted , stepwis e regressio n analysi s wa s don e for bot h systoli c an ddiastoli c bloo dpressure . Th e ne w variable s consiste do

f th e linea r

interactio n term s betwee n th e final variable s i n th e mode l (show n i n Tabl e 2 ) an dth e linea r for mo f

al l th e othe r

variable s originall y considere dfo r

th e initial stepwis e regressio n (Tabl e 1) . Thi s mean t

runnin g astepwis e regressio n with 16 2 interactio n term s adde dt o th e final regressio n model s for systoli c an ddiastoli c bloo dpressures . Usin g suc h a larg e se t o f variable s gav e ahig h probability tha t som e variable s woul dente r

a t th e 5 % leve l b y chance . However , th e purpos e wa s no t t o determin e i

f thes e variable s wer e independentl y significant , bu t rathe r t o furthe r tes t th e significanc e an dindependenc e o f th e relationshi p betwee n bloo dpressur e an d bloo dlead . A s expected , severa l interactio n term s entere dth e systoli c an ddiastoli c regressions , bu t i n eac h regressio n th e lea dcoefficient

varie dles s tha n 10

% fro mit s origina l valu e an dremaine dsignifican t (p < 0.015) .P. 5

1 8 / . SCHWARTZ 

## Marginall y Insignifican t Variable s Thre e othe r

analyse s wer e don e t o ensur e tha t thi s relationshi p wa s robust . First , th e origina l weighted , stepwis e regressio n wa s extende dt o includ e variable s significan t

throug h th e 15 % leve l t o se e i f marginall y insignifican t

variable s influence dth e significanc e o f lead . Fo r bot h systoli c an ddiastoli c pressures , lea d remaine dsignifican t

an dther e wa s littl e chang e i n th e magnitud e o

f th e coefficien

t Oes s tha n 10%) . Second , for

diastoli c bloo dpressure , al l th e variable s wer e include dtha t

wer e significan t

betwee n th e p = 0.0 5 an dth e p = 0.1 5 levels , an dever y possibl e com binatio n o f thos e variable s (take n 1 , 2 , 3 , 4 , 5 , 6 , 7 , an d8 a t atime ) wa s considered . Al l 25 5 combination s wer e adde dt o th e variable s tha t wer e significan t

a t th e 5 % levels , an daregressio n wa s performe do n eac h set . Th e coefficien t

o f bloo dlea dvarie db y onl y +10 % t o -10 % fro mth e valu e tha t

w e obtaine dwhe n w e onl y include dsignifican t

variables , an dlea dwa s alway s significan t

(p < 0.01) . Thi s analysi s wa s no t repeate d fo r systoli c bloo dpressure . Th e las t analysi s wa s th e mos t

demandin g tes t

o f th e independenc e o

f th e relationshi p betwee n bloo dpres sur e an dbloo dlead . Model s fo r systoli c an ddiastoli c bloo dpressur e wer e fit

b y weighted , stepwis e regressio n usin g th e origina l candidat e variable s (Tabl e 1 ) bu t excludin g lead . Thi s gav e al l o f th e othe r

variable s an d thei r curvilinea r

transformation s th e maximu m opportunit y t o explai n variatio n tha t coul dals o b e explaine db y lead . After obtainin g thes e new , final models , asingl e regressio n fo r eac h outcom e wa s ru n addin g th e lea dvariabl e t o th e variable s o f thi s model . Fo r bot h systoli c an ddiastoli c bloo dpressures , lea dwa s stil l statisticall y significan t (p < 0.016 ) an dth e mag nitud e o f th e lea dcoefficien t

change dles s than . 10

% fromthos e obtaine di

n th e origina l analyses . Becaus e som e peopl e hav e foun dtha t smal l amount s o f ethano l ar e associate dwit h reduce dbloo dpressure , ethano l wa s als o modele da s aquadrati c functio n o f alcoho l consumption , an dals o wit h tw o dumm y var iable s fo r lo w an dhig h consumption . Th e stepwis e re gressio n wa s repeated , an dresult s di dno t change . Th e result s o f thes e analyse s indicat e tha t th e strengt h an d independenc e o

f th e relationshi p betwee n bloo dlea d pressur e wa s remarkabl y stable . 

## Demographi c an dPersona l Histor y Variable s W e nex t considere dth e possibilit y tha t inclusio n o f th e variable s show n i n Tabl e 3 woul daffec t th e stabilit y o f th e lea dregression . Hypertensio n medicatio n an d lo w sal t die t wer e teste dt o se e i

f th e respons e t o lea dwa s altere db y thes e factors . Th e inclusio n o f thes e factor s an dinteractio n term s betwee n the man dlea ddi dno t chang e th e lea dcoefficien t appreciably , an dth e interactio n term s wer e insignificant . A s hypertensio n medicatio n i s amarke r fo r hig h bloo dpressure , it s itiui e o . rnuiuiuinuu n vunuuie Variable s Demographi c Famil y income Poverty inde x Regio n o f th e countr

y Seaso n o f th e yea r Degre e o f urbanizatio n Residenc e insid e centra l cit y Educational leve l Hypertensio n Hypertensiv e medicatio n Lo w sal t die t s lesie u u i ui e aiepwia tlegicsaiuu .

Othe r persona l history variable s Tricep t skinfol d Subscapula

r skinfol d Recreationa

l exercis e Work-relate dexercis e Recent weight los s Family history o

f hypertensio n Kidney diseas e Seru mcreatinin e a l l e ~ P ' a : C' : O ! w r < aP. " l e inclusio n i n amode l i s no t ver y informative . Al l o f th e subsequen t

analyse s wer e performe dwit h an dwith

ou t th e inclusio n o f

hypertensio n medication . Th e othe r

variable s i n Tabl e 3 wer e teste di n tw o ways . First , th e stepwis e regressio n procedur e wa s repeate dusin g th e variable s i n Tabl e 3 an donl y th e nutritiona l an dbiochemica l variable s tha t ha dbee n significan t

a t th e 15 % leve l i n th e previou s analysis . Again , lea dwa s selecte dfo r bot h systoli c an ddiastoli c bloo dpressur e (p < 0.005 ) an dit s coefficien t wa s withi n 10 % o f th e origina l mode l tha t containe donl y age , age 2 an dbod y mas s index . Th e variable s i n Tabl e 3 wer e the n adde dt o al l o f thos e i n Tabl e 1 , includin g thei r curvilinea r

trans forms , an dth e stepwis e proces s wa s repeated , yieldin g th e sam e results . Finally , w e re-ra n th e stepwis e regressio n usin g al l o f th e variable s i n Table s 1 an d3 excep t fo r lead , allowin g maximu mopportunit y fo r colinea r factor s t o enter . Lea dwa s the n inserte di n the resultin g model s fo r

systoli c an ddiastoli c bloo dpres sure . I t wa s stil l significan t

(p < 0.01 ) wit h les s tha n a 10 % chang e i n it s coefficient . I n addition , smokin g an ddrinkin g wer e force dint o th e regressio n models , an dlea dremaine dsignifican t (p < 0.01) , wit h n

o noticeabl e chang e i n it s coefficient . Previou s analyse s hav e show n tha t abou t hal f of th e lea di n peopl e i n th e NHANE S I I sampl e cam e fro m gasolin e (18,19). Tetraethy l lea dha s littl e cadmiu m contamination , s o confoundin g wit h cadmiu mi s unlikely . However , occupationali y expose dworker s ar e als o expose dt o cadmium , s o w e repeate dth e regressio n excludin g al l person s i n jo b categorie s cite db y NIOSH a s havin g potentia l lea dexposure . Lea dremaine d significan t

fo r bot h systoli c an ddiastoli c bloo d pressur e (p <0.01) . 

## Principa l Component s Analyse s Becaus e nutritiona l variable s ar e ofte n colinea r wit i eac h othe r

an dma y i n fac t

onl y b e importan t

i t complexes , asecon dapproac h wa s take n t o dealin g wit i nutritiona l an dserologica l variables . Principa l co m ponent s analysi s wa s don e t o findth e linea r combin e tion s o f th e nutritiona l an dserologica l factor s th a explaine dth e greates t amoun t o f thei r commo n va

r C o

b i C< ; h ; si

ol.

- ri

al

dl . St. . fl i o b se. M, . D re v a en . re ; di ; jus .

Fic i I . I . b r E I f b !P. 6

BLOOD LEAD AND BLOOD PRESSURE 1 9 egression . iriable s ation . Thes e principa l component s wer e the n entere d

int o th e stepwis e regressio n t o allo w thos e factor s t o explai n agreate r

amoun t o f th e variatio n in bloo d pressur e befor e colinearit y prevent s an y mor e vari

able s fro mentering . Fo r

instance , th e first five prin

cipa l component s o

f th e variable s i

n Tabl e 1 explai n 50

% o f their variation . Whe n thes e principa l component s wer e use dinsteado

f th e ra w variable s an dth e stepwis e regressio n wa s repeated , lea dagai n wa s significantl y associate dwith bot h systoli c an ddiastoli c bloo d pressur e (p < 0.01) , an dit s coefficient wa s change db y les s tha n 10 % fromit s origina l value . 15 0

O ) 134 - 15 2 5 3 5

BLOO D LEAD LEVE L (ug/dl ) Al l o f th e an dwith

a d in tw o • dur e wa

s i onl y th e ha dbeen analysis . ••1 diastoli c .-.'a s withi n onl y age , : i t o al l o f .a r trans - .1 , yieldin g stepwis e ? s 1 an d3 (unity fo r fte din th e loo d pres es s tha n a

. smokin g , n models , j , with n o

. half o f th e am e fro m cadmium dmiu mis

. orker s ar e

. regressio n

. b y NIOSH ; remaine d jli c bloo d

ilinear wit h ' iportan t i n ! dealin g wit

h icipal com

- ', i r combina

- .actor s tha

t mmo n vari



## Colinearit

y an dInfluenc e Diagnostic s Althoug h al l o f thes e analyse s mak e i t clea r tha t colinearit y i s no t th e caus e o

f lead' s correlatio n wit

h bloo dpressure , varianc e inflatio n factor s wer e compute dfo r ou r final models . N o significan t variabl e ha davarianc e inflatio n facto r abov e 1.4 . T o ensure tha t

th e significanc e o

f lea di n th e regres sio n wa s no t du e t o th e presenc e o

f afe w influential observations , influenc e diagnosti c procedure s wer e run . Residual s wer e plotte dfor al l th e observations , an dth e larges t

residual s wer e clustere dnea r th e mid

dl e o f th e data , wher e thei r

influenc e i s slight . Cook' s D statistics , astandar dmeasur e o f a n observation' s in

fluence o n aregression , wer e als o compute dfor eac h observation . Th e highes t

Cook' s D wa s 0.02 9 an dth e secon dhighes t wa s 0.023 , both o

f whic h ar e ver

y small . Moreover, o

f th e 1 0 observation s wit

h th e larges t

Cook' s D statistics , 6 hadpositiv e residual s an d4 ha dnegativ e residuals , indicatin g tha t th e mos t

influentia l obser

vation' s split

almos t evenl y o n ho w the y woul dinflu

enc e th e lea

dcoefficient . Figure s 1 an d2 sho w th e relationshi p betwee n bloo dlea dan dbot h systoli c an d diastoli c bloo dpressur e in thi s population , afte r ad

justin g fo r al l o f th e othe r significan t

covariates .

5 15 2 5 3 5 BLOO D LEA

D LEVE L (ug/dl ) FIGUR E 1 . Adjuste

ddiastoli c bloo dpressur e an dadjuste dbloo dlea d level s fo r whit e male s ag e 4 0 to 59 . Bot

h bloo dpressur e an dbloo d lea dhav e been adjuste db y regressio n fo r th e effect s o

f age , age 2 , bod y mass , an dothe r significan t variable s liste di

n Table s 2 and3 . Eac h poin t represent s th e mea

n bloo dpressur e an dmea n bloo d lea dfo r 2 4 consecutiv e observations , sorte din increasin g orde r o f bloo dlead . FIGUR E 2 . Adjuste dsystoli c bloo dpressur e an dadjuste dbloo dlead level s fo r whit e male s ag e 4 0 to 59 . Bot

h bloo dpressur e an dbloo d lea dhav e bee n adjuste dby regressio n fo r th e effect s o

f age , age 2 , bod y mass , andothe r

significan t variable s liste di

n Table s 2 and3 . Eac h point

represent s th e mea

n bloo dpressur e an dmea n bloo d lea dfo r 2 4 consecutiv e observations , sorte di n increasin g orde r

o f bloo dlead . 

## Result s fo r

Al l Adul t

Me n Th e 40

- t o 59-year-oldag e grou p represent s abou t one thir do f adul t male s an di s th e onl y grou p wher e th e confoundin g o

f ag e an dbloo dlea dca n b e eliminate d unambiguously . Additiona l regression s wer e per formed , however , t o confirmth e relationshi p i n th e ful l populatio n o

f adul t me n ( > 2 0 year s o

f age) . Again , ou r analysi s bega n b y lookin g at th e basi c variable s clearl y linke dt o bloo dpressure : age , race , an dbod y mass . Ag e wa s agai n modele dwit h bot h alinear

an d quadrati c ter mt o accoun t for th e nonlinea r

depen

dence . I n thi s analysis , black s wer e included , an da dumm y variabl e for

rac e wa s include din th e regres sio n becaus e th e sampl e siz e wa s no w larg e enoug h t o permi t separatin g th e rac e effect . Leadwa s onc e mor e foun dt o b e asignificant

predicto r

o f both systoli c an d diastoli c bloo dpressur e (p < 0.01) . 

## Test s of Robustnes s W e nex t include dal l o

f th e variable s i

n Tabl e 1 an d Tabl e 3 , alon g wit

h thei r squar e an dlo g transforms , i n astepwis e regressio n analysis , t o tes t whethe r inclusio n o

f thes e othe r

variable s coul daffect

th e lead

bloo dpressur e relationship . Leadwa s selecte da s sig

nifican t fo r both systoli c an ddiastoli c bloo dpressur e (p < 0.01) . Thi s resul t

hel dwhethe r

o r no t hypertensiv e medicatio n wa s include di n th e stepwis e regression . Figure s 3 an d4 sho w th e relationshi p betwee n bloo d lea dan dbot h systoli c an ddiastoli c bloo dpressur e i n all adul t me n after

controllin g for

all covariates . T o assur e tha t

lea dwa s no t

actin g for

avariabl e tha t di dno t ente r th e regressio n becaus e i t wa s colinea r wit h lead , w e re-ran th e stepwis e regressio n usin g all o f th e variable s in Table s 1 an d3 excep t for lead . Lea dwa s the n inserte di n th e resultin g mode l an dit s sig

nificanc e checked . Leadwa s significantl y relate dt o bot h systoli c an ddiastoli c bloo dpressur e (p < 0.01) .P. 7

2 0 / . SCHWARTZ

L J z > c n c n u i 6 4 c c a a o o

- 1 B2 - 0 3 U

_ l o 1 - 80 - t n < a o

o o o ° ° < p "a-af c °

° o o o 0 0 o 0 '

•

.

•

I S 2 5 3 5 4 5 BLOO D LEA

D LEVE L (ug/dl ) FIGUR E 3 . Adjuste ddiastoli c bloo dpressur e an dadjuste dbloo dlead level s fo r male s ag e 2

0 to 74 . Bot

h bloo dpressur e an dbloo dlea d hav e bee n adjuste dby regressio n fo r th e effect s o

f age , age 2 , bod

y mass , an dothe r

significan t variable s liste di

n Table s 2 an d3 . Eac h point represent s th e mea

n bloo dpressur e an dmea n bloo dleadfo

r 5 0 consecutiv e observations , sorte di n increasin g orde r

o f bloo d lead . 13 8

UJ cc c n U J I 13 4 1 a a 3 13 2 C D U " 13 0

15 2 5 3 5

BLOO D LEA

D LEVE L (ug/dl ) FIGUR E 4 . Adjuste dsystoli c bloo dpressur e an dadjuste dbloo dlea d level s fo r male s ag e 20 t o 74 . Bot

h bloo dpressur e an dbloo dlea d hav e bee n adjuste db y regressio n fo r th e effect s o

f age , age 2 , bod

y mass , an dothe r

significan t variable s liste di

n Table s 2 an d3 . Eac h poin t represent s th e mea

n bloo dpressur e an dmea n bloo dleadfo

r 2 4 consecutiv e observations , sorte di n increasin g orde r

o f bloo d lead . 

## Interaction s with Hypertensio n o r Hypertensiv e Medicatio n T o assur e tha t

aspuriou s correlatio n wa s no t occur ring du e t o a

n interactio n o

f lea dlevel s wit

h hyper

tensiv e medicatio n o r

du e t o kidne y diseas e elevatin g both bloo dpressur e an dbloo dlea dlevels , severa l addi

tiona l analyse s wer e performed . Th e stepwis e regres sion s wer e repeate dexcludin g al l person s o n hyper

tensiv e medication . Again , al l variable s in Tabl e 1 wer e considered , no t

t o determin e whethe r

the y wer e tru e predictor s o

f bloo dpressure , bu t

t o allo w maximu m possibility for

anothe r facto r t o explai n th e correlatio n betwee n bloo dpressur e an dlead . Leadwa s signifi

cantl y relate dt o bot h systoli c an ddiastoli c bloo dpres sur e (p < 0.01) . Seru mcreatinin e wa s force dint o th e regression , an dlea dremaine dsignifican t (p < 0.01) . Next , th e stepwis e regressio n wa s repeate dincludin g

hypertensiv e medicatio n a s avariable . Lea dwa s agai n selecte dfo

r bot h systoli c an ddiastoli c bloo dpressur e (P< 0.01) , an da

n interactio n ter mbetwee n lea d an d hypertensiv e medicatio n wa s no t significant . Finally , al l me n wit

h diastoli c bloo dpressur e abov e 9 0 m mH g wer e exclude dfro mth e sample , an dth e stepwis e regressio n wa s repeated . Lea dwa s agai n chose n a s sig

nificantl y relate dt o bot h systoli c an ddiastoli c bloo d pressur e (p< 0.01) . 

## Othe r Ag e Group s Th e mos t robus t wa y t o chec k

for adifferential lea d effect in different

ag e group s i s t o us e interactio n terms , thereb y maintainin g sampl e size . W e use d dumm y variable s for

th e ag e group s 2 0 t o 3 9 an d6 0 t o 7 4 an d interactio n term s betwee n the man dlead . Th e inter

actio n term s wer e highl y insignifican t (p > 0.35) , indicatin g th e sam e magnitud e effect i n al l ages . A s afurthe r

check , w e separatel y ra n th e stepwis e regression , usin g al l o

f th e variable s i n Table s 1 an d3 , for th e ag e group s 2 0 t o 4 5 an d4 5 t o 74 . Th e large r ag e group s wer e use dt o compensat e fo r th e increase d colinearit y wit

h age . Leadwa s chose n a s significan t fo r bot h ag e groups , fo

r both systoli c an ddiastoli c bloo d pressure . Next , th e regressio n fo r al l adul t male s wa s repeated , bu t

an interactio n ter mfor

th e 2 5 sequentia l ag e group s (20-49 , 21-5 0 45-74 ) wa s teste din 5 0 separat e regression s (on e fo r eac h ag e group , fo

r both diastoli c an dsystoli c bloo dpressure) . Leadwa s sig

nifican t i n eac h regression , an dth e interactio n ter m wa s insignificant , agai n indicatin g aunifor mrela

tionshi p in al l ag e groups . Finally , th e regression s fo r bot h systoli c an ddiastoli c bloo dpressur e wer e repeate d i n eac h o f th e 2 5 ag e groups , an dlea dwa s significan t in al l 5 0 regressions . Figur e 5 show s th e coefficient s o f diastoli c bloo dpressur e plotte dagains t th e media n ag e for eac h o f th e 2 5 subgroups . Th e slop e appear s lower , althoug h insignificantl y so , i n th e younges t ag e groups . Fo r

th e remainin g 2 0 ag e groups , th e slop e oscillate s abou t

amea n o f approximatel y 3. 4 (o n th e lo g scale) , indicatin g tha t

adro p in bloo dlea dlevel s from 1 8 u.g/d L t o 1 0 Mg/d

L woul dreduc e diastoli c bloo d pressur e b y 2 m

mHg . 

## Tim e Trend s Th e introductio n o

f unleade dgasolin e i n 197 5 create datim e tren din bloo dlea dlevel s in th e Unite d States . Thi s downwar dtren daccelerate din 197 8 when furthe r regulation s restricte dth e amoun t o f lea di n leade dgasoline . Sinc e th e NHANE S I I bloo dlea ddata wa s collecte dfro mFebruar y 197 6 t o Februar y 1980 , ther e i s atim e tren di n th e bloo dlea d data . I f ther e wer e atim e tren di

n bloo dpressur e becaus e o f anothe r factor , an dtha t facto r wer e omitte dfro mth e analysis , thi s woul dconfoun dth e relationship . Examinatio n o f th e bloo dpressur e level s in th e Nationa l Health Surve y i n tl

th ' tl

N . ti: . tl. : Sl " p. . p < it : T, P i f a tl . SI,, : tii

T.7, e. » i n ov a m; . oi, . u i fe : Nl. bl. . Wl; , th e W L CO . th W ( e n ac P th . b y al l ni fP. 8

BLOOD LEAD AND BLOOD PRESSURE 2 1 din g cgai n ssur e i an d .ially , r n H g mis e ssig

oloo d

. 1 lea d •.erms , jmm y 4 an d inter

0.35) , epwis e an d3 , .;er ag e rease d ..ificant abloo d e s wa s ,uentia l di n 5 0 o r bot h a s sig

n ter m

. n rela

- * on s fo r epeate d .nifican t ient s o f iia n ag e s lower , .•s t ag e , e slop e

. th e lo g ^l s from c bloo d

in 197 5 e Unite d ,7 8 whe n

. lea di n .ead dat a ir y 1980 , ter e wer e •e r factor, | ./sis , thi s .i n o f th e Surve y i n z U J L-L u 3. 5

a < u j o 2.5 - o

_ i C D 2. 0 3 4 3 8 4 2 4 6 5 0 5 4 5 8 MEDIA N AG E FIGUR E 5 . Coefficien

t o f lo g bloo dlead(in aregressio n fo r diastoli c bloo dpressure ) versu s media

n ag e fo r th e 2 5 subgroups . th e 1960s , i n th e NHANE S I from197 1 t o 1975 , an di n th e NHANE

S II , sho w tha t

level s in NHANE S I I wer e th e same a s in th e 1960 s bu t somewha t

lowe r tha n in NHANE S I . Thus , n o clea r

tren di n bloo dpressur e ove r tim e i s evident . Th e dat aar e qualitativel y suggestiv e o f th e relationshi p w e hav e foun dwithi n th e NHANE S I I survey , sinc e gasolin e lea dus e peake ddurin g th e perio do f th e NHANE S I survey . Nevertheless , i t i s im

portant t o mak e sur e tha t

th e relationshi p w e hav e identifiedi s no t

confounded . Other Covariates That

Might Change Over Time. Tim e trend s in othe r causa l factor s o

f bloo d pressur e wil l onl y confoun dth e analysi s i f thos e factors ar e omitted , an dth e first approac h i s t o includ e them . Obesity , exercise , diet , seru mcholestero l levels , smoking , etc. , ar e al l include di n th e model ; change s i n thes e factor s wil

l no t confoun dth e lea drelationship . The dietar y variable s ar e sensitiv e enoug h t o measure , e.g. , change s i n saturate dversu s polyunsaturate dfat s i n th e diet . Increase dus e o f hypertensiv e medicatio n ove r tim e wa s similarl y controlle dfor , an di n fact , n o majo r externa l determinan t

o f bloo dpressur e ha s bee n omitte dfro mth e analysis , makin g confoundin g unlikely . Modeling Time Trend. Becaus e bloo dleadlevel s fel l a t amuc h faste r

rat e i n th e las t

2 year s o

f th e NHANE S I I survey , th e slop e o

f th e correlatio n betwee n bloodleadan dan omitte dtime-dependen t covariat e woul dhav e change di

n th e secon dhalf

o f th e survey . I

f th e correlatio n betwee n bloo dlea dan dbloo dpressur e wa s du e t o bloo dlea dcorrelatin g wit h thi s omitte d covariat e becaus e both o

f the mhav e atim e trend , the n th e slop e o

f th e bloo dlead-bloo dpressur e relationshi p woul dals o chang e in th e secon dhalf . W e teste dthi s b y enterin g a n interactio n ter min ou r model . Th e inter

actio n termwa s highl y insignifican t (p = 0.7 5 systolic , p = 0.79 diastolic) , indicatin g tha t th e majo r

chang e in th e decline o

f bloo dlea dove r

time wa s no t

accompanie d b y an y chang e in th e relationshi p wit h bloo dpressure . Next , w e inserte dater mfor

time int o ou r

mode l for al l adul t me n an dre-estimated . Leadwa s agai n sig

nifican t a s apredicto r

o f bot h systoli c an ddiastoli c bloo dpressur e (p < 0.05) . W e conclude dtha t a n omitte d time tren di s no t

confoundin g thi s analysis . 

## Geographica l Variatio n Sinc e th e surve y too k

dat ai n 6

4 locations , i t

i s pos sibl e tha t ther e ar e desig n effect s in th e data . Th e SURREG Rregressio n packag e tha t w e use daccount s fo r th e desig n effect s b y estimatin g th e covarianc e usin g aTaylo r

serie s approximatio n fo r th e off

diagona l effects . A

n alternativ e i s t o assum e adifferent intercep t for eac h samplin g unit . Thi s als o examine s th e time tren dissu e i n adifferent way . A s th e site s wer e sample dat

different times , th e differen t

sit e intercept s represen t eithe r sit e o r time differences . A s th e 64 PSU s wer e randoml y selecte dfro mcandidat e PSU s t o represen t th e U . S . population , w e hav e use darando m effect s mode l (20). Usin g thi s mode l t o includ e sit e effects , w e foun dtha t

lea dwa s stil l asignifican t predicto r o f bot h systoli c an ddiastoli c bloo dpressur e (p < 0.05 ) fo

r both al l adul t

male s an dth e 40

- t o 59-year

ol dag e group . Th e regressio n coefficient s ar e reduce d abou t 25 % in thes e models . W e conclud e tha t th e relationshi p i s no t

confounde db y eithe r

sit e o r tim e effects . 

## Conclusion s Ther e i s arobus t

relationshi p betwee n low-level lea d exposur e an dbloo dpressur e i n th e NHANE S I I data . Thi s relationshi p hold s whethe r w e onl y examin e th e ag e grou p wit

h minima l ag e confoundin g o r whethe r w e examin e al l adul t

men . I t i s no t confounde db y an y plausibl e dietary , demographic , o r anthropometri c variables . I t

hold s after

controllin g for

th e tim e tren d in th e dat aan dma

y b e th e caus e o

f tha t trend . Th e anima l evidenc e clearl y indicate s acausa l rela

tionship betwee n lea dexposur e an dbloo dpressur e i n severa l species . Th e anima l dat aals o sho w tha t lea d interfere s wit

h cellula r

calciu mmetabolis mi n way s tha t woul db e expecte dt o increas e bloo d pressure ; thes e mechanism s als o regulat e bloo dpressur e in humans . Essentiall y al l o

f th e recen t

huma n studie s hav e foun dapositiv e associatio n betwee n bloo dlea dan d bloo dpressure . I n mos t

o f th e studie s th e associatio n ha s bee n significant , i n som e o f th e other s th e mag nitud e o f th e insignifican t

associatio n wa s similar t o th e magnitud e i n th e significan t findings . Althoug h mos t o f th e studie s hav e bee n in men , recentl y Rab

inowit z e t al . (21) hav e reporte dtha t umbilica l cor d bloo dlea dwa s significantl y associate dwit h both bloo d pressur e a t

deliver y an dth e presenc e o f pregnanc y hypertensio n i n asampl e o f 320 0 liv e birth s i n Bosto n wit h lo w lea dlevel s (mea n bloo dlea d= 6. 9 fig/dL) . Give n thes e result s an dth e strengt h o f th e anima l models , th e conclusio n tha t ther e i s acausa l associatio n seem s warranted . Smal l change s in bloo dpressure , eve n a t level s belo w thos e define da s hypertension , wer e associate d wit hP. 9

2 2 / . SCHWARTZ increase dris k

o f hear t attacks , strokes , an ddeath s i n th e Framingha mstud y (22). Whil e studie s suc h a s thes e ca n onl y inferentiall y implicat e lea di n thes e seriou s outcomes , th e likelihoo dtha t lowerin g bloo dpressur e reduce s thos e risk s i s considere dhig h enoug h t o warran t givin g drug s wit

h seriou s sid e effect s t o per son s wit h diastoli c bloo dpressur e abov e 9 0 m mHg . It seem s pruden t

t o als o recommen dtha t reductio n in exposur e t o atoxi c substanc e tha t raise s bloo dpressur e i s als o warranted . Moreover , whil e thes e dat ad o no t allo w adirec t

assessmen t

o f th e effec t

o f lea do n car diovascular

deaths , ther e ar e tw o recen t studie s tha t addresse dtha t

issue . Kher ae t

al . (23) foun dsigni

ficantly highe r

level s o

f bloo dan durin e lea di n hospita l outpatient s bein g treate dfor hypertensio n o r cardiovascula r

diseas e tha n i n controls . Voor s e t al . (24) foun dahighl y significan t associatio n betwee n lea dlevel s in th e aort ao

f a n autops y serie s an dwhethe r th e patien t

ha ddie do

f cardiovascular

disease . Again , i t seem s likel y tha t

measure s t o reduc e lea dexposur e in th e U . S . populatio n wil

l lea dt o small , bu t

important , reduction s in cardiovascula r risk .

1 2 .

3 .

5 . REFERENCE S Iannaccone , A. , Carmignani , M. , an dBoscolo , P . Cardiovascula r reactivit y i n th e ra t followin g chroni c exposur e t o cadmiu man d lead . Ann . 1s t

Super . Sanita17:655-66 0 (1981) . Carmignani , M. , Boscolo , P. , Ripanti , G. , an dFinelli , V . N . Effect s o f chroni c exposur e t o cadmiu mand/o r lea do n som e neurohumora l mechanism s regulatin g cardiovascula r function in th e rat . In : Internationa l Conferenc e o n Heav y Metal s in th e Environment , Heidelberg , Wes t Germany , Septembe r

1983 . CEP Consultants , Ltd. , Edinburgh , 1983 , pp . 557-560 . Revis , N . W. , Zinsmeister , A . R. , an dBull , R . Atherosclerosi s an d hypertensio n inductio n b y lea dan dcadmiu mions : A n effec t prevente db y calciu mion . Proc . Natl . Acad . Sci . (U.S. ) 78 : 6494-649 8 (1981) . Webb , R. C , Winquist , R. J. , Victery , W , andVander , A . J . I n viv o an din vitr o effect s o

f lea do n vascular

activit y i n rats . Am . J . Physiol . H211-H21 6 (1981) . Perry , H . M. , an dErlanger , E . J . Presso r effect s o f chronicall y feedin g cadmiu man dlea dtogether . In : Trac e Substance s i n Environmenta

l Health , Vol . 1 2 (D . D . Hemphill , Ed.), Universit y o f Columbia , Columbia , MO , 1978 , pp . 268-275 . 6 . Kopp , S . J. , Barany , M. , Erlanger , M. , Perry , E . F. , an dPerry , H . M. , Jr . Tli e influenc e o

f lo w level cadmiu mand/o r

lea dfeedin g on th e myocardia l contractilit y relate dt o phosphorylatio n o f cardia c myofibrilla

r proteins . Toxicol . Appl . Pharmacol . 54:48-5 6 (1980) . 7 . Skoczynska , A. , Juzwa , W„ Smolik , R. , Szechinski , J. , an dBehal , F . J . Respons e o f th e cardiovascula

r syste mto catecholamine s i n rat s given smal l dose s o

f lead . Toxicolog y 39:275-28 9 (1986) . 8 . Piccinini , F. , Favalli , L. , an dChiari , M . C . Experimenta l investigation s o n th e contractio n induce db y lea di n arteria l smoot h muscle . Toxicolog y 8:43-5 1 (1977) . 9 . Pounds , J . G . Effec

t o f lea dintoxicatio n o n calciu mhomeostasi s an dcalciummediate dcel l function : A review . Neurotoxicolog y 5 : 295-33 2 (1984) . 10 . Goldstein , G . W . Lea

dencephalopathy : Th e significanc e o f lead inhibitio n o

f calciumuptake b y brai n mitochondria . Brain Res . 136 : 185-18 8 (1977) . 11 . Kim , C . S. , OTuama , L A. , Cookson , S . L , an dMann , J . D . Th e effect s o f lea dpoisonin g on calciu mtransport by brai n i

n 30<lay

old albin o rabbits . Toxicol . Appl . Pharmacol . 52 : 491^19 6 (1980) . 12 . Rosen , J . F . Th e metabolis mo f lea din isolate dbon e cel l populations : Interaction s betwee n lea dan dcalcium . Toxicol . Appl . Pharmacol . 71:101-11 2 (1983) . 13 . Pounds , J . G. , Wright , R. , an dKodell , R . L . Effec t o f lea don calciumhomeostasi s i

n th e isolate dra t

hepatocyte . Toxicol . Appl . Pharmacol . 63:389-^10 1 (1982) . 14 . Goldstein , G . W. , andAr, D . Lea dactivate s calmoduli n sensitiv e processes . Lif

e Sci . 33:1001-100 6 (1983) . 15 . Pirkle , J . L. , Schwartz , J. , Landis , J . R. , an dHarlan , W . R. Th e relationshi p betwee n bloo dlea dlevel s an dbloo dpressur e andit s cardiovascula

r ris k implications . Am . J . Epidemiol . 121 : 246-25 8 (1985) . 16 . Schwartz , J . Bloodlea

dandbloo dpressure . In : Proceeding s o f th e Fift h Internationa l Conferenc e o n Heav y Metal s i n th e Environment , Septembe r

1985 , Athens , Greece . CEP Consultants , Ltd. , Edinburgh , 1985 . 17 . Barthel , W . F. , Smrek , A . L. , Angel , G . P. , Liddle , J . A. , Landrigan , P . J. , Gehlback , S . H. , an dChisholm , J . J . ModifiedDelve s Cu p atomi c absorptio n determinatio n o f leadi n blood . J . Assoc . Off

. Anal . Chem . 56 : 1252-125 6 (1973) . 18 . Annest , J . L , Pirkle , J . L. , Makug , D. , Neese , J . W. , Bayse , D . D. , an dKovar , M . G . Chronologica

l tren di n bloo dlea

dlevel s between 1976-1980 . N . Engl . J . Med . 308:1373-137 7 (1983) . 15 . Schwartz , J. , Janney , A. , andPitcher , H . Th e relationshi p betwee n gasolin e lea dan dbloo dlead . U . S . Environmenta l Protectio n Agency , Offic

e o f Polic y Analysis , 1983 . 20 . Fuller , W

. A. , an dBattese , G . E . Transformatio n fo r th e estimatio n o f linea r model s wit

h nested-erro r

structure . J . Am . Sta t

Assoc . 6 8 626-63 1 (1973) . 21 . Rabinowitz , M. , Bellinger , D. , Leviton , A. , Needleman , H. , an d Schoenbaum , S . Pregnanc y hypertension , bloo dpressur e during labor , an dbloo dlea

dlevels . Hypertensio n 10 : 447-45 1 (1984) . 22 . Shurtleff

, D . Som e characteristic s relate dt o th e incidenc e o f cardiovascula r

diseas e an ddeath : Framingha mstudy , 18-yea r follo w up . Sectio n 30 . DHE W Publicatio n no . (NIH ) 74-599 . Governmen t

Printin g Office , Washington , DC , 197 4 23 . Khera , A . K. , Wibberley , D . G. , Edwards , K . W. , andWaldron , H . A Cadmiu man dlea dlevel s in bloo dan durin e i n aserie s o f cardiovascula

r an dnormotensiv e patients . Int . J . Environ . Stud . 14 : 309-31 2 (1980) . 24 . \bors , A . W. , Johnson , W . D. , an dShuman , M . S . Additiv e statistica l effect s o f cadmiu man dlea

don heart-relate ddiseas e i n aNort h Carolin aautops y series . Arch . Environ . Healt h 37 : 98-10 2 (1982) . 

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