P. 1 

# OAR Box 1126 Prepped by Ollie Stewart



### Document

Number: 

# 125)11-1-33 9 Docket Number: 

# A-83-2 2

Printed 4/18/20089:58:27

AM Sheet 125 of 182P. 2



### Lead , Bloo dPressure , an dCardiovascula r Diseas e i n Me n an dWomen

Joe l Schwart z U.S . Environmenta l Protectio n Agency PM22 1 Offic e o f Polic y Analysi s Washington , D.C . 2046 0



# '« P"-*z 

# £H £P. 3



### ABSTRAC

T Lead , Bloo dPressure , an dCardiovascula r Diseas e i n Men an dWome

n Joe l Schwartz , U.S . Environmenta l Protectio n Agency

Leadha s bee n show n t o b e associate dwit h elevate dbloo dpressur e i n male s i n th e NHANE S I I survey , an di n numerou s othe r studies . Thi s stud y confirm s th e associatio n i n male s age d20-74 , an ddocument s asignificant , althoug h weake r association , i n female s a s well . Prospectiv e cardiovascula r diseas e studie s suc h a s th e Framingha m stud y indicat e tha t

increase s i n bloo dpressur e shoul db e associate dwith increase dris k o f cardiovascula

r disease . Usin g electrocardiogramdat afromNHANE S II , thi s stud y confirm s th e expecte dassociatio n o f leadwit h lef t ventricular

hypertroph y (

p < 0.01) . Suc h a n associatio n with permanen t cardiovascula

r change s add s weigh t

t o th e bloo d pressur e findings . Th e logisti c ris k coefficient s fromth e Framingha mstud y ca n b e combine dwith thi s study' s associatio n betwee n leadan dbloo dpressur e t o examin e it s implicatio n fo

r mor e seriou s outcomes . Th e result s sugges t tha t ahalvin g o

f th e populatio n mea n bloo dlea dleve l woul dreduc e myocardia l infarction s b y approximatel y 24,00 0 event s pe r

year , an dincidenc e o

f al l cardiovascula

r diseas e b y ove

r on e hundre d thousand . Thes e number s sugges t asmal l attributabl e risk , compare dt o th e vas t incidenc e o

f cardiovascula

r diseas e i n th e U.S. , bu t

alarg e attributabl e ris k compare dt o mos t environmenta l toxins . Several biologica l mechanism s hav e been identified , with differen t implication s fo

r th e us e o

f bon e leada s a n exposure measure .P. 4



### INTRODUCTIO

N Whil e numerou s studie s i n animal s an dhuman s hav e implicate dlea dexposure a s afacto r i n increasin g bloo dpressure , the y hav e often focuse donly o n male s an do n restricte dag e ranges . Studie s o f direc t cardiovascula

r outcome s hav e been hampere db y th e lo w relativ e risk s implie db y th e bloo dpressur e relationship s tha t hav e bee n found . T o addres s thes e issues , dat afromth e Secon dNationa l Healt h an dNutritio n Examinatio n Surve y (NHANE S II ) wer e examine dfo r male s an dfemale s age d2 0 year s an dolder . Th e NHANE S I I include delectrocardiogram s a s wel l a s bloo dpressur e measurements , an dth e associatio n o f lea dwit h both outcome s wa s examined . Thi s allowe dadirec t

examinatio n o

f th e assumptio n tha t

increase dbloo dpressur e du e t o lea dwil l hav e cardiovascula r implications . DAT A AN D METHODS Th e secon dNationa l Health an dNutritio n Examinatio n Surve y wa s conducte d betwee n Februar y 197 6 an dFebruary 1980 . Th e sampl e wa s chose n t o b e representativ e o

f th e civilia

n non-institutionalize dU.S . population , age d6 month s t o 7 4 years . Medica

l histories , seru mbiochemistries , an ddietary questionnaire s wer e obtaine d (1) . Bloo dlea dlevel s wer e obtaine do n asub-sampl e o f 9,932 . Extensiv e analyse s o f th e relationshi p betwee n bloo dleadan dbloo dpressur e i n male s hav e been presente d previousl y (2,3,4) , an dthe y provid e detail s o f th e medica

l histor y questionnaire , bloo d biochemistry methods , dietary information , an dphysica l examinations . Electrocardiogram s wer e performe do n al l subject s age d25-7 4 years , usin g a standar d1 2 lea dECG . Result s were digitall y encoded , an dthe n classifie daccordin g t o th e Minnesot aCode s o

f Electrocardiographi c Finding s (5 ) usin g th e Novacode r programP. 5



### o f Dalhousi e University (6,7) . Usin g variable s identifie da s importan t i n thos e earlie r

studies , th e relationshi p betwee n bloo dlea dan dbloo dpressur e wa s examine di n both male s an dfemales , age d 2 0 -7 4 years . Tabl e 1 show s th e covariate s considere di n th e analysis . Th e bloo dpressur e dat awer e analyze di n stages . First , separat e regression s wer e performe dfo

r male s an dfemales . Diastoli c bloo dpressur e wa s regresse do n age , age 2 

### , race , Quetelet' s bod y mas s inde x (weight/height 2 

### ) , an dth e natura l logarith mo f bloo dlead . If

lea dwa s significant

i n thi s first

step , the n astepwis e regressio n wa s performed , usin g th e variable s show n o n Tabl e 1 . A n interactio n ter mwa s use dt o asses s th e possibilit

y o f aracial differenc e i n th e effec t o f lead . Fina l model s wer e estimate dusin g SURREGR , aprogramtha t incorporate s th e desig n effect s i n th e stud y (8) . Th e probability o

f lef t ventricular

hypertroph y wa s modele dusin g logisti c regression . Sinc e th e definitio n o f lef t ventricular

hypertroph y incorporate s bod y habitus , bod

y mas s inde x an dtrice p skinfol dwer e no t include di n thes e regressions . Stepwis e logisti c regressio n o f th e remainin g covariate s o n Tabl e 1 wa s use dt o identif y amodel . Th e desig n effect s wer e incorporate dusin g RTILOGI T (9) . Becaus e o

f th e limite dnumbe r

o f cases , se x difference s i n an y leadeffect wer e investigate dusin g a n interactio n term . A

n interactio n ter mwa s als o use dt o tes t fo r racial differences . RESULTS Bloo dlea dwa s asignificant predicto r o f bloo dpressur e i n both males , ( p < 0.01 ) an dfemale s (

p < 0.01 ) i n th e first

stag e regressions , controlUn g fo r age , race , an d bod

y mas s index . I n separat e stepwis e regression s fo r male s an dfemales , lea dcontinue dt o b e significantl y relate dt o diastoli c bloo dpressure . Th e final model s fo r bloo dpressure ,P. 6



### incorporatin g th e desig n effect s o f th e surve y ar e show n o n Tabl e 2 . Whil e th e coefficien t o f bloo dlea dwa s lowe

r i n female s tha n i n males , th e differenc e i n magnitude s i s no t

significant . Thi s wa s confirme di n aregressio n wit h both sexes , usin g a n interactio n ter mt o tes t fo r adifferen t

slope . Th e interactio n wa s insignifican t ( p > 0.30) . A

n interactio n ter mfo

r rac e wa s similarl y insignificant . Rac e wa s no t significant i n th e regressio n fo

r males , presumabl y becaus e racial difference s i n th e biologica l ris k factor s explaine dth e racial differenc e i n bloo dpressure . Sinc e black s hav e highe r

bloo dlea dlevel s tha n whites , th e rac e ter mwa s force dint o th e regressio n t o giv e aconservativ e estimat e o f th e effect

o f lead . Bloo dlea dwa s als o asignificant predicto r o f lef t ventricular

hypertrophy . Tabl e 3 show s th e logisti c regressio n model , incorporatin g th e desig n effects . Th e interactio n term s fo r se x o r rac e difference s i n th e cardiovascula r effect s o f leadwer e als o insignifican t

(p > 0.20) . A s i n previou s analyse s (2,3) , th e natura l logarith mo f bloo dlea dwa s mor e significant tha n bloo dlea di n predictin g bloo dpressure . Thi s implie s arelationshi p with alarge r

margina l impac t

o f bloo dleadchange s a t

lo w bloo dlea dlevel s tha n a t hig h bloo dlea dlevels . I n contrast , th e linear for mo f bloo dlea dwa s mor e significan t a s apredicto r

o f lef t ventricular

hypertrophy . DISCUSSIO

N Th e existenc e o

f astron g associatio n betwee n bloo dlea dan dbloo dpressur e acros s th e entir e adul t

ag e rang e ha s already bee n note di n male s i n thi s survey . Thi s analysi s demonstrate s tha t asignificant

associatio n i s presen t

i n female s a s well . Th e associatio n appear s somewha t weake r i n magnitud e an di n significanc e leve l tha n tha t fo r males . Whil e mos t

othe r epidemiolog y studie s hav e focuse do n males , Rabinowitz e tP. 7

al . (10 ) hav e reporte da n associatio n o f lea dwit h bot h bloo dpressur e an dpregnanc y hypertensio n i n females . Victer y e t al . (11 ) hav e reporte dase x differenc e i n th e effec t o f lea do n bloo dpressur e i n rats , wit h insignifican t effect s i n females . However , Perr y an dErlande r

(12 ) hav e reporte dasignifican t associatio n i n femal e rats , i n adie t lowe r i n calcium . A larg e bod y o f

experimenta l data , bot h i n viv o an di n vitro , show s tha t lea d increase s bloo dpressur e i n severa l specie s o f rats , pigeons , an ddog s (13-18) . Thes e studie s hav e als o documente dincrease dreactivit y t o alph aadrenergi c stimulatio n (14,16) , an da n interactio n wit h calciu mmetabolis m(15) . Man y o f thes e studie s examine dsevera l dos e levels , an dVicter y (19 ) ha s summarize dthe ma s indicatin g a biphasi c response , wit h astron g effec t o f lo w leve l exposur e tha t disappear s a t

hig h levels . A simila r

patter n ha s bee n see n i n th e presso r effect s o f

cadmiu m(20) . Thes e findings i n th e experimenta l Uteratur e ar e consisten t wit h th e logarithmi c dos e respons e relationshi p foun di n thi s study . Prospectiv e studie s o f

cardiovascula r

disease , suc h a s Framingha m(21 ) clearl y demonstrat e tha t

th e ris k o f cardiovascula r

diseas e varie s continuousl y wit h bloo d pressure . N o plausibl e reaso n exist s t o assum e tha t increase s i n bloo dpressur e du e t o lea dexposur e woul dno t hav e th e sam e impact . Studie s o f th e us e o f

dru g therap y t o reduc e bloo dpressur e hav e bee n mor e mixed , wit h th e Hypertensio n Detectio n an d FoUowup Stud y (22 ) finding significan t reduction s i n risk , bu t no t th e MRFI T stud y (23) . However , hypertensiv e medicatio n ha s advers e sid e effects , includin g disturbance s o f potassiu mmetaboUsm , tha t ma y counteract , i n whol e o r part , th e beneficia l impact s o f bloo dpressur e reduction . Reducin g lea dexposur e ha s n o simila r counter-risk , sinc e lea dha s onl y harmfu l effect s i n th e body . I t therefor e seem s pruden t t o assum e tha t reducin g bod y lea dburden s wil l reduc e bloo dpressur e an dcardiovascula r diseas e i n bot h th e ne w generatio n o f adults , wh o wi

U no t becom e exposed , a s we U a s th e curren tP. 8



### one , whos e exposur e wil l b e reduced . Nevertheless , direc t

evidenc e fo

r acardiovascula

r effec t o f leadwoul dclearl y strengthe n thes e conclusions . Th e regressio n coefficient s i n Tabl e 2 indicat e tha t a halvin g o f bloo dlea dlevel s i n th e Unite dState s woul dreduc e th e mea n mal e bloo d pressur e b y ove

r 2 mmHg , an dth e mea n femal e bloo dpressur e b y ove r 1 mmHg . Th e logisti c ris k

coefficient s fro mth e Framingha mstud y predic t tha t thes e change s woul d resul t i n abou t 24,00 0 fewe

r myocardia

l infarction s pe r

year , an dover

100,000 fewe

r case s o f cardiovascula

r disease . Whil e thes e ar e larg e number s compare dt o mos t ris k assessment s fo

r environmenta l toxins , the y represen t relativ e risk s o

f abou t 1.05 , du e t o th e hig h backgroun drat e o f thes e outcomes . Suc h relativ e risk s ar e unlikel y t o b e detecte di n an y prospectiv e study . ElectrocardiogramabnormaUtie s indicativ e o f lef t ventricular

hypertroph y represen t

a n earl y indicato r

o f cardiovascula

r diseas e tha t

i s mor e commo n tha n myocardia l infarctions . Lef

t ventricular

hypertroph y i s als o a prevalence , rathe r

tha n incidenc e measure . Thi s increase s th e powe r t o detec t adirec t cardiovascula

r impac t o f lead . Th e finding o

f asignificant

associatio n betwee n bloo d leadlevel s an dlef

t ventricular

hypertroph y i n both me n an dwomen , leave s Uttl e doub t tha t lea dexposur e i s no t

merel y raisin g bloo dpressure , bu t producin g th e expecte d cardiovascula

r impacts . Whil e cardiovascula

r effect s o f leadintoxicatio n hav e lon g been noted , EC G outcome s hav e been studie dinfrequentl y a t th e exposur e level s o

f curren t concern . Kirkb y an dGyntelber g (24 ) note da20 % increas e ( p < 0.01 ) i n ischemi c changes , a s code do n th e Minnesot aCodes , i n leadworker s compare dt o control s matche do n age , race , sex , height , weight , alcoho l consumption , an dsmoking . Kopp (25 ) i n a n EC G stud y o f rats , foun dprolonge dP

Rintervals , an ddepresse dcontractility , protei n phosphorylation , an dhig h energ y phosphat e levels . Hejtmanci k an dWilliam s (26 ) hav e reporte dincrease dsusceptibiUt y t o arrhythmia s i n lea dexpose drats . Whil e no t directl yP. 9

parallel , Kher a(27 ) di dnot e increase dbloo dan durin e lea dlevel s i n cardiovascula r patient s compare dt o hospita l controls . Potentia l Mechanism s an dBon e Lea d Th e experimenta l studie s provid e mor e tha n simpl e biologica l suppor t fo r th e epidemiologica l findings. The y als o provid e insigh t int o severa l possibl e biological mechanism s fo r

th e effec t

o f lea do n bloo dpressure . Th e tw o majo r mode s o f

actio n identifie dar e i n th e calciu mmetaboUs mo f th e vascula r

smoot h muscle , an drena l effect s mediate dthroug h th e renin-angiotensi n system . I n addition , direc t cardiovascula r

effect s ma y als o occur . Piccinin i an dcoworker s (18 ) foun dtha t lea dinduce dcontractio n an dhyper

reactivit y i n perfuse dra t tai l arteries . Tissu e analysi s indicate dth e lea dexpose d vascula r smoot h muscl e ceU s ha dincrease dfre e cytosoU c calcium , an dincrease dtota l calciu mstores . Thi s i s consisten t wit h th e findin g tha t

lea dincrease s ceUular calciu m concentratio n i n brai n capiUarie s (28) , neuron s (29) , hepatocyte s (30) , an dothe r tissues . Hyper-reactivit y ha s als o bee n note db y lannaconn e an dcoworker s (131) , Carmignan i e t al . (14), Boscol o an dCarmignan i (31 ) an dWeb b an dassociate s (16) . Thes e findings sugges t amechanis mwit h increase dintracellula r calciu mstores , leadin g t o increase d releas e o f

calciu mi n respons e t o stimulation , an dhenc e increase dcontractiUt y vi a calcium' s rol e i n mediatin g muscl e contraction . Supportin g thi s hypothesi s i s th e observatio n o f

Cha i an dWeb b (32 ) tha t methoxamin e induce dcontraction s i n th e tai l arterie s o f

lea dexpose drat s wer e les s sensitiv e t o calciu mchanne l blockers , an drelaxe d a t aslowe r rat e tha n unexpose darteries . A secon dmod e o f

actio n fo r

lea di n disturbin g th e calciu mmediate dcontro l o f vascula r reactivit y an dtensio n ma y b e viadisturbanc e o f protei n kinas e C metaboUsm .P.1 0

Machova c an dGoldstei n (33 ) hav e show n tha t lea dactivate s protei n kinas e C i n ra t brai n microvessels . Protei n kinas e C i s involve di n th e phosphorylatio n o f protein s involve di n contractio n (34) . Recen t studie s b y Cha i an dWeb b (32 ) hav e show n tha t isolate dstrip s o f

rabbi t tai l arter y contracte di n respons e t o lead . Thi s contractil e respons e wa s enhance db y protei n kinas e C activators , bu t attenuate db y aselectiv e inhibito r o f protei n kinas e C . Bot h o f th e above mechanism s see mdependen t o n th e curren t

concentratio n o f lea da t th e membran e o r

i n th e cytoso l o f

th e smoot h muscl e ceU . Thi s suggest s tha t th e appropriat e measur e o f exposur e i s on e tha t

i s relativel y contemporaneous . Bloo d lea di s suc h ameasure . Th e entir e effec t canno t b e considere dinstantaneous , sinc e bot h Victer y an dcoUeague s (11 ) an dPerr y an dErlange r (12 ) foun dtha t

ra t bloo d pressur e di dno t

reac h it s equiUbriu melevatio n unti l severa l month s afte r bloo d lea d level s equiUbrated . Bon e lea dmeasurement s tha t ar e targete dt o shorte r residenc e compartments , possibl y includin g trabecula r bone , ma y b e asuperio r measur e o f exposure , bu t

thi s remain s t o b e seen . A mechanis mmor e consisten t wit h cumulativ e exposur e measure s postulate s permanen t

kidne y change s resultin g i n effect s o n th e renin-angiotensi n system . Th e anima l an dhuma n dat ao n th e effec t o f lea do n thi s syste mi s confusing , wit h finding s o f bot h increase dan ddecrease dplasm areni n activit y foUowin g lea dexposure . Vande r an dassociate s (35 ) hav e postulate da n elevatio n o f plasm areni n activit y upo n initia l exposure , foUowe db y a n eventua l reductio n afte r chroni c exposure . Thi s hypothesi s come s closes t

t o makin g sens e ou t

o f th e conflictin g data , an daccord s wit h th e finding o f Boscol o an dCarmignan i (14 ) o f asimila r

patter n i n huma n exposure . A U o r som e o f th e abov e mechanism s ma y b e importan t i n lea dinduce d hypertension , bu t

the y ar e consisten t

wit h differen t

averagin g time s fo r

th e bes t measur e o f

exposure . I t

seem s mos t

likel y tha t

shor t ter mexposure , an daltere dp.l l



### calciu mmetaboUs mar e th e mos t importan t

pathway s fo

r bloo dpressur e elevation . Cardiovascula

r outcome s see mUkel

y t o var y wit h duratio n a s we

U a s leve l o

f bloo d pressur e change , suggestin g amor e cumulativ e exposure measur e woul db e appropriat e fo r them . FinaUy , i t

shoul db e note dtha t

Revi s e t al.(15 ) foundleadassociate dwith atherosclerosi s i n pigeons . Thes e findings , plu s some o f th e direc t

cardiovascula

r effect s note db y Kopp (25) , als o sugges t tha t cumulativ e measure s o

f lea dma y b e importan t

fo r assessin g cardiovascula

r disease . Fina l resolutio n o f th e appropriat e exposur e measur e wi U awai t studie s us e a

U o f them .P.1 2

REFERENC E 1 . Nationa l Cente r

fo r Healt h Statistics . Pla n an dOperatio n o f th e Secon dNationa l Healt h an dNutritio n Examinatio n Surve y 1976-1980 . Washington , D.C . Vita l an dhealt h Statistics , Serie s 1 , No . 15 . 2 . Pirkle , J L Schwart z J , Landi s JR , Harla n WR . Th e relationshi p betwee n bloo dlea d level s an dbloo dpressur e an dit s cardiovascula r ris k impUcations . Am . J . Epidemiol . 198 5 121:246-258 . 3 . Schwart z J . Th e relationshi p betwee n bloo dlea dan dbloo dpressur e i n th e NHANE S I I survey . Enviro n Hlt h Pers p 78:15-2 2 1988 . 4 . Harla n WR , Landi s JR , Schmoude r RL , Goldstei n NG , Harla n LC . Bloo dlea dan d bloo dpressur e relationshi p i n th e adolescen t an dadul t

U.S . population . JAM A 253:530

- 53 4 1985 . 5 . Blackbur n H , Key s A , Simonso n E , Rautaharj u PM , Punsa r S . Th e Electrocardiogra m i n populatio n studies : aclassificatio n system . Circulation , 21:1160-1175 , 1960 . 6 . Wol f HK , Maclnni s PJ , Stoc k S , Helpp i RK , Rautaharj u PM . Th e Dalhousi e Program : A comprehensiv e analysi s progra mfor res t an dexercis e electrocardiograms . In : Zyweit z c an dSchneide r

B Eds . Compute r

Application s o n EC G an dVC G analysis . Nort h HoUand . Amsterdam-Londo n 1973 : pp231-40 . 7.Rautaharj u PM , Brost e SK , Prinea s RJ , Eifle r WF , Cro w RS , Furber g CD . QuaUt y contro l procedure s fo r

th e restin g electrocardiogra mi n th e Multipl e Ris k Facto r Interventio n Trial . J . Controlle dClinica l Trial s 7:465-655 , 1986 . 8 . Sha h BV . SURREGR : Researc h Triangl e Institute , Researc h Triangl e Park , N.C . 1982 . 9 . Sha h BV . RTILOGIT:Researc h Triangl e Institute , Researc h Triangl e Park , N.C . 1987 . 10 . Rabinowit z M , Bellinge r D , Levito n A , Needlema n H , Schoenbau mS . Pregnanc y hypertension , bloo dpressur e durin g pregnancy , an dbloo dlea dlevels . Hypertensio nP.1 3

10:447-45 1 1987 . 11 . Victer y W , Vande r

AJ , Shula k

JM , Schoep s P , JuUu s S . Lead , hypertension , an d th e renin-angiotensi n syste mi n rats . J La b Cli n Me d99:354-36 2 1982 . 12 . Perr y H M Erlange r

EJ . Presso r

effect s o f

chronicaU y feedin g cadmiu man dlea d together . In:Trac e Substance s i n Environmenta l Health , Vo l 1 2 (D D Hemphil l Ed ) Universit y o f

Columbia , Columbi aM O 268-27 5 1978 . 13 . Iannaccone , A , Carmignan i M , Boscol o P . Cardiovascula r reactivit y i n th e ra t foUowin g chroni c exposur e t o cadmiu man dlead . Ann . 1s t Supe r Sanita , vo l 1 7 655-66 0 1981 . 14 . Carmignan i M , Boscol o P , Ripant i G , Finel U GN . Effect s o f chroni c exposur e t o cadmiu man dlea do n som e neurohumora l mechanism s regulatin g cardiovascula r functio n i n th e rat . 198 3 Proceeding s o f th e fourt h Internationa l Conferenc e o n Heav y Metal s i n th e Environment . I 557-560 . 15 . Revi s NW , Zinsmeiste r AR , Bul l R . Atherosclerosi s an dhypertensio n induce db y lea d an dcadmiu mions : a n effec t prevente db y calciu mion . Pro c Nat l Aca dSc i (US ) 8:6494

- 649 8 (1981) . 16 . Web b RC , Winquis t RJ , Victer y W , Vande r AJ . I n viv o an di n vitr o effect s o f lea do n vascula r reactivit y i n rats . A mJ Physio l 214:H211-21 6 1981 . 17 . Skoczynsk aA , Juzw aW , Smolo k R , Szechinsk i J , Beha l FJ . Respons e o f th e cardiovascula r

syste mt o catecholamine s i n rat s give n smal l dose s o f lead . Toxicol . 39 : 275-28 9 1986 . 18 . Piccinini , F , FavaU i L , Chiar i MC . Experimenta l investigation s o n th e contractio n induce db y lea di n arteria l smoot h muscle . Toxicol . 8:43-5 1 1977 . 19 . Victer y W . Evidenc e fo r effect s o f

chroni c lea dexposur e o n bloo dpressur e i n experimenta l animals : A n Overview . Enviro n Hlt h Pers p 78:71-76 . 1988 . 20 . Perr y H M Jr , Erlange r MW , Perr y EF . Hypertensio n followin g chroni c ver y lo w dos eP. M

cadmiu mfeeding . Pro c So c Ex p Bio l Me d156:173-176 . 1977 . 21 . Shurtlef

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

diseas e an ddeath : Framingha mstudy , 18-year foUo w up . Sectio n 30 , DHE W Pu b N o (NIH ) 74

- 59 9 1974 . 22 . Hypertensio n Detectio n an dFoUowup Progra mCooperativ e Group . Th e effec t o f treatmen t

o n mortaUt y i n mil dhypertension . Ne w En g J Me d307:976-8 0 1983 . 23 . Multipl e Ris k

Facto r Interventio n Trial : Ris k facto r change s an dmortaUt y results . Multipl e Ris k

Facto r Interventio n Tria l Researc h Group . JAM A 248:1465-7 7 1982 . 24 . Kirkb y H , Gyntelber g F . Bloo dPressur e an dothe r cardiovascula r

ris k factor s o f long-ter mexposur e t o lead . Scan dJ Wor k Enviro n healt h 11:15-1 9 1985 . 25 . Kop p SJ , Bake r

JC , D'Agros aLS , Hawle y PL . Simulataneou s recordin g o f Hi s bundl e electrogram , electrocardiogram , an dsystoU c tensio n fro mintac t modifie d Langendorf

f ra t hear t preparation s I : effec t

o f perfusio n time , cadmium , an dlead . Toxico l App l Pharmaco l 46:475-48 7 1978 . 26 . Hejtmanci k

MR , WilUam s BJ . Effec t o f chroni c lea dexposur e o n th e direc t an d indirec t component s o f

th e cardia c respons e t o norepinephrine . Toxico l App l Pharmaco l 51:239-24 5 1979 . 27 . Kher aAK , Wibberle y DG , Edward s KW , Waldro n HA . Cadmiu man dlea dlevel s i n bloo dan durin e i n aserie s o f cardiovascula r

an dnormotensiv e patients . In t J Eviro n Stu d14:309:31 2 1980 . 28 . Goldstei n GW . Lea dencephalopathy : th e significanc e o f lea dinhibitio n o f

calciu m uptak e b y brai n mitochondria . Brai n Res . 136:185-18 8 1977 . 29 . Ki mCS , O'Tuam aLA , Cookso n SL , Man n JD . Th e effect s o f lea dpoisonin g o n calciu mtranspor t

b y brai n i n 30-day-ol d albin o rabbits . Toxico l Ap p Pharmaco l 52:491

- 49 6 1980 . 30 . Pound s J G Effec t

o f lea dintoxicatio n calciu mhomeostasi s an dcalcium-mediate dcel lP.1 5



### function : A review . Neurotoxicolog y 5 : 295-33 2 (1984) . 31 . Boscolo P , Carmignan i M . Neurohumora l Bloo dPressur e Regulatio n i n Lead Exposure . Enviro n Hlt h Pers p 78:101-10 6 1988 . 32 . Cha i S , Web b RC . Effect s o

f Leado n Vascula

r Reactivity . Enviro n Hlt h Pers p 78:85

- 8 9 1988 . 33 . Machova

c J , Goldstei n GW . Lea

dinduce dactivatio n o

f protei n kinas e C i n ra t

brai n microvessels . J Ce

U Bioche m(suppl ) 10c:L5 3 1986 . 34 . Rasmusse n H , Takuw aY , Par k S . Protei n kinas e C i n th e regulatio n o f smoot h muscl e contraction . FASE B J 1:177-18 5 1987 . 35 . Vande r

AJ . Chroni c Effect s o

f Leado n th e Renin-Angiotensi n system . Enviro n Hlt h Pers p 78:77-8 3 1988 .P.1 6

TABL E 1 VARIABLE S CONSIDERE D I N TH E REGRESSION S Ag e (years ) Race + Sex * Bod y Mas s Inde x (kg/m 2 ) Cigarettes/da y Trice p Skinfol d(mm ) Famil y histor y o f

Hypertensio n Recreationa l Exercise * ln(Seru mZinc ) ln(Bloo dLead ) Dietar y Potassiu m Dietar y Sodiu m Seru mCholestero l Heigh t (m ) ln(Dietar y Vitami n C )

+ 2=black , 1=whit e * Left Ventricula r

Hypertroph y regression : 2=females , 1=male s # 1 = Uttle , 2=moderate , 3=substantia lP.1 7

TABL E 2 REGRESSIO N RESULT S FO RDIASTOLI C BLOO D PRESSUR E MALE S Variabl e Intercep t Ag e Age 2 Bod y Mas s Inde x Rac e Famil y Histor y Cholestero l Bloo dLead * Heigh t Cigarette s Zin c Trice p Coefficien t

29.8 6 .607 3 -0.005 7 .731 2 1.54 9 2.54 3 .024 7 2.92 8 12.8 9 -.05 7 -4.3 7 .011 0 Intercep t ag e age - 5 Bod y Mas s Inde x Rac e Zinc * Famil y Histor y Bloo dLead * Trice p Cholestero l 57.6 4

.613 5 -.00 5 .685 7 2.40 8 -5.5 4 1.14 5 1.64 0 .008 4 .011 3 

### S

E p -valu e 10.9 0 .088 7 .001 0 .093 2 .895 5 .421 0 .007 1 1.00 2 3.25 1 0.02 3 1.49 1 0.00 5 FEMALE S 7.57 8 .110 5 .001 2 .058 2 .792 0 1.64 6 .368 8 .696 3 .003 5 .005 5 -

< 0.000 1 < 0.000 1 < 0.000 1 0.093 4 < 0.000 1 0.001 6 0.006 3 0.000 4 0.018 3 0.006 2 0.049 0

. < 0.000 1 0.000 1 < 0.000 1 0.004 7 0.002 0 0.004 0 0.024 7 0.020 3 0.047 7

•natura l logarith m

### TABL E 3 LOGISTI C REGRESSIO N RESULTS : LEF T VENTRICULA RHYPERTROPHY Variabl e Intercep t Ag e Rac e Se x lea d Coefficien t

-3.9 4 .014 0 1.35 7 -1.0 1 .028 3 S.E .

.508 1 .005 2 .201 7 .164 9 .010 0 p -valu e

. .011 7 <0.000 1 < 0.000 1 0.008 7