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Sheet 118 of 162K , Environmental Health Perspectives Vol. 78, pp. 139-155, 1988 P. 2



# Summar y o f Discussio n Sessions : Symposiu m o n Lead-Bloo d Pressure Relationship s b y W . Victery, * H . A . Tyroler, * R . Volpe, * an d L. D . Grant * Th e Internationa l Symposiu mo n Lead-Bloo dPres

sure Relationship s wa s hel din Chape l Hill , NC , Apri l 27-29 , 1987 , wit

h sponsorshi p fro mth e Council s o n Hypertensio n an dEpidemiolog y o f th e America n Hear t Association ; th e Departmen t o f Epidemiology , Universit y o f Nort h Carolina ; th e Internationa l Lead Zin c Researc h Organization ; an dth e U.S . Environ

menta l Protectio n Agency . Th e progra mwa s struc ture ds o a s t o first

presen t a n overvie w o

f theorie s an d finding s in th e genera l are ao f huma n hypertensio n an dthe n to hav e speaker s revie w th e extan t literatur e o n lea dan dbloo dpressur e relationships , includin g paper s o n th e huma n observationa l studie s o f lea dan d hypertension ; relate dstudie s o f lea dan dhuma n hypertension ; occupationa l studie s o f lea dan dhyper

tension ; experimenta l studie s o f lea dan dhyper

tension ; an dpaper s presentin g relate dinformatio n fro mwor k i n progress . Invite ddiscussants , invite d speakers , an dothe r

worksho p participant s wer e encourage dt o as k

question s an dt o discus s need s fo r futur e research . Thi s repor t summarize s ke y ex change s o

f informatio n durin g discussion s afte r individua l paper s wer e presente do r durin g separat e discussio n sessions . It

als o summarize s presentation s b y severa l speaker s wh o decline dto publis h i n thes e proceeding s full-lengt

h paper s o n ongoin g work . I n th e first plenar y session , th e thre e speaker s (H . A . Tyroler , A . Chobanian , an dC . Hennekens ) gav e over vie w presentation s o n th e epidemiolog y o f hyperten- . sio n a s apubli c healt h problem , mechanism s o f hy

pertension , an dth e impac t o f reducin g hig h bloo d pressur e o n mor e seriou s cardiovascula r sequelae . Thes e talk s oriente dth e audienc e an dparticipant s t o •Environmental Criteri aan dAssessmen t Office , U.S . Environmenta l Protection Agency , M

D 52 , Researc h Triangl e Park , N C 27711 . fDepartmen t

o f Epidemiology , Schoo l o

f Publi c Health , Universit

y o f Nort h Carolina , Chape l Hill , N

C 27599 . ^Internationa l LeadZin c Researc h Organization , Inc. , P.O . Bo x 12036 , Researc h Triangl e Park , N C 27709 . th e type s o f studie s an dmethod s o

f analysi s necessar y t o conside r

th e possibl e influenc e o

f leadon bloo d pres sur e an dothe r

cardiovascular

effect s an dreviewe d th e multiplicit y o

f mechanism s tha t

ma y influenc e th e measure doutcom e o

f achang e i

n bloo dpressure . Onl

y limite ddiscussio n followe dthes e introductor y papers , wit h resultin g clarificatio n o f certai n ke y point s con cernin g th e relativ e rol e o f variou s know n o r

suspecte d ris k factor s fo

r hypertensio n an dassociate dsequelae . Th e nex t plenary sessio n include daserie s o f paper s tha t discusse dhuma n observationa l studie s o f lea d an dhypertension , with specia l emphasi s o n addi

tiona l analyse s o

f Nationa l Healt h an dNutritio n Surve y I I (NHANE S II ) dat aan dfurthe r analyse s o

f dat afro mth e Britis h Regional Hear t Survey . Durin g discussion s following thes e presentations , aspect s o f th e NHANE S analyse s wer e clarified . J . Schwart z (U.S . EPA) commente dtha t h e use d P . Gartside' s (Universit y o f Cincinnati ) regressio n model s wit

h interactio n term s fo

r ag e an dfoun d non e o f th e interactio n term s t o b e statisticall y significant . Usin g somewha t

large r ag e group s tha n Gartsid e did , h e foun dtha t

lea dwa s statisticall y significantl y associate dwit

h both systoli c an ddiastoli c pressur e i n all 3 0 ag e groups . H e questione dwhethe r o r no t th e failure o f Gartsid e to observ e statisticall y significan t effect s wa s du e t o smal l sampl e siz e subgroups . Gartsid e doubte dtha t

th e differenc e betwee n th e 20

- an d30-yea r ag e grouping s wa s meaningful . H e note dtha t i t wa s no t infrequen t

for tw o individual s analyzin g th e sam e dat ase t

t o com e u p wit

h totall y different

results . Schwartz , althoug h agreein g wit h thi s an dnotin g it s relevanc e t o Fort' s finding s (Schwart z obtaine d statis

ticall y significan t

coefficient s o n regressio n analyse s fo r bot h systoli c an ddiastoli c pressur e includin g al l 6 4 geographi c site s in hi s regression) , pointe dou t tha t a n Expert Pee r Revie w Pane l convene db y EPA , a s well a s arevie w committe e o

f th e EP A Scienc e Advisor

y Board studyin g bot h hi s an dth e othe r NHANE S analyses , accepte dth e Schwart z version . Schwart z adde dtha tP. 3

14 0 VICTERYETAL. inclusio n o

f th e 6 4 site s i n hi s regressio n analyse s reduce dth e magnitud e o

f th e regressio n coefficient s b y abou t 30% , no t by th e state dfactor

o f three . 0 . Carte r (NCHS ) questione dwhethe r th e Hispanic

NHANE S analysi s wa s restricte dt o Mexican

Americans . B . F . For t

(Ethy l Corporation ) answere d i n th e affirmative , bu t

pointe dou t

tha t th e analyse s presente dt o dat e wer e preliminar y an dtha t

acorrecte d dat ase t wa s to b e analyze di

n th e future . Carte r

pointe d ou t tha t th e revision s involve donly thre e person s an d tha t should , no t

chang e th e analyses . Carte r empha

size dtha t

other s usin g th e Hispanic-NHANE S dat a shoul ddistinguis h amon g Mexican-Americans , Puert o Ricans , an dCuban-Americans . Carte r note d tha t acculturation , whic h ma y affec t bloo dpressur e levels , an dbirth plac e shoul db e explore dfo r thei r rela

tionship s t o lea dan dbloo dpressure . K . Mahaffey (NIOSH ) questione dwhethe r ther e wa s acontinua

tio n i n th e declin e o

f bloo dlea dlevel s i

n th e Hispani c NHANES . Schwart z responde dthat , althoug h th e bloo dleadlevel s i

n Hispanic-NHANE S wer e lower than i n NHANE S II , on e mus t acknowledg e tha t

ther e ar e populatio n differences . An y attemp t t o separat e ou t

th e Hispanic s i

n NHANE S I

I woul db e subjec t

t o th e diffi

cultie s o f smal l sampl e sizes . S . J . Pococ k (Universit

y o f London , UK

) note dtha t

th e regressio n coefficien t whic h For t

obtaine dfor

th e relationshi p o

f lea dt o diastoli c bloo dpressur e wa s 1.96 , avalu e quit e simila r t o th e coefficien

t o f 2. 1 i n th e Britis h data . H e als o note d tha t whe n adjustin g for

site , th e Britis h coefficien t move dfromzer o t o slightl y positive . Th e NHANE S coefficients , whe n adjuste dfo r site , wer e reduce dt o value s tha t

wer e stil l positiv e bu t o f smalle r mag nitude . Ther e wa s adiscussio n regardin g th e reproduci

bilit y o f result s base don analysi s o f th e sam e dat aset . For t an dGartsid e reporte dtha t the y wer e unabl e to reproduc e Schwartz' s results , wherea s th e University o f Nort h Carolin agrou p obtaine dexactl y th e sam e result s a s Schwartz , usin g precisel y th e sam e subjects , variables , models , an danalyti c techniques . P . Boscol o (University o f Chieti , Italy ) state dtha t lea dexposur e i s associate dwit h cadmiu man dothe r pollutan t exposure s an dtha t

interactio n effect s hav e t o b e considered . L . Gran t (U.S . EPA) opene dth e genera l questio n sessio n b y identifyin g severa l ke y issues : th e signi

ficance o f adjustmen t

fo r site , fo r geographica l location , analyse s withi n differen t ag e groupings , an dth e implication s o

f any bloo dlead-bloo dpressur e associ

ation s fo r

majo r morbidit y an dmortalit y cardiovas

cula r outcomes , suc h a s stroke s o r hear t attacks . D . Rox e (Northwester n University ) inquire dabou t th e measuremen t

technique s use dfo

r lea dan dbloo d pressure , whethe r

subset s o

f th e population s ha dha d recen t acut e exposur e an dwha t environmenta l source s ar e considere dth e majo r source s o

f lead . Schwart z reporte dtha t

NHANE S bloo dleadmeasurement s wer e take n i n speciall y loade dvacutainer s tha t wer e treate d t o b e trac e element-free . Qualit y contro l indicate da coefficient o f variatio n o

f blood-lea dlevel s o

f approx imatel y 15% , equivalen t t o aconfidenc e interva l o f approximatel y ± 2 ug/d L o n th e blood-lea ddetermin

ation . W . R . Harla n (Universit y o f Michigan ) com mente dtha t

bloo dpressur e i

n NHANE S I

I wa s take n on thre e occasions , seate da t th e beginning , supin e midwa y through , an dasecon dseate dbloo dpressur e nea r th e en do

f th e examination . Systoli c pressur e wa s recorde da s th e initiatio n o f Korotkof

f sound s an d diastoli c pressur e a s cessatio n o f sound s (K-5) . Ther e wer e alarg e numbe r

o f observers , traine dt o recor d bloo dpressur e in astandar dmanner . Regardin g acut e exposure s t o lead , th e onl y histori c informatio n wa s th e 24-h

r dietary recall . Thos e peopl e wh o hav e ha d asignifican t

numbe r o f calorie s o n th e day prio r t o examinatio n wer e als o th e peopl e reportin g th e highes t intake s o

f alcoho l a s thei r

habitua l consumption . Schwart z remarke dtha t th e half-lif

e o f lea di n th e bloo dwa s typicall y 3 0 day s an dtha t asingle , higher

than-averag e exposur e dos e i s no t goin g t o hav e majo

r perturbin g effect s on adults ' bloo dlea dlevels . Individ

ual s wh o wor

k fo r lea dexposur e industries , a s classi

fiedby NIOSH , wer e exclude dfromth e sample . Exclu

sio n o f thes e individual s resulte di n aslightl y highe r regressio n coefficient , whic h wa s stil l significant . Pococ k remarke dtha t

th e methodolog y o

f bloo dlea d wa s mor e importan t

tha n th e methodolog y o f obtain

in g bloo dpressur e i

n thes e studies . Bloo dlea d wa s measure dunde r

stric t quality contro l method s a t th e leadin g Britis h laboratory . Bloo dpressur e wa s recorde don th e Londo n Schoo l o f Hygien e zero-mud

dle r sphygmomanometer . Ther e wer e thre e observer s pe r town . I n additio n t o trainin g to correc t fo r observer variation , observe r

difference s wer e adjuste dfo r i n the analyses . Pococ k

doubte dtha t

singl e exposure s t

o alcoho l woul dhav e meaningfu l effects . It wa s hi s opinio n tha t

foo dan dwate r

source s woul db e im

portan t cause s o f bloo dleadlevel s i

n th e genera l popu

lation , i n additio n t o effect s o

f heav y drinkin g an

d smoking . Lea

di s stil l i

n Britis h gasolin e an di s bein g remove dgraduall y an di s lowe r tha n i t wa s pre viously . Thi s wil

l influenc e th e lea din dust , air , an d food . H e wa s no t

awar e o f any occupationa l o r

ambien t environmenta l problem s fro mlea dsmelter s influenc

in g hi s data . Schwart z commente dtha t i n th e Unite

d State s ther e wa s alarge r amoun t o f lea d i n th e genera

l populatio n comin g fro mgasolin e tha n i n Englan d an dlowe r

amount s comin g fromwater . H e estimate d tha t approximatel y half

th e lea din th e genera l pop u ' latio n i n th e 1970 s wa s base don gasolin e a s th e pr' " mar y exposure , accountin g fo r highe r level s i n urba n areas . M . Galvi n (NIEHS ) questione dth e difference s H | sampl e siz e betwee n th e Schwart z an dDuPo ° analyses . Schwart z responde dtha t DuPon t di dno t u s th e sam e covariate s tha t h e di dan dtha t

give n soiJ J missin g covariat e value s ther e wer e resultin g sligfy

different sampl e sizes . Gran t

adde dtha t

ther e ar e a' s som e difference s i

n th e subject s include do r excluded ' R . Lili s (Mt . Sinai , NY

) raise dquestion s regardiTMP. 4

DISCUSSION

SUMMARY 14 1

.u g comparability o

f th e Britis h an dAmerican studie s n th e distributio n o

f th e bloo dlea dlevel s in th e tw o populations , th e existenc e o f asimila r secula r tren din jhe Unite dKingdo man dth e Unite dStates , an d information regardin g trend s i n bloo dpressur e level s i n th e Unite dKingdo mcompare dt o th e Unite dStates , jvlahaffe y inquire dabou t

hypertensive s receivin g medication i

n th e British'studies , wer e the y excluded , a t wha t leve l o f bloo dpressur e woul dmedicatio n b e prescribed , an dregardin g th e distributio n o f bloo d lea dlevels , wha t

informatio n i s availabl e regardin g qualit y contro l an dintak e o

f lead ? Pococ k

though t ther e migh t b e asligh t

tendenc y t o highe r

bloo dlea d level s i n NHANE S I I bu t tha t i n genera l th e distribution s woul db e similar . Schwart z indicate d tha t th e mean'bloo d lea dleve l i n th e NHANE S populatio n wa s approximatel y 1 7 ug/dL . Pococ k indicate dtha t

i t wa s 0.7 6 umole/ L (equivalen t t o 1 3 o r 1 4 ug/dL ) i

n th e Britis h studies . Th e proportio n o f individual s wit

h value s ove r

3 0 ug/d L wa s small , suggestin g generall y similar range s o

f bloo dlea di

n the tw o studies . Pococ k

suggeste dtha t

ther e ar e no t goodepidemiologi c dat aa t presen t o n trend s in bloo d lea dlevel s i n th e Britis h experience . Suc h dat aar e bein g assemble dno w an dfor monitorin g ove r

tim e wit h th e remova l o

f lea dfromgasoline . P . Elwood , Medica l Researc h Counci l (MRC , UK ) ha s assemble dsevera l differen t approache s t o thi s questio n an dh e reporte dconsistenc y amon g the mo f a fal l o f abou t 4 % pe r year ove r th e las t 1 0 year s i

n bloo d lea dlevel s prio r

t o reductio n o

f lea di n gasoline . Pococ k commente dtha t

ther e ar e no t

goo ddat ao n trend s i

n bloo dpressure , bu t

h e suspecte dtha t

ther e hav e no t bee n substantia l trends . H e adde dtha t hypertensiv e medicatio n i s no t

a s intensiv e in th e U.K . a s in th e U.S . Further , i t

wa s hi s opinio n tha t

treatmen t

wa s no t initiate dunti l relativel y hig h level s o f diastoli c bloo d pressur e wer e observed . Elwoo dconcurre dtha t bloo d pressur e change s ove r

tim e hav e bee n minima l an d tha t ther e i s n o goo devidenc e eithe r i n trend s i n bloo d pressur e o r

antihypertensiv e treatmen t in Grea t Brit

ain . Lili s referre dt o dat afro mScotlan drelatin g level s o f lea di n drinkin g wate r

t o bloo dlead , kidne y function , an dhypertension , dat awhic h wer e no t presente db y Pococ k i n hi s formal paper . Pococ k responde dtha t

h e restricte dhi s analyse s t o th e bloo dlead-bloo dpressur e relationship . Lili s remarke dtha t Pocock' s dat asug geste dtha t

th e localitie s whic h ha dhighe r bloo dlea d level s wer e th e area s o

f sof t wate r an dtha t th e sourc e o

f lead , whethe r

i t come s fro mwater , air , gasoline , o r othe r sources , i s actuall y o

f secondar y importanc e i n thi s discussio n o

f th e effec t

o f lea do n bloo dpressure . Pococ k concurre dan djustifie dhi s discussio n o f th e associatio n o

f highe r bloo dpressur e with wate r soft

nes s i n hi s presentatio n a s o f backgroun ddescriptiv e interes t only . Pococ k

adde dtha t

h e include dindivid

ual s o n hypertensiv e medicatio n in hi s analyse s sinc e thei r exclusio n coul dlea dt o abia s du e t o thei r highe r than averag e bloo dpressur e values . For t commente d o n studie s o f tw o town s in Massachusett s i n whic h a n associatio n wa s detecte dbetwee n sodiu mchlorid e conten t o f th e wate r suppl y an dbloo dpressur e level s o f schoo l children , controllin g fo r othe r relevan t variables . H e questione dwhethe r ther e wer e othe r variable s dependin g o n location , wate r supply , an d sodiu mchlorid e specifically , whic h coul daffect bloo d pressure , an dha dno t

bee n controlle dfo

r i n th e dat a set s unde r

consideration . D.-L . Zhu (University o f Nort h Carolina ) inquire d abou t th e relationshi p betwee n erythrocyt e protopor phyrin , bod y burde n o

f lead , an dbloo dpressur e in th e NHANE S cohort . Schwart z note dtha t erythrocyt e pro toporphyri n di dno t

correlat e with bloo dpressur e level s i n th e NHANE S studies . H e indicate dtha t in th e genera l adul t

population , erythrocyt e protoporphyri n i s dominate db y iro n statu s an di s apoo r predicto r

o f lea dstatus ; thi s i s in contras t t o achil deatin g lea d paint chip s wh o ha s marke delevatio n o f bloo dleadan d marke delevatio n o

f protoporphyrin . S . T . Weis s (Harvar dMedica l School ) commente d o n th e implication s o

f adjustin g fo

r sit e by pointin g ou t tha t sit e ma y i n fac t b e alink in th e causa l chai n o

f th e bloo dlead-bloo dpressur e association , becaus e sit e i s associate dwith wate r

o r ai r source s o

f lea dand , consequently , i s th e major determinan t

o f bloo d lead . It wa s hi s opinio n tha t

thi s distinctio n betwee n whethe r sit e i s aconfounde r

o r alink i n th e causa l chai n coul d no t b e resolve dwit

h cross-sectiona l dat aan dtha t a longitudina l stud y o

f change s i

n bloo dlea dan dbloo d pressur e wa s on e potentia l wa y o f resolvin g th e issue . A . J . Vande r

(Universit y o

f Michiga n Medica l School ) questione dth e relationshi p betwee n decrease s in lea dan dth e tim e necessar y fo r a n associate d declin e in bloo dpressure , assumin g tha t lea dha dcontribute d t o aris e i n bloo dpressure . In particular , h e inquire d abou t th e effect o n statistica l association s i f ove r a4-yea r perio dwhe n lea dwa s decreasing , bloo dpressur e di d no t decrease . Schwart z responde dtha t th e questio n di d no t relat e to th e observations , sinc e controllin g fo r all othe r factors , bloo dpressur e di dchang e over tim e wit h change s i n bloo dlead . Vande r

wa s skeptica l abou t

th e tim e change s in bloo dpressure , but , assumin g tha t bloo dpressur e actuall y di ddecline , di di t d o s o fo

r reason s othe r

tha n lead ? Schwart z responde dtha t elaborate , detaile dmodels , includin g contro l fo r man y potentia l confounders , faile dt o eliminat e th e bloo d lead-bloo dpressur e association . Thi s include dsite

an dtime-relate dvariables . W . Kanne l (Bosto n University Schoo l o f Medicine ) commente do n bloo dpressur e trends . I t wa s hi s opinio n tha t

ther e wa s n o wa

y t o kno w whethe r

bloo d pressur e actuall y change din th e genera l population . Ther e ha s bee n amassiv e amoun t o f treatmen t

intro

duce dove r

time , th e indication s for treatmen t

hav e change dove r

tim e a s well , an dcurrently , physician s i n th e Unite dState s ar e treatin g peopl e wit h lowe r bloo dpressure . Unde r

thes e circumstances , i

t i s diffi

cul t t o determin e whethe r

th e prevalenc e o

f hyperten

sio n ha s change dove r

time . Harla n note dtha t com -P. 5

14 2 V1CTERYETAL. pariso n o

f th e distribution s o

f bloo dpressur e i

n NHANE S I an dNHANE S II , i.e. , betwee n th e earl y an d th e lat e 1970s , an dsuggeste dtha t th e difference s wer e primaril y a

t th e uppe r

en do f th e bloo dpressur e dis

tributio n an dsuggeste dtha t treatmen t

i s on e o f th e major reason s fo

r th e declin e an dtha t

ther e ar e only smal l change s in mea n values . Schwart z indicate d tha t thi s i s on e reaso n hi s grou p di danalyse s exclud

in g peopl e on hypertensiv e medication , althoug h h e acknowledge dtha t

thi s approac h result s i

n truncatin g th e sample . D . G . Beever s (Universit y o f Birmingham , Scot

land ) attempte dt o reconcil e th e apparen t disparitie s betwee n th e U.S . NHANE S an dth e Britis h Regional Heart Studies . H e suggeste dtha t participan t

selectio n ma y hav e bee n partiall y responsibl e i n tha t ther e wa s oversamplin g o

f disadvantage dperson s o f relativel y lowe r socia l clas s i

n NHANE S an dunintentiona l se lectio n o f highe r socia l clas s individual s in th e Re

giona l Hear t

Study . Pococ k

indicate dtha t

a n attemp t wa s mad e to selec t

agenera l practic e tha t

wa s represen tativ e o f it s communit y i

n eac h tow n i

n th e Britis h Regiona l Survey . However , ther e wa s onl y a78 % respons e rat e o

f individual s comin g i

n fo r screening . H e note dtha t

th e distributio n o

f manua l t o nonman ua l worker s i

n th e sampl e wa s generall y simila r to tha t i n Grea t Britain ; however , ther e wa s asligh t under

representatio n o

f unskille dmanua l worker s an da sligh t overrepresentatio n o

f th e professional classes . Schwart z indicate dtha t ther e wa s in fac t

a n oversamplin g o

f lowe r socia l statu s individual s i n NHANES , bu t

thi s wa s don e by desig n i n advanc e an d sampl e weight s wer e created , s o tha t by weighin g thes e peopl e les s tha n other s i t wa s possibl e i

n aweighte d analysi s to ge t

bac k to asampl e representativ e o f th e U.S . population . Weight s als o wer e assigne dt o adjus t fo r nonparticipatio n i

n examinations , base don th e fac t tha t 97% o f th e person s selecte dha ddemographi c an d medica l histor y informatio n obtaine dfromahom e interview . Gran t opene dth e questio n an ddiscussio n perio do f th e panelists . H . Smit

h (Statistical Consultant ) querie d Pococ k an dSchwart z a s to whethe r eac h ha dcarrie d ou t regressio n analyse s withi n eac h site , whic h woul d permi t site-specifi c estimatio n o f th e bloo dlead-bloo d pressur e associatio n controllin g fo r th e othe r

majo r covariates . Pococ k

indicate dtha t

hi s final mode l con taine dadjustment s fo

r bod y mass , age , alcoho l con sumption , socia l class , an dsmokin g categorie s i n additio n to 2 3 dummy variable s t o adjus t fo r differ

ence s betwee n towns . Th e numbe r o f individual s withi n eac h site , approximatel y 300 , wer e to o fe w to permi t site-specifi c detaile danalyse s wit h multi-co

variables . Schwartz responde dtha t h e coul dno t

d o site

specifi c regressio n analyse s becaus e fo r th e 4 0 to 5 9 year old s ther e wer e 54 3 peopl e i n 6 4 sites , an dth e informa

tio n availabl e pe r

sit e woul db e markedl y limited . Smit h inquire dabou t

separat e analysi s a

t eac h sit e an dthe n ameta-analysi s o f th e derive dcoefficien t acros s all sites . Smit

h suggeste dthi s (whic h ha dno t bee n done ) woul db e similar t o th e Landi s approach , whic h wa s apoolin g usin g th e Mantel-Haensze l statisti c acros s subgroups . Smit h reiterate dtha t

wha t h e wa s intereste di

n wa s th e magnitud e o

f th e regres sio n coefficient

acros s th e group s an dno t th e signifi

canc e level . Th e magnitud e o f th e estimate d chang e i

n bloo dpressur e pe r

uni t chang e o

f bloo dlea dwa s o

f primar y interes t t o se e i f an y associatio n detecte dwa s o f importance . H e state dtha t inferenc e wa s th e issue , not th e tes t o f hypothesis . Further , h e argue dtha t th e selectio n criterio n for

admittin g variable s i

n astep wis e procedure , whic h mandate s establishin g asig

nificanc e leve l t o admi t o r discar davariable , i s somethin g tha t

ough t t o b e avoide do r

use donl y wit

h caution . Schwart z responde dby indicatin g tha t h e ha dadopte damode l wit

h variable s generall y agree dt o b e associate dwit

h bloo dpressure , i.e. , sex , age , bod y mass , an drace, an dthen , sinc e bloo dpressur e ha s bee n hypothesize dt o b e amultifactoria l outcome , t o have include dalarg e numbe r o f dietary , seru mmicro

nutrient , demographic , an dothe r factor s whic h have bee n foun dassociate dwit h bloo dpressur e in som e studies . Hi s approac h wa s to se e ho w stabl e th e bloo d lea dcoefficien t

was , includin g o r

excludin g thes e variable s an dunde r

tha t circumstanc e usin g th e step wis e regressio n analysi s approach . Schwart z empha

size dtha t thi s approac h wa s no t

use dt o establis h a mode l fo r bloo dpressure , bu t

rathe r t o tes t fo r the stabilit y o f th e bloo dlead-bloo dpressur e relationshi p a s h e expande dfromth e biologi c mode l tha t include d universall y accepte dvariable s t o model s tha t include d variable s tha t

other s hav e speculate dabout . Smit h querie dR. Landi s (Universit y o f Michigan ) regardin g th e rational e fo r adoptin g th e procedure s h e ha duse dan dwhic h ar e discusse di n detai l i

n hi s forma l paper . Hi s respons e wa s tha t th e expecte dvalu

e an dvarianc e i

n eac h subtabl e i s compute d conservativel y unde r

afixe dmargi n assumption . I t ca n b e viewe da s arandomizatio n mode l i n whic h th e bet

a coefficien t a t eac h sit e ca

n b e estimated . Give

n th e expecte dvalu e an dth e varianc e fo r tha t componen t

base d o n th e fixe dmargin s o

f aconservativ e Fishe r

exac t kin do f hypergeometri c framework , yo u ca n se e whethe r o r no t th e observe dcross-produc t tend s t o excee dit s expecte dvalu e o n averag e acros s ver y smal l subgroup s o

f individuals . I

n th e extreme , thi s woul d b e th e matche dpai r

desig n adjustin g for

all th e co

variates ; althoug h no t

don e yet , i

t coul db e don e an

d t o determin e whethe r

o n average , th e matche dpair tends to favo r th e elevate dleve l o

f pressur e bein g associated wit h elevate dleve l o

f lead . Landi s prefer s thi s t o a multiple-regressio n mode l wit h 6 3 sit e parameters ' Additionally , th e procedur e permit s adjustmen t fo r t n rol e o f 6 4 site s withou t

incorporatin g th e sit e effe c into th e estimatio n o

f th e partial bet acoefficient . Al l t n statistica l power

i s focuse don estimatin g on e betac° e ficient adjuste dfo

r al l th e othe r

covariates . Tha

t b e coefficien t ha s ates t

statisti c tha t

i s nearl y identica

l th e Mantel-Haenszel . I

n respons e t o aquestio n fr ° Grant , Smit

h responde dtha t

h e ha dneve r

seenDISCUSSION SUMMARY 143 Mantel-Haenszel procedur e applie dthi s wa y before an d u e was no t

certai n whethe r

th e applicatio n wa s appro priate . Kanne l commentedtha t

i t wa s necessar y to retur n to basi c epidemiologi c principle s an d t o evaluat e whethe r 0 r not acausa l associatio n i s present . H e se t ou t th e followin g criteria : t o determin e whethe r th e observe d relationship wa s foun dconsistently , whethe r th e asso ciatio n i s strong , whethe r

i t i s dos e related , i

f i t i s bio

logicall y plausible , whethe r

i t can b e reproduce dex perimentally , an d finally , i f i t i s presen t

whe n takin g confoundin g variable s int o account . Base do n th e informatio n presented , h e believe dth e effect o f lea don bloo dpressur e appear s t o b e modest ; however , withi n a populatio n context , give n ubiquitou s exposure , th e populatio n attributabl e ris k can b e large , an d thi s ha s publi c healt h implications . However , h e believe s tha t mor e informatio n i s needed . Th e shap e o f th e dose

respons e relationshi p o

f lea dt o bloo dpressur e i s no t clear . I s ther e an effec t o n bloo dpressur e at

toxi c exposure s ove r

th e limi t o f 3 0 o r 4 0 ug/dL ? Mor e in

formatio n i s require dregardin g mechanisms . I s th e effec t shor t ter mo r lon g ter man d cumulative ? Kanne l notedtha t

for hypertensio n in general , eve n fo r th e stronges t o f know n populatio n ris k factor s suc h a s obesity , mechanism s ar e unclear an d s o th e absenc e o

f thi s knowledg e i s no t

uniqu e t o lead . In assessin g th e role o f potentia l confounders , Kanne l fel t that , i n plac e o f "mindles s statistica l numerology, " i t woul db e pref

erabl e to hav e an d tes t

specifi c hypothese s a s to ho w lea d migh t affect bloo dpressur e i

n apopulation . Finally , h e notedtha t lac k o f knowledg e i s no excus e fo r inaction , i f w e kno w tha t

ther e i s apossibl e relationshi p an d a modifiabl e populatio n environmenta l exposure . How

ever , Kanne l di d feel tha t

ther e i s anee dt o establis h th e nature o f th e associatio n mor e precisely . H . Dusta n (Universit y o f Alabama ) summarize d he r reactio n t o th e material s presente db y statin g tha t sh e regarde dth e evidenc e a s quit e unclea r whethe r lea dha s a n effec t o n bloo dpressur e i n larg e popula

tions . Sh e agree dwit

h Kanne l tha t

i t wa s difficult

t o kno w whic h o

f th e multitud e o

f analyse s with dif

feren t result s wa s correct . Th e nex t plenary sessio n wa s devote dt o fou r relate d studie s o f lea dan d hypertension . Followin g D . Krom

hout' s (Stat e Universit

y o f Lieden ) presentatio n o n th e Zutphe n Communit y Stud y o f elderl y men , Boscol o commente dtha t

th e effect s o

f lea dexposur e ar e ver

y differen t in youn g an d ol d persons . H e suggeste dtha t th e effect s o

f lea dexposur e in younge r individual s woul db e mediate dvi amechanism s regulatin g bloo d pressur e throug h th e brai n an d kidneys . Pococ k questione dwhethe r

Kromhou t

woul dhav e publishe d hi s finding s ha d the y no t bee n statisticall y significan t (referrin g t o th e issu e o

f publicatio n bias) . Kromhou t answere dtha t

h e woul dhav e publishe dth e findings regardles s o

f th e outcome , bu t

woul dno t

hav e pub

lishe dth e bloo dlead-bloo dpressur e result s separately . Lilis.commente d tha t

remova l o

f on e outlie r

obser

vatio n o f a n individua l with hig h bloo dlea dan d ver y hig h bloo dpressur e resulte di n th e absenc e o

f a significan t relationshi p betwee n bloo dlea dan d bloo d pressur e in Kromhout' s presentation . Kromhou t responde dtha t

remova l o

f th e on e outlie r

resulte do n univariat e analysi s i

n aborderlin e statisticall y sig

nificant relationshi p betwee n bloo dlea dan d systoli c bloo dpressur e an d absenc e o f a n associatio n o

f bloo d lea dan d diastoli c pressure , bu t tha t th e associatio n n o longe r wa s statisticall y significan t upo n adjustmen t fo r bod y mas s inde x an d age . Lili s furthe r

discusse dth e appropriatenes s o f in

cludin g o r

excludin g th e outlie r

i n th e final analysis . Smith commente dtha t

th e decisio n rest s upo n th e rang e o f inferenc e to b e made . If

, i n fact , th e outlie r

i s i n th e rang e o

f inference , the n obviousl y i t ha s t o remai n i n th e study . Alternatively , i f th e rang e o

f inferenc e i s restricte dt o lowe r

values , the n i t

woul db e inappro

priat e t o includ e it . Schwart z questione dth e effec t o n th e magnitud e o

f th e regressio n coefficient includin g an dexcludin g th e outlier . Kromhou t responde dtha t ther e wa s onl y asmal l chang e in th e magnitud e o f th e regressio n coefficient , bu t th e p valu e becam e 0.06 , i.e. , n o longe r

conventionall y statisticall y significant . W . Le e (Universit

y o f Manchester , UK

) raise dth e pos sibilit y o f athreshol drespons e o f bloo dpressur e t o bloo dleadlevels . H e interprete dth e dat apresente da s showin g ver

y littl e effec t

o f low bloo dlevel s on bloo d pressure , suggestin g ahorizonta l dose-respons e rela

tionshi p wit

h a n uptur n i

n bloo dpressur e respons e a t som e threshol dvalue . Recognizin g th e limitation s i n on e observation , h e suggeste dtha t perhap s th e outlie r migh t indicat e wher e th e dose-respons e curv e fo r th e bloo dlead-bloo dpressur e relationshi p i s beginnin g t o tur n up . Landi s disagree dwith Lee' s interpretatio n o f th e dose-respons e relationship . H e interprete d th e NHANE S dat aa s showin g an associatio n o f bloo d pressur e wit

h bloo dlea ddow n t o level s o f 5 ug/dL . H e suggeste dthat , i

f anything , ther e i s evidenc e tha t th e respons e o

f bloo dpressur e ma

y tape r of f at th e highe r level s o f lead . Landi s commente dtha t i f ther e i s a threshold , i t

i s fo r highe r level s tha n thos e observe din th e NHANE S data . Schwart z reporte dtha t h e ha d trie d fittin g athreshol dmode l i n th e NHANE S dat aan d ha dfailedt o fin

d evidenc e o

f athreshold . H e disagree d wit h th e characterizatio n o f a n outlie r in th e Krom

hou t data , arguin g tha t

th e singl e valu e doe s no t chang e th e slop e o

f th e relationshi p muc h whil e bein g influential wit

h respec t t o th e significanc e level , an d therefor e i

t wa s no t a n outlie r i n th e sens e tha t

ther e i s adifferen t

relationshi p at

th e observe dleve l an d at lowe r levels . Afte r T . Moreau's (INSERM ) presentation , H . Gonic k (Cedar s Sinai , CA

) requeste dsom e clarificatio n o f th e conclusion s regardin g lead' s effec t o n re d cel l mem bran e lea dconten t

an d catio n transpor t

systems . I

f lea d bindin g t o re d bloo dcell s affect s Na + /K + ATPase , on e woul dexpec t

t o se e apositiv e correlatio n betwee n th e two . Sinc e tha t

di d no t occur , on e coul drevers e th e questio n an d as k

i f th e tota l bloo dlea do r

membrane

-P. 7

14 4 V1CTERYETAL. boun dlea di s areflectio n o f a n activ e transpor t

abnor- , mality characteristi c o

f hypertension . Dusta n als o querie dMorea u concernin g th e lac k o f correlatio n betwee n membrane-boun dlea dan dcotranspor t sys tems , i n particular , ho w calciu mma y interac t

with lead . Morea u indicate dtha t hi s grou p wa s disap

pointe di n thi s particular

finding , bu t

ther e ma

y b e a positiv e relatio n o

f membran e lea dan dK + channels . H e suggeste dtha t

th e sulfhydry l group s o f th e Na/ K ATPas e enzym e ar e probabl y reactin g wit h lead , eve n thoug h th e enzym e activit y wa s no t affected . A . John s (University o

f Miami ) aske di

f inhibitio n o f thi s cotranspor t

syste mcoul db e responsibl e fo r th e increase dcontractility i

n smooth muscl e cell s o

f bloo d vessels . Morea

u replie di

n th e affirmative . John s sai da similar pump exist s i

n uterin e smoot h muscle s tha t appear s t o b e furosemid e insensitiv e bu t i t i s stil l responsiv e t o agonist s causin g contraction . Followin g th e presentatio n o f th e pape r

by Weiss , Schwart z questione dth e finding s ove r tim e an d whethe r o r no t asingl e measuremen t

o f bloo dleadlos t powe r a s apredicto r

o f bloo dlea dlevel s i

n successiv e years . Weis s responde dtha t i n th e contex t

o f thi s model , i t wa s necessar y t o trea t

bloo dlea da s afixed covariate , i.e. , th e assumptio n ha dt o b e mad e tha t bloo d lea ddoe s no t

chang e ove r

time . Landi s aske dwhethe r lea dwa s analyze da s acontinuou s variable , rathe r tha n categoricall y a s intermediat e an dhigh . Thi s wa s o f importance , sinc e ther e wa s alarg e representatio n i n th e uppe r levels , i.e. , 22

% o f th e men . Weis s indicate d tha t thi s ha dno t

bee n done ; th e dat awer e simpl y categorize dat

th e star t o f th e analysis . Landi s indicate dtha t

th e Weis s stud y includeda larg e proportio n wh o woul db e i n th e uppe r

en do f th e distributio n o

f th e genera l population , i.e. , i n NHANE S II . Kanne l questione dth e association s o f alcoho l intak e wit h bloo dpressur e i

n th e stud y an daske dwhethe r o r no t Weis s wa s implyin g tha t th e alcohol-bloo dpres sur e associatio n i s entirel y du e t o lead . Weis s re sponde dtha t

th e distributio n o

f reporte dalcoho l con sumptio n i

n hi s sampl e wa s simila

r t o tha t reporte dby th e averag e American . H e suggeste dhi s finding s ma y reflec t reportin g bias . Regardin g th e associatio n wit h bloo dpressure , h e pointe dou t tha t al l me n i n th e stud y wer e normotensiv e an dtha t th e finding s migh t

resul t fromarelativel y smal l stud y o f limite dpower . H e di d no t believ e any o

f hi s result s vitiate dany o f th e earlie r studie s regardin g th e relationshi p o f alcoho l t o hypertensio n o r

alcoho l t o bloo dlea dlevels . I t wa s jus t tha t th e alcoho l associatio n wit h bloo dpressur e wa s no t demonstrabl e i

n hi s (small ) cohort . Gonic k aske dth e first

questio n abou t

R . Wedeen' s (V . A . Medical Center , E . Orange , NJ ) presentation ; i t concerne dwhethe r

th e EDT A lea dmobilizatio n tes t

o r th e X-ra y fluorescenc e bon e lea dmeasure s o f lea d burde n ha dbee n correlate dwit h any bloo dpressur e measurements . Wedee n responde dtha t th e limite d numbe r o f subject s di dno t

mak e suc h analysi s suit

able . A follow-u

p questio n fro

mGonic k

aske dth e rela

tionshi p o

f thes e tw o measure s o

f lea dt o tha t

i n th e postulate dtarge t tissu e for

hypertensiv e effects , e.g. , vascula r tissue . Wedee n di dno t

feel thi s wa s likel y t o b e th e targe t tissue . H e plan s t o examin e platelet s an dthei r calciu mmetabolis mfurther , a s wel l a s endothelia l repair . Moreover , lea dconcentration s ma y no t b e per ceptibl y highe r

i n an y targe t

tissue . Gonic k

aske d Wedee n t o conside r

a s toxic , th e lea di

n th e ionize d for mcirculatin g in extracellula r fluid , platelet s o r vascula r tissue . Wedee n agree dtha t lea di n bon e (whil e bein g th e bes t

measur e o

f pas t exposures ) wa s unlikel y t o b e indicativ e o f damag e t o th e bones ; however , i

t i s availabl e for

exchang e wit

h extracellular fluidan dconsequentl y t o othe r tissues . P . Grandjea n (Odens e University , Denmark ) brough t u p variou s concern s abou t th e us e o

f X-ra y fluorescenc e for

lea dburde n measurements ; th e tech

niqu e involve s us e o

f X-rays , i t

i s expensive , an dth e measuremen t

obtaine dvarie s with bon e type . I n addition , in rena l failur e dialysi s patients , th e seru m leve l o f aluminu mi s elevated . Aluminu mbind s t o an daffect s bon e hydroxyapatite , especiall y it s abilit y t o respon dt o homeostasi s o f seru mcalciu mb y para thyroi dhormone . Therefore , bon e metabolis mo f lea d ma y b e considerabl y altere di n thos e patient s wit h concomitan t

bon e disease . Wedee n (in collaboratio n with scientist s in th e Netherlands ) ha s histomor

phometri c evidenc e tha t

th e amoun t

o f lea din bone s o

f rena l diseas e i s no t

altered . Dusta n querie di

f ther e i s adifferenc e betwee n race s wit h regar dt o rena l disease . Accordin g t o Wedeen , black s ar e overrepresente di n dialysi s units ; i

n spit e o f smal l numbers , h e foun dthes e black s ha d highe r lea d levels . Unfortunately , i

n clinical research , th e numbe r o f patient s studie di s necessaril y limited . Vande r aske dfor

clarificatio n o n th e abilit y o f th e X-ra y fluorescenc e metho dto detec t low leve l lea dexpo sure . Dr . Wedee n indicate dat presen t tha t detectio n limit s ar e approximatel y 1 0 pp mwit h a n erro r o f 1 0 t o 20% . Value s i

n th e genera l populatio n ar e expecte dto b e 6 ppm ; therefore , th e techniqu e may b e usefu l i n selectin g hig h ris k

groups . Vande r

wa s actuall y mor

e concerne dabou t

th e lac k o f correlatio n i

n th e bon e lea

d conten t with respec t

t o th e constan t

amoun t o f lea d measure din th e EDTA mobilizatio n test . Wedee n state dtha t

th e tota l numbe r

o f patient s ha s bee n rathe r limite dwhe n compare dt o th e number s i n epidem

iologi c studies . Th e nex t plenary sessio n consiste do f thre e presen tation s on person s wh o wer e occupationall y expose dt o lead . Followin g th e presentatio n o f W . C . Coope r

(phy

sician-consultant ) on his . lea dmortalit y study , ther e wa s aquestio n fromP . Pontze r (Federate dFr

y Metal s Company ) a s t o whethe r Coope r ha dattempte dt

o correc t fo r incompletenes s o

f dat aon th e death certifi

cate s use di

n th e study . Coope r

responde di

n th e nega

tiv e becaus e h e fel

t tha t th e sam e correctio n coul dnot b e don e for th e comparis'o n groups . Kanne l the n ques tione dwh

y lea dbatter y worker s wer e separate dfro m smelte r workers , sinc e h e felt

tha t i f yo u combine dth

e 

# I

# w

DISCUSSION SUMMARY 14 5 P. 8

Hat ao f lead-expose dworker s an dcompare dthes e dat ato i e general population , aleve l o f statistica l significanc e woul d b e achieve dfo

r som e o f th e outcomes . Coope r ndicate dtha t he , ha dcarrie dou t

suc h a n analysis , bu t ' t di dno t alte r th e result s enoug h t o b e justified . Furthermore , thes e tw o group s o f worker s ar e i

n dif

feren t plan t operation s an dthu s hav e differen t pos sibilitie s fo r

confoundin g exposure s whic h ar e important ^ o r assessin g relationship s with variou s type s o f cancer , specificall y lun g cance r an dstomac h cancer . Coope r

suggeste dtha t

i f th e ag e distribution s an d different

hir e distribution s o

f thes e population s wer e examined , on e woul dfeel mor e comfortabl e see in g thes e tw o group s separated . j . Bosc h (Georg e Washingto n University ) aske d whether ther e wa s an y knowledg e o f worker s tha t develope dchroni c rena l failur e an dthe n died , t o whic h Coope r indicate dtha t

h e di dno t

kno w abou t suc h cases . Lili s suggeste dt o Coope r tha t sinc e highe r exposur e level s wer e foundi

n th e smelter s a s compare d t o th e batter y plant s an dhighe r mortalit y rate s for chroni c rena l diseas e wer e see n in th e smelters , thi s woul dindicat e tha t

ther e i s adose-respons e relation

ship . Coope r

responde dtha t

th e dat aappeare dcon sisten t wit h tha t hypothesis . Smit h the n aske dwha t

th e tota l populatio n o f worker s availabl e t o exposur e wa s in th e smelte r an d batter y plant s an dthei r

person-year s experience . Coope r state dtha t

batter y plant s ha droughl y 100,00 0 person-year s an dth e smelter s ha d50,000 person-years . Afte r S . Selevan' s (U.S . EPA) paper , Gonic k aske da questio n concernin g Selevan' s designatio n o f hig h lea dvs . hig h lead/lo w othe r for exposur e level s in he r study . Gonic k

fel t tha t th e hig h lead/lo w othe r designatio n migh t

b e differen t

for chroni c nephritis , tha n fo r cancer . Fo r

example , arseni c doe s no t hav e an advers e effec t

o n kidne y function , bu t i s presumabl y carcinogenic . O n th e othe r hand , silicon , copper , cadmium , an dperhap s gol dan dsilve r d o hav e an advers e affect

o n th e kidney . Gonic k

suggeste dtha t

a regroupin g o

f th e hig h lead/lo w othe r classificatio n lookin g specifically fo

r th e silico n an dcadmiu meffect s o n chroni c nephriti s migh t giv e asomewha t

differen t insigh t to th e curren t

grouping s i

n th e study . Seleva

n responde dtha t

ther e woul donl y b e fairl y mino r differences , sinc e th e expecte dan dobserve dwere s o low . Seleva n suggeste dtha t

NIOS H tak e aloo k

at Gonick' s suggestion . R . Goyer (University o

f W . Ontario , Canada ) the n questione dwhethe r

th e us e o

f autops y material , a s wel l a s informatio n fro mdeat h certificates , migh t giv e a bette r vie w o f th e natur e o

f th e rena l diseas e an d possibly th e incidenc e o f rena l tumor s i

n th e stud y population . Selevan agree dan dindicate dtha t NIOS H ha drecentl y collecte dsom e patholog y report s fo r suc h a purpose . Dusta n the n note dtha t ther e wa s n o increas e i n hypertension-relate ddeaths , bu t wondere dwhethe r there wa s an increas e in hypertensio n in th e overal l cohort . Selevan indicate dtha t ther e wa s n o informa

tio n on thi s becaus e th e mortality stud y only include d thos e thing s whic h findthei r wa y t o th e deat h cer tificate . Dusta n suggeste dtha t thi s informatio n migh t b e foun dthroug h annua l physica l examinatio n records . Seleva

n state dtha t

thi s wa s no t

necessaril y s o sinc e ther e wa s no t

alo t o f informatio n on bloo dlead s i n th e olde r

medical record s an dsinc e annua l physica l exam s wer e no t

carrie dou t

at th e plant . H . A . Tyrole r

(University o

f Nort h Carolina ) the n aske dwhethe r

Seleva n examine dmultipl e caus e codin g an dwhethe r

o r no t i n proportionat e mortality term s o r in relationshi p t o hig h exposures , ther e wer e mor e instance s o

f hypertensio n an dhypertension

relate dcondition s a s secondary cause s o f death . Seleva

n indicate dtha t

asecondary analysi s wa s no t don e excep t fo r silicosis . Tyrole r

suggeste di t

migh t b e informativ e to d o asecondary analysis . Boscol o note d tha t

Selevan' s cohor t

consiste d o

f a peculia r populatio n o

f worker s expose dno t

onl y t o lead , bu t als o t o cadmium , arsenic , copper , an dothe r elements , no t

only at work , bu t

at home . H e fel

t i t woul d b e difficult , therefore , t o compar e th e dat ao f thi s stud y t o othe r dat ao n peopl e expose donl y t o lead . Seleva n agree dwit

h thi s observation , remarkin g tha t i t wa s difficul t t o kno w what

typ e o f interactiv e effect s ma

y b e occurrin g an dwha t

effect s ma

y b e cause db y othe r kind s o f exposures . I t

i s extremel y har dt o determin e definite conclusion s fromthi s typ e o f work . Followin g W . L . A . M . d e Kort' s (Ministry o f Socia l Affair s an dEmployment , th e Netherlands ) paper , Dusta n note dtha t

a n increas e i

n th e averag e arteria l pressure s fo

r both systoli c an ddiastoli c bloo dpressure s wa s observed . Also , amon g th e lea dworker s a s oppose d t o "th e controls , ther e wa s abi t o f an ag e differenc e betwee n th e tw o group s wit h th e worker s bein g alittl e olde r tha n th e controls . Dusta n note dtha t thi s ag e differenc e become s ver

y importan t

in regar dt o bloo d pressures . Dustan the n aske dwhethe r ther e "wer

e peopl e wit h rea l hypertension ; peopl e wit h diastoli c pressure s greate r tha n 105 , o r

wa s thi s jus t

par t o f th e agin g process , d e Kort--responde d tha t mixe dpai r

analyse s ha dbeenjlon e an dconsistentl y adifferenc e i n systoli c bloo dpressur e wa s found . Th e diastoli c bloo dpressur e wa s no t statisticall y significan t i n th e mixe dpair s analyses . d e Kor t note dtha t

ther e wer e problem s i

n obtainin g exposur e level s a t

th e plant . Ther e wa s a

n indicatio n tha t th e time-weighte daverage s appeare dlowe r tha n th e threshol dlimi t

value , whic h wa s 10

5 ug/m 3 at

th e time , bu t pea k value s ofte n exceede d10-fol d thi s threshol dlimi t

value . Lili s state dtha t

sh e though t

tha t no t adjustin g for bod y mas s in ahypertensio n stud y wa s suc h adraw

bac k tha t on e coul dno t

possibl y dra w any conclusions , d e Kor t disagree dwit

h this , statin g tha t

h e ha dno t see n studie s wher e bod y mas s inde x an dbloo dlead s wer e highl y correlated , and , furthermore , i f bod y mas s inde x ha dbee n included , ther e woul dhav e bee n aris k o f overmatchin g in suc h asmal l grou p whic h woul d b e very serious , d e Kor t the n note di

n respons e t o anothe r questio n b y Smit

h tha t th e tim e fram e o

f hi sP. 9

14 6 VICTERYETAL. dat acollectio n wa s on e month . Le e note dfro

mlistenin g to al

l paper s presente ds o fa

r a t th e conferenc e tha t

ther e appeare dto b e aver y sligh t ris e o f bloo dpressur e ove r

arang e o

f bloo dleads , somethin g like a2-m

mHg/1 0 u g Pb/d L blood . Yet , i n th e first tw o mortalit

y papers , ther e wer e observation s o f peopl e dyin g fromrena l diseas e an dperhap s hyper

tensiv e disease , fro msom e rathe r ill-define dbu t generall y accepte dver

y hig h bloo dleadlevels . Le e sug geste dtha t

perhap s somethin g wa s occurrin g at highe r level s o f exposur e o r

tha t lea dwa s havin g a

n effec t i n highe r dose s an dproducin g rena l diseas e withou t producin g marke dhypertension , d e Kort responde dtha t

whe n peopl e ar e expose dto hig h lead levels , effect s wil

l sho w u p tha t

wil l no t necessaril y sho w u p a

t lowe r levels . Also , d e Kor

t state dtha t

h e disagree dwit

h th e theor y pu t

fort h b y Wedee n tha t

th e kidne y i s o

f importanc e i

n th e hypertensio n rela

tionship . H e believe s i

t i s th e vascula r

wal l tha t

i s important . However , i

f on e i s expose dt o insolubl e lead components , mos t

o f th e materia l remain s in th e lungs . So , perhap s th e lun g i s th e targe t orga n wher e th e angiotensi n convertin g enzym e play s arol e in generatin g vasoactiv e agents . Schwart z remarke dtha t h e wa s disturbe db y hearin g peopl e talkin g abou t ver y smal l effect s an d calle dth e audience' s attentio n bac k t o th e origina l comment s mad e at

th e beginnin g o

f Monday' s sessio n o n attributabl e versu s relativ e risk . H e state dtha t h e di dno t believ e tha t

anybod y wh o ha s don e wor k on lea dan dbloo dpressur e think s tha t leadi s th e principal determinan t

o f bloo dpressure . Furthermore , everyon e agree s tha t

th e slop e o

f th e relationshi p wit

h bod y mas s i s muc h bigge r

an dmor e stabl e tha n bloo dlead . Th e proble mi s tha t

i t i s ver y difficul t t o chang e people' s body mas s index . I

t i s eve n mor e difficult

t o chang e thei r age , an dtha t

goe s i n on e directio n a s fa

r a s we ca n tell . I n terms,o f

aslop e o

f 2 m mfo r a1 0 ug/d L chang e i n bloo dlead , Schwart z fel t tha t tha t wa s roughl y i n th e ballpar

k o f th e result s tha t

h e foundi

n hi s stud y an dtha t

Pococ k foun di n hi s study . T o pu t tha t int o perspective , Schwart z note dtha t ther e ha d bee n almos t

a1 0 ug/d L chang e i

n th e averag e bloo d lea dleve l o

f American adul t

male s sinc e th e mid-1970s . If , i n fact , 1 0 u g lowere dth e averag e systoli c bloo d pressur e i

n th e Unite dState s b y 2 m mHg , the n everythin g w e hav e see n fromprospectiv e cardiovas

cular diseas e studie s suggest s tha t whil e i t woul dno t produc e dramati c change s i n th e relativ e ris k

o f th e larges t caus e o f deat h i n th e Unite dStates , i

t migh t hav e som e importan t

publi c healt h consequences , whic h i s th e real issu e here . Tyrole r the n expande don Schwartz' s poin t by statin g tha t

ther e hadbee n amean differenc e o f only abou t 5 m mo f diastoli c H g betwee n th e treate dan dth e contro l grou p i

n th e Hypertensio n an dDetectio n Fol

low-u p Progra m(HDFP) . Tha t wa s attende dby almos t a20 % reductio n i

n all-caus e mortality amon g middle

age dadult s an ds o aseemingl y smal l mean difference , 2 m mHg , a t th e populatio n leve l woul db e associate d wit h a s muc h a s a

n 8 t o 10 % decreas e in all-caus e mortality . I t i s no t trivia l in term s o

f it s publi c healt h im

pact . Schwart z the n remarke dtha t arelativ e ris k

o f 1.08 , whil e importan t

fo r publi c healt h consequences , i s rathe r har dt o findin studie s lookin g at specifi c mor

tality ratios . Vande r note dtha t

ther e appeare dt o b e som e unanimity . H e agree dwit h Le e tha t

ther e ma

y ver y well b e adifferenc e i

n th e dos e respons e fo

r rena l diseas e an dfor hypertensio n in experimenta l animals . Mos t o f th e publishe dwor

k o n experimenta l animal s show s certai n dose s o

f lea dwill produc e hig h bloo dpressur e an da s on e goe s higher , th e hig h bloo dpressur e vanishes . Give n th e difficult y o f doin g epidemiolog y studies , Vande r

felt tha t what h e ha d hear ds o fa

r wa s in pretty goo dagreement . In fact , Vande r felt tha t ther e wa s aremarkabl e agreemen t i n term s o

f th e expecte d ris e in bloo dpressur e tha t woul doccu r

fo r agiven ris e in bloo dlead . I

f on e use s thos e doublin g doses , th e valu e tha t on e come s u p wit

h fromlowerin g bloo dlea d from1 6 dow n t o 4 , an d4 i s stil l quit e ahig h numbe r for preindustrialize dsocieties , i s in th e ballpark o f 5 m mHg . Tha t

i s avery larg e reductio n in bloo dpres sur e for th e genera l population . In term s o f wha t wa s hear do n Monday , Vande r note dtha t

approximatel y 40 % o f peopl e woul dg o frombein g labele d hypertensiv e t o bein g labele dnormotensive . H e felt tha t thes e ver y smal l change s i n bloo dpressur e ar e extraordinaril y important . J . Rose n (Alber

t Einstei n Medica l School . NY ) the n clarifie dsom e statement s concernin g th e K X-ra y fluorescenc e instrumentatio n tha t Wedee n spok

e about . H e note dtha t

hi s instrumentatio n at Brook

haven , a t Einstein , an da

t Montefior e Medical Cente r wa s completel y differen t fro mth e instrumentatio n use db y Wedee n i

n Eas t Orange , NJ . Rosen' s instru

mentation , whic h i s base dupo n sof t L X-ray s o

f lead , ha s aminimu mdetectio n limi t o f 2 ppm . I

t als o ha s th e capabilit

y o f exposin g childre n a s wel l a s pregnan t wome n to virtuall y n o radiatio n othe r tha n wha

t on e woul danticipat e o n atri p t o Denver , CO . Rose n believe s hi s instrumentatio n i s widel y applicabl e t o th e genera l U.S . populatio n an dnote dtha t h e woul db e presentin g hi s dat ao n 6 6 childre n usin g L X-ra y fluorescenc e at

a n ope n meetin g followin g th e conference . Th e pane l o

f invite ddiscussant s the n gav e thei r view s o n th e session . Kanne l mad e som e genera l comment s on th e occupationa l epidemiolog y studies

H e fel t th e studie s seeme dt o rel y heavil y o n deat h certificat e evidenc e o

f outcom e an dtha t

thes e ca n b e imprecise , particularl y i

n respec t t o th e hypertensio n en dpoin t dependin g upo n whethe r on e use s multip

1 *

- caus e certification , underlyin g caus e o f death , or stat e cause s o f death . Kanne l als o fel

t tha t th e studie s relie

d upo n externa l controls , o r comparisons ; tha t

is , standardize dmortality ratio s whic h h e fel t rathe r uneas . about . H e als o note dtha t th e health y worke r

effec t ca n ofte n appea r

i n epidemiologi c studie s becau

investigator s often us e th e genera l populatio n ex pDISCUSSION SUMMARY 14 7 P.1 0

rience a s a

n externa l control . Ther e i s als o alac k o f djustmen t o r informatio n o n majo r confoundin g variable s suc h a s relativ e weight , alcoho l intake , cigarett e smoking , an dfactor s relate deithe r t o lea do r t o hyP ertens ' o n

- Kanne l felt ther e wa s a

n imprecis e measurement

o f th e actua l exposur e to lea di n thes e studies . Ther e ar e arbitrar y decision s a s t o wher e cu t noints ar e mad e whe n th e exac t dose-respons e rela

tionshi p i s poorl y defined . Ther e als o seem s to b e low powe r t o detec t som e o f th e exces s mortalit

y fo r som e o f th e uncommo n cause s whic h ar e bein g sough t afte r makin g i t ver y difficult t o dra w conclusion s abou t th e relationships . Whe n on e finds a n exces s o

f perhap s 3 0 t o 40 % whic h i s significant , th e significanc e tes t merel y tell s yo u tha t

yo u canno t

plac e muc h confi

denc e i n you r estimate . I t

i s alway s troublesom e to find amajo r exces s tha t

woul db e significan t

fromapubli c healt h standpoint , bu t

no t b e abl e t o sa

y whethe r

you r estimat e i s precis e enoug h t o judg e whethe r i t i s true . Smit h felt tha t on e shoul db e carefu l abou t sayin g tha t th e paper s presente dwer e movin g i n th e sam e direction . H e note dC . Henneken' s (Harvar dMedica l School ) pape r o n th e combinatio n o

f clinical trial s tha t pointedou t

very clearl y th e difficult y o f combinin g informatio n fro macros s awid e variet y o f experi

ments . Henneke n thre w ou t half o f th e trial s an dende d u p wit h aver y smal l se t

becaus e th e investigator s di d no t adher e t o stric t

protoco l an dstric t

collectio n o

f information . On e must , therefore , b e very carefu l wit h acombinationa l typ e o

f inferenc e whe n comparin g group s o f studies . Dusta n the n gav e he r

comments . Sh e state dtha t th e evidenc e presente ds o fa r suggeste dtha t

ther e i s a relationshi p betwee n bloo dlea do r lea dexposur e an d bloo dpressure . Sh e note dtha t ther e wa s n o informa

tio n abou t th e mechanis mo

f thi s relationship ; th e relationshi p seeme dt o b e o f relativel y lo w power , bu t coul db e significant . Dusta n aske dwhethe r ther e i s an experimenta l mode l for

th e effec t

o f chroni c lea d intoxicatio n o n bloo dpressure , an di f suc h amode l exists , whethe r

tha t mode l i s differen t

tha n acut e intoxication . I

f i t i s no t differen t

i n term s o

f it s determinant , the n Dusta n suggeste dusin g acut e intoxicatio n fo r

afurthe r

study . Dusta n remarke d tha t thi s i s on e o

f th e majo r

issue s tha t

need s t o b e addresse dbecaus e i

t i s th e influenc e o

f lea don th e bloo d pressure o f th e populatio n tha t

seem s t o b e s o subtl e an d tha t i s ver y difficul t

t o determine . Dusta n note d another confoundin g factor . A s w e reduc e th e lea di n th e environmen t

throug h th e reductio n o f lea di n gasoline , ar e w e the n goin g t o se e a n importan t decreas e i n th e mean bloo dpressur e o f th e population . Dusta n felt tha t i f i t doe s happen , i t

woul db e nic e t o kno w wha t th e decreas e i s du e t o an dquestione d whethe r w e woul deve r

kno w what

i t i s du e to. Dusta n suggeste dtha t

in th e discussion s tha t

followe dlate r

i n the mornin g an dafternoo n perhap s on e woul dge t som e ide aa s t o whethe r

ther e ar e experimenta l model s o f chroni c lea dintoxicatio n tha t sugges t lea dhavin g a rol e i n producin g hypertension . Investigator s wh o hav e performe dresearc h i n ex perimenta l setting s o n th e effect s o f lea do n th e cardio

vascula r syste mspok e a t

th e subsequen t

session . W . Victery (U.S . EPA) presente dashor t overvie w o

f chroni c exposur e protocols , usin g bot h hig h an dlo w exposur e levels , whic h wer e evaluate dfo r bloo dpres sur e effects . Vande r

reviewe dfindings o

f alea deffect

o n th e reni n angiotensi n system , an dR . Web b (Uni

versity o f Michigan ) discusse dth e effect s o f lea dexpo sur e o n vascular

reactivity . Thes e talk s wer e followe d b y S . Kopp' s (Chicag o Colleg e o f Osteopathi c Medicine ) finding s o n cardiotoxi c effect s o f lead ; th e final pres entatio n b y Boscol o wa s o n neurohumora l effect s o f lea dexposure . Followin g th e presentatio n o f Kop p o n cardiotoxi c effect s o f lead , ther e wa s aquestio n fromd e Kor t o n th e effec t o f anesthetic s o n th e bloo dpressur e an dcardia c effect s observe din th e experimenta l animals . Kop p indicate dtha t

the y n o longe r

us e pentobarbita l becaus e i t tend s t o blun t

th e measure deffect s o f lea do r cadmiu mo n th e cardiovascula r syste mbu t

hav e foun dtha t

amixtur e o

f Ketamin e an dXylozin e ar e effective . I n addition , pentobarbita l depresse s th e car diovascular

syste mresponse s o

f lead-expose danimal s mor e tha n thos e o

f contro l animal s s o tha t th e dif

ference s see n betwee n th e group s i s an underestimat e rathe r tha n a n overestimate . Ther e wa s aquestio n directe dt o th e speaker s regard

in g an y evidenc e tha t

th e hig h reni n level s observe d i n th e lead-expose danimal s wer e relate dto sodiu mo r flui dimbalance . Vande r

responde dby indicatin g tha t in othe r publishe dreport s fro mth e Michiga n group , animal s wit

h simila r lea dexposur e ha dasubtl e defec t in sodiu mreabsorptio n b y th e kidney . Th e animal s initiall y responde dt o asodium-restricte ddie t b y excretin g mor e sodiu mtha n contro l animals . Ther e wer e n o difference s i

n steady-stat e sodiu mbalance . Whethe r thi s findin g wa s correlate dt o th e reni n leve l wa s no t determined , e.g. , by usin g blockin g drug s fo r th e reni n angiotensi n syste mto determin e th e causa l rol e o f renin . Lili s aske dfor

clarificatio n regardin g Boscolo' s remark s abou t

apossibl e geneti c componen t t o susceptibility t o bloo dpressur e change s relate dt o lea d exposure . Th e tw o agree dtha t thi s hypothesi s woul d requir e furthe r

study . Wedee n indicate dtha t human s with essentia l hypertensio n may hav e exces s bod y burden s o

f lea dtha t

ar e no t remedie db y chelatio n therapy . O n th e othe r

hand , patient s wit

h elevate d bloo dpressur e durin g a n acut e lea dpoisonin g respon dt o chelatio n therap y b y reductio n i n bloo d pressure . Vande r

pointe dou t

tha t ther e i s n o experi

menta l evidenc e tha t

remova l o

f lea dfromth e animal s wil l lowe r bloo dpressure . Ther e wer e additiona l com ment s b y th e speaker s wh o indicate dtha t w e shoul d recogniz e tha t

th e dat aar e quit e differen t whe n animal s ar e expose dt o chroni c low level s o f lea dcompare dto acut e effect s o

f highe r leve l leadexposure . Thi s appear s t o b e th e cas e in anima l experiment s bu t i s probabl y als o th e cas e in th e tw o type s o f huma n expo -

# • ¥

14 8 VICTERYETAL.

sure . Kopp explaine dtha t th e cardia c effect s see n wit h acut e versu s chroni c exposur e ar e clearl y differen t (wit h acut e o r

high-leve l chroni c exposur e bein g car diodepressiv e whil e lo w leve l exposur e produce s enhance dcontractility) . Th e tw o invite ddiscussants , Goye r an dJohns , wrappe du p th e session . Goyer, apathologis t wel l know n for

hi s studie s o

f ultrastructura l an dchemica l change s i

n meta l nephrotoxicity , indicate dtha t from hi s viewpoint , bloo dlea dlevel s resultin g fromlowe r dose s o f lea dwil l no t b e reflecte din rena l lea dcon centratio n i

n rat s o f mor e tha n 2 t o 3 ug/g . Patho

logica l change s in th e kidne y ar e usuall y no t observabl e unti l th e rena l concentratio n exceed s 1 0 t o 1 5 ug/g . A

t th e hig h level s o

f exposure , ther e ar e measurabl e change s i

n intracellula r

calciu mtha t

ar e s o sever e tha t

th e cell s ar e unabl e t o performthei r functions . A

t thi s point , h e woul dno t

expec t to se e any physiologica l respons e t o presso r amines , change s i

n reni n levels , o r

othe r regulatory systems . Thes e level s o f lea dexposur e ar e quit e differen t fromth e exposur e level s see n i

n th e genera l population . Fo r experimenta l studies , documentatio n o f th e rang e o

f bloo dlea d associate dwit

h th e rang e o

f observe dbloo dpressure s i s needed . Finally , Goyer

urge dtha t

researcher s conside r th e essentia l meta l conten t o f th e dietar y regime n administere dwit

h th e leaddos e becaus e th e toxicit y o f aspecifi c lea ddos e can var y 20-foldb y reducin g calciu mconten t

i n th e diet . Simila

r effect s can b e obtaine db y alterin g iro n o r zin c levels . Severa l othe r scientist s indicate dtha t th e relativ e inconsistenc y betwee n administere ddos e an dbloo dlea dleve l achieve dshoul db e considere dwhe n considerin g th e effect o r lac k thereo f o n bloo dpressure . I

n addition , becaus e th e ra t

kidne y accumulate s muc h mor e lea d fo r aparticular

bloo dleve l tha n d o huma n kidneys , w e nee dt o determin e lea dconcentratio n o f othe r critica l targe t organ s (includin g vascular smoot h an dcardia c muscle , an djuxtaglomerula r cells ) i n orde r t o deter

min e whic h respond s i

n paralle l wit

h bloo dlead . John s propose danumbe r o f critica l experiment s t o understan dho w leadma y b e affectin g bloo dpressur e an dwhethe r

bloo dpressur e change s ca n b e reverse db

y removin g lea dfromth e diet . Inhibitor s o f angio

tensi n convertin g enzym e shoul db e trie dt o deter

min e i f thi s prevent s th e pressur e increas e durin g lea d exposure . Level s o

f intracellula r

calciu mshoul db e measure dan dcalciu mo r potassiu mchanne l blocker s might reduc e th e effect s o

f lead . Th e discussio n o

f th e las t fe w minute s o

f thi s sessio n delve dint o why som e experimenta l difference s i n bloo dpressur e were s o muc h greate r than see n by othe r investigator s (fo

r example , th e 5 0 m

mHg increas e see n b y th e Italia

n scientists) . Ar

e w e actuall y dealin g wit

h a mode l that

i s analogou s to th e huma n situation , o r d o w e nee dt o determin e a n animal mode l tha t

demon

strate s only afe

w millimeter s o

f mercur y increas e i

n bloo dpressur e whic h i s attributabl e to lea dexposure ? Ther e wer e tw o session s devote dt o mostl y unpub

lishe dstudies . Some o

f thes e ar e t

o b e foun delsewher e i

n thi s volume ; th e mai n finding s comin g fro mth e othe r studie s wil l b e summarize dher e for sak e o f completeness . H . Perr y (Washingto n Universit y Schoo l o f Medi

cine , St . Louis ) presente dne w finding s o n low-leve l lea dexposur e i

n experimenta l animals . H e note dtha t i n apilo t experimen t

the y foun dtha t

i f lea dexposur e wa s terminate dfor

2 month s after

a6-mont h exposure , th e 0. 1 pp mlead-expose drat s becam e normotensiv e whil e th e 5 pp mdi dnot , an d1 pp mwer e betwee n th e two . In respons e t o aquestio n fromGoyer , Perr y gav e th e specifi c trac e minera l component s o f th e ra t cho w used . Several audienc e member s trie dt o evaluat e thes e lea ddose s wit

h respec t t o tha t see n in th e human population . A calculatio n mad e b y Wedee n illustrate d th e tota l amoun t

th e ra t ingest s i s o

f th e sam e orde r

a s th e huma n bod y burde n ove r alifetime . Vande r pointe dou t

tha t th e tru e lea dburde n in th e ra t i s muc h lowe r

becaus e o

f th e lowe r

gastrointestina l absorptio n rat e o

f lea di n rat s compare dt o humans , d e Kor t pointe dou t

tha t whe n anesthetic s ar e use dt o obtai n bloo dpressure s in animals , ther e ma y b e a n effect o f lea do n th e effec t

o f th e anestheti c o n bloo d pressure . Perr y agree dan dindicate dtha t animal s ar

e currentl y studie dwithou t anestheti c (whic h result s i n highe r contro l bloo dpressur e measurements) , bu t th e level s see n i

n th e metal-expose danimal s ar e unchanged . I

n addition , ther e i s mor e consistenc y i n th e reading s an dlowe r

standar ddeviations . I n th e discussio n followin g Gonick' s talk , i t wa s note dtha t

accurat e an dsensitiv e method s for measurin g plasm alea da s theV importan t biologica l indicato r o f lea dexposur e ar e no t

availabl e a s yet . C . Morri s (Orego n Healt h Science s Center ) in

forme dth e audienc e abou t th e findings i

n aclinica

l tria l wit h calciu msupplementatio n i n patient s wh

o ha dthei r bloo dlea dan derythrocyt e protoporphyri n (EPP ) measure dan dbloo dpressur e monitored . The y foundthat , i

n spit e o f modes t bloo dleadlevels , ther

e wa s apositiv e correlatio n betwee n bloo dlead , EPP , an d diastoli c bloo dpressure . I n addition , the y believ e tha t th e bloo dpressur e respons e tha t occur s wit

h calciu m supplementatio n i s probabl y independen t o f change s i n bloo dlea dconcentration . F . Hodgso n (Universit

y o f Pittsburgh ) presente dth e pape r originall y expecte dt o b e give n by Parkinson . Cross-sectiona l dat afromapproximatel y 25 0 occupationall y expose dU.S . worker s an d17 0 control s wer e reanalyze dt o examin e th e contributio n o f current , recent , an dcumulativ e indicator s o f lea dexposure t

o systoli c an ddiastoli c pressure . Onl y TW A 0 1Ilie ' weighte daverage ) lea dexposur e (whic h wa s colline a wit h age ) wa s statisticall y significantl y correlate ^ wit h both systoli c an ddiastoli c bloo dpressure . Non e th e indice s o

f leadexposur e accounte dfo r mor e t n 2 % o f th e variance . Thi s regressio n coefficien t i s f a l • simila r to tha t derive di n th e NHANE S data . J Schwart z querie dElwoo dregardin g th e b I pressur e dat afromth e Caerphill y Study i n tha t ^ value s wer e highe r

tha n thos e obtaine di

n th e re sDISCUSSION SUMMARY 14 9 Wales . Elwoo dnote dtha t th e dat afromth e Wels h Hear t Progra mar e standardize dt o ag e 40 , whil e th e Caerphi^ y me n ha damea n ag e o f 54 . Thei r

bloo d oressur e value s ar e appropriat e fo r th e ag e differences . Grandjea n reporte do n astud y o f bloo dlead-bloo d pressur e relationship s wit

h alcoho l consumptio n an d hemoglobin value s a s confounders . Th e populatio n studie dwa s approximatel y iOO O me n an dwome n bor n i n 193 6 in 3. 5 municipalitie s wes t o f Copenhagen , Denmark, wh o wer e presume dt o b e representativ e o f t h e entir e countr y o

f Denmark . Bloo dlea dwa s significantl y associate dwit h bot h systoli c an d diastoli c pressure s with adoublin g o f bloo dlea d associatedwit

h a n increas e i

n bloo dpressur e o

f 2 t o 3 m mHg . Amon g severa l predictors , onl y bloo dhemo

globi n an dalcoho l intak e wer e tru e confounders . Whe n take n int o consideratio n i n th e regressio n analysis , al l statistica l significanc e wa s lost . Ther e wa s als o a n associatio n o

f bloo dlea dwith smoking ; smokin g i s als o a

n importan t

ris k facto r fo r increase d bloo dpressure . Kannel questione dth e findin g o f apositiv e rela

tionshi p betwee n bloo dpressur e an dcigarett e smok

ing , wherea s mos t

epidemiologi c studie s sho w a n in

vers e relationship , i.e. , thos e wh o smok e hav e some wha t lowe r bloo dpressure s whic h ma y b e attributabl e t o lowe r relativ e weight s amon g smokers . Grandjea n responde dt o Kannel' s questio n by indi

catin g tha t smokin g wa s treate da s adiscret e variable , categorize dint o five different group s an dtha t

smoker s wh o smok e betwee n 1 5 an d2 4 cigarette s pe r

da y actu all y hadalowe r

bloo dpressur e tha n di dnonsmokers . Dusta n questione dGrandjean' s interpretatio n o f th e hemoglobin , bloo dlead-bloo dpressur e associatio n an d questione dwhethe r

o r no t i t wa s no t possibl e tha t

th e causa l chai n wa s i

n th e opposite direction , i.e. , hyper

tensive s ten dt o hav e lowe r bloo dplasm avolume s an d subsequentl y can hav e increase dhematocrits . In tha t circumstance , th e hemoglobi n an dhematocri t woul d b e th e explanatio n for

th e increase dbloo dlead . Grandjea n accepte dtha t

interpretation . Schwart z confirme dKannel' s observatio n an d note dtha t ther e wa s anegativ e associatio n betwee n smokin g an dbloo dpressur e i n th e NHANE S I

I an d tha t wa s presen t

controllin g fo

r bot h body mas s inde x an dbod y fat . Smit

h questione dth e natur e o f th e uni

variate associatio n betwee n smokin g an dbloo d pressure prio r

t o adjusting . Schwart z coul dno t recal l th e associatio n i

n th e NHANE S data . Kanne l note dtha t i t wa s negativ e in Framingham , i.e. , tha t th e negativ e univariate associatio n wa s change dt o apositiv e on e afte r additio n o

f th e contro l variables . Schwart z als o reporte dtha t

i n NHANE S th e hemoglobi n di dno t see mto b e responsibl e fo

r th e bloo dlead-bloo dpressur e association , a s stratifying b y hemoglobi n level s di d no t chang e th e regressio n coefficient o f bloo dpressur e o n blood

- lead . Grandjean indicate dtha t th e associatio n wit h smokin g wa s comple x in hi s stud y an dbloo d pressure wa s highe r

amon g thos e wh o smok e betwee n 1 an d1 4 g o f tobacco/day , wherea s i

t wa s lower

i n thos e wh o smoke 1 5 t

o 2 4 g . Kromhou t

inquire dabou t

th e associatio n betwee n chang e i n bloo dlea dan dchang e i n bloo dpressure . Grandjean di dno t

hav e thos e dat ai

n afor mavailabl e fo r presentation . Pococ k

requeste dinformatio n re gardin g regressio n coefficient s rathe r tha n signifi

canc e levels . Grandjea

n responde dtha t

th e coefficient s whic h approache dstatistica l significanc e wer e positiv e an dthos e tha t

wer e no t

statisticall y significan t

wer e both positiv e an dnegativ e bu t ver y clos e to zero . Pococ k questione dth e evidenc e regardin g alcoho l consumptio n havin g an acut e metaboli c effect . Grandjean responde dtha t thi s i s base do n a

n experi

menta l stud y performe din Yugoslavi awherei n afe w "shot s o f ethanol " resulte di

n a n increase dbloo dlea d leve l after afe w hours . Thus , eve n i

f participant s ha d ha da13-h

r fast , ther e coul db e aresidua l metaboli c effect o f alcohol . Pococ k

questione dth e statemen t tha t ther e i s n o lea di

n cigarette s an dpointe dou t tha t h e foun drelationship s tha t persiste deve n after

adjust

men t fo r alcoho l consumption . Grandjea n reporte d tha t studie s o

f live r enzyme s suggeste dunder

reportin g o

f alcoho l consumption , particularl y i n wome n in who mth e correlatio n o f smokin g wit

h bloo dleadpersist s afte

r adjustin g fo

r alcoho l intake , i.e. , tha t ther e probabl y wa s underreportin g o f alcoho l intake . Pococ k

continue dquestionin g regardin g th e chang e i n lea dconten t

o f cigarette s i

n recen t years . Grandjea n reporte dtha t ther e wa s definitel y avery hig h lea dconten t

3 0 o r 4 0 year s ago ; a

t th e time , lea d arsenat e wa s use dfo

r sprayin g tobacc o fields , apractic e no t followe dan y longer . Recen t analyse s hav e indi

cate dther e i s muc h les s leadi n tobacc o a

t present . Lili s commente do n th e exquisit e contro l for ag e i n Grandjean' s study , whic h migh t b e to o narro w t o b e abl e t o comprehensivel y asses s an y relationshi p betwee n bloo dleadan dhypertension . Sh e requeste dmor e detai l regardin g th e distributio n o f bloo d lea dlevel s an dsystoli c an ddiastoli c bloo dpressur e i n Grand

jean' s stud y t o permi t

compariso n wit

h othe r cohorts . Followin g th e presentatio n by L . Neri (Universit y o f Ottawa , Canada) , ther e wa s som e discussio n abou t th e fact tha t th e value s fo

r som e bloo dlea dmeasurement s wer e s o low tha t

no paramete r

valu e wa s obtained . Th e author s trie dsevera l differen t method s to correc t

fo r thes e i n th e overal l regressio n analysis . Beever s describe dstudie s performe di n th e cit y o f Birmingham , an industria l cit y wit h worker s occu pationall y expose dt o lead . I n 1976 , Beever s publishe da repor t o n thes e worker s i n whic h onl y awea k associatio n betwee n bloo dlea dan dbloo dpressur e wa s found . In ane w study , additiona l analyse s an dclin

ical measure s hav e bee n obtaine do n approximatel y 70 0 lea dworkers . N o exces s prevalenc e o f hypertensio n wa s foun di n th e lea dworkers . Worker s wit h mea n bloo dleadvalue s o

f 33. 6 ug/d L sho w awea

k (r = 0.09) , bu t statisticall y significan t (p < 0.01) , associatio n betwee n bloo dlea dan dbloo dpressure ; thi s tren dDISCUSSION SUMMARY 14 9

. s Elwoo dnote dtha t

th e dat afro mth e Wels h u r t Progra mar e standardize dt o ag e 40 , whil e th e -phill y me n ha damea n ag e o f 54 . Thei r

bloo d ssure . value s ar e appropriat e fo r th e ag e differences . '"Vrandjea n reporte do n astud y o f bloo dlead-bloo d eS sur e relationship s wit

h alcoho l consumptio n an d • jfmoglobi n value s a s confounders . Th e populatio n die d wa s approximatel y 100

0 me n an d wome n bor n ? 193 6 in 3. 5 municipalitie s wes t o f Copenhagen , Denmark , wh o wer e presume dt o b e representativ e o f m e entir e countr y o

f Denmark . Bloo dlea dwa s significantl y associate dwit h bot h systoli c an d diastoli c pressure s with adoublin g o f bloo dlea d associate dwit h a n increas e in bloo dpressur e o f 2 t o 3 m mHg . Amon g severa l predictors , only bloo dhemo

globi n an dalcoho l intak e wer e tru e confounders . Whe n take n int o consideratio n in th e regressio n analysis , all statistica l significanc e wa s lost . Ther e wa s a ] s o a n associatio n o

f bloo dlea dwith smoking ; smokin g i s als o a

n importan t

ris k facto r fo r increase d bloo dpressure . Kannel questione dth e findin g o f apositiv e rela

tionshi p betwee n bloo dpressur e an dcigarett e smok

ing , wherea s mos t

epidemiologi c studie s sho w a n in

vers e relationship , i.e. , thos e wh o smok e hav e some wha t lower bloo dpressure s whic h ma y b e attributabl e t o lowe r relativ e weight s amon g smokers . Grandjea n responde dt o Kannel' s questio n b y indi

catin g tha t smokin g wa s treate da s adiscret e variable , categorize dint o five different group s an dtha t

smoker s wh o smoke betwee n 1 5 an d2 4 cigarette s pe r

da y actu all y hadalowe r

bloo dpressur e tha n di dnonsmokers . Dusta n questione dGrandjean' s interpretatio n o f th e hemoglobin , bloo dlead-bloo dpressur e associatio n an d questione dwhethe r

o r no t i t wa s no t possibl e tha t

th e causa l chai n wa s i

n th e opposit e direction , i.e. , hyper

tensive s ten dto hav e lowe r bloo dplasm avolume s an d subsequentl y ca n hav e increase dhematocrits . In tha t circumstance , th e hemoglobi n an dhematocri t woul d b e th e explanatio n for

th e increase dbloo dlead . Grandjea n accepte dtha t

interpretation . Schwart z confirme dKannel' s observatio n an d note dtha t

ther e wa s anegativ e associatio n betwee n smokin g an dbloo dpressur e in th e NHANE S I I an d tha t wa s presen t

controllin g fo

r bot h bod y mas s inde x an d bod y fat . Smit

h questione dth e natur e o f th e uni

variat e associatio n betwee n smokin g an dbloo d pressur e prio r

t o adjusting . Schwart z coul dno t recal l the associatio n i

n th e NHANE S data . Kanne l note dtha t i t wa s negativ e i

n Framingham , i.e. , tha t th e negativ e univariate associatio n wa s change dt o apositiv e on e afte r additio n o

f th e contro l variables . Schwart z als o reporte dtha t

in NHANE S th e hemoglobi n di dno t seemt o b e responsibl e fo

r th e bloo dlead-bloo dpressur e association , a s stratifying b y hemoglobi n level s di d not chang e th e regressio n coefficient o f bloo dpressur e o n bloo dlead . Grandjean indicate dtha t th e associatio n wit h smokin g wa s comple x in hi s stud y an dbloo d pressur e wa s highe r

amon g thos e wh o smok e betwee n 1 an d1 4 g o f tobacco/day , wherea s i

t wa s lower

i n thos e wh o smok e 1 5 t o 2

4 g . Kromhou t

inquire dabou t

th e associatio n betwee n chang e i n bloo dlea dan dchang e i n bloo dpressure . Grandjean di dno t

hav e thos e dat ai

n afor mavailabl e for presentation . Pococ k

requeste dinformatio n re gardin g regressio n coefficient s rathe r tha n signifi

canc e levels . Grandjea

n responde dtha t

th e coefficient s whic h approache dstatistica l significanc e wer e positiv e an dthos e tha t

wer e no t

statisticall y significan t

wer e both positiv e an dnegativ e bu t ver y clos e t o zero . Pococ k questione dth e evidenc e regardin g alcoho l consumptio n havin g a n acut e metaboli c effect . Grandjean responde dtha t thi s i s base do n a

n experi

menta l stud y performe di n Yugoslavi awherei n afe w "shot s o f ethanol " resulte di

n a n increase dbloo dlea d leve l after afe w hours . Thus , eve n i

f participant s ha d ha da13-h

r fast , ther e coul db e aresidua l metaboli c effect o f alcohol . Pococ k

questione dth e statemen t tha t ther e i s n o lea di

n cigarette s an dpointe dou t tha t h e foun drelationship s tha t persiste deve n after

adjust

men t fo r alcoho l consumption . Grandjea n reporte d tha t studie s o

f live r enzyme s suggeste dunder

reportin g o

f alcoho l consumption , particularl y in wome n i n who mth e correlatio n o f smokin g wit

h bloo dleadpersist s afte

r adjustin g fo

r alcoho l intake , i.e. , tha t ther e probabl y wa s underreportin g o f alcoho l intake . Pococ k

continue dquestionin g regardin g th e chang e i n lea dconten t

o f cigarette s in recen t

years . Grandjea n reporte dtha t ther e wa s definitel y avery hig h lea dconten t

3 0 o r 4 0 year s ago ; at

th e time , lea d arsenat e wa s use dfo

r sprayin g tobacc o fields , apractic e no t followe dany longer . Recen t analyse s hav e indi

cate dther e i s muc h les s lea di n tobacc o a

t present . Lili s commente do n th e exquisit e contro l for ag e in Grandjean' s study , whic h migh t b e to o narro w t o b e abl e t o comprehensivel y asses s any relationshi p be

twee n bloo dleadan dhypertension . Sh e requeste dmor e detai l regardin g th e distributio n o f bloo dlea dlevel s an dsystoli c an ddiastoli c bloo dpressur e in Grand

jean' s stud y t o permi t

compariso n wit

h othe r cohorts . Followin g th e presentatio n b y L . Neri (Universit y o f Ottawa , Canada) , ther e wa s som e discussio n abou t th e fact tha t th e value s fo

r som e bloo dlea dmeasurement s wer e s o low tha t

n o paramete r

valu e wa s obtained . Th e author s trie dsevera l differen t method s t o correc t

fo r thes e i n th e overal l regressio n analysis . Beever s describe dstudie s performe di n th e cit y o f Birmingham , a

n industria l cit

y wit h worker s occu pationall y expose dto lead . I n 1976 , Beever s publishe da repor t o n thes e worker s in whic h onl y aweak associatio n betwee n bloo dlea dan dbloo dpressur e wa s found . I n ane w study , additiona l analyse s an dclin

ica l measure s hav e bee n obtaine do n approximatel y 70 0 lea dworkers . No exces s prevalenc e o f hypertensio n wa s foun di n th e lea dworkers . Worker s wit h mea n bloo dlea dvalue s o

f 33. 6 ug/d L sho w awea

k ( r = 0.09) , bu t statisticall y significan t [p < 0.01) , associatio n betwee n bloo dlea dan dbloo dpressure ; thi s tren d15 0 VICTERYETAL.

remaine dsignifican t

afte r analysi s o

f covarianc e whic h too k

int o accoun t

age , bod y mas s index , an d duratio n o

f lea dexposure . N

o convincin g relationshi p wa s foun dbetwee n bloo dleadan dalcoho l intake , bu t cigarett e smoker s di dhav e highe r bloo dlea dlevel s tha n nonsmokers . Ther e wa s n o correlatio n betwee n systoli c o r

diastoli c bloo dpressur e an dzin c proto porphyri n levels . I

n th e commen t

perio dafte r

thi s presentation , Boscol o indicate dtha t i t wa s ver y im

portan t t o recogniz e tha t

thes e worker s wer e carefully monitore dby thei r

employe r

an dtha t

thi s wa s no t alway s th e cas e i

n factor y settings . Hodgso n reminde d Beever s tha t

i n hi s origina l publicatio n i t appeare d ther e migh t

b e adifferent

(even negative ) correlatio n betwee n bloo dlea dat

hig h level s an dbloo dpressure . Regressio n coefficient s determine db y dividin g th e bloo dlea drang e int o four segment s appeare dt o b e different . Beever s ha dno t don e thi s i

n th e presen t stud y bu t though t i t woul db e helpfu l i

n additiona l analysis . Rosen aske di

f ther e appeare dt o b e arelation

shi p betwee n bloo dpressur e an dlengt h o f exposur e bu t Beever s sai dthat

the y hadno t

foun dthi s to b e th e case . Th e followin g discussio n too k plac e after

D . Sharp' s (Universit y o

f Californi aa

t Berkeley ) presentation . Sharp questione dth e inclusio n o f cigarett e smokin g i n regressio n analyse s i

f i t i s no t relate dto bloo dpres sure . Smokin g can ac t

a s avehicl e fo

r lea dexposure . Similarly , eve n thoug h ther e i s som e evidenc e tha t alcoho l intak e i s relate dt o increase dbloo dpressure , ther e i s eve n bette r

evidenc e tha t

alcoho l ca

n ac t a s a vehicl e fo r leadexposure . Thi s ma

y bia s th e bloo dlead

bloo dpressur e relationshi p towar dzer o by overcon trollin g fo

r leadexposure . Pococ k

responde dtha t

thi s ha s bee n a

n are ao f controvers y an dha di t bee n excluded , h e migh t

hav e bee n accuse do

f missin g a

n importan t factor . Weis s indicate dthat , fo r avariabl e to b e aconfounder , i

t ha s to b e associate dboth wit h th e exposur e an dcausall y wit h th e outcom e variable . Pococ k felt tha t th e definitio n o

f aconfounde r

an d criteri ao f a n appropriat e covariat e fo r inclusio n i

n th e mode l wer e tw o different things . H e note dtha t

amon g mos t o f th e studie s presente dther e wa s awea k associa

tio n betwee n bot h smokin g an dalcoho l an dbloo d pressure . Sinc e th e bloo dlead-bloo dpressur e associa

tio n i s wea

k an dbecaus e th e associatio n o f th e covari

ate s an dth e outcom e variable s var y amon g differen t dat aset s an dar e themselve s weak , thi s migh t b e on e o f th e reason s wh

y different

result s wer e bein g see n i n different studies . Kanne l note dtha t

causa l inferenc e i s th e issue . H e cite dth e analog y o

f overweigh t

i n relatio n to coronar y disease , whic h disappeare da s aris k facto r whe n on e too k int o accoun t

variable s suc h a s bloo dpressure , glucose , cholesterol , an duri c acid . This , however , merel y indicate dlink s i

n th e causa l chain ; a s weigh t increased , th e intervenin g variable s lef t n o variatio n to b e explaine dby weight . H e pointe dout th e necessity t o kee p th e processe s i n min dwhe n drawin g causa l inferences . Smit h pointe dou t tha t th e difficulty in inter

pretatio n relate s t o th e researc h design . I n th e idea

l model , on e coul ddetermin e th e causa l effect s inde

penden t o f eac h other . Th e difficultie s wit h th e experi

menta l researc h relat e t o tw o factors ; one , absenc e o f hypothese s regardin g th e causa l model s and , second , i n demographi c surve y researc h ther e i s n o uniqu e model . Carte r reporte dexperiment s i n rat s tha t

indicate d tha t rat s wit h ver y hig h bloo dlea dlevel s wer e th e one s tha t ingeste dmor e alcoho l an dcautione dagains t th e interpretatio n o

f cross-sectiona l association s o f bloo d lea dan dalcoho l consumptio n i n term s o

f th e causa

l direction . Schwart z decline dt o commen t o n whethe r

people wit h highe r bloo dlea dvalue s drin k mor e o r not . H e commente dtha t

studie s i

n human s sho w variabilit y i n th e associatio n o

f alcoho l consumptio n wit h bloo d pressure . Similarly , ther e wa s variatio n amon g th e studie s betwee n th e relationshi p o f bloo dleadandbloo

d pressure . I

f alcoho l i s asourc e o

f lead , the n th e obser

vationa l studie s wil l b e unabl e t o distinguis h th e independen t

causa l contributio n o

f lea dan dalcoho l t

o bloo dpressure . Pococ k

sai dtha t h e di dno t

se e thi s as a majo r proble mbecaus e alcoho l remain s arelativel y mino r sourc e o

f lead . H e note dtha t

ther e ar e num

erou s individual s wh o ar e eithe r nondrinker s o

r fairl y ligh t

drinker s wh o stil l hav e measurabl e lea d level s an dtha t

i t wa s possibl e t o trea t

thes e two a

s separabl e statisticall y an detiologically . Grandjea n indicate dtha t in hi s populatio n a reporte dintak e o

f tw o "shots " o

f alcoho l pe r

da y wa s associate dwit

h a n increas e o

f bloo d leacLb y abou

t 1 ug/dL , whic h wa s no t

insignificant . I

n th e presenc e o

f awea k association , adjustmen t for alcoho l ma

y eliminat e abloo dlead-bloo dpressur e association . H e suggested , i

n prospectiv e studies , tha t th e cohort s b

e restricte dt o individual s wh o inges t jus t acertai n amoun t o f alcoho l pe r

da y an dcan the n b e followe d ove r time , i.e. , for

example , bein g measure dwhe n hire dan dthe n late r

a s expose dlea dworkers . War e pointe dou t

tha t th e anima l experimenta l wor k indicate dn o influenc e o

f alcoho l on absorptio n o

f lea d an dthat , i

n hi s opinion , th e questio n wa s ho w muc h lea dther e i s i

n th e alcoholi c beverage . H e suggested tha t thi s varie s amon g studie s performe di n differe n countrie s an dtha t

h e di dno t

believ e tha t

thi s wa s a significan t

questio n i

n thi s country . M . Velasque z (Georg e Washingto n University ; Washington , DC ) questione dwhethe r anyon e h

a studie dth e bloo dlea dlevel s amon g apopulatio n ° ^ essentia l hypertensive s an dwhethe r thes e we

r differen t fro mth e norma l population . Further , questione dKanne l abou t th e associatio n o

f bod y m a- inde x t o bloo dpressur e i n th e hypertensiv e ran ° j Kanne l responde dtha t

th e regressio n betwee n bi o pressur e an dweigh t

appeare dfairly linear , tha t regressio n betwee n weigh t gai n an dchang e i

n bi p pressur e als o appear s t o b e quit e linea r an dextend s 

# J

# r

DISCUSSION SUMMARY 15 1 P.1 5

•h e hypertensiv e range . Kanne l disagree dwit h Velasquez' s interpretatio n o f aflattenin g o

f th e bloo d oressure , bod y mas s inde x relationshi p fo r bloo d nressure s abov e 15 0 systoli c o r 9 0 diastoli c m

mHg . Smit h cite dth e us e o

f standardize dregressio n coefficients i

n th e socia l scienc e literatur e an dques tione dwhethe r o r no t conversio n o

f th e NHANE S dat a t o tha t for mmigh t b e awa y o f comparin g associatio n acros s studie s an dals o withi n studie s whe n control

lin g f° r °t n e r variables . Ther e wa s no respons e to thi s suggestion . Gonic k

advance da

n additiona l possibl e mechanis mregardin g alcohol . Th e diuresi s associate d wit h alcoho l consumptio n coul dlea dt o hemocon

centration , increas e th e hemoglobi n an dtherefor e secondarily increas e th e measure dtota l bloo dlead . H e suggeste dtha t

analyse s shoul dcontro l fo r hemoglobi n levels . Tyrole r introduce dth e fina l sessio n o f th e symposiuman dstate dtha t i t wa s planne dt o provid e a synthesi s an dovervie w o

f th e materia l presente da t th e symposium . Th e objective s o f th e symposiu mwer e t o have th e principa l investigator s revie w thei r pub

lishe dresearc h an dt o hav e ope n discussion s amon g theman dth e audience , an dto presen t al l identifie d ongoin g relevan t

researc h tha t

ha dno t

ye t bee n published . A

n assemble dpane l o

f discussant s wer e t o synthesiz e th e observationa l epidemiologic , clinical , an danima l experimenta l materials . Question s tha t wer e to b e considere dinclude dth e following : What d o w e thin k th e assemble dinformatio n means ? I s ther e a n associatio n betwee n bloo dpressur e an dbloo dlea d level s i n epidemiologi c studies ? I f ther e is , what

i s it s strengt h an ddoe s i t

vary amon g subpopulations ? Combine dwit

h th e clinica l an dexperimenta l obser

vations , d o w e believ e tha t ther e i s a

n associatio n whic h persist s afte r

controllin g for

potentia l con founders ? D o w e believ e tha t i t i s causal ? Insofa

r a s thos e question s can no t

b e answere ddefinitively , ad

ditiona l researc h need s ar e t o b e identified . Th e summar y tha t

follow s highlight s th e discus

sion s i n th e orde r

o f thei r presentation . Considerabl e editin g ha s bee n introduced ; however , ever y effor t wa s made t o preserv e th e sens e o f th e comment s mad e an d t o conve y th e informatio n presente dwithou t eithe r a n exhaustiv e o r

alitera l recordin g o

f all comments . Althoug h no t

liste da s adiscussan t

in th e program , Pococ k wa s calle do n t o presen t aquantitativ e overvie w h e ha dprepare do

f th e effect measure s derive dfromth e differen t epidemiologi c studie s presented . Th e ke y element s o

f Pocock' s overvie w analysi s an dhi s inter

pretatio n o

f the mwer e incorporate dint o hi s manu script , whic h ha s bee n include din thes e proceedings . I n hi s summarizatio n remark s presente ddurin g th e overvie w discussion , Pococ k suggeste dtha t

th e poin t estimat e o

f th e regressio n coefficient o f bloo dpressur e associate dwit

h bloo dlea dan dth e confidenc e interva l around

- tha t

estimat e for

eac h stud y indicate doverla p amon g th e variou s genera l populatio n epidemiologi c studies , wit

h evidenc e o

f compatibility o

f estimates . It wa s hi s opinio n tha t

azer o increas e in systoli c bloo d pressur e with adoublin g o f bloo dlea dwa s no t compatibl e wit

h th e overal l data , no r

wa s a n increas e o

f 3 m mH g i n systoli c bloo dpressur e compatible . Hi s impressio n wa s tha t

adoublin g o

f bloo dlea dseeme d associate dwit

h a n increas e o

f abou t 1 m mH g i n systoli c bloo dpressure . Further , h e fel t tha t th e under

standin g o

f an dth e contro l o

f confoundin g factor s wer e quit e differen t

amon g studie s an dincomplet e i n some . H e cite dth e exampl e o f alcoho l an dsuggeste d tha t othe r confoundin g factor s remaine dt o b e discovere dand , obviously , adjustment s for uniden- . tifie dfactor s can no t

hav e take n plac e i

n th e obser

vationa l studie s reporte dt o date . Althoug h th e overvie w wa s consisten t wit h a n associatio n betwee n bloo dlea dan dbloo dpressure , i t wa s hi s impressio n tha t i t wa s smal l i

n magnitude , wea

k i n strength , an d tha t th e overal l evidenc e di dno t permi t a n inferenc e regardin g acausa l relationshi p betwee n bloo dleadan d bloo dpressur e values . Followin g Pocock' s remarks , th e sessio n hear dfro

mth e planne dpane l discussants . Smit h state dtha t

h e woul dpla

y th e rol e o

f devil' s advocat e and , despit e hi s bein g impresse dby th e amoun t an dqualit y o

f wor k reported , tha t

hi s comment s generall y woul db e o f acritica l nature . In particular , h e pointe dou t tha t th e quantitativ e over view , whic h suggeste dagenera l tren do f positiv e coefficient s o

f th e relationshi p o

f bloo dpressur e t

o bloo d lea dlevels , wa s fraugh t

wit h difficulties . Th e model s use damon g th e studie s wer e for th e mos t

par t different . Th e numbe r

an dtyp e o

f covariant s include d wer e no t th e sam e amon g th e model s use dan dth e mathematica l treatmen t o f th e variable s include d acros s model s often varied ; fo r example , th e squar e o

f ag e wa s use di

n som e studie s an dno t

i n others . H e suggeste dtha t

althoug h th e us e o

f thes e covariant s migh t no t mak e muc h differenc e i n term s o

f th e estimator , i t

coul dmak e amajor

differenc e in term s o

f confidenc e intervals . Smith calle dattentio n t o th e poin t o f th e impli

cation s o f apolic y decisio n t o eliminat e lea dfromgas olin e focusin g o n ne w healt h outcome s base do n alternativ e products . H e emphasize dth e importanc e o f thi s i n th e cas e o

f th e relativel y smal l effect associate d wit h lea dwhic h th e overvie w analysi s ha dindicated . Smit h pointe dou t

som e fundamenta l difference s betwee n th e researc h design s use din experimenta l biologi c researc h an dth e multivariat e typ e measure ment s an danalyse s performe din th e epidemiologi c studies . H e focuse dparticularl y o n th e nee dfo r mor e detaile danalysi s o

f th e relationshi p o

f bloo dlea dt o bloo dpressur e acros s th e multipl e NHANE S stud y site s an dinquire dabou t

th e consistenc y o

f apositiv e associatio n whe n thi s wa s done . H e als o raise dth e poin t o f difference s in th e bloo dlead-bloo dpressur e relationshi p amon g demographi c subgroups , wit h th e possibilit y o f anegativ e associatio n fo r women . Goye r presente dan overvie w o f agenera l natur e regardin g what

h e regarde da s th e tw o majo r objective s o f experimenta l work : on e wa s t o confir mhuma n observation s an danothe r t o defin e mechanism s an d 

## i j !DISCUSSION SUMMARY 15 3 dat aavailable , sh e wa s impresse dwit h th e strikin g findin g tha t peopl e wh o hav e die do f lea dnephropath y o r hav e die d o

f rena l failure hav e no t

ha dsecondar y hypertension . Fo r

futur e research , sh e calle dfor detaile danalysi s o

f th e blac k

examinee s in th e NHANE S sample , notin g th e somewha t highe r bloo d l ea d level s an dwell-know n exces s o f hypertensio n i

n blacks . I n thes e analyses/studie s of seru mcreatinin e migh t provid e insigh t

int o whethe r

o r no t hyper

tensio n in th e blac k

i s kidney-relate di

n eithe r o f tw o ways : one , th e kidne y a s avicti mo f elevate dpressure , an dth e other , th e kidne y a s th e culprit . Kanne l presente dasynthesi s o f th e studie s an da communit y perspective . H e reviewe dth e rule s o f evidenc e in determinin g whethe r a n observe d associatio n reflect s acausa l relationship . H e note d consistenc y o

f result s with asimilarit y o f trend s amon g populatio n surveys , althoug h i n som e instance s th e result s wer e no t statisticall y significan t an dothe r time s whe n ris k

factor s othe r

tha n lea dwer e no t take n int o account . H e calle dfo r prospectiv e studie s o n th e predictiv e valu e o f lea dfor

subsequen t hypertensio n an dth e nee dt o stud y it s effect o n ag e trend s i n bloo dpressur e ove r

time . Th e strengt h o

f th e bloo dlead-bloo dpressur e relationshi p i s rathe r wea k anddoe s no t

fulfil l th e usua l criterio n fo r causality . Th e wea k associatio n doe s no t

lea dt o aclea

r dose

respons e relationshi p an dth e shap e o f th e dose

respons e curv e i s no t

know n wit

h certainty . Ther e seem s t o b e som e los s o

f effec t a t highe r o r toxi c dose s o

f lead . I f th e relationshi p doe s hol da t ambien t level s o f lead , thi s i s o

f grea t publi c healt h importanc e owin g to th e larg e attributabl e ris k an dth e modifiabl e natur e o f lea da s apotentia l ris k facto r for hypertension . Althoug h th e effect

seem s t o b e independent , mor e dat a ar e neede dconcernin g th e associate dcadmiu man d calciu mintak e an dexploratio n fo r possibl e interaction s shoul db e carrie dout . Th e final criterion , biologi c plausibility , i s partiall y met . Althoug h a numbe r o f possibl e mechanism s hav e bee n postulated , i t i s no t clea r fromth e evidenc e reviewe dwhic h ar e operative . I n summary , Kanne l suggeste dtha t th e availabl e informatio n suggeste dapossible , bu t b y n o mean s certain , causa l relationship ; however , th e publi c healt h implication s ar e larg e i n vie w o f th e curren t ubiquitou s exposure , th e effect s o f low-lea dexposur e o n bloo dpressure , an dth e possibilit y o f modification . Kanne l felt

tha t in term s o

f populatio n research , ther e wa s anee dfo

r ongoin g prospectiv e studie s to includ e bloo dlea di

n thei r nex t roun do f exam s an d the n stud y prospectivel y th e relationshi p to th e trend s in bloo dpressur e ove r

time . Ther e will als o b e th e opportunit y t o tak e advantag e o f area s wit

h declinin g lea dexposur e an dmeasur e bloo dpressur e before , during , an dafter

change . Tw o particula r deficiencie s in th e dat aavailabl e a s identifie db y Kanne l wer e thos e regardin g information.o n th e associatio n in women , wher e th e effect

seem s t o b e les s pronounce dtha n fo r men , an dth e nee dfor mor e informatio n o n th e contributio n o f bloo dlea ddifference s to th e well-known black/whit e difference s i

n bloo dpressure . I n openin g th e genera l discussion , ther e wer e comment s fromGoyer , Smith , an dVande r regardin g th e interpretatio n o

f epidemiologi c finding s compare d wit h thos e derive dfro mexperimenta l work . Smith emphasize dth e poin t

that th e independen t

effec t o f on e facto r wa s no t

wha t wa s relevan t

t o th e huma n circumstance , bu t

rathe r th e potentia l fo

r interactio n o

f lea dwit h othe r factors . Thi s wa s agree dto b y th e experimentalist s wh o ha ddemonstrate d positiv e interactiv e effect s wit h cadmiu man dnegativ e interactiv e effect s wit

h calcium . Schwart z elaborate d o n th e poin t

an dsuggeste dtha t

thi s migh t

explai n wh y i n Perry' s experiment s elevatio n i n bloo dpres sur e wa s see n at

lowe r dose s o f lea din contras t

t o Vander' s experiments ; on e possibilit y i s Perr y ma y hav e ha dles s calciu mi

n th e die t o f hi s rat s tha n wa s presen t i n th e experiment s performe dby Vander . Pococ k indicate dtha t

h e ha dbloo dcadmiu mmea sure s o n 700 0 o

f th e me n in hi s studie s an dtha t cadmiu mdi dno t

see mrelate dt o bloo dpressure ; how

ever , h e adde dh e ha dno t ye t teste dfo

r interactio n effects . Further , h e pointe dou t tha t cigarett e smokin g i s amajo r

sourc e o

f cadmiu man dtha t

i f cadmiu m wer e affectin g bloo dpressure , on e woul dexpec t a positiv e bloo dpressur e smokin g relationshi p whic h wa s no t observe di

n hi s study , d e Kor

t adde d tha t

h e to o observe dth e absenc e o f a n associatio n betwee n cadmiu man dbloo dpressur e i n asmal l stud y o

f lea d worker s i n th e Netherlands . Kanne l emphasize dth e desirabilit y o f performin g anima l experiment s whic h hav e relevanc e t o hyper

tensio n i n humans , an dthi s le dt o discussio n o f th e desirability o

f stud y o f exposure s earl y i

n life . Vande r advance dth e ide ao

f beginnin g animal experiment s o f thi s typ e base don lea dexposur e in utero. Wedee n returne dto th e questio n o f th e absenc e o

f hypertensio n in associatio n wit

h lea dexposur e in th e presenc e o f rena l disease . H e suspecte dtha t thi s follow s fro

mth e epidemiologi c ascertainmen t o f th e genera l populatio n with norma l pressur e an dblood-lea dlevels , an d exclusio n o

f disease dpersons . H e advance dth e hy

pothesi s tha t

th e massiv e overrepresentatio n o f blac k male s i n dialysi s unit s coul db e relate dto leadexposur e i n childhoo dcombine dwit h lowe r calciu mintake s an dth e associatio n wit

h alcohol . Web b returne dt o th e associatio n o f calciu mwit

h hypertensio n an dpointe dou t tha t th e evidenc e sug geste dtha t

th e proble mwa s no t

s o muc h on e o

f con centratio n bu t

regulatio n o

f th e wa y calciu mmove s (flux) o r activate s contractil e responses . H e suggeste d tha t studie s shoul db e directe dt o regulatio n in term s o f calciu minteraction s wit h lead . In respons e t o aquestio n tha t returne dto th e issu e o

f th e associatio n o

f bloo dlea dan dbloo dpressur e i n blacks , Schwart z indicate dtha t in som e o

f hi s analyses , bloo dlea dexplain s som e o f th e black

- exces s in hig h bloo dpressure , bu t

no t al l o f it . Schwart z returne d t oP.1 7

15 4 " V VICTERYETAL. th e questio n raise db y Smit h regardin g th e issu e o f what replace dlea dwhe n i

t wa s t o b e remove dfrom gasolin e an dh e cite dcos t benefi t analyse s prepare dfo

r regulator y hearings . Th e possibility o f som e increas e in emissio n o

f carcinogens , secondar y t o increase s in th e aromati c conten t

an dbranchin g paraffin s o f gasoline , wer e estimate dt o resul t in markedl y lowe r effect s o n health tha n thos e putativel y associate dwit h lead . J . Col e (ILZRO) aske dth e pane l t o discus s acommen t tha t Schwart z mad e tha t

a1 m mH g ris e i

n bloo d pressur e coul db e associate dwit h a1 % increas e i n ischemi c hear t

disease . Pococ k

state dtha t

a1 % hear t diseas e rat e chang e wa s roughl y tha t estimate dt o b e associate dwit

h a1 m mH g chang e i

n bloo dpressure ; •however , h e argue dtha t i t wa s necessar y t o recogniz e tw o link s i

n th e chai n o

f th e argument , th e lea dbloo d pressur e link

an dth e bloo dpressur e ischemi c hear t diseas e link . H e suggeste dtha t th e bloo dpressur e ischemi c hear t

diseas e link

relate s t o th e long-ter m patter n o f bloo dpressur e an dit s associatio n wit h th e ris k o f ischemi c hear t

diseas e in lat e middl e age , wherea s th e lea dbloo dpressur e associatio n ma y b e o f a muc h mor e short-ter mnatur e an dwhethe r o r no t i t reflect s achroni c associatio n i s unknown . Tyrole r an d Kanne l eac h advance dth e ide atha t th e huma n experimenta l data , i.e. , th e clinica l trial s evidence , clearl y showe dtha t

lowerin g bloo dpressur e decrease s direc t pressur e relate dphenomen asuc h a s renal , cerebral , an dcongestiv e hear t failure sequelae ; how

ever , clea r

evidenc e o

f efficac y o

f bloo dpressur e reductio n in preventio n o f atheroscleroti c complica

tions , suc h a s ischemi c hear t disease , wa s no t

available . Mahaffe y raise dth e questio n o

f th e bod y burde n o

f leadan daske dwhat

recommendation s woul db e mad e t o thi s end . Wedee n suggeste dtha t th e measuremen t

o f bon e store s o

f leadby in vivo X-ra

y fluorescenc e wa s a

n approach . Grandjea n state dtha t hi s grou p ha s develope dametho do

f analyzin g lea di

n teet h usin g th e lea dleve l in circumpulpa l dentine . Ther e wa s som e debat e a s t o whethe r

pulpa l dentin e o r

X-ra y fluo

rescenc e wa s amor e vali dinde x o f lea daccumulate d ove r alifetime . Vande r

repeate dasuggestio n h e ha d mad e regardin g th e possibilit y o f estimatin g ultra

filtrable lea din plasma . Althoug h theoreticall y ideal , h e emphasize dtha t

i t ha dbee n impossibl e i

n th e pas t becaus e o

f contamination , bu t

tha t rigorou s meth

odologi c techniques , includin g absolutel y ultraclea n laborator y setting s for

determination , woul dmak e thi s feasible . H e suggeste dals o tha t isotopi c equili

bratio n o f plasm awit

h a n isotop e o

f lead , followe db y ultrafiltration , migh t

provid e atechniqu e applicabl e t o larg e surveys . Grandjea n pointe dou t tha t a n addi

tional reaso n fo

r no t usin g plasm alea dothe r tha n th e difficult y o f it s measuremen t

i s it s marke dvariability wit h tim e an dBernar dindicate dtha t th e half-lif

e o f plasm alea di s only hour s t o perhap s afe w days . \ S . Snedeke r

(NIEHS ) expande dupo n th e implica

tion s o f dealin g wit

h interactiv e effect s o

f minerals \ Sh e pointe dou t

tha t thi s cover s differen t

level s o ' research : th e effect o f calciu man dothe r

mineral s on lea dbioavailability an dth e lea dbod y burden . Thes e migh t b e substantiall y differen t tha n th e interactiv e effect s o f lea dan dcalciu mo n tissu e levels , suc h a s vascular tissu e o r th e kidney . Snedeke r

als o pointe dou t tha t ther e ar e som e subgroup s tha t hav e no t bee n dis

cusse da t length , in particular , wome n a t th e meno pause . Th e releas e o

f calciu man dth e effect s o f hormon e treatmen t wer e worth y o

f investigatio n sinc e som e preliminar y dat aindicate daslightl y highe r bloo d lead-bloo dpressur e slop e in th e 40

- t o 55-yea r ag e rang e wit h subsequen t

levelin g off

. Schwart z indicate dtha t hi s grou p ha s apape r

in manuscrip t

suggestin g tha t bloo dlea dlevel s increas e immediatel y afte r menopaus e an dtha t astatistica l interactio n ter mfo r ag e suggest s tha t the y the n declin e an dtha t thi s i s similar

to th e patter n o f calciu mreleas e after

menopaus e following calciu mmobilizatio n fro mbone . A presentatio n an drevie w o f th e desig n an dplan s for th e Nationa l Healt h an dNutritio n Examinatio n Surve y (NHANES ) III wer e considere dan dserve da s a basi s fo r discussio n regardin g studie s tha t coul db e adde dt o thi s surve y to furthe r elucidat e th e bloo dlead

bloo dpressur e relationship . S . Hayne s (NCHS ) describe dth e plan s fo r NHANE S III . Sh e indicate dtha t

with asampl e siz e o

f 16,000 i t woul db e large r

tha n th e previou s tw o surveys . Th e pla n i s t o star t

th e surve y i n 198 8 an dt o complet e i t b y 1994 ; however , estimate s fro mth e fieldwil l b e available b y 199 1 for

black s an dwhite s an dat th e en d o

f th e 6 year s for Mexica n American s an dPuert o Ricans . Plannin g i s movin g forwardt o d o amortalit y follow

u p o f th e populatio n usin g th e nationa l deat h index . Ther e als o ar e plan s t o hav e areexaminatio n o r reintervie w o

f th e NHANE S II I population , probabl y i n 1996 . Amon g th e element s o f th e examination , sh e mentione daspecia l kidne y exa mwhic h will b e mor e extensiv e tha n other s previousl y don e in th e NHANE S survey s t o follo w u p person s a t ris k o f kidne y diseas e wit h specia l reexamination s for glomerula r

filtration rat e i n clinical centers . Wedee n pointe dou t tha t infor

matio n coul db e derive dfro mdetaile danalysi s o f seru mcreatinin e an dHayne s indicate dtha t amanuscrip t wa s i n preparatio n base do n analyse s o f th e seru mcreatinin e value s o f NHANE S I I an dtha

t additiona l studie s o

f thei r relationship s t o bloo dlea d woul db e feasibl e b y secondar y analysi s o f thes e extan

t data . Hayne s adde dtha t

ahom e examinatio n i s t o b e adde dt o th e mobil e uni t survey . In thi s hom e surveylimite dexamination s wil l includ e bloo dpressure s s o tha t i t will b e "possibl e t o iiav e hom e bloo dpressure s measure s a s wel l a s clini c measure s for th e enti r population . Thi s wil l permi t bette r definition s - hypertension . In respons e t o aquestio n by Sffl" t • Hayne s pointe dou t

tha t detaile dplan s fo

r analys ^ hav e bee n develope di

n advanc e t o identif

y th e ba s question s tha t

nee dt o h e addresse dfollowing com p tio n o f thi s survey . Hayne s als o indicate d that ther eP.1 8

DISCUSSION

SUMMARY 15 5

an e w philosoph y a

t th e Nationa l Cente r

fo r Health Statistic s in disseminatin g results . Th e first targe t i s earl y publicatio n i

n medica l journal s an dfollowin g that , publicatio n o

f th e materia l i

n Cente r reports . I

n summar y o f th e overal l scop e o

f th e exam , excludin g the environmenta l components , Hayne s indicate dtha t ther e wil l b e a n electrocardiogram , kidne y exam , ora l glucos e toleranc e test , hearin g exam , visual an ddenta l exams , a24-h

r die t recall , an daserie s o

f neurologi c tests , measuremen t

o f height , weight , anthropometrics , bod y impedance , an dbon e densitometr y t o determin e osteoporosis . G. Provenzan o (U.S . EPA ) summarize dth e EP A plan s for measuremen t

o f environmenta l aspect s withi n NHANE S III . Th e exposur e measurement s wil l b e base don estimatio n o f exposur e primaril y i

n th e home . Thes e wer e ascertaine db y expandin g th e househol dintervie w t o provid e informatio n o n factors tha t

affect indoo r ai r quality , suc h a s type s o f heatin g equipment , cookin g equipment , siz e o f indoo r spaces , numbe r

o f rooms , etc . Th e questionnair e informatio n wa s t o b e supplemente db y som e indoo r ai r monitoring , e.g. , rado n measurement . Tap wate r i s t o b e analyze dfor

toxi c an dessentia l metals . I n additio n t o environmenta l measurements , measure ment s o f individual s ar e t o b e performe dboth to asses s exposure an dfo

r effect s estimation . Amon g th e effect s measurement , i

n additio n to bloo dpressure , ther e wil l be aneurobehaviora l tes t battery . Th e bod y measure ment s wil l includ e thos e determine dfro mserum , whole blood , an durin e an dinclud e alarge r numbe r o f toxi c metal s an dessentia l metal s tha t wer e no t measure din NHANE S II . Th e final lis t o f metal s t o b e analyzedin additio n t o lea dha s no t bee n determined , but wil l includ e cadmium , an dmos t probabl y seru m selenium , manganese , an daluminum , an durinar y arsenic . Seru mcotinin e wil l b e assesse dt o provid e sensitiv e an dobjectiv e evidenc e o f exposur e to tobacc o smoke . Provenzan o conclude dwit h th e posin g o

f thre e type s o f question s relevan t

t o th e bloo dlead-bloo d pressur e question . First , wha t laborator y analysi s protoco l shoul db e use dfo r measurin g lea di

n bloo din th e NHANE S III ? D o w e nee dincrease dsensitivity i n vie w o f th e anticipate dmarkedl y lower bloo dleadlevel s i n th e earl y 1990s ? Wil l w e b e abl e t o detec t lo w level s wit h appropriat e precisio n an daccuracy ? Wil l i t b e possibl e to detec t

th e shap e o

f th e dos e respons e function a t ver y low bloo dlea dlevels ? Second , whic h covariate s shoul db e includedi

n NHANE S III ? Despit e th e ver y long lis t availabl e an danalyze din NHANE S II , what othe r potentia l confounder s wer e missin g fro m NHANE S I I an dshoul db e adde dt o th e NHANE S III ? Finally , wha t

ar e th e recommendation s for th e tech

nique s fo r bloo dpressur e measuremen t i n NHANE S III . Schwart z reinforce dProvenzano' s comment s regardin g th e anticipate dmuc h lowe r level s o f bloo d lea di

n NHANE S III an demphasize dth e nee dfo r mor e accurat e an dprecis e measurement s o f bloo dlea dlevels . Schwart z questione dwhethe r ther e wer e goin g to b e hom e dus t

sample s analyze dfo

r route s o f exposur e to metal s othe r

tha n drinkin g water . Provenzan o indicate dtha t

th e difficultie s i

n samplin g fo

r metal s mad e i t unlikel y tha t

thi s woul db e attempted . Mahaffe y emphasize dth e nee dt o develo p indice s o f integrate dexposur e to lead . Wedee n suggeste dtha t th e estimatio n o

f bon e densit y migh t

provid e technique s clos e t o thos e use dt o measur e bon e lead . V . Bona r pointe dou t

tha t ther e i s considerabl e evidenc e tha t social variable s ar e relate dboth t o bloo dpressur e an d bloo dlea dan dinquire dregardin g th e measure s o f potential , social confounder s in NHANE S III . Lili s emphasize dth e importanc e o f estimatio n o

f alcoho l an dsmokin g an dadde dtha t thes e tw o plu s wate r

wer e majo r source s o

f leadexposure . Col e pointe dou t

th e limitation s i

n th e observationa l epidemiologi c dat aavailabl e i n th e pas t

an durge da systemati c planne dapproac h t o NHANE S II I t o contributet o th e questio n o f whethe r o r no t any observe dassociatio n wa s causal . Tyrole r notecKtha t

th e morning' s sessio n bega n wit h a n overvie w by^Rocock

an daske dSchwart z i

f h e woul dconclud e th e sessio n wit h hi s perspectiv e O

n th e overvie w o

f th e bloo dpressut^jloj3d_Jea.d-relationship . Schwart z indicate dtha t h e generall y agree dwit h Pocock' s summarization , tha t is , tha t ther e i s abroa d consistenc y in th e result s acros s studies , tha t th e coefficien t relatin g bloo dleadto bloo dpressur e on th e lo g scal e indicate dtha t doublin g o

f bloo dlea dwa s associate dwit

h a1 t o 2 m

mchang e i

n mercury . Thus , base do n th e epidemiologi c data , h e conclude dtha t ther e i s a n association , i

t i s no t larg e i n respec t o f th e millimeter s mercur y explained , an dth e studie s ar e consistentl y positivel y aroun dtha t range . H e disagree dwit

h Pococ k

regardin g th e causa l inter

pretatio n an dsuggeste dtha t althoug h causa l infer

ence s coul dno t

readily b e draw n fromth e epide

miologi c dat aper

se, tha t the y wer e consisten t

wit h th e anima l dat aan dtha t

for th e anima l dat ai t

wa s no t difficult t o dra w acausa l inference . Informatio n wa s emergin g withi n th e anima l studie s regardin g mechanism s suc h a s exaggerate dalph aadrenergi c responses , an ddisturbanc e o f calciu mmetabolis man d tha t simila r mechanism s hav e bee n postulate d for mil dhypertensio n in humans . Base do n thes e obser

vations , Schwart z conclude dtha t ther e i s probably , althoug h no t

definitivel y established , acausa l rela

tionship . Schwart z emphasize dtha t lea di s acontrol

labl e elemen t

i n th e environmen t

an dtha t remova l o

f exposur e earl y i

n lif e coul dpreven t

th e emergenc e o

f elevate dbloo dpressure , a n approac h muc h safe r

tha n tha t o f treatin g elevate dbloo dpressur e after i t ha d emerged .