P. 1 

# OAR Box 1126 Prepped by Ollie Stewart



## Document

Number: 

# 78 ) 11-1-29

2 Docket Number: 

# A-83-2 2

Printed 4/18/2008 9:58:24

AM Sheet 78 of 182ie s m | er >ta i •teria i | s tasi s TS V 5 : lea d 136 : •Th e •May . 0) . ? cel l Appl . » d o n Appl . isitiv e

' • Th e m dit s 6-25 8 ofth e n th e ltants , •rigan , s Cu p c Off . D . D „ :twee n :twee n ectio n natio n soc . 6 8 and durin g ) . ne e o f 8-yea r : 4-599 . .H.A . ."ie s o f ud . 14 : itistica l Nort h 982) . Environmental Health Perspectives Vol. 78, pp. 23-30, 1988 P. 2



# Th e Relationshi p Betwee n Bloo d Lead , Bloo d Pressure , Stroke , an d Hear t Attack s i n Middle-Age d Britis h Me n b y S . J - Pocock, * A . G . Shaper, * D . Ashby/ H . T . Delves, * and B . E . Clayton *

Th e relationshi p betwee n bloo dlea dconcentratio n an dbloo dpressur e i s examine di n asurve y o f 737 1 me n age d4 0 t o 5 9 Iro m2 4 Britis h towns . After allowanc e fo r

relevan t confoundin g variables , includin g town o f

residenc e an dalcoho l consumption , ther e exist s aver y wea k bu t statisticall y significan t positiv e associatio n betwee n bloo dlea dan dbot h systoli c an ddiastoli c bloo dpressure . Thes e cross-sectiona l dat aindicat e tha t a n estimate dmea n increas e o f 1.4 5 m mH g i n systoli c bloo d pressur e occur s fo r

ever y doublin g o

f bloo dlea dconcentratio n with a95 % confidenc e interva l o f 0.4 7 t o 2.4 3 m mHg . Afte r 6 year s o f

follow-up , 31 6 o

f thes e me n ha dmajo r

ischemi c hear t

disease , an d6 6 ha da stroke . Afte

r allowanc e fo r

th e confoundin g effect s o f cigarett e smokin g an dtow n o f residenc e ther e i s n o evidenc e tha t

bloo dlea di s aris k

facto r fo r thes e cardiovascula r

events . However , a s th e bloo d lead-bloo dpressur e associatio n i s s o weak , i t i s unlikel y tha t

an y consequen t

associatio n betwee n lea dan dcardiovascula r

diseas e coul db e demonstrate dfro mprospectiv e epidemiologica l studies . A n overvie w o f

dat afro mthi s an dothe r larg e epidemiologica l survey s provide s reasonabl y consisten t

evidenc e o n lea dan dbloo dpressure . Whil e NHANE S I I dat ao n 225 4 U.S . me n indicat e aslightl y stronge r

associatio n betwee n bloo dlea dan dsystoli c bloo dpressure , dat afro mtw o Wels h studie s o n ove r

200 0 me n di dno t

sho w astatisticall y significan t association . However , th e overlappin g confidenc e limit s fo r al l thes e studie s sugges t tha t ther e ma y b e awea k positiv e statistica l associatio n whereb y systoli c bloo dpressur e i s increase db y abou t 1 m mH g for.ever y doublin g o

f bloo dlea dconcentration . Nevertheless , suc h statistica l associatio n canno t b e take n a s establishin g acausa l effec t o f low-leve l lea dexposur e o n bloo dpressure , particularl y sinc e ther e ar e importan t confounders , e.g. , alcoho l consumption , whic h ar e muc h mor e strongl y relate dt o bloo d pressure . 

### Introductio n Th e hypothesi s tha t

moderat e elevation s in bloo d lea dconcentration ar e associate dwit h increase dbloo d pressur e i n human s i s supporte db y considerabl e experimenta

l evidenc e i

n laborator y animal s (1,2). Sinc e direc t experimenta l evidenc e i n human s canno t b e obtained , th e principal investigationa l approac h i n lmman s ha s bee n wit

h observationa l studie s i n repre sentativ e sample s o

f eithe r th e genera l adul t

populatio n o r occupationali

y expose dgroups . 'Departmen

t o f Clinica l Epidemiolog y an dGeneral Practice , Roya l i-n * Hospita

l Schoo l o f Medicine , London NW 3 2PF , UK. iii93Bv a i rtmen t

° f Communit y Health , Th e University , Liverpool , departmen t

o f Chemical Patholog y an dHuma n Metabolism , niv er Sl t y o f Southampton , Southampton , U K Thi s pape r describe s cross-sectiona l result s fro mon e larg e survey , th e Britis h Regiona l Hear t Stud y (BRHS) . Sinc e ou r

origina l publicatio n o n thi s topi c claimin g alac k

o f associatio n betwee n bloo dlea dan d bloo dpressur e (3), studie s o f dat afromth e Unite d State s Nationa l Healt h an dNutritio n Examinatio n Surve y (NHANE S II ) hav e conclude dtha t ther e i s a n importan t associatio n (4,5). Hence , i t i s opportun e to re examin e ou r

data , payin g carefu l attentio n t o th e rol e o f confoundin g factor s suc h a s tow n o f residenc e an d alcoho l consumption . I n addition , th e BRHS i s aprospectiv e study , an dth e me n ar e bein g followe dfo r fata l o r nonfatal cardio

vascula r event s sinc e initia l screening . Hence , ne w result s ar e presente dconcernin g whethe r moderat e elevation s i

n bloo dlea dar e relate dto ris k o f ischemi c hear t diseas e (IHD ) o r

stroke .

## v^ P. 3

2 4 POCOCK ETAL. I t i s unrealisti c t o expec t

an y singl e epidemiologica l stud y t o provid e definitiv e answer s concernin g bloo d lead-bloo dpressur e relationships . Therefore , thi s pape r als o present s a

n overvie w o

f th e collectiv e evidenc e fro mal l th e majo r

survey s i

n thi s fieldan d demon

strate s agreate r

consistenc y o

f evidenc e than migh t

b e achieve dfromseparat e perusa l o f th e finding s an d conclusion s fromeac h individua l study . 

## Method s Th e BRH S examine d773 5 me n age d4 0 t o 5 9 wh o wer e randoml y selecte dfromth e age-se x register s o f representativ e genera l practice s in 2 4 Britis h towns . Detail s o f th e selectio n o

f town s an d genera l practice s an dth e method s o

f screenin g an d dat acollectio n hav e previousl y bee n reporte d(6). Eac h man' s bloo dpres sur e wa s measure dtwic e in successio n wit h th e Lon

do n Schoo l o

f Hygien e sphygmomanometer , with th e subjec t seate dan d hi s armsupporte do n acushion . Diastoli c bloo dpressur e wa s recorde dat disappearanc e o

f sound s (phas e V) . Th e mean o f tw o reading s o

f bloo d pressur e wa s adjuste dfor observe r variatio n withi

n eac h tow n t o allo w for

an y inconsistencie s amon g th e thre e observer s (7) . Bloo dsample s for

lea danalysi s wer e obtaine dfro m 737 9 me n (95%) . Bloo dlea dconcentration s wer e analyze da t th e Universit y o

f Southampto n with flam e microsamplin g atomi c absorptio n spectroscopy . A stric t qualit y contro l protoco l wa s maintained , an d th e performanc e o

f th e laborator y wa s continuall y moni

tore db y participatio n i n nationa l an d international quality assessmen t

scheme s for

analysi s o

f bloo dlea d concentration . Alcoho l consumptio n wa s recorde dusin g question s o f frequenc y an d quantity . A drin k wa s define d a s hal

f apin t o f beer , on e glas s o

f wine , o r asingl e sho t

o f spirits . Fo r

dat aanalysis , eigh t

drinkin g categorie s wer e used : nondrinker , occasiona l drinker , weeken d drinke r (1-2 , 3-6 , o r

> 6 drink s aday) , an d dail y drinke r (1-2 , 3-6 , o r

> 6 drink s aday) . Fo r illustration , i n Figure s 1 an d 2 thes e ar e combine dt o 16 0 O ) I E E 15 0 14 0 C D

- o O O

. Q C ro 0 ) Systoli c

90 1 8 0 7 0

No.

c n I E E :. 6 .6 - .9 - 1.2 - 1.5 - 1.8 - Bloo d lea d (/imol/l ) otmen: 1984 3381 1420

386 126

74 160 " Sys'.oli c 150 - 140 - Q ) Q .

- a o o J D c ro C D 9 0 8 0 - Diastoli c

Non e o rLigh t Moderat e Heav y Occasiona l Alcoho l intak e 160 150 "

14 0

9 0

8 0 Systoli c

Diastcli c

160 n 15 0

140 " <22. 5 22.5

- 24.5

- 26.5

- 28.5

-

Bod y Mas s Inde x (kg/m 2 ) . 1256 1764

2043

1419

1243 Systoli c

90 - 80 - D'sstoli c

40-4 4 45-4 9 50-5 4

Ag e 55-5 9

No. otmen:

3033 2911 947 830

1636 1896

1974

2021 FIGUR E 1 . Mea n systoli c an d diastoli c bloo dpressure s fo r me n categorize db y bloo dlea dconcentration , bod y mas s index , alcoho l consumption , $ age . 

## I '(r r

# r

BZ.OO D L£4 D AW D BLOOD PRESSURE

IN BRITISH

MEN 2 5 P. 4

fou r drinkin g categories : nondrinke r o r f° r m . ona l drinker , ligh ^ drinke r (1- 2 dail y o r

o n ° cC t S 'nds ) moderat e (3- 6 dail y o r o n weekends) , an d drinker ( > 6 daily o r

o n weekends) , ^r^arett e smokin g habit s derive dfro mastandard

A questionnair e wer e a s follows : neve r smoke d tte s ex-cigarett e smoker , an dcurren t cigarett e Cig nker at'fou r level s (1-19 , 20 , 21-39 , > 4 0 pe r day) . Ex

- • ett e smoker s wh o currentl y smoke dapipe/cigar s ""'^lude d j nex-cigarett e smokers . Thos e me n wh o hVonl y ever

smoke dpipe/cigar s ar e include din r smoke dcigarettes . Fo r bot h curren t

an dex neve . er s th e numbe r

o f year s ama n ha dsmoke dcig

s m ° e s ^ a s als o recorded , thi s variabl e (smokin g years ) rT'ne. astron g smoking-relate dpredicto r o f IH D ris k (8) Al l o f th e 773 5 me n wh o wer e initiall y examine d fro m197 8 to 1980 wer e schedule dt o b e followe du p for bot h morbidit y an dmortality for

8 years . S o far , 99

% o f th e origina l cohor t stil l aliv e an dlivin g i n Grea t Britai n ar e bein g followe dup . Detail s o f th e follow-u

p procedure s hav e bee n publishe d(9). Al l case s o f major IH D an dstrok e occurrin g betwee n screenin g an d Augus t 198 5 are include din thi s paper .

~ 1.0 1

- 0. 9 X)

0. 7 y 0. 6 0. 5 

## Result s Persona l Factor s Relate dt o Bloo d Pressur e an dBloo dLea d Figur e 1 show s asimpl e displa y o f th e univariat e associatio n betwee n bloo dlea dan dbloo dpressur e i n th e 737 1 me n fo

r who mbot h wer e measured . Ther e i s som e suggestio n o

f aris e i n mea n systoli c pressur e a s bloo dlea dincreases , bu t th e correlatio n coefficient i s onl y 0.03 . However , ther e ar e severa l persona l charac

teristic s i n middle-age dme n tha t ar e know n t o b e associate dwit

h bloo dpressure . Fo r

example , Figur e 1 als o show s th e trend s in mea n systoli c an ddiastoli c pressur e for

thes e sam e me n groupe daccordin g t o bod y mas s index , age , an dalcoho l consumption . Clearly , bod y mas s inde x an dag e ar e importan t determinant s o

f individual bloo dpressure , bu t alcoho l consumptio n i s als o an importan t confoundin g vari

abl e in vie w o

f it s substantia l associatio n wit h bloo d lea dconcentratio n (10,11) (Fig . 2) , a s wel l a s wit h bloo d pressur e (6,12). Tw o othe r relevan t persona l factor s ar e cigarett e smokin g an dsocia l class . Th e forme r i s clearl y associate dwit

h bloo dlea dconcentratio n (10,11) (Fig . 2) ; th e latte r

ha s weak

association s with bot h bloo dpressur e an dbloo dlead . 

## Geographi c Differenc e Ther e ar e majo r

geographi c difference s i n bot h mea n systoli c bloo dpressur e an dmea n bloo dlea d concentratio n (Fig . 3) . Althoug h ther e i s n o evidenc e o f astatistica l associatio n for th e between-tow n dif

ference s i n bloo dpressur e an dbloo dlead , i t i s stil l relevan t tha t tow n o f residenc e shoul db e take n int o accoun t whe n studyin g thi s potentia l lead-bloo dpres sur e relationshi p i n individuals . Non e o r Occasiona l Ligh t Moderat e

Alcoho l intak e Heav y

an d No. of

men 2887 aa ? L O I 2759 922 805

-a o " D O O a 0.9 " 0. 8 0. 7 0.6 - 0. 5 Neve rE x 1-1 9 2 0 21-3 9 >4 0 •r Curren t pe rda

y Cigarett e smokin g Wo . ot men 1741 2597

1132

790

803

300 <• ' R K 2 . Mea n bloo dlea dconcentratio n fo r me n categorize db y thei r ("portedalcoho l consumptio n an dcigarett e smoking . 16 0

Q . C Q •2 15 0 o ti 5 > . U ) c •to <D E c 3 o 14 0

13 0 0. 5 — t — 0. 8 - T

0. 9 0. 6 0. 7 Tow n mea n bloo d lea d (/tmol/l ) — 1 1. 0 FIGUR E 3 . Th e tow n mea n systoli c bloo d pressur e plotte d agains tth e tow n mea n bloo d lea d concentratio n fo r th e me n residen ti n eac h o f 2 4 Britis h towns .P. 5

26 ' POCOCK ETAL. 

## Bloo dPressur e an dBloo dLea d (Unadjusted ) Figur e 4 provide s amor e detaile ddisplay o f mea n systoli c an ddiastoli c bloo dpressur e accordin g t o bloo d lea dconcentration . Fo r

bloo dlea dbetwee n 0. 4 an d1. 1 |imole/L , mea n pressure s ar e show n for eac h 0. 1 umole/ L interva l o

f bloo dlead . Abov e 1. 1 umole/L , me n ar e groupe dint o tw o categories , 1.2 t o 1. 3 (xmole/ L an d1. 4 jimole/ L o r

more , s o a s t o preserv e approx imatel y 300 me n i

n eac h category . Al

l th e displaye d95 % confidenc e interval s overlap wit h on e another , an d als o th e mea n systoli c an ddiastoli c bloo dpressure s i n th e highes t

bloo dlea dcategor y sho w n o elevatio n abov e th e average . Thus , detaile dunivariat e analyse s sho w n o encouragemen t

for th e hypothesi s tha t

bloo d lea dan dbloo dpressur e ar e positivel y associated . 

## Bloo dPressur e an dBloo dLea d (Adjuste dfo r

Otiie r Factors ) Th e situatio n appear s t o chang e onc e relevan t persona l factor s ar e take n int o account . A n analysi s o

f covarianc e techniqu e ha s bee n use dt o obtai n adjuste d mea n systoli c an ddiastoli c bloo dpressur e for eac h bloo dlea dcategory , adjustmen t bein g fo r

bod y mas s index , age , alcoho l consumptio n ( 8 categories) , ciga

rett e smokin g ( 6 categories) , social clas s ( 6 categories) , an dtow n o

f residenc e (2

4 categories) . Th e consequen t plot s o f adjuste dmean systoli c an ddiastoli c bloo dpres sur e b y bloo dlea d i n Figur e 5 sho w sign s o f awea k positiv e association . Particularly , for th e diastoli c pressur e ther e i s astead y increas e in adjuste dmea n fro maroun d8 1 mmH g fo r bloo dlea dbelo w 0. 6 umole/ L t o aroun d83. 5 m mH g fo r bloo dlea dove r

1. 0 umole/L .

I E E , C D t _ </ > O ) a> a .

- o o o o ~o T o > . w 15 2

14 8

14 4

14 0

— I 1 1 1 1 1 1 1 1 1 0. 0 0. 2 0. 4 0. 6 0. 8 1. 0 1. 2 1. 4 1. 6 1. 8 2. 0 W o

I </ > tal a ) Q . T 3 o o

- Q U ~o m Bloo d lead (ftmol/l ) of men: 255

1084 1204 682 295 644 1209

967 443 298 8 6 - | 289

8 4

8 2

8 0

7 8 I 1 1 1 1 1 1 1 1 1 0. 0 0. 2 0. 4 0. 6 0. 8 1. 0 1. 2 1. 4 1. 6 1. 8 2. 0 W o Bloo d lea d (^mol/l ) of men: 255

1084 1204 682 295 644 1209

967 443 298 289 

## Multipl e Regressio n Analysi s Thi s associatio n can b e furthe r explore db y multipl e regression s o

f systoli c an ddiastoli c bloo d pressur e o n lo g (bloo dlead ) an dth e covariate s jus t mentioned . Table

0

- C 0 o 0 3 > , tn c C D <D E D < 15 0 14 8 14 6 14 4 14 2 14 0

Q m

TO 7 3 c ( 0 0 ) E " D B t o < 8 5 8 4 8 3 8 2 -

8 0 - i 1 1 0. 0 0. 2 0. 4 0. 6 0. 8 1. 0 1. 2 1. 4 1. 6 1. 8 2. 0

Bloo d lea d (/^mol/l )

- i 1 1 r - i 1 r 0. 0 0. 2 0. 4 0. 6 0. 8 1. 0 1. 2 1. 4 1. 6 1 . 2. " FIGUR K 4 . Mea n systoli c an ddiastoli c bloo dpressure s (andthei r 95 % confidenc e limits ) fo

r me n categorize di

n interval s o

f 0. 1 umole/L o

f bloo dlea dconcentration . (The tw o highes t bloo dlea

dgrouping s are 1. 2 to 1. 3 pmole/ L and1.

4 vimole/L. ) Bloo d lea d (/imol/l ) FIGUR K 5 . Mea n systoli c anddiastoli c bloo dpressure s by bloo dle * concentratio n afte r

adjustmen t

for bod y mas s index , alcoh consumption , cigarett e smoking , socia l class , andtow

n o f resident -P. 6

BLOOD LEAD AND BLOOD PRESSURE IN BRITISH MEN 27 how s th e regressio n coefficient s fo r lo g (bloo dlead ) ) r thre e differen t

models : a) unadjuste dfor othe r fetors ; b ) adjuste dfor

age , bod y mas s index , alcohol , rnoking , and socia

l class ; an dc ) adjuste dals o fo r tow n f residence . Th e lo g transformi s use dbecaus e bloo d ° J ^3 5 alognorma l distribution , th e regressio n fit i s liirhtl y improved , and . als o th e finding s ar e the n S or e directl y comparabl e wit h othe r studies . I n th e "nadjuste d regression , systoli c (bu t no t diastolic ) bloo d "ressur e i s significantl y associate dwith lo g (bloo d P J \Adjustmen

t for persona l characteristics , bu t no t tow n o f residence , render s bot h th e systoli c an ddias

toli c regression s on lo g (bloo dlead ) insignificant . Thi s s chiefl y becaus e alcoho l consumptio n i s a n importan t confounder , bein g positivel y relate dt o bot h bloo dpres sur e an dbloo dlead . Introducin g a n extr aadjustmen t fo r tow n o f residenc e make s bot h th e systoli c an ddias

toli c regression s highl y statisticall y significan t (p = 0 00 3 an d0.001 , respectively) . However , i t shoul db e note dtha t thes e adjuste dstatistica l association s ar e stil l ver y weak, partial correlatio n coefficient s bein g 0.04 an d0.0 5 fo r th e systolic-bloo dlea dan ddiastolic-bloo d lea dassociations , respectively , s o tha t statistica l sig

nificanc e i s achieve donl y becaus e o f th e larg e numbe r o f subject s i n th e survey . A s amean s o

f quantifyin g th e magnitud e o f thes e adjuste drelationships , on e can us e th e regressio n coef

ficien t an dit s standar derro r

for log(bloo dlead ) t o obtai n th e estimate dincreas e in bloo dpressur e fo r eac h doublin g o f bloo dlea dconcentration . Thi s i s 1.4 5 m m H g fo r systolic pressur e (95 % confidenc e interval , 0.47

- 2.4 3 m mHg ) an d1.2 5 mmH g for

diastoli c pressur e (95 % confidence interval , 0.65-1.8 5 m mHg) . 

## Separat e Analyse s Withi n Eac h Tow n I t i s importan

t t o remembe r

th e geographi c basi s o

f th e BRH S whereb y th e sampl e o

f 737 1 me n analyze d her e com e fro m2 4 towns , approximatel y 30 0 me n pe r town . Tabl e 2 show s th e result s o

f separat e univariat e regressio n analyse s o

f bloo dpressur e o n lo g (bloo dlead ) fo r th e me n i n eac h town . Thes e finding s demonstrat e tha t th e weaknes s o

f th e bloo dlead-bloo dpressur e Tabl e 2 . Separat e univariate regressio n analyse s fo r th e me n i n eac h town . Regressio n coefficien

t (SE ) Tow n Newcastl e Burnle y Dewsbur y Wiga n Southport Harrogat e Merthy r Tydfi l Darlingto n Mansfield Falkir k Shrewsbur

y Grimsb y Guildfor d Ipswich Scunthorp e Ay r Exete r Carlisl e Lowestof t Maidston e Dunfermlin e Hartlepoo l Bedfor d Gloucester Systoli c bloo d

pressur e on ln(Pb ) 11.4 10. 6 5. 8 5. 6 5. 6 5. 5 5. 5 5. 0 5. 0 4. 2 3. 8 2. 8 2. 5 2. 0 1. 9 1. 6 1. 5 1. 3 1. 0 0. 9 0. 6 -1. 4 -1. 7 -3. 1 (4.3 ) (3.4) (3.5 ) (3.1 ) (4.3 ) (4.1 ) (4.2 ) (3.5 ) (4.4) (4.0 ) (4.3 ) (2.9 ) (3.8 ) (2.9 ) (2.8 ) (2.8 ) (3.0 ) (3.0 ) (3.9 ) (2.9 ) (3.5 ) (3.4) (4.5 ) (4.4) Diastoli c bloo d

pressur e on ln(Pb ) 4. 4 7. 2 2. 7 2. 6 3. 8 4. 8 3. 2 -3. 0 6. 1 -0. 4 1. 9 1.6 2. 5 -0. 5 3. 0 0. 7 -0. 4 1. 8 -2. 2 1. 2 -0. 2 0. 8 5. 1 2. 4 (2.9 ) (2.2 ) (2.4) (1.8 ) (2.3 ) (2.5 ) (2.3 ) (2.2) (2.6) (2.8 ) (2.6) (1.7 ) (2.3 ) (1.9 ) (1.7 ) (1.8 ) (2.2) (1.8 ) (2.4) (1.9 ) (2.2 ) (2.0 ) (2.8 ) (2.8 ) associatio n i s suc h tha t

studie s base do n afe

w hundre d me n contai n to o muc h rando mvariatio n an dcanno t b e expecte dt o produc e consistent , precis e findings . Fo r instance , th e within-tow n regression s o f systoli c bloo d pressur e o n lo g (bloo dlead ) produce dlarg e significan t coefficient s in Newcastl e an dBurnley , whil e at th e othe r extreme , ther e wer e thre e towns , Hartlepool , Bed

ford , an dGloucester , wit h smal l negativ e coefficients . In fact , frominspectio n o f th e standar derror s o

f eac h suc h coefficient , on e can se e tha t suc h difference s ar e largel y attributabl e t o rando mvariation , an dthe y ar e al l in broa dagreemen t

wit h atru e averag e regressio n coefficient o f 3.0 . Adjustmen t

for alcoho l consumptio n a s aconfounde r

reduce s thi s coefficien

t t o 2.0 , whic h i s th e overal l poole destimat e alread y derive din th e multipl e regressio n i n Tabl e 1 . Tabl e 1 . Regression s o f

systoli c an d diastoli c bloo d pressur e o n ln(bloo d lead ) wit

h an d withou tadjustment s fo r othe r persona l factors an d town o f

residence . Systoli c bloo dpressure Unadjuste d Adjuste dfo r bod y mas s ""iex , age , alcohol , smoking , -an d socia l clas s Adjuste dalso fo r tow n J'astoli c bloo dpressure Unadjuste d juste d fo r bod y mas s '"dex . age , alcohol , smoking , w d socia l clas s -^iH!!siakofortow n Regressio n coefficien t fo r l n (bloo dlead ) Rvalu e 1.68 4 0.67 5 2.08 9 0.30 2 -0.06 3 1.80 9 0.009

0.2 8 0.00 3 0.4 6 0.8 7 0.00 1 

### Bloo d Lea d an d Cardiovascula r Event s

Tabl e 3 show s th e mean bloo dlea dconcentratio n for 31 6 me n wh o hav e experience dmajo r ischemi c hear t diseas e sinc e initial screenin g compare dwit h th e 706 3 othe r men . Th e mea n bloo dleve l concentratio n i s significantl y highe r

in thes e IHD case s (p = 0.01) , bu t thi s i s withou t

takin g accoun t

o f importan t

con foundin g variables . In particular , cigarett e smokin g i s a n establishe drisk

facto r fo r IHD , whic h als o elevate s bloo dlea dconcentration s (Fig . 2) . Th e town s with highe r IH D mortalit y ten dt o hav e slightl y highe r bloo dlea dconcentrations , perhap s becaus e bloo dlea d level s ar e highe r

in sof t wate r area s (13), whic h ar e know n t o hav e highe r

IH D mortality (14,15). There

fore , analysi s o

f covarianc e ha s bee n use dt o obtai n anP. 7

2 8 POCOCK ETAL. Tabl e 3 . Mean bloo d lea d concentration s fo r me n wit h subsequen tischemi c hear tdiseas e an d strok e compare d wit h othe r men , with an d withou tadjustmen tfo r age , smokin g years , an d town o f residence . No . o f me n Mea n bloo dlead , pmole/L Differenc e i

n mean s ± S E Differenc e i

n mean s ± S E afte r adjustmen

t fo r age , smokin g years , andtow

n IH D case s 31 6 0.78 6 0.05 1 0.01 4 Othe r me n 706 3 0.73 5 ±0.01 9 ±0.01 5 Stroke

case s 6 6 0.80 8 0.07 1 0.03 3 Othe r

men 731 3 0.73 7 ±0.049 ±0.03 3 adjuste ddifferenc e i n mea n bloo dlea dbetwee n IH D case s an dothe r

me n adjustmen t

bein g fo r age , numbe r o f year s smokin g cigarettes , an dtow n o f residenc e (2

4 categories) . Thi s adjustmen t ha s reduce dth e mea n exces s in bloo dlea damon g IH D case s fro m0.05 1 umole/ L t o 0.01 4 umole/L , whic h i s n o longe r sig

nificantly differen t

fromzero . Tabl e 3 als o show s sim

ila r result s for

th e 6 6 case s o

f strok e compare dwit

h othe r men . A n alternativ e metho do

f studyin g bloo dlea da s a possibl e IHD ris k

factor i s t o estimat e th e relativ e odd s o f becomin g a

n IHD cas e fo

r differen t interval s o

f bloo d lead . Usin g th e 198 6 me n wit h bloo dlea dconcentra tio n unde r

0. 6 umole/ L a s areferenc e group , Figur e 6 show s tha t

th e odd s (o r

risk ) o f IH D i s somewha t greate r at highe r bloo dlea dconcentrations , partic

ularl y at 1. 2 umole/ L o r

more . However , us e o

f logisti c regressio n analysi s t o obtai n relativ e odd s adjuste dfor age , smokin g years , an dtow n o f residenc e show s n o evidenc e o

f a n exces s risk

o f IH D at thes e highe r

bloo d lea dconcentrations . 

## Overvie w of

Othe r Larg e Studie s of Bloo dLead-Bloo dPressur e Relationship s I n any specifi c fieldo

f epidemiologica l research , n o singl e observationa l stud y ca n b e relie dupo n t o provid e adefinitiv e answer , particularl y whe n th e relationshi p unde r

stud y i s quit e wea k

an d i n th e presenc e o

f stron g potentia l confounders . I n thi s pre liminar y attemp t

t o presen t

th e collectiv e evidenc e fromour s an dothe r

studie s o

f th e lead-bloo d pressur e relationship , attentio n i s confine dt o th e large r studie s fo r whic h appropriat e regression s o f systoli c bloo d pressur e o n bloo dlea dar e available . A s alread y illus

trate di n Tabl e 2 , studie s o n afe

w hundre dsubject s ca

n produc e highl y variabl e estimate s o f th e lead-bloo d pressur e association . Also , th e availabl e dat ai n suc h smalle r studie s ar e liabl e t o suffer fro mpublicatio n bias , whereb y th e mor e positiv e smal l studie s ar e more likel y t o b e published . Studie s o f unde r 50 0 subject s wil

l therefor e no t

b e mentione dfurther . Al l result s pre sente drefer

t o male s only . Fo r eac h stud y w e presen t

th e estimate dchang e i

n mea n systoli c bloo dpressur e for adoublin g o

f bloo d lead . Thi s i s obtaine dfro mth e principa l regressio n analysi s tha t

th e author s selected . Thes e finding s ar e displaye din Figur e 7 wit h th e 95 % confidenc e limits . Fo r th e BRH S thes e result s ar e directl y obtainedfro m th e regressio n coefficien t for lo g (bloo d lead ) afte

r adjustmen t

fo r tow n o f residenc e an dothe r

covariate s (Tabl e 1) . Fo r

NHANE S II , th e result s ar e similarl y determine dfromdat ao n 225 4 male s age d2 0 t o 74 afte r adjustmen t

for sit e an dsevera l othe r biochemical , dietary , an dpersona l factor s (16). Fo r th e tw o Wels h studie s o n 116

4 an d86 5 men , respectively , linea r regressio n wa s used , adjustin g fo r ag e only , an dhenc e w e hav e plotte dth e mea n chang e i n systoli c bloo d pressur e fo

r on e specifi c doublin g o f bloo d lea d con

centratio n ( 8 t o 1 6 ng/dL ) in th e middl e o f thei r blood lea ddistributions . Th e tw o Wels h studie s sho w n o significan t asso ciation , wherea s NHANE S I I dat asho w an estimate d increas e o

f 2.2 4 m mH g in systoli c bloo d pressur e fo r a doublin g o

f bloo dlea dconcentration , whic h i s larger tha n in th e BRHS . However , th e overlappin g confidenc e interval s indicat e tha t thes e finding s ar e no

t consistent , an dal l studie s ar e compatibl e wit h apos sibl e increas e i n systoli c bloo dpressur e o f approxi

2.0 1 D ^ 1.5- 1 1.0 - 0.5 " 0. 0 No . o f Me n No . o f IH D case s <0. 6

198 6 6 8 0.6-0. 8

338 5 15 2 0.9-1. 1 >1. 2 /imol/ l

1421 6 4 58 7

3 2 FIGUR E 6 . Relative odd s o

f majo r IH D fo r men categorize dby bloo dlea d concentration : (• ) bas e grou p ( < 0. 6 umole/L) ; (• ) unadjuste dfo r othe r factors ; ( x ) adjuste dfo r age , smokin g years , an dtow n o f residence , togethe r

wit h 9 5 % confidenc e limits . BRHS(N=7371 ) NHAN E S I I (N-=2254

) Caerphill y (N = 1164 ) Wale s (N=865 )

• 2 - 1 0 , . 1 2 3 4 Estimate d chang e i n mea n systoli c bloo d pressur e (m m Hg ) to ra doublin g o t bloo d lea d FIGUR E 7 . A n overvie w o

f fou r larg e studie s relatin g systoli c blo° , pressur e to bloo dlea

dconcentration . Th e grap h show s eac h study

estimate dchang e i

n mea n systoli c bloo dpressur e fo r eac h doubli" * o f bloo dlea d(e.g. , fro

m8-1 6 pg/dL ) togethe r

wit h 95 % confiden

t limits . (Tw

o othe r larg e studie s in Canad aan dDenmar k showed" significan t association , bu t

estimates.ar e no t

know n to us. )P. 8

BLOOD LEAD AND BLOOD PRESSURE IN BRITISH MEN 29

od y' s n g ice n o t

i v 1 to 2 mmH g for

adoublin g o

f bloo dlea d 111 3 ntration . j t

s houl d als o b e note dtha t tw o othe r conc e die s i n Canad a(18) an dDenmark (19) o n 219 3 an d Q^ O subjects , respectively , hav e foun dn o significan t ociation , bu t

w e d o no t

hav e thei r

regressio n result s aSS

. , jji e a s yet . Thi s woul dimply tha t th e lowe r

figure 3 f 1 m mHg systoli c increas e pe r doublin g o

f bloo dlea d ° s mor e plausible . 

## Discussio n Bloo d Lea d an d Bloo d Pressur e i n BRH S ^ d NHANE S I I Earlie r publication s o n lea dan dbloo dpressur e from th e BRH S (3) an dNHANE S I I (5 ) hav e appeare dt o reac h widel y divergen t

conclusions ; thi s journa l issu e provide s a n opportunity fo

r reassessmen t

o f thes e tw o studie s usin g comparabl e statistica l approaches . Whil e NHANE S I I continue s t o sho w amarkedl y stronge r relationshi p i n th e selecte dsubgrou p o f whit e male s age d4 0 t o 59 , thi s discrepanc y i s largel y remove donc e on e compare s regressio n result s fo r al l adul t male s i n th e tw o studies . Alcoho l Consumptio n The choic e o

f othe r covariate s a s potentia l con founder s ha s ha da n importan t effec t o n th e tw o studies ' results . I n th e BRHS , alcoho l consumptio n i s o f particula r importance , bein g positivel y relate dt o bloo dpressur e an dbloo dlead . I t shoul db e note dtha t the alcohol-bloo dpressur e relatio n in th e BRH S i s virtuall y unaffecte db y adjustmen t fo r bloo dlea dlevels , indicatin g that alcohol' s effect

o n bloo dpressur e i s no t produce db y any lead-relate dmechanism , suc h a s th e lea dcontent o f alcoholi c drinks . Thi s support s th e vie w tha t alcohol i s agenuin e confounder . I t i s impossibl e t o obtai n afull y comprehensiv e measur e o f alcoho l con sumptio n by simpl e questionnair e (e.g. , in th e BRHS , al l me n drinkin g ove r

si x unit s pe r

da y ar e groupe d together , an dthi s ma

y mea n tha t

th e alcohol-relate d componen t i n th e univariat e lead-bloo dpressur e rela

tionshi p i s no t completel y allowe dfor

i n th e multipl e regression . Thi s sam e poin t relate s t o NHANE S II , a s thei r informatio n o n alcoho l wa s no t very detailed . 

## Allowanc e fo r

Geographi c Difference s Bot h NHANES I I an dth e BRH S ar e cross-sectiona l survey s amon g individual s fro mman y geographica l areas . The y hav e atwo-stag e design , th e first bein g nonrandomselectio n o

f geographi c location s an dth e secon dbein g rando mselectio n o f individual s fro ma define dsamplin g fram e i n eac h location . I t ha s no w becom e recognize dtha t

particularly whe n studyin g a w ea k statistica l associatio n suc h a s lea dan dbloo d pressur e i t

i s importan t

t o tak e accoun t

o f thi s geographica

l componen t

t o th e study . I n th e BRHS , failur e to adjus t

for tow n o f residenc e actuall y under

playe dth e significanc e o f th e statistica l association . However , in NHANE S II , th e strengt h o f associatio n wa s reduce dafter

adjustmen t

fo r site , perhap s becaus e site s wit h highe r mea n bloo dpressur e tende dt o hav e highe r mea n bloo dlea dlevels , possibl y a s aconse quenc e o f th e tim e trend s in both bloo dleadan dpercen t urba n dweller s at

th e samplin g sites . 

## Overvie w o

f Majo r Studie s I n ou r overvie w o

f th e majo r

studie s i n thi s field (Fig . 7 ) w e hav e aime dfor a n objectiv e quantificatio n o f th e magnitude s o

f associatio n betwee n bloo dlea d an dsystoli c bloo dpressure . Subjectiv e assessmen t o f suc h dat aten dt o classif

y studie s a s eithe r

significan t o r nonsignificant , bu t

thi s dichotomou s attitud e towar dassessmen t

o f scientifi c hypothese s i s over simplisti c an dcounter-productive . I t fail s t o tak e accoun t o f th e limite dpowe r

tha t individua l studie s hav e t o detec t

wea k relationships . W e hav e bee n abl e t o demonstrat e som e consistenc y betwee n th e large r studie s suggestiv e o

f avery wea

k positiv e association , bu t i t i s als o importan t

t o realiz e th e limitation s o f thi s approach . Specifically , th e differen t studie s hav e adopte dver

y different strategie s towardth e selectio n o f othe r covariate s t o b e use di n th e regressio n models . Fo r instance , th e BRH S selecte dalimite dse t o f persona l covariate s relate dt o bloo dpressur e an dbloo dlead , wherea s NHANE S I

I di da n extensiv e selectio n proces s acros s awid e rang e o

f personal , biochemical , an d dietar y data . Th e Wels h analyse s undertake n thu s fa r hav e onl y adjuste dfor

age . Greate r

consistenc y in th e handlin g o

f confounder s woul dprovid e mor e reas suranc e a s t o th e validit y o f ou r overvie w approach . However , apreviou s NHANE S I I repor t (5) ha s claime dastability o

f bloo dlead-bloo dpressur e asso ciatio n fo r

severa l differen t

approache s t o selectin g covariate s in thei r

data . Therefore , i t

seem s plausibl e t o argu e tha t

th e overal l assessmen t o f th e dat ao n al l availabl e studie s i s no t

likel y t o b e change dsubstan

tiall y b y furthe r

statistica l analysis . 

## Interpretatio n o f

th e Statistica l Associatio n Th e crucia l issu e i s whethe r thi s evidenc e o

f awea k statistica l associatio n i s evidenc e o f acausa l effect

o f low

leve l lea dexposure . Her e w e nee dt o accep t th e limita

tion s o f observationa l epidemiology , whic h canno t provid e definitiv e evidenc e o f acausa l link . Further

more , th e strengt h o

f statistica l evidenc e her e i s no t substantial . Th e difficult y o f completel y allowin g for importan t confounders , e.g. , alcoho l consumptio n an d th e fac t tha t onl y tw o o

f th e si x larges t

studie s hav e achieve dstatistica l significance , woul dsugges t tha t thi s i s on e are awher e th e epidemiologica l approac h canno t provid e aclear

answer . It

woul db e prematur e t o conclud e tha t

thes e statistica l findings ar e o f practica l relevanc e t o publi c health .P. 9

3 0 POCOCK ETAL. 

## Bloo dLead , Hear t

Attacks , an dStroke s W e ar e no t

awar e o

f an y previou s prospectiv e epidemiologica l studie s o f coronar y hear t

diseas e an d strok e tha t

hav e include dbloo dlea da s apotentia l ris k factor . However , i t

ha s bee n hypothesize dtha t trac e metal s suc h a s lea dma

y explai n th e relationshi p be

twee n sof t wate r an dcardiovascula r

diseas e an dals o tha t clinica l lea dpoisonin g include s sign s suggestiv e o f atoxi c effect

on th e hear t

(20). Also , Pirkl e e t

al . (5 ) hav e extrapolate dfro mthei r bloo dlead-bloo dpressur e relationshi p in NHANE S I I dat at o argu e tha t ther e coul db e substantia l reduction s i n th e number s o f stroke s an dhear t

attack s a s aresul t

o f th e declin e i n bloo dlea dlevel s i n th e Unite dState s sinc e th e mid

1970s . I n thi s pape r

w e hav e show n tha t

mea n bloo dlea d level s ar e somewha t

highe r i n individual s wh o sub

sequentl y hav e ahear t

attac k o r stroke . However , after allowanc e for

cigarett e smokin g an dtow n o f residence , thi s associatio n i s n o longe r statisticall y significant . On e canno t

automaticall y infe r

tha t low-leve l lea d exposur e ha s n o effect

on ris k o f strok e an dhear t

attack , bu t th e evidenc e clearl y indicate s tha t lea di s no t

a major contributo r

t o ris k o f cardiovascula

r disease . I t

i s stil l wort h considerin g whethe r apossibl e bloo dlead

bloo dpressur e relationshi p coul dhav e implication s fo r ris k o f majo r cardiovascula r

events , bu t

th e estimate s provide db y earlie r researc h (5 ) woul dsee m extravagant , a s th e collectiv e evidenc e suggest s amuc h weake r bloo dlead-bloo dpressur e relationshi p tha n the y hav e previousl y claimed . Thus , ther e remain s th e possibilit y tha t

an extremel y smal l proportio n (les s tha n 1% ) o f stroke s an dhear t

attack s coul db e prevente d b y substantia l reduction s i n mea n bloo dlea dconcen tratio n i n th e genera l population . Thi s inferenc e depend s o n acausa l interpretatio n o f statistica l asso ciations , bu t

w e hav e n o direc t

evidenc e tha t

change s i n populatio n lea dlevel s woul dactuall y affec t th e population' s bloo dpressure , an dther e eve n remain s controvers y ove r

whethe r lowerin g o

f bloo dpressur e reduce s th e risk

o f hear t attack s (21). I n conclusion , w e se e n o convincin g epidemiologica l evidenc e a t presen t t o suppor t

th e clai mtha t

moderat e elevation s in bod y lea dburde n ar e o

f relevanc e t o th e ris k

o f cardio

vascular disease . Th e Britis h Regional Hear t Stud y i s aBritis h Hear t Foundatio n Researc h Grou p an di s als o supporte db y th e Medica l Researc h Council , Departmen t

o f Healt h an dSocia l Security , th e Scottis h Endowmen t

Researc h Trus t

an dth e Ches t

Hear t an dStrok e Association . Estimatio n o

f bloo dlea dconcentration s wa s supporte db y th e Departmen t

o f Healt h andSocia

l Security . REFERENCE S 1 . Kopp , S . J. , Glonek , T. , Erlanger , M. , Perry , E . F. , Perry , H . M. , an d 2 . 3 . 4 . 5 . Barany , M . Cadmiuman dleadeffect s o n myocardia l functio n an d metaboUsm . J . Environ . Pathol . Toxicol . 4:205-22 7 (1980) . Victery , W. , Vander, A . J. , Shulak , J . M. , Schoeps , P. , an dJulius , S . Lead , hypertensio n an dth e renin-angiotensi n syste min rats . J . Lab . Clin . Med . 99 : 354-36 2 (1982) . Pocock , S . J. , Shaper , A G. , Ashby , D. , Delves , T. , an dWhitehead , T P . Bloo dleadconcentration , bloo dpressur e an drena l function . Br . Med . J . 289 : 872-87 4 (1984) . Harlan , W . R. , Landis , J . R. , Schmouder , B . L. , Goldstein , N . G. , an d Harlan , L . C . Bloo dleadan dbloo dpressure : Relationshi p i n th e adolescen t an dadul t US population . JAM

A 253 : 530-53 4 (1985) . Pirkle , J . L. , Schwartz , J. , Landis , J . R. , an dHarlan , W . R. Th e relationshi p betwee n bloo dlea dlevel s an dbloo dpressur e an dit s cardiovascula

r ris k implications . Am . J . Epidemiol . 121 : 246-25 8 (1985) . Shaper , A . G. Pocock , S . J. , Walker , M. , Cohen , N . M. , Wale , C . J. , an dThompson , A . G . Britis h Regiona l Hear t Study : Cardiovascula

r ris k factor s in middle-age dme n in 2 4 towns . Br . Med . J . 283 : 179-18 6 (1981) . Bruce , N . G. , Shaper , A . G. , Walker , M. , an dWannamathee , G . Observe r bia s in bloo d pressur e studies . J . Hypertension , i n press . Shaper , A G. , Pocock , S . J. , Walker , M. , Phillips , A . N. , Whitehead , T P. , an dMacfarlane , P . W . Ris k factor s fo

r ischaemi c hear t disease : Th e prospectiv e phas e o f th e Britis h Regiona l Hear t Study . J . Epidemiol . Communit y Healt h 39:197-20 9 (1985) . Cook , D . G. , Shaper , A . G. , Pocock , S . J. , an dKussick , S . J . Givin g up smokin g an dth e risk

o f hear t attack . Lance t

ii : 1376-8 0 (1986) . Grandjean , P. , Olsen , N . B. , an dHollnagel , H . Influenc e o f smokin g an dalcoho l consumptio n o n bloo dlea dlevels . Int . Arch . Occup . Environ . Healt

h 48 : 391-39 7 (1981) . Shaper , A . G. , Pocock , S . J. , Walker , M. , Wale , C . J. , Clayton , B. , Delves , H . T.,,an d Hinks , L . Effect s o f alcoho l an dsmokin g o

n bloo dleadin middle-age dBritis h men . Br . Med . J . 284 : 299-30 2 (1982) . Shaper , A . G „ Ashby , D. , an dPocock , S . J . Bloo dpressur e an d hypertensio n i n middle-age dBritis h men . J . Hypertension , i n press . 13 . Pocock , S . J. , Shaper , A . G. , Walker , M. , Wale , C . J. , Clayton , B. , Delves , T , Lacey , R. F. , Packham , R. F. , an dPowell , P . Effects o f ta p wate r lead , wate r

hardness , alcohol , an dcigarette s o n bloo d lea dconcentrations . J . Epidemiol . Community Healt h 37 : 1- 7 (1983) . 14 . Nationa

l Academ y o f Sciences . Geochemistr

y o f wate r i n relation t o cardiovascula

r disease . NAS , Washington , DC , 1979 . Pocock , S . J. , Shaper , A G. , Cook , D . G. , Packham , R. F. , Lacey , R. F. , Powell , P. , an dRussell , P . F . Britis h Regiona l Heart Study : Geographi c variation s i

n cardiovascula

r mortality , an dth e rol e o

f water quality . Br . Med . J . 280:1243-124 9 (1980) . Schwartz , J . Evidenc e for aBloo dLead-Bloo dPressur e Rela

tionshi p (memorandu mt o th e Clea n Ai r Scienc e Advisor

y Committee) . Environmental Protectio n Agency , Washington , DC , 1985 . Elwood , P . C , Davey-Smith , G. , Oldham , P . D. , an dToothill , C Two Wels h survey s o

f bloo dlea dan dbloo dpressure . Environ , Healt h Perspect . 78:119-12 1 (1988) . Neri , L . C , Hewitt , D. , an dOrser , B . Bloo dlea dan dbloo d pressure : Analysi s o

f cross-sectiona l an dlongitudina l dat afro m Canada . Environ . Healt

h Perspect . 78:123-12 6 (1988) . Victery , W. , Tyroler , H . A. , Volpe , R. , an dGrant , L . D . Summar y ° f Discussio n Sessions : Symposiu mo n Lead-Bloo dPressur e Relationships . Environ . Healt h Perspect . 78:139-15 5 (1988) . Shaper , A . G . Cardiovascula r diseas e an dtrac e metals . Proc . Roy * Soc . Londo n B 205:135-14 3 (1979), . 21 . Medica

l Researc h Council Workin g Party . MR C tria l o f treatmen t o f mil dhypertension : Principal results . Br . Med . J . 291 : 97-10 4 (1985) . 8 .

10 . 1 1 1 2

15 . 1 6 1 7 1 8 1 9 2 0