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### I P If'ii 1 Environmental Health Perspectives Vol. 78, pp. 53-56, 1988



### EP A AI R DOCKE T 

# Th e Relationshi p o

f Bloo d Lea d t o Systoli c Bloo d Pressure i n a Longitudina l Stud y o f Policeme n b y Scott T . Weiss,* 1 , 

# Alvar o Munoz, * Am y Stein, f 

# Davi d Sparrow, 8 

# an d Fran k E . Speizer +

W e examine d th e relationshi p o f bloo d lea d leve l t o systoli c an d diastoli c bloo d pressur e i n a longitudina l stud y o f

8 9 Boston , MA

, policemen . A

tth e secon d examinatio n bloo d lea d leve l an d bloo d pressur e wer e measure d i n triplicate . Bloo d pressur e measurement s wer e take n i n a simila r fashio n i n year s 3 , 4 , an d 5 . Multivariat e analysi s usin g a first-orde r autoregressiv e mode l reveale d tha tafte r adjustin g fo r previou s systoli c bloo d pressure , bod y mas s index , age , an d cigarett e smoking , a n elevate d bloo d lea d leve l wa s a significan tpredicto r o f subsequen tsystoli c bloo d pressure . Bootstra p simulation s o f thes e model s provide d supportin g evidenc e fo r th e observe d association . Thes e data sugges ttha tbloo d lea d leve l ca n influenc e systoli c bloo d pressur e eve n withi n th e normal range . 

### Introductio n A variet y o f epidemiologi c studie s hav e suggeste da smal l bu t statisticall y significan t

effec t o f bloo dlea d leve l o n systoli c bloo dpressur e an dsugges t aweake r associatio n wit

h diastoli c bloo dpressur e a s wel l (1-4). Thes e studie s wer e cross-sectiona l in desig n an din

volve dlarg e number s o

f subjects . W e examine dth e relationshi p betwee n bloo dlea d leve l an dlongitudina l chang e in bloo dpressur e in a smal l grou p o f policeme n unde r

observatio n fo

r healt h outcome s relate dt o environmenta l work exposures . Usin g computer-intensiv e statistica l techniques , w e demonstrate da

n effect o f bloo dlea do n systoli c bloo d pressure simila

r t o tha t see n in larg e cross-sectiona l surveys . 

### Material s an d Method s Th e population s o

f subject s studie dha s bee n char

acterize din previou s report s (5-7). Th e me n o f tw o 'Charles A . Dan aResearc h Institut e an dth e HarvardThorndik e ' Laborator y o f th e Bet h Israe l Hospita

l an dDepartmen t

o f Medicine , Harvar dMedica l School , Boston , M

A 02115 . tChannin g Laboratory , Brigha man dWomen' s Hospita l an d Departmen

t o f Medicine , HarvardMedica l School , Boston , M

A 02215 . ^Departmen t

o f Epidemiology , John s Hopkin s Schoo l o f Publi c Health, Baltimore , M

D 21218 . §Normativ e Aging Study , V

A Outpatien t

Clinic , Boston , MA. separat e unit s o f th e Bosto n Polic e Departmen t wer e see n a t thei r respectiv e statio n house s durin g norma l workin g hours . Preliminar y observation s include d measure s o

f height , mad e wit

h subject s i

n stockin g feet , an dweigh t

o f subject s wearin g stree t

clothing , withou t jacket s ad d usua l accessor y equipment . A detaile d questionnair e containin g demographic , smoking , occupational , an dresidentia l history , an damodifie d versio n o f th e Britis h Medica l Researc h Counci l Res

piratory Diseas e Questionnair e wer e administere d b y traine dinterviewers . In addition , informatio n abou t cardia c complaint s wer e obtainedb y astandar dver sio n o f th e Ros e Angin aQuestionnair e (8). Pulmonar y functio n testin g wa s measure do n a water-fille dspiromete r

an di s th e subjec t

o f aseparat e repor t (7). A bloo dspecime n wa s obtaine dt o determin e hematocri t

concentratio n an dt o mak e periphera l smear s t o asses s basophili c stippling . Bloo dlea d con centratio n wa s determine do n asmal l sampl e o f sub

ject s t o validat e thei r

traffi c exposur e histories . Bloo d lea dconcentratio n wa s determine dusin g th e tech

niqu e o f atomi c absorptio n spectrophotometr y (9). Bloo dpressur e wa s measure dwit h arando mzer o bloo dpressur e machin e t o minimiz e digi t preference . With th e subjec t

seated , systoli c pressur e an d fifthphas e diastoli c pressur e wa s measure di n th e lef t arm to th e neares t

2 m mHg . Th e stud y wa s alongitudina l investigatio n with initia l screenin g beginnin g in 1969-197 0 an dwit hP. 3

5 4 WEISS ETAL. observation s complete di n 1974-1975 . Bloo dpressur e (i n m mHg ) wa s recorde din year s 2 throug h 5 . Th e mean o f triplicat e measure s o

f systoli c pressur e an d diastoli c pressur e at

eac h visi t

wa s use dfo

r analysis . Ag e in years , bod y mas s inde x (i n kg/m 2 ) , an dcur ren t smokin g statu s (recorde da s 1 = current , 0 = neve r o r exsmoker ) wer e availabl e for year s 1 throug h 5 . Curren t cigarett e smoker s wer e define da s subject s wh o smoke da s man y a s on e cigarett e ada y in th e stud y year . Bloo dlea dvalue s (i n ug/10 0 mL) wer e collecte d onl y i n year 2 . Base don th e distributio n o f bloo dlea d value s in ou r

sampl e an di

n tha t o f th e Unite dState s populatio n (10), bloo dlea dvalue s wer e divide dint o hig h ( > 3 0 ug/10 0 mL

) an dlow (

> 20 an d< 3 0 ug/10 0 mL) group s for

purpose s o

f th e regressio n analysis . Thi s gav e comparabl e number s o f subject s in eac h category . Thes e tw o group s wer e compare dwit h ou r referenc e grou p i

n whic h value s wer e < 20 ug/10 0 mL . T o examin e th e relationshi p o f bloo dlea dconcen tratio n t o chang e i

n bloo dpressur e ove r

th e 4 year s o

f th e study , aMarko v typ e autoregressiv e mode l wa s use d(11). In thi s model , bloo dpressur e (systoli c o r diastolic ) at

tim e r(F t ) i s relate dto bloo dpressur e a t t-1 (y t_i ) an dth e level s o

f othe r covariate s at

tim e t o r a t previou s time points . Specifically , th e mode l take s th e for m y , M+C(r l

_ 1 )+B 1 A 11 +B 2 X 2 t + ...+e t Thi s mode l ha s severa l advantage s fo r th e analysi s o

f longitudina l dat asets . Specifically , th e mode l use s th e dat aefficientl y sinc e an y individua l fo r who m complet e dat aar e availabl e for an y tw o consecutiv e year s (t an dt-1) will contribut e dat at o th e model . Secondly , th e mode l doe s no t impos e aparticular

shap e (i.e. , linearity ) o n th e relationshi p betwee n th e depen

den t an dindependen t

variables . Finally , thi s mode l can b e fittedusin g ordinar y statistica l software pack

ages . Th e mode l assume s tha t th e residua l e's ar e independen t

wit h constan t

varianc e (0 2 ) bot h withi n an dbetwee n individuals . A n additiona l assumptio n i s tha t th e relationshi p betwee n th e outcom e variabl e an d th e independen t

variable s i s th e sam e for al l indi

vidual s (fixe

deffect s model) . A cross-validatio n was . undertake n t o determin e i f th e magnitud e an dsignificanc e o f th e regressio n coefficient s obtaine dfo r th e bloo dlea dvariable s wer e th e resul t o f th e disproportionatel y larg e contributio n o f value s fromafe

w individual s (12). T o determin e i f a n individual wa s a

n outlier , w e use damodificatio n o f Tukey' s fence s applie dt o th e cross-validatio n exercis e (13). Afte r th e ful l cross-validation , w e determine dth e subjec t whos e exclusio n ha s th e larges t influenc e on an y regressio n coefficien t (measure di n unit s o f interquartil e rang e awa

y fro meithe r

th e first o r th e thir dquartile s o

f th e distributio n o

f th e value s o

f al l th e regressio n coefficient s obtaine dfro mth e cross validation) . Thi s individua l wa s the n remove dan d th e cross-validatio n repeated . Thi s proces s wa s con tinue dunti l all regressio n coefficient s resultin g fro m across-validatio n exercis e wer e withi n fiv e inter

quartil e rang e unit s awa y fromeithe r

th e first o r th e thir dquartiles . T o determin e th e variability o f th e regressio n coef

ficients, withou t

th e assumptio n tha t

th e residual s ar e normall y distributed , abootstra p analysi s wa s per forme d(14). I n thi s analysis , w e generate d100 0 (bootstrap ) sample s equa l in siz e t o th e origina l sampl e b y randoml y samplin g wit h replacemen t

fro mth e origina l poo l o

f individuals . Th e distributio n o f th e coefficient s fo

r th e bootstra p sample s can b e considere d a s thoug h the y wer e comin g fro mrea l samples , and thu s the y provid e ameasur e o f th e statistica l precisio n o f th e original estimate s on th e regressio n coefficients . 

## Result s Tabl e 1 present s th e cross-sectiona l dat afo r th e vari

able s use din th e longitudina l regressio n analysis . I n th e secon dyea r

o f th e study , whe n bloo dlea dwa s initiall y measured , th e averag e subjec t wa s anormo tensive , middle-age dma n wh o wa s overweight . Roughl y half

o f al l subject s wer e cigarett e smokers , and one-quarte r

o f all subject s ha daconcentratio n o f bloo d lea d> 3 0 ug/10 0 mL . A tota l o f 9 5 me n ha dbloo dlea ddetermination s out o f atota l o f 31 4 (30%) . Informatio n for si x me n wa s missin g for

al l covariates . Th e othe r 8 9 me n wer e entirel y comparabl e t o me n withou t bloo d lea dmeasurement s fo

r al l covariate s (17). W e modele dth e leve l o

f curren t systoli c bloo dpres Tabl e 1 . Cros s sectiona l dat a fo r bloo d pressure , age , bod y mas s index, bloo d lead , an d smokin g fo r Bosto n policeme n by stud y year . Yea r 2 Yea r 3 Yea r 4 Yea r 5 Paramete r Systoli c pressure , m

mH g Diastoli c pressure , m

mH g Age , year s Bod y mas s index , kg/m 2 Bloo dlead , ug/10 0 m

L <2 0 20-2 9 >3 0 Curren t smokers , % n

24 6 24 6 26 7 25 3 3 6 3 3 2 6 18 2 Mea n 126. 7 84. 8 46. 6 27. 8 40. 4 37. 1 22. 5 46.1 % SD 20. 1 13. 8 8. 5 3. 2 n

19 9 19 8 20 0 20 0

21 3 Mea

n 126. 6 83. 9 47. 3 28. 1

47.8 % SD 17. 6 10. 7 9. 0 3. 3 «

14 9 16 7 19 2 189

206 Mea

n 128. 7 82. 7 48. 1 28. 1

49.9% SD 17. 6 11. 3 8. 5 2. 9 H

19 4 19 4 19 3 18 5

19 2 Mea n 130. 9 85. 4 49. 3 28. 0

48.4 % S D 17. 3 10. 6 8. 1 3. 2

_ 

# LP. 4

BLOOD LEAD AND SPECIFIC BLOOD PRESSURE 5 5 sur e a t tim e t a s afunctio n o

f previou s systoli c bloo d pressur e a t

f-1 , othe r

independen t

variable s know n t o influenc e bloo dpressur e an dbloo dlea d(Tabl e 2) . Sevent y individual s provide d16 2 pair s o f dat a (consecutiv e examinations ) for thi s regression . Ther e wa s astatisticall y significan t associatio n (p = 0.036 ) between ahig h (

> 3 0 ^g/10 0 mL

) leve l o f bloo dlea d andsubsequen t

systoli c bloo dpressure . Simila r modelin g wa s performe dfo r diastoli c bloo dpressure , but n o significan t

associatio n wa s foun d(15). T o investigat e whethe r

th e observation s note dabov e wer e th e produc t

o f afe w influential points , a

n iterativ e cross-validatio n analysi s wa s undertaken . Fo r systoli c pressure , thre e individual s wer e exclude ds o tha t al l regressio n coefficient s resultin g fro macross-valida

tion wer e withi n five interquartil e rang e unit s awa y fro meithe r th e first o r th e thir dquartile . Th e regres sio n wa s repeate dwithou t

th e dat ao

f thes e subjects , an d th e result s ar e presente din Tabl e 3 . Althoug h th e associatio n betwe n hig h systoli c pressur e an dhig h bloo dlea dleve l note dabov e i s onl y o f borderlin e sig

nificanc e (p = 0.097) , th e magnitud e an ddirectio n o f th e observe drelationship s ar e essentiall y unchanged . O n th e othe r

hand , th e effec t

o f th e othe r

covariate s (age , bod y mas s index , an dsmoking ) i s mor e con sisten t wit h know n effect s o

f thes e variable s o n bloo d pressure . I n summary , th e exclusio n o f influentia l point s improve dth e relationshi p betwee n systoli c pressur e an dth e independen t variable s (prio r

systoli c Tabl e 2 . Relationshi p o f systoli c bloo d pressur e i n Bosto n policeme n a ttim e t

t o prio r systoli c bloo d pressure , bod y mas s index , age , smoking , an d bloo d lead. 3 Variabl e Coefficien t S E Intercep t 125.38 3 Prio r bloo dpressure , 12 7 m mH g 0.51 8 Bod y mas s index , 2 8 kg/m 2 0.58 0 Age , 4 7 year s 0.17 6 Smoker b 2.32 4 Bloo dlead , low : 0.22 4 Bloo dlead , high d5.80 4 0.05 9 0.34 3 0.13 2 2.08 2 2.25 1 2.74 8 < 0.00 1

0.09 3 0.18 5 0.26 6 0.92 1 0.03 6 "Regressio n wa s don e o n 16 2 pair s contribute db y 7 0 subjects . b l - yes ; 0 = no . <Lo w = 20-2 9 ug/10 0 mL . d Hig h = > 3 0 ug/10 0 mL . Tabl e 3 . Relationshi p o f systoli c bloo d pressur e i n Bosto n policeme n a ttim e t

t o independen tvariable s excludin g influentia l points. " Variabl e Coefficien t Intercep t 125.35 7 Prio r bloo dpressure , 12 7 m mH g 0.49 7 Bod y mas s index , 2 8 kg/m 2 0.65 5 Age , 4 7 year s 0.21 0 Smoker b 4.44 6 Bloo dlead , low * -1.41 5 Bloo dlead , high d4.46 7 S E 0.06 4 0.33 0 0.13 0 2.06 6 2.23 3 2.67 2 P

< 0.00 1 0.04 9 0.10 8 0.03 3 0.52 7 0.09 7 a

<

_ i a o o

- 1 C D *

_ l c c o u . r-CIEFFI U I O O

FlG U degressio n wa s don e o n 15 5 pair s contribute db y 6 7 subjects . b l » yes ; 0 = no . c Lo w = 20-2 9 pg/10 0 mL . d Hig h = > 3 0 ug/10 0 m L pressure , body mas s index , age , smokin g status ) an d di dno t dramaticall y chang e th e relationshi p betwee n systoli c pressur e an dhig h bloo dlead . Thi s provide s furthe r suppor t fo r th e observe dassociatio n o f thes e variables . I n a n attemp t t o estimat e th e variabilit y (withou t

th e normality assumption ) o f th e paramete r

estimate s fo

r bloo dlead , bootstra p simulation s o f th e mode l wer e performe dfo

r systoli c pressur e (Fig . 1) . Fo r thi s pur pose , w e generate d1000 separat e rando msample s b y samplin g wit

h replacemen t

fro mth e 7 0 subject s wh o provide ddat ao n systoli c pressure . Figur e 1 suggest s tha t th e coefficient

fo r hig h bloo dlea di s greate r tha n zer o wit h amea n valu e o

f 5. 8 (C . I . 90% , 1.5-11. 5 mm Hg) . Thi s bootstrappin g simulatio n confirm s th e associatio n betwee n hig h bloo dlea dan dhig h systoli c pressur e withou t

th e nee dt o assum e normality o f th e residuals . 

## Discussio n Thi s longitudina l analysi s demonstrate s tha t bloo d lea dlevel s at

th e uppe r

rang e o f norma l ar e associate d with mil delevation s i n systoli c bloo dpressur e in normotensiv e workin g men . Th e powerfu l statistica l technique s use din thi s analysi s hav e allowe du s t o estimat e a

n effect o f bloo dlea do n bloo dpressur e quit e simila r t o tha t observe di n larg e cross-sectiona l survey s (2-4). It

i s wort h notin g tha t

ou r modelin g approac h woul dhav e allowe dfor repeate dmeasure ment s o f bloo dlead . Greate r

precisio n i

n th e measur e o

f exposur e shoul dhav e enhance dth e statistica l powe r o f th e analysis . Selectio n bia s i s unlikel y t o accoun t fo r th e observe d 2 0

1 5 10

- 5 -1 0 

### t i .

• • mmm m • • 4 • • • • • •

-1 0 - 5 0 5 1 0 1 5 COEFFICIENT S FO R HIG H BLOO D LEA D 2 0 FIGUR E 1 . Plo t

o f 100 0 bootstra p coefficient s fo r hig h an dlo w bloo dlea d effec t o n systoli c bloo dpressure . On e do t ma y represen t

multipl e dat apoints . (* ) Coefficien t fo r bloo dlea dincludin g al l subjects , Tabl e 2 ; (A ) coefficien t fo r bloo dlea dexcludin g influentia l subjects . Tabl e 3 .P. 5

5 6 WEISS ETAL. relationships , a s subject s wit h bloo dlea dwer e essen tiall y simila r

subject s withou t

bloo dlea d(17). In addition , n o appreciabl e selectiv e los s t o follow-u p coul d b e observe di

n thi s cohort

(Tabl e 1) . In additio n t o possibl e bias , th e smal l numbe r o f subject s coul dinfluenc e th e precisio n o f th e regressio n coefficients . Th e cross-validatio n an dsubsequen t stud y o f influentia l dat apoint s (Tabl e 3 ) provid e a n estimat e o f th e smokin g effec t

mor e consisten t

wit h publishe d dat atha n tha t

observe dwit

h all th e dat a(Tabl e 2) . In addition , th e dose-respons e relationshi p for lo w an d hig h bloo dlea di s mor e internall y consisten t whe n th e influentia l dat apoint s ar e exclude d(Tabl e 3) . Th e influentia l point s wer e exclude din ablinde d fashion , i.e. , withou t

regar dt o th e magnitud e o r di

rectionality o

f thei r effect o n th e paramete r

estimates . Althoug h th e exclusion s d o influenc e statistica l sig

nificance , th e paramete r

estimate s fo

r th e effect o f hig h bloo dlea do n systoli c pressur e ar e similar in bot h analyse s (Table s 2 an d3) . Thi s suggest s tha t ou r result s ar e no t drive n b y dat afro mafe w individuals , a

n importan t consideratio n mor e likel y in asmal l dat a set . Th e bootstra p analysi s assesse s th e statistica l preci

sio n fo r th e effect

o f bloo dlea don bloo dpressur e an d indicate s tha t

th e 90 % confidenc e interva l for th e paramete r estimat e fo

r th e effect o f hig h bloo dlead(i.e. , > 3 0 ug/10 0 mL

) o n systoli c pressur e range s 1. 5 t o 1 1 m mHg . Wha t

remain s unclea r

i s th e reaso n for

th e elevatio n i

n bloo dleadin thes e men . Thes e 90 % confidenc e limit s encompas s al l o f th e poin t estimate s fro mlarge r

cross-sectiona l surveys . Indeed , th e estimat e o

f a5 m mH g increas e in systoli c bloo dpressur e wit

h hig h bloo dlea di s almos t identica l t o tha t observe di

n NHANE S wit

h 8000 subject s (3,4). Previou s investigation s b y Pococ k e t al . (15) an d Shape r e t al . (16) hav e suggeste darol e fo r both alcoho l consumptio n an dcigarett e smokin g a s environ

menta l source s o

f lea dexposur e othe r

tha n drinkin g water . W e teste dalcoho l in ou r mode l an dcoul dfind n o independen t

effect o f alcoho l consumptio n o n bloo d pressur e eithe r

cross-sectionall y o r

longitudinally . Th e fac t tha t bloo dlea dcontribute dindependentl y t o ou r mode l (Table s 2 an d3 ) whe n cigarett e smokin g wa s includedsuggest s tha t

bloo dlea dleve l itself

, rathe r tha n cigarett e smoking-induce dbloo dlea delevation , ha s a n influenc e o n systoli c pressure . Recently , calciu mintak e ha s bee n show n t o influ

enc e bloo dpressur e an dbloo dlea d(18). W e hav e n o informatio n o n calciu mfo r thi s cohor t

an dthu s coul dno t examin e thi s relationship . Clearly , furthe r

epidemiologi c an dphysiologi c wor k i s necessar y t o elucidat e th e mechanism s fo r th e bloo dlead-bloo dpressur e relationship . However , ther e seem s t o b e remarkabl e consistenc y in th e epidemio

logi c data , suggestin g asmal l bu t consisten t

increas e in systoli c bloo dpressur e wit h elevate dbloo d lea d levels . Thi s wor k i s supporte din par t

by Gran t

#HL1917 0 fromth e Division o f Lun g Diseases , Nationa

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