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BLOO D LEAD-BLOO D PRESSUR E RELATIONSHIPS : ALCOHO L INTAK E AN

D HEMOGLOBI NA S CONFOUNDER S

P.Grandjean, 1 H.Hollnagel, ^ L.Hedegaard, ^ J.M.Christensen ^ an d S.Larsen ^P. 3

Grandjea n e t al
. pag e 2

'Departmen t o f Environmenta l Medicine , Odens e University , J.B.Winslowsve j 19 , 500 0 Odense , Denmar k ^Th e Populatio n Studie s i n Glostrup , Copenhage n Count y Hospital , Glostrup , Denmar k ^Danis h Nationa l Institut e o f Occupationa l Health , Copen

hage n , Denmar k Decease d Reprin t request s t o Dr . Philipp e Grandjean , Departmen t o f Environmenta l Medicine , J.B.Winslow s ve j 19 , 500 0 Odens e C , Denmark
. Thi s wor k wa s supporte d b yth e Danis h Healt h Insuranc e Foundation , th e Danis h Hear t Foundation , an d th e Danis h Medica l Researc h Council
.

Runnin g head : Bloo d lead an d bloo d pressur eP. 4

Grandjea n e t a l pag e 3 Grandjean , P . (Departmen t o f Environmenta l Medicine , Odens e University , 500 0 Odense , Denmark) , H.Hollnagel , L.Hedegaard , J.M.Christensen , S . Larsen . Bloo d lead-bloo d pressur e relationships : Alcoho l intak e an d hemoglobi n a s confounders
. A mJ Epidemio l 1988;... : Acohor t o f 50 4 me n an d 54 8 wome n bor n i n 193 6 an d residin g i n th e Glostru p area , Denmark , wer e firs t see n a t ag e 40 , an d 45 1 me n an

d 41 0
wome n underwen t a complet e re-examinatio n 5 year s later
. Th e examination s include d bloo d lead concentratio n an d bloo d pressur e assessmen t unde r carefu l qualit ycontrol
. Th e bloo d lead level s average d 1 3 an d 9 ug/10 0
m l a t ag e 4 0 an

d 9 an d 6 ug/10 0 m l a t ag e 4 5 year s i n me n an d women , respectively
. Aslightl yincrease d bloo d lead wa s see n i n 40-year-ol d
wome n wit h a systoli c bloo d pressur e abov e 14 0 mmH g and/o r a diastoli c pressur e abov e 9 0 mmHg . Systoli c bloo d pressur e i n me n an d wome n an

d diastoli c bloo d pressur e i n wome n correlate d significantl ywit h lo g bloo d lea d a t ag e 4 0 years , bu t no t a t ag e 45 , a doublin g i n bloo d lead being associate d wit h a n increas e i n bloo d pressur e o f 3 mmH g o r less
. O f nin e potentia l confounder s assessed , onl ybloo d hemoglobi n an d allege d ilcoho l intak e wer e significantl yassociate d wit h bot h bloo d lead an d loo d pressure . I f on e o r bot h confounder s wer e entere d int o a multipl e egressio n analysis , al l association s betwee n bloo d lea d an d bloo d
ressur e becam e non-significant , i n some case s wit h a negativ e regressio n coefficient
. Also , th e bloo d lead/hemoglobi n rati o wa s poorl yassociate d wit h bloo d pressure , i n particula r i n individual s wit h a lo w alcoho l intake
. A s bot h hemoglobi n leve l an d alcoho l intak e appea r t o b e biologi

call yplausibl e confounders , an yindependen t effec t o f low-leve l lead exposur e o n bloo d pressur e coul d no t b e determined
. alcoho l drinking ; bloo d pressure ; hemoglobins ; hypertension ; lead ; prospectiv e studies
.P. 5

Grandjea

n e t al . page 4
Bot hhistorica l evidenc e an d recent epidemiologica l studie s sugges t a

nincrease

d ris k o f hypertensio nwit hexcessiv

e bloo d lea d level s (1) . O f particular public-healthinteres t i s th e findin g tha t thi s tendenc y ma y occu r at bloo

d lea d level s pre valent in industrialize d population s withou t occupationa l ex posur e t o lea

d (2-5) . I f confirmed , environmenta l lea d pollutio

n woul d be implie

d a s a caus e o f hypertensio ni n a large numbe r o f patients . However , a correlatio n betwee

n bloo d lea d level s an d bloo d pressure s ma

y no t necessaril y

indicat e a causa l re lationship . Althoug hth e studie s i

n concer t ten

d t o suppor t th

e hypothesis , weaknesse s ca n b e identifie

d i neac ho f them , a s i s norma l in epidemiologica l research . Thus , th e studie s ar e cross sectiona l an

d includ

e different age groups ; age adjustment s hav e been used , althoug hno t necessaril y

improvin

g th e validity o f th e relationshi p betwee n bloo d lea d an d bloo d pressure . Othe r possibl e confounders , suc ha s alcoho l intak

e an d bloo d hemo globin , wer e no t examine d an d coul d hav

e influence

d th e relation ship . Alcoho l intak e ma y be a significant predicto r for bloo d pressur e (6,7) , an

d th e sam e hold s tru

e fo r th e hemoglobi nleve l (8) . A s bloo

d lea d i s associate

d withbot halcoho l intake (9 )
an d hemoglobi n (10) , thes e parameter s coul d b e important con founder s . W e hav e examine

d th e relationshi p betweenbloo d lea d an d bloo d pressur e i

nconnectio

nwit hth

e populatio

nstudie s in Glostrup , Denmark . Dat a relatin g t o bloo

d pressur e an

d lea d exposur e hav

e previousl y

beenpublishe

d fro m thes e studie s (9 - 13) . The 193 6 birt hcohor t fro m Glostru

p ha s been examined twice , at age s 4 0 an

d 4 5 years . Correlation s betweenbloo d lea d an dGrandjea n e t al . page systoli c an

d diastoli c bloo

d pressure s ca

ntherefor e b

e deter mine d at tw o point s o f time . Also , bloo d pressure s a t age 4 5 year s ca

n be relate

d t o th e bloo d lea d fiv e year s previously . P. 6

MATERIAL S AN

D METHOD S A tota l o f 1,05 2 individual s (50 4 menan d 54 8 women ; 88 %
o f th e eligibl e population ) wer e firs t see nat 4 0 year s o f ag e i n1976 . Al l individual s went throug ha comprehensiv

e physica l examination , intervie w an d bloo d chemistr

y (bloo d sample s take

n i n th e mornin

g afte r a 12-hou

r fast)(14) . Fiv

e year s later , 96 6 individual s wer e re-examined . Currently , a stud y o f th e sam e individual s at age 51 i s bein g carrie

d out . Bloo d fo r lea d analysi s wa s take ni n10-m l polypropylene tube s wit hEDT

A (ethylenediaminetetraacetate ) a s anticoagulant . Th e samplin

g techniqu

e wa s foun

d t o giv

e ris e t o negligibl e contaminatio

n(10) . Bloo

d lea d wa s measure

d in th e majority

o f th e cohor t a t bot h4 0 an d 4 5 year s o f age , i.e. , a tota l o f 86 9 individual s (45 4 men an d 41 5 women) . Th

e analytica l technique an d th e bloo d lea d result s at 4 0 year s hav e beendescribed b

y Olsen e t al . (10) . The sam e analytica l technique wa s used fo r th e stud y at 4 5 years , but th e instrumentatio

n wa s update

d (Perkin-Elme r AA

S mode l 5000 , HGA-50 0 wit hdeuteriu m backgroun

d correction) . Quality contro l procedure s wer e include d i n th e dail y routine (10) . For th e sample s at 4 5 years , analytica l quality wa s secure

d b y analysi s o f a

n externa l referenc e materia l
an d b y participatio

ni n a ninternationa l interlaborator y com pariso n stud y (15) . Th

e correlatio

nwit hothe r laboratorie s wa s excellen t ( r = 0.96) .P. 7

Grandjea

n et al . page 6
Bloo d pressur e measurement s at th e tw o examination s wer e performe

d b y th e sam e standardize

d metho d accordin

g t o WHO recommendation s (16) . W

e use d th e mercur

y sphygmomanomete r designed
at th e Londo n Schoo l o f Hygien

e an d Tropica l Medicine (17) ; o n thi s instrument , th e systoli c an

d diastoli c pressure s are rea d afte r completio

no f th e test , thu s minimizin g observe r variatio n an d bias . Diastoli c pressur e wa s determine d a t th e disappearanc e o f Korotkof f phas e 5 . Daily calibratio

n o f th e instrument s wa s carrie d out , an

d al l bloo

d pressur e measurement s durin g th e da y wer e measured wit ha 1 2 x3 3 c m cuf f an

d b y th e sam e observe r a s describe

d b y Hollnage l (18) . Eachparticipan t fille d i na n extensiv

e questionnair e befor e th e examination , an

d th e answer s wer e the

nreviewe

d wit hth

e physician ; appropriat e group s wer e use d fo r classificatio

no f th e answer s (18) . Th

e followin

g parameter s fro

m th e question nair e wer e selecte

d a s relevant predictor s in relatio n t o lea

d exposur e an

d bloo d pressure : exercis e (three groups) , smokin g (non-smokers , ex-smoker s an d thre e group s o f smokers) , alcoho l intak e (tota l numbe r o f unit s consume d durin g th e week prio r t o th e examination , one uni t correspondin g t o one beer ) an

d occu patio n (presenc e or absenc e o f potentia l lea d exposure) . Bod

y weight wa s transforme d int o a height-adjusted weigh t inde xgive n in percen t o f th

e optima l weight (18) . Bloo d chemistr

y wa s performed at th

e Departmen t o f Clinica l Chemistr y a t th e Univer sit y Hospita l in Glostru p an d include

d bloo d hemoglobin , seru

m cholestero l an

d seru m triglyceride s (18) ; thes e parameter s wer e selecte d fo r confounde r analysi s a s well . Bloo d pressur e an

d a logarithmi c transformatio no f th eP. 8

Grandjea

n e t al . pag e 7
bloo d lea d level s approache

d a Gaussia

n distribution . Thus , statistica l analysi s include d Pearson' s correlatio n coefficien t
an d multipl e regressio nanalysis . However , fo r association s wit hsom

e predictor s (exercise , season , smokin g an d occupationa l exposure) , non-parametri c test s wer e use d (Kruskal-Walli s one wa y analysi s o f varianc e an d Mann-Whitne

y U-test) .

RESULT S O f th e 86 9 individual s wit hbloo d lea d result s at bot h4 0
an d 4 5 year s o f age , complet e bloo d pressur e dat a wer e availabl e fo r 86 1 (45 1 menan

d 41 0 women , correspondin g t o 79 % an

d 66 % o f th e eligibl e population , respectively) . The result s reported belo w relat e t o thes e individual s only , unles s otherwis e indi cated . The median bloo d lea d at age 4 0 wa s 1 3 ug/10 0 m l i nmale s an d 9 in females ; at ag e 4 5 years , th

e level s ha

d decreased t o 9 i n male s an

d 6 ug/10 0 m l in females . Thi s decreas e occurred simultaneousl y

wit ha reductio

n i n th e amount o f lea

d additive s allowe d ingasoline . Durin g th e five-year interval , averag e bloo d pressure s change

d only little , but bod

y weigh t inde

x increase

d slightly , seru

m lipid s increased , exercis e increased , smokin g decreased , an

d alcoho l intak

e increased . I n accordanc e wit hinternationa l agreements , hypertensio n wa s define

d a s a systoli c bloo d pressur e at o r abov e 16 0 mmH

g and/or a diastoli c pressur e a t o r abov e 95 ; i nhealth

y indivi duals , th

e systoli c bloo

d pressur e shoul d b e at or belo

w 14 0 mmH g an d th e diastoli c at or belo w 90 . A s th

e numbe r o f patient s wit hhypertensio

nwa s rather small , a combine d grou p wa s forme

d
o f al l individual s wit ha bloo d pressur e no t considered norma lP. 9

Grandjea

ne t al . pag e 8 accordin

g t o th e abov e definition . Th

e bloo d lea d level s i

nmen an d women a t age s 4 0 an d 4 5 year s i

n relatio

nt o hypertensiv

e treatmen t an

d bloo d pressur e classificatio nar e show

ni ntable s 1 an d 2 . Excep t fo

r a slightly

highe r bloo

d lea d inwomenwit h increase

d bloo d pressur e at age 4 0 years , th e bloo d lea d level s appea r t o var

y withou t an

y relationshi p t o hypertension . Despit e th

e lack o f differenc e i n bloo d lea d betweenhyper tensiv e an d non-hypertensiv

e groups , bloo

d lea d showe d weak , bu t significan t association s wit hsystoli c an d diastoli c bloo

d pressures , mainl y

i n men . Althoug

hstatisticall y

significant , suc hcorrelation s coul d b e due t o confounding . Thus , whenin clude d wit hth

e above-mentione

d nine predictor s i nmultipl e regressio

n analyse s withbloo d pressur e a s dependen t variable , bloo d lea d showe d n o significant relationshi p wit hbloo d pressure . However , wit ha multitude o f parameter s available , eve n relevan t correlation s ma y b e explaine

d awa y b y spuriou s relationships . Confoundin

g bia s coul d be cause d i f a predicto r i s meaning fully associate

d wit hbothbloo

d lea d an d bloo d pressur e withou t bein g a lin k i n th e causa l chai nexamined . The statistica l associatio

n o f relevan t predictor s wit hbloo d lea d an d bloo d pressure s wa s therefor e examine d fo r th e 40-year-ol d menan d
women(tabl e 3) . Exercise , seaso nan d weigh t inde

xdi d no t correlat e wit hbot hbloo d lea d an d bloo d pressur e an

d coul d therefor e b

e exclude

d fro m further consideration . Wit hincreasin g seru m cholestero l or triglycerides , highe r bloo d pressure s wer e seen . Surprisingly , bloo d lea d level s als o tende d t o increase . Due t o th

e lack o f an

y explanatio

n fo r thi s finding , th

e associa -P.1 0

Grandjea

n e t a l page 9 tio n wa s considere

d spuriou s fo

r th e purpose s o f th

e presen t study . Wit hregar

d t o smoking , th

e highes t bloo

d lea d level s wer e see

n in th e heav y smoker s ( > 2 4 g/day , wit hone cigarett e correspondin

g t o 1 g o f tobacco) , whil e th e highes t meanbloo d pressure s wer e see

ni nex-smoker s whos e bloo d lea d level s wer e clos e t o average . A s bloo d lea d tende d t o increas e wit hincrease d smoking , an

d bloo d pressur e di d not , smokin g wa s regarded ir relevan t wit hregar d t o confoundin

g bias . Th

e sam e applie s t o th e slightl y

lowe r diastoli c bloo d pressure s see

ninth e smal l numbe r o f male s in occupation s wit hpotentia l lea d exposure . A s hemoglobi n concentratio nan d alcoho l intak

e correlate

d wit h bot hbloo

d lea d an d bloo d pressure , an

d thes e association s appeare d meaningful , thes e potentia l confounder s wer e selecte d fo r a detailed analysis . Th e increas e i

nbloo d pressur e associate d wit ha doublin

g in bloo d lea d i s show

n i ntable s 4-6 . Thi s increas e i s calcu late d b y multiplyin

g th e regressio

n coefficien t fo

r lo g bloo d lea d v s bloo

d pressur e b

y 0.3010 . Th

e regressio

n coefficient s wer e determined separatel y fo r th e dat a a t 4 0 years , a t 4 5 years , an d fo r th e dat a at 4 5 year s withbloo d lea d at age 40 . Both confounder s generall y correlate

d bette r wit hbloo

d pressur e tha n di d bloo

d lead . When one or bot ho f th e tw o potentia l confounder s wer e include d i n th e regressio

nanalysis , an

y stat istica l significanc e o f th e relationshi p between bloo d lea d an d bloo d pressur e wa s lost . Alcoho l intak

e tende d t o becom

e a n insignifican t predicto r fo r bloo d pressur e whenbloo d lea d wa s force

d a s th e firs t independen t variable . Bloo d hemoglobi n remaine d significan t i nP.1 1

Grandjea

n e t al . page 1 0
al l analyses , except fo r diastoli c pressur e in45-year-ol d women wher e hemoglobi n becam e a n insignificant predictor i f entere d afte r bloo

d lead . Wit hdiastoli c bloo d pressur e i n 40-year-ol d male s (tabl e 4) , adjustment fo r hemoglobi n resulte d in a nega tive , thoug

hno t statisticall y significant , regressio ncoeffi cient fo

r bloo d lead . Thi s observatio n ma y sugges t that , when enterin g hemoglobi nint o th e regressio

n analysi s befor e bloo d lead , a n overadjustmen t ma y result . A n additiona l serie s o f analyse s wa s therefor e carrie d ou t usin g th e rati o betwee

n bloo d lea d an d hemoglobi na s th

e indepen dent variable . Again , thi s paramete r showe d a poore r correlatio n wit hbloo

d pressur e tha

ndi d th

e unadjuste

d bloo d lead , thoug

h somewha t bette r tha nbloo d lea d afte r introductio n o f hemoglobi n in th e regressio

n analysis . Thus , th e correlatio

n wit hsystoli c an d diastoli c bloo

d pressur e i

n 40-year-ol d women approached statistica l significanc e ( p < 0.1 ) wit hpredicted increase s o f 2. 4 an d 1. 9 mmHg , respectively , fo r eac hdoublin

g o f th e lead/ - hemoglobi n rati o (cf . tabl e 4) . Thi s analysi s wa s the n repeate

d fo r th e individual s wh

o ha d ingeste

d les s tha

n7 unit s o f alcoho l durin g th e wee k prio r t o th e examination . Inth e 17 6 mal e abstainer s or light drinker s at ag e 4 0 years , a doublin g o f th e lead/hemoglobi nrati o wa s associate

d wit ha significant decreas e indiastoli c bloo d pressur e o f 4. 7 mmH g ( p < 0.05) ; th

e sam e tendency , thoug

hnon significant , wa s alread y observe

d i nth e tota l grou

p o f 45 1 men (tabl e 4) . I n contras t t o thi s revers e relationship , th e com parabl e grou

p o f 31 7 womenat th e sam e age showe

d a n increas e in diastoli c bloo

d pressur e o f 2. 3 mmH g wit ha doubled lead /Grandjea n e t al . pag e 1 1 hemoglobi n rati o ( p < 0.1) ; thi s increas e i s highe r tha n th e one associated wit ha doublin g in unadjuste

d bloo d lea d (tabl e 4) . Al l othe r regressio n coefficient s wer e non-significant . P.1 2

DISCUSSIO

N The associatio

n between bloo

d lea d an d bloo d pressur e see

n i n th e presen t stud

y i s similar t o o r slightl y weake r thanthos e reporte d in previou s populatio n studie s (2-5) . A

weake r associa tio n coul d partl y

b e du e t o th e ver y lo w bloo d lea d level s i

n Denmark , i

nparticula r at th

e tim e o f re-examinatio

n o f th e population . Also , an y stron g relationshi p woul d no t be expecte d
at age s 4 0 an

d 4 5 year s wher e th e prevalenc e o f hypertensio ni s fairly low . Th

e homogeneou s characte r o f th e cohor t at well define d age s woul d ten

d t bsuppor t th

e reliability

th e results , a s woul d th

e fac t tha t nin

e potentia l confounder s wer e evaluated . Th e interna l validit

y o f th e finding s i s supporte d b y th e simila rit y o f th e result s at tw

o examination s fiv

e year s apart . O

n th e othe r hand , non-respons e an d los s t o follow-u

p ma y hav e in fluence d th e stud y outcome , althoug

hthi s weaknes s i s no t unique . Also , th

e statistica l powe r o f a stud y o f les s tha

n1,00 0 indi vidual s i s perhap s no t sufficient when dealin g wit hsmal l dif ferences . I n addition , th e logarithmi c transformatio no f th e bloo d lea d dat a impose s a non-linea r relationshi p t o bloo d pressures , th

e biologica l plausibility o f whic hremain s t o be determined . However , a similar transformatio n ha s been use

d i n othe r populatio

n studie s an

d compariso

ni s therefor e facilitated . The majo r observatio ninthi s stud

y i s tha t bloo

d hemoglobi n an d alleged alcoho l consumptio nma y caus e confoundin

g bias .P.1 3

Grandjea

ne t al . page 1 2
Afte r inclusio

n o f th e tw o parameter s i

na multipl e regressio n analysis , association s betwee n bloo d lea d an d bloo d pressur e wer e n o longer statisticall y significant . However , th e biologica l validity

o f suc hpossibl e confoundin g shoul d be carefull y assessed . Tha t bloo

d lea d tend s t o increas e withth e numbe r o f unit s o f alcoho l consume

d durin g th e las t 7 day s ha s previousl y been documented i

nth e sam e cohor t at 4 0 year s o f age ; th e increas e i s als o relate

d t o smokin

g (whic hi n tur

ni s relate

d t o alcoho l consumption ) (9) . Thi s associatio n wa s subsequentl y

confirmed , eg. , in a Britis hstud y (19 ) an

d ma y b e due t o alcohol-related change s i nlea

d metabolis

m and/or lea

d presen t insom

e alcoholi c beverages , i

nparticular wine . Alcoho l ha s significan t an d deleteriou s physiologi c an d biochemica l effect s on th e hear t an d ha s been identifie d a s a ris k facto

r fo r hypertensio

n(20) . Alcoho l intak

e wa s significantl y associate

d wit hsystoli c an

d diastoli c bloo

d pressure s i

nth e NHANE S I stud

y (8) . Additiona l epidemiologica l studie s hav e als o show

n a n associatio

nbetween alcoho l intake an

d bloo d pressur e (6,7,11,21) . However , th e associatio

n ma y no t b e linear (22) , an

d th e effec t o f lo

w alcoho l intak e o n bloo d pressur e i s stil l unclear . Thus , availabl e evidenc e support s th e notio ntha t at leas t hig halcoho l intak

e i s a n independent caus e o f increase d bloo d pressur e an

d als o o f increase

d bloo d lea d levels ; i t i s therefor e a likel y confound er fo r th e bloo d lead-bloo

d pressur e relationship . T o illustrat e thi s further , a

n average consumptio no f 3 0 ml o f ethano l pe r da y in one stud

y appeare

d t o produc e a

nincreas e o f 2- 6 mmH g i n systoli c bloo

d pressur e (6) . A

nalcoho l consumptio n o f thi sP. M

Grandjea

n et al . page 1 3 magnitude woul d caus e a n increas e inbloo

d lea d level s o f about 1. 5 ug/10 0 m l i

n male s an

d somewha t mor e i

n female s (9) . Similarly , th

e biologica l plausibility fo r hemoglobi n a s a confounde r mus t b e criticall y

assessed . Althoug

hthi s paramete r appeared t o be th

e mos t important confounder , les s extensiv e informatio

ni s at han

d t o examin

e th e possibl e mechanism s in volved . Almos t al l lea d i n th e bloo d i s boun

d t o th e erythro cytes , an

d misleadingl y

lo w bloo d lea d level s ma

y b e see n in anemia ; adjustmen t o f bloo d lea d t o a certai nhemoglobi nleve l i s therefor e appropriate . Som e laboratorie s repor t lea d con centration s inrelatio nt o erythrocyte , rathe r tha n whol e bloo

d volume . Accordingly , a hig hhemoglobi nwa s associated wit ha slightl y

increase

d bloo d lea d in th e Danis hcohor t whe n examine d
at 4 0 year s o f age (10) . Thi s relationshi p simply indicate s tha t a highe r proportio no f th e bod y burde no f lea

d i s carrie

d b y th e erythrocytes , no t tha t th e lea d exposur e wa s greater . Further , increase

d hemoglobi nma

y b e a n important ris k factor fo r hypertension . Again , th e NHANE S I stud

y documented a signifi cant correlatio

nbetween hemoglobi n an d bloo d pressur e (8) , an

d th e sam e tendenc

y wa s see

n i nth e NHANE S I I (3) . Further , i n th e Framingha

m study , change s i

n hematocri t wer e significantl y associate

d wit hchange s i

n bloo d pressur e in men , thoug hno t in women (23) . Althoug hthi s correlatio

ncoul d b e due t o change s i n bloo d viscosity , bothhemoglobi nan d bloo d pressur e ar e als o relate d t o bod

y size , an

d th e relationshi p coul d b e a n indirec t one . Thus , a s hemoglobi n i s apparentl y associate

d wit hbloo

d lea d an d bloo d pressur e b

y independent mechanisms , confoundin g woul d be expected .P.1 5

Grandjea

n e t al . page 1 4
The biologica l relevanc e o f th e tw o predictor s assesse d woul d therefor e sugges t tha t th e statisticall y

significan t associatio

n between bloo

d lea d an d bloo d pressur e i n th

e presen t stud y coul d b

e at leas t partiall y explaine

d b y confoundin

g bias . However , a causa l rol e o f low-leve l lea d exposur e wit hregar d t o a smal l increas e i nbloo d pressur e canno t b e rule d out . In othe r studie s wit hles s confoundin g bias , bloo

d lea d coul d wel l be a n important predictor fo r bloo d pressure . The evidenc e tha t low-leve l lea d exposure s ma

y caus e a

n increase

d bloo d pressur e mainl y

relate s t o cross-sectiona l dat a o n individual s a

t different age s (2-5) . Adjustmen t fo r age , bod y weight , etc . wa s include d i nth e analyses , an

d th e re gressio n coefficient s foun d wer e similar t o thos e see nfo r th e unadjusted dat a in th e present study . However , th e significanc e o f hemoglobi n an

d alcoho l a s possibl e confounder s canno t b e determine

d fro m th e publishe

d data , an

d th e validity

o f th e association s foun

d i n th e previou s populatio nstudie s (2-5 ) i s therefor e unclear . Othe r studie s hav

e show na relationshi p betweenoccupationa l lea d exposur e an

d increase

d bloo d pressur e (24,25) . Despit e th e smal l number s an

d th e possibl e selectio nbia s instudie s i n occupationa l epidemiology , th e evidenc e i s suggestiv e o f a causa l relationship . Further , in a case-referen t stud y (26) , a signifi cantl y increase

d number o f hypertensiv e patient s ha

d a bloo

d lea d leve l abov

e 2 umol/ 1 (41 ug/10 0 ml) . I ncontrast , th e presen t stud

y deal t wit hmuc

hlower bloo

d lea d levels , bu t potentia l occupationa l exposur e t o lea d i n a smal l numbe r o f individual s wa s associate d wit ha slightl y

decreased bloo

dGrandjea n e t al
. pag e 1 5

pressure . Th e same revers e tendenc yha s bee n reporte d fo r a large r grou

p o f lead-expose d worker s (21) . Th e experimenta l evidenc e i s growin g tha t lea d maycaus e a rang e o f pathologica l change s whic h ma yb e associate d wit h
a n increase d bloo d pressur e (1) . Th e hypothesi s tha t thi s effec t
ma yals o occu r i n human s i s therefor e plausible , bu t th e public

healt h significanc e o f suc h a relationship , shoul d i t exist , canno t b e determine d a t thi s time
. I n conclusion , th e presen t stud yha s show

n tha t lea d ex posur e i s relate d t o increase d bloo d pressure . However , th e statistica l significanc e o f thi s associatio n disappear s whe n alcoho l intak e an

d hemoglobi n ar e include d i n a multipl e re gressio n analysis
. Bot h parameter s ar e plausibl e confoundin g factor s an

d nee d t o b e carefull ycontrolle d t o asses s th e charac

te r o f th e bloo d lead-bloo d pressur e relationship
.P.1 7

Grandjean e

t a l page 1 6

Reference s

1 . U. S Environmenta l Protectio nAgency . Lea

d effect s o

ncardio vascula r function , early development , an

d stature : A

naddendu

m t o U.S . EP

A Ai r qualit

y criteri a fo

r lea d (1986)(EPA-600/8 - 83/028aF , Vol . 1) . Researc hTriangl e Park , NC : 1986 . 2 . Kromhou t D , Wibow o AAE , Herbe r RF

M e t al . Trac e metal s an d
coronar y hear t diseas e ris k indicator s in15 2 elderl y men(th

e Zutphe n study) . A

m J Epidemio l 1985 ; 122 : 378-85 . 3 . Pirkl e JL , Schwart z J , Landi s J Re t al . The relationshi p between bloo

d lea d level s an

d bloo d pressur e an

d it s cardio vascula r ris k implications . A m J Epidemio l 1985 ; 121 : 246-58 . 4 . Pococ k SJ , Shape r AG , Ashb y D e t al . Bloo

d lea d concentration , bloo d pressur e an

d rena l function . Br Me d J 1984 ; 289 : 872-4 . 5 . Pococ k SJ , Shaper AG , Ashb y D et al . Bloo

d lea d an d bloo d pressur e in middle-age d men . In : Lekka s TD , ed . Heav y metal s in th e environment , Vol . 1 . Edinburgh : CE P Consultants , 1985 : 303-5 . 6 . Criqu i MH , Wallac e RB , Mishke l M e t al . Alcoho l consumptio n an d bloo d pressure . Hypertensio n 1981 ; 3 : 557-65 . 7 . Klatsk

y AL , Friedma

nGD , Siegelau

bA B e t al . Alcoho l con sumptio n an d bloo d pressure . N

Eng l J Med 1977 ; 296 : 1194-1200 . 8 . Harlan WR , Hul l AL , Schmoude r R L et al . Bloo

d pressur e an

d nutritio

ni nadults , Th

e Nationa l Healthan d NutritionSurvey . A m J Epidemio l 1984 ; 120 : 17-28 . 9 . Grandjea

n P , Olse

n NB , Hollnage l H . Influenc e o f smokin g an d alcoho l consumptio

no nbloo d lea d levels . In

t ArchOccu

p Enviro

n Healt h1981 ; 48 : 391-197 .P.1 8

Grandjea

n e t al . page 1 7
10 . OlsenNB , Hollnage l H , Grandjea nP . Indicator s o f lea d exposur e in a

nadul t Danis hsuburba npopulation . Dan Med Bul l 1981 ; 28:168-76 . 11 . Ibse

nH , Christense

n NJ , Rasmusse

nS e t al . The influenc e o f chroni c hig

halcoho l intak

e o n bloo d pressure , plasm

a nor adrenaline concentratio n an d plasm a reni n concentration . Cli n Sc i 1981 ; 61 : 377s-9s . 12 . Schrol l M . A

ten-year prospectiv e study , 1964-1974 , o f cardiovascula r ris k factor s i n men an

d women fro

m th e Glostru

p populatio

n bor nin1914 . Da

n Me d Bul l 1982 ; 29 : 213-52 . 13 . Schrol l M , Kirkb y H , Kirchhof f M . Arteria l hypertensio na s a ris k factor fo

r cerebrovascula r disease . 15-year s follow-u p o f th e 1914-populatio

n inGlostrup . Act a Med Scan d 1983 ; 676 : 33-36 . 14 . Hollnage l H . Th e healthstructure o f 40-year ol d menan d
women in th

e Glostru

p area , Denmark . A

n epidemiologica l survey . Da n Med Bul l 1980 ; 27 : 121-30 . 15 . Berli n A . Assessmen t o f exposur e t o lea d o f th e genera l populatio

n in th e Europea

n communit

y throug hphysiologica l monitoring . Enviro

nMonito r Asses s 1982 ; 2 : 225-31 . 16 . Ros e GA , Blackbur n H . Cardiovascula r surve y methods . (WH

O monograp

hserie s 56) . Geneva : Worl d Healt hOrganization , 1968 . 17 . Ros e GA , Hollan d WW , Crowle

y EA . A sphygmomanomete r for epidemiologists . Lance t 1964 ; 1 : 296 . 18 . Hollnage l H . Th e healt hstructur e o f 40-year-ol d men an d
women in th

e Glostru

p area , Denmark - a n epidemiologica l survey . Dan Med Bul l 1980 ; 27 : 121-30 . 19 . Pococ k SJ , Shape r AG , Walke r M e t al . Effect s o f ta p wate rP.1 9

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n et a l page 1 8
lead , wate r hardness , alcohol , an d cigarette s o

nbloo d lea d concentrations . J Epidemio l Com m Health1983 ; 37 : 1-7 . 20 . Sege l LD , Klausne r SC , Gnadt JTH e t al . Alcoho l an d th e heart . Me

d Cli n Nort hAmeric a 1984 ; 68 : 147-61 . 21 . Parkinso

n DK , Hodgso

n MJ , Brome t E

J e t al . Occupationa l lea d exposur e an

d bloo d pressure . Br J In d Me d 1987;44:744-8 . 22 . Jackso

n R , Stewar t A , Beaglehol e R et al . Alcoho l consump tio n an d bloo d pressure . A

m J Epidemio l 1985 ; 122 : 1037-44 . 23 . Kanne l WB , Sorli e P . Hypertensio ni nFramingham . In : Pau l O , ed . Epidemiolog

y an d contro l o f hypertension . Ne w York : Stratton , 1975 : 553-92 . 24 . Kort , WLA

M de , Verschoo r MA , Wibow o AA E e t al . Occupationa l exposur e t o lea

d an d bloo d pressure : A

stud y in 10 5 workers . A m J In d Med 1987 ; 11 : 145-56 . 25 . Kirkb

y H , Nielsen CJ , Nielse nV Ke t al . Healt hexaminatio n o f person s wit hlong-ter m occupationa l exposur e t o lea d (i n Danish) . Ugeskr Lag 1987 ; 149 : 942-5 . 26 . Beever s DG , Erskin e E , Robertso

n M et al . Bloo

d lea d an d hypertension . Lance t 1976 ; 2 : 1-3 .P.2 0

Grandjea

n et al . page 1 9

Tabl e 1 Median bloo

d lea d leve l (i

nug/10 0 ml ) (10t

han d 90th percentile s i

nparenthesis ) in 45 4 menan d 41 5 women at age 4 0 year s i

n relatio

nt o hypertensiv

e treatment
an d blood-pressur e classificatio n

Me n Women

Number Bloo

d lea d Numbe r Bloo

d lea d

Treatmen t N o treatmen t

Increase

d bloo d pressur e 5 9 Norma l bloo

d pressur e 5

44 9

5 9 39 2 1

1 1 3

1 3 1 3 (9-17 ) (8-20 )
(8-21 ) (8-20 ) 11

40 2

1 9 39 1 9 (5-13 )

9 (6-13 )
10*(5-23 ) 9 (6-13 )

p < 0.0 5 (Mann-Whitne y U-test )

iv..P.2 1

Grandjea

n e t a l page 2 0

Tabl e 2 Median bloo

d lea d leve l (i

n ug/10 0 ml ) (10t

han d 90th percentile s i

n parenthesis ) i

n45 4 me

nan d 41 5 women at age 4 5 year s i

n relatio

nt o hypertensiv

e treatment
an d blood-pressur e classificatio n

Men Women

Numbe r Bloo

d lea d Numbe r Bloo

d lea d

Treatmen t N o treatment

Increase

d bloo d pressur e 4 4 Norma l bloo

d pressur e 1 8

43 5

4 4 41 0 1 0

9

9 9 (5-13 ) (5-14 )
(5-15 ) (4-14 ) 21

39 2

1 7 39 6 6

6

6 6 (4-9 ) (4-10 )
(5-14 ) (4-10 )Grandjea n et al . page 2 1

Tabl e 3 Statistica l significanc e fo r associatio

n o f potentia l confounder s wit hbloo d pressur e (BP ) an

d bloo d lea d in 45 1 me

nan d 41 0 wome

nage d 4 0 year s

Confounde r

Exercise * Season + Weight index § Cholesterol ^ Triglycerides § Smoking

4 " Occupationa l exp. " Hemoglobin ^ Alcohol § Systo l

Men

N S N S

** *

•

* * N S N S

* *

• .i c B P

Wome n

N S N S

** * N S

** * N S N S

** *

* * Dia s

Men

N S N S

• * *

** *

** *

* * *

** *

* * toli c B P

Women

N S N S
• * * N S N S N S N S N S N S Bloo

d

Men

N S

• • • N S

* • *

* *

* • *

* •

* * *

• * * lea

d

Women

N S

** * N S N S

* * * *

* • *

** * i

j i Statistica l significanc e determine d b y + Kruskal-Walli s one wa y analysi s o f variance , §Pearson' s correlatio n coefficient , an

d "Mann-Whitne

y U-tes t
* p < 0.05 ; ** p < 0.01 ; *** p < 0.001 ; N S p > 0. 1Grandjea ne t al . page 2 2

Tabl e 4 Increas e i

n bloo d pressur e (B

P i nmmHg ) wit ha doublin g in bloo d lea d i n45 1 men an

d 41 0 womena t age 4 0 years , a s adjuste

d fo r possibl e confounders'* '
Systoli c BP Diastoli c B P

Men Women Men Women
Unadjusted Adjusted for : alcoho l intak

e hemoglobi n bot h 2.6 '

2. 0 1. 5 1. 1 

### 3. T

1. 8 1. 9 -1. 0

-1. 6 2.1 '

1. 6 1. 7 1. 2

+ onl y indicate

d i f p < 0.5 ; * p < 0.0 5Grandjea n e t al . pag e 2 3

Tabl e 5 Increas e i

nbloo d pressur e (B

P inmmHg ) wit ha doublin g i n bloo d lea d i n45 1 menan

d 41 0 wome

nwhenre-examined
at age 4 5 years , a s adjuste d fo r possibl e confounders'* '
Systoli c BP Diastoli c BP

Men Women Men Women
Unadjusted Adjusted for : alcoho l intak

e hemoglobi n bot h 2. 2

1 . 2 1. 3

_ 1. 1

0. 6 1. 3

1 . 2 1 . 2 1. 0

+ onl y indicate

d i f p < 0. 5P.2 5



# L Grandjean e t al . page 2 4

Tabl e 6 Increas e i n bloo

d pressur e (B

P in mmHg ) in45 1 men an d 41 0 women a t ag e 45 , a s relate d t o a doublin

g inbloo

d lea d a t ag e 4 0
an d adjuste

d fo r possibl e confounder s at age 4 5 years"* "
Systoli c BP Diastoli c B P

Men Women Men Women
Unadjusted Adjusted for : alcoho l intak

e hemoglobi n bot h 3.0 "

2. 3 2. 1 1. 4 2. 3

2. 2 2. 2

_ 1. 1

0. 7 0. 7

+ onl y indicate

d i f p < 0.5 ; * p < 0.0 5