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# f*~*3- » Offic e o f Researc h an d Developmen t Washington , D C 2046 0 

### \IA EP A 600/8-8 9 049 F Augus t 199 0 

# xr-jr- /jtfr 

# AEP A Ai r Qualit y Criteri a fo r Lead : Supplemen t t o th e 198 6 Addendu mP. 3



### EP A 600/8-89/049 F Augus t 199 0



# MT Qualit y Criteri aior

Lead s ^pplemen t

t o th e 1OT

@ Addendu m

Environmenta l Criteri a an d Assessmen t Offic e Offic e o f Healt h an d Environmenta l Assessmen t Offic e o f Researc h an d Developmen t U.S . Environmenta l Protectio n Agenc y Researc h Triangl e Park , N C 2771 1

BmP. 4

DISCLAIME

R 4 . Thi s documen

t ha s been reviewe d in accordanc e wit h U.S . Environmenta

l Protectio n Agency polic y and approve d fo r publication . Mentio n o f

trad e name s o r

commercia

l product s doe s no t constitut e endorsemen

t o r recommendatio n fo

r use .

1 1 

# JCONTENT S P. 5

Pag e TABLES FIGURE S PREFAC E ABSTRAC

T AUTHORS I . INTRODUCTIO N H . RELATIONSHI

P O F BLOOD PRESSUR

E T O LEA

D EXPOSUR

E ffl. NEUROBEHAVIORA L AN D GROWT

H EFFECT S IN INFANT S AN D CHILDRE

N . IV . REFERENCE S i v v i vi i vii i i x 1 2 24 6 5

i nP. 6

I V TABLES Numbe r 1 Coefficient s fo

r th e natura

l lo g of bloo d lea d concentratio n (logPbB ) vs . bloo d pressure (BP) in me n wit h and without adjustmen t fo r sit e variable s 8 2 Infants ' menta

l developmen

t index score s accordin g t o cor d bloo d lea d group 2 5 3 Chang e i n McCarth y genera l cognitiv e index (GCI ) an d subscal e score s associate d wit h eac h natura l lo g unitincreas e in bloo d lea

d leve l 2 7 4 Result s of

multipl e regressio n analyse s examining th e relationshi p betwee

n bloo d lea

d leve l an d performanc e o n th e Bayle

y Menta l Index a t 3-2 4 month s of

ag e . 2 9 5 A Th e relationship o f feta l (materna l an d cord ) bloo d lea

d (PbB ) level s wit

h later developmenta

l outcome s 3 4 5 B Th e relationship of prio r and current

postnata l bloo d lea

d (PbB ) level s wit

h late r developmenta

l outcome s 3 4 6 Th e relationship of prenata l an d postnata l lo g bloo d lea

d wit h I Q a t ag e fou r years , te n month s 3 5 7 Estimate d coefficient s o f lo g bloo d lea

d concentratio n fro

m simpl e and multipl e regressio n analyse s of McCarth y score s a t th e ag e o f fou r year s 3 8 8 Regressio n of

developmenta

l indice s o n materna l and cor d bloo d lea d level s 4 0 9 Regressio n of

developmenta

l indice s a t 4 8 month s on curren t and prio r bloo d level s 4 2 1 0 Unexplaine d correlation s between lo g dentin e lea d level s takin g into accoun

t tes t reliability , confounding covariates , sampl e selectio n factors , an d revers e causalit y vi a pic a4 6 

# JP. 7

Numbe r 

### 1 1 TABLES (continued)

Produc t momen t correlation s betwee

n materna l o r teache r behavio r rating s and lo g dentin e lea d value s 

### 1 2 Stronges t

relationship s betwee

n bloo d lea

d measure s a

t specified times and later

neurobehaviora

l outcome s a s detecte d b y prospectiv e studie s Pag e 4 8

6 0FIGURE S P. 8

Numbe r Compariso n of

stud y result s fromfou

r larger-scal e epidemiolog y studie s of lead-bloo d pressure relationship s in adul t me n ... . 

### 1 4 Norma l distribution s wit

h mean s of

9 6 and 10

0 and standar

d deviation s of

1 6 

### 6 4

v iP. 9

PREFAC E Thi s documen

t update s th e Addendu

mt o th e 198 6 EP

A Air Quatity Criteria

for Lead. A draf t o f thi s Supplemen

t wa s prepare d in March 198 9 and reviewe d b y th e Clea n Air Scientifi c Advisor

y Committe e (CASAC ) at

apubli c meeting on Apri l 27 , 1989 . Comment s on th e draf

t Supplemen

t wer e receive d fro

mth e publi c unti l Jun e 12 , 1989 . Th e CASA C informed th e EP

A Administrator

in aletter date d Januar

y 13 , 199 0 tha

t th e 198 6 Lea

d Criteri aDocument , Addendum , and Supplemen t afforded " ascientificall

y balance d and defensibl e summar

y of ou r current knowledg e of

th e effects of

thi s pollutant , providin g a n adequat e scientifi c basi s fo

r EP A t o retai n o r

revis e primar

y and secondar

y NAAQ S [Nationa

l Ambien t Air Qualit y Standards ] fo

r airborn e lead. " Thi s draf

t final Supplemen

t differ s fro

m th e 198 9 draf

t onl y i n mino r correction s an

d additions .

v nP.1 0

ABSTRAC

T Th e 198 6 U.S . EP

A documen

t Air Quality Criteria

for Lead (EPA-600/8-83/02 8 aF-dF ) evaluate d in detai l th e mos t pertinent scientifi c information concernin g sources , routes , and level s of

lea d exposur e an d associate d healt

h effects an

d potentia l risks . A n Addendum , issue d a s par

t of Volum e 1 , page s A1-A67 , of

th e 198 6 Criteri aDocument , focuse d o n additiona l emergin g studie s concernin g th e effects o f lea d on cardiovascula

r function and o n earl y physica

l an d neurobehaviora

l development . Thi s Supplemen t t o th e abov e material s evaluate s stil l newe

r informatio n concernin g (1 ) lea d effects on bloo d pressure an d other cardiovascula

r endpoints , an

d (2 ) th e effects o

f lea d exposur e prenatally and/o r

postnatall y o n birt h outcome s an

d early physica

l and neurobehaviora

l developmen

t of children . Th e evaluation s containe d in thi s Supplemen t an d th e 198 6 Criteri aDocumen t and Addendu

mar e t o serv e a s scientifi c input s to decision-makin g wit h regar d to th e review and revision , a s appropriate , of

th e Nationa

l Ambien t Air Qualit y Standard s (NAAQS ) fo

r lead .



### v mP.1 1

AUTHORS

Dr . J . Michael Davis , Environmenta l Criteri aand Assessmen

t Office (MD-52) , OHEA , ORD , U.S . Environmenta

l Protectio n Agency , Research Triangl e Park , NC 2771 1 Dr . Leste r D . Grant , Environmenta

l Criteri aand Assessmen

t Office (MD-52) , OHEA , ORD , U.S . Environmenta

l Protectio n Agency , Research Triangl e Park , N C 2771 1 Dr . Winon aW . Victery , Environmenta l Criteri aan d Assessmen

t Office (MD-52) , OHEA , ORD , U.S . Environmenta

l Protectio n Agency , Research Triangl e Park , N C 2771 1

REVIEWERS Dr . Davi d Bellinger , Harvar d Medica l School , Children' s Hospital , Boston , M A 0211 5 Dr . Ki mN . Dietrich , Institut

e o f Environmenta

l Health , Universit

y o f Cincinnati , Colleg e o

f Medicine , Cincinnati , O

H 45276-005 6 Dr . Davi d J . Svendsgaard , Healt h Effects Research Laborator y (MD-55) , OHR , ORD , U.S . Environmenta

l Protectio n Agency , Research Triangl e Park , N C 2771 1

i xP.1 2

SUPPLEMEN T T O TH E 198 6 AI R QUALIT Y CRITERI A FO R LEAD ; ADDENDU M

I . INTRODUCTIO N I n th e mid-1980s , th e 197 7 EP A criteri adocument , Air

Quality Criteria

for Lead (U.S . Environmenta

l Protectio n Agency , 1977 ) wa s updated and revise d pursuant to Section s 108

- 10 9 of th e Clea n Ai r Act , a s amended , 4 2 U.S.C . 740 8 an d 7409 . Th e final versio n o f th e update d criteri adocumen

t (U.S . Environmenta

l Protectio n Agency , 1986a) , incorporatin g revision s mad

e in respons e to publi c comment s an d revie w of

earlier draft s b y th e Clea

n Ai r Scientifi c Advisor

y Committe e (CASAC) , wa s complete d in 198 6 to b e use d a s abasi s fo r revie w and , a s appropriate , revisio n of th e Nationa

l Ambien t Ai r Qualit y Standar d (NAAQS ) fo r lead . A n Addendu

m(U.S . Environmenta

l Protectio n Agency , 1986b ) t o th e revise d document , Air

Quatity Criteria

for Lead (U.S . Environmenta

l Protectio n Agency , 1986a) , wa s als o complete d in 198 6 and evaluate d newl y publishe d informatio n concernin g tw o topics : (1 ) th e relationship betwee

n bloo d lea

d level s and cardiovascula

r effects , and (2 ) lea

d exposur e effect s on early developmen t an d stature . I n th e thre e year s sinc e th e 198 6 Addendu mwa s prepared , informatio n pertainin g to th e healt h effects of

lea d ha s continue d to emerg e wit h regar d t o th e topic s addresse d in tha t Addendum . Although newe r findings hav e bee

n generally consisten

t wit h th e stat e of understandin g tha

t wa s articulate d in th e 198 6 Addendum , the y stil l nee d to b e evaluate d a s part o f a n updated assessmen

t of th e lates t scientifi c informatio n tha

t characterize s th e healt

h effects of lea d (Pb ) wit h clea r relevanc e fo

r decision-makin g on potentia l revisio n of

th e existin g lea

d NAAQS . Th e present

updat e focuse s primarily on ke

y findings tha

t hav e emerge d i n th e literature sinc e 198 6 i

n th e area s o

f lea d effects o n (1 ) bloo d pressure an d relate d cardiovascula

r endpoint s an

d (2 ) chil d development . I t doe s no t attemp t to b e comprehensiv e in reviewin g thi s literature , nor

doe s i t attemp t t o addres s al l th e topic s covere d in th e 198 6 Ai r Qualit y Criteri aDocumen

t an d Addendum . Rather , it s explici t purpos e i s to describ e and interpre t th e critica l effects o f lea d tha t hav e greates t

significanc e fo

r impending regulator

y decision s regardin g thi s environmenta l pollutant , wit

h discussio n focussin

g on ke y newe r paper s publishe d sinc e completio n o f th e earlier

198 6 Addendum . 1P.1 3

II . RELATIONSHI P O F BLOO D PRESSUR E T O LEAD EXPOSURE Th e 198 6 Addendu

m(U.S . Environmenta

l Protectio n Agency , 1986b) addresse d th e issu e o f lea d effect s o n th e cardiovascula r syste mi n arevie w of

th e findings wit

h regar d t o overtl y lead-intoxicate d individuals , epidemiologi c studie s of association s between lea

d exposur e and increase d bloo d pressure , toxicologi c dataprovidin g evidenc e fo r lead-induce d cardiovascula

r effects in animals , an

d informatio n o n th e possibl e mechanism s of actio n of lea d o n cardiovascula

r function . Th e amoun

t and qualit y of th e evidenc e availabl e a

t tha t time were adequat

e t o provid e a

n initia l evaluatio n of

th e topic , but

di d no t com e to afull y definitiv e consensu s wit

h regar d to th e contributor

y rol e o f lea d exposur e to hypertension . Als o no t full y resolve d wa s th e exten

t to which lead-induce d hypertensio n o r other type s of lead-induce d pathogeni c effects contribut e t o mor e seriou s morbidit

y (hear t attack , stroke ) and mortalit y of th e huma n population . Fo r th e purpose s of

thi s Supplement , primar

y emphasi s i s bein g place d on updated discussion s of

ke y huma n population-base d studie s whic h reflect primaril y non-occupationa l exposur e to lead . Th e larges t

stud y population s hav e bee

n th e secon

d Nationa l Healt h an d Nutritio n Examinatio n Surve y (NHANE S II ) fo

r th e U.S . populatio n (performed durin g th e year s 1976-80 ) and th e Britis h Regiona l Hear t Stud y (BRHS) , a

n ongoing evaluatio n of

me n age d 4 0 to 5 9 from2

4 Britis h towns . Thes e studie s wer e earlier describe d in detai l i

n th e publishe d literature (Harla

n et al. , 1985 ; Pocock

e t al. , 1984 ; Pirkl e et

al. , 1985 ; Shape

r e t al. , 1981) ; and furthe

r analyse s of

th e subject

dataset s hav e bee

n presente d an

d discusse d extensively a

t a198 7 U.S . EP

A co-sponsore d Internationa l Symposiu

mo n Lead-Bloo d Pressure Relationship s and in other recent publications . I

n addition , analyse s of

severa l othe r dat aset s hav e bee

n presente d b y other

investigator s a

t th e 198 7 Symposiu

mo r elsewher e i n th e publishe d literature sinc e th e 198 6 Addendu mwa s prepared . Th e 198 6 Addendu

m(U.S . Environmenta

l Protectio n Agency , 1986b ) note d tha t severa l then-recently-publishe d studie s provide d generally consisten t evidenc e fo

r increase d bloo d pressure bein g associate d wit h elevate d lea

d bod y burden s i

n adults , especially a s indexe d b y bloo d lea d level s in variou s cohort s of adult men . Non e o

f th e individua

l studies , i t

wa s noted , provide d definitiv e evidenc e establishin g causa l relationship s betwee

n lea d exposur e and increase d bloo d pressure , but the y collectively provide d considerabl e qualitativ e evidenc e indicativ e of

significan t association s betwee

n bloo d lea

d and bloo d pressure levels . I t wa sP. M

fiujhe r emphasized tha

t estimate s of

quantitativ e relationship s between bloo d lea d level s an

d bloo d pressure increase s derive d fro msuc h stud y result s ar e subject

t o muc h uncertainty , give n th e relatively small sampl e size s and limite d populatio n group s typically studied . O n th e othe r hand , th e above-note d larger-scal e studie s (NHANE S n and BRHS ) of genera l populatio n groups , were single d out a s providin g reasonably goo d base s fo r estimatio n o

f quantitativ e blood-lead/blood-pressur e relationships . A s reviewe d in th e 198 6 Addendu m(U.S . Environmenta

l Protectio n Agency , 1986b) , i n th e BRHS , Pocock

e t al . (1984 ) evaluate d relationship s between bloo d lea d concentrations , hypertension , an

d rena l function indicator s in aclinica l surve y of 7,73 5 middle-age d me

n (age d 40-49 ) fro

m24 Britis h towns . Eac

h man' s bloo d pressure , whil e seated , wa s measure d twic e i n succession b y mean s of

aLondon Schoo l of

Hygien e sphygmomanometer . Diastoli c pressure was recorde d a

t phas e V disappearanc e o

f sounds . Th e mea

n of th e tw o reading s o

f bloo d pressur

e wa s adjusted fo

r observe d variatio n within each town to correc t fo r an y difference s amon

g thre e observers . Result s fo r 7,37 1 me n include d i

n dataanalyse s indicate d correlatio n coefficient s o

f r = +0.0 3 and r

= +0.0 1 fo

r association s between systoli c an d diastoli c bloo d pressure , respectively , and bloo d lea d levels . Th e systoli c bloo d pressure correlation , thoug

h small in magnitude , wa s nevertheles s statistically significan t a t p <0.01 . However , analyse s o

f covarianc e using datafo

r me n categorize d accordin g to bloo d lea d concentration s onl

y suggested increase s i

n bloo d pressure a

t lowe r bloo d lea d levels ; n o furthe r significan t increment s in bloo d pressure wer e observe d a

t highe r bloo d lea d level s eithe r befor e o r afte r adjustmen

t fo r factor s suc

h a s age , town , bod

y mas s index , alcoho l consumption , socia

l class , and observer . Evaluatio n o f prevalenc e of

hypertension , defined a s systoli c bloo d pressure over 16 0 m mmercur y (Hg) , reveale d n o significan t overal l trend ; bu t o f thos e me n wit h bloo d lea

d level s ove

r 3 7 /ug/dl , alarger

proportio n (3 0 percent) ha d hypertensio n whe

n compare d wit

h th e proportio n (2 1 percent) fo r al l other me n combine d ( p = 0.08) . Simila

r result s were obtained , fo

r diastoli c hypertensio n defined a s > 10 0 m m Hg , i.e. , agreate

r proportio n (1 5 percent) of me n wit h bloo d lea

d level s ove

r 3 7 jxg/d l ha d diastoli c hypertensio n in compariso n wit h th e proportio n ( 9 percent) fo r al l other me n (p = 0.07) . Pococ k e t al . (1984 ) interprete d thei r findings a s bein g suggestiv e of increase d hypertensio n a

t bloo d lea d level s ove

r 3 7 /tg/dl , bu t

no t a t lowe r concentration s typicallyP.1 5

foun d i n Britis h men . However , furthe r analyse s reporte d b y Pococ k e t al . (1985 ) fo

r th e sam e dat aindicate d sigmfisantly higher statistica l association s between bot

h systoli c ( p =0.003 ) and diastoli c ( p < 0.001 ) bloo d pressure an d bloo d lea d levels , whe

n adjustment s were made fo

r variatio n du e t o sit

e (town ) in multipl e regressio n analyses . Th e regressio n coefficient s fo

r lo g bloo d lea

d versu s systoli c an

d diastoli c pressure were +2.08 9 and +1.809 , respectively , whe n adjusted fo

r site a s well a s bod

y mass , age , alcohol , smoking , socia l class , an d observer . Notin g th e small magnitude of th e associatio n observe d and th e difficult y i n adjusting fo

r al l potentially relevant

confounders , Pocock

e t al . (1985 ) cautione d a t tha t time agains t

prematurely concludin g tha t elevate d bod

y lea d burden ha s acausa

l influenc e o n bloo d pressure . Th e 198 6 Addendu

m(U.S . Environmenta

l Protectio n Agency , 1986b ) als o note d tha t relationship s betwee

n bloo d lea

d and bloo d pressure among America n adult s ha

d begun to b e evaluate d in anothe

r large-scal e study , a s reporte d by Harla n e t al . (1985) , Pirkl e e t

al . (1985) , an d Schwart

z (1985a,b ; 1986a,b) . Thes e analyse s wer e base d o n evaluatio n of NHANE S n data , whic

h provid e careful bloo d lea d and bloo d pressure measurement s o n a large-scal e sampl e representativ e ofth e U.S . populatio n and considerabl e informatio n o n a wid e variet

y o f potentially confounding variable s a s well . A s such , thes e analyse s avoide d th e problemo f

selectio n bias , th e healthy-worke r effect , workplac e exposure s to other toxi c agents , and problem s wit

h appropriate choic e o

f contro l group s tha

t ofte n confounded o r complicate d earlier , occupationa l studie s o f

blood-lead/blood-pressur

e relationships . Thre e bloo d pressure reading s were recorde d fo r eac h subject : whil e seated earl y in th e examination , supine midwa y in th e examination , and seated nea r th e end . Firs t

and fifth phas e sound s wer

e take n a s systoli c and diastoli c pressures , respectively . Th e secon d seated bloo d pressure wa s used i n statistica l analyses , bu t

analyse s usin g th e first

seate d pressure o r

a mea n o f th e first an d secon d seated pressure yielde d simila r results . Blood lea

d values , determine d b y atomi c absorptio n spectrometry , were transforme d to lo g value s fo r statistica l analyses . Relationship s betwee

n bloo d pressure an

d other variable s wer

e evaluate d in tw o ways . First , me n and wome

n were stratifie d into normotensiv e and hypertensiv e categorie s and mea n value s fo

r relevan t variable s contraste d acros s th e categories . Fo r age s 21-5 5 yr , diastoli c high bloo d pressure (£9 0 m mHg ) mal e subject s (N = 475 ) ha d significantl

yP.1 6

( p < 0.005 ) highe

r Pb B levels , bod

y mas s index values , an

d calciumfood s tha

n di d normotensiv e mal e subject s (N = 1,043) . Simila r result s wer

e obtaine d fo

r age d 21-5 5 yr diastoli c hig

h bloo d pressure female s ( N = 263 ) i n compariso n t o normotensiv e female s (N = 1,316) . Fo r

subject s aged 56-7 4 years , significantly (p <0.05 ) highe r Pb B level s were foun d fo r female subject s (but

no t males ) defined a s havin g isolate d systoli c hig h bloo d pressure (i.e. , systoli c t

16 0 and diastoli c <9 0 m

mHg) . Simpl e conelatio n analyse s an d step-wis e multipl e regressio n analyse s were carrie d out a s asecon

d statistica

l evaluatio n approach ; Pb B value s wer

e entere d into predictiv e model s fo r systoli c and diastoli c pressure a s well a s severa

l other pertinent variable s (such a s age , bod y mas s index , etc. ) entere d sequentially accordin g to greates t magnitud e o f varianc e explaine d fo

r th e dependen

t variable . Th e simpl e conelatio n analyse s reporte d b y Harla n e t al . (1985 ) demonstrate d statistically significan t linea r association s (

p < 0.001 ) betwee

n bloo d lea

d concentration s and bloo d pressure (bot

h systoli c an

d diastolic ) amon

g male s an

d females , age d 1 2 to 7 4 years . Usin g multipl e regressio n analyse s controllin g fo r anumbe r of other potentiall y confounding factors , however , th e blood-lead/blood-pressur e association s remaine d significan t fo r male s but no t fo r wome n afte r adjusting fo

r th e effects o

f othe r pertinent variables . Additiona l analyse s of

NHANE S I I datareporte d b y Pirkl e e t al . (1985 ) focused o n whit e male s (aged 4 0 to 5 9 years ) i n order to avoi d th e effects of

collinearit

y between bloo d pressure and bloo d lea

d concentration s eviden

t a t earlier age s and becaus e o f

les s extensiv e NHANE S I I databein g availabl e fo r non-whites . I

n th e subgrou

p studied , Pirkl e e t

al . (1985 ) foun

d significan

t association s betwee

n bloo d lea

d and bloo d pressure even afte r includin g i

n multipl e regressio n analyse s al l know n factor s previously establishe d a s bein g conelate d wit

h bloo d pressure . The relationship als o hel d whe n teste d agains t

ever y dietar y an d serologi c variabl e measured in th e NHANE S U study . Inclusio n o f bot h curvilinea

r transformation s an

d interactio n term s altere d Uttl e th e coefficient s fo

r bloo d pressure association s wit

h lea d (th e stronges t

relationship wa s observe d between th e natura l lo g o f bloo d lea d and th e bloo d pressure measures) . Th e regressio n coefficient s fo r lo g bloo d lea

d versu s systoli c and diastoli c bloo d pressur e wer e 8.43 6 and 3.954 , respectively . N o evident threshol d wa s foun

d belo w which bloo d lea

d leve l wa s no t

significantl

y relate d t o bloo d pressur e acros s arang e of

7 to 3 4 /ig/dl . I

n fact , th e dose-respons e relationship s characterize d b y Pirkl e e t

al . (1985 ) indicat

e tha t larg e initia

l increment s in bloo d pressureP.1 7

occur a t relativel y lo w bloo d lea

d levels , followed b y levelin g of f o f bloo d pressure increment s a

t higher blood : lea d levels . Pirkl e et

al . (1985 ) als o foun

d lea d t o b e asignifican

t predicto r of diastoli c bloo d pressure greater tha n o r equa l to 9 0 m mHg , th e criterio n bloo d pressure leve l no w standardly employe d in th e Unite d State s to define hypertension . Additiona l analyse s were performe d b y Pirkl e e t al . (1985 ) to estimat

e th e likely publi c healt

h implication s of

thei r finding s concernin g blood-lead/blood-pressur e relationships . Change s in bloo d pressure tha

t migh t result from aspecified chang e in bloo d lea d level s were first estimated . Then coefficient s fromth e Poolin g Projec t an d Framingha

mstudie s (Poolin g Projec t Research Group [1978 ] an d McGe e and Gordon [1976] , respectively ) of cardiovascula

r diseas e were use d a s base s to : (1 ) estimat e th e risk fo r incidenc e of

seriou s cardiovascula

r event s (myocardia

l infarction , stroke , o r

death ) a s aconsequenc e of lead

induce d bloo d pressure increases , and (2 ) predic t th e chang e in th e numbe

r o f seriou s outcome s a s th e resul t

o f a3 7 percent

decreas e in bloo d lea

d level s fo r adult whit e male s (aged 40-5 9 years ) observe d durin g th e cours e of th e NHANES I I surve

y (1976-1980) . Th e earlier

Addendu m(U.S . Environmenta

l Protectio n Agency , 1986b ) als o note d tha t question s ha

d been raise d b y Gartside (1985 ) an d E . I . DuPon

t d e Nemour s (1986 ) regardin g th e robustnes s of

th e findings derive d fro

mth e analyse s o

f NHANE S n datadiscusse d abov e and a s to whethe

r certai n time trend s in th e NHANE S n datase t ma y hav e contribute d to (or accoun t for ) th e reporte d blood-lea

d blood-pressur

e relationships . Gartside reporte d analyse s of NHANE S I I data , which foun d tha t th e obtaine d siz e and leve l of coefficien t statistica l significanc e varie d dependin g upo n specifi c dataaggregation s used in analyzin g th e data . Th e larges t an d mos t significan t coefficient s fo

r bloo d lea d versu s bloo d pressure wer e obtaine d b y Gartsid e fo

r dat aaggregate d b y ag e group s tha t approximate d tha

t of th e 40-5 9 yr

mal e aggregatio n describe d b y Pirkl e e t al . (1985) , wit

h coefficient s fo

r mos t younge r cohor t group s aggregate d b y varyin g 20-yr ag e interval s (e.g. , 21-40 , 22-4 1 yrs , etc. ) o r older group s no t

alway s bein g significan

t a t p <0.05 . A s fo

r th e time tren d issue , bot

h bloo d lea

d and bloo d pressure decline d substantially durin g th e 4-y r NHANE S J

J stud y an d differen t geographi c site s wer

e sampled without

revisitatio n o

f th e sam e sit e ove r th e surve y period . Thus , variation s in th e sampling site s ove r time, coinciden

t wit h change s in bloo d lea

d and/o r bloo d pressure , migh

t contribute t o an

y observe d association s betwee n bloo d lea

d and bloo d pressure . E . I . DuPon

t d e Nemour s (1986 ) reporte d tha t multipl e regressio n coefficient sP.1 8

decrease d in magnitude and som e becam e non-significan

t (p > 0.05 ) whe

n adjusted fo

r geographi c sit

e in analyse s of

NHANE S J

J data , includin g analyse s fo r th e mal e grou

p (aged 12-74) reporte d b y Harla

n e t al . (1985 ) an

d fo r male s (aged 40-59 ) reporte d b y Pirkl e e t al . (1985) . Fo r

example , E . I . DuPon

t d e Nemour s reporte d unpublishe d reanalyse s of NHANES J

J dataconfirming significan t associations , fo

r male s aged 12-7 4 year s a s well a s 40-5 9 years , betwee

n lo g bloo d lea

d and systoli c o r

diastoli c bloo d pressure unadjusted fo r geographi c site , but

smalle r coefficient s (nonsignifican t fo r diastolic ) whe

n geographi c sit

e wa s include d i

n th e analysis . However , neithe r th e Gartside no r

E . I . DuPon

t d e Nemour s analyse s adjusted fo

r al l of th e variable s tha

t were selected fo

r stepwis e inclusio n i

n th e Harla n et al . (1985 ) and Pirkl e e t

al . (1985 ) publishe d analyse s b y mean s o f a priori decisio n rule s fo r inclusio n of

variable s having significan t association s wit

h bloo d pressure . Also , othe r difference s existe d in regar d to specifi c aspect s o

f th e modeling approache s employed , makin g i t extremely difficul

t to asses s clearl y th e potentia l impac t of variatio n in selectio n of ag e group s an

d geographi c sit

e adjustmen

t o n NHANE S J

J analyse s results . I n order to addres s th e "site " issu e mor e definitively , Schwart

z (1985a,b ; 1986a,b ) carrie d ou t aserie s o f additiona l reanalyse s of

th e NHANE S J

J data . Thos e analyse s confirmed tha

t th e regressio n coefficient s remain significan t fo r bot h systoli c and diastoli c bloo d pressure whe

n sit e i s include d a s avariabl e in multipl e regressio n analyses . O f severa l differen t approache s used b y Schwartz , th e mos t direc t wa s holdin g al l aspect s of th e origina

l Pirkl e et al . (1985 ) analyse s th e sam e excep t fo r th e additio n of

avariabl e controllin g fo

r th e 6 4 geographi c site s sampled in NHANE S IJ . Usin g thi s approach , th e coefficient s fo r lo g bloo d lea d in relatio n to either

diastoli c o r

systoli c bloo d pressure droppe d somewha t fro m thos e o f th e origina

l analyse s whe

n sit e wa s controlle d fo

r (i.e. , fro m8.44 to 5.0 9 fo

r systoli c and from3.9 5 to 2.7 4 fo

r diastoli c bloo d pressure) , but th e coefficient s fo

r each stil l remaine d significan

t a t p <0.05 . Whe

n stil l other

approache s wer

e use d to contro l fo

r site along wit h variation s i n other

variable s include d in th e analyses , statistically significan t result s wer e stil l consistently obtaine d bot h fo r male s age d 40-5 9 an

d fo r male s age d 20-74 . Th e result s obtaine d b y Schwart z (1985a,b ; 1986a,b ) vi areanalysi s o f NHANE S I I data (unadjuste d versu s adjusted fo

r geographi c site ) ar e presente d i n Tabl e 1 in compariso n to result s reporte d b y E . I . DuPon t d e Nemour s (1986 ) and in relatio n to th e findings presente d by Pocock e t al . (1984 , 1985 ) fo

r Britis h me

n (als o unadjusted versu s adjusted fo r site) .P.1 9

TABLE 1 . COEFFICIENT S FO R TH E NATURAL LO G O F BLOO D LEAD CONCENTRATIO N (logPfoB ) VS . BLOO D PRESSUR E (BP) I N ME N WIT H AN D WITHOU T ADJUSTMEN T FO R SIT E VARIABLE S Analysis Performe d b y Pococ k e tal . (1984 , 1985)

Schwart z (1985a,b )

E . I . DuPon

t d e Nemour s (1986 ) Schwart z (1986a,b )

E . I . DuPon

t d e Nemour s (1986 )

. i II.IHI^- ^ i^-,-,,.-,-,-,.-,.,,.-., ^ MI W m u i i l.ll . 1 1 Stud y Grou p Britis h Regiona l Hear tStud y Whit e male s age d 40-5 9 Systolic (n=7371 ) Diastolic (n=7371 ) NHANE S n Male s age d 20-7 4 Systolic (n=2254 ) Diastolic (n=2248 ) NHANE S n Male s age d 12-7 4 Systolic (n=2794 ) Diastolic (n=2789 ) NHANES D Whit e male s age d 40-5 9 Systoli c (n=543 ) Diastolic (n=565 ) NHANES H Whit e male s age d 40-5 9 Systolic (n=553 ) Diastolic (n=575 ) Coefficien to f lo g Pb B vs . B P Unadjuste d fo r Sit e

1.68* * 0.3 0 5.23** * 2.96** * 3.43** * 2.02** * 8.44* * 3.95* * 6.27* * 4.01* * Adjuste d fo r Sit e

2.09* * 1.81** * 3.23* * 1.39 * 1.95 * 0.3 6 5.01 * 2.74 * 3.46 * 1.93 *

*p <0.0 5 ** p <0.0 1 *** p < 0.00 1 Th e 198 6 Addendu

m(U.S . Environmenta

l Protectio n Agency , 1986b ) conclude d that , overall , th e analyse s o f

dat afromth e tw o large-scal e genera l populatio n studie s (Britis h Regiona l Hear t Stud y an d U.S . NHANE S J

J Study ) discusse d abov e collectivel y provid e highly convincin g evidenc e demonstratin g small bu t statistically significan

t association s between bloo d lea

d level s an d increase d bloo d pressure in adult men . Th e stronges t association s appeare d t o exis t fo r male s age d 40-5 9 and fo

r systoli c somewha

t more s o tha

n 

### 8fo

r diastoli c pressure . Virtually al l o f th e analyse s reveale d positiv e association s fo r th e 40

- 5 9 age d group , whic

h remain o r

becom e significan

t (a t p <0.05 ) whe

n adjustment s ar e made fo r geographi c site . Furthermore , th e result s of thes e large-scal e studie s were note d to b e consisten t wit h simila r findings of

statistically significan

t association s between bloo d lea d level s and bloo d pressur

e increase s a s derive d fromother smaller-scal e studie s discusse d i n th e Addendum , whic

h als o mainl

y foun d stronge r association s fo

r systoli c pressure tha

n fo r diastolic . Th e Addendu

m(U.S . Environmenta

l Protectio n Agency , 1986b ) furthe r conclude d tha

t non e of th e observationa

l studie s in an

d of themselve s ca

n b e state d a s definitively establishin g causa

l linkage s between lea

d exposur e an d increase d bloo d pressure o f hypertension . However , th e Addendu mnote d tha

t th e plausibilit

y of th e observe d association s reflecting causa l relationship s between lea d exposur e and bloo d pressure increase s wa s supporte d by : (1 ) th e consistenc y o f th e significan

t association s foun

d b y numerou s independen

t investigator s fo

r avariet y o f stud y populations , an

d (2 ) extensiv e toxicologica l datadiscusse d i n th e 198 6 Addendu mwhich clearl y demonstrate d increase s i n bloo d pressure fo r anima l model s unde

r well-controlle d experimenta l conditions . Th e precis e mechanism s underlyin g relationship s betwee n lea d exposur e and increase d bloo d pressure , th e Addendu m furthe r stated , appeare d to b e complex , an d mathematica

l model s describin g th e relationship s stil l remaine d t

o b e mor e definitivel

y characterized . A

t th e time of

th e Addendum , lo g blood

lead/bloo d pressur

e model s appeare d to fit

bes t th e availabl e data , but

linea r relationship s betwee n bloo d lea

d an d bloo d pressure coul d no t b e rule d out . Th e mos t

appropriate coefficient s characterizin g thes e relationship s als o remaine d to b e more precisely determined , although thos e liste d i

n Tabl e 1 obtaine d b y analyse s adjusting fo r sit e appeare d t o b e th e cunentl y bes t

availabl e an

d mos t reasonabl e estimate s of

th e likely strengt

h of th e associatio n fo r adult me n (i.e. , generally in th e rang e of 2.0-5. 0 fo

r lo g bloo d lea

d versu s systoli c and 1.4 to 2. 7 fo

r lo g bloo d lea

d versu s diastoli c bloo d pressure) . Th e 198 6 Addendu mwen t o n t o not e tha t th e ful l rang e of bloo d lea d level s tha

t ma y b e associate d wit

h increase d bloo d pressure als o remaine d to b e mor e clearl y defined . However , th e collectiv e evidenc e from th e abov e studie s point s towar d lo w o r moderately elevate d bloo d lea d level s a s bein g associate d wit

h bloo d pressure increases , wit h certai n evidenc e (e.g. , th e NHANE S I I dat aP.2 1

analyse s and som

e other stud y results ) als o indicatin g significan t relationship s between bloo d * pressure elevation s and bloo d lea d level s rangin g down , possibly , t o a s lo w a s 7 jtg/dl . Th e earlie r

Addendu m(U.S . Environmenta

l Protectio n Agency , 1986b ) furthe r state d tha t th e quantificatio n o

f likely consequen

t risks fo r seriou s cardiovascula

r outcomes , a s attempte d b y Pirkl e e t

al . (1985) , als o remaine d to b e mor e precisely characterized . Th e specifi c magnitude s of

risk obtaine d fo

r seriou s cardiovascula

r outcome s in relatio n to lea d exposure , estimate d o n th e basi s of lead-induce d bloo d pressure increases , depend cruciall y upon : th e for

mof th e underlyin g relationship an d siz e of th e coefficient s estimate d fo r blood

lead/blood-pressur

e associations ; lea

d exposur e level s a t which significan

t elevation s in bloo d pressure occur ; and coefficient s estimatin g relationship s between bloo d pressure increase s an d specifi c mor

e seriou s cardiovascula

r outcomes . I t

wa s note d tha

t uncertaint y stil l exist s regardin g th e mos t

appropriat

e mode l an d blood-lead/blood-pressur e coefficients , mading i t difficul t t o resolv e which specific coefficient s should b e use d in attemptin g to projec t

mor e seriou s cardiovascula

r outcomes . Similarly , i t

wa s indicate d tha

t i t i s difficul t to determin e appropriate bloo d lea

d level s a t whic h an y selected coefficient s migh t b e appropriatel y applie d in model s predictin g mor

e seriou s cardiovascula

r outcomes . Lastly , i t

wa s note d tha

t th e selectio n of

appropriat

e model s an

d coefficient s relatin g bloo d pressure increase s to mor e seriou s outcome s i s als o fraught wit h uncertainty . Question s exis t regardin g th e genera

l applicabilit

y of coefficient s derive d fromth e Pooling Project s an d Framingha

mStud y to me n age d 40-5 9 in th e genera

l U.S . population . Further analyse s of

additiona l large-scal e epidemiologi c datasets , i t

wa s stated in th e Addendum , would b e necessar y to determin e mor e precisely quantitativ e relationship s betwee n blood-lea

d an d blood-pressure , and mor e seriou s cardiovascula

r outcome s a s well . Th e Addendu

m(U.S . Environmenta

l Protectio n Agency , 1986b ) wen t o n to note furthe

r tha t th e abov e findings, whil e pointin g towar d alikely causa

l effec t of lea d in contributin g to increase d bloo d pressure , need t o b e place d in broade r perspectiv e i

n relatio n t o other

factor s involve d in th e etiolog y of hypertension . Th e underlyin g cause s of increase d bloo d pressure o r "hypertension " (diastoli c bloo d pressure abov e 9 0 m mHg) , which occur s in a s man y a s 2 5 percent o f Americans , ar e no t

yet full y delineate d (Frohlich , 1983 ; Kaplan , 1983) . However , i t

i s ver y clea r tha t man y factor s contribut

e to developmen

t of thi s disease , includin g hereditar

y traits , nutritiona

l factors , and environmenta l agents . Th e relativ e role s of 1 0P.2 2

variou s dietar

y and environmenta

l factor s in influencing bloo d pressure and th e mechanism s by which the

y do s o are amatte

r of intens e investigativ e effor

t an d debate (se e proceeding s of conferenc e "Nutritio n an

d Bloo d Pressure : Cunen t Statu s o f Dietar y Factor s and Hypertension, " McCano n and Kotchen , 1983) . Th e contributio n o f lead , compare d to man

y other factor s evaluate d in variou s analyse s discusse d above , appear s t o b e relativel y small , usuall y no t accountin g fo

r mor e tha n 1- 2 percent o f th e variatio n explaine d b y th e model s employe d whe

n other significan t factor s ar e controlle d fo

r i n th e analyses . Man y o f th e abov e issue s and question s hav e bee n furthe r addresse d sinc e th e 198 6 Addendu mwa s completed , in par

t a t th e 198 7 Lead-Bloo d Pressure Symposiu mand in other recen t publication s a s well . Presentation s an d discussion s a

t th e 198 7 Symposiu

m(se e Victery , 1988a

) wer e contribute d b y (1 ) man

y of th e ke y scientist s who hav e carrie d out importan t investigation s of

th e relationship o

f lea d exposur e an d hypertensio n (includin g observational , epidemiologic , and experimenta l reports) , a s well a s (2 ) other expert s in hypertensio n an

d cardiovascula

r diseas e in general . Severa l speaker s reviewe d thei r

analyse s of th e NHANE S I I data(Harlan , 1988 ; Schwartz , 1988 ; Gartside , 1988 ; Landi s and Flegal , 1988 ) an d th e Britis h stud

y (Pocock et al. , 1988) . Elwoo d et

al . (1988a

) als o summarize d th e result s of tw o ne w large-scal e Wels h studies . Pocock furthe r provide d ane

w compariso n of th e relativ e magnitud

e o f th e contributio n o

f lea d exposur e t o bloo d pressure change s base d o n intercompariso n o

f th e result s of

th e NHANE S II , British , an d Wels h studies . A numbe r of other relevan t paper s describe d studie s of lead-bloo d pressure relationship s in selecte d population s o

f nonoccupationally expose d individuals , a s well a s worker s (Kromhout , 1988 ; Morea u e t al. , 1988 ; Weis s e t

al. , 1988 ; Wedeen , 1988 ; Cooper , 1988 ; Seleva n e t al. , 1988 ; d e Kor t an d Zwennis , 1988 ; Elwoo d et al. , 1988 ; Ner

i et al. , 1988 ; Staesse

n e t al. , 1988 ; Shar p e t al. , 1988) . Othe

r presentation s addresse d pertinen t toxicologica

l findings fro

min vivo o r in vitro anima

l studie s (Vander , 1988 ; Cha i an d Webb , 1988 ; Kop

p e t al. , 1988 ; Boscol o an

d Carmignani , 1988 ; Weile r e t al. , 1988 ; Victery , 1988b) . Wit h regar d t o ne w finding s reporte d a

t th e 198 7 Symposium , afurthe r alternativ e analysi s of th e datafromNHANE S J J (using ageneralize d Mantel-Haenzel test) wa s reporte d b y Landi s an

d Flega l (1988) . I

n order to mor e definitivel

y asses s th e robustnes s of

th e earlier NHANE S J

J result s (Harla

n e t al . 1985 ; Pirkl e e t

al. , 1985 ) and , also , t o evaluate possibl e time-trend effects confounded b y variation s in sampling sites , Landi s and Flega l (1988 ) 1 1P.2 3

carrie d ou t

furthe r analyse s fo

r NHANE S J

J males , age d 12-74 , usin g arandomizatio n mode.1

- base d approac h t o tes t

th e statistica

l significanc e o f

th e partia l conelatio n between bloo d lea d an d diastoli c bloo d pressure , adjusting fo r age , bod y mas s index , an

d th e 64 NHANE S I I sampling sites . Simpl e linea r and multipl e regressio n coefficient s betwee n lo g bloo d lea

d an d diastoli c bloo d pressure fo r al l male s (aged 12-74 ) were 0.1 5 an d 4.90 , respectively ; fo

r variou s group s broken out b y ag e (<20 , 21-39 , >4 0 yrs ) and bod y mas s index levels , th e respectiv e coefficient s range d from0.0 4 t o 0.1 2 and from1.2 9 to 3.5 5 (predominantly between 2. 3 and 3.6) , displayin g considerabl e consistenc y acros s age-bod y mas s compariso n groups . Also , th e mos t

stringen t o r "conservative " approac h used t o calculat e arandomize d model statisti c controllin g fo r effect s du e to 64 sampling site s yielde d ates t statisti c of

4.6 2 (stil l significan

t at p <0.05) . Th e author s note d that : (1 ) th e associatio n mus t b e sufficientl

y robus t t o persis t acros s 47 8 subgroup s formed on th e basi s of factor s als o having a

n associatio n wit

h th e level s of

bloo d lea d an d bloo d pressure ; and (2 ) nevertheless , eve n wit h th e sever e adjustment s b y sampling sites , age , and Quetelet index , th e diastoli c bloo d pressure/bloo d lea

d relationship remaine d statistically significan t a t th e p <0.0 5 level . I

n summary , their

analyse s indicat

e tha t th e significan

t linea r associatio n betwee

n blood-lea

d level s an d diastoli c bloo d pressure reading s canno t b e dismisse d a s du e to concunen t secula r trend s i n th e tw o variable s acros s th e 4-yea r surve y period . Finally , th e author s note d that , even though thes e partial conelation s ar e no t large , th e magnitud

e of th e regressio n coefficient s suggest s tha

t elevate d bloo d lea

d level s ma

y b e a n importan

t risk facto r fo r elevate d bloo d pressures , a s develope d i n considerably greater detai l fo r th e restricte d group o f white me n 4 0 to 5 9 year s of

ag e (a s describe d in Pirkl e e t al. , 1985) . Als o reporte d a

t th e 198 7 Symposiu

mwer e tw o survey s i

n Wale s tha

t evaluate d possibl e relationship s between bloo d lea d and bloo d pressure (Elwoo d e t al. , 1988a,b) . Th e Wels h Hear t Programme wa s carrie d out i n 198 5 throughout

Wales , using astratifie d cluster rando m sampl e o f 21,00 0 households , wit

h 2,01 0 mal e and femal e adult subject s bein g include d in th e survey populatio n fo

r who mbloo d lea

d determination s were made . Complet e bloo d lead , bloo d pressure , an d other

ke y dat awere availabl e fo

r 86 5 me n an d 85 6 women . Mea

n bloo d lea d value s fo

r me n were 12. 4 /xg/d

l and fo r wome n 9. 6 jtg/dl . Blood lea

d increase d wit

h ag e ( 1 /xg/d

l ever y 15. 6 year s in me

n and ever y 13. 1 year s in women) . Th e partial regressio n coefficient s wit

h standar d eno r were reporte d afte

r th e effec t o f ag e ha d bee n remove d b y 

### 1 2P.2 4

cubi c regression . In males , th e coefficient s fo r systoli c an d diastoli c pressure were 0.8 2 ± 1.4 9 and 1.2 9 ± 0.95 , respectively . Fo r females , thes e coefficient s were 0.1 9 ± 1.4 6 and 0.5 4 + 1.00 . In neithe

r se x wa s th e relationship statistically significant . Categorizin g th e datab y bloo d lea

d increment s demonstrate d n o tren d in th e bloo d pressure levels . Th e secon d grou p studied wa s about

half o f th e planne d subject s in th e Caerphilly Collaborativ e Hear

t Diseas e study ; thi s stud

y o n ischemi c hear

t diseas e wa s base d o n acohor t o f me n age d 45-59 , living i

n Caerphilly , asmall town i n Wales . Severa l risk factor s fo r ischemi c hear

t diseas e wer

e considered . Blood pressure wa s measure d wit h arandom-zero muddle r sphygmomanomete

r afte r a5-minut e res t and durin g acol d presso r

test . Th e conelatio n coefficient s fo

r restin g systoli c an

d diastoli c pressure were 0.018 3 and 0.0230 , respectively , an

d fo r th e rise in pressure wit

h th e col d presso r

test , 0.034 2 and 0.007 8 respectively . None wer e significan

t a t p < 0.05 . Ranking th e bloo d pressure reading s accordin g to bloo d lea

d group s di d no t

revea l an y tren d i n th e percentag e of subject s wit

h systoli c bloo d pressure greate r tha n 16 0 m mHg . Th e author s (Elwoo d e t

al. , 1988a,b ) onl

y conecte d fo

r ag e a s aconfounding factor , becaus e al l other

factor s wer

e positively conelate d wit

h bot h bloo d pressure an

d bloo d lead . The y conclude d that , in th e even t thes e other

factor s (e.g. , cigarette us e an d alcoho l consumption ) were controlle d for , the y would probably reduc e th e alread y trivial (and nonsignificant

) relationship s foun

d b y the mfo r bloo d lea d and bloo d pressure measurement s i n th e tw o Wels h studies . A t th e 198 7 Symposium , Pocock compare d th e result s of

th e NHANE S J

J dat aanalyse s a s discusse d b y Schwart

z (1988) , hi s analyse s of

th e Britis h stud

y (Pocock e t al. , 1988) , and th e tw o Wels h studie s (Elwoo d e t al. , 1988a,b) . Figur e 1 show s th e magnitude s of effect s obtaine d fo

r adult me n i n thes e fou

r large-scal e studies , relatin g systoli c bloo d pressure t o bloo d lea d concentration , a s depicte d b y Pococ k etal . (1988) . Th e grap h show s eac h study' s estimate d chang e in mea

n systoli c bloo d pressure fo r eac h doublin g of

bloo d lea d (e.g. , from 8 to 1 6 ftg/dl) , togethe

r wit h 95 % confidenc e limits . Pococ k conclude d tha

t a n overvie w of datafromthes e larg e epidemiologica l survey s provide s reasonably consisten t evidenc e o n lea

d and bloo d pressure . Tha

t is , wherea s th e NHANE S J J dat ao n 2,25 4 U.S . me

n indicate a slightly stronge

r associatio n betwee

n bloo d lea

d an d systoli c bloo d pressure tha n Pocock' s

1 3BRH S ( N = 7371 )

NHANE S I I ( N = 2254 ) Caerphill y ( N =1164 ) Wale s ( N = 865 )

• l 

### I | 

### I

r "- • •



# 1

l 

## 1

• C 

# D

—- ~ " i D



# A 1

n 1 

# B i 

### i i 

### i

r - 1 -



### - 2 - 1 ESTIMATE D C

(nun n 

### 0 G E 

### 1 * J MEAN SYSTOLI C BLOO D PRESSUR E DOUBLIN G O F BLOO D LEAD Figur e 1 . Compaiiisomo

f stud y result s fromfou r

larger-scal e epidemiolog y studie s o f lead-bloo d pressur e relationship s i n adul t men . Depicte d ar e eac h study' s estimate d change s i n mea n systoli c bloo d pressur e (i n m mHg ) fo r eac h doublin g of

bloo d lea d (e.g. , from 8 t o 1 6 jig/dl ) togethe r wit h 95 % confidenc e limits . A = Britis h Regiona l Hear t Stud y (BRHS ) analyses , describe d b y Pococ k e t al . (1988) ; B = Nationa l Healt h an d Nutritio n Evaluatio n Surve y (NHANE S H ) analyse s describe d b y Schwart z (1988) ; C an d D = Caerphill y an d Wales'studie s describe d b y Elwoo d e t al . (1988a,b) . Source : Pococ

k e t al . (1988) . 8/16/9 0 1 4P.2 6

Britis h study , th e datafrqmth e tw o Wels h studie s o n ove r 2,00 0 me n als o showe

d asmal l positiv e (bu t

no t statistically significant

) association . Pococ k

note d tha t 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 d pressure i n adult me n i s increase d b y abou

t 1 m mHg fo r ever y doublin g of

bloo d lea d concentration . Ther e wa s a

n additiona

l repor t o f a n analysi s of

cross-sectiona

l datafromCanada(Ner

i e t al. , 1988 ) presente d a

t th e 198 7 Lead-Bloo d Pressure Symposium . Thi s stud y was performe d on datacollecte d durin g 1 0 month s of 1978-197 9 fo

r 2,19 3 subjects age

d 2 5 to 64 . Th e zero-order

conelatio n betwee

n diastoli c bloo d pressure and bloo d lea d leve l was foun

d to b e 0.115 . Th e author s concluded that , although thi s associatio n i s awea k on e (a s was als o th e cas e i n th e NHANE S I I data) , it s statistica l significanc e i s no t

i n doub t ( p <0.001) . The y furthe r conclude d tha

t (1 ) th e Canadia

n dat awere a

t leas t weakl y supportiv e o

f th e inferenc e draw n fro

mNHANES II , i

n tha t elevatio n o f

bloo d lea d di d see mt o entai l som

e ris k of bloo d pressure elevation , but (2 ) i t woul d b e premature , in th e absenc e o f longitudina

l data , to infe

r tha t thi s i s acause-and-effect

relationship . Ner

i e t al . (1988 ) the

n reporte d th e findings fo

r agroup o f subjects studie d longitudinally fo r bloo d lea d level s an

d bloo d pressure . I

n thi s stud y o f lea d foundr y workers , a

n associatio n wa s foun

d betwee n short

ter mchange s i

n a n individual' s bloo d lea

d leve l an d contemporar

y change s in diastoli c pressure , which remaine d significan t afte r allowanc e fo

r ag e (o r time ) trend s an

d fo r effects attributabl e to change s i

n bod y weight . Th e author s als o note d tha t short-ter mchange s i

n urinar y cadmiumwer

e similarl y predictiv e of

diastoli c bloo d pressure levels . There wer e severa l othe r report s presente d a

t th e 198 7 Symposiu

mwit h regar d t o smaller-scal e observationa

l studie s o f bloo d lea d an d bloo d pressure in tw o type s o f occupationali y lead-expose d groups : bu s driver s (Shai p e t al. , 1988 ) and policeme

n (Weis s et al. , 1988 ; Morea

u e t al. , 1988) . Thes e studie s al l yielde d finding s tha t are als o indicativ e o f lead-induce d increase s i

n bloo d pressure . I n other recent report s beside s thos e presente d a t th e 198 7 Symposium , severa l ne w studie s (wit

h generally smal

l cohorts ) o

f occupationaliy expose d worker s hav e yielde d furthe r result s wit h regar d t o lea d effects on bloo d pressure o r other cardiovascula

r outcomes . Fo r example , Parkinso n et

al . (1987 ) reporte d findings on datacollecte d in 198 2 fro m27 0 lea d worker s and 15 8 nonexposed worker s i n Pennsylvania . Four

measure s of

lea d exposur e wer e 1 5P.2 7

used : (a) employmen

t a t lea d exposur e vs . contro l plants ; (b ) cunen t bloo d lea d value s a t time o f examinatio n (exposed group mea n = 39. 9 /*g/d

l vs . 7. 4 /ig/d l fo

r controls) ; (c ) zin c protoporphyri n value s a

t time o f examination : (d) time weighte d averag e (TWA ) bloo d lea

d value s for lead-expose d worker s sinc e date of hire . Othe

r risk factor s (age , year s of education , etc. ) wer

e als o include d in th e regressio n analysis . O f th e thre e lea

d measures , onl y TW A bloo d lea

d wa s significantly , although modestly , conelate d wit h bloo d pressure . Afte r controllin g fo

r other predictiv e risk

factors , includin g age , th e effec t of TW A on bloo d pressur e wa s n o longe

r significan t and th e author s di d no t

find evidenc e o

f rena l disease . Also , i n 1987 , d e Kor

t and colleague s reporte d finding astatistically significan t increas e i n systoli c an d diastoli c pressure in 5 3 exposed male s compare d wit h 5 2 control s (de Kor

t e t al. , 1987) . Bloo d lea

d average d 47. 4 jig/d l fo

r th e expose d worker s vs . 8. 1 fo r controls . Bloo d an d urin e cadmiu

mwer e als o highe

r tha n in controls ; there were n o advers e effects on kidne y function . Th e prevalenc e of clinically defined hypertensio n (systoli c greater tha n 16 0 m mH g and/o r

diastoli c greate

r tha n 9 5 m mH g and/o r

under treatment fo r hypertension ) wa s highe r i n th e expose d group , bu t th e observe d relativ e risk

wa s no t different . On th e other

hand , Shar

p et al . (1989 ) di d fin

d astatistically significan

t (p <0.036 ) relationshi p between bloo d lea d level s an

d bloo d pressure (diastoli c bu t no t systolic ) level s amon g asubsampl e o f

bu s driver s evaluate d i n thei r earlie r stud y (Shar p e t al. , 1988 ) wh o wer e under

beta-blocker

treatmen t fo r hypertension . Th e associatio n betwee n diastoli c bloo d lead an d bloo d pressure wa s significan t a t th e state d leve l eve

n afte r controllin g fo

r other relevan t ris k factors , and non e o f

th e bloo d lea

d level s a t th e time o f

bloo d pressure testin g exceede d 1 8 jtg/dl . I n additio n t o th e abov e stud y result s which focused primaril y o n lead-bloo d pressure effect s i n adul t

males , som

e additiona

l analyse s of

suc h relationship s in female s hav e become availabl e sinc e th e 198 6 Addendu man d th e 198 7 Lead-Bloo d Pressure Symposium . Fo r example , Schwart

z (1989 ) ha s recentl y reporte d th e result s of stil l furthe

r analyse s o

f th e NHANE S J

J dataset . Thes e lates t

analyse s used variable s identifie d a s bein g importan t i n earlie r NHANE S U analyse s and examined th e relationship between bloo d lea d an d bloo d pressur e i n bot

h male s an

d females , aged 20-7 4 years . Th e analyse s wer e carrie d out

in stages , wit

h separat e regression s first

being performed fo

r male s and females . Diastoli c bloo d pressur e wa s regresse d on age , ag e squared , Quetelet' s bod y mas s index , an

d th e natura

l lo g 

### 1 6P.2 8

of .blood lead . If

, i n thi s first

step , lea d wa s significant , then astepwis e regressio n wa s carrie d out

takin g into accoun

t anumbe r of covariate s o r

potentially confounding cofactor s (e.g. , dietar

y sodium , smoking) , and final model s were then ultimately estimate d usin g SURREG R ( aprogra

mconectin g fo

r stud y desig n effects a s well) . Statistically significan t relationship s were foun

d betwee n bloo d lea

d and bloo d pressure i n bot h male s (p <0.01 ) an d female s ( p <0.01 ) in th e first

stag e regressions , conectin g fo r th e above-note d covariates . Lea d als o continue d to b e significantl y relate d t o bloo d pressure i n th e separat e stepwis e regression s fo

r male s an d females . Th e final model s yielde d asmalle r bu t statistically significan t ( p <0.03 ) bloo d lea

d coefficien

t (1.640 ) fo

r female s tha

n th e coefficien

t fo r male s (2.928 ; p < 0.006) . Thes e result s therefor e (1 ) ten d t o confir mth e earlier

findings of Schwart z an d other investigator s demonstratin g significan t association s betwee

n bloo d lea

d and bloo d pressure increase s in adult male s in th e NHANE S I I stud y population , and (2 ) demonstrat

e analogou s although somewha t smalle r effect s in wome

n fro mth e sam

e stud y population . However , th e strengt h of th e relationship (bloo d lea d coefficient

) fo r wome n remain s to b e mor

e precisely defined in term s of adjustment s fo

r geographi c site effects analogou s to thos e describe d abov e fo r earlier analyse s fo

r NHANE S J

J and BRH S mal e subjects . I n anothe r study , Grandjea

n e t al . (1989 ) evaluate d lead-hypertensio n relationship s i n a cohor t o f 504 me n and 54 8 wome

n bor n in th e sam

e yea r and residin g in th e Glostru p are aof Denmark . Bot

h bloo d lea

d concentration s an

d bloo d pressure determination s wer e first obtaine d a t ag e 4 0 an d then , again , five year s later fo r 45 1 me n an d 41 0 o f th e women . Th e averag e bloo d lea

d level s fo r me n a t ag e 4 0 an d 4 5 year s were 1 3 and 9 A*g/dl , respectively ; fo r wome n the y wer e 9 an d 6 /*g/dl , respectively , a

t ag e 4 0 an d 4 5 years . A

t ag e 40 , wome

n wit h systoli c bloo d pressure abov e 14 0 m mH g and/o r

diastoli c abov e 9 0 m

mHg ha d slightly elevate d bloo d lead s compare d t o non-hypertensiv e women ; bu t n o difference s wer

e foun d fo r bloo d lea d level s in me

n wit h increase d versu s norma

l (i.e. , 14 0 o r 9 0 m mHg , respectively , fo r systoli c and diastolic ) bloo d pressure . Significan t conelation s wer

e foun d betwee n lo g bloo d lea d and systoli c bloo d pressure in bot h me n an d wome n and diastoli c bloo d pressure i n wome n onl y a t ag e 40 , bu t

no t a t ag e 45 . Th e relationship a t ag e 4 0 indicate d adoublin g o f bloo d lea d bein g associate d wit

h a* 3 m mHg increas e i n bloo d pressure . Whe n bloo d hemoglobin an d alcoho l intak e (the onl y tw o of nin e potentia

l confounder s assessed tiiat were 1 7significantly relate d t o bot h bloo d lea

d and bloo d pressure ) wer

e entere d int o multipl e regressio n analyses , then al l blood-lea d blood-pressur

e association s becom

e non-significant . Grandjea n e t al . (1989 ) note d tha

t th e initial associatio n foun d between bloo d lea

d an d bloo d pressure wa s simila

r o r slightly weake

r tha n thos e earlier

reporte d fo

r th e BRH S (Pococ k e t al. , 1985 ) o r

th e NHANE S J

J (Pirkl e e t

al. , 1985 ) dataanalyses . Th e impac t of alcoho l an d bloo d hemoglobin o n th e subsequen t multipl e regressio n outcome s indicate d clea r confounding-wit

h bloo d lea

d an d a n inabilit y in thi s stud

y to separat

e out relativ e contribution s du e t o thos e factor s versu s lea d (wit h bloo d lea

d increasin g wit

h numbe r of umt s o f alcoho l consume d a s documente d i n th e stud y cohor t a t ag e 40 , fo

r example) . Th e author s (Grandjea n e t al. , 1989 ) furthe

r note d tha t non-respons e an

d los s t o follow-up , th e ver y lo w rang e of bloo d lea d values , and th e limite d statistica l powe r of th e stud y (wit h fewe r tha n 1,00 0 subjects ) t o detec t

small effect s ma

y hel p to accoun

t fo r their observe d patter

n of results . Th e issu e o f

lea d effect s o n mor

e seriou s cardiovascula

r diseas e outcomes , possibl y mediate d b y lea

d effect s i n bloo d pressure o r vi aother lead-induce d pathogeni c processe s ha s been furthe

r addresse d sinc e th e 198 6 Addendu mto th e EP

A Lea d Criteri aDocumen

t wa s prepared . Som

e of th e newe r evidenc e ha s been derive d fromstudie s of occupationali y expose d worker s and other ne w result s hav e emerge d fromstil l furthe r analyse s o f

th e tw o larger-scal e BRH S an d NHANE S I I datasets . Th e cause s of

mortalit y of lea d worker s in th e Unite d Kingdombetween 192 6 and 1985 , fo r example , hav e recently been update d i n acase-contro l stud y reporte d b y Fannin g (1988) . There wer e 86 7 death s i n me

n wit h relatively hig

h occupationa

l exposur e to lea d durin g thes e years , and 120 6 death s durin g th e sam e perio d in me

n whos e exposur

e ha d been lo w o r absent . Durin g th e perio d betwee n 194 6 an d 196 5 there was asignifican

t exces s of death s fromcardiovascula

r disease ; bu t

there wa s n o differenc e betwee n th e tw o group s over

th e pas t 2 0 years . Also , n o statistically significan t exces s i n th e numbe

r of death s frommalignan

t neoplasm s wa s evident . Fannin g conclude d tha t th e previou s evidenc e of

a n increase d risk

of deat h fromcerebrovascula

r diseas e (in lea

d workers ) wa s therefor

e confirmed , bu t

i t woul d see mtha t wit h th e introductio n of

stricter standard s of

lea d contro l thi s increase d risk ha s now disappeared , a s ha s an

y margina l risk of deat h frommalignan

t disease . 1 8P.3 0

' Anothe r occupationa

l exposur e study , a n analysi s of

cause s of deat h i n U.S . batter

y and lea d productio n worker s durin g th e year s 194 7 to 1980 , wa s presente d a t th e 198 7 Lead

Bloo d Pressure Symposiu

mb y Coope

r (1988) . Mortalit

y cause s wer

e code d accordin g to th e sevent h (1955 ) revisio n of

th e Internationa

l Classificatio n o f

Diseases . Dat awer e fromdeath s o f 4,51 9 batter

y plant worker s an

d 2,30 0 lea

d productio n o r

smelte r worker s durin g thi s time period . Coope

r reporte d tha

t there wer e significan

t exces s death s fo

r "othe r hypertensiv e disease " (444-447 ) and "chroni c nephritis " (592-594) ; but death s fromother

hypertension

relate d disease s di d no t

show comparabl e excesse s and rena l cance r death s were fewe

r tha n expected . Also , Seleva

n e t al . (1988 ) reporte d a

t th e 1987 Symposiu

mtha t a n analysi s of cause s of mortalit y in 1,28 1 lea

d smelte r worker s employed a

t a n Idah o smelte

r between 194

0 an d 1965 did no t

sugges t a n associatio n betwee

n occupationa

l lea d exposur e an d mortalit

y fro mhypertension . O

n th e other

hand , th e datad o sugges t

a n associatio n between lea

d an d renal diseas e and , possibly , rena l cancer . Th e 198 7 Symposiu

mrepor t b y Pocock

et al . (1988 ) not

onl y reviewe d relationship s between bloo d lea

d concentratio n an

d bloo d pressure a s determine d in th e Britis h Regiona l Hear t Survey , but

als o looke d a

t relationship s betwee

n lea d an d mor e seriou s cardiovascula

r outcomes . Th e result s o f

thes e furthe

r analyse s of

th e BRH S datase t were reporte d b y Pococ k et al . (1988 ) to show that , b y 6 year s of follow-up , 31 6 of

th e me n ha d majo r ischemi c hear

t diseas e and 6 6 ha

d astroke . Afte

r controlUn g fo r th e confounding effects of cigarette smokin

g and town o

f residence , statistica

l analyse s di d no t

yiel d statistically significan t association s between bloo d lea d level s an

d suc h cardiovascula

r events . However , a s th e bloo d lead-bloo d pressure associatio n i s s o weak , Pocock e t al . (1988 ) noted , i t

i s unlikely tha

t an y consequen

t associatio n betwee

n lea d an d cardiovascula

r diseas e coul d b e demonstrate d fro

mprospectiv e epidemiologica l studies . O n th e other

hand , Schwart

z (1989 ) ha s recently reporte d result s derive d fro mne w NHANE S I I dataanalyses , which provid e evidenc e fo r significan t association s between bloo d lea d level s and electrocardiogra m(ECG) abnormalitie s indicativ e o f lef t ventricula

r hypertroph

y (LVH) . Suc

h EC G abnormalitie s represent a n early indicato r

o f cardiovascula

r diseas e tha

t i s muc h mor e commo n tha n frank myocardia

l infarctions . Th e logisti c regressio n analyse s employed b y Schwart z (1989 ) yielde d asmall (0.028 ) but statistically significan

t ( p <0.01 ) coefficien

t fo r a n associatio n betwee

n bloo d lea

d level s and increase d prevalenc e 1 9P.3 1

o f LVH , takin g into accoun

t age , race , and se

x (al l of which were significantl

y relate d to , LV H at p <0.01 , < 0.0001 , and < 0.0001 , respectively) . Th e interactio n term s fo r se x o r rac e differences , however , were non-significan t (p >0.20 ) wit

h regar d to th e cardiovascula

r effect s o f lead . Th e Schwart

z (1989 ) result s ar e consisten t wit h previou s report s of

cardiovascula

r effect s bein g associate d wit h high level s o f

lea d exposure , e.g. , Kirkb y and Gyntelberg' s (1985 ) repor

t of a20 % increas e ( p <0.01 ) i n ischemi c change s a s code d o n th e Minnesota Code s i n lea

d worker s compare d t o control s matched o n age , race , and severa l other pertinent factors . Th e newfinding s b y Schwartz , however , point towar d smal l bu t

no t inconsequentia

l increase d risks fo

r seriou s cardiovascula

r outcome s bein g associate d wit h th e relativel y lo w rang e o f bloo d lea d level s encountere d i n th e genera l U.S . adul t

population . I t

remain s to b e determine d t o wha

t exten t th e observe d lea

d effects o n lef

t ventricula

r hypertroph

y o r other cardiovascula

r function s ar e du e t o alead-induce d increas e in bloo d pressure o r t o som e other lead-relate d pathogeni c mechanism . A t th e 198 7 Symposium , there wa s extensiv e discussio n concernin g controvers y in th e publishe d epidemiolog y literature about th e nature of

arelationship between bloo d lea d and bloo d pressure . A s summarize d b y Tyroler (1988) , th e genera

l populatio n studie s discusse d abov e were see

n a s pointin g towar

d acausa l relationship between increase s in bloo d lea d level s and significan

t increase s in bloo d pressure , extendin g t o value s belo w thos e cunentl y considere d to b e clinically significan t hypertension . Tyroler

furthe r note d tha t th e associatio n ha s no t been foun d i n al l studie s and , whe

n present , ha s bee

n suc h tha t th e increas e in bloo d pressure wit

h increas e in bloo d lea

d level s ha s been of

small absolute magnitude and no t constan t acros s age , sex , and rac e subgroups . Nevertheless , despit e th e seemingl

y small elevation s i n bloo d pressure whe n viewe d fro

mth e clinica

l perspectiv e of

each individual , Tyroler furthe r note d tha t th e potentia

l publi c healt

h importanc e of

ablood-lea

d blood

pressure relationship i s considerabl e du e t o th e stron g associatio n of bloo d pressure wit

h cardiovascula

r morbidit y an d mortality , th e leadin g cause(s ) of deat h in our society , and th e larg e numbe

r of individual s exposed . Of importanc e fo

r substantiatin g th e plausibilit y of th e blood-lead/blood-pressur e association s observe d in huma n population s representin g causa l relationships , th e physiologica

l and pharmacologica

l regulatio n of

bloo d pressure ha s been studie d extensively 2 0P.3 2

by , experimenta

l investigators . Muc

h of th e the n availabl e informatio n on th e subject wa s discusse d in th e 198 6 Addendu m(U.S . Environmenta

l Protectio n Agency , 1986b) . I t i s now understoo d tha

t variou s hormona

l regulator y systems , vascula

r smoot h muscle , an d hear

t contractilit y al l contribute t o th e developmen t o f bloo d pressure changes . Severa l o f th e speaker s a t th e 198 7 Symposiu

m(Victery , 1988a

) als o reviewe d findings o f change s i n th e cardiovascula

r syste mi n animal s expose d t o lead . Fo r example , Victer

y (1988b ) reviewe d th e experimenta

l studie s tha

t hav e been conducte d fo

r ove r 4 0 year s o n th e effect s of

lea d o n bloo d pressure . Difference s in animal s species , ag e a t beginnin g o

f exposure , leve l o

f lea d exposure , and th e effects of lea d o n bloo d pressure wer

e described . I t

wa s note d tha

t i n severa l of th e high-dos e experiments , hypertensio n wa s observed , bu t nephrotoxicit

y of lea d ma y hav e contribute d t o it s development . I n on e experiment , high lea d exposur e ma y hav e reduce d a n elevate d bloo d pressure . In contrast , lower dos e experiment s consistently demonstrate d ahypertensiv e effect . Th e dat asugges t tha t abiphasi c dose-respons e relationship ma

y exist . Future researc h should b e abl e to characteriz e in animal s dose

respons e relationship s fo

r bloo d pressure effect s acros s low-level lea d exposur e range s mos t applicabl e to th e genera

l huma n population . Wit h regar d to mechanism s potentially underlyin g lead-bloo d pressure relationships , Vande r (1988 ) reviewe d th e chroni c effect s of lea d on th e renin-angiotensi n syste m(on e of th e primar y regulator

y hormone s fo

r bloo d pressure) . Th e change s observe d in bot h animal s and human s ar e highly variabl e and ar e dependen t o n th e lea d exposur e level , th e time of exposure , and other

stimuli o f th e renin-angiotensi n system . Th e huma n dataar e consisten

t wit h th e tentativ e hypothesi s tha t lead-expose d person s ma

y hav e highe

r plasm areni n activit

y tha n norma l durin g period s of

modes t exposur e bu t norma l o r depresse d plasmareni n activit y following mor

e chroni c sever

e exposures . I n anothe r 198 8 Symposiu

mpaper , th e effects o

f lea d on vascula

r reactivit y wer e describe d b y Cha

i an d Web b (1988) . There i s convincin g evidenc e tha t lea d alter s vascula

r reactivit y in lead-expose d animals , which demonstrate d a15-20 m mHg increas e in systoli c bloo d pressure . Increase d presso r responsivenes s to catecholamine s ha s bee n demonstrate d i n chronically lea

d expose d animal s and a

n enhance d contractio n o f

isolate d vascula

r smoot h muscl e to adrenergi c agonist s occur s in rat s wit h lead-induce d hypertension . Furthe r experimenta

l evidenc e suggest s tha

t there ar e alteration s in th e mechanism s tha t regulate 2 1P.3 3

intracellula

r calciumconcentratio n an

d tha t thi s ma y contribute to th e abnorma l vascula r functio n in lead-induce d hypertension . There wer e furthe r report s of

morphological , biochemical , and functiona l alteration s i n cardiovascula r tissue in th e report s b y Kop p et al . (1988 ) and Boscol o and Carmignan i (1988) . Th e paper

b y Kop p e t al . (1988 ) in th e Symposiu mvolume review s th e cardiovascula r action s of lead , includin g evidenc e tha t lea d exposur e (a t leas t at high levels ) lead s t o morphological , biochemical , and functiona l derangement s o f

th e heart . Th e experimenta l literature als o confirmed finding s of cardiovascula

r complication s in experimenta l animals . Finding s include myocarditis , electrocardiographi c disturbances , heightene d catecholamin e anhythmogenicity , altere d myocardia l contractil e responsivenes s t o inotropi c stimulation , degenerativ e structura l an d biochemica

l change s affecting th e musculatur e of th e hear t an d vasculature , hypertension , hypercholesterolemia , atherosclerosis , an d increase d vascula

r reactivit y t o alpha-adrengergi c agonists . Th e precis e nature of th e exposure-respons e relationship s tha t appl y ar e stil l poorly characterized , a s wel l a s th e exac t pathogeni c mechanism s fo r th e effects of

lea d on th e cardiovascula

r system ; bu t

importantly , th e experimenta l result s provid e clea

r evidenc e fo

r lea d causall y affecting cardiovascula

r function . I n th e 198 7 Symposiu

mdiscussio n session (Victer y e t al. , 1988) , on e o f

th e invite d discussants , Dr . Anthon

y John s propose d anumbe r o f critical experiment s to understand ho w lea d ma y b e affecting bloo d pressure an d whethe r bloo d pressure change s ca n b e reverse d b y removing lea

d fromth e diet . Inhibitor s o f th e angiotensin-convertin g enzym e (now used a s antihypertensiv e therapeuti c agents ) coul d b e trie d to determin e if thi s ca n prevent th e bloo d pressure increas e durin g lea d exposure . Th e level s of

intracellula

r calciu mshould b e measured in vascula

r tissue and th e pharmacologi c agent s tha t bloc k calciumo r

potassium channel s i n cel l membrane s should b e examine d to determin e if the y migh t reduc e th e effects of lead . CONCLUSION S . Wit h regar d t o th e effect s o f

lea d on bloo d pressure , th e ne w informatio n emergin g sinc e preparatio n of

th e 198 6 Addendum , overall , substantiate s furthe r th e mai n conclusion s state d in tha

t Addendum . Sufficien

t evidenc e exist s fro

mbot h th e fou r large-scal e genera

l populatio n studie s discusse d abov e (NHANE S JJ , BRHS , and th e tw o Wels h studies ) and 2 2P.3 4

numerou s othe

r smaller-scal e studie s t o conclude tha t asmall bu t

positiv e associatio n exist s between bloo d lea

d level s and increase s in bloo d pressure . Quantitatively , th e relationship appear s t o hol d acros s awide rang e o f blood-lea d values , extendin g possibly down t o a s lo w a s 7 /ig/d l fo

r middle-age d me

n and , furthermore , a

n estimate d mea

n increas e of

about 1.5

- 3. 0 m mHg i n systoli c bloo d pressure appear s t o occu r fo r ever y doublin g of

bloo d lea d concentratio n in adult

male s an d something les s tha

n 1.0-2. 0 m

mH g fo r adult females . Th e plausibilit y o f thes e relationship s observe d in epidemiologi c studie s of huma n population s bein g o f acausa l natur e i s supported by controlle d experimenta l anima l studie s demonstratin g increase d bloo d pressure effects clearly attributabl e to lead , wit h a n apparen t biphasi c dose

respons e relationship bein g involve d (i.e. , bloo d pressure elevation s a t lo w lea d dos e level s an d possibl e bloo d pressure reduction s a t ver y high lea d exposur e levels) . Th e implication s of

lead-induce d blood-pressur e increase s wit

h regar d to potentia

l increase d risk

fo r other , mor

e seriou s cardiovascula

r outcome s stil l remain to b e mor e clearl y delineated . A s noted b y Tyrole r and othe r discussant s a

t th e 198 8 Symposiu

mmentione d above , essentially an

y increas e i

n bloo d pressure carrie s wit h i t likely increase d risk

(albeit howeve r small ) fo r stroke , hear

t attack , and/o r

associate d mortality . A s such , projection s of potentia l lea d effects on suc

h outcomes , a s wer

e modeled b y Pirkl e e t

al . (1985 ) an

d discusse d in th e 198 6 Addendum , ar e no t unreasonabl e i n view of

th e potentially ver

y larg e pubh c healt

h impacts ; however , muc

h cautio n mus t

b e exercise d in acceptin g th e validit y of an y specifi c quantitativ e estimate s derive d fromsuc h projection s in view of

th e uncertaintie s associate d wit

h selectio n o

f th e specifi c coefficient s used fo r (1 ) blood-lea

d blood-pressur

e relationship s an

d (2 ) relationship s betwee

n bloo d pressure increase s an d mor e seriou s cardiovascula

r outcomes . Th e difficult

y in directly demonstratin g association s betwee n lea d exposur e an d stroke , hear

t attacks , etc. , lie s in th e ver y larg e stud

y cohort s (man

y thousand s o f subjects ) tha

t would b e necessar

y to hav e sufficien

t statistica l powe r t o detec t th e relativel y small increase d risk

level s expecte d fo

r th e mor e seriou s cardiovascula

r outcomes . Som

e newl y availabl e result s (i.e. , thos e of Schwartz , 1989 ) froma

t leas t on e large-scal e stud

y help to illustrate th e possibilit

y o f detectin g indication s of

suc h small increase d risks i n th e genera l population .

2 3fflo NEUROBEHAVIORA L AN D GROWT H EFFECTS. M INFANT S AN D CMILBREN A majo r advanc e i n th e epidemiologica l investigatio n of

th e healt h effect s of

lea d occurre d wit

h th e advent

of independen

t bu t somewha t coordinate d prospectiv e studie s o f chil d development . Som

e o f th e result s of

fou r suc h studie s were discusse d in th e 198 6 Addendu m(U.S . Environmenta

l Protectio n Agency , 1986b) . Muc h o f th e sam e information , wit h updating , wa s als o presente d in acritical review an d interpretatio n by Davi s and Svendsgaar

d (1987) . Th e fou

r prospectiv e studie s in questio n were conducte d in Boston , Cincinnati , Cleveland , an d Por t Pirie , Australia . Base d o n a n assessmen

t of thes e studies , th e 198 6 Addendu mconclude d tha

t feta l lea d exposure coul d hav e undesirabl e effect s o n infan t menta l development , lengt

h o f gestation , and possibly other

aspect s of

feta l development , wit

h th e mos t consisten t evidenc e pertainin g t o neurobehaviora

l function . I

n particular , "All of

thes e studie s taken togethe r sugges t tha t neurobehaviora

l deficits , includin g decline s in Bayle y Menta l Developmen

t Index score s and other assessment s o f

neurobehaviora

l function , ar e associate d wit h prenata l bloo d lea

d exposur e level s o n th e order

of 1 0 to 1 5 /*g/d

l and possibl

y eve n lower , a s indexe d b y materna l o r cord bloo d lea

d concentrations " (U.S . Environmenta l Protectio n Agency , 1986b) . Thi s updat

e summarize s an d assesse s th e evidenc e fro mthes e an d other , more recent studies , bot

h individually and collectively , and draw s conclusion s regardin g thei r implication s fo r regulator y decision-making . A s note d i n th e 198 6 Addendum , aserie s o f report s b y Bellinger , Needleman , and thei r colleague s (Bellinge

r e t al. , 1984a , 1985 , 1986a,b ) describe d th e result s of alongitudina

l stud y of early neurobehaviora

l developmen

t throug h th e first

tw o year s of

lif e in acohor

t of Boston children . More recent update s o n thi s wor

k hav e sinc e bee

n publishe d b y Bellinge

r e t al . (1987a , 1989a) , coverin g th e sam e perio d of

development . Th e latter

report s confir

m tha t performanc e o n th e Bayle y Menta l Developmen

t Index (MDI ) a

t 6 , 12 , 18 , and 2 4 month s postnatally i s inversely relate d t o cord bloo d lea d level s a t birt h an d tha t th e amoun t of performanc e deficit

in infant s wit

h cor d bloo d lea

d level s o f 10-2 5 jxg/d

l i s 0.25-0. 5 standar

d deviations , o r

approximately 4- 8 point s on th e MD I (Tabl e 2) . Moreover ,

2 4P.3 6

TABLE 2 , INFANTS ' MENTA L DEVELOPMEN T INDE X SCORE S ACCORDIN G T O COR D BLOO D LEA D GROU P Cor d Blood Lea d Grou p Unadjuste d scor e Lo w Mediu m High 6 Month s

109. 2 ± 12. 9 108. 6 ± 12. 0 106. 1 ± 11. 1 Controlle d fo

r potentia l confounders * Low 110. 2 ± 1. 3 Mediu m108. 0 ± 1. 3 High 105. 9 ± 1.4 p value* * No . o f infant s 0.09 5

20 1 Menta l Developmen

t Inde x Scor e 1 2 Month s 1 8 Month s Mea n ± Standar

d Deviatio n 113. 1 ± 12. 5 115. 4 ± 12. 9 108. 7 ± 12. 8 Mea n ± Standar

d Erro r 114. 7 ± 1. 6 114. 4 ± 1. 5 108. 9 ± 1. 6 0.02 0 19 9 113. 4 ± 15. 5

116. 6 ± 16. 7 109. 5 ± 17. 5

116. 2 ± 1. 9 114. 8 ± 1. 9 109. 5 ± 2. 0 0.04 9 187 24 Month s

115. 9 ± 17. 2 119. 9 ± 14. 4 110. 6 ± 16. 5

118. 9 ± 1. 8 117. 8 ± 1. 7 111. 1 ± 1. 8 0.00 6 18 2 *Least-square s mea

n ± standar

d error , derive d fro

mregressio n equation s tha t include d 1 2 potentia

l confounders an

d cor d bloo d lea

d group coded a s tw o indicator variables . ""•Indicate s p valu e associated wit h th e F rati o tha

t evaluate s whethe

r th e mea n Menta l Developmen

t Inde x fo r an y cor d bloo d lea

d grou p differed significantl

y fro mth e commo

n mea n afte r potentia l confounder s were controlle d for . Source : Bellinge

r e t al . (1987a) . Bellinge r et al . (1989a

) foun d tha t thi s associatio n wa s eviden t in severa l differen t regressio n model s an d wa s no t a n artifac t of th e approac h the

y used in analyzin g th e data . In addition , mor e detaile d analyse s showe

d tha t th e averag e MD I deficit

in high cor

d lea d infant s (bloo d lea d level s of 10-25 /ig/dl ) wa s no t

du e to adisproportionat

e influenc e o f

result s frominfant s a t highe r (e.g. , > 1 5 /ig/dl ) bloo d lea d levels . Tha

t is , th e MD I effec

t wa s eviden

t acros s th e entire rang e o

f bloo d lea d level s startin g a

t 1 0 /ig/dl , which reinforce s th e previou s selectio n o f 10-1 5 /tg/d l a s abloo d lea d leve l of concer n fo r earl y developmenta

l deficit s (U.S . Environmenta

l Protectio n Agency , 1986b) .

2 5P.3 7

Othe r recent analyse s b y Bellinge

r e t al . (1988 ) hav e focused o n th e interactio n of lead- * relate d Bayle

y MD I deficit s wit

h socioeconomi c statu s (SES) . Eve n i n th e relatively advantage d cohor

t of th e Boston study , infant s fromles s tha n th e highes t

SES groupin g tende d t o hav e lowe

r covanate-adjuste d score s o n th e MDI . Moreover , th e second-yea r MD I performanc e o f

thes e "lower " SES children wa s adversely affected a t lowe r bloo d lea d level s tha n wa s th e performanc e o f

th e highe r SES children . Specifically , withi n th e lowe r SE S grouping , infant s wit

h mid-rang e cor

d bloo d lea

d level s o f 6- 7 /ig/d l score d significantl y wors e o n th e Bayle

y MD I tha

n infant s wit

h lo w cor d bloo d lea

d level s of < 3 /ig/dl . Bellinge r e t al . (1987b , 1989b ) hav e als o recently reporte d preliminar y result s of

later testin g of 17 0 children of

th e Bosto n cohor t a t about 5 year s (5 7 months ) o

f ag e on th e McCarth y Scale s o f

Children' s Abilities . They foun d tha t th e associatio n betwee

n cor d bloo d lea d and cognitiv e performance , a s measured b y th e Genera l Cognitiv e Index (GCI ) o

f th e McCarth y Scales , wa s n o longe

r statistically significan

t a t 5 7 months . However , th e relationship between bloo d lea d leve l a t 24 month s postnatally and GC I score s wa s statis

tically significant , eve

n afte r adjusting fo

r covariate s and confounder s (Tabl e 3) . Th e mea n 24-mont h bloo d lea

d leve l wa s 6. 8 /ig/d l (S D = 6.3) . Othe r postnata l bloo d lea

d measurement s a

t 1 8 an d 5 7 month s were consisten t wit h thi s associatio n bu t

faile d to achiev e statistica l significance . Th e siz e of th e deficit

amounte d to approximately 3 GC I point s fo r ever y natura l lo g uni t incremen t in bloo d lea

d level . Bellinge r e t al . (1989b ) examine d th e chang e in cognitiv e performanc e o f children from 24 t o 5 7 month s of

ag e in relatio n t o pre - an

d postnata l lea d exposur e level s an d variou s sociodemographi c variables . Improvemen t i n relativ e performanc e wa s associate d wit h lowe r bloo d lea d level s a t 5 7 months , highe

r SES , highe

r HOME scores , highe

r materna l IQ , an d female gender . Conversely , th e ris k o f a n earl y deficit

persistin g t o 5 year s of

ag e wa s increase d in children wit

h highe r prenata l lea d exposur e (10-2 5 /ig/dl ) an

d either hig h postnata l exposur e o r les s favorabl e sociodemographi c factors . Fo r example , "i

f tw o children wit h high cor d bloo d lea

d achieve d th e sam

e MD I scor

e a t 24 months , bu t

on e ha d alo w bloo d lea d leve l [< 3 /ig/dl ] at

5 7 month s whil e th e other ha d ahigh [ > 1 0 /ig/dl ] level , th e chil d wit h lowe r exposur e woul d b e expecte d t o hav e aGC I scor e tha t i s 0.6 1 standar

d nonna l deviate unit s higher... , [which ] conespond s t o adifferenc e of 9. 8 points " (Bellinge

r e t al. , 1989b) . Simila

r comparison s of

male s and female s wit

h high cor d bloo d lea

d level s 

### 2 6TABLE 3 . CHANG E I N McCARTH Y GENERAL COGNITIV E INDE X (GCI ) AN D SUBSCALE SCORE S ASSOCIATED WIT H EAC H NATURAL LO G UNI T INCREAS E I N BLOO D LEAD LEVE L Ag e a t Measuremen

t of Blood Lea d Level (months ) 6 1 2 1 8 2 4 5 7 GC I

0.2 8 ± 1.29 * .83* * -1.4 3 ± 1.2

5 .2 5 -1.6 2 ± 1.3 9 .2 5 -2.9 5 ± 1.4

2 .04 0 -2.2 8 ±1.8 8 .2 3 Verba

l 0.7 5 ± 0.9 3 .4 2 -0.9 8 ± 0.8 9 .2 7 -0.1 9 ± 1.0 1 .8 5 -0.4 1 ± 1.0

4 .6 9 -1.0 6 ± 1.3 8 .4 4 Perceptual

Performanc e -0.7 2 ± 0.7 7 .3 5 -0.6 4 ± 0.7 9 .4 2 -0.7 2 ± 0.8 7 .4 1 -2.5 8 ± 0.8 8 .00 4 -2.3 3 ±1.1 3 .04 2 Quantitativ e

0.0 0 ± 0.7 6 .9 9 -0.0 9 ± 0.7 4 .9 0 -1.2 0 ± 0.8 2 .1 5 -1.4 5 ± 0.8 5 .08 8 0.1 3 ± 1.1 3 .9 1 Memor

y 0.8 2 ± 0.8 3 .3 3 -0.0 9 ± 0.8 1 .9 1 -0.5 2 ± 0.9 1 .5 7 -0.6 6 ± 0.9 4 .4 9 0.4 9 ± 1.2

5 .7 0 Motor

0.0 2 ± 0.8 1 .9 8 -0.8 2 + 0.8 0 .3 1 0.3 0 ± 0.8 9 .7 4 -0.9 0 ± 0.9 2 .3 3 -1.8 9 ± 1.1 5 .1 0 *Paramete r estimate ± standar

d enor . p-valu e associate d wit

h th e nul l hypothesi s tha

t th e paramete

r estimat e i s zero . Source : Bellinge

r et al . (1987b) .P.3 9

indicate d tha

t boy s score d 7. 7 point s lowe r tha n girl s o n th e GCI , an

d children in th e lower « SE S groupin g score d 13. 3 point s lower tha n thos e in th e highe

r SE S grouping . Bellinge r e t al . (1987b ) als o evaluate d th e degre e o f disparit y in McCarth

y subscal e performance , sinc e learnin g disabilitie s ar e ofte n highly specific t o certai n cognitiv e functions . A greater numbe r o f subscal e discrepancie s wa s associate d wit h highe r ( > 1 0 /ig/dl ) concurrent

(5 7 month) bloo d lea

d levels . Interi mresult s of

alongitudina

l stud y o f inner-cit y children bor

n in Cincinnati , Ohi o were reporte d b y Dietric h e t al . (1986 , 1987a

) and summarized in th e 198 6 Addendum . Structura l equatio n modeling , astatistica l metho d of

examining relationship s among factor s tha t ma y b e bot h independen

t an d dependen

t variable s o r

mediator s of

effects , indicate d tha

t prenata l lea d exposur e ha d a n indirec t effec t on 6-mont

h MD I and PD I (Psychomotor Developmen

t Index ) score s through it s effect s o n gestationa l ag e and/o r

birt h weight . Highe

r prenata l (maternal ) bloo d lea

d level s were associate d wit h reduce d gestationa

l ag e and reduce d birt h weight , which i n tur

n wer e significantly associate d wit h reduce d MD I an

d PD I performance . Although th e Cincinnat

i subject s were no t

groupe d b y bloo d lea

d level s fo r thes e analyses , separat

e analyse s o f

birt h weigh t effects b y Bornschei

n et al . (1989 ) investigate d th e dose-respons e relationship b y groupin g into five 6-/ig/d l intervals . A

n increas e in th e percentag e of

lo w birthweight

newborn s between th e 7-1 2 /ig/d l groupin g and th e £ 1 3 /ig/d l groupin g implie d th e possibilit y of athreshol d fo

r lo w birthweigh

t effects (categorically defined a s les s tha

n 275 0 g ) in th e vicinit

y o f 12-1 3 /ig/dl , although aprecis e determinatio n i s no t possibl e and coul d extend a s lo w a s 7 /ig/d l o r perhap s a s high a s 1 8 /tg/dl . T o th e extent tha t lo w birthweight

mediate d th e effect

of lea d o n Bayle

y score s in th e Cincinnat

i study , th e infene d informatio n i s consisten t wit h th e conclusio n (U.S . Environmenta l Protectio n Agency , 1986b ) tha

t abloo d lea

d leve l of 10-1 5 /ig/dl , an

d possibly lower , constitute s aleve l o f concer n fo r impaire d performanc e o n th e Bayle y MDI . Dietric h e t

al . (1987b , 1989a,b ) late r reporte d mor

e complet e result s fo

r variou s neurobehaviora

l developmenta

l outcome s i n approximately 30 0 infant s fromth e Cincinnat i stud y (Tabl e 4) . Th e children were teste d o n th e Bayle y Scale s at

3 , 6 , 12 , and 24 month s of 28P.4 0

TABL E 4 . RESULT S O F MULTIPL E REGRESSIO N ANALYSE S EXAMININ G TH E RELATIONSHI P BETWEEN BLOO D LEA D LEVE L AN D PERFORMANC E O N TH E BAYLE

Y MENTA L INDE

X AT 3-2 4 MONTH S O F AGE * Bloo d Lea d Measur e (/tg/dl ) Prenata l Umbilica l cor d 1 0 da y 3 mont h N Bet a Standar

d Erro r 22 8 8 0 26 1 n.r . 3-mont

h MD I -.3 4 -.6 0 .0 6 -.2 3 0.1 7

0.2 6 0.2 2 0.1 8

*Beta s adjuste d fo r differen t set s o f covariate s fo

r eac h ag e o f MD I testing . **Two-tailed values . Sources : Dietric h e t

al . (1987b , 1988 , 1989b) . t Valu e -1.9 6 -2.3 0 0.2 6 -1.3 0 P

Value* * .0 5 .0 2 .7 9 .2 0 Prenata l Prenata l b y Chil d Se x 1 0 da y 1 0 da y b y SE S Prenata l Umbilica l cor d 1 0 da y 1 Prenata l 1 1 0 da

y 1 3 mont h 1 Maximum 1stYear 1 Maximum 2n d Year 1 2 4 month s 24 9

28 3

25 8 9 8 25 7 23 7 27 0 27 0 27 0 27 0 27 0 6-mont

h MD I -0.8 9 1.5 3 -3.1 5 0.1 6 12-mont h MD I 0.0 9 -0.1 7 -0.6 2 24-mont h MD I 0.5 1 -0.0 2 0.2 4 0.2 4 0.1 0 0.1 3 0.3 4

0.5 1 1.3 0 0.0 8 0.2 6 0.3 6 0.3 1 0.2 2 0.2 5 0.2 1 0.1 0 0.0 7 0.0 9 -2.6 0

2.9 8 -2.4 3 2.1 3

n.r . n.r . n.r . 2.3 1 -0.0 7 1.1 2 1.3 9 1.3 9 1.4 5 0.00 9

0.00 3 0.01 6 0.03 4 N.S . N.S . <0.0 4 0.02 2 0.94 8 0.26 2 0.16 6 0.16 6 0.14 9

2 9P.4 1

age . Afte r adjusting fo

r covariates , deficit s in 3

- an d 6-mont h Bayle y MD I score s wer

e significantl y associate d wit

h prenata l (maternal ) an

d cor d bloo d lea

d levels , confirming th e earlier , preliminar

y analyse s of

Dietric h e t

al . (1987a) . Th e magnitude of th e deficit

in th e 3-mont h MD I amounte d to 6 point s fo r ever y 10-/tg/d l incremen t in cor d bloo d lead ; th e conespondin g 6-mont

h MD I deficit

wa s nearly 7 points . Also , aconservativ e reanalysi s (Dietric h et

al. , 1989b ) of

th e 6-monti

i datausin g al l potentia

l covariate s an

d confounder s confirmed earlier

findings, although interactiv e effects wit h gende r and SES wer

e eviden t (se e below) . However , neithe

r prenata l nor cor d bloo d lea

d measure s wer

e significantl

y relate d to 12-mont h MD I scores , although th e associatio n betwee n neonata l (10-day ) bloo d lea

d level s an d 12-mont h (a s wel l a s 6-month) MD I score s remaine d statistically significan t (Dietric h e t al. , 1989a) . I t

should b e note d tha

t analyse s ofth e 12-mont

h dataar e no t

yet final. B y 2 4 months , n o statistically significan t negativ e relationship s wer e detectabl e betwee

n lea d exposur e variable s (eithe

r pre - o r postnatal ) an

d MD I score s (Dietric h e t

al. , 1989b) . Onl y on e parameter

estimat e (fo r prenata l bloo d lead) achieved statistica l significanc e (p = 0.022) , an d i t wa s positiv e rather

tha n negative . I n addition , th e Bayle

y Infan t Behavio r Recor d (IBR ) was administere d a

t 1 2 an d 24 month s t o asses s th e infants ' socia l and emotiona

l developmen

t (Dietric h et

al. , 1989a,b) . Facto r analysi s of

th e 3 0 IB R item s a

t 24 month s yielde d principa l factor s o f Sustaine d Attention , Activit

y Level , and Positiv e Mood , whic h wer e use d in regressio n analyse s to asses s th e effec

t of lea d exposure . Lowe

r score s on Sustained Attentio n an d Positiv e Mood factor s were bot

h significantl

y associate d wit

h increase d neonata

l (10-day ) bloo d lea

d levels , consisten t wit h th e 12-mont

h MD I relationship to neonata l bloo d lea d (Dietric h e t

al. , 1989a) . However , non e of

th e 24-mont

h IB R result s achieved statistica l significance . Bayle

y PD I result s were incomplete . Dietric h e t

al . (1987b , 1989b ) als o foun d tha t gende r an d SES interacte d wit

h th e lea d exposure-MD I relationship . Mal e infant s and children fromth e lowe r half of th e SE S distributio n fo

r thi s cohor

t were mor e sensitiv e t o th e effects o

f early lea d exposur e on neurobehaviora

l development . Fo r

example , male infant s showe d a n 8.67-poin

t deficit on th e 6-mont h MD I fo r ever y 10-/ig/d l incremen

t i n prenata

l bloo d lead , and infant s belo w th e sampl e media

n SES scor

e ha d a7.57-point

defici t fo r ever y 10-/ig/d l incremen

t in neonata

l bloo d lea d (Dietric h e t

al. , 1989b) . 3

0P.4 2

Dietric h et

al . (1989b ) interprete d their failur e to detec t apersistent

effect o f feta l lea d exposur e o n th e 24-mont

h Bayle y Scale s a s probably du e t o aneurobehaviora l catch-up response , simila

r to tha t observe d in infan

t twin s (Wilson , 1986) o r

other infant s compromise d durin g prenata l developmen

t (Tanner , 1981) . Explorator y analyse s indicate d tha t th e greates t

percentag e increas e in MD I ra w score s (numbe

r o f item s passed) fromag e 3 month s t o 24 month s wa s inversely relate d to prenata l lea d exposure , birt

h weight , gestation , an

d hea d circumferenc e (Dietric h et al. , 1989b) . Thus , thos e infant s wit h th e highes t prenata l bloo d lea

d levels , lowes t

birt h weight , shortes t

gestation , o r

smalles t hea d circumferenc e showe

d th e greates t

degre e of catch-u p i n postnata l neurobehaviora

l development . A s previously noted , th e Cincinnat i stud y ha s als o produce d evidenc e o f direc t effect s of prenata l lea d exposur e on infan t physica l developmen

t a t birth . Bornschein e t

al . (1989 ) reporte d tha

t initia l result s fro

m20 2 infant s showe

d a n invers e relationship between materna l bloo d lea d level s an

d bot h birt h weigh t an d length . Materna

l bloo d lea

d sample s were obtaine d a t th e first prenata l visi t (betwee n 6 and 2 8 week s o

f gestation ; mea

n = 1 6 wks) . Th e mea n materna l bloo d lea

d level wa s 7. 6 /ig/d l (range : 1-2 6 /tg/dl) . Exclusio n criteri a include d birt

h weigh t les s tha n 150 0 g , les s tha

n 3 5 week s gestationa

l ag e a t birth , twin birth , an d seriou s medica

l conditions . Regressio n analyse s considere d 2 1 potentia l confounder s and covariates . Th e final regressio n mode l fo r birt h weigh t showe d tha t lo g materna

l bloo d lea d wa s significantl

y relate d to birt

h weight , but

interacte d wit

h materna l ag e to produc e a significan t ( p < 0.007 ) reductio n i

n covanate-adjuste d birt

h weight . Thus , th e effec

t of eac h natura l lo g incremen

t in bloo d lea

d varie d fro

mabirthweigh

t reductio n of

58. 1 g fo r 18

- year-ol d mother s to areductio n o f 600. 1 g fo

r 30-year-ol d mothers . Materna l bloo d lea

d an d rac e interacte d to produc e asignifican t reductio n i n birt

h lengt h in whit e infant s (p < 0.025) . Thus , th e birt

h lengt h o f whit e infant s decrease d ~ 2. 5 cmfo r eac h natura l lo g incremen

t i n materna l bloo d lead . Materna

l bloo d lea

d showe d n o significan

t relationship to covariate

adjusted hea

d circumferenc e o r

gestatio n length . Obstetrica l complication s and Apga

r score s als o showe

d n o relationship wit

h lowe r birt h weigh t o r lea d exposure . Separat e analyse s o

f 86 1 wome

n (includin g th e 20 2 subject s jus t described) fro

mth e Cincinnat i cohort , but

includin g pregnancie s o

f no t les s tha n 2 0 week s duration , als o showe d ahighly significan

t (p < 0.0006 ) negativ e relationship betwee n materna l bloo d lea

d leve l and 3 1P.4 3

covanate-adjuste d birt

h weigh t (Bornschein e t

al. , 1989) . Overall , thi s cohor t ha d adecrease * o f approximately 11 4 g i n birt h weigh t fo r eac h natura

l lo g incremen

t i n materna

l bloo d lead . Analyse s o f

postnata l growt h rate s i n acohor

t of 26 0 children fromth e Cincinnat i stud y suggeste d a

n interactiv e effect

o f prenata l an d postnata

l lea d exposur e (Shukl ae t

al. , 1987 , 1989) . Splittin g prenata

l bloo d lea

d level s and th e averag e increas e in postnata l bloo d lea

d level s at th e media

n (7. 7 /tg/d l fo

r prenatal , 3. 4 /tg/d l fo

r th e postnata

l increase ) provide d a matri x o f low/low , low/high , high/low , an d high/hig h exposur e conditions . Analysi s o f

dat a fo r 129 subject s in th e high prenata l exposure classificatio n indicate d tha t covariate-adjuste d growt h rate s fo r stature over

3-1 5 month s of

ag e wer e significantl

y (p = 0.006 ) and negatively relate d t o th e postnata l increas e in bloo d lea

d level . N o effect

wa s see n fo r th e lo w prenata

l exposure group . Thus , fo r infant s whos e prenata

l bloo d lea

d level s were greater tha n 7. 7 /tg/dl , ther e woul d be , o n average , a2-cmdifferenc e in heigh t a t 1 5 month s o f

ag e between thos e infant s wh o experience d n o increas e in postnata l bloo d lea

d and thos e wh o experience d a

n increas e of

~ 1 0 /tg/dl . Other neurobehaviora

l tes t result s fromth e Cincinnat i stud y hav e als o bee n reporte d b y Bhattachary ae t

al . (1988 , 1989) . Postura l swa y wa s assessed b y a

n automate d apparatu s i

n 3 3 childre n at

6 year s of

ag e (Bhattachary ae t

al. , 1988) . Initia

l result s indicate d tha

t maximu mbloo d lea

d leve l durin g th e secon

d yea r of lif e wa s significantly relate d t o degre e o f postura l swa y o r imbalanc e a

t 6 years . Bloo d lea

d level s in thi s sampl e peake d durin g th e secon d year , averagin g 25. 6 /tg/d l (range : 9.3-49. 4 /tg/dl) , measured quarterly . Th e later repor t b y Bhattachary ae t

al . (1989 ) cover s 6 3 children an d confirm s th e earlier

result s showing asignifican

t relationship betwee

n swa y and secon

d yea r maximu mbloo d lea

d ( r = 0.34 , p = 0.02) . Although mor e tes t result s are needed t o full

y explore thes e effects , thes e preliminar y finding s provid e additiona l indication s of

neurobehaviora

l dysfunction durin g earl y childhoo d exposure t o lead . Clevelan d A s note d i n th e 198 6 Addendu m(U.S . Environmenta

l Protectio n Agency , 1986b) , th e prospectiv e stud

y conducte d b y Emhar

t and he r colleague s ha s provide d som e direc t a s wel l a s indirec t evidenc e o f

a n effect of prenata l lea d exposur e on neurobehaviora

l development . Emhar t e t al . (1985a , 1986 ) reported significan t association s between cor

d bloo d lea

d level s 3 2P.4 4

an d measure s o

f Abnorma l Reflexe s (o

n th e Brazelto n Neonata

l Behaviora

l Assessmen

t Scale : NBAS ) and Neurologica

l Sof t Sign s (o n th e Graham-Rosenblit

h Behaviora

l Examinatio n fo

r Newborns : G-R) . Also , th e G- R Muscl e Tonu s measur

e wa s significantl

y relate d to materna

l bloo d lea d level s a t delivery . However , restrictin g th e analyse s to only 13 2 pair s of mother

infan t data , Emhar

t e t al . foun d only th e G-R Neurologica l Sof t Sign s t o b e significantl

y relate d to cor

d bloo d lead . A brie f

repor t o n later outcome s in thi s sam

e cohor t mentione d a significan t associatio n betwee

n performanc e o n th e G-

R Neurologica

l Sof t Sign s scal e and 12

- mont h MD I score s (Wol

f e t al. , 1985) . Thus , i t

i s possibl e to infe

r arelationship between cor d bloo d lea

d level s an

d 12-mont h MD I performanc e in th e Cincinnat i study , although Ernhar t e t al . (1985a , 1986) di d no t

conclude tha

t suc h a n associatio n exists . Sinc e th e mea n cor d bloo d lea

d wa s 5.8 4 /tg/d l and th e maximu mwa s only 14. 7 /tg/dl , an y effec t of prenata l lea d exposur e necessarily occune d a

t bloo d lea d level s belo w 1 5 /tg/dl . Later report s b y Ernhar

t and he r colleague s (Ernhar

t e t al. , 1987 , 1988 ; Ernhar

t and Monow-Tlucak , 1989 ) presente d mor e complet e result s fro

mthei r continuin g longitudina

l stud y (Tabl e 5) . Th e Bayle

y MD I wa s administere d a t 6 , 12 , an d 24 months ; th e Bayle

y PD I an d th e Ken t Infan t Developmen

t Scal e (KID ) a

t 6 months ; an

d th e Stanford-Bine

t I Q tes t at 3 6 months . Postnata

l bloo d lea

d level s were measured a

t 6 , 24 , an d 3 6 months . A tota

l of 28 5 children fro

mth e origina

l cohor t o f 38 9 were sampled fo

r bloo d lea d levels ; N' s fo

r individua l analyse s range d fro

m10 9 to 165 . Afte

r contro l fo

r covariates , materna

l bloo d lea

d accounte d fo

r asignifican

t amoun t o f th e varianc e i

n 6-mont h MDI , PDI , and KI

D scores . Althoug h thes e thre e relationship s wer e al l negativ e (highe

r Pb B associate d wit

h lowe r developmenta

l scores) , concunen t

bloo d lea d wa s positively relate d to th e 6-mont h KI D and accounted fo

r nearly a s muc

h varianc e a s di d materna

l bloo d lead . Materna

l bloo d lea

d level s average d 6.5 0 /tg/dl , wit

h amaximu

mof 11. 8 /tg/dl ; 6-mont

h bloo d lea

d level s average d 10.0 5 /tg/dl , wit

h amaximu

mo f 24.0 0 /tg/dl . Mor e recen t result s fro

mtestin g thes e children a

t ag e 4 years , 1 0 month s o n th e Wechsle r Preschoo l an

d Primar y Scal e of Intelligenc e (WPPSI ) wer e reporte d b y Emhar

t an d Monow-Tluca

k (1987) . Analyse s wer

e base d o n N' s rangin g fro m11 7 t o 211 . Although bivariate conelation s were statistically significan t fo r al l PbB-WPPS I relationship s excep t 6-mont h PbB , in n o cas e di d Pb B accoun t fo r asignifican

t amoun t of th e varianc e (by two-taile d t

test ) afte r contro l fo

r 1 3 covariate s (Tabl e 6) .

3 3

### TABL

E SA . TH

E RELATIONSHI

P O F FETA

L (MATERNA

L AN D CORD) BLOO

D LEA D (PbB ) LEVELS WIT

H LATE R DEVELOPMENTA

L OUTCOME

S

Bloo d Lea d Measur e Developmental

Measure N Covariat e Varianc e Incrementa l Regressio n Mode l PbB Wit h Rac e b y Pb B Covariat e Control Interaction s Varianc e Varianc e Materna l

Cord

* p <0.05 , 6 Mont

h MD I 6 Mont h PD I 6 Mont h KID 1 Yea r MD I 2 Yea r MD I 3 Yea r S- B IQ 6 Mont h MD I 6 Mont h PD I 6 Mont h KI D 1 Yea r MD I 2 Yea r MD I 3 Yea r S- B I Q p <0.01 , p 12 7

12 7 11 9 14 5 14 2 13 8 11 3 11 3 10 9 12 7 12 5 12 0

= 0.002 , -.2 4

-.21 * -.28* * -.1 4 -.1 4 -.1 0 -.1 4 -.1 1 -.1 0 -.24* * -.1 5 -.21 * two-taile d tests . 0.246 0

0.248 5 0.146 4 0.188 7 0.366 4 0.389 4 0.239 4 0.189 1 0.141 8 0.232 7 0.374 6 0.439 3 0.030 2

0.029 5 0.077 9 0.000 2 0.002 0 0.005 9 0.004 6 0.000 6 0.010 7 0.014 6 0.000 3 0.012 5 -2.12 *

-2.12 * -3.2 2 -0.1 6 +0.4 8 + 1.0 9 -0.7 6 -0.2 6 -1.0 7 -1.4 7 -0.2 1 -1.5 4 0.016 1

0.009 3 0.018 2 0.002 6 0.000 0 0.002 0 0.005 6 0.024 9 0.005 1 0.014 3 0.000 2 0.008 6 -1.5 7

-1.1 9 -1.5 6 -0.6 4 -0.0 1 -0.6 3 -0.7 4 + 1.7 3 +0.7 4 -1.4 6 -0.1 3 -1.2 8

TABL E SB . TH E RELATIONSHI P O F PRIO R AN D CURREN T POSTNATAL BLOO D LEA D

Bloo d Lead Measure 6 mont h

2 yea r 3 yea r (PbB ) LEVEL S WIT H LATE R DEVELOPMENTA L OUTCOME S

Developmental Measure 6 mont h MD I 6 mont h PD I 1 yea r MD I 2 year MD I 3 yea r S- B I Q 2 yea r MD I 3 yea r S- B I Q 3 yea r S- B I Q N

14 6 14 6 13 1 12 6 12 6 16 5 15 3 16 7 Simpl e

Correlatio n r -.0 9 .0 6 .0 8 -.0 3 -.0 4 -.2 5 -.3 1 -.2 7 P

.2 9 .4 9 .4 0 .7 4 .6 5 Covariate s

.1 8 .1 9 .1 4 .3 0 .2 9 .00 0 .3 2 .00 0 .3 1 .00 0 .3 6 P

.00 0 .00 0 .0 2 .00 0 .00 0 .00 0 .00 0 .00 0 Incrementa

l Regressio n Mode l Pb B with Covariat e Control .0 1 .0 1 .0 1 .0 0 .0 0 .0 0 .0 1 .0 0 P

.3 1 .3 2 .2 5 .9 5 .4 9 .9 5 .2 9 .9 8 Interactio n p

.0 1 .0 0 .0 0 .0 0 .0 0 .0 1 .0 0 .0 1 .3 4

.4 8 .5 1 .6 3 .8 7 .0 7 .3 2 .0 8 Two-taile d statistical test . Abbreviations : MD I = Bayle y Mental Developmen tIndex ; PD I = Bayle y Psychomoto r Developmen tIndex ; KI D = KentInfan t Developmen tScale ; S- B I Q = Stanford-BinetIntelligenc e Quotien t Source : Ernhar

te tal . (1987 , 1988) . 3 4P.4 6



### TABL E 6 . Bloo d Lea d Measur e Prenata l Materna l Cor d Postnata l 6 Month s 2 Year s 3 Year s Mea n 

### TH

E RELATIONSHI

P 0 1 F PRENATA

L AN D POSTNATA

L L 1 

### BLOO D LEA D WIT H I Q A T AG E FOU R YEARS , TE

N MONTHS

N

13 4 11 7 12 1 14 9 15 4 21 1 Ful l Scale 

### 1>

-.23* * -.21 * -.0 6 -.38* * -.32* * -.26* * t

-0.2 7 4).5 4 -0.0 8 -0.6 9 +0.3 0 +0.4 8 IQ *

Verba l Scale T -.25* * -.22 * -.0 7 -.36* * -.39* * -.30** t

-0.4 9 -0.7 8 -0.2 6 -1.4 1 -1.5 8 -1.0 0 

### OG

Performanc e Scale r -.23* * -.20 * -.0 8 -.34* * -.30* * -.26* * t

-0.4 8 -0.7 8 +0.1 0 +0.2 2 +0.9 6 +0.5 6

aWPPS I score s except

fo r tw o S- B I Q scores ; latte

r tw o case s wer

e necessaril

y exclude d fro

mth e test s o f

th e Verba l an d Performanc e Scales . r describe s th e unadjusted relationship of th e Pb B an d I Q measures ; t

i s th e tes t o f th e incremen

t i n varianc e associated wit

h th e additio n o f

Pb B t o th e covariat

e varianc e i n th e I Q model . * p <.05 , ** p <.01 , two-taile d tests . Source : Ernhar

t an d Morrow-Tluca

k (1987) . Languag e developmen

t in th e Cleveland cohor

t wa s als o assessed a

t ag e 1,2 , and 3 year s (Monow-Tluca

k and Emhart , 1987) . Th e Sequenced Inventor y of Communicatio n Developmen

t (SICD ) wa s administere d t o asses s expressiv e and receptiv e languag e development . I

n addition , productiv e speec h (quantity , lengt

h o f utterance , vocabulary , communicativ e intent , an

d intelligibility ) wa s assesse d a t about 2 years . Th e numbe

r of subject s fo r eac h of th e analyse s wa s no t

reported , but

th e numbe

r of bloo d lea d measurement s over

th e perio d fromdeliver

y t o 3 year s range d from14 6 t o 169 . Alph awa s se t a t 0.01 . Severa

l bivariate conelation s achieve d statistica l significance , bu t

n o relationship achieve d significanc e in multivariat e F tests , although th e regression analysi s fo r cor d Pb B and mea n lengt h o f utteranc e wa s significan

t a t p = 0.03 . B y backwar

d elimination , lea

d (cor d PbB ) remaine d in th e mode l (a t p ^0.05 ) fo

r tw o measure s of

languag e development : mea n lengt h o f utteranc e and on e aspec t

of communicativ e intent

("expande d repetitions") . 3 5P.4 7

However , concurrent

(2-year) bloo d lea

d wa s positively relate d to on e aspec t of intelligibilit

y ( adecreas e in "unintelligibl e utterances") . Preliminar y analyse s of

physica l growt h in th e preschoo l perio d (u p t o 4 years , 1 0 months ) revealed n o significan t negativ e relationship between either cord bloo d lea

d o r integrate d postnata

l bloo d lea

d and heigh

t o r weigh t i n a n unspecified numbe

r of childre n fromth e Cleveland stud

y (Marle r an d Emhart , 1987) . Earlier

analyse s (Ernhar

t e t al. , 1986 ) o f birt h weight , length , and hea

d circumferenc e ha

d show n n o significan

t effect of either materna l bloo d lea

d (N = 185 ) o r

cor d bloo d lea

d (N = 162) . Vimpan i e t al . (1985 ) reporte d preliminar y neurobehaviora

l result s fo

r th e prospectiv e stud y conducte d in Por

t Pirie , Sout

h Australia . Th e Bayle

y MD I and PD I were administere d t o 59 2 childre n at

ag e 2 4 months . Initia

l result s indicate d tha

t adeclin e i n 24-mont

h MD I performanc e wa s significantl y associate d wit

h postnata l bloo d lea

d level s bot

h a t 6 month s and integrate d over

th e 2 4 month s afte

r birth . Althoug

h severa l covariate s were taken int o accoun t i n thes e partial linea

r regressio n analyses , materna l I Q ha d bee n measure d fo

r only par t of th e cohor t an d HOME score s ha

d no t yet bee n include d in th e analyses . Nevertheless , a s note d i n th e 198 6 Addendum , th e availabl e information suggested tha t result s fro

mth e Por t Piri e stud y wer e consisten

t wit h th e othe r prospectiv e studie s in pointin g to deficit s o n th e Bayle y MD I a s afunction of

perinata l lea d exposure . Although postnata

l rather tha n prenata l lea d exposur e appeare d to pla

y agreater

rol e in th e MD I deficit s o f

th e Por t Piri e cohort , i t

ha s bee n note d tha

t bloo d lea d level s increase d considerably afte

r birth , particularl y from 6 to 1 5 month s of age , an d tha t earlie r testin g on th e Bayle y Scale s (e.g. , a

t 6 months ) migh

t hav e reveale d amor

e significan

t relationship wit

h ameasur e of prenata l lea d exposur e (U.S . Environmenta

l Protectio n Agency , 1986b ; Davi s and Svendsgaard , 1987) . Indeed , th e Por t Piri e investigator s hav e sinc e state d tha t "th e likel y greater impac t of th e muc h highe r level s of Pb B encountere d postnatally " ma y hav e accounte d i n par t fo r th e differenc e in thei r

result s versu s th e othe

r prospectiv e studie s (Wig g e t al. , 1988) . Later report s fromth e Por

t Piri e stud y hav e noted tha

t th e effec t of postnata l bloo d lea

d level s o n th e 2-yea

r MD I wa s attenuate d a s mor e complet e control s fo

r materna l I Q an d 

### 3 6. HOME score s wer e incorporate d into th e analysis , althoug h al l regression coefficient s fo r postnata l bloo d lea

d measure s remaine d negativ e (Vimpan i e t al. , 1989 ; Wig g e t

al. 9 1988 ; Baghurs t e t al. , 1987) . Elevation s in 6-mont h bloo d lea

d continue d t o hav e th e greates t measurabl e impac t

on 2-yea r MD I scores , althoug h th e regressio n coefficien t fo r 6-mont h bloo d lea d wa s only -0.16 , wit

h p = 0.07 , afte

r controllin g fo

r at leas t 1 5 covariates . Th e result s indicate d tha

t "wit h other factor s remainin g constant , achild' s MD I a t 24 month s wil l b e 1. 6 point s (equivalen

t t o 1.5% ) lowe

r fo r ever y 1 0 /ig/d l rise in Pb B a

t 6 month s of

age . Moreover , in view of

th e fit of alinea r model i n multipl e regressio n analysis , thes e findings provid e n o evidenc e of

athreshol d effect " (Wig g e t al. , 1988) . Continuin g stud

y o f th e Por t Piri e cohor

t ha s yielde d result s fo

r neurobehaviora

l developmen

t a t ag e fou r year s (McMichael e t

al. , 1988) . Th e McCarth

y Scale s of

Children' s Abilitie s were administere d to 53 7 children within 6 month s of their fourt h birthday ; N' s fo

r individua l analyse s range d fro

m46 3 to 534 . Multipl e regressio n analyse s incorporatin g 1 8 covariate s indicate d tha

t score s o n th e McCarth

y GC I wer

e significantl

y relate d to log

transforme d postnata

l bloo d lea

d level s at 6 , 24 , an d 3 6 month s a s wel l a s a n integrate d averag e fo r th e four-yea

r postnata l perio d (Tabl e 7) . Simila r effects wer

e als o evident

fo r th e McCarth y Perceptual-Performanc e and Memor y Scales . Th e larges t

singl e coefficien

t (-15.0 ; p = 0.04 ) wa s fo r th e GC I and integrate d postnata l averag e bloo d lea

d relationship , which indicate s tha t GC I score s decrease d b y 1 5 point s fo r ever y 10-fol d incremen

t in bloo d lead . Alternatively stated , GC I score s decline d approximately 7. 2 point s a s bloo d lea d level s increase d from1 0 t o 3 0 /tg/dl . Furthe r analyse s indicate d tha

t th e relationship betwee

n lea d exposur e and GC I wa s a s stron g o r eve n stronge r a t bloo d lea d level s belo w 2 5 /tg/d l tha n i t was overal l (geometri c mea n bloo d lea

d leve l peake d a t 2 years : 21. 2 /tg/dl ; integrate d postnata l average : 1 9 /ig/dl) . Othe r analyse s reveale d n o indicatio n tha

t GC I performanc e a

t fou r year s wa s especially influence d b y more recen t bloo d lea d levels ; rather , th e effect

of lea d o n th e GC I appeare d t o b e cumulativ e acros s th e entire postnata

l period . Pregnanc y outcome s were als o evaluate d in th e Por t Piri e cohor

t (McMichael e t

al. , 1986) . A significantl

y elevate d risk

of preter m(<3 7 weeks ) deliver

y wa s associate d wit

h materna l bloo d lea

d level s abov e 1 4 /tg/dl . Neithe r birt h weigh t no r spontaneou s abortion s (<2 0 weeks ) showe

d asignifican

t associatio n wit

h bloo d lea

d levels . However , bloo d lea d 3 7TABL E 7 . ESTIMATE D COEFFICIENT S O F LO G BLOO D LEA © CONCENTRATIO N FRO M SIMPL E

AN D MULTIPL E REGRESSIO N ANALYSE S O F McCARTH Y SCORE S A T TH E AG E O F FOU R YEARS C

Bloo d Sampl e Genera l Cognitiv e Index Simpl e Partia l Perceptual-Performanc e Scal e

Simpl e Partia l Memor y Scal e

Simpl e Partia l

o o Prenata

l averag e Deliver y Cor d 6 Mont h 1 5 Mont h 2 4 Mont h 3 6 Mont h 4 8 Mont h Integrated postnata

l averag e -15. 1 ± 4. 7 (0.001 ) -10. 4 ± 3. 9 (0.008 ) -6. 1 ± 3. 4 (0.08 ) -15. 1 ± 3. 8 (<0.001 ) -14. 3 ± 3. 8 ( < 0.001 ) -25. 8 ± 4. 3 (<0.001 ) -25. 1 ± 4. 3 (<0.001 ) -20. 1 ± 4. 1 (<0.001 ) -28. 9 ± 5. 5 (<0.001 ) -1. 8 ± 5. 7

(0.75 ) -0. 4 ± 4. 5 (0.93 ) 3. 3 ± 4. 1 (0.42 ) -8. 5 ± 4. 4 (0.05 ) -3. 5 ± 4. 8 (0.46 ) -11. 1 ± 5. 4 (0.04 ) -13. 1 ± 5. 6 (0.02 ) -5. 5 ± 5. 1 (0.29 ) -15. 0 ± 7. 3 (0.04 ) -9. 5 ± 2. 7

(<0.001 ) -5. 1 ± 2. 3 (0.03 ) -3. 0 ± 2. 0 (0.13 ) -7. 8 ± 2. 2 ( < 0.001 ) -8. 2 ± 2. 2 ( < 0.001 ) -13. 5 ± 2. 5 (<0.001 ) -13. 6 ± 2. 5 (<0.001 ) -11. 2 ± 2. 4 (<0.001 ) -15. 1 ± 3. 2 (<0.001 ) -4. 1 ± 3. 3

(0.22 ) 0. 2 ± 2. 7 (0.95 ) 1. 6 ± 2. 4 (0.50 ) -4. 8 ± 2. 5 (0.06 ) -3. 2 ± 2. 8 (0.26 ) -6. 2 ± 3. 2 (0.05 ) -7. 7 ±3. 3 (0.02 ) -4. 0 ± 3. 0 (0.18 ) -8. 3 ± 4. 1 (0.05 ) -4. 8 ± 2. 7

(0.07 ) -4. 9 ± 2. 2 (0.03 ) -3. 0 ± 2. 0 (0.12 ) -4. 9 ± 2. 2 (0.03 ) -5. 3 ± 2. 2 (0.01 ) 13. 4 ± 2. 4 ( < 0.001 ) 12. 7 ± 2. 4 (<0.001 ) 10. 3 ± 2. 3 (<0.001 ) 13. 3 ± 3. 1 (<0.001 ) 2. 0 ± 3. 3

(0.54 ) -0. 4 ± 2. 6 (0.89 ) 2. 6 ± 2. 5 (0.27 ) -2. 4 ± 2. 5 (0.34 ) -0. 5 ± 2. 7 (0.87 ) -7. 3 ± 3. 1 (0.02 ) -7. 2 ± 3. 2 (0.27 ) -4. 1 ± 3. 0 (0.17 ) -7. 9 ± 4. 2 (0.06 ) Th e partia

l regressio n coefficient s ar e fro m analyse s incorporatin g 1 8 covariates . Th e p value s are fo r assessment s o f th e two-side d hypothesi s tha tth e estimate s ar e no tzero . Source : McMichael etal . (1988) .P.5 0

level s of mother s wh o ha

d stillbirth s were significantl y lower tha n thos e who ha

d liv e birth s (7. 9 vs . 10. 4 /tg/dl) . A s discusse d in th e 198 6 Addendu man d b y Davi s an

d Svendsgaar

d (1987) , thi s seemingl

y paradoxica

l relationship migh

t reflec t increase d transfe

r o f lea d from th e mothe r t o th e fetus , resultin g in greater feta l toxicit y an d stillbirth . Vimpan

i e t al . (1989 ) reporte d preliminar

y result s of

a n analysi s of

tissue lea d concentration s in cor

d and placenta

l membrane and bod

y tha t ar e consisten

t wit h thi s hypothesis . Placenta l membrane an

d bod y concentration s of

lea d wer e higher in case s of

late feta l death s an

d preter mbirth s tha

n fo r norma l births . However , th e numbe r of case s analyzed wa s limite d (e.g. , 6 stillbirths , 2 3 preter mbirths ) an

d statistica l analyse s hav e no t

bee n completed . sydne y Report s hav e recently starte d t o emerg e fro malongitudina

l stud y o f children in Sydney , Australi a(Coone

y e t al. , 1989a , 1989b ; McBrid e et al. , 1989) . O

f a n origina l cohor t of 318 , 29 8 mother s an

d infant s wer

e sampled fo

r bloo d lea d level s a t birth . Afte

r 3 years , 21 5 children remaine d in th e study . A secon d cohor t o f 12 3 children was als o recruited becaus e of "concer n ove r th e possibl e contaminatio n of som e o f th e early capillar

y bloo d samples " (Coone

y et al. , 1989b) . However , th e result s reporte d by Coone y et al . (1989a

) apparently pertai n t o th e origina l cohor t only . Geometri c mea

n bloo d lea

d level s fo r mother s an d infant s a t birt h wer e 9. 1 an d 8. 1 /tg/dl , respectively (overal l range : 0-2 9 /tg/dl) . Although bloo d lea

d measure s wer

e als o take n a t 6 , 12 , 18 , 24 , 30 , an

d 3 6 month s (McBrid

e et al. , 1989) , th e postnata

l value s wer

e no t considere d i

n th e analysi s o

f neurobehaviora

l outcome s durin g th e first

thre e years . Th e Bayle

y MD I an d PD I wer e administere d a

t 6 , 12 , an d 2 4 months , an

d th e McCarth

y GC I an d Motor Scale s wer

e administere d a

t 3 6 months . Othe r outcome s wer

e als o evaluate d but

th e result s hav e not

yet bee n reported . Unadjusted bivariate conelation s betwee n bloo d lea

d level s (eithe

r materna l o r cord ) and cognitiv e an

d psychomotor

outcome s (eithe

r Bayle y o r McCarth y Scales ) wer

e generally small , positive , an

d nonsignifican

t (Tabl e 8) . Th e onl

y statistically significan

t simpl e conelation s wer

e fo r th e relationship betwee

n cor d bloo d lea

d an d th e 12-mont

h Bayle y MD I ( r = 0.153 , p <0.05 , two-tailed ) an d PD I ( r = 0.167 , p <0.05 , two-tailed) . However , th e directio n of

th e relationship wa s positive , i.e. , a s bloo d lea d increased , Bayle

y score s increased . Afte

r adjustmen

t fo r covariates , th e contributio n of bloo d lea d to th e varianc e in 3 9P.5 1

TABL E 8 . REGRESSIO N O F DEVELOPMENTA L INDICE S O N MA '

AN D COR D BLOO D LEA D LEVEL S Age 6 Month s Cognitiv e Psychomoto

r 1 2 Month s Cognitiv e Psychomoto

r 2 4 Month s Cognitiv e Psychomoto

r 3 6 Month s Cognitiv e Psychomoto

r Simpl

e Materna l -.04 4 .03 5 .01 5 .08 1 .00 6 .02 1 .04 0 .01 5 Correlation

s Cor d -.06 1 .02 5 .153 * .167 * .05 3 -.06 0 .04 5 .01 0 Effec

to f Covariate s R * .13 6 .15 3 .177 .10 6 .21 9 .08 1 .16 5 .08 1 F p

3.1 6 <.00 1 3.6 3 <.00 1 d f = 13,26 1 4.0 8 <.00 1 2.2 3 <.0 1 d f = 13,24 5 4.7 9 <.00 1 1.4 9 >.1 0 d f = 13,222 3.1 1 <.00 1 1.39 >.1 0 d f = 13,20 4 Incrementa l Effec t o f Lea d R z F p .00 8 1.2

2 >.2 5 .00 3 0.4 6 > .6 0 d f = 2,25 9 .00 8 1.1 7 >.3 0 .01 9 2.6 0 .0 8 d f = 2,24 3 .00 1 .1 9 >.7 0 .01 3 1.54 >.2 0 d f = 2,22 0 .00 1 .1 3 >.7 0 .00 1 .1 0 >.9 0 d f = 2,20 2

*p < .05 , two-taile

d test . Source : Coone

y e tal . (1989a) . th e regressio n model approache d significanc e only fo r th e positiv e relationship between cor d bloo d lea d and 12-mont

h Bayle y PD I (p = 0.08 , two-tailed) . Regressio n analyse s an

d pat h model s indicate d tha

t th e greates t

influence s o n MD I an

d PD I score s a

t 6 and 1 2 month s wer

e gestationa

l ag e and HOME scores , whil e a t late r age s HOME and parenta

l characteristic s (materna

l I Q an d education ) wer

e th e more important influence s o n cognitiv e measures . Th e fac t tha t Bayle y score s accounte d fo

r asignifican

t amoun t of th e varianc e i

n regressin g HOM

E score s o n prio r

HOME score s i n tw o instance s (12-mont h PD I fo r th e 12

- versu s 6-mont

h HOM E and 36-mont

h MD I fo r th e 36

- versu s 24-mont h HOME) raise s th e questio n of whethe r lea d exposur e (e.g. , materna

l bloo d lead ) migh t hav e covarie d wit

h HOME scores . Thi s particula r relationship apparently wa s no t 4 0P.5 2

examine d b y th e investigators . However , th e author s di d examin e th e relationship s between maternal/cor

d bloo d lea

d an d gestationa

l age , which were show

n t o b e statistically nonsignifican

t (a s wer e als o birt h weight , obstetrica

l complication , an

d postnata l risk factors) . Coone y et al . (1989b ) reporte d th e result s o f testin g th e Sydne

y cohor t a t 4 year s of

ag e on th e McCarth

y GC I an d Moto r Scales . A

t 4 years , 20 7 children of

th e origina

l cohor t remaine d i

n th e study . I

n additio n to materna

l and cor d bloo d lea

d sample s a

t delivery , postnata l bloo d lea

d sample s wer

e take n ever y 6 months . Geometri c mean s fo r capillar y and venou s bloo d sample s combined ros e from1 5 /tg/d l a t 6 month s to apea

k averag e of 16. 4 /tg/d l a

t 1 8 month s an

d the n decline d t o 10. 1 /tg/d l a

t 4 8 months . Bivariat e and partia

l (conectin g fo

r venou s versu s capillar

y collection ) conelation s between 48-mont

h McCarth

y Scale s an

d bloo d lea

d level s a t differen t age s wer e generally quite small , mixed i

n sign , an d uniforml y nonsignificant . Analyse s using composit e bloo d lea d measurement s (averaged ove r 12-mont h periods ) produce d onl

y on e significan

t relationship , a. positive conelatio n ( r = 0.160 ; p <0.05 , two-tailed) betwee n first yea r bloo d lea d and GC I performanc e (Tabl e 9) . However , afte r allowin g fo

r covariates , regressio n analysi s showe

d th e relationship t

o b e onl y marginally significan

t ( p <0.07) . Analysi s o f covarianc e di d no t

indicat e tha t chang e in developmenta

l outcom e from3 6 to 4 8 month s wa s significantl y relate d to eithe

r cunen t (4 8 month) o r

cumulativ e (cunen t

and prior ) pas t

lea d exposure , although cumulativ e lea d wa s abetter

predicto r ( p = 0.14 ) tha

n cunen t lea d exposur e alon e (p = 0.36 ) fo

r GC I scores . HOME scor e wa s stated t o b e th e mos t importan t covariate fo

r th e GCI , apar

t fromth e 36-mont

h GCI . Mexic o City Preliminar y result s o f apilo t stud y i n Mexic o Cit

y fo r alongitudina

l investigatio n of developmenta

l outcome s relate d to lea

d exposur e and other

factor s hav e been reporte d b y Rothenber g et al . (1989a,b) . Approximatel y 5 0 mother s wer

e sampled fo

r bloo d lea d level s a t 3 6 weeks (M36 ) o

f pregnanc y an

d deliver y (MD) ; umbilica

l cor d bloo d lea

d (UC ) wa s als o sampled a t delivery . Mea

n bloo d lea

d level s were : M36 , 15. 0 /tg/dl ; MD , 15. 4 /tg/dl ; and UC , 13. 8 /tg/dl . Th e Brazelton Neonata l Behaviora

l Assessmen

t Scal e (NBAS ) wa s administere d to th e infant s a t 4 8 hour s an

d 1 5 and 3 0 day s afte

r birth . Th e datawere analyze d b y calculatin g th e trend of th e NBA S subscal e score s ove

r th e first 3 0 day s b y linea

r 4 1P.5 3

TABL E 9 . REGRESSIO N O F DEVELOPMENTA L INDICE S AT 4 8 MONTH S

O N CURREN T AN

D PRIO R BLOO D LEVEL S Ag e Prenatal : Cognitiv e Motor Firs t Year : Cognitiv e Moto r Second Year : Cognitiv e Motor Third Year : Cognitiv e Motor Fourt h Year : Cognitiv e Moto r Al l Prio r an d Cunent : Cognitiv e Motor AR 2

.00 4 .00 1 .02 3 .00 3 .00 1 .00 1 .00 1 .00 8 ,00 1 .00 5 .04 4 .02 2 Unadjusted

d f 2,20 4 2,20 4 1,205 1,205 1,20 5 1,205 1,205 1,20 5 1,20 5 1,205 6,20 0 6,20 0 P

.3 6 .9 1 .0 3 .4 6 .8 2 .6 0 .7 0 .2 0 .8 8 .3 2 .1 7 .7 2 AR

2

.00 9 .00 2 .01 3 .00 1 .00 2 .004 .00 3 .00 6 .00 1 .00 1 .02 8 .01 8 Adjusted

d f 2,19 9 2,19 9 1,19 9 1,19 9 1,19 9 1,19 9 1,19 9 1,19 9 1,19 9 1,19 9 6,19 3 6,19 3 P

.1 4 .5 5 .0 7 .6 7 .6 0 .3 3 .7 6 .2 6 .7 6 .9 6 .1 4 .5 6 Source : Coone

y e t al . (1989b) . regressio n analysi s and b y computin g th e differenc e i n M3 6 and M D value s o r M3 6 an d UC values . Th e relationship s among th e variou s primar y an d secondar

y measure s were then examine d through bivariate conelation s an d multivariat

e regressio n analyses . Base d o n preliminar

y dataanalyse s reporte d a

t a198 6 conference , Rothenber g e t al . (1989a ) initially reporte d tha

t statistically significan

t bivariate conelation s were found : between UC bloo d lea

d an d th e 30-da

y trend in NBA

S Abnorma

l Reflexe s (

p <0.05) ; between th e M36-M

D bloo d lea

d differenc e an

d Regulatio n o

f State s ( p <0.05) ; an

d betwee n 4 2th e MD-U C bloo d lea d differenc e and Abnorma

l Reflexe s (p <0.01 ) —al l reflecting impairmen t o f function . Also , stepwis e regressio n modeling wit h al l covariate s entere d befor e lea d wa s reporte d t o show that : bloo d lea d differential s (M36-MD ; MD-UC ) accounte d fo r a significan t portio n o f th e varianc e in th e Abnorma l Reflexe s trend ; th e M36-MD differentia l accounte d fo

r asignifican

t amoun t o f varianc e i n Regulatio n o f

States ; bu t

U C alon e wa s n o longe r significantl

y relate d t o Abnorma

l Reflexes . Rothenber

g e t al . (1989a

) als o reporte d tha t evaluation s o

f physica l developmen

t outcome s a

t birt h i n their cohor t indicate d that : M36-M D an d M36-UC each accounte d fo r asignifican

t amoun t of varianc e i n birthweight (p <0.05) ; M36-UC accounte d fo r significan t amoun t of varianc e in ches t

circumferenc e ( p < 0.054) ; an

d U C and M36-U C accounted fo r asignifican

t amoun t of th e varianc e i n trunk lengt h (p - 0.06 ) Upo n furthe

r analysi s o f

thei r dataset , however , Rothenber g e t al . (1989b ) reporte d tha

t Abnorma l Reflexe s wer

e no t significantl

y associate d wit

h an y o f th e lea d measure s and n o simpl e lea d measur e yielde d significan

t effects o n an y of th e perinata

l outcome s in multipl e regressio n analyses . O

n th e other

hand , severa

l outcom e variable s (Regulation of

States , Autonomi c Regulation , and Gestatio n Age) were statistically significantl y relate d t o composit

e lea d measure s (i.e. , M36-MB , MB-UC , M36-UC) . Generally , increase s in th e bloo d lea d of th e mothe r durin g th e las t

mont h o f pregnanc y (indexed b y th e M36-M B an d M36-UC differentials ) o r

a n umbilica

l cor d lea d highe r tha n th e mother' s bloo d lea

d (MB-U C differential ) wer

e associate d wit

h deleteriou s change s in th e last-note d outcom e variables . Rothenber g e t al . (1989b ) interprete d thei r findings a s indicatin g tha

t either (1 ) th e deleteriou s effects wer

e relate d to increase s in bloo d lea d level s o f th e mothe

r an d fetu s durin g th e las t severa l weeks of pregnanc y o r

durin g deliver

y (regardles s of

initia l materna l bloo d lea

d value s befor e th e increase ) o r

(2 ) th e negativ e outcome s wer e relate d to increase d stres s factor s durin g late pregnanc y o r

deliver y tha t als o raise d materna

l and feta l bloo d lea

d levels . Yugoslavi a A longitudina

l stud y involvin g tw o communitie s i n Yugoslavia , Titov aMitrovic aan d Pristina , ha s bee

n undertaken b y Grazian o e t al . (1989a,b ; Murph

y et al. , 1990) . T . Mitrovic ai s amajo

r lea d smelte r an d industria l site , wherea s Pristina , 4 0 k mt o th e south ,

43P.5 5

serve s a s arelatively non-expose d contro l community . Th e analyse s complete d thu s fa r have , been retrospectiv e a s wel l a s prospective . Onl y reproductiv e outcome s hav e bee n reported . Of th e first 103 2 wome

n enrolle d in th e study , 63 9 (30 4 in T . Mitrovica ; 33 5 in Pristina ) ha

d ha d at leas t on e pregnanc y (only firs t

pregnancie s were considere d in th e analysis ) and ha

d live d a t their cunen t addres s a t leas t sinc e their

first pregnancy . Geometri c mea n bloo d lea

d level s a t th e time of

initia l intervie w wer

e 15. 9 /tg/d l in T . Mitrovic aan d 5. 1 /ig/d l in Pristina . Th e rate of spontaneou s abortion s (feta l los s prio r

t o 7t h month) wa s no t significantl

y differen t i n th e tw o communities : 16.4 % of T . Mitrovic awome

n versu s 14.0 % of Pristin awome

n reporte d suc

h loss . Grazian o e t

al . (1989b ) note d tha

t they ha d systematically attempte d t o demonstrat e a n associatio n betwee

n lea d exposur e an d spontaneou s abortio n and tha

t thei r failur e t o detec t suc h a n associatio n suggested tha t i t di d no t exis t a t th e level s of

exposur e encountere d in thei r

samples . A preliminar

y analysi s o

f prospectiv e datafrom90 7 birth s (40 1 in T . Mitrovica ; 50 6 i n Pristina) indicate d tha

t mea n birthweight s di d no t

diffe r significantl

y between th e tw o communities : 330 8 g (S D = 566 ) in T . Mitrovic aversu s 336 1 g (S D = 525 ) in Pristina . Geometri c mea

n bloo d lea

d level s were 17. 1 /tg/d l in th e forme r an d 5. 1 /tg/d l in th e latter mothers . Regressio n analysi s controllin g fo r severa l covariate s als o failed to show an y significan t relationship betwee

n mid-pregnanc y bloo d lea d level s and birthweight . Glasgo w Followin g across-sectiona l duplicat e die t stud y tha t showed , among other

things , a n invers e relationship betwee n gestationa

l ag e and lea

d exposur e durin g pregnanc y (Moor e e t al. , 1982a) , Moor

e e t al . (1982b ) initiate d aprospectiv e stud y o f th e neurobehaviora

l effect s of lea d in children bo mi n Glasgow , Scotland . A majo r sourc e o f lea d exposur e fo r thi s populatio n wa s it s plumbosolven t drinkin g water . However , subsequen t t o asuccessfu

l progra mt o contro l th e plumbosolvenc y of th e wate r suppl y fo r Glasgow , averag e bloo d lea d level s decline d substantially (Richard s and Moore , 1984) . Notwithstandin g thi s complicatio n in th e desig n of

their prospectiv e investigation , Moor e et al . (1989 ) undertoo k

t o asses s whethe r prenata l o r perinata l lea d exposur e wa s associate d wit

h birt h outcome s o r

postnata l neurobehaviora

l development .

44P.5 6

Thei r stud y sampl e consiste d of

15 1 subject s draw n froma n initial poo l of

88 5 families . Base d o n materna

l bloo d lea

d level s durin g pregnancy , thre e groups , matched fo r socia l class , wer e created : high fe30 /tg/dl , mea n = 33.05) , mediu

m(15-2 5 /tg/dl , mea

n = 17.73) , an d lo w (^1 0 /tg/dl , mea

n = 7.02) . Infan

t bloo d lea d level s were measure d a

t 1 and 2 year s of age , bu t were no t include d in th e reporte d analyse s becaus e o f incomplet

e records . Although birt

h weigh t appeare d t o b e inversely relate d to materna l bloo d lea

d ( a reductio n of

nearl y 10 0 g fo r each incremen

t in bloo d lea

d grouping) , n o statistica

l analysi s o f th e datawa s reported . Birt h lengt h showe d asligh t tren d in th e opposit

e direction , and other pediatri c measure s (hea

d circumference , Apga

r scores , obstetri c complications ) showe d n o evident tren d in either

direction . Unadjusted Bayle

y score s (MDI , PDI , an

d mean) a t 1 and 2 year s generally decrease d wit h increasin g materna

l bloo d lea

d grouping . However , stepwis e linea r regressio n analyse s indicate d tha

t birt h weight , socia

l class , an d HOM E score s accounte d fo

r Bayle y Scale s performanc e better

tha n lea d exposur e (a s represente d b y materna l bloo d lead , wate

r lea d concentration , o r

reporte d histor

y of pica) . Sinc e birt

h weigh t wa s significantl

y relate d inversely to lea

d exposure , i t

wa s remove d fromth e mode l t o se e i f th e explanator

y powe r of on e of th e lea d variable s coul d b e improved . Onl y secon d yea r pic ashowed anotabl e improvement , althoug h HOME scor e alon e stil l ha

d greater predictiv e abilit

y fo r 2-yea r Bayle y score s tha

n pic acoupled wit

h HOM E score . A

n analysi s of

th e Bayle y IB R reveale d n o consisten

t directio n o

f associatio n betwee

n lea d exposur e an d IB R factors . Moor

e e t al . (1989 ) conclude d tha

t thei r datase t provide d "n o firmevidenc e fo r either adirec t o r a n indirec t contributio n of

lea d to decrement s in cognitiv e development. " Christchmrc h Fergusso n and hi s colleague s (Fergusso n an d Purchase , 1987 ; Fergusso n e t al. , 1988a,b,c ) collecte d she

d deciduou s teet

h frommor

e tha n 100 0 childre n i n Christchurch , New Zealan d t o asses s thei r long-ter mlea d exposur e an d th e relationship o f

such exposure t o neurobehaviora

l outcomes . Blood lea

d level s wer

e no t measured . A s reporte d b y Fergusso n e t al . (1988b) , IQ , readin g ability , and schoo l performanc e were assesse d in relatio n to dentin e lea d level s in sample s of

664-88 6 childre n froma

n origina l cohor t o f 126 5 draw n fromth e Christchurc h Chil d Developmen t Study . Th e subject s 4 5P.5 7

were evaluate d at

age s 8 and 9 year s o n th e WISC-R , th e Bur t Reading Test , and b y teachers ' rating s o f reading , writte n expression , spelling , mathematics , an d handwriting . Al l bivariat e conelation s between thes e outcome s an d dentin e lea

d level s wer

e in th e predicte d directio n (negative) , and al l bu t

on e (ou t of 18 ) were statistically significan t at p <0.0 5 (one-tailed) . Afte r conectin g fo

r tes t unreliability , dentin e lea

d measuremen

t enor , sampl e selectio n factors , an d severa l covariates , th e coefficient s fo r th e readin g tes t

an d al l five teache

r rating s a t bot h age s 8 and 9 year s remaine d significant . Further conectio n fo

r pic a(to tes t

fo r th e reverse causalit

y hypothesi s tha

t reduce d cognitiv e abilit

y result s in mor

e pica , which i

n tur n result s in greate

r lea d exposure ) reduce d th e siz e o f th e conelation s eve

n mor e (rangin g from-0.0 7 to -0.14) , bu t

7/1 2 o f th e conelation s remaine d statistically significan t a t p <0.0 5 (Tabl e 10) . TABLE 10 . UNEXPLAINED CORRELATION S BETWEE N LO G DENTIN E LEA D LEVEL S TAKIN G INT O ACCOUN T TES T RELIABILITY , CONFOUNDIN G COVARIATES , SAMPL E SELECTIO N FACTORS ,

AN D REVERS E CAUSALIT Y VIA PIC A

Measure Verba l I Q Performance I Q Total I Q Bur treadin g tes t Teache r rating s Readin g Writte n expressio n Spellin g Mathematic s Handwritin g 8 year s r -0.0 3 -0.0 2 -0.0 4 -0.0 7 -0.1 3 -0.1 3 -0.1 4 -0.0 8 -0.1 2 p *

N.S . N.S . N.S . <0.0 5 <0.00 1 < 0.00 1 <0.00 1 <0.1 0 <0.0 5 9 years

r -0.0 2 -0.0 2 -0.0 3 -0.0 8 -0.0 8 -0.0 8 -0.0 9 -0.1 0 -0.0 8 p *

N.S . N.S . N.S . <0.0 5 <0.1 0 N.S . <0.1 0 <0.0 5 <0.1 0 *One-taile d test . Source : Fergusso n e tal . (1988b) . Fergusso n e t

al . (1988c ) als o investigate d th e hypothesi s tha t th e demonstrate d relationship betwee

n lea d exposur e an d schoo l performanc e wa s du e to lead-relate d deficit s in 4 6P.5 8

attentiona l processes . Mothers ' an

d teachers ' rating s of

sign s o f restles s activit

y and inattentio n a

t age s 8 an d 9 year s were conelate d wit h dentin e lea

d level s o f 88 8 children (Tabl e 11) . Severa

l aspect s of

th e rating s wer

e significantl

y conelate d wit

h dentin e lead , wit h bivariate conelation s fo

r tota l ratin g score s rangin g between 0.0 8 ( p <0.05 ) an d 0.1 4 ( p <0.01 , one-tailed) . Teachers ' rating s were mor e highly conelate d wit

h lea d and wer e als o judge d to b e amor

e accurat e measur e of th e children' s behavior

tha n were materna

l ratings . Afte

r conectin g fo

r measuremen

t enors , sampl e selectio n factors , covariates , an d pica , th e conelatio n betwee n dentin e lea

d an d inattention/restles s behavior wa s 0.0 8 ( p <0.01 ) a

t bot h 8 and 9 year s of

age . Although small , th e conecte d conelation s betwee n dentin e lea

d an d variou s outcome s reflecting schoo l behavior

an d performanc e were consisten t and stabl e ove

r aone-yea r interva l i n th e Christchurc h study . Th e uniformit y an d stabilit y of thes e result s acros s time provid e compellin g reaso n t o judg e th e effect s a s real . However , thi s sam e stud y provide d n o evidenc e tha

t intelligence , a s measured b y th e WISC- R a t 8 o r 9 year s o f

age , wa s relate d t o dentin e lea

d levels . Th e lac k of bloo d lea d measurement s make s i t

difficul t t o interpre t

th e Christchurc h stud y fo r dose-respons e information . However , th e mea n dentin e lea

d valu e i n thi s stud

y wa s 6 /tg/g , wliic

h ma y b e compare d to amea

n dentin e lea

d level of ~ 14. 5 /tg/g foun

d b y Needlema n et al . (1979 ; see als o Bellinge r et al. , 1984b ) fo

r asampl e of

233 5 Bosto

n children . Give

n th e comparabilit

y of th e method s employed b y Fergusso n (Fergusso n an d Purchase , 1987 ; Fergusso n e t al. , 1988a,b,c ) and b y Needlema n e t al . (1979) , an

d a n estimate d mea

n bloo d lea

d leve l o n th e order

of 3 0 /tg/d l a

t ag e 2- 3 year s i n th e stud

y b y Needlema n et a L (1979) , i t

i s possibl e t o infe

r tha t th e averag e bloo d lea

d leve l of th e Christchurc h cohor

t coul d hav e bee

n roughly on th e order

of <1 5 /tg/d l a

t ag e 2- 3 years . Althoug h thi s estimat

e i s rather imprecis e an

d base d on severa

l assumptions , i t

suggest s tha

t th e leve l o f lea d exposur e in th e Christchurch stud

y populatio n wa s roughly comparabl e to population s i n som

e of th e othe r studie s unde

r consideratio n here . Norderiha m- Stollber

g A s note d in th e 198 6 Addendum , Winnek e e t al . (1985a,b ) enrolle d 11 4 children in 198 2 from apopulatio n of

38 3 children bo m6- 7 year s previousl y in Nordenham , Federa l 4 7TABLE 11 . PRODUC T MOMEN T CORRELATION S BETWEE N MATERNA L

O R TEACHE R BEHAVIO R RATING S AN D LO G DENTIN E LEA D VALUE S

Measure 8 year s p * 9 year s

Materna l rating s Activit y Restless , overactiv e Excitable , impulsiv e Constantl y fidgeting Alway s climbin g Squirmy , fidgety Attentio n Shor tattentio n spa

n Inattentive , easil y distracte d Can' tsettl e t o task s Total Scor e Teache r rating s Activit y Restless , overactiv e Excitable , impulsiv e Squirmy , fidgety Very restles s Attentio n Inattentive , easil y distracte d Shor tattentio n spa

n Poo r concentratio n Total Scor e 0.0 7 0.0 7 0.0 3 0.0 7 0.0 3 0.0 9 0.0 9 0.0 6 <0.0 5

<0.0 5 N.S . <0.0 5 N.S . <0.0 1 <0.0 1 <0.0 5 0.0 5

0.0 5 0.0 4 0.0 4 0.0 6 0.0 8 0.0 5 0.0 4 <0.1 0

<0.1 0 N.S . N.S . <0.0 5 <0.0 1 <0.1 0 N.S . 0.1 1 <0.0 1 0.0 8 <0.0 5

0.0 9 0.0 3 0.1 1 0.1 0 0.1 6 0.1 1 0.1 3 <0.0 1

N.S . <0.00 1 <0.00 1 <0.00 1 <0.00 1 <0.00 1 0.1 1

0.1 0 0.1 3 0.1 3 0.1 4 0.1 2 0.1 2 <0.00 1

<0.00 1 <0.00 1 <0.00 1 <0.00 1 <0.00 1 <0.00 1 0.1 3 <0.00 1 0.1 4 <0.00 1 ""One-taile

d test . Source : Fergusso n e tal . (1988c) . Republi c of

Germany . A

n ongoin g federa

l screenin g progra

mof th e Nordenha

mresident s ha d taken bloo d sample s frommother s an d cord s a t delivery . Th e materna

l geometri c mea

n bloo d lea d leve l wa s 9. 3 /xg/d

l (range : 4-31) ; fo

r umbilica l cord , i t wa s 8. 2 /tg/d l (range : 4-30) . Whe

n teste d a t ag e 6-7 , th e children' s averag e bloo d lea d leve l wa s again 8. 2 /tg/dl , 4 8bu t

distribute d differentl

y (range : 4-23) . I

n term s o f accountin g fo

r asignifican

t amoun t o f varianc e in variou s measure s of reactio n time performance , materna l bloo d lea

d wa s better tha n cord ; th e combinatio n o f materna l an d cor d bloo d lea

d wa s better

tha n either alone ; an d th e combinatio n wa s about a s goo d a s concunen t

bloo d lead . Thes e relative standing s ar e probabl y only roug h comparisons , sinc e difference s in th e qualit y of th e sample s from differen t source s an

d a t differen t times coul d hav e affecte

d thes e result s (Winnek

e e t al. , 1985a) . Retestin g of

7 6 o f th e Nordenha

mchildren a

t ag e 9 , wit

h bloo d lea

d level s then averagin g 7. 8 /tg/d l (range : 4-21) , indicate d som e persistin g deficit s in reactio n time tes t performanc e relate d t o bloo d lea d level s 3 year s earlier

(Winnek e e t al. , 1989a,b) . WISC- R performanc e wa s als o significantl y relate d to th e precedin g bloo d lea d level s afte

r conectio n fo r confounding . Concunen t bloo d lea d di d no t significantl

y accoun t fo r either reactio n time o r WISC- R performanc e a

t ag e 9 , although i t

ha d (fo r reactio n time enors ) at

ag e 6-7 . N o result s were reporte d fo

r th e relationship o

f 9-yea r outcome s to perinata

l bloo d lea

d measures . Analogou s result s a s fo

r th e Nordenha

mchildren hav e recently bee n reporte d b y Winnek e e t al . (1989 ) fo

r anothe r cohor t of 6 to 9 y r ol d children (N = 109 ) fromStolberg , Wes t German y whos e bloo d lea

d level s average d 7. 4 /tg/d l (rang e 4.2-18. 0 /tg/dl) . Performanc e deficit s o n aseria l choic e reactio n tas k

wer e foun d to b e significantl

y relate d t o lea d exposur e afte r conectio n fo

r confounders . Th e author s note d tha t certai n feature s o f

th e performanc e deficit

resemble d clinica

l observation s fo

r children wit

h attentio n deficit disorder . BjrfffalQ

A prospectiv e stud

y wa s recently initiate d in th e Buffalo , N Y are ab y Shucar

d et al . (1988a,b) . Cor

d bloo d level s average d ~4. 4 /tg/d l fo r 80 2 newborns . Outcome s hav e no t yet been reported . Othe r Recen t Studie s In additio n t o th e longitudina l studie s discusse d above , severa l other studie s of neurobehaviora

l function in lead-expose d children hav e bee n reporte d sinc e th e 198 6 Addendum . Although mos t appea r to b e well conducted , man y of thes e studie s ar e of 4 9P.6 1

hig h bloo d lea

d levels , o r

thei r primar y relianc e o n toot

h lea d a s a n exposur e indicator . Despit e it s limitations , bloo d lea

d i s cunentl y th e bioindicator o f greates t utilit y fo r regulator y decision-makin g purposes . Consequentiy , th e followin g studie s wil l b e discusse d in les s detai l tha n th e prospectiv e longitudina l studie s describe d above . A cross-sectiona

l stud y of cognitiv e abilitie s an

d educationa

l attainmen

t in apopulatio n of school-ag e childre n fromcentra l Edinburgh , Scotlan

d ha s bee n reporte d b y Fulto n e t

al . (1987 ) an d Raa

b e t al . (1989) . Th e geometri c mea n bloo d lea

d leve l fo r th e 50 1 childre n i n th e stud y sampl e wa s 11. 5 /tg/d l (range : 3.3-34.0) . Multipl e regression analyse s indicate d significan t relationship s between log-transforme d bloo d lea d level s and composit

e score s o n th e Britis h Abilit

y Scale s (p = 0.003 ) an d betwee n bloo d lea

d level s an d attainment

tes t score s fo r quantitativ e (p = 0.04 ) and readin g ( p = 0.001 ) skills , eve

n afte r allowin g fo

r 3 3 covariates . Groupin g th e subject s b y bloo d lea d level s showe

d aclea r dose-respons e relationship withou t

an y evident threshol d down t o th e lowes t subgrou p mea n bloo d lead leve l of 5. 6 /tg/dl . More recently , Thomso n e t al . (1989 ) reporte d tha

t significan t association s were foun d fo r th e Fulto n Edinborough stud y cohor t betwee n lo g bloo d lea

d level s and teacher' s rating s o n th e Rutte r scal e o f aggressive/anti-socia

l hyperactive , and overal l deviate behavior . Hatzaki s e t

al . (1987 , 1989 ) conducte d neuropsychologica l testin g o n 50 9 childre n livin g nea r alea d smelte r i n Lavrion , Greece , and foun d impairment s i n WISC- R I Q score s an d reactio n time performanc e scores . Thes e effects wer e significantl

y associate d wit

h bloo d lea

d level s afte r controllin g fo

r a s man y a s 2 3 covariate s in multipl e regressio n models . Bloo d lea d concentration s range d fro m7. 4 t o 63. 9 /tg/d l and average d 23. 7 /tg/dl . Dependin g o n th e numbe r o f .covariate s include d in th e model , ful l scal e I Q decrease d b y 2.4-2. 7 point s fo r ever y 10-/ig/d l increas e in bloo d lea

d concentration . Subject s were groupe d b y bloo d lea d level s (10-/tg/d l increments ) t o analyz e dose-respons e relationship s fo r I Q a s wel l a s reactio n performanc e scores . A nonlinearit y i n th e dose-respons e patter n fo r I Q make s i t

difficul t t o interpre t thes e dat afo

r athreshold . However , reactio n time performanc e showe d n o evident threshold . Wolf e t al . (1987 ) use d structura

l equatio n modeling to evaluat e th e variable s relate d t o low-leve l lea

d exposur e and infan

t menta l developmen

t in a n urba n populatio n i n Cost aRica . Bloo d lea d level s average d 10. 8 /tg/d l (range : 5.4-21. 5 /tg/dl ) in 18 2 subject s whos e averag e 

### 5 0P.6 2

Bloo d lea d level s average d 10. 8 /tg/d l (range : 5.4-21. 5 /tg/dl ) i n 18 2 subject s whos e averag e ag e wa s 16. 6 month s (range : 12-2 3 months) . Blood lea d ha d neithe r direc t no r indirec t effect s o n th e Bayle

y MDI . However , bloo d lea d di d hav e asignifican

t negativ e relationship wit h birt h weigh t (p = 0.05 ) an

d mother' s heigh

t (p = 0.001) , a s well a s apositiv e relationship wit

h mother' s ag e (p = 0.01) , afte r adjustmen

t fo r covariates . Birt

h weight , iro n deficiency anemia , and child' s ag e ha d significan

t direc t effects o n MDI . Vivol i e t al . (1989 ) and Bergom

i e t al . (1989 ) measure d lea

d concentration s i n blood , teeth , and hair , a s well a s ALA- D activity , in 23 7 childre n fromSassuolo , Italy . A t th e time o f th e study , bloo d lea

d level s average d ~ 11. 5 /tg/dl . Although concunen t bloo d lea d measure s showe

d n o significan

t relationship t o covariate-adjuste d score s on an y of six neurobehaviora

l tests , toot

h lea d wa s significantl

y relate d t o ful

l scal e an d verba l WISC- R scores . Moreover , ALA- D wa s significantl y associate d wit

h on e verba

l subtes t of th e WISC

R an d wit h delayed reactio n time performance . Toot h lea d als o accounte d fo

r asignifican

t amoun t of th e varianc e i n WISC- R ful l scal e and verba l I Q a s well a s Bende

r Gestal t visua l motor tes t performanc e i n 15 6 children from . Aarhus , Denmar

k (Hanse n e t al. , 1989) . Circumpupa

l toot h lea d level s average d 10. 7 /tg/g . A stud y of children in Brussel s (Cluydt s an d Steenhout , 1989 ) showe

d marginally significan

t (p <0.10 ) covariate-adjuste d regressio n coefficient s fo r toot h lea d and neurobehaviora

l outcome s (WISC-R , reactio n time and attentiona l performance) , despit

e th e small (

N = 41 ) numbe r of children evaluated . I n separat e bu t simila r studie s conducte d i n Rhode Island and Lavrion , Greece , Faus t and Brow n (1987 ) and Benetou-Marantidou e t al . (1988) , respectively , administere d neurobehaviora

l tes t batterie s to small group s (N' s of 15-30) of children whos e bloo d lea

d level s ha d bee n measured a

t ~ 30-6 0 /tg/dl . Significantl y impaire d performanc e wa s eviden t b y compariso n to matched controls , eve n afte r bloo d lea d level s ha

d bee n belo w 3 0 /tg/d l fo

r a t leas t on e yea r (Faus t an d Brown , 1987 ) o r

afte r a4-yea r intervenin g perio d befor

e follow

up testin g (Benetou-Marantidou e t al. , 1988) . In analyse s of

datafro mth e secon

d Nationa l Healt h and Nutritio n Examinatio n Survey , Schwart z an d Ott o (1987 ) hav e als o foun

d evidenc e of

retarde d neurobehavioral.developmen t an d impaire d neurosensor

y capabilit y in relatio n t o low-leve l lea d exposure . Th e age s a

t which achil d first

sa t up , walked , an

d spok e wer e significantl

y associate d wit

h bloo d lea

d 5 1

B HP.6 3

wit h other evidenc e linkin g low-leve l lea d exposur e to electrophysiologica

l change s i n th e auditor y syste m(reviewe d i n U.S . Environmenta l Protectio n Agency , 1986a) . Wit h regar d t o feta l growt h effects , arecent

repor t b y War d e t al . (1987 ) indicate d tha

t placenta l lea d concentration s were highly significantl y conelate d wit

h reduction s i n birt

h weight , hea

d circumference , and placenta l weigh t in 10 0 obstetricall y norma

l birth s i n England . Gestationa

l ag e wa s conelate d a

t borderlin e statistica

l significanc e (p <0.10) . Dividin g th e dataint o tw o birthweigh t groups , lo w (OOO O g ) and high.(>400 0 g) , reveale d ahighly significan

t differenc e in mea

n placenta l lea d concentrations : 2.34 9 /tg/g (S.D . = 0.883 ) versu s 1.122 /tg/g (S.D . = 0.361 ) fo r lo w an d high weigh

t groups , respectively . O

f th e 3 7 element s analyzed , lea d and cadmiu

mshowe d th e mos t

consisten t negativ e relationship s wit

h thes e feta

l outcomes . Othe

r factors , suc

h a s parity , se

x of neonate , socia

l class , an d histor

y o f miscarriage , di d no t

appea r to th e author s t o significantl y confoun d their results . Cottdtosion s A s note d in th e 198 6 Addendu m(U.S . Environmenta

l Protectio n Agency , 1986b) , prospectiv e studie s offe

r amajo r advantag e ove

r cross-sectiona

l an d eve n man y retrospective studie s i n tha

t they provid e abetter

histor y of lea d exposure . Thi s ke

y differenc e i s th e reaso n wh y more weigh

t i s place d on findings fro

mprospectiv e studies . However , notwithstandin g thi s advantage , prospectiv e studie s ma y hav e variou s type s of

shortcoming s in common wit

h other epidemiologica

l studies . One problemo

f particula r importanc e i s statistica l power , especially i n longitudina l studie s tha

t typically experienc e attritio n an d declinin g sampl e size s ove r th e cours e o

f th e study . Th e studie s reviewe d here diffe r considerably in populatio n siz e and , eve n withi n som

e studies , in th e numbe

r of subject s include d in individua l analyses . T o illustrate , th e first results fromth e Boston prospectiv e stud y were base d o n analyse s involvin g 20 1 infant s out of acohor t of 24 9 (Bellinge

r e t al. , 1987a) . B y 5 years , th e analyse s wer e base d on 17 0 children (Bellinge

r e t al. , 1989b) . Whil e thi s rat e of attritio n i s certainly no t

high , i t doe s nevertheles s mak

e i t increasingly difficul

t t o detec t a n effec t of low-level lea

d exposure . Accordin g t o Cohe

n (1977) , a

n N o f ove r 40 0 subject s would b e require d t o detec t a n effec t siz e (AR

2 ) o f 0.0 1 wit h apowe r of 0.8 0 a t a n alph aof 0.05 , one-sided . Thi s calculatio n 5 2, assume s tha t th e analysi s include s 1 3 covariate s having a n R 2 of 0.30 . I f th e covariat

e R 2 i s overestimate d in th e analysi s fo r som e reaso n (e.g. , becaus e of

spuriou s sampl e conelation s betwee n covariate s an

d bloo d lea

d o r becaus e th e covariate s ar e involve d in causa l pathway s linkin g lea d exposur e t o development) , then regressio n method s ma y fai l to detec t atrul y significan t associatio n between lea

d an d developmenta

l outcomes . Anothe r facto r tha t ca n affec t th e power

t o detec t asignifican

t relationship in thes e studie s i s th e amoun

t o f varianc e i n th e sampl e bloo d lea d measures . A small standar d deviatio n in th e independen t variabl e (e.g. , bloo d lead ) wil l necessarily reduc e an y conelatio n betwee n i t and adependen

t variabl e (e.g. , MD I scores) . Also , th e presenc e of asignifican

t effect o f anothe r variabl e o n th e outcome s under consideratio n wil l mak

e i t mor e difficul t t o detec t th e effect of lea d exposur e b y regressio n analysis . Fo r example , ove

r 5 0 percent

of th e mother s enrolle d in th e Cleveland stud y were determine d t o b e alcoholic , an d significan

t earl y developmenta

l effect s were show

n t o b e alcohol-relate d i n th e Cleveland stud y populatio n (Ernhar t etal. , 1985b) . Perhap s th e mos t

surprisin g outcom

e o f th e prospectiv e studie s a s awhole , then , i s tha t s o man y of the mar e abl e to detec t

an y effect of lea d a t all . Give n th e limitation s of

sampl e siz e an d powe r of mos t of th e studie s unde

r consideration , one' s confidenc e i n th e realit y of an y detecte d effect s tha

t achiev e statistica

l significanc e i s enhanced . Conversely , i t i s difficul t t o interpre t

afailur e t o detec t alea d effect a s suggesting th e absenc e of a n effect , i f

th e analyse s in questio n wer

e base d o n fewe

r tha n 40 0 subjects , a s wa s generally th e case . Despit e thes e limitations , som

e important

conclusion s emerg e fromth e findings reporte d above . Variou s line s o f

evidenc e stil l relate neurobehaviora l effects t o bloo d lea

d level s o f "10-1 5 /tg/dl , and possibly lower, " a s wa s previously conclude d i n th e 198 6 Addendu m(U.S . Environmenta

l Protectio n Agency , 1986b) . Further analyse s fromth e Bosto

n study , which ha s provide d th e mos t

direc t informatio n bearin g o n dose-respons e relationship s fo r neurobehaviora

l effects , no t

only supporte d th e 10-1 5 /tg/d l leve l of concer n bu t indicate d tha

t MD I deficit s ca

n b e detecte d i n relatio n t o cord bloo d lea d level s o f 6- 7 /tg/d l i n lower

SE S children (Bellinge

r e t al. , 1988) . Sinc e th e Boston cohor t wa s mostl

y middl e to uppermiddl e class , "lower " SES merel y refers t o les s tha

n th e highes t

SES level s and i s probabl y i n fact muc h closer t o th e media

n o f th e U.S . populatio n tha

n th e ter msuggests . Although th e postnata l lea d exposur e level s were somewha

t higher in th e Por

t Piri e study , analyse s o f

th e 

### 5 3P.6 5

relationship betwee

n postnata l bloo d lea

d level s and covariate-adjuste d MD I score s provide d "n o evidenc e of

athreshol d effect " (Wig g e t al. , 1988) . Indeed , restrictin g th e analysi s to childre n wit

h bloo d lea

d level s belo w 2 5 /tg/d l in th e Por t Piri e stud y yielde d a

n eve n stronge r associatio n betwee

n covariate-adjuste d McCarth y GC I score s an

d integrate d postnata

l bloo d lea d measure s (McMichae

l e t al. , 1988) . Supporting evidenc e fo

r th e state d leve l of

concer n ma y als o b e derive d fro

mother studies . Althoug

h McCarth

y Scal e result s fro

mth e Bosto

n stud y hav e no t bee n analyze d in a manne r t o allo w direc t

extractio n o f

dose-respons e information , th e averag e bloo d lea d leve l significantl y associate d wit

h covariate-adjuste d performanc e o n th e McCarth y Scale s (GC I an

d Perceptual-Performanc e subscale ) wa s 6. 8 /tg/d l (S D = 6.3 ) (Bellinge r et al. , 1987b) . Similarly , analyse s relatin g cor d bloo d lea

d level s t o th e G-R Neurologica l Sof t Sign s and , indirectly , to 12-mont

h MD I score s were previously reporte d fo r th e Cleveland stud

y (Emhar t e t al. , 1986 ; Wol

f e t al. , 1985) , alon g wit

h mor e recent significan t results , b y mor

e tha n on e analysis , relatin g cor

d bloo d lea

d to Lengt h of Utterance , ameasur

e o f languag e developmen

t i n 24-month-ol d infant s (Monow-Tluca k and Emhart , 1987) . Significan t relationship s wer

e als o indicate d fo

r materna l bloo d lea

d and deficit s in 6-mont

h MDI , PDI , and KI

D score s i n th e Cleveland cohort , but

result s of other analyse s wer

e mixed (Emhar

t et al. , 1987) . An

y significan t neurobehaviora

l effects associate d wit

h cor d bloo d lea

d in th e Cleveland stud

y necessarily occune d a

t level s belo w 1 5 /tg/d l sinc e th e maximu msingl e cor

d bloo d lea

d leve l measure d was onl

y 14. 7 /tg/d l (mean : 5.8 4 /tg/dl) . Moreover , th e fac t tha t significan t evidenc e o

f lead-associate d impairment s wa s foun d in arelatively smal

l cohor t (N' s <200 ) suggest s tha

t th e wor k wa s carefull

y conducte d an

d tha t th e result s are credible . Som e evidenc e fromrecen

t cross-sectiona

l studie s i s als o consisten

t wit h th e identifie d leve l o f concern . Th e Edinburgh stud y (e.g. , Fulto n e t

al. , 1987 ) show s asignifican t relationship betwee

n bloo d lea

d level s averagin g a s lo w a s 5. 6 /tg/d l an d covariate-adjuste d score s o f cognitiv e abilit

y an d educationa

l attainment . A s noted b y Gran t an d Davi s (1989) , thi s finding appear s t o closel y paralle l th e result s of

Schroede r an d Haw k (1987) , whos e Nort h Carolin across-sectiona

l stud y populatio n showe

d I Q deficit s i

n relatio n to bloo d lea

d extendin g to level s a s belo w 1 0 /tg/dl . Th e latter stud y wa s describe d i

n detai l an d evaluate d i n th e 198 6 Air

Quality Criteriafor

Lead (U.S . Environmenta

l Protectio n Agency , 1986a) . I n

5 4P.6 6

addition , th e reactio n time performanc e result s of Hatzaki s e t

al . (1989 ) showed n o eviden t threshol d ove

r abloo d lea

d rang e of 7. 4 to 63. 9 /tg/dl . Base d on al l of th e abov e considerations , abloo d lea d concentratio n of

10-1 5 /tg/dl , and possibl y lower , remain s th e leve l o f concer n fo r impaire d neurobehaviora

l developmen

t in infant s and children . Give n th e fac t tha t suc h effects hav e bee

n associate d wit

h bloo d lea

d measure s in pregnan

t women , umbilica

l cords , an

d infant s up t o at

leas t 2 year s o f

age , there i s n o apparen

t distinctio n a

t present a s t o whethe

r thi s leve l of

concer n applie s t o only fetuse s o r infant s o r preschool-ag e children . Thus , abloo d lea d leve l of 10-1 5 /tg/dl , and possibly lower , ough

t to b e avoide d i n pregnan

t women , fetuses , infants , and youn g children , althoug h i t i s recognize d tha

t pregnant wome n per s e ar e no t necessarily apopulatio n a t risk . Variou s line s o f

evidenc e sugges t

tha t lowe r SES and mal e gende

r ma y b e additiona

l risk factor s fo r th e developmenta

l effects o f low-level lea

d exposure . Increase d vulnerabilit y in lowe r SE S children ha s bee

n indicate d in analyse s o f

MD I score s (Bellinge

r e t al. , 1988 ) and MDI-GC I chang e score s in th e Bosto n stud y (Bellinge

r e t al. , 1989b ) an d i n th e MD I result s fromCincinnat

i (Dietric h et

al. , 1987b , 1989b) . Also , som e I Q result s fromcross sectiona l investigation s ar e consisten t wit h th e view tha

t lowe r SES childre n ar e mor

e vulnerabl e to lead-induce d cognitiv e impairmen t (Harve y e t al. , 1984 ; Lansdown e t

al. , 1986 ; Schroede r an d Hawk , 1987) . Greate

r susceptibilit

y of mal e infant s t o lea

d developmenta

l toxicit y ha s bee n eviden t in analyse s o

f MDI-GC I chang e score s in th e Boston stud y (Bellinge r et al. , 1989b) , in MD I result s fromth e Cincinnat i stud y (Dietric h e t

al. , 1987b , 1989b) , i n reanalyse s of

I Q datafromth e Southampton cross-sectiona l stud y (Pocock e t al. , 1987) , an d in som e earl y dataon se

x ratio s o f stillbirth s i n Por

t Piri e and other

location s (Scrag g et al. , 1977) . However , McMichae l e t al . (1988 ) foun

d tha t th e bloo d lead-GC I regressio n coefficien

t wa s slightl

y highe r fo r girl s tha n fo r boys , although stratificatio n b y gende r di d no t significantl

y improv e their

mode l in repeate d analyses . Th e evidenc e regardin g pregnanc y outcome s an d physica l growt h effects relate d to prenata l lea d exposur e i s les s consisten

t tha n tha t fo r neurobehaviora

l outcomes . Suc

h wa s th e cas e a t th e time of

th e 198 6 Addendu

m(U.S . Environmenta

l Protectio n Agency , 1986b ) and i s stil l th e cas e simpl

y becaus e relatively littl e additiona l informatio n pertainin g to pregnanc y outcome s and growt h ha s appeare d sinc e th e 198 6 assessment .

5 5P.6 7

A s fa r a s growt h effect s ar e concerned , th e Cincinnat i stud y ha s show

n asignifican

t covariate-adjuste d reductio n in birt h weigh t associate d wit

h prenata l (maternal ) bloo d lea

d level s (Bornschein e t

al. , 1989) . In addition , earl y postnata l growt h rate s (ove

r 3-1 5 months ) hav e als o been associate d wit h lea d exposure pre - and postnatally in th e Cincinnat i stud y (Shukl ae t al. , 1987 , 1989) . (Interaction s wit h other variable s were evident

i n bot h of thes e cases , which wil l b e discusse d furthe r below. ) Som e supportin g evidenc e o f

lead-relate d reduction s in birt h weigh t als o come s fromth e Boston stud

y and , possibly , th e Glasgo w study . Although birt h weigh t per se showed n o relationship t o cor

d bloo d lea

d i n th e Boston study , there wa s a n exposure-relate d tren d in th e percentag e of

small-for-gestationa

l ag e infant s tha

t approache d statistica

l significanc e (Bellinge r e t al. , 1984a) . In Glasgow , th e high materna l bloo d lea

d infant s (mean : 33.0 5 /tg/dl ) weighe d 3.3 2 kg , o n average , at birth , wherea s th e mediu

mbloo d lea

d group (mean : 17.7 3 /tg/dl ) weighe d 3.4 3 k g an d th e lo w group (mean : 7.0 2 /tg/dl ) weighe d 3.5 1 k g (Moor e e t al. , 1989) . However , thes e dat awere no t adjusted fo

r covariate s and were no t

teste d fo r statistica l significance . N o other prospectiv e stud

y ha s show

n asignifican

t associatio n betwee

n reduce d birt

h weigh t an d lea d exposure . Th e Yugoslavia n stud y (Grazian o e t

al. , 1989b ; Murph

y e t al. , 1990) , in particular , ha s failed thu s fa r t o yiel d an

y evidenc e of

lead-relate d birthweight reduction s i n more tha

n 90 0 births , eve n at

relativel y high bloo d lea

d levels . Also , analyse s b y Ernhar t e t al . (1986 ) showed n o significan t effec t of lea d on birt h weight , birt

h length , o r hea d circumference ; nor , accordin g t o preliminar y analyses , wa s an

y effect evident o n postnata l growt h (Marler and Emhart , 1987) . However , th e cross-sectiona l stud y b y War d et al . (1987 ) di d indicate highly significan t simpl e relationship s between placenta l lea d concentration s and reduce d birt h weigh t and hea d circumference . Th e Por t Piri e stud y provide d stron g evidenc e relatin g prenata l lea d exposure t o increase d risk

of preter mdeliver y ( < 3 7 week s gestation ) in asampl e of 74 9 pregnancie s (McMichael e t

al. , 1986) . Also , asmall bu t significan t relationship betwee

n prenata l lea d and gestationa

l maturit y wa s observe d in th e structura l analyse s o

f th e Cincinnat

i stud y (e.g. , Dietric h e t

al. , 1987b) . However , regressio n analyse s o f adifferen t sampl e fro

mth e Cincinnat i stud y di d no t revea l asignifican

t associatio n betwee

n prenata l lea d and preter

m (<3 5 weeks ) deliverie s (Bornschein e t al. , 1989) . Also , a s previously discusse d in th e 198 6 

### 5 6P.6 8

Addendum , th e Bosto

n prospectiv e stud

y showe d apositiv e but

nonsignifican

t relationship betwee n cor d bloo d lea

d and gestatio n lengt

h (Bellinge

r et al. , 1984a) , wherea s th e cross-sectiona

l stud y of Moor e e t al . (1982a

) foun d significan

t negativ e association s between gestationa l ag e an d materna l a s well a s cor

d bloo d lea

d afte r allowin g fo

r anumbe r of covariates . A reductio n in gestationa l ag e wa s associate d wit

h a n increas e in materna

l bloo d lea d leve l betwee

n th e 36t h wee k of pregnanc y an

d deliver y i n th e Mexic o Cit

y pilo t stud y (Rothenber

g et al. , 1989b) . Placenta

l lea d concentration s appeare d t o b e inversely relate d t o gestatio n lengt

h in th e analyse s of

Vimpan i et al . (1989 ) an

d War d e t al . (1987) , bu t

were o f uncertai n statistica

l significance . There are man

y possibl e explanation s fo

r thes e apparen

t inconsistencie s among studies . Th e lack of asignifican

t differenc e in pregnanc y outcome s between th e high exposur e an d referenc e communitie s in Yugoslavi a(Grazian o e t al. , 1989a,b ; Murph

y e t al. , 1990) coul d reflec t th e difficult

y o f assessing feta

l lea d exposur e by mean s of

materna l bloo d lea

d levels . Wit h regar d to gestatio n length , Bornschein e t al . (1989 ) note d tha

t their analysi s wa s restricte d to pregnancie s of a t leas t 3 5 weeks . A simila

r cutof f of 3 4 weeks wa s used in th e Bosto n prospectiv e stud

y (Bellinge

r et al. , 1984a) . Constrainin g th e datain thi s fashion coul d mak e i t mor e difficul t to detec t a n effect o f lea d on gestation . Also , there wer e interaction s involvin g mother' s ag e an

d rac e evident

i n th e Cincinnat

i stud y (Bornschein e t

al. , 1989) . Thus , difference s i

n th e ag e o

f th e mothers , racia

l make-up , other

populatio n characteristics , sample sizes , level of

lea d exposur e (pas t a s well a s cunent) , and approache s to analyzin g datacould underli e th e varyin g result s of differen t studies . Base d on th e evidenc e reviewe d here and in th e 198 6 Air Quatity Criteria

for Lead (U.S . Environmenta

l Protectio n Agency , 1986a) , i t seems likely tha

t prenata l lea d exposur e pose s apotentia

l hazar d to th e developin g fetu s i n term s o f reduce d gestationa

l lengt h and possibly othe

r aspect s of feta l growt h (in additio n to postnata

l neurobehaviora

l development , a s alread y noted above) . I t

i s difficult , however , to deriv e adefinitiv e dose-respons e relationship fo

r feta l outcome s fromth e availabl e data , although som e indication s point

t o a leve l of concer n startin g in th e regio n o f

10-1 5 /tg/dl . Th e averag e materna l bloo d lea

d level s in th e studie s wher

e th e pre-ter

mdeliver y effec t wa s cleares t

(Por t Piri e and Glasgow ) were in th e 10-1 5 /tg/d l range , in contras t t o somewha

t mixed findings in th e Cincinnati , Boston , and Cleveland studie s wher e th e materna

l o r cor d bloo d lea

d level s average d belo w 1 0 /tg/dl . 5 7P.6 9

A simila r patter n seem s t o hol d fo

r birt h weigh t a s well . Th e stronges t

evidenc e o f

a birthweigh

t effec t come s fromth e Cincinnat i study , wit

h som e o f thei r analyse s suggesting tha t suc h a n effect coul d star

t in th e regio n of

12-1 3 /tg/dl , but

possibly extendin g fro

m7 t o 1 8 /tg/dl . However , othe

r prospectiv e studie s provid e n o suppor t fo r thi s conclusion , an

d s o i t mus t b e considere d a

n ope n issu e awaitin g mor

e definitiv e resolution . Th e issu e o f

th e persistenc e of

th e neurobehaviora

l effect s need s t o b e considere d i n a n assessmen t of th e risk o f low-level lea

d exposure . I

f decrease d score s o n th e Bayle y Scale s reflecte d merel

y atransien

t dela y in children' s neurobehaviora l developmen

t - aminor perturbatio n tha

t children coul d quickl

y "gro w out

o f - the n th e publi c healt

h significanc e o

f lea d exposur e a t bloo d lea d level s o f 10-1 5 /tg/d l would perhap s b e diminished . Som e recen t result s fro mtw o o f th e studie s tha

t ha d convincingly demonstrate d alink between prenata

l lea d exposur e (eithe r matema l o r cor d bloo d lea

d levels ) and early deficit s on th e Bayle y Menta l Developmen

t Index no w sugges t tha t th e associatio n betwee

n prenata l lea d exposur e an d cognitiv e developmen

t ma y no t hol d up a t later ages . Th e Cincinnat

i stud y foun d a declinin g influenc e of

prenata l exposur e indicator s on MD I score s a t 1 2 month s an

d 2 4 months : only 10-da

y bloo d lea

d measure s were significantl y associate d wit

h MD I score s a t 1 2 months , an

d n o significan

t negativ e PbB-MD I relationship s were eviden t a t 24 month s (Dietric h e t

al. , 1989b) . Although th e Boston stud y di d continu e to find asignifican t relationship betwee

n prenata l lea d exposur e (cor d bloo d lead ) an

d MD I performanc e a

t 24 months , n o relationship coul d b e show n fo r prenata l lea d exposur e an d cognitiv e abilitie s at 5 7 month s o n th e McCarth y Scale s (Bellinge

r e t al. , 1987b) . Thus, , on e implicatio n of thes e findings migh

t b e tha t th e effects of

prenata l lea d exposur e on neurobehaviora

l developmen

t ar e no t permanent . Suc h aconclusio n coul d b e valid , but th e evidenc e availabl e to suppor t i t i s no t adequate . Th e inabilit

y to detec t

acontinuin g significan

t associatio n betwee

n prenata l lea d exposure and neurobehaviora l functio n a t ag e 2 i n th e Cincinnat

i stud y o r ag e 5 i n th e Bosto

n stud y coul d resul t

from, amon

g other things , alac k

of adequat e statistica l power , a s note d above . Othe

r factor s coul d als o interfer

e wit h detectin g suc

h arelationship an

d possibly accoun t fo r differing result s in separat e studies . Fo r

example , i t

i s not clea r which measur

e o f bloo d lea d provide s th e bes t

indicator of exposur e durin g critica

l period s of

organogenesis . Th e Cincinnat

i stud y primarily used materna

l bloo d sample s obtaine d durin g th e firs t o r 5 8P.7 0

secon d trimester

of pregnanc y to indicat

e prenata l lea d exposure . Prenata

l exposur e wa s als o reflected in sample s taken fromth e Cincinnat i infant s 1 0 day s afte

r birt h (gestationally conected) , bu t

comparatively fe

w cord bloo d sample s were availabl e fo r dat aanalysis . Th e Bosto n stud y relie d exclusively on cor d bloo d sample s whil e other studie s hav e als o sampled th e mother' s bloo d aroun d th e time of delivery . A s suggested previously (U.S . Environmenta

l Protectio n Agency , 1986b ; Davi s an d Svendsgaard , 1987 ) and supporte d b y preliminar y result s fro

mth e Mexic o Cit

y stud y (Rothenber

g et al. , 1989a,b) , there ma

y b e difference s in thes e measures , particularl y durin g th e las t mont h o r s o of pregnancy , tha

t reflect importan t biokineti c transfer s of

lea d betwee n compartments , bot

h within th e mothe

r an d infan t individually and betwee

n them . I n additio n to th e nature an d exten t of suc h biokineti c transfers , their timin g (an

d th e point a t whic h bloo d lea

d i s sampled

) coul d mak

e a n importan

t differenc e in th e ontogenesi s o f neura l structure s and , consequently , later neurobehaviora

l function . I t

i s interestin g to note , fo r example , tha

t almos t n o significan

t negativ e association s hav e been found , afte r covariat e adjustment , betwee

n concunen t

bloo d lea d level s an

d postaata l outcome s i

n an y of th e prospectiv e studie s reviewe d here . Rather , cumulativ e pas t exposur e (e.g. , averag e postnata l bloo d lea

d levels ) or , in severa

l instances , bloo d lea

d level s severa

l month s o r

year s prio r to agiven outcom

e hav e show

n th e stronges t

relationship t o postnata

l neurobehaviora

l effects . Suc

h alagge d effec

t ha s bee n suggested b y severa

l findings, a s show

n in Tabl e 12 . Whe n significan

t positive (unpredicted) relationship s betwee n ameasur

e of bloo d lea d and som e outcom e hav e occasionally bee

n found , the

y generally involve d concunen t bloo d lea d levels . Thus , i t ma y well b e tha

t th e abilit y to detec t

asignifican

t relationship betwee

n low

leve l lea d exposur e and neurobehaviora

l outcome s depends , a

t leas t i n part , o n wher

e an d whe n th e measur

e o f bloo d lea d i s obtained . Sinc e th e fetu s an d infan t constitut e th e populatio n a

t greates t risk, i t woul d b e preferabl e t o measur e adirec t indicato r o f their exposure . However , tha

t approach ha s no t

bee n a s feasibl e a s measuring arelate d indicator , suc h a s materna

l o r cor d bloo d lead . (Eve

n cor d bloo d i s sampled fro

mth e placenta

l rather tha n th e feta l side and ma

y therefor e no t full y reflect feta l exposure. ) Consequently , measure s suc

h a s matema

l an d cor d bloo d lea

d levels , whil e reasonably goo d indicator s of

5 9P.7 1

TABLE 12 . STRONGES T RELATIONSHIP S BETWEEN BLOO D LEAD MEASURES ' A T SPECIFIE D TIME S AN D LATE R NEUROBEHAVIORA L OUTCOME S A S DETECTE D B Y PROSPECTIV E STUDIE S

Stud y Boston (Bellinge r etal. , 1987a,b ) Cincinnat i (Dietric h etal. , 1987b , 1988 ; Bhatta

chary aetal. , 1988 , 1989 ) Cleveland (Ernhar t etal. , 1986 , 1987 ; Wol f e t al. , 1985 ; Monow-Tluca

k & Ernhart , 1987 ) Pt . Piri e (Wig g et al. , 1988 ; McMichael etal. , 1988 ) Sydne y (Coone y etal. , 1989b ) Time/Typ e

of Blood Lea

d Measur e Delivery/cord 2y r Prenata l (x : 1 6 wk)/materna

l 1 0 da y 2y r Delivery/cord Delivery/materna

l Delivery/cord 6 mont h 6 , 24 , 3 6 mont

h and integrate d postnata

l Cumulativ e (prio r

plu s cunent ) Outcom e 6- , 12- , 18- , and 24-mont h MD I 5-y r McCarth y 3

- an d 6-mont h MD I 12-mont h MD I 6-y r postura l swa y 12-mont h MD I (vi a30-da

y G- R sof t signs ) 6-mont h MDI , PDI , KI

D 2-y r languag e acquisitio n ( 2 measures ) 2-y r MD I 4-y r McCarth y 3 6 t o 4 8 mont

h chang e in cognitiv e developmen

t (p = 0.14 , two-tailed )

prenata l lea d exposure , ma

y no t affor d th e mos t

accurat e predictor s of

later neurobehaviora

l outcomes . Anothe r facto r tha t coul d obscur

e arelationship between prenata l lea d exposur e and postnata l neurobehaviora

l function and tha

t coul d accoun

t fo r som e difference s i

n result s 6 0P.7 2

among studie s i s th e rather precipitou s increas e in lea d exposur e observe d in mos t

o f th e prospectiv e studie s durin g th e first 2- 3 year s of

life . Sizeabl e rises in postnata l bloo d lea

d level s wer e noted in th e Cincinnati , Cleveland , and Por t Piri e studies , but

no t in th e Bosto

n study . None o

f th e firs t thre e studie s showe

d asignifican

t associatio n between prenata l lea d exposur e indicator s an

d 2-yea r MD I scores , bu t

th e Bosto n stud y did . Whil e analyse s from th e Bosto n stud y als o indicate d tha

t continuin g "high " lea

d exposur e ( > 1 0 /tg/dl ) contribute d t o apersistenc e of

neurobehaviora

l deficit s a

t later ages , ahigh postnata

l bloo d lea

d in th e Bosto n cohor t was no t a s high a s th e averag e fo

r an y of th e other prospectiv e studie s a

t ag e 2 years . Thus , th e relationship betwee n lea d exposur e a t acritica l stag e o f earl y developmen

t and subsequen

t neurobehaviora

l functio n coul d b e obscure d b y differentia l lea d exposur e (mos t often , but no t always , increase d exposure ) in th e intervenin g period . B y thi s lin e o f

reasoning , on e would perhap s expec t tha t increase d postnata

l bloo d lea

d measure s shoul

d the n show asignifican

t relationship to later

neurobehaviora

l outcomes . Thi s wa s in fac t th e cas e in th e Por

t Piri e study , wher

e sampl e siz e wa s mor

e clearl y larg e enough t o affor d relatively goo d statistica l power . (Thi s als o point s up , a s discusse d above , wh y i t i s no t possibl e a t present t o discriminat

e between prenata

l an d postnata l lea d exposur e in statin g abloo d lea

d level of concer n fo r developmenta

l neurobehaviora

l effects. ) I t should als o b e kep t

i n min d tha t score s o n test s suc

h a s th e Bayle

y o r McCarth y Scale s ar e onl

y indicator s o r

reflection s of

neurobehaviora

l function . Suc

h variable s ma

y b e vali d an d reliabl e measures , but

the y do no t fiill y represent

al l aspect s of

achild' s cognitive , social , an d emotiona

l development . Thus , considerabl e cautio n mus t b e exercise d i n drawin g conclusion s from findings of "n o effect. " No t

only ar e there man

y facet s to achild' s developmen

t tha t need to b e assessed , but

thes e facets ma

y interac t in complex way s tha

t ma y b e quite difficul

t to detec t o r evaluate . Fo r

example , achild' s emotiona l and socia

l adaptatio n (includin g suc

h notion s a s "self-esteem" ) ma y b e influenced i n subtl e a s wel l a s obviou s way s b y hi s o r he r cognitiv e abilities . Finding s o f lead-relate d aggressive/antisocia l behavior in th e Edinburgh cohor

t (Thomson e t

al. , 1989 ) suppor

t thi s view . Suc h complexitie s mak

e i t difficul t to presum

e tha t afailur e to detec t acontinuin g associatio n betwee

n a n indicator

of prenata l lea d exposur e and , fo r example , score s on th e McCarth y Scale s a t 5 year s i s evidenc e of

n o permanen

t effect . I t i s well known tha

t th e nervou s syste

mi s capabl e of

adaptin g t o an

d eve n compensating fo

r variou s insult s durin g 

### 6 1P.7 3

earl y development . Bu

t i t i s als o tru e tha

t th e ful l realizatio n o

f developmenta

l potentia l ca n ver y muc h depend on event s durin g critica l stage s of ontogeny . A paralle l ma

y b e drawn wit h impaire d languag e acquisitio n in children whos e hearin g ha s bee n affecte d b y chroni c otiti s medi a(e.g. , Kavanagh , 1986) . Although otiti s medi aitself ma y b e transient

an d full y reversible , it s secondar

y effects on languag e developmen t in young children ma

y b e muc h longer lived . A s note d b y Jenkin s (1986) , "Wit h afluctuating hearin g loss , suc h children ma y receiv e inconsisten

t an d inadequat

e information , o r

ma y hav e to devot

e s o muc h attentio n t o th e decoding proces s itself tha t there i s littl e capacit

y lef t ove r fo r higher-orde

r cognitiv e operations . I

f children are , in fact , doing something differen t o r expendin g mor

e resource s o n lowe r level s of speec h perception , w e ma

y se e deficit s in other

processe s a

t alater period. " Importan t ne w evidenc e fo

r th e long-ter

mpersistenc e of

lead-induce d intellectua

l an d behaviora l deficit s ha s recently bee

n reporte d b y Needlema

n e t al . (1990) . I

n a n 11-yea r follow-u p of children studie d earlier

a t ag e 6- 7 years , thos e children originall y having high denti n lea d level s (>2 0 ppm

) ha d markedl y highe r rate s of having areadin g disabilit

y an d o f droppin g out

of high schoo l tha

n lowe r lea d children (dentin lea

d < 1 0 ppm) . Also , highe r lea d level s i n earlier

childhoo d wer

e significantl

y relate d to lowe

r clas s standing , increase d absenteeism , lowe

r verba l scores , an

d poorer sensory-motor

performance . Thes e persistin g effect s wer

e detecte d adecade later

whe n bloo d lea

d level s ha

d decline d t

o 7 /tg/d l o r

lowe r (i n contras t to th e high-lea

d dentin grou

p wit h bloo d lea

d level s averagin g approximately 3 4 /tg/d l a t th e time of

th e origina

l study) . I t i s als o importan

t to not e th e convergenc e o

f anima l findings, particularl y thos e showing impairment s i n higher-leve l behaviora l processe s suc

h a s discriminatio n reversa l learnin g in primate s a s well a s rodent s a t bloo d lea d level s belo w 2 0 /tg/dl . Althoug h i t i s difficul t to precisely equat

e bloo d lea

d lead s in differen

t species , th e parallel s betwee n human s and animal s i

n th e developmenta

l neurotoxicit

y o f lea d ar e strikin g in man

y respect s (Davi s e t al. , 1990) . Indeed , th e similarit y of th e anima l findings in th e absenc e o

f socioeconomi c and other comple x variable s tha

t sometime s complicat

e interpretatio n o

f th e huma n data provid e compelling suppor t fo r concluding tha

t lo w leve l lea

d exposur e an d developmenta

l neurotoxicit

y i n children ar e causally relate d an d no t merel y associate d artifactually .

6 2A remainin g issu e i s whethe r th e effect s discusse d here ar e larg e enough t o constitut e a significan t risk t o publi c health . Valuabl e information ha s bee n provide d b y variou s prospectiv e studie s o n th e magnitud e of neurobehaviora

l deficit s relativ e to increment s in bloo d lea d levels . Despit

e differen t approache s t o treatin g their data , thre e of

th e prospectiv e studie s provid e result s suggesting tha t Bayle y MD I score s declin e b y 2- 8 point s fo r approximately ever

y 10-/tg/d l increas e i n bloo d lea

d level . Th e Boston stud

y foun d 4- 8 point difference s in 6 - to 24-mont h MD I score s betwee

n high (mean : 14. 6 /tg/dl ) and lo w (mean : 1. 8 /tg/dl ) cor

d bloo d lea

d groups . Th e Cincinnat

i stud y showe d a s muc h a s a n 8.4-poin t declin e i n boys ' 6-mont

h MD I score s fo

r ever y 10-/tg/d l incremen t in matema

l bloo d lead . Also , th e Por

t Piri e stud y demonstrate d a1.6-poin

t decreas e i n th e 24-mont

h MD I per 1 0 /tg/d l o f

bloo d lea d a t 6 months , and a~3.5-poin t decreas e i n GC I score s fo r ever y 1 0 /tg/d l in averag e postnata l bloo d lead . Th e implication s of

suc h deficit s are mor

e apparen t whe n considere d in populatio n rather tha n individua

l term s (Needleman , 1983 ; Davis , 1990) . Figure 2 illustrate s th e effec t o f shiftin g anorma l distributio n o

f MD I score s downwar

d by 4 points . Th e lighter shaded are a i s 50 % o f th e darker

area , which represent s th e children in apopulatio n wh o scor e 8 0 o r lower . Thus , eve

n a4-poin t shif t in averag e performanc e result s i n aconsiderabl e increas e in subnorma l scores . Sinc e th e MD I ha s astandar d deviatio n of

16 , ascor

e of 8 0 i s on e standar d deviatio n belo w amea

n o f 9 6 an d provide s aconvenien

t referenc e point

fo r illustratio n purposes . However , th e impact of suc h ashif t appUes acros s th e entire distributio n of

scores , reducin g th e numbe r o f children scoring abov e th e nor ma s well a s increasin g th e numbe

r scoring belo w th e nor

m(Weiss , 1988) .

6 3CTl -P . 2 5 -

2 0 X H 5

n o -

I0L , 5

4 0 6 0 8 0 10 0 H20 M O •

J S O Figur e 2 . Norma l distribution s wit h mean s of

9 6 an d 10 0 an d standar d deviation s of 16 . Source : Davi s (1990) .W . REFERENCE S

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, B. ; Jimenez , E . (1987 ) Lead and infan tdevelopmen ti n a developin g country . In : v ' ' Lindberg , S . E. ; Hutchinson , T . C , eds . Internationa l conference : heav y metal s i n th e environment , v . 1 ; September ; Ne w Orleans , LA . Edinburgh , Unite d Kingdom : CEP Consultants , Ltd. ; pp . 165-167 .

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