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Determinant s o f ElevatedBloo dLea ddurin

gPregnancy

i na PopulationSurroundin ga Lea dSmelte r inKosovo , Yugoslavi a Running Head : Determinant s o f Elevate d Bloo d Lead during

Pregnancy Josep hH . Graziano 3 , Dusan Popovac b , Pa m Factor-Litvak a , Patric k Shrout ac , Jenni e Kline ac , MaryJ . Murphy a , Yu-hu a zhao a , Al i Mehmeti d , Gemai l Ahmedi b , Biljana Rajovic d , Zoric a Zvicer b , DragoslavU . Nenezic b , Nanc yJ . LoIacono a , Zena Stein a c

Addres s reprin t request s t o Dr . JosephH . Graziano , Departmen t o f Pharmacology , Columbi a University , Colleg e o f Physician s & Surgeons , Ne wYork , Ne wYor k 10032 . (Tel : 212-305-4001 )

a Columbi a University , Colleg e o f Physician s & Surgeons , Ne wYork , N Y1003 2 bUniversit yo f Pristina Medica l School , Pristina , Yugoslavi a

c Ne wYor k Stat e Psychiatri c Institute , Ne wYork , N Y1003 2 dMedicinsk i Centar , Titova Mitrovica , Yugoslavi aP. 3

Acknowledgement s Wit hfinancia l suppor t fro m th e Nationa l Institut e o f Environmenta l Healt hScience s (RO l ES-03460 ) , th e U . S . Environmenta l Protectio n Agenc y(7D1763NASA) , th e Andre wMello n Foundation , an

d th e Lucill e P . Marke yCharitabl e Trust .P. 4

Abstz-ac t W e air e prospectivel yexamining th e relatio nbetwee nenvironmenta l lead exposur e an

d pregnanc youtcome i ncohort s o f wome nexpose d t o a wid e rang e o f ai r lead concentrations . Titova Mitrovica , Yugoslavia , i s th e sit e o f a larg e lead smelter , refineryan d batteryfactory . A t mid-pregnancy , 60 2 wome n i nT . Mitrovic a an d 90 0 wome n i n Pristina , a non-Pb-expose d contro l town , wer e interviewed . Bloo d wa s obtaine d fo r bloo d lead (BPb ) , hemoglobin , erythrocyt e protoporphyri n (EP ) an d seru mferriti n measurements . Wome n wer e see n agai n a t delivery , a t whic htime materna l an

d umbilica l cord bloo d sample s wer e obtained . Whil e man

ydemographi c an

d socia l characteristic s wer e simila r acros s th e tw o towns , wome ni n Pristina wer e mor e likel yt o repor t employmen t outsid e th e home , cigarett e smoking an d alcoho l us e during pregnancy . A s expected , BPb' s wer e substantiall y highe r i n th e smelte r town . A t mid-pregnancy , BP bgeometri c mean s wer e 17. 1 ug/d l i n T . Mitrovic a an d 5. 1 ug/d l i n Pristina ; 86 % o f th e pregnan t wome ni n T . Mitrovica , compare d t o 3.4 % o f thos e i n Pristina , had BPb' s > 1 0 ug/dl . Withi n T . Mitrovica , distanc e betwee nth e hom e an d th e smelte r wa s th e mos t importan t predicto r o f BP ba t mid-pregnanc yan d delivery . Husband' s employmen t i hth e lead industrywa s associate d wit ha significan t increas e i nmaterna l BPb' s independen t o f plac e o f residence . Highe r materna l seru mP. 5

ferriti n concentration s wer e associate d wit hlowe r BPb's , suggesting tha t dietaryiro n inhibit s lead absorption . Overall , th e placent a wa s a poo r barrie r t o lead ; th e relationshi p betwee n materna l BP ban

d umbilica l cord BP bwa s linea r acros s a wid e rang e o f BPb's .P. 6

Introductio n Th e effect s o f environmenta l lead hav e onl yoccasionall ybee n examine d i nrelatio n t o huma n reproduction , mos t ofte n i n population s wit hextremel yhighexposure . Evidenc e o f possibl e effect s o f lead o n pregnanc yfirs t appeare d i n th e literatur e nea r th e tur no f th e century(1 ) . Wome nemploye d i nth e lead industrywer e reporte d t o hav e mor e miscarriages , stillbirths , prematur e infant s an d neonata l death s a s compare d t o wome ni n othe r occupations . Severa l mor e recen t review s hav e reporte d an exces s o f spontaneou s abortion s among lead-expose d wome n working i n th e printing industryi nItal yan d German

y(2-4) . Nordstrom e t a l (5 ) , i n Sweden , foun d a significantl yincrease d frequency o f spontaneou s abortion s an d lowbirthweigh t infant s (apparentl y intrauterin e growt hretardatio n [IUGR] ) among femal e employee s workin g i na lead smelter . Simila r observation s wer e mad e o n population s living i nclos e proximit yt o tha t smelte r (6 , 7 ) . Needlema n an

d co-worker s hav e describe d a nincrease d rat e o f mino r malformation s among newborn s wit hcord BPb' s o f 8 ug/d l o r mor e (8 ) , th e firs t evidenc e o f suc ha n effec t i n associatio n wit hextremel ylowexposure . Mor e recently , however , a prospectiv e stud

yo f wome n living i nPor t Pirie , a smelte r tow n i n Australia , reporte d n o associatio nbetwee nbloo d lead concentratio n(BPb ) an d spontaneou s abortion , lowbirthweigh t (fo r term

births) , IUGR , prematur e ruptur e o f membranes , an d congenita l anomalie s (9 ) .P. 7

Wit hth e exceptio n o f th e latte r tw o reports , thes e studie s hav e no t adequatel ycontrolle d fo r importan t factor s known t o b e associate d wit hreproductiv e outcomes , suc ha s materna l weight , height , parity , smoking an d socioeconomi c statu s (SES) . Wit h thi s i n mind , w e embarke d upo na prospectiv e stud yo f lead exposur e during pregnanc ywhic hwil l ultimatel yfollowgrowt han d developmen t during earl ychildhood .

W e hav e examine d th e relatio n betwee n environmenta l lead exposur e an d pregnanc youtcome i n cohort s o f wome nexpose d t o relativel y highan d lowai r lead concentrations . Th e Autonomou s Provinc e o f Kosovo , Yugoslavia , i s a mountainou s far mregio ncurrentl yi nth e proces s o f industrializatio ndu e t o it s vas t minera l an d coa l reserves . Alarg e lead smelter , refineryan d batteryfactoryar e majo r element s o f th e econom yo f th e cit yo f Titova Mitrovica , whic hi s approximatel y4 0 k m nort ho f Pristina , th e capito l cit y o f Kosov o (Figur e 1 ) . Survey s conducte d i n 197 8 an d 198 0 foun

d th e populatio no f T . Mitrovic a t o hav e markedl yelevate d BPb' s du e t o industria l ai r lead emission s (10 ) . I ncontrast , lead exposur e i n Pristina i s minimal ; mea nBPb' s i n childre n (10 ) ar e lowe r tha n thos e reporte d fo r U.S . childre n (11) . Thi s pape r ha s tw o objectives . First , w e introduc e th e stud y desig nan

d method s use d i n th e stud yo f pregnanc youtcomes . Second , w e explor e predictor s o f elevate d BP bduring pregnancy . Tw o subsequen t paper s wil l describ e th e actua l pregnanc youtcomeP. 8

\ findings , th e preliminaryresult s o f whic hwer e presente d a t thi s conference . Method s Th e stud

yrecruite d subject s fro m area s i n an

d around th e Yugoslavia ncitie s o f T . Mitrovic a an d Pristina . Nea r th e cente r o f eac htown , ther e i s a singl e out-patien t clini c whic hprovide s routin e prenata l care . Attendanc e i nth e clinic s i s largel y determine d b

ydistanc e fro

mth e home . During th e perio d fro m May , 1985 , throughDecember , 1986 , wome n wh o wer e approximatel y 12-2 0 week s gestatio n wer e invite d t o participat e i nth e study . Sinc e traine d staf f wer e occasionall yunavailable , no t al l wome n wh o came t o th e clini c wer e aske d t o participate . Becaus e o f th e promis e o f a photographo f th e bab ya t birth , th e vas t majorit y o f thos e aske d agree d t o participate . Th e fina l sampl e siz e consiste d o f 90 0 wome ni nPristina an d 60 2 i n T . Mitrovica ; th e unequa l sampl e size s reflec t th e difference s i nth e size s o f th e clinics , Pristin a being th e large r o f th e two .

Tw o predominan t language s ar e spoke n i n th e region : Serbo

Croatia n an

d Albanian . Therefore , a t intak e wome nwer e interviewe d b ya bilingua l nurs e o nsociodemographi c characteristics , medical , reproductive , and occupational historie s o f th e bot hparents , an d cigarett e smoking an d alcoho l consumptio n during pregnancy . Height , weigh t an d bloo d pressur e wer e measured , an d a urin e specime n obtaine d an d examine d fo rP. 9

blood , bilirubin , ketones , sugar , protei n an d pH . Withi n approximatel y1 2 hour s o f delivery , eac hwoma nwa s agai n interviewed . Materna l bloo d an d umbilica l cord bloo d wer e obtaine d fo r four measurement s describe d below . Th e placent a wa s trimme d o f membranes , weighed , an d a piec e froze nfo r subsequen t biochemica l analyses . Atraine d neonatologis t examine d every baby , utilizing a structure d examinatio nfo r gestationa l ag e (12 ) an d malformations . Fo r thos e wome n wh o di d no t delive r i n hospital , a visiting nurs e wa s sen t t o th e hom e t o determin e th e outcome o f th e pregnancy . Bloo d sample s wer e obtaine d a t intak e an d a t deliveryfo r th e measuremen t o f BP b(13) , E P (14) , seru mferriti n(15) , an d hemoglobi nconcentrations . Bloo d specimen s wer e refrigerate d o n sit e an d transporte d o nwe t ic e t o Columbi a Universit y(CU ) wher e al l bloo d analyse s wer e conducted . Th e CUlabparticipate s i n th€ ! CDC' s BP ban

d E P qualit ycontro l programs , an d i s certifie d b yOSHA . Ove r th e cours e o f th e study , agreement s wit hCD C value s fo r BP ban d EP , measure d b yintraclas s correlatio n coefficients , wer e 0.9 5 an d 0.99 , respectively . Addres s locatio n i n relatio nt o th e smelte r serve d a s an indicato r fo r exposur e t o airborn e lead . Zone s wer e define d b y concentri c circle s o f 2 , 4 , 6 an d 8 k mi n radiu s drawn around th e lead smelter-refinerycomple xi nZvecan , a nimmediat e subur bo f 8P.1 0

\ T . Mitrovica ; thes e wer e designate d a s zone s 1 through4 ,

respectivel y(Figur e 1 ) . Th e cit yo f T . Mitrovic a fel l withi n Zon e l . Zon e 5 consiste d o f al l territoryfro m 8 k mo f T . Mitrovic a t o Pristina , whil e zon e 6 wa s Pristina itsel f an d al l area s t o th e south . O f th e 150 2 subject s i n th e study , w e wer e unabl e t o assign a zon e t o 2 4 women . Statistica l Analysis : Th e relationshi p betwee nBP b(a t bot hmid

pregnanc yan

d delivery ) an

d social , demographi c an d biologi c variable s wa s examine d using leas t square s multipl e regressio n analysis . Independen t variable s o f interes t wer e addres s zon e o f residence , husband' s plac e o f employment , an d materna l iro n store s (i.e. , serumferriti n concentrations) ; referenc e categorie s fo r thes e variable s wer e th e Pristin a zon e (zone 6) , employmen t outsid e th e lead industry , an d seru mferriti n> 1 0 ng/ml , respectively . Potentiall yconfounding variable s wer e identifie d a prior i an d assesse d b

yevaluating change s i nth e regressio n coefficient s o f th e independen t exposur e variables . Thes e include d cigarett e smoking , materna l age , ethni c group , an d materna l education . Result s Tabl e 1 compare s demographi c an d socia l characteristic s o f wome n i n th e tw o towns . A t entryt o th e study , th e gestationa l ag e o f wome n i n Pristin a wa s 131. 4 days , a s compare d t o 118. 3 day s i nT . Mitrovica . Wome n i nT . Mitrovic a were , o n average , si xmonth s 9P.1 1

younge r an

d mor e likel yt o b e o f neithe r Serbia n no r Albania n ethnicity . Thei r spouse s wer e o f simila r ag e an d ethnicit yt o spouse s o f wome n i nPristina . Mitrovic a wome n wer e slightl y shorter , a resul t consisten t wit hth e fewe r numbe r o f Albanian s among them . Alcoho l us e (defined a s consumptio no f an yalcoho l during pregnancy ) wa s les s commo n i n T . Mitrovic a (5.1% ) tha n i n Pristin a (9.3%) . I neac htown , o n average , th e wome nhad ha d mor e tha ntw o previou s pregnancies . Mor e wome ni nPristin a reporte d having a joboutsid e th e home , althougho f thos e wit h jobs , comparabl e proportions , abou t 75% , wer e stil l workin g a t th e tim e o f th e interview . Mea n monthl yhousehol d income wa s therefor e slightl ylowe r i n T . Mitrovica . Th e wome n wer e similar , however , wit hrespec t t o othe r measure s o f socioeconomi c status , no t al l o f whic har e shown .

Th e mea n monthl yBPb' s a t intak e i n T . Mitrovic a fluctuate d substantiall yfro

mmonth-to-month , presumabl ya consequenc e o f th e highl yvariabl e industria l lead emissions , an d wer e highe r tha n i n Pristina , wher e theyvarie d littl e (Figur e 2 ) . Th e frequenc ydistributio n o f BPb' s reveale d tha t 86. 0 % o f th e pregnan t wome n i nT.Mitrovica , bu t onl y3.4 % i n Pristina , had BPb' s > 1 0 ug/d l (Figur e 3 ) . Th e geometri c mean s fo r BP bwer e 17. 1 ug/d l i nT . Mitrovic a an d 5. 1 ug/d l i n Pristin a (Tabl e 2) . Elevate d E P concentration s ar e considere d t o b e indicativ e o f lead toxicit yand/o r iro n deficiency . Th e mea n seru mferriti n 1 0P.1 2

concentration , a measur e o f th e adequac yo f tissu e iro nstores , wa s slightl yhighe r i nT . Mitrovic a tha ni nPristina . Despit e th e highe r iro n stores , th e mea nE P wa s elevate d i nT . Mitrovic a (Tabl e 2) , clearl yreflecting some degre e o f metaboli c inhibitio n o f re d cel l hem e synthesi s du e t o lead . Withi n T . Mitrovica , zon e o f residenc e wa s th e mos t importan t predicto r o f elevate d materna l BPb , bot ha t mid-pregnanc y(Tabl e 3 ) an d delivery(Tabl e 4 ) ; BPb' s decline d a s th e distanc e fro m th e smelte r t o th e home increased . Husband' s employmen t i nth e lead smelter , refineryo r batteryfactory , wa s associate d wit han increas e i nadjuste d mea n materna l BPb , bot ha t mid-pregnanc y (Tabl e 3 ) an

d a t term(Tabl e 4 ) , independen t o f addres s zone . Thi s finding i s illustrate d graphicall yi n Figur e 4 . Cigarett e smoking wa s no t a particularl yimportan t predicto r o f BPb , eithe r i n th e entir e stud

ypopulatio no r i nT . Mitrovic a alone .

Materna l educatio n wa s associate d wit hth e BP ba t delivery(Tabl e 4 ) , bu t no t BP ba t mid-pregnanc y(Tabl e 3) . Ethni c grou p wa s an importan t predicto r o f bot hth e mid-pregnanc yan d deliveryBPb's ; Albania n wome n ha d th e lowes t BPb's . W e suspec t tha t th e Albania n custom

o f removing shoe s a t th e entranc e t o th e hom e reduce s th e tracking o f soi l an d dus t lead int o th e home . Th e non-Albania n an

d non-Serbia nwomen , a grou p consisting primaril y o f Gypsies , exhibite d highe r BPb' s tha nth e Albanian s o r Serbian s afte r holdin g constan t othe r variables . 1 1P.1 3

Th e rol e o f nutritiona l factor s o ngastrointestina l Pbabsorptio n ha s bee n addresse d i n earlie r presentation s a t thi s symposiu mb y Drs . Mahaffe y(16 ) an d Ziegle r (17) . W e hav e had th e opportunit y t o examin e tw o nutritiona l factor s i n thes e analyses : iron , a s assesse d b

yseru m ferriti nconcentrations , an d mil k consumptio n during pregnancy . A t mid-pregnancy , wome n wh o had seru mferriti n concentration s o f < 5 ng/m l had significantl yhighe r BPb' s tha n thos e wit hferritin s o f 1 0 ng/m l o r mor e (Tabl e 3) . [WH O consider s 1 0 ng/m l t o b e th e lowe r limi t o f norma l i nnon pregnan t wome n (18)] . B ydelivery , however , a strong dose

respons e effec t wa s observe d (Tabl e 4 ) ; th e highe r th e seru m ferritin , th e lowe r th e BPb . Whe n w e examine d th e influenc e o f mil k consumptio n during pregnanc yo n materna l BPb , th e dat a initiall ysuggeste d tha t BP b wa s positivel yassociate d wit hmil k consumptio n(dat a no t shown) . Thi s associatio npersiste d i nmultipl e regressio nanalyses . W e hypothesize d tha t th e effec t o f mil k woul d b e stronges t i nthos e addres s zone s mos t heavil yexpose d t o lead . However , contraryt o expectations , th e relationshi p betwee nBP ban d mil k consumptio n wa s no t consisten t i n al l addres s zones . Furthe r analysi s showe d tha t thi s apparen t relationshi p wa s du e t o extremel yelevate d BPb' s i n severa l wome n wh o wer e mil k drinkers ; thei r elevate d BPb' s prove d t o b e du e t o othe r factors .

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Finally , w e hav e examine d th e relationshi p betwee nmaterna l BPb a t deliveryan

d th e umbilica l cor d BP bi n88 8 mother-infan t pair s wh o wer e betwee n 2 8 an d 4 4 week s o f gestation . Th e strong relationshi p betwee n materna l BP ban d umbilica l cor d BP b(Figur e 5 ) (slop e = 0.928 , r = 0.920 ) wa s linea r acros s a wid e rang e o f BPb's . Discussio n Becaus e lead readil ydistribute s fro mbloo d int o bone , BP bi s considere d t o b e a marke r o f recen t exposur e t o lead , rathe r tha n tota l bod

ylead burden . I t i s therefor e no t surprising tha t th e BPb' s o f pregnan t wome n i nT . Mitrovic a wer e highes t among thos e residing neares t th e smelter , wher e ai r lead concentration s ar e th e highest . A198 0 surveyo f BP bi n resident s o f zon e 1 reporte d a mea n(arithmetic ) BPbo f 32. 4 ug/d l i n non-pregnan t women , reflecting th e extremel yhighmea n monthl yai r lead concentration s whic hrange d fro m21. 3 t o 29. 2 ug/m 3 (10) ; th e allowabl e concentratio n o f ai r lead i s 0. 7 ug/m 3 i n Yugoslavia . Immediatel yprio r t o th e curren t study , a s a resul t o f th e constructio n o f a ne wsmokestac k an d ai r filtratio n systema t th e smelter , ai r lead concentration s fel l int o th e rang e o f 0. 9 t o 12. 8 ug/m 3 (dat a no t shown) . While , thi s represent s some improvemen t i nai r quality , an d BPb' s hav e decline d somewhat , resident s o f T . Mitrovic a ar e obviousl yexpose d t o unacceptabl y highai r lead levels .

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Th e transfe r o f lead dus t o n th e clothing , ski n an d hai r o f lead

worker s fromworkplac e t o th e home ha s bee ndocumente d a s a majo r sourc e o f hazar d t o childre no f lead worker s (19-21) . W e hav e observe d a ris k o f undu e lead absorptio ni npregnan t wive s o f lead-workers . Thus , sinc e lead freel ycrosse s th e placenta , paterna l employmen t i nth e lead-industrypose s a ris k o f lead exposur e t o th e unbor nchild . W e therefor e urg e th e lead industryt o institut e highl yeffectiv e occupationa l hygien e measure s capabl e o f preventing th e transpor t o f lead fro mth e workplac e int o th e home . Among ou r subject s i nT . Mitrovica , wive s o f batteryworker s ha d highe r BPb' s tha n thos e o f smelte r o r refineryworkers .

I n hi s presentatio n a t thi s symposium , Dr . Ziegle r ha s correctl y pointe d ou t tha t nutritiona l supplementatio ni s no t a "solution " t o th e problemo f undu e lead absorptio n(17) . Ou r finding concerning th e apparen t protectiv e effec t o f adequat e iro nstore s agains t lead absorption , however , shoul d no t b e overlooked . Clearly , certai n subset s o f th e population , suc ha s pregnan t wome n an

d childre n o f lowSES , requir e iro nsupplementatio n simpl yt o preven t th e syndrome o f iro ndeficiency . Thos e same subsets , however , ar e mos t a t ris k fo r th e consequence s o f undu e lead absorption . Sinc e iro n deficienc yincrease s th e ris k fo r elevate d lead absorption , th e healt hcar e systemcoul d reduc e th e prevalenc e o f elevate d BP bb yredoubling it s effort s t o preven t iro n deficienc yi n population s a t risk . Baghurs t and co-workers , 1 4P.1 6

i n a stud

yo f pregnan t wome n living nea r th e Por t Piri e lead smelter , hav e previousl yreporte d tha t wome nwh o receive d iro n supplementatio n during pregnanc yhad lowe r BPb' s tha nthos e no t supplemente d (22) . Observation s mad e mor e tha na centuryag o suggeste d tha t mil k consumptio n prevente d th e occurrenc e o f plumbis mi nworker s i n th e white-lea d industr y(23) . Sinc e tha t time , anima l studie s hav e reveale d tha t some component s o f milk , suc ha s lactos e (24

- 27 ) an d fa t (24 , 28) , increas e gastrointestina l lead absorption , whil e others , suc ha s calciu m(29) , decreas e absorption ; th e Por t Piri e stud

yha s reporte d lowe r mea nBP bamong wome nwh o consume d les s tha n50 0 mg dietarycalcium/dayi ncompariso nt o thos e wh o consume d large r amount s (22) . T o ou r knowledge , th e presen t stud yrepresent s th e firs t attemp t t o examin e th e influenc e o f mil k consumptio n o n BP bi n humans . Th e failur e o f thi s stud yt o documen t a n associatio n betwee n mil k consumptio nan d BP bsuggest s tha t th e effect s o f th e biochemica l constituent s o f mil k o nlead absorptio nmaycounterac t eac hother .

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- 57 0 (1976) . 4 . Hamilton , A. , an d Hardy , M.L . Lead , Xn , Industria l Toxicology . Publishing Science s Group , Littleto n Mass. , 1974 , pp . 85-121 . 5 . Nordstrom , S. , Beckman , L. , an d Nordenson , I . Occupationa l an d environmenta l risk s i n an d around a smelte r i n norther n Sweden . V . Spontaneou s abortio namong femal e employee s an d decrease d birt hweigh t i n thei r offspring . Heredita s 90 : 291

- 29 6 (1979) . 6 . Nordstrom , S. , Beckman , L. , an d Nordenson , I . Occupationa l an d environmenta l risk s i n an d around a smelte r i nnorther n Sweden . I . Variation s i n birt hweight . Heredita s 88 : 43-4 6 (1978) .

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7 . Nordstrom , S. , Beckman , L. , an d Nordenson , I . Occupationa l an d environmenta l risk s i nan d around a smelte r i n norther n Sweden . III . Frequencie s o f spontaneou s abortion . Heredita s 88 : 51-5 4 (1978) . 8 . Needleman , H.L. , Rabinowitz , M. , Leviton , A. , Linn , S. , an d Schoenbaum , S . Th e relationshi p betwee nprenata l exposur e t o lead an d congenita l anomalies . J . Amer . Med . Assoc . 251 : 2956

- 295 9 (1984) . 9 . McMichael , A.J. , Vimpani , G.V. , Robertson , E.F. , Baghurst , P.A. , an

d Clark , P.D . Th e Por t Piri e cohor t study : materna l bloo d lead an

d pregnanc youtcome . J . Epidemiol . Comm . Healt h40 : 18-2 5 (1986) . 10 . Popovac , D. , Graziano , J. , Seaman , C , Kaul , B. , Colakovic , B. , Popovac , R. , Osmani , I. , Haxhiu , M. , Begraca , M. , Bozovic , Z. , an d Mikic , M . Elevate d bloo d lead i n a populatio nnea r a lead smelte r i n Kosovo , Yugoslavia . Arch . Environ . Healt h37 : 19-2 3 (1982) . 11 . Mahaffey , K.R. , Annest , J.L. , Roberts , J. , an d Murphy , R.S . Nationa l estimate s o f bloo d lead levels : Unite d State s 1976

- 1980 . Associatio n wit hselecte d demographi c an d socioeconomi c factors . N . Eng . J . Med . 307 : 573-57 9 (1982) .

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12 . Ballard , J.L. , Novak , K.K. , an d Driver , M . Asimplifie d scor e fo r assessmen t o f feta l maturatio n o f newl ybor ninfants . J . P€id . 95 : 769-77 4 (1979) . 13 . Fernandez , F. , an d Hilligoss , D . An improve d graphit e furnac e metho d fo r th e determinatio n o f lead i n bloo d using matri xmodificatio nan d th e L'vovplatform . Atomi c Spectr . 3 : 130-13 1 (1982) . 14 . Piomelli , S . Amicrometho d fo r fre e erythrocyt e porphyrins : Th e FE P test . J . Lab . Clin . Med . 81 : 932-94 0 (1973) . 15 . Miles , L.E.M. , Sipschitz , D.A. , Bieter , C.P. , Cook , J.D . Measuremen t o f seru mferriti n b

ya 2-sit e immunoradiometri c assay . Anal . Chem . 61 : 209-22 4 (1974) . 16 . Mahaffey , K . Referenc e th e presentatio na t thi s sypmosium . 17 . Ziegler , E . Referenc e th e presentatio na t thi s symposium . 18 . Worl d Healt hOrganizatio n (WHO) . Contro l o f nutritiona l anaemi a wit hspecia l reference s t o iro ndeficiency . WH O technica l repor t serie s 58 0 (1975) .

1 819 . Baker , E.L . Jr. , Folland , D.S. , Taylor , T.A. , Frank , M. ,

Peterson , W. , Lovejoy , G. , Cox , D. , Houseworth , J. , an d Landrigan , P.H . Lead poisoning i nchildre no f lead workers : hom e contaminatio n wit hindustria l dust . N . Eng . J . Med . 296 : 260-26 1 (1977) . 20 . Morton , E. , Saah , A.J. , Silberg , S.L. , Owens , W.L. , Roberts , M.A. , an

d Saah , M.D . Lead absorptio ni nchildre no f employee s i n a lead-relate d industry . Amer . J . Epidemiol . 115 : 549-55 5 (1982) . 21 . Moore , M.R . Source s o f lead exposure , In , Lead Toxicity : Historyan

d Environmenta l Impac t (R . Lansdown , an d W . Yule , eds.) , Th e John s Hopkin s Universit yPress , Baltimore , 1986 , pp . 168-177 . 22 . Baghurst , P.A. , McMichael , A.J. , Vimpani , G.V. , Robertson , E.F. , Clark , P.D. , an d Wigg , N.R . Determinant s o f bloo d lead concentration s o f pregnan t wome nliving i nPor t Piri e an d surrounding areas . Med . J . Australi a 146 : 69-7 3 (1987) . 23 . Tanquere l de s Planches , L . Lead Diseases : ATreatise . Wit hNote s an

d Addition s o n th e Us e o f Lead Pip e an d Substitutes . Translate d b

yS.L . Dana , Danie l Bixb yan d Co. , Lowel l Mass. , 1848 , pp . 333-334 . 1 9P.2 1

24 . Stephens , R. , an d Waldron , H.A . Th e influenc e o f mil k an d relate d dietaryconstituent s o nlead metabolism . Foo d Cosmet . Toxicol . 13 : 555-56 3 (1975) . 25 . Bell , R.R. , an d Spickett , J.T . Th e influenc e o f mil k i nth e die t o n th e toxicit yo f orall yingeste d lead i n rats . Foo d Cosmet . Toxicol . 19 : 429-43 6 (1981) . 26 . Bushnell , P.J. , DeLuca , H.F . Lactos e facilitate s intestina l absorptio n o f lead i n weanling rats . Scienc e 211 : 61-6 3 (1981) . 27 . Bushnell , P.J. , DeLuca , H.F . Th e effect s o f lactos e o nth e absorptio n an

d retentio n o f dietarylead . J . Nutr . 113 : 365

- 37 8 (1983) . 28 . Barltrop , D. , an d Khoo , H.E . Th e influenc e o f nutritiona l factor s o n lead absorption . Postgrad . Med . J . 51 : 795-80 0 (1975 ) . 29 . Mahaffey-Six , K. , Goyer , R . A . Experimenta l enhancemen t o f lead toxicit yb

ylowdietarycalcium . J . Lab . Clin . Med . 76 : 933-94 1 (1970) .

2 0Tabl e 1 : Characteristic s o f the Populations *

Numbe r o f Wome ni nStud y Gestatio n a t Intervie w (days ) Materna l Ag e (yrs ) Paterna l Ag e (yrs ) Materna l Ethnicity : % Albania n % Serbia n % Othe r Paterna l Ethnicity : % Albania n % Serbia n % Othe r Materna l Weigh t (kg ) Materna l Heigh t (cm ) % Cigarett e Smoker s % Alcoho l User s T . Mitrovic a

118. 3 26. 4 30. 5 56. 2 25. 3 18. 5 59. 4 25. 0 15. 5 63. 5 159. 3 24. 8 5. 1 60 2 (26.0 ) (5.3 ) (6.1 )

(10.9 ) (7.4 ) Pristin a

131. 4 26. 9 30. 5 61. 2 24. 8 14. 0 61. 8 22. 9 15. 3 63. 9 161. 6 28. 3 9. 3 90 0 (29. 6 (5.0 ) (5.7 )

(10.2 ) (5.9 )

Numbe r o f Previou s Pregnancie s % Wit ha Jo b % Workin g during Pregnancy

b Materna l Educatio n (yrs ) Paterna l Educatio n(yrs ) Monthl yIncome i n Hom e (U.S . dollars) 0 2. 1 (2.2 ) 32. 5 76. 4 8. 9 (4.2 ) 11. 7 (2.8 ) 2. 3 (2.4 )

45. 6 75. 8 9. 0 (4.1 ) 11. 4 (3.1 ) 237. 7 (161.8 ) 259. 9 (176.1 ) Typ e o f Home : % Hous e % Apartmen t % Far m % Ownin g Thei r Home s 50. 6 27. 0 22. 5 29. 6 64. 8

20. 7 14. 5 26. 3

a Dat a ar e mean s + standard deviatio n(sd ) bO f thos e wit ha jo b c I n orde r t o adjus t fo r inflation , th e mea n monthl ydina r income wa s converte d t o U.S . dollar s using th e rat e effectiv e during th e mont ho f th e interview . 2 1P.2 3

Tabl e 2 : Hematologi c Finding s a t Mid-Pregnancy 3 Mitrovic a Pristin a BP b(ug/dl ) 17. 1 (6.9 , 42.6 ) 5. 1 (2.5 , 10.6 ) E P (ug/dl ) 36. 0 (9.9 , 130.3 ) 25. 4 (10.4 , 61.7 ) Seru m ferriti n(ng/ml ) 14. 1 (2.0 , 98.0 ) . 11. 5 (1.5 , 88.3 ) Hemoglobi n (g/dl ) 12. 4 (10.3 , 14.5 ) 12. 3 (10.0 , 14.7 )

a Dat a fo r BPb , E P an d seru mferriti n ar e geometri c mean s (95 % confidenc e intervals) . Geometri c mean s wer e calculate d a s 1/ n [logi o (xi ) + logi 0 (x 2 ) +...+logi p (x n )] . Th e mean s fo r hemoglobi n concentration s ar e arithmetic .

2 2Tabl e 3 : Regressio nMode l fo r th e Predictio n o f Mid-Pregnanc y

Bloo dLea dConcentration 3 P.2 4

Variabl e Estimat e S.E . 95 % C.l J p valu e Addres s Zone : < 2 kmv s Pristin a 0.555 5 2- 4 km v s Pristin a 0.450 6 4- 6 km v s Pristin a 0.391 3 6- 8 km v s Pristin a 0.408 5 >= 8 km v s Pristin a 0.107 2 Husban d Employe d i n th e Lea d Industry : Ye s v s N o 0.049 1 Ethni c Group : Serbia nv s Albania n 0.033 5 Othe r v s Albania n 0.043 3 Seru m Ferritin : <5. 0 v s >=10. 0 0.025 5 5.0-9. 9 v s >=10. 0 0.007 8 .011 5 .5780,.533 0 <.000 1 .031 1 .5116,.389 6 <.000 1 .024 0 .4383,.344 3 <.000 1 .031 9 .4710,.346 0 <.000 1 .016 6 .1397,.074 7 <.000 1

.016 0 .0805,.017 7 .002 2 .011 1 .0553,.011 7 .002 5 .013 2 .0692,-017 4 .001 0 .012 3 .0496,.001 4 .039 3 .011 5 .0303,-.014 7 .496 1 Intercep t 0.670 7 Mode l N= 145 2 Mode l R 2 = 69.1 % lo g (bas e 10 ) o f bloo d lea d (ug/dl ) adjuste d t o hemoglobi n o f 12. 0 (g/dl ) confidenc e interva l

2 3Tabl e 4 : Regressio nMode l fo r th e Predictio no f Materna l Bloo dLea dConcentratio na t Variabl e Addres s Zone : < 2 km v s Pristin a 2- 4 km v s Pristin a 4- 6 km v s Pristin a 6- 8 km v s Pristin a >= 8 km v s Pristin a Husban d Employe d i n th e Lea d Industry : Ye s v s N o Ethni c Group : Serbia n v s Albania n Othe r v s Albania n Cigarett e Smoking : Ye s v s N o Materna l Age : Materna l Education : Seru m Ferriti n a t Delivery : <5. 0 v s > = 10. 0 5.0-9. 9 v s > = 10. 0 Intercept : Mode l N= 98 9 Mode l R 2 = 75.5 % Estimat e 0.577 8 0.535 7 0.465 8 0.498 5 0.160 2

0.041 6 0.036 1 0.061 1 -0.019 3 0.002 8 0.003 0

0.052 7 0.033 1 0.703 5

3 lo g (bas e 10 ) o f bloo d lea d 12. 0 (g/dl ) " confidenc e interva l S.E . .012 5 .038 2 .027 1 .039 2 .019 9

.017 1 .012 5 .016 1 .011 8 .001 1 .001 4

.012 8 .012 1 Delivery 3

95 % C.I.f e .6023,.553 3 .6106,.460 8 .5189,.412 7 .5753,.421 7 .1992,.121 2

.0751,.008 1 .0606,.011 6 .0927,.029 5 .0038,-.042 4 .0050,.000 6 .0057,.000 3

.0778,.027 6 .0568,.009 4 p valu e

<.000 1 <.000 1 <.000 1 <.000 1 <.000 1

.015 0 .004 0 .000 2 .101 6 .009 9 .015 0

<.000 1 .006 4

(ug/dl ) adjuste d t o hemoglobi n o f

2 4 \ \

• r 1



### iLegend s t o Figures :

Figur e 1 : Th e Autonomou s Provinc e o f Kosovo , Yugoslavia . Zone s o f residenc e wer e define d b yth e concentri c circle s o f 2 , 4 , 6 an d 8 k mi nradiu s draw n aroun

d th e lead smelter/refinery complex ; thes e wer e designate d a s zone s 1 throug h4 , respectively . Th e cit yo f T . Mitrovic a fel l withi n Zon e 1 . Zon e 5 consiste d o f al l territoryfro m8 k m o f T . Mitrovic a t o Pristina , whil e zon e 6 , th e referenc e zone , wa s Pristin a itself . Figur e 2 : Mea n mid-pregnanc yBP b(ug/dl ) o f wome nrecruite d int o th e stud

yduring th e month s o f May , 198 5 throughJanuary , 1987 . Eac hpoin t represent s a differen t grou p o f women , i.e. , thos e recruite d during tha t month . Figur e 3 : Frequenc ydistributio no f mid-pregnanc yBPb' s (ug/dl ) fo r subject s i nPristina ( N= 900 ) an d T . Mitrovic a ( N= 602) . Figur e 4 : Mea nBPb' s (ug/dl ) o f wome n residing i nzone s 1 through6 ; se e legen d t o Figur e 1 fo r zon e definitions . withi n eac hzone , wive s o f lea dworker s had highe r mea n BPb' s tha nwive s o f non-lea d workers . Figur e 5 : Astrong linea r relationshi p wa s observe d betwee n materna l BP ba t deliveryan d umbilica l cor d BP b( N= 888 , slop e = 0.928 , r = 0.920) .

2 5P.2 7

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