P. 1


### VII-4 1 Tabl e 7-11

. Maximu m Individua l Bloo d Lea d Level s fo r99.5 % o f Childre n Unde rDifferen tAi rLea d Levels , Base d o n Mea n Pb B Prediction s fro m C

O Disaggregat e Mode l (se e Tabl e 7-10 ) an d Assumin g Differen tGeometri cStandar d Deviation s

Predicte d Geometri c Ai r Lea d Mea nPb B Maximu mPb B (ug/dl ) (ug/m 3 ) (ug/dl ) GS D K 3 4 1.3 9 0 4.4 2 9. 4 10. 3 0.2 5 6.4 9 13. 8 15. 1 0.5 0 8.5 1 18. 1 19. 9 0.7 5 10.6 2 22. 5 24. 8 1. 0 12.6 9 26. 9 29. 6 1.2 5 14.7 6 31. 3 34. 4 ^ 5 0 16.8 2 35 J 3JK 2 d ) Summar yo f Predicte d Pb B Level s unde r Alternativ e Ai r Lea d Level s Tabl e 7-1 2 present s th e variou s estimate s o f Pb B level s fo r childre n (bot hmea nand individua l maximu mfo r 99.5 % o f th e population ) unde r differen t averag e (monthl yo r quarterly ) ai r lea d level s base d o n th e thre e modelin g approache s discusse d i n thi s sectio nand o n th e assumptio n tha t th e populatio nGS D i s a constan t betwee n1.3 4 and 1.39 . I t mus t b e emphasize d tha t fo r presen t purposes , eac ho f th e ai r lea d level s ar e considere d constant . I n reality , i f al l area s ar e i n attainmen t wit ha standard , ai r lead level s ar e generall ybelo wth e standar d s o thes e result s ma yb e interprete d a s conservative . Analyse s ar e underwa yt o bette r represen t actua l exposure s i n th e futur e unde r alternativ e lead NAAQS . Th e range s o f Pb B estimate s unde r eac hai r lea d leve l reflec t th e difference s amon g th e availabl e modelin g approaches . Eve nwithi nth e individua l approaches , ther e ar e range s o f estimate s fo r bot hestimate d mea nPb B level s and estimate d individua l maximu mPb B level s amon g 99.5 % o f th e population . Thi s reflect s th e uncertaint ysurroundin g manyo f th eTabl e 7-12 . SUMMARYO F ESTIMATE D BLOO D LEAD LEVEL S UNDE RDIFFEREN T AI RLEAD LEVEL S USINGTHRE E MODELLIN GAPPROACHES 3

Mode l 0.2 5 Ai rLea d Leve l (tig/m 3 ; monthl yo rquarterl yaverage ) 0. 5 0.7 5 1. 0 1.2 5 1. 5 Integrate d Uptake / Biokinetic b Urban /

Rural : Poin t Source : 4.0-4. 4

(1.9 ) 5.9-6. 5 (2.8 ) 7.9-8. 6

(3.7 ) 12.1-13. 3

(5.7 ) 16.3-18. 0

(7.7 ) 21.0-23. 1

(9.9 ) 14.0-15. 4 (6.6 ) 18.9-20. 8

(8.9 ) 23.6-25. 9

(11.1 ) 31.8-35. 0

(15.0 ) 24.2-26. 6

(11.4 ) 35.8-39. 4 (16.9 ) Aggregat e Model c 11.5-18. 9 (5.4-8.1 ) 13.6-22. 4

(6.4-9.6 ) 15.7-25. 9

(7.4-11.1 ) 17.8-29. 4

(8.4-12.6 ) 20.0-32. 9

(9.4-14.1 ) 22.1-36.4

(10.4-15.6 ) Criteri a Documen t Disaggregat e Model d 13.8-15. 1 (6.49 ) 18.1-19. 9

(8.51 ) 22.5-24. 8

(10.62 ) 26.9-29. 6

(12.69 ) 31.3-34. 4

(14.76 ) 35.7-39. 2

(16.82 ) r

o

a Pb B level s ar e give n i n jjg/d l an d represen t th e estimate d level s (usin g specifie d GSDs ) tha t 99.5 % o f childre n wil l no t excee d fo r a give n ai r lead level . Estimate d populatio n mea n Pb B level s ar e give n i n parentheses . b Rang e o f Pb B level s represen t bes t estimate s fo r individua l childre n ( 2 year s old ) livin g i n eithe r genera l urban/rura l area s o r withi n 2- 5 k mo f a lea d poin t sourc e and reflec t rang e o f GSD s use d (1.34-1.39 ) t o conver t populatio n mea n Pb B level s int o 99.5 % maximumindividua l levels .
c Ranq e o f Pb B level s reflect s rang e o f possibl e value s fo r differen t parameters : Blood/ai r lea d slop e ug/m 3 ) ; non-ai r Pb B contributio n (4.4-6. 6 ng/dl) ; GS D (1.3 4 - 1.39) . (4- 6 yg/d l pe r

d Rang e o f Pb B level s (fo r 2 yea r ol d children ) reflect s rang e o f GSD s use d (1.3 4 - 1.39 ) t o conver t populatio n mea n Pb B level s int o 99.5 % maximu mindividua l levels .P. 3

VII-4 3 parameter s use d i nth e separat e models , a s wel l a s actua l variabilit yi n thes e parameters . Fo r example , range s o f averag e absorptio n rates , hour s spen t outdoors , and soi l and dus t concentration s wer e necessar yi n th e integrate d uptake/biokineti c mode l t o captur e th e physiologica l and behaviora l variabilit yamon g childre nand significan t variabilit yand uncertaint y surroundin g th e relationshi p betwee nai r lea d and soil/dus t lea d levels . I naddition , th e futur e impact s o f th e recen t revision s t o EPA' s lead-in-gasolin e phasedow nschedul e o n atmospheri c lea d contribution s t o dietar ylea d consumptio n wer e necessar yt o projec t unde r alternativ e ai r lea d levels . A s discussed , th e Pb B estimate s tha t ar e presente d fo r th e integrate d uptake/biokineti c mode l fo r childre nlivin g i ngenera l urban/rura l area s and nea r poin t source s ar e th e lowe r boun d estimate s fro m thi s mode l tha t ar e considere d b yth e staf f t o b e bes t estimate s give nth e availabl e dat a and th e necessar y assumption s use d i nth e model . (Individua l Pb B level s tha t woul d no t b e exceede d fo r 99.5 % o f th e populatio ngive ndifferen t populatio nmea n Pb B level s wer e calculate d fo r th e integrate d uptake/biokineti c mode l usin g th e sam e procedur e (an

d th e sam e GS D value s o f 1.3 4 t o 1.39 ) presente d previousl y i nthi s section) . Bot hepidemiologica l approaches , th e aggregat e and disaggregat e models , rel yo n estimate s o f bloo d lead/ai r lea d slopes , non-ai r Pb B contributions , an d GSDs , al l o f whic hcontai nrange s o f inter

pretations . A s i nth e integrate d uptake/biokineti c model , thes e epidemio

logica l model s attemp t t o accoun t fo r th e contributio n o f ai r lea d vi a al l exposur e pathway s and t o adjus t non-ai r Pb B contribution s accordin g t o recen t and futur e trend s i nvariou s source s (e.g. , canne d food , pain t lead) . Fo r eac hai r lea d level , th e protectio npredicte d b yth e thre e model s i s comparable . Fo r example , th e integrate d lea d uptake/biokineti c mode l estimate s that , assumin g a GS D betwee n1.3 4 and 1.39 , a nai r lea d leve l o f 0.7 5 ug/m 3 woul d resul t i nPb B level s n o highe r tha n 20. 8 ug/d l amon gP. 4

VII-4 4 2-yea r ol d childre nwithou t excessiv e exposure s t o non-atmospheri c lea d (e.g. , pain t chips) . Similarly , usin g th e mos t conservativ e parameter s i n th e "aggregated " blood/ai r lea d slop e mode l (i.e. , blood/ai r lea d slop e o f 6 , non-ai r lea d o f 6. 6 yg/dl , GS D o f 1.34) , a 0.7 5 yg/m 3 ai r lea d leve l woul d protec t 99.5 % o f childre nfro m exceein g 25. 9 yg/dl , whil e usin g intermediatel yconservativ e parameter s (i.e. , blood/air lea d slop e o f 5 , non-ai r lea d o f 4.4 , GS D o f 1.34 ) result s i n a maximu mPb B o f 19. 0 yg/dl . I ncomparison , th e criteri a document' s estimate s yiel d maximu m individua l Pb B level s (fo r 99.5 % o f children ) betwee n22. 5 and 24. 8 yg/d l fo r an ai r lea d leve l o f 0.7 5 yg/m 3

. I t ca n b e conclude d tha t unles s th e leas t conservativ e parameter value s ar e assume d i n th e aggregat e epidemiologica l mode l (i.e. , aggregat e blood/ai r slop e o f 4 , non-ai r Pb B contributio n o f 4. 4 yg/dl ; se e Tabl e 7- 8 and 7-9) , th e model s predic t tha t i f th e curren t lea d NAAQ S leve l wa s jus t me t s o tha t th e averag e ai r lea d concentratio n wa s a constan t 1. 5 yg/m 3 , som e fractio nwithi nth e 99.5 % o f childre nwoul d no t b e protecte d fro m exceedin g 2 5 yg/dl , assumin g a constan t GS D betwee n1.3 4 and 1.3 9 fo r th e entir e distributio no f bloo d lea d levels . I nfact , i f 2 0 yg/d l i s determine d t o b e th e maximu macceptabl e Pb B fo r anindividua l child , regardles s o f whic h modelin g approac hi s accepted , a n ai r lea d leve l n o highe r tha n1.2 5 yg/m 3 woul d b e require d t o protec t 99.5 % o f th e population , i f tha t ai r lea d leve l
wa s constan t and assumin g th e sam e "constan t GSD " range . Shoul d onl yon e modelin g approac hb e accepte d a s providin g reliabl e estimates , thes e prediction s woul d b e revise d accordingly . Fo r example , i f onl yth e criteri a document' s disaggregat e mode l i s considered , assumin g a constant GS D o f 1.3 4 - 1.39 , anai r lea d leve l n o highe r tha n 0.7 5 yg/m 3 woul d b e require d t o protec t 99.5 % o f childre n fro mexceedin g 2 5 yg/dl , and
n o highe r tha n 0. 5 yg/m 3 i norde r t o protec t agains t Pb B level s abov e 2 0 yg/dl . Roughl ysimila r prediction s fo r ai r lea d level s o f 0. 5 t o 0.7 5P. 5

VII-4 5

ug/m 3 tha t ar e jus t a t attainmen t woul d b e mad e usin g onl yth e aggregat e epidemiologica l model . However , th e aggregat e epidemiologica l mode l and th e integrate d uptake/biokineti c mode l predic t tha t a t highe r ai r lea d level s somewha t greate r protectio nma yb e provide d compare d t o th e disaggregat e model . Fo r example , accordin g t o th e uptake/biokineti c mode l a leve l possibl y a s hig ha s 1. 0 yg/m 3 woul d b e sufficien t t o protec t childre nlivin g nea r poin t source s fro m

exceedin g Pb B level s o f 2 5 yg/m 3 , an d tha t 1. 0 yg/m 3
ma yprotec t 99.5 % o f childre nlivin g awayfro mpoin t source s fro mPb B level s abov e 2 0 yg/m 3 i f th e ai r level s wer e jus t met , assumin g a constan t GS D betwee n1.3 4 an d 1.39 . I f onl yth e leas t conservativ e paramete r value s ar e assume d i nth e aggregat e epidemiologica l model , a nai r lea d leve l tha t i s jus t attaine d a t th e curren t standar d leve l o f 1. 5 yg/m 3 ma yprotec t 99.5 %
o f childre nfro m

exceedin g 2 5 yg/m 3 , whil e a leve l jus t attaine d a t 1.2 5 yg/m 3
ma yb e protectiv e agains t Pb B level s abov e 2 0 yg/m 3

. I norde r t o protec t agains t Pb B level s abov e 1 5 yg/dl , anai r lea d leve l tha t i s jus t attaine d
a t n o highe r tha n0. 5 yg/m 3 woul d b e required , regardles s o f whic hmode l i s accepted , assumin g GSD s i nth e rang e o f 1.3 4 and 1.39 . Finally , i f th e percentag e o f th e populatio nt o b e protecte d i s change d fro m99.5 % t o 99.0 % o r 99.9% , fo r example , o r th e GS D valu e tha t i s use d change s t o 1.4 7 t o reflec t th e overal l valu e fo r a heterogeneou s populatio n th e abov e calculation s woul d b e revise d accordingly . e ) Alternativ e Statistica l Approac ht o Estimat e Bloo d Lea d Distribution s • Th e thre e exposur e model s use d i nthi s sectio nt o predic t th e Pb B level s associate d wit hvariou s ai r lea d level s wer e designe d t o estimat e mea nbloo d lea d level s o f hypothetica l population s give nth e availabl e dat a and assumption s use d i neac ho f th e models . I ngeneral , thes e model s di d no t attemp t t o accoun t fo r change s i nPb B level s amon g childre nexpose d t o ver yhig hlevel sP. 6

VII-4 6

o f lead , typicall yfro mlea d i npaint . Give n a populatio n geometri c mea n PbB , th e 99. 5 percentil e o f eac ho f th e bloo d lea d distribution s fo r thes e population s wa s the ncalculate d usin g geometri c standar d deviation s (GSDs ) derive d fro mNHANE S I I i norde r t o estimat e th e degre e o f protectio nagains t alternativel yconsidere d individua l Pb B level s determine d t o b e associate d wit hsom e healt hris k (i.e. , 1 0 t o 2 5 ug/dl) . Thi s approac hha s bee nquestione d i ntha t th e distributio no f Pb B level s i nchildre ni s reall yth e su mo f tw o distributions , on e fro mgenera l exposur e t o ai r lead , foo d lead , etc. , and on e fro m ver yhig hexposur e t o lea d pain t o r othe r hig hconcentratio nsource s (Schwartz , 1985) . Give n tha t th e su m o f lognorma l distribution s i s no t lognormal , error s coul d b e introduce d b y tryin g t o fi t a distributio na t hig hlevel s usin g on e overal l GSD . Sinc e on e woul d no t expec t th e Pb B level s o f highl yexpose d childre n t o fal l pro portionatel ya s th e mea n Pb B leve l falls , th e underestimat e o f th e "fatness " o f th e tai l woul d b e expecte d t o increas e a s th e mea n Pb B leve l fel l (Schwartz , 1985) . Thi s theoretica l poin t i s supporte d b yth e CD C and NCH S analysi s o f NHANE S I I dat a i nwhic hth e sampl e wa s divide d int o tw o periods , befor e and afte r th e increas e i n th e rat e o f chang e o f Pb B level s (Annes t e t al. , 1983) . Fo r th e secon d period , th e GS D o f bot hblac k and whit e children' s Pb B level s wa s approximatel y1.43 . However , th e GS D tha t correctl ypredicte d th e percen t o f childre nabov e 3 0 ug/d l wa s 1.54, i.e. , th e extrem e tai l i s fatte r tha npredicte d b yth e GS D tha t bes t fit s th e entir e distribution . Moreover , th e differenc e i nthes e GSD s wa s large r i n th e secon d period , whe nmea n Pb B level s wer e lowe r tha ni t wa s i nth e firs t period , indicatin g tha t th e erro r increase s a s th e mea nPb B leve l fall s (Schwartz , 1985) . Thus , i t i s possibl e tha t b yusin g a constan t GS D fo r anentir eP. 7

VII-4 7 distributio ni nsettin g a lea d NAAQS , th e numbe r o f childre ni nth e tai l
o f th e cumulativ e distributio nfunctio na t hig hPb B level s woul d b e under

predicted , and tha t th e error s associate d wit hestimatin g thei r Pb B level s woul d chang e wit hth e mea nPb B level . Analternativ e approac htha t ha s bee npropose d relie s o na logisti c regressio nanalysi s o f ho wth e percentage s o f childre ni n NHANE S I I wh o wer e abov e 1 5 ug/dl , 2 0 ug/dl , and 2 5 ug/d l varie d wit hth e mea no f th e lo g o f children's bloo d lead s fo r eac hstudyquarte r (Schwartz , 1985) . Thi s approac hmake s n o assumptio nabou t th e shap e o f th e distributio n curve , bu t merel yfit s th e tai l are a a t th e appropriat e cutof f (e.g. , 2 0 o r 2 5 ug/dl )
an d therebyavoid s th e proble mo f usin g a constan t GS D a s wel l a s incorporatin g th e actua l NHANE S I I dat a o nchildre nabov e thos e alternativ e targe t levels . Th e result s ar e showni nTabl e 7-13 . Usin g th e result s o f thi s analysis , i t i s possibl e t o calculat e th e mea nPb B leve l tha t correspond s t o a give n choic e o f critical ' lea d leve l and a give n fractio n o f th e populatio nt o b e hel d belo wtha t critica l level . Fo r example , i f th e critica l leve l i s 2 0 ug/d l and th e critica l fractio ni s 99.5 % o f th e children , th e followin g equatio ni s used : l n(p/l-p ) = "15.50 6 + 5.24 6 mea nl n (lead ) fo r th e 99.5 % level , p = 0.00 5 and p/(l-p ) = 0.00502 5 yieldin g -5.293 3 = "15.50 6 + 5.24 6 mea nl n(lead ) whic hca nb e solve d fo r th e geometri c mea n Pb B level . Tabl e 7-1 4 compare s estimate d mea nPb B level s usin g thi s regressio n analysi s t o thos e presente d i nTabl e 7- 6 derive d b yusin g th e rang e o f constan t GSD s presente d i nth e C D an d derive d fro m NHANE S I I fo r eac hcritica l targe t PbB , assumin g tha t 99.5 % protectio ni s th e goal . A s discussed , th e thre e modelin g approaches presente d earlie r i n thi s sectio nestimate d th e populatio n mea nPb B level s predicte d unde rTabl e 7-13 . RESULT S O F LOGISTI C REGRESSIO NANALYSI S O F NHANE S I I DATA

Probabilit yo f bein g over : Coefficien t Intercept/Mea n Ln (Lead ) Standar d Erro r Intercept/Mea n Ln (Lead ) t-Statisti c Intercept/Mea n L n (Lead )
1 0 ug/d l 1 5 pg/d l 2 0 pg/d l 2 5 pg/d l _ a •13.41 8 /

4.99 8 -15.50 6 /

5.24 2 •16.20 2 /

5.05 3 _ a 0.81 8 / 0.30 4 1.12 3 / 0.40 9 1.75 7 / 0.63 6 _ a 9.2 2 / 7.9 4 13.8 1 / 12.3 3 16.4 0 / 16.4 4

a Give n th e limite d sampl e size , a stabl e estimat e coul d no tb e calculated

. Source : Schwartz , 1985

. Tabl e 7-14

. POPULATION MEA N BLOO D LEA D LEVEL S (pg/dl ) REQUIRE D T O PREVEN

T99.5 % O

F U.S

. CHILDRE N FRO M EXCEEDIN

G SPECIFIE D BLOO

D LEA D LEVEL S ESTIMATE D FRO

M ALTERNAT

E TECHNIQUES Maximu m Acceptabl e Bloo d Lea d Leve l (pg/dl ) 2 5 2 0 1 5 1 0 i 0 0

Logisti c Regression 3 Constan t GSD C 1.3 9 1.3 4 8. 7

10. 7 11. 8 7. 0

8. 6 9. 4 5. 1

6. 4 7. 1 _ b

4. 3 4. 7

a Fro mresult s i n Schwartz , 198 5 base d on analysi s o f NHANE S I I data . b Give n th e limite d sampl e size , a stabl e estimat e coul d no t b e calculated .
c Derive d fro manalyse s o f homogenou s population s sample d b yNHANE S I I (CD , p . 11-30) ,

0 0P. 9

VII-4 9
variou s ai r lea d levels , and th e Pb B level s a t th e 99. 5 percentil e wer e calculate d fo r eac hmea nPb B and assumin g a constan t GS D (eithe r 1.3 4 o r 1.39 ) (Se e Tabl e 7-12) . Fo r example , th e criteri a documen t "disaggregate " mode l estimate s tha t a t anaverag e ai r lea d leve l o f 0. 5 pg/m 3 , th e populatio nmea nPb B leve l amon g childre nwoul d b e approximatel y8. 5 ug/d l whic hcorrespond s t o keepin g 99.5 % o f childre nfro mexceedin g a Pb B leve l
o f 18. 1 o r 19. 9 ug/d l (dependin g o nwhic hGS D i s assumed) . I ncontrast , accordin g t o result s o f th e Schwart z (1985 ) regressio nanalysis , a popula

tio nmea nPb B leve l o f 8. 7 ug/d l woul d correspon d t o preventin g 99.5 %
o f childre nfro m

exceedin g a Pb B leve l o f 2 5 ug/dl . Obviously , signifi

cantl ydifferen t impact s woul d b e predicte d unde r variou s ai r lea d level s usin g eithe r o f thes e tw o statistica l technique s t o characteriz e th e tai l
o f a cumulativ e distributio no f Pb B level s whil e relyin g o nth e sam e thre e exposur e model s presente d previousl yb ythi s paper . Anothe r illustration , usin g th e aggregat e epidemiologica l model , indicate s tha t anai r lea d leve l
o f 0.7 5 pg/m 3 woul d resul t i na populatio nmea nPb B leve l aroun d 7. 4 pg/dl , assumin g blood/ai r lea d slope s o f 4 and a non-ai r Pb B contributio no f 4. 4 pg/dl . Thi s mea nPb B leve l correspond s t o preventin g 99.5 % o f childre n fro mexceedin g eithe r 15. 7 o r 17. 3 pg/d l fo r GSD s o f eithe r 1.3 4 o r 1.39 , respectively . I ncontrast , accordin g t o th e Schwart z (1985 ) regressio n analysis , a mea nPb B leve l o f 7. 0 pg/d l woul d correspon d t o 99.5 % o f childre nfro mexceedin g Pb B level s abov e 2 0 pg/dl ; i.e. , anai r lea d level ' o f 0.7 5 pg/m 3 , usin g th e sam e exposur e model , woul d b e significantl yles s protectiv e base d o nth e Schwart z (1985 ) analysi s compare d t o th e analysi s usin g constan t GSD s o f 1.3 4 t o 1.39 . I t appear s tha t th e propose d approac h b ySchwart z (1985) , b ymor e full yaccountin g fo r childre ni nth e tai l end
o f th e distribution , focuse s o nho wthos e excessivel yexpose d t o source s o f lea d no t affecte d b yatmospheri c emissions , suc ha s pain t lead , ar eP.1 0

VII-5 0 affecte d b

yincrementa l change s i nai r lead . Becaus e o f th e significantl y differen t prediction s possibl e unde r thes e alternativ e approaches , th e staf f seek s CASA C guidanc e o nth e appropriat e technique s fo r estimatin g th e tai l en d o f Pb B distribution s unde r alternativ e ai r lea d level s an d estimate d populatio nmea nPb B levels . D . Summar yo f Staf f Conclusion s and Recommendation s Th e majo r staf f conclusion s and recommendation s mad e i nSectio nVII , A- C
ar e briefl ysummarize d below : 1 ) Th e quarterl yaveragin g perio d use d fo r th e curren t lea d standar d allow s significantl yelevate d monthl yaverag e concentrations , and repeate d monthl yexcursion s abov e a quarterl ystandar d leve l ma yproduc e Pb B level s elevate d ove r thos e tha t woul d b e predicte d unles s th e standar d wa s exceeded . Becaus e suc helevation s ma yb e associate d wit hsom e increase d healt hrisk , th e staf f recommend s tha t consideratio nb e give nt o a monthl yaverag e sinc e i t woul d b e mor e protectiv e o f children' s healt htha nth e curren t quarterl ystandard . Guidanc e i s requeste d fro mCASA C o nwhethe r th e adde d protectio nprovide d b ya chang e t o a monthl ystandar d woul d warran t a revisio no f th e curren t quarterl yaveragin g period . Th e staf f als o request s commen t o nwhethe r th e availabl e informatio nsuggest s th e nee d fo r an averagin g perio d les s tha na month . Shoul d a monthl yaverag e lea d NAAQ S b e chosen , i t woul d b e necessar yt o revis e th e curren t on e i nsi xdayai r lea d samplin g schedule . Analyse s ar e underwa yt o determin e th e mos t appropriat e samplin g schedule s unde r a monthl ystandard . 2 ) Th e primar ylea d NAAQ S shoul d b e expresse d i na statistica l for m rathe r tha nth e curren t deterministi c form . Th e decisio no nth e statistica l approac ht o b e adopted , wit hpossibl ymor e frequen t sampling , shoul d b e mad e i nconjunctio nwit hestablishin g a leve l fo r th e standard .P.1 1

VI1-5 1 3 ) Lea d affect s manydifferen t orga nsystem s and biochemical/physiologica l processe s acros s a wid e rang e o f exposur e levels . Thes e effect s rang e fro mbiochemica l change s i nenerg ymetabolism , neurotransmission , an d bloo d enzym e activit ydetectabl e a t ^tery lo wdosage s wit hn o apparen t threshol d
o na subcellular-molecula r level , t o severe , irreversibl e centra l nervou s syste mdamag e manifeste d b ymenta l retardation , encephalopath yand possibl y deat ha t Pb B level s abov e 80-10 0 yg/dl . 4 ) Base d o nrecen t studies , th e Pb B leve l o f 3 0 yg/d l use d a s th e maximu m saf e leve l fo r a nindividua l chil d i nsettin g th e 197 8 lea d NAAQ S contain s littl e o r n o margi no f safet yfo r childre nfro msevera l advers e healt h effects . Base d o nanassessmen t o f th e availabl e healt heffect s data , th e staf f conclude s tha t a chil d wit ha Pb B o f 25-3 0 yg/d l i s a t ris k o f signifi

can t alteration s i nhem e synthesi s (a s indicate d b yelevate d EP) , depressio n i nvitami nD metabolism , an d possibl yneurobehaviora l disturbances , whic h collectivel yma yrepresen t impaire d functionin g an d deplete d reserv e capacitie s o f manydifferen t tissue s and organs . Belo w25-3 0 yg/dl , th e ris k as sociate d wit hobserve d reduction s i nhem e and vitami nD hormon e synthesis , a s wel l a s altere d brai nwav e activit yand smal l decrement s i ncognitiv e functio nand behavio r hav e no t bee nfull ydetermined . Th e CD C ha s revise d th e Pb B leve l use d t o identif ychildre nwit hexcessiv e lea d exposur e i nth e lea d poisonin g preventio nscreenin g progra mfro m3 0 t o 2 5 yg/dl , a medica l "intervention " leve l tha t represent s a compromis e betwee nth e amoun t o f tolerabl e ris k and th e practica l limit s o f effectivel yimplementin g th e existin g screenin g program . Th e staf f conclude s tha t a Pb B fo r anindividua l chil d o f 2 5 yg/d l appear s t o contai nlittl e o r n o margi no f safet yfro m significan t risk s o f multi-orga nimpairment s and possibl e neurologica l dysfunction .P.1 2

VII-5 2 5 ) Fairl yconsisten t result s wer e provide d b yth e thre e modelin g approache s use d t o estimat e Pb B level s amon g childre nunde r alternativ e ai r lea d concentration s assume d t o b e maintaine d a t constan t levels : th e integrate d lea d uptake/biokineti c model , th e aggregat e epidemiologica l bloo d lead/air lea d slop e approach , and th e disaggregat e epidemiologica l approac hpresente d i nth e criteri a document . Calculation s wer e performe d o nth e assumptio n tha t th e geometri c standar d deviatio n(GSD ) fo r th e chil d populatio ni s constan t and i nth e rang e o f 1.3 4 t o 1.3 9 a s cite d i nth e CD . Base d o n thi s premise , al l thre e model s predicte d tha t i norde r t o preven t 99.5 %
o f childre nfro mexceedin g 2 5 pg/dl , anai r lea d leve l constantl ya t attainment , n o highe r tha nth e curren t standar d leve l woul d b e required , and possibl yn o highe r tha n0.7 5 pg/m 3 , depending o nth e assumption s and calculation s use d i nth e differen t models . Shoul d a Pb B o f 2 0 pg/d l b e determine d t o b e th e maximu macceptabl e saf e Pb B leve l and assumin g a goa l
o f 99.5 % protection , GSD s betwee n1.3 4 an d 1.39 , and a nai r leve l tha t i s constantl ymaintained , the na leve l n o highe r tha n0.5-0.7 5 pg/m 3 woul d b e require d - unles s th e leas t conservativ e aggregat e epidemiologica l mode l alon e i s considered , i nwhic hcase , a leve l o f 1.2 5 pg/m 3 ma yb e sufficient . Aleve l tha t i s maintaine d a t 0. 5 pg/m 3 , and possibl ya s lo wa s 0.2 5 pg/m 3 , woul d b e require d t o preven t 99.5 % o f childre nfro mexceeding Pb B level s abov e 1 5 pg/dl , dependin g o nwhic hmode l i s considered , and assumin g a constan t GS D betwee n1.3 4 and 1.39 . Calculation s wer e als o performe d base d o na differen t characterizatio n o f th e tai l end o f th e distributio no f children' s Pb B levels . Thi s alternativ e statistica l approac hindicate s tha t somewha t differen t averag e ai r lea d level s woul d b e require d fo r equivalen t healt hprotectio nusin g th e sam e thre e exposur e modelin g approaches . Fo r example , th e criteri aP.1 3

VII-5 3

documen t "disaggregate " mode l estimate s tha t a t anaverag e ai r lea d leve l
o f 0. 5 pg/m 3 , th e populatio nmea nPb B leve l amon g childre nwoul d b e approximatel y8. 5 ug/d l whic hcorrespond s t o keepin g 99.5 % o f childre nfro m exceedin g a Pb B leve l o f 18. 1 o r 19. 9 pg/d l (dependin g o nwhic hGS D i s assumed) . Incontrast , accordin g t o result s usin g th e alternativ e statistica l approac h(whic hi s base d o na logisti c regressio nanalysi s o f NHANE S I I data) , a populatio nmea nPb B leve l o f 8. 7 pg/d l woul d correspon d t o preventin g 99.5 % o f childre nfro mexceedin g a Pb B leve l o f 2 5 pg/dl . Furthe r informatio nand CASA C guidanc e i s sough t on : a ) whethe r thes e modelin g approache s ar e vali d give nth e availabl e dat a and ho wthe yca nb e improved ; b ) appropriat e value s o f specifi c parameter s withi nth e variou s models , e.g. , blood/ai r lea d slope , non-ai r Pb B contribution ; and c ) th e appropriat e statistica l techniqu e t o characteriz e th e tai l end o f th e bloo d lea d distributio nunde r alternativ e ai r lea d level s a s predicte d b yth e variou s models , i.e. , shoul d a "constant " GS D b e use d t o represen t th e entir e distributio no f children' s bloo d lea d level s (an d i f so , wha t th e appropriat e GS D valu e is) , o r whethe r th e alternativ e approac hbase d o n logisti c regressio nanalysi s o f NHANE S I I dat a woul d b e animprovement .P.1 4

VIII . CRITICA L ELEMENT S I NTH E REVIE WO F TH E SECONDAR YSTANDAR D Thi s sectio ninclude s a discussio no f informatio ndraw nfro mth e criteri a documen t tha t appear s mos t relevan t t o th e revie wand possibl e revisio no f th e curren t secondar yNAAQ S fo r lead . I t focuse s o nfiel d
and laborator ystudie s tha t identif ypotentia l effect s o f lea d i nbiot a o f terrestria l and aquati c ecosystem s a t level s o f exposur e relevan t t o natura l habitats . Withi neac hcategory , th e sectio npresent s 1 ) a brie f summar yo f th e relevan t scientifi c information ; 2 ) a nevaluatio no f th e potentia l quantitativ e relationship s betwee nlea d and effects ; and 3 )
a nevaluatio no f th e quantitativ e relationship s betwee nlevel s o f lea d i nth e natura l habita t and biologicall yavailabl e lead . Apreliminar y staf f recommendatio ni s als o presented , recognizin g th e majo r uncertaintie s i nth e availabl e data , tha t consideratio nb e give nt o makin g th e secondar y standar d equivalen t t o th e primar ystandar d i nal l respects . I . Terrestria l Ecosystem s Anthropogeni c emission s o f lea d deposi t o nterrestria l ecosystem s vi a we t and dr ydeposition . Afte r initia l depositio no nvegetatio nand othe r surfaces , th e migratio nand distributio no f lea d i nth e soi l reservoi r depen d o na numbe r o f environmenta l factor s tha t influenc e th e immobilizatio n o f lea d vi a precipitation , surfac e adsorptio nan d io nexchang e reaction s (Zimdah l and Skogerboe , 1977 ; Mille r & McFee , 1983 ; Camerlync k & Kiekens , 1982) . Onc e inth e soi l reservoir , lea d i s relativel yinsolubl e and immobil e (NAS , 1980 ; Nriagu , 1978 ) and i s no t readil yremove d b ysuc h mechanism s a s leachin g and strea mrun-of f (CD , p . 8-7 , 8-13) . A s a result , lea d accumulate s i nth e soi l reservoi r eve nwhe nth e depositio nrat e i s relativel ylow .P.1 5

VIII- 2 A . Mobilit yan d Bioavailabilit yo f Lea d Zimdah l an d Skogerbo e (1977 ) identifie d soi l p H an d catio nexchang e capacit y(CEC ) a s primar ydeterminant s o f a soil' s capacit yt o bin d lead . Base d o nthei r empiricall yderive d equation , th e bindin g capacit yfo r lea d fo r variou s soi l type s wa s estimated . Althoug hth e reliabilit yo f thi s equatio nt o predic t soi l bindin g capacit yi s questionabl e (du e t o it s linea r for mwhic hma yno t b e appropriat e fo r hig hCEC's) , thi s analysi s suggest s tha t whil e th e capacit yo f certai nsoil s t o immobiliz e lea d i s large , i t i s finite . Whe nexaminin g th e potentia l impac t o f lea d o nterrestria l ecosystems , a distinctio nmus t b e mad e betwee ntota l soi l lea d conten t an d th e availabl e o r potentiall yavailabl e fractions . Th e fractio no f soi l lea d tha t ma yb e biologicall yavailabl e include s th e potentiall yavailabl e lea d (exchangeabl e form s determine d b

ychemica l extraction ) an d th e actuall yavailabl e wate r solubl e form s (lea d i nsoi l moisture ) (CD , p . 6-29) . Th e generall ylo w solubilit yo f lea d an d th e apparentl ysmal l percentag e (1-12% ) o f tota l soi l lea d tha t i s exchangeabl e (Camerlync k an d Kiekens , 1982 ; Mille r an d McFee , 1983 ; Hughes , 1981 ; Atkin s e t al. , 1982 ) sugges t tha t th e bioavail

abilit yo f thi s pollutan t i s quit e limited . Th e potentia l effec t o f aci d precipitatio nt o increas e th e relativ e mobilit yo f lea d i nsoi l (Tyler , 1978 ; Hutchinson , 1980 ) i s o f clea r concer na s a mechanis mtha t ma yincreas e th e bioavailabilit yo f thi s heavymetal . Give nth e varyin g capacit yo f differen t soi l type s t o immobiliz e lea d unde r differen t environmenta l condition s an d th e limite d usefulnes s o f chemica l extractio nstudie s t o provid e reliabl e estimate s o f exchangeabl e soi l lea d fractions , i t i s difficul t t o predic t th e percentag e o f tota l soi l lea d tha t i s biologicall yavailabl e (actua l o r potential) . A s a result , i t i s difficul t t o predic t th e magnitud e o f increas e i ntota l soi l lea d concentratio ntha tP.1 6

VIII- 3 result s i na soi l moistur e lea d concentratio nassociate d wit hlevel s o f biologicall yavailabl e lea d tha t ma ycaus e advers e effects . B . Effect s i nTerrestria l Biot a Thi s section , base d o nth e scientifi c literatur e summarize d i n th e criteri a document , include s a revie wo f th e effec t o f lea d i n component s o f th e terrestria l ecosystem , i.e. , flora , microbe s and fauna . Th e lowes t level s o f exposur e a t whic heffect s hav e bee nobserve d i n fiel d and laborator ystudie s ar e emphasized . Th e biologica l o r ecologica l significanc e o f certai nlead-induce d effect s i s unclear . Thi s i s primaril y du e t o th e difficult yi ndeterminin g th e long-ter msignificanc e o f subtl e change s i necosyste m structur e and function . Give nth e availabl e data , i t i s difficul t t o asses s th e exten t t o whic hlead-induce d effect s constitut e shor t o r long-term , advers e environmenta l impacts . 1 . Flor a a . Exposure , Uptak e and Translocatio n Plan t exposur e t o lea d occur s vi a roo t uptak e fro mth e nutrien t mediu m(soi l moisture ) (CD , p . 8-14) . Althoug h90 % o r mor e o f lea d take n up vi a th e root s ma yremai ntightl yboun d i nth e root s (Koeppe , 1981) , fiel d and laborator ystudie s provid e evidenc e tha t som e lea d i s translocate d t o physiologicall yactiv e tissue s i nvascula r plant s (CD , p . 8-1 5 t o 8-17) . Recen t isotopi c and mas s balanc e studie s sugges t th e mechanis mo f folia r uptak e a s anothe r rout e o f exposur e o f plant s t o lea d (Facchett i
and Geiss , 1982 ; Lindber g and Harriss , 1981) . Whil e th e relativ e signifi

canc e o f folia r uptak e ha s no t bee nclearl ydetermined , i t i s potentiall y quit e hig hsinc e surfac e depositio no f lea d i s estimate d t o accoun t fo r 90 % o f tota l plan t lea d (CD , p . 8-38) . Elevate d lea d burden s i nplant s nea r smelter s and alon g roadsides , fo r example , hav e bee nattribute dP.1 7

VIII- 4 primaril yt o surfac e depositio n(Get z e t al. , 1977 ; Nriagu , 1978 ; Smith , 1976) . Take ntogether , thes e studie s sugges t tha t depositio n o n vegetativ e surface s and folia r uptak e ma yb e o f greate r importanc e tha npreviousl y thought . b . Experimenta l Dat a fro mHydroponicall yGrow nPlant s Experimenta l dat a o nlead-induce d effect s i nplant s ar e availabl e primaril yfro m

laborator ystudie s o f agricultura l plant s grown i nartificia l nutrient medi a (i.e. , hydroponi c solution) . Thes e studie s (Tabl e 8-1 ) repor t tha t a t relativel ylo wconcentrations , rangin g fro m2-1 0 p g Pb/ g solution , inhibitio n o f photosynthesis , alteratio n i n enzym e activit y and reductio n i ngrowt hca n occur . Whil e th e physiologica l and biochemica l change s observe d i nthes e studie s ar e biologicall ysignificant , th e result s canno t b e readil yextrapolate d t o th e varie d condition s presen t i nnatura l habitats . Suc hfactor s a s lengt ho f treatmen t (exposure) , chemica l for mo f lead , leve l o f nutrient s i n solution , and ag e and specie s o f plan t ca n influenc e th e experimenta l result s (Koeppe , 1981 ; Paivoke , 1979 ) and limi t th e extrapolatio n o f controlle d experimenta l result s t o th e natura l habitat . Th e absenc e o f dat a t o clearl ydefin e th e quantitativ e relationshi p betwee nsoi l moistur e lea d and tota l soi l lea d furthe r limit s th e usefulnes s o f laborator ystudie s o f hydroponicall ygrow n plant s fo r environmenta l impac t prediction . Du e t o th e absenc e o f data , i t i s difficul t t o accuratel yasses s th e potentia l effec t o f lea d i nterrestria l flora . Lead

induce d effect s hav e bee n evaluate d fo r a limite d numbe r o f plan t processe s (CD , p . 8-17 ) and th e dat a bas e o n effect s i nnon-agricultura l plant s and tree s (Smith , 1981 ) i s inadequate .

c . Experimenta l Dat a o f Plant s Grow n i nLead-Amende d Soil s Studie s involvin g th e artificia l additio no f lea d salt s t o soi l hav e evaluate d lead-induce d change s i nplant s a t specifie d soi l lea d concentrations ,Tabl e 8-1 . LEAD-INDUCE D EFFECT S I NHYDROPONICALL YGROWNVASCULARPLANT S Effec t Specie s Lea d concentratio n (pg Pb/ g solution ) Specie s o f Lea d Sal t Lengt ho f

Treatmen t Referenc e

Inhibitio n o f germinatin g roo t elongatio n 50 % reductio n roo tgrowt h Ry e gras s seedling s < 2. 5



### 1. 7 Lea d nitrat e 1 4 day s Won g and Bradsha w (1982 )

Absenc e o f roo t growt h Inhibitio n o f carbo n fixatio n pathwa y Reductio n i n elongatio n Tomat o chloroplast s Whea t seedling s 

### 5
10.3 5 

### 1 0 Lea d nitrat e Lea d chlorid e Lea d nitrat e -

4 8 hour s Mile s e t al . (1972 )

Lan e e t al . (1978 ) Inhibitio n o f AT P conten t Kidne ybea n seedlin g leave s 

### 1 0 Lea d nitrat e 1 5 day s Sun g and Yan g (1979 ) Buckwhea t seedlin g leave s i Reductio n i n synthesi s chlorophyll- a chlorophyll- b' Oa t seed s 

### 1 0 Lea d chlorid e 7 2 hour s Hamp p an d Lendzia n (1974 ) 60 % increas e i n aci d phosphatas e a t 6 days , followe d b

ydecreas e a t 1 2 day s Inhibitio n o f roo t growt h Pe a seedling s

Inhibitio n o f roo t growt hBarle yseedling s Lea d acetat e 1 2 day s

Lea d chlorid e 1 2 day s Lea d nitrat e 1 0 day s Paivok e (1979 )

Garlan d and Wilkin s (1981 )P.1 9

VIII- 6

I ngeneral , highconcentration s o f tota l soi l lea d ar e necessar ybefor e physiologica l effect s i nplant s ar e observed . Kha n and Franklan d (1983 ) repor t significan t growt hreductio ni nradis hplant s wit hexposur e t o 100 0 p g Pb/ g soi l and complet e growt hinhibitio n a t 500 0 pg Pb/ g soil . Thes e tota l soi l lea d concentration s ar e foun d i n certai n hig hlea d environments , i.e. , nea r roadside s and smelter s (Wheele r and Rolfe , 1979 ; CD , p . 7-30 ; Atkin s e t al. , 1982) . I t i s unclear , however , whethe r lead-induce d effect s woul d occu r unde r natura l soi l condition s wher e th e availabilit yo f lea d i s influence d b ynutrien t levels , organi c matte r content , CEC , and pH o f th e soi l (Koeppe , 1981) .

d . Fiel d Evidenc e o f Lead-Toleranc e Furthe r indicatio n o f th e effec t o f lea d i s provide d b yth e identificatio no f lea d toleran t plan t communitie s nea r roadside s and poin t sourc e emission s (CD , p . 8-38 ; Antonovic s e t al. , 1971 ; Atkin s e t al. , 1982) . Potentia l change s i nspecie s compositio ni nthes e area s hav e implication s fo r th e long-ter m effec t o f lea d o necosyste mfunctio nand stability . A t relativel ylo wtota l soi l lea d concentration s (11 2 p g Pb/ g soil) , Atkin s e t al . (1982 ) sugges t tha t selectio n pressur e du e t o soi l lea d resulte d i nth e evolutio n o f lea d toleranc e i n a roadsid e grass . 2 . Microbe s Availabl e dat a sugges t tha t th e impac t o f lea d i nterrestria l eco system s mayb e eviden t firs t i nth e component s o f th e soi l and litte r microcos m(e.g. , fungi , bacteri a and algae ) (Tyler , 1972 ) tha t pla ya critica l rol e i nth e decompositio no f organi c matte r and i nnutrien t cyclin g (Doelma nand Haanstra , 1979a ; Doelman , 1978) .

a . Experimenta l Studie s o f Lead-Induce d Effect s Experimenta l studie s provid e evidenc e o f lead-induce d effect s i nP.2 0

VIII- 7 soi l microbe s a t soi l lea d concentration s a s lo wa s 750-500 0 pg Pb/ g soi l (Tabl e 8-2) . I nth e presenc e o f lea d (150 0 pg Pb/ g soil) , th e compositio no f microb e communitie s ma yshif t t o mor e lead-toleran t population s (Doelma nan d Haanstra , 1979b ) and , a t soi l lea d concentration s foun d nea r roadway s and poin t source s (750-200 0 pg Pb/ g soil) , soi l microbia l activit yma yb e sufficientlyreduce d t o inhibi t th e decompositio n and nitrificatio n processe s (Smith , 1981 ; Doelma nand Haanstra , 1979a ; Lian g an d Tabatabai , 1978) . Inhibitio no f growt hand activit yi nsoi l microbe s ha s occurre d a t lea d concentration s i nsolutio no f 10-5 0 pg Pb/m l (Tabl e 8-2) . Whil e thes e dat a sugges t tha t certai nsoi l microbe s ca nb e affecte d b y lea d a t soi l lea d concentration s found nea r roadside s an d poin t sources , th e dat a ar e inadequat e t o dra wan ygenera l conclusion s abou t th e toleranc e o f soi l microbe s t o lea d (Doelman , 1978 ) an d lead' s effec t o nthi s ecosystemcomponen t a s a whole . Th e inhibitor yeffec t o f lea d appear s t o varywit hdifferen t type s o f microbe s (Johnso ne t al. , 1982 ; Marti nand Coughtrey , 1981) . I naddition , becaus e microbe s exhibi t a diversit yo f function s tha t interac t i nway s tha t ar e no t wel l define d (Swif t e t al. , 1979 ; CD , 8-22 , 8-23) , a broade r dat a base , encompassin g variou s taxonomi c groups , i s require d fo r environmenta l impac t prediction . Eve ndrawin g quantitativ e conclusion s abou t th e microbe s studie d i nthes e experiment s i s constraine d b

yexperimenta l condition s tha t influenc e th e bioavailabilit y o f lea d and resul t i nuncertaintie s associate d wit hextrapolatin g laborator y result s t o th e natura l habitat . Th e long-termsignificanc e o f lead-induce d change s i nsoi l microbia l population s i s unclea r and depend s onwhethe r th e ecosyste m

ha s th e abilit yt o compensat e fo r suc hperturbations . Th e critica l rol e o f soi l microbe s i nterrestria l ecosystemprocesse sTabl e 8-2 . EXPERIMENTA L EVIDENC E O F LEAD-INDUCE D EFFECT S RELATIN GT O SOI L MICROBIA L ACTIVIT Y Effec t Microb e Lea d Concentratio n Referenc e Possibl e inhibitio no f decompositio n Bacteri a 200 0 - 500 0 pg Pb/ g soi l Smit h(198 1 ) a

Dela yand inhibitio no f decom

positio no f organi c compound s Bacteri a 75 0 - 150 0 p g Pb/ g soi l Lea d chlorid e Doelma nan d Haanstr a (1979a )
14 % inhibitio no f nitrificatio n Bacteri a 100 0 p g Pb/ g soi l Lea d acetat e Lian g an d Tabataba i (1978 )
Chang e i n compositio no f micro

flor a afte r 3 year s (Selectio n o f toleran t strains ) Bacteri a 150 0 p g Pb/ g soi l Lea d chlorid e Doelma nan d Haanstr a (1979b ) ' 0 0

Inhibitio n i n 50 % o f microbia l strain s Fung i Bacteri a Actinomycete s 5 0 pg Pb/ml b Lea d acetat e William s e t al . (1977c )

Inhibitio no f growt h Fung i 10-50 p g Pb/ml b Lea d nitrat e Babic h an d Stotzk y(1979 )

a A s cite d i n Criteri a Document , p . 8-2 2 b Not e lea d concentratio n i n solutio n

h oP.2 2

VIII- 9 (decompositio nand nutrien t cycling ) suggests , however , th e seriou s natur e o f th e potentia l inhibitio no f microbia l activit yb ylea d and indicate s th e nee d fo r additiona l researc ht o mor e clearl ydefin e th e effec t o f lea d i nthi s ecosyste mcomponent .

b . Fiel d Evidenc e o f Altere d Microbia l Activit y Reduce d abundanc e and altere d compositio no f microflor a population s hav e bee nobserve d i n th e vicinit yo f poin t sourc e emission s o f lea d and i n a nare a contaminate d wit hmeta l min e waste . Correspondin g t o thes e changes , th e accumulatio n o f litte r and alteration s i n soi l parameter s hav e bee n reported . Lea d wa s th e predominan t heavymeta l contaminan t i n thes e area s (Jackso n and Watson , 1977 ; Bisessar , 1982 ; William s e t al. , 1977c) . Althoug hthes e fiel d observation s sugges t th e inhibitor yeffec t o f lea d o nmicrobia l activit yi ncertai nheavil ycontaminate d areas , thei r usefulnes s i n assessin g th e environmenta l impac t o f lea d i s limite d fo r th e followin g reasons : 1 ) th e inabilit yt o isolat e th e effec t o f lea d fro mth e confoundin g effect s associate d wit hothe r component s o f poin t sourc e emission s and othe r heav

ymetals ; and 2 ) th e lac k o f quantitativ e informatio nconcernin g th e effec t o f othe r environmenta l factor s tha t influenc e th e decompositio nrate , i.e. , temperatur e and moistur e condition s (Smith , 1981) . 3 . Faun a a . Exposur e Th e principa l pathwa yo f exposur e fo r faun a i s throug hdietar yintak e (CD , p . 8-26) . Faun a o f th e grazin g food-chai nar e affecte d mos t directl y b ydepositio no f lea d o nvegetation . Others , suc ha s predators , ar e affecte d mor e indirectl yb ylea d movin g throug hth e food-chain , thu sP.2 3

VIII-1 0 raisin g concern s abou t th e potentia l accumulatio nand biomagnificatio n o f lea d a t highe r trophi c levels . Whil e biomagnificatio n(biologica l concentratio no f lea d fro mon e trophi c leve l t o th e next ) ha s no t bee n observe d i nvertebrat e food-chain s (NAS , 1980 ; Williamso nan d Evans , 1972) , availabl e dat a sugges t tha t th e biomagnificatio no f lea d doe s occu r i ninvertebrat e food-chain s (NAS , 1980 ; Get z e t al. , 1977 ; Wad e e t al. , 1980 ; Watso ne t al. , 1976) . Thus , non-toxi c level s o f lea d take nu p and accumulate d b yinvertebrate s ma yproduc e toxi c effect s i n thei r predators . Althoug hsuppor t fo r thi s potentia l rout e o f exposur e i s provide d (Bul l e t al. , 1983a ; Get z e t al. , 1977 ; Gis hand Christensen , 1973) , th e occurrenc e o f lea d burden s i npre yhig henoug ht o caus e toxi c effect s i npredator s i s variabl e (Wad e e t al. , 1980) . b . Fiel d and Laborator yEvidenc e o f Lead-Induce d Effect s Th e availabl e dat a o nlead-induce d effect s i ninvertebrate s ar e ver y limite d and ar e no t sufficien t t o establis hquantitativ e relationships . Decrease d soi l invertebrate.abundance , suggestin g potentiall ysignificant alteration s i nsoi l decompositio nprocesses , ha s bee nobserved , however , i nth e vicinit yo f poin t sourc e emission s o f lea d an d i nth e are a o f a meta l min e wast e sit e (Watso ne t al. , 1976 ; William s e t al. , 1977c ; Bisessar , 1982) . Du e t o th e presenc e o f othe r pollutant s and heav ymetal s i nthes e areas , i t i s no t possibl e t o attribut e th e observe d reduction s t o lea d alone . Ver yfe wfiel d studie s reportin g lea d exposures , bodyburden s and associate d effect s i nwildlif e ar e available . Unusuall yhig hlea d exposure s resultin g i ntoxi c effect s hav e occurre d primaril yi nwaterfow l and livestock . Source s o f thes e exposure s hav e typicall yinclude d lea d wastes , pain t and spen t lea d sho t (unrelate d t o airborn e lea d emissions) , and contaminate dP.2 4

VIII-1 1 forag e nea r lea d smelter s (NAS , 1980 ; Forbe s and Sanderson , 1978) . Wit h th e exceptio n o f cattl e and waterfowl , incidenc e rate s o f lea d poisonin g i nterrestria l faun a ar e generall yunavailabl e (Forbe s and Sanderson , 1978 ; Botts , 1977 ) and difficul t t o verify . Althoug hlea d burden s i nmammal s ar e elevate d relativ e t o natura l backgroun d level s (CD , p . 8-29 , 8-30) , wit hburden s positivel ycorrelate d wit hproximit yt o roadway s (Williamso nand Evans , 1972 ; Quarle s e t al. , 1974) , i t i s uncertai n i f exposure s ar e resultin g i nanima l burden s hig h enoug ht o b e o f concern . Thi s uncertaint yresult s fro ma limite d dat a bas e o f fiel d observation s tha t repor t conflictin g findings . Bodyburden s o f lea d tha t hav e bee nidentifie d t o caus e effect s i n animal s hav e no t bee n observe d i ncertai nhig hlea d environments , i.e. , roadside s and smelte r area s (Forbe s and Sanderson , 1978 ; Get z e t al. , 1977) . Othe r studies , however , indicat e tha t elevate d lea d burden s associate d wit heffect s ma y occu r i nlivestoc k grazin g nea r smelter s and i nsmal l mammal s i narea s adjacen t t o highways , minin g site s and smelter s (NAS , 1980 ; Clark , 1979 ; Quarle s e t al. , 1974) . Whe nassessin g th e effect s o f lea d o ndomesti c animal s and wildlife , i t i s importan t t o conside r th e mor e subtl e effect s tha t ar e no t readil y discernibl e i n fiel d observationa l studies . Drawin g o n anima l toxicologica l studie s discusse d i nth e C D and referre d t o i nAppendi xD , i t i s clea r tha t lead ca naffec t a wid e rang e o f critica l function s suc ha s hem e synthesis , neurobehaviora l function , and reproductio n and development . Investigatio n o f thes e effect s ha s bee nlimited , however , primaril yt o laborator yanimals . I npar t becaus e o f specie s difference s i n suscepti

bilit y(Forbe s and Sanderson , 1978 ) and a lac k o f sufficien t quantitativ e exposure/uptake/respons e dat a i nnatura l habitats , result s fro mcontrolle dP.2 5

VIII-1 2 anima l studie s hav e no t bee n extrapolate d t o animal s i nnatura l environments . Whil e curren t analyse s and understandin g o f th e potentia l effect s o f lea d i ndomesti c animal s and wildlif e specie s ar e considerabl yles s definitiv e tha nfo r humans , th e availabl e dat a strongl ysugges t tha t animal s ma yb e a t risk . Whe nassessin g muc ho f th e sam e dat a i n1980 , th e Committe e o n Lea d i nth e Huma nEnvironmen t o f th e Nationa l Academyo f Science s conclude d tha t anima l sensitivit yt o lea d migh t equa l o r excee d tha t o f ma n (NAS , 1980) . II . Aquati c Ecosystem s A . Behavio r o f Lea d i nWate r and i nSediment s Th e capacit yo f surfac e water s t o retai nlea d i n solutio n a t equilibriu m i s dependen t upo nth e physica l and chemica l wate r qualit yparameter s o f th e particula r aquati c environment (NAS , 1980) . I nadditio nt o physica l and chemica l parameter s tha t determin e lead' s solubility , biologica l condition s ca ninfluenc e th e behavio r o f lea d i naquati c system s (Rickar d and Nriagu , 1978) , and , hence , it s availabilit yand potentia l impac t i naquati c biota . Althoug hlea d i s readil ycomplexe d i n natura l wate r system s (CD , p . 6-33) , concentration s exceedin g 10 0 p g Pb/ 1 (lea d i nsolution ) hav e bee nreporte d fo r surfac e water s receivin g urba nrunof f and sewag e and industria l effluent s (NAS , 1980) . Du e t o th e lac k o f majo r export s o f lea d fro mfreshwate r ecosystems , thes e system s functio n a s potentia l sink s fo r lea d loadin g (McNurne ye t al. , 1977 ; Get z e t al. , 1977) , wit hth e sedimen t a s th e primar ysink fo r lea d simila r t o soi l i nterrestria l ecosystem s (Rickar d an d Nriagu , 1978) . Th e sedimentatio no f lea d depend s o n a numbe r o f environmenta l factor s (CD , p . 8-13) , and th e retentio no f thi s heavymeta l withi n th e sedimen t i s influence d b yth e substrat e typ e (McNurne ye t al. , 1977 ;VIII-1 3

Wershaw , 1976 ; Newma nand Mcintosh , 1982) . Ove r th e pas t century , a tren d o f increasin g depositio no f lea d i n th e sediment s o f freshwate r system s ha s bee n observe d (CD , p . 5-1 , Figur e 5-1) , wit helevate d lea d concentration s observe d i nsediment s drainin g urba n area s relativ e t o rura l area s (McNurne ye t al. , 1977 ; Get z e t al. , 1977) . A s a resul t o f th e accumulatio no f lea d i nth e sediment s o f fresh

wate r systems , th e solubl e fractio ncomprise s onl ya smal l percentag e o f th e tota l lea d burde n(Rickar d and Nriagu , 1978 ; Wershaw , 1976) . Becaus e o f potentia l regeneration , however , th e reservoi r o f lea d i nth e sedimen t ca nbecom e a sourc e o f solubl e lea d eve nafte r th e discontinuatio no f lea d input s (Wershaw , 1976) . Th e significanc e o f thi s mechanis mt o increas e th e availabilit yo f waterborn e lea d t o aquati c biot a mayb e mos t pronounce d i nwate r bodie s i nwhic hcomplexe d lea d i nth e sedimen t remain s a t th e water-sedimen t interface . Fiel d observation s indicat e tha t thi s situatio ndoe s occu r (Get z e t al. , 1977) . B . Effect s i nAquati c Biot a Thi s discussio no f th e effect s o f lea d i n aquati c biot a focuse s o n vertebrate s (fish ) becaus e thi s componen t o f aquati c ecosystem s appear s mos t sensitiv e t o thi s heav ymeta l and , relativ e t o othe r taxonomi c groups , a mor e extensiv e dat a bas e i s available . Ther e i s som e evidence , however , o f effect s o f lea d i nothe r aquati c biot a a t lo wconcentration s o f waterborn e lead . Althoug hth e dat a ar e limited , lead-induce d effect s (e.g. , increase d mortality , impaire d reproduction ) i n certai naquati c invertebrate s hav e bee nreporte d a t concentration s a s lo wa s 1 9 - 3 0 pg Pb/ 1 (CD , p . 8-33 , 8-34 ; Borgman n e t al. , 1978 ; Biesinge r an d Christensen , 1972) . Hematologica l and neurologica l change s hav e bee n observe d i nfis h expose d unde r laborator ycondition s t o waterborn e lea d concentration s betwee nP.2 7

VI11-1 4 8-12 0 p g Pb/ 1 (Tabl e 8-3) . Whil e th e hematologica l syste mo f fis hma y b e capabl e o f compensatin g fo r lead-induce d changes , th e neurologica l effects , blac k tail s (a nearl yindicato r o f spina l deformity ) and spina l curvatur e (whic hincrease s mortalit yand prevent s successfu l reproduction )
ar e o f clea r concer n (Hodso ne t al. , 1978a) . Thes e finding s ar e conservativ e becaus e sensitivit yt o lea d i s species-specifi c and trou t exhibit increase d susceptibilit yt o lea d relativ e t o othe r fis h(Won g e t al. , 1978) , and th e effect s observe d a t th e lowe r limit s o f th e concentratio n rang e ma y hav e bee nenhance d b yth e relativel ysof t wate r condition s use d i n th e experiment s (Davie s e t al. , 1976) . Extrapolatin g thes e result s t o natura l system s i s constraine d b yth e manyfactor s tha t influenc e th e toxicit yand bioavailabilit yo f lead , i.e. , formo f lead , rout e and lengt ho f exposure , pH , hardnes s and temperatur e o f water , and lif e stag e of-organis m(Hodson , 1979 ; Hodso ne t al. , 1978b , 1979 ; Won g e t al. , 1978) . Decrease d pH leve l appear s t o increas e th e uptak e o f waterborn e lea d b yfis halthoug hth e precis e mechanis mo f actio n i s unclea r (Hodso ne t al. , 1978b) . Thes e dat a sugges t tha t lea d wil l hav e it s greates t effec t o nfis hi nsof t water , lo wpH aquati c system s becaus e thes e system s hav e a greate r capacit yt o retai n lea d i n solutio n a t equilibriu mbefor e reachin g chemica l saturatio n(Hem , 1976) , and th e advers e effect s o f lea d i n fis har e closel yrelate d t o dissolve d lead conten t (Hodso ne t al. , 1978b ; Won g e t al. , 1978) . Il l . Staf f Conclusion s and Recommendation s Th e availabl e laborator yand fiel d dat a indicat e tha t a t concentra
tion s a t o r belo wthos e foun d i ncertai n hig hlea d environments , lea d
can : 1 ) affec t certai nplant s (e.g. , inhibitio n o f photosynthesis , reduce d growth , change s i ncomposition) , microbe s (e.g. , reduce d abundance) , andTabl e 8-3 . EFFECT S OF WATERBORNE LEADI N AQUATI C VERTEBRATE S (FISH ) Effec t Fis h Exposur e Condition s Wate r Parameter s Referenc e Neurologica l changes , enzym e activit y inhibition , behaviora l changes 3 Trout , sunfish , goldfis h Variabl e exposur e t o Variable 0 10-10 0 u g Pb/ 1 Won ge t al , (1978 )

Neurologica l change s (Blac ktails , spina l curvature ) Rainbo w trout (eggs ) Chroni c exposur e t o 8 p gPb/ 1 Hardnes s 2 8 mg/ l a s CaC0 3 (sof t water ) p H6.7-7. 3 Davie s e t al . (1976 )

Neurologica l chang e (Blac ktails ) Rainbo w trou t (egg s an dyoun g fish ) 3 0 wee kexposur e t o 2 2 p gPb/ 1 Hardnes s 13 5 mg/ l a s CaC.03 , pH8. 2 Hodso ne t al . (1979 ) Neurologica l chang e (Blac ktails , spina l curvature ) Rainbow trou t (youngfish ) 3 0 wee kexposur e t o 12 0 pg Pb/ 1 N R Sippe l e t al , (1983 ) Hematologica l change s (increase dnumbe r redbloodcell s (rbc) , decrease drbc volume , decrease drb c ALA- D activity ) Neurologica l chang e (Blac ktails ) Rainbo w trou t (youngfish ) U pt o 3 2 wee kexposur e t o 1 3 p g Pb/ 1

3 2 wee kexposur e t o 12 0 p y Pb/ 1 Hardnes s 13 5 mg/ l a s CaC.03 , pH7. 7 Hodso ne t al . (1978a ) 1 1 — » c n

Hematologica l change s Decrease dglutami c transaminas e activit y (GOT ) Decrease dhemoglobi n Oecrease dGO T activit y Brooktrou t (youngfish ) 2 wee kexposur e t o 3 4 pgPb/ 1 2 wee kexposur e t o 5 8 pg Pb/ 1 8 wee kexposur e t o 5 8 pg Pb/ 1 N R

^Compilatio no f severa l sources . "Limite dinformatio nindicate s sof t wate r condition s ( < 5 0 mg/ l hardnes s a s CaC0 3 ) . N R-No t reported . Christense ne t al , (1977 )

ro 0 0P.2 9

VIII-1 6
fis h(e.g. , neurologica l changes) ; and 2 ) alte r th e compositio no f microbia l communitie s and inhibi t invertebrat e activit yresultin g i n delaye d decomposition , reduce d nutrien t supply , an d altere d soi l propertie s (e.g. , lowe r organi c content) . Wit hrespec t t o domesti c animal s an d wildlife , a qualitativ e assessmen t o f th e availabl e fiel d studie s and anima l toxicologica l dat a suggest s tha t animal s ma yb e a s susceptibl e t o th e effect s o f lea d a s humans . Th e availabl e dat a als o rais e concer nabou t th e continuin g accumulatio n o f lea d i nth e soi l reservoi r tha t function s a s a finit e sin k o f undefine d capacity . Du e t o th e persistenc e o f lea d i nth e environment , suc haccumula

tion s ar e expecte d t o continu e a s lon g a s input s excee d outputs . Thus , eve na t relativel ylo wdepositio nrate s lea d coul d affec t th e ecosyste m ove r th e long-term . Th e availabl e dat a are limited , however , and do-no t permi t an y definitiv e finding s wit hrespec t t o concentration-respons e function s associate d wit hth e observe d effect s o r provid e clea r quantitativ e relationship s betwee nconcentration s o f lea d i nth e natura l habita t and biologicall y availabl e lead . Dat a ar e no t available t o determin e quantitativ e relationship s betwee nambien t concentration s o f lea d an d effect s i nth e biot a o f terrestria l
and aquati c ecosystems . Thes e limite d dat a d o suggest , however , tha t effects o f lea d o nthes e ecosystem s ca nb e significant , althoug hpoorl y defined , particularl ywit hrespec t t o thei r long-ter mimplications . Th e effect s o f lea d o necosystem s ar e probabl ymor e closelyrelate d t o th e depositio nand long-ter maccumulatio no f lea d tha nt o curren t ambien t ai r qualit ylevels . Thi s suggest s tha t a secondar ystandar d fo r lea d i nth e for mo f a depositio nrat e ma yb e mor e appropriat e tha non e expresse d a s anairborn e concentratio nlevel . Suc ha depositio nstandar dP.3 0

VIII-1 7 i s conceptuall yappealin g becaus e i t coul d b e a mor e effectiv e metho d t o provid e protectio nagains t th e welfar e impact s o f lead . It s applicatio n a t thi s tim e i s constrained , however , b ypractica l consideration s suc ha s th e absenc e o f sufficien t dat a t o develo p appropriat e depositio ntarget s and th e lac k o f reliabl e method s fo r measurin g bot hwe t and dr ydeposition . Althoug hquantitativ e relationship s ar e no t wel l enoug hdevelope d t o specif yth e mos t appropriat e secondar ystandard , th e ke yquestio ni s whethe r th e rang e o f alternativ e ai r qualit ylevel s discusse d i nSectio nVI I woul d provid e adequat e welfar e protection . Whil e thi s questio ncanno t b e answere d definitively , al l bu t on e o f th e ai r qualit ylevel s discusse d i nSectio n VI I woul d likel yreduc e curren t ambien t lea d loading . Thes e reductions , couple d wit hreduction s achieve d b yth e continue d phase-dow no f lea d i n gasolin e (gasolin e consumptio naccount s fo r 85-90 % o f tota l airborn e lea d emissions) , woul d likel ymitigat e th e potentia l risk s o f lead-induce d ecosyste meffect s occurrin g i nmos t area s o f th e country . I nurba ncenters , alon g roadsides , and i nth e immediat e vicinit yo f majo r poin t source s tha t hav e experience d a long-term , historica l accumulatio no f lead , and wher e th e natura l soi l sink s fo r lea d mayb e approachin g o r hav e exceede d thei r capacit yt o bin d lead , th e mor e sensitiv e component s o f th e ecosyste m (e.g. , soi l microbes ) ma yremai na t som e ris k tha t i s difficul t t o quantif y a t present . Th e leve l o f th e primar ystandar d chose nfro mai r qualit y range s discusse d i nSectio nVI I could , however , provid e adequat e protectio n fro mambient-relate d exposure s fo r most , i f no t al l mammal s bot hdomesti c and wild . Therefore , give nth e availabl e dat a alon g wit hthei r majo r uncertainties , th e staf f recommend s tha t consideratio nb e give nt o makin g th e secondar ystandar d equivalen t t o th e primar ystandar d i nal l respects .P.3 1

APPENDI XA . LEAD METABOLIS MAN D PHYSIOLOGICA L MEASUREMEN T 1 . Lea d Absorptio n Environmenta l lea d compound s ca nb e absorbe d int o th e bloodstrea mfro m th e lun g afte r inhalation , fro mth e gastrointestina l trac t afte r ingestion , o r t o a limite d exten t fro mdirec t derma l contact . I naddition , fetuse s absor blea d throug hth e placenta . Som e lea d tha t i s inhale d o r ingeste d passe s ou t o f th e bodybefor e bein g absorbed , and som e lea d tha t i s absorbe d fro mth e lung s o r th e gu t i s remove d fro mth e bloo d and excreted . Th e absorptio nkinetic s fo r eac hpathwa yar e dependen t upo na numbe r o f factors , includin g th e physica l and chemica l natur e o f th e lea d compound s a t th e tim e o f exposur e and th e presenc e o f othe r modifyin g agent s (e.g. , dietar yconstituents , othe r pollutants) . Onc e inorgani c lea d i s abosrbe d int o th e bloodstrea m i t i s readil ytransporte d t o othe r location s i nth e bodyand doe s no t normall yretai nanycharacteristic s associate d wit hit s exposur e o r absorptio nroute . Derma l absorptio ni s potentiall ysignifican t onl yfo r hig horgani c lea d exposur e i noccupationa l setting s o r othe r specia l circumstances . Thi s route , therefore , wil l no t b e addresse d further . a ) Respirator yAbsorptio n Althoug hlea d aerosol s i nambien t ai r ca nencompas s a broa d siz e rang e dependin g o nproximit yt o source s and meteorologica l conditions , mos t urba n and rura l airborn e lea d mas s i s associate d wit hsubmicro nparticles , wit ha distinc t pea k o f larg e particle s i nth e uppe r en d o f manyo f th e siz e distri

bution s (Davidso nand Osborn , 1984) . Particl e siz e distribution s o f airborn e lea d mass , collecte d fro mvariou s urban , rura l and poin t sourc e area s wer e combine d wit hrecen t lun g depositio ndat a (Cha nand Lippmann , 1980 ) t o estimat e th e mas s fractio ndeposite d i neac hcompartmen t o f aP.3 2

A- 2 mouth-breathin g adult' s respirator ytrac t (Davidso n an d Osborn , 1984) . Base d o n thes e calculations , i t i s estimate d tha t o n average , abou t 2 6 t o 42 % o f airborn e lea d particle s i n thes e differen t location s ar e capabl e o f depositio n int o th e respirator ytrac t o f adults . Thi s i s generall y consisten t wit hdepositio n dat a o n lea d particle s generate d i n laborator y chamber s (Kehoe , 1961 ; Gross , 1981 ; Nozaki , 1966 ; Chamberlai n e t al. , 1978 ) and nea r a highwa y(Chamberlai n e t al. , 1978 ) i n restin g adult s breathin g throug hmouthpieces . I t i s estimate d tha t 10-26 % o f thes e submicro n particle s deposi t i n th e alveola r regio n (Davidso n an d Osburn , 1984 ) wher e absorptio n int o th e bloodstrea m appear s t o b e rapi d and nearl ycomplete , regardles s o f th e inhale d lea d particles ' chemica l form (Chamberlai n e t al. , 1978 ; Rabinowit z e t al. , 1977 ; Morro we t al. , 1980 ; Barry , 1975) . Th e remainin g 16 % o f th e lea d particles , mainl yi n th e coars e mod e (>2. 5 pm ) i s estimate d t o deposi t i n th e extrathoraci c and tracheobronchia l compartment s o f th e respirator ytract . Clearanc e o f
mos t o f thi s materia l t o th e esophagou s ma yb e rapid , excep t fo r non-hygroscopi c particle s lodge d i n th e tracheobronchia l region . Fro mth e esophagous , th e lea d particle s ar e eithe r expectorate d o r swallowed . Lea d absorptio n int o th e bloo d throug hth e gu t i s abou t 40 % b ymas s o f coarse-mod e inhale d particle s (MME D ~ 2. 9 pm ) (Kehoe , 1961) . Tota l respirator yabsorptio n o f inhale d lea d particle s fo r adult s ca n b e calculate d b yaddin g th e product s o f depositio n and absorptio n rate s fo r eac hregio n o f th e respirator ytract . Thus , (1 0 t o 26 % x100% ) fo r th e alveola r regio n i s adde d t o (16 % x40% ) fo r th e combinatio n o f extrathoraci c and tracheobronchia l regions , yieldin g an estimat e o f 16-32 % fo r tota l respirator yabsorptio n o f inhale d lea d particle s amon g adult s i n variou s U.S . atmospheres .P.3 3

A- 3 Give ntha t particle s large r tha n1 t o 3 p mwhic hpredominat e nea r lea d smelter s (withi n2- 5 km ) and othe r stationar ysource s (Jennet t e t al. , 1977 ; Davidso nan d Osburn , 1984 ) ar e likel yt o deposi t i nth e respirator y trac t wit hincreasin g efficienc ya s particl e siz e increase s (Cha nand Lippmann , 1980) , th e abov e estimate s ma yunderestimat e respirator ydepositio n and absorptio no f lea d particle s i nthes e areas . Fo r example , i t i s estimate d tha t 15-55 % o f 5 y mparticle s b

ymas s deposi t i nth e alveola r regio nand 8-45 % deposi t i nth e tracheobronchia l regio no f mouth-breathin g adult s (Cha nand Lippman , 1980) . Th e uppe r bound s o f thes e range s ar e 2 - 3 time s highe r tha nthos e estimate d fo r airborn e lea d particle s i n variou s urban , rural , and poin t sourc e atmospheres , previousl ydiscussed . I nth e absenc e o f extensiv e lea d particl e siz e dat a aroun d lea d poin t source s tha t woul d allo wa separat e analysi s t o calculat e respirator y depositio nand absorptio nfo r thes e area s specifically , i t i s assume d tha t fo r adults , tota l respirator yabsorptio no f inhale d lea d particle s i s approximatel ytwic e a s efficien t (i.e. , 30-60% ) aroun d poin t source s compare d t o th e genera l cas e representin g typica l urba nand rura l areas . Becaus e atmospheri c particl e siz e distribution s and individua l depositio n characteristic s (e.g. , mout hversu s oronasa l breathers ) a s wel l a s othe r factor s (e.g. , ventilatio nrates ) var ywidely , th e abov e discussio nma y no t addres s potentiall yimportan t exposure/depositio ncases . Thi s i s especiall ytru e fo r children , whos e respirator ydepositio nand absorptio n characteristic s hav e no t bee nstudie d experimentally . Age-dependen t difference s i nrespirator ygeometry , ai r flo wconditions , metabolism , and bodycompartmen t weigh t mus t b e applie d t o mak e projections fro madul t data . Th e criteri a documen t cite s a mode l tha t account s fo r som e o f thes e difference s i nestimatin g tha t submicro nparticle s deposi t i nth e respirator yP.3 4

A- 4

trac t o f a 10-yea r chil d 1. 6 - 2. 7 time s mor e efficientl ytha ni na n adul t (James , 1978) . Althoug hth e autho r state s th e mode l shoul d yiel d a "reasonabl e approximation " fo r younge r childre n whos e lung s ar e no t full y developed , Hoffma n e t al . (1979 ) calculate d significantlyhighe r alveola r retentio nrate s fo r submicro n nuclid e aerosol s i n 2- 8 yea r ol d childre n compare d wit h1 0 yea r olds . Anothe r limitatio n o f th e Jame s mode l i s it s assumptio no f unifor mdepositio nthroughou t th e entir e lun g surface , ignorin g enhance d depositio ni nairwa ybifurcation s and othe r "ho t spots " i nlarg e bronch i (Schlesinge r an d Lippmann , 1978 ; Martonen , 1983) . Thi s ma yb e a nimportan t facto r eve nfo r submicro nlea d aerosol s whos e toxicit y i s largel ysystemic , sinc e clearanc e fro m suc hho t spot s wil l b e diminishe d
and becaus e absorptio no f solubl e lea d compound s ca n occu r i nth e uppe r bronchia l airways . Consequently , i t i s uncertai n whethe r th e depositio n and absorptio nfacto r rang e o f 1.6-2. 7 derive d fro mJame s (1978 ) i s applicabl e t o children , especiall ythos e i nth e ag e rang e o f ou r sensitiv e population . Assumin g tha t thi s mode l i s applicabl e t o younge r children , th e absorptio n facto r becomes : (0.1 6 t o 0.32 ) x(1. 6 t o 2.7 ) = (0.2 6 t o 0.86 ) fo r mouth-breathin g childre ni n genera l urban/rura l atmosphere s and similarly , 0.4 8 t o 1. 6 fo r mouth-breathin g childre nlivin g nea r poin t sources . (Obviously , a respirator ydeposition/absorptio n efficienc yfacto r greate r tha n 1. 0 i s impossible. ) Sinc e mos t peopl e shif t t o mout hbreathin g onl ytemporaril ydurin g exercis e o r othe r activities (e.g. , conversation )
o r durin g illnes s (e.g . congestion) , thes e estimates , base d o nmouth-breathin g individuals , likel yoverestimat e tota l respirator ydepositio nand absorptio n ove r th e cours e o f a day . Therefore , dail yrespirator yabsorptio nrate sP.3 5

A- 5

o f 2 5 t o 50 % an d 50 % t o 75 % ar e assume d fo r childre nlivin g i ngenera l urban /
rura l area s and nea r poin t sources , respectively . b ) Gastrointestina l Absorptio n Th e absorptio ni nth e gastrointestina l (GI ) trac t o f lead-containin g compound s presen t i nfood , water , soil , dust , pain t chips , o r othe r material s tha t a chil d ma yinges t i s dependen t upo nth e physical/chemica l for mo f th e material , th e compositio no f th e diet , and th e ag e and physiologica l statu s o f th e individual . Youn g childre nhav e a highe r intak e o f lea d o na bodyweigh t basi s becaus e o f highe r requirement s fo r calories , fluid , and ai r (Mahaffe yand Michaelson , 1980) . I nadditio nt o ingestin g mor e lead , childre nu p t o 8 year s o f ag e absor bbetwee n4 2 an d 53 % o f ingeste d dietar ylea d compare d wit h7 t o 15 % i nadult s (Alexande r e t al. , 1973 ; Ziegle r e t al. , 1978 ; Kehoe , 1961 ; Chamberlai ne t al. , 1978 ; Rabinowit z e t al. , 1980) . Thes e rate s d o no t reflec t th e wid e degre e o f inter-subjec t variabilit y observe d i nth e studie s no r othe r factor s tha t influenc e absorptio ni n children . Fo r example , absorptio nrate s 2 t o 4 time s highe r wer e observe d i nadult s followin g fastin g period s o f 4 t o 1 6 hour s (Blake , 1976 ; Chamberlai n e t al. , 1978 ; Hear d and Chamberlain , 1982 ; Rabinowit z e t al. , 1980) . Suc hincrease s ca nb e expecte d amon g childre nwh o ski p meals , a particula r proble mamon g lowe r incom e group s (Kohand Caples , 1977) . Regula r eatin g pattern s d o no t insur e minimize d dietar ylea d absorption , however . Base d
o nsevera l anima l studies , clinica l investigations , and epidemiologica l surveys , childre nwit hdiet s deficien t i ncalcium , iron , phosphate , zinc , copper , vitami nD , protein , lipids , o r lactos e ca nb e expecte d t o absor b
and retai nlea d t o a greate r degre e (Mahaffe yan d Michaelson , 1980 ; Rose n e t al. , 1981 ; Chilsolm , 1981 ; Hear d and Chamberlain , 1982 ; CD , Tabl e 10-4) .P.3 6

A- 6 Thi s phenomeno nma ypartiall yexplai nth e enhance d neurotoxicit yo f lea d i nanimal s wit hnutritiona l deficit s (Mahaffe yan d Michaelson , 1980) . Th e importanc e o f nutritiona l interaction s wit hlea d absorptio nan d possibl y toxicit yi s particularl ysignificant fo r youn g childre nbecaus e o f thei r larg e fluxe s i nrelativ e nutrien t status . Thes e interaction s ca nonl yb e estimate d qualitativel ywit hpresen t information , however . Althoug h nutritiona l deficiencie s ar e mor e pronounce d amon g lowe r incom e childre n (Mahaffe yand Michaelson , 1980 ; Owe nan d Lippmann , 1977 ; Hambidge , 1977) , the yexis t i nchildre no f al l socio-economi c strat a (CD , p . 10-41) . Th e ingestio no f non-foo d item s suc ha s dust , soi l and dir t throug h
norma l hand-to-mout hactivitie s i nchildre nconstitute s th e greates t contributio no f atmospheri c lea d t o a typica l child' s tota l lea d exposur e (CD , Tabl e 7-25) . Anima l experiment s indicat e tha t lea d o f variabl e chemica l for mi nsoi l o r dus t i s a s availabl e fo r absorptio na s foo d lea d (Dacr e and Te r Haar , 1977 ) and i nvitr o studie s demonstrat e tha t th e acidit yo f th e huma nstomac hi s adequat e t o extensivel ysolubiliz e lea d assimilate d fro m soi l and dus t (Daye t al. , 1979 ; Harrison , 1979 ; Dugga nand Williams , 1977) . Base d o nthes e dat a and th e fac t tha t ingestio no f suc hmaterial s occur s othe r tha na t mealtimes , allowin g fo r potentiall yenhance d absorptio ndu e t o th e previousl ydiscusse d fastin g factor , th e C D estimate s tha t 30 %
o f th e lea d ingeste d i ndus t and soi l i s absorbe d i na chil d (CD , p . 10-10) . A ninvers e relationshi p wa s foun d betwee nparticl e siz e and gastrointestina l absorptio no f lead , especiall yi nth e rang e o f 1-10 0 ym , suc htha t a 6 u m dietar ylea d particl e wa s absorbe d fiv e time s a s efficientl ya s a 19 7 y m particl e (Barltro p and Meek , 1975) . Ther e i s littl e informatio nt o asses s whethe r th e conversio ni nth e physica l for mo f atmospheri c lead-containin g particle s onc e insid e th e comple xgeochemica l matri xo f soi l o r a s dus tP.3 7

A- 7 woul d affec t thei r bioavailabilit yand , consequently , toxicity . Thus , al l atmospheri c lea d particle s tha t hav e deposite d ar e considere d t o hav e th e sam e absorptio nrat e (30% ) i f ingested . 2 . Transplacenta l Transfe r Lea d uptak e vi a thi s pathwa yoccur s rapidl ybeginnin g i nth e twelft h
wee k b f gestatio nand increase s throughou t developmen t (Barltrop , 1969) . Cor d Pb B level s ar e slightl ylowe r tha nmaterna l level s and ar e significantl y correlate d wit hmaterna l exposur e (Alexande r and Delves , 1981 ; Rabinowit z and Needleman , 1982 ; Ryu e t al. , 1978) . 3 . Physiologica l Retention , Distribution , an d Excretio n Th e initia l uptak e o f lea d fro mth e lung s o r gu t i s t o plasma , wher e i t i s rapidl ydistribute d t o red bloo d cells , bone , and virtuall yal l o f th e organ s and tissue s o f th e body(Chamberlai ne t al. , 1978) . Th e leve l
o f lea d a t an

yon e sit e and tim e i s determine d b ycomplex , dynami c interchange s amon g th e variou s tissue s and fluid s tha t affec t thei r respectiv e affinitie s fo r lead . Wit hconsisten t exposur e fo r anextende d period , a nea r steady-stat e distributio nwithi nth e bodyi s achieve d (CD , p . 10-13) . Aprimar ygoa l o f
mor e refine d lea d uptak e estimate s t o b e use d i nconjunctio nwit hth e biokineti c mode l discusse d i nSectio nV.A. 2 wil l b e t o asses s ho wshort-ter mexposure s superimpose d o na long-ter muptak e patter naffec t thi s steady-stat e distributio ni nchildren . a ) Retentio nan d Excretio n I nchildren , 4 7 t o 58 % o f ingeste d lea d o naverag e i s eliminate d i n th e fece s withou t prio r gastrointestina l absorptio n(Alexande r e t al. , 1973 ; Ziegle r e t al. , 1978) , whil e a t leas t a s grea t a percentag e o f inhale d lea d particle s fai l t o deposi t i na child' s respirator ytract , assumin g tha t th e previously-discusse d Jame s (1978 ) mode l i s accurate . I nadults , 40-60 % o f th e lea d absorbe d fro mth e gu t o r lung s int o th e bloo d i sP.3 8

A- 8 excrete d i nurin e wit ha half-lif e betwee n1 8 and 3 7 day s dependin g o ninitia l bloo d lea d o r dosag e (Chamberlai n e t al. , 1978 ; Rabinowit z e t al. , 1976 ; Griffi ne t al. , 1975) . Thi s rapidl yexcrete d fractio ni s estimate d t o b e onl y16 % o f th e absorbe d lea d i ninfant s (CD , Tabl e 10-3 , base d o n Ziegle r e t al. , 1978) . Lea d i s excrete d int o th e urin e b yth e kidneys , bot hb yglomerula r filtratio nand transtubula r flo w(Goyer , 1968) . Lead-induce d rena l effect s (Appendi xD.4 ; CD , Sectio n12-5 ) ma ycompoun d toxicit yb yinterferin g wit hurinar ylea d excretion . Absorbe d lea d ca nals o pas s fro mth e bloo d throug hth e intestina l wal l int o th e gu t and b e eliminate d wit hth e feces , a s i s th e ingeste d and inhale d lea d tha t i s swallowe d and no t absorbe d (Chamberlai ne t al. , 1978) . Th e excretio n rat e o f thi s "endogenous " feca l lea d appear s t o b e roughl y equa l i nchildre nand i nadult s (CD , Tabl e 10-3) . Asmal l portio n o f absorbe d lea d i s excrete d i nswea t and milk , o r i s store d i n tissue s tha t ar e late r she d (e.g. , hair , nails , deciduou s teeth ) (Rabinowit z e t al. , 1973) . Th e balanc e o f th e absorbe d lea d i s transporte d t o sof t tissue s and bone s wher e i t ma yb e store d fo r month s t o year s o r reabsorbe d int o th e blood . I n adults , betwee n1 and 4 % o f dail ylea d intak e i s retaine d i nth e body(Chamberlai n e t a l . , 1978 ; Rabinowit z e t al. , 1977 ; CD , Tabl e 10-3 ) whil e childre n( 2 month s t o 8 year s o f age ) ar e estimate d t o retai n betwee n1 8 and 33 % (Alexande r e t al. , 1973 ; Ziegle r e t al. , 1978 ; CD , Tabl e 10-3) . b ) Distributio n Lea d tha t remain s i nth e bod yca nb e divide d conceptuall yint o separat e physiologica l pools . Th e larges t poo l i s skeleta l (i.e. , bone s and teeth ) whic haccount s fo r abou t 94 % o f tota l bodylea d i nadult s and abou tP.3 9

A- 9 73 % i nchildre nunde r 1 6 year s o f ag e (Rabinowit z e t al. , 1974 ; Barry , 1975) . Th e remainin g bodyburde no f lea d reside s i nsof t tissu e and blood . Unde r typica l conditions , mor e tha n99 % o f bloo d lea d i s boun d withi nre d bloo d cells , primaril yt o hemoglobi n(DeSilva , 1981) , althoug h i t i s th e verysmal l fractio ntransporte d i nplasm a and extracellula r flui d tha t carrie s lea d t o th e variou s bodyorgan s (Baloh , 1974) . Th e selectiv e accumulatio no f lea d i nth e hear t (aorta) , kidne ycortex , and live r (Barry , 1975 , 1981 ; Gros s e t al. , 1975 ) ma yb e associate d wit h th e sensitivit yo f thes e organ s t o elevate d lea d exposure . Th e greate r capacit yo f youn g animal s t o retai nlea d i nthei r tissues , particularl y i nth e brain , ma yhel p t o accoun t fo r th e persistenc e o f neurotoxi c effect s o f variou s type s i nyoun g animal s (CD , 12.4.3.1.5 ) an d childre n (CD , 12.4.2.2.2 ) lon g afte r externa l lea d exposur e ha s cease d and Pb B level s hav e decline d t o "normal" . Furthermore , relativ e uptak e characteristic s and distributio npattern s o f lea d amon g th e region s o f th e brai nmayb e factor s i nlea d neuropatholog y(Grandjean , 1978 ; Klei nand Koch , 1981) . Withi nth e cell , ther e i s selectiv e uptak e o f lea d int o nuclea r inclusio nbodie s an d mitochondri a (Barltrop , e t al. , 1971 ; Castellin o an d Aloj , 1969) , whic hi s consisten t wit hlead-induce d interferenc e o f
norma l processe s i nthes e organelle s suc ha s disrupte d energ ymetabolis m and io ntransport , and possibl e genotoxicit y(CD , 12.2. 1 an d 12.7) . 4 . Kinetic s and Physiologica l Indice s o f Lea d Exposur e Skeleta l lea d i s relativel yinactiv e physiologically , wit hanapproximat e biologica l half-tim e i nnormall yexpose d human s o f 17-2 8 year s (Rabinowit z e t al. , 1976) . Whe nlea d exposur e i s reduce d o r terminated , lea d i s release d fro mth e skeleto ns o tha t th e decline s i nbloo d lea d level s andP.40 ^

A-1 0 excretio nrate s ar e les s tha n woul d b e predicte d fo r th e amoun t absorbed . Thi s i s especiall yeviden t i n occupationall yexpose d adult s (O'Flahert y e t al. , 1982) . Lea d turnove r rate s i ndens e cortica l bone s (e.g. , teeth , tibia , femur ) ar e substantiall yslowe r tha ni n spong ytrabecula r bone s (e.g . rib , vertebrae ) (Steenhout , 1982) . Long-ter mresorptio n rate s o f lea d store d i nth e skeleton , thoug hdifficul t t o measure , hav e bee n derive d fro misotopi c rati o and radiolabe l trace r studie s (Chamberlai n e t al. , 1978 ; Manton , 1977) . Abou t 25 % o f an adult' s Pb B i s estimate d t o resul t fro meventua l re-entr yo f skeleta l lea d (Chamberlai ne t al. , 1978) . Chamberlai n(1983 ) propose s tha t th e bloo d lead/ai r lea d ratio s discusse d i n Sectio nV.B . b e multiplie d b ya facto r o f 1. 3 t o allo wfo r possibl e re-entr yint o th e bloo d o f lea d transferre d t o bon e o r othe r long-ter m storage . Th e releas e o f lea d fro m th e skeleto n ma yb e accelerate d unde r som e stressfu l conditions , suc ha s chelatio ntherapy , nutritiona l deficiencies , hormona l imbalances , bacteria l infections , and possibl ylactatio n wit h subsequen t transfe r o f bot hlea d and calciu mfro mmothe r t o fetu s o r newbor n (Bethe a and Bethea , 1975 ; Rose n and Wexler , 1977 ; Kelle r and Doherty , 1980 ; Gros s an d Pfitzer , 1974) . A s a result , children , whos e skeleta l system s ar e mor e pron e t o som e o f thes e demineralizin g conditions , ar e a t increase d ris k o f remobilizatio n o f skeleta l lead . Th e lead conten t o f deciduou s teet hprovide s an inde xo f historica l exposur e ove r severa l year s sinc e teet haccumulat e lea d up t o th e tim e o f sheddin g o r extraction . Toot hlea d level s appea r t o b e proportiona l t o exposur e (Needlema nand Shapiro , 1974 ; Steenhou t and Pourtois , 1981 ) and t o bloo d lea d level s (Shapir o e t al. , 1978) , and ar e becomin g mor e commonl y use d a s a n exposur e inde xi npopulatio n studie s o f lea d healt heffect s i n childre n(e.g. , Needlema ne t al. , 1979 ; Winnek e e t al. , 1982a , 1983 ;P.4 1

A-l l Ernhar t e t al. , 1981 ; Smit he t al. , 1983) . Unifor mmeasuremen t technique s ar e require d t o insur e comparabilit yi nfutur e studie s sinc e th e absorptio n o f lea d varie s dependin g o nth e typ e o f toot h(e.g. , inciso r versu s molar )
and th e constituen t matri xwithi nth e toot h(e.g. , primar yand secondar y dentine , enamel) . Althoug htoot hlea d level s ar e no t usefu l i nappraisin g curren t exposure , reliabl e technique s o f i nsit u toot hanalysi s ar e bein g develope d suc ha s X-rayfluorescenc e (Shapir o e t al. , 1978 ) which , whe n combine d wit hseria l bloo d measurements , coul d provid e indice s o f ongoin g uptak e o f lea d i ntarge t organs . Whil e mos t o f th e bodyburde no f lea d appear s t o b e toxicologicall y inactiv e du e t o it s storag e i nbon e and othe r possibl y"protective " pool s i nsof t tissu e suc ha s nuclea r inclusion s and atheroscleroti c plaqu e deposit s (Crame r e t al. , 1974 ; Barry , 1975) , th e fractio no f mobil e lea d i nsof t tissu e and bloo d availabl e t o biologica l site s o f actio ndetermine s th e degre e o f potentia l toxicit yt o th e organism . Th e mos t usefu l inde xo f thi s activ e fractio nand o f imminen t toxicit yma yb e th e amoun t tha t i s excrete d i nrespons e t o administratio no f a chelatin g agent , suc ha s EDT A o r penicillamin e (CDC , 1985 ; Chilso me t al. , 1976 ; Chilso mand Barltrop , 1979 ; Saenge r e t al. , 1982 ; Piomell i e t al. , 1984) . Chelatabl e lea d apparentl ycomprise s a fairl ylarg e labil e bod ypoo l mad e u

p o f sof t tissu e lea d and a mobil e compartmen t withi nbon e (CD , p . 10-25) . I ncontras t t o skeleta l lead , turnove r i nsof t tissue s and bloo d i s rapid , wit ha residenc e tim e o f fou r t o si xweek s i nadult s (Rabinowit z e t al. , 1976 ; Griffi ne t al. , 1975) , and possibl ymuc hshorte r i nchildre n (Duggan , 1983) . Despit e thi s transience , lea d adde d t o and remove d fro m thes e pool s reache s equilibriu mwit hrelativel yconstan t exposure . A chang e i nlea d exposur e and absorptio nshift s th e balanc e t o a ne wA-1 2

stead ystat e o f dynami c equilibriu mwithi nabou t 6 0 day s althoug hchange s i nPb B level s ma yb e note d immediatel y(Tol a e t al. , 1973 ; Rabinowit z e t al. , 1973 ; Griffi ne t al. , 1975) . Th e equilibratio nperio d i nchildre n ma yb e quit e differen t give nthei r accelerate d skeleta l metabolis mand apparentl yincrease d lea d resorptio nrate s fro mbone , a s wel l a s th e shorte r half-lif e o f lea d i nthei r bloo d (Duggan , 1983) . I t doe s no t appea r tha t wit hcontinuou s dosin g lea d accumulate s i nth e blood , althoug h i t ma yd o s o i nothe r tissue s (Kehoe , 1961 ; Purse r e t al. , 1983) . Incontras t t o toot hlea d measurement s whic hreflec t lea d exposure s integrate d ove r years , a singl e bloo d lea d measuremen t i s limite d t o reflectin g primaril ysteadystat e exposure s ove r recen t months , althoug h
a Pb B leve l ma yrespon d t o short-ter mchange s i nexposur e i nproportio n t o th e initia l Pb B content . Unde r condition s o f intermitten t exposure s and rapi d growth , a s i s th e cas e wit hchildren , bloo d lea d provide s onl y a stati c pictur e o f a dynami c proces s tha t include s intake , excretion , storage , and mobilization . Ahig hdegre e o f variabilit yi nPb B level s wa s frequentl yobserve d i nchildre nsample d semi-annuall yfro mbirt h throug htw o year s o f ag e (Rabinowit z e t al. , 1984a) , whil e olde r childre n (4-1 2 years ) displa ygreate r stabilit y(Davi d e t al. , 1982) . Inaddition , bloo d lea d i s onl ya nindirec t indicato r o f lea d level s a t critica l site s i nth e variou s organ s and tissue s (Aza r e t al. , 1973 ; Gran t e t al. , 1980) . Fo r instance , level s o f mobilizabl e lead (CaNa 2 - EDTA ) i n26 % o f "asymptomatic " childre nwit hmoderat e elevation s i nbloo d lea d (30-4 9 pg/dl )
wer e simila r t o chelatabl e lea d value s obtaine d i nchildre nwit hover t lea d toxicit y(Piomell i e t al. , 1984) . Again , thi s limitatio no f bloo d lea d a s a ninde xi s especiall yeviden t wit habrup t change s i nexposur e becaus e o f lead' s shorte r retentio ntim e i nbloo d compare d wit hothe rP.4 3

A- l 3 part s o f th e body , particularl yi nth e brai no f th e developin g organis m (Bjorklun d e t al. , 1981 ; Momcliovi c and Kostial , 1974) . Despit e th e limitations , bloo d lea d ha s bee nth e mos t widel yuse d inde xo f exposur e becaus e o f th e eas e and relativ e safet yo f it s collectio n and measurement . I nfutur e researc hther e shoul d b e increase d us e o f seria l bloo d measurement s i ncombinatio nwit htoot hlea d analysis , o r othe r indice s tha t reflec t change s i ntissu e lea d burden s wit hchange s i nexposure .P.4 4

APPENDI XB . ESTIMATE S O F LEAD UPTAK E Fo r eac ho f th e numbere d line s i nTabl e 5- 1 i nth e integrate d lea d uptake / biokineti c model , th e assumption s and estimate s use d i ncalculatin g averag e lea d uptak e fo r childre nfro mth e variou s exposur e pathway s ar e discusse d i nth e correspondingl ynumbere d paragraph s below . 1 . Outdoo r ai r lead : Fo r purpose s o f thi s analysis , i t i s assume d tha t eac hai r lea d concentratio nanalyze d i s maintaine d a t a constan t leve l and therefor e represent s th e maximu maverag e (e.g. , eithe r quarterl y o r monthly ) allowabl e unde r anygive nconcentration . Th e possibl e impac t o f dail yvariation s i nai r concentration s o nuptak e i s assume d t o b e smal l give nth e equilibratio nperio d fo r lea d i nbloo d ( 2 month s i nadults) , th e relativel ysmal l contributio ndirec t inhalatio no f lea d ha s o ntota l exposure , and th e modulatio no f lea d level s afte r depositio nand integratio no f lea d particle s i nth e environment . I t i s als o necessar yt o addres s potentia l difference s betwee nlea d level s monitore d b ystationar ysampler s and actua l exposure s o f childre nt o airborn e lead . Suc hdifference s aris e fro mvariou s vertica l and horizonta l dispersio npattern s o f lea d ove r comple xmicrometeorologica l condition s (e.g. , urba nstree t canyons) . Fo r instance , lea d level s decreas e significantl ywit hdistanc e and wit hheigh t nea r roadway s and poin t source s (Huntzicke r e t al. , 1975 ; Landriga ne t al. , 1975 ; PEDCo , 1977 , 1981) . Short

- and long-ter mroof-to p lea d level s i nNe wYor k Cit ywer e abou t 60-80 % o f stree t leve l reading s (Lio ye t al. , 1980 ; Bauma ne t al. , 1982) . Despit e suc hspatia l gradient s and inter-sit e variability , i t i s assume d tha t th e currentl ydesigne d lea d monitorin g networ k wil l adequatel ydifferentiat e pollutan t variabilit yand instance s o f significan t excursions , and tha t give nth e relativel ysmal l contributio no f inhale d outdoo r airborn e lea d t o tota l exposur e t o atmospheri c lead , th e leve l monitore d b ya fixe d sample r i s a reasonabl e representatio no f outdoor , inhalabl e lea d exposure .P.4 5

B- 2 2 . Indoo r ai r lead : Th e penetratio no f atmospheri c lea d int o residentia l structure s depend s o nth e siz e o f th e lea d particles , meteorologica l conditions , and th e permeabilit yo f th e windows , doors , and wall s o f th e home . Arang e o f indoor/outdoo r ratio s ha s bee nfoun d (0.3-0.8 ) fo r differen t citie s and structure s (Yoco me t al. , 1971 ; Yocom , 1982 ; Genera l Electri c Company , 1972 ; Moscheandra s e t al. , 1981 ; Halpern , 1978 ; Ber k e t al. , 1981 ; Tosteso n e t al. , 1982 ) and i s applie d t o th e urba nsituation . Nea r poin t source s wher e larg e particle s predominat e and infiltratio n int o home s i s low , th e rati o appear s t o b e close r t o 0. 3 (Cohe nand Cohen , 1980) . 3 . Tim e spen t outdoors : Th e amoun t o f tim e spen t betwee nindoo r and outdoo r environment s varie s amon g youn g childre n dependin g o nthei r stag e o f developmen t (i.e. , infant , toddler , pre-school) , season , geographica l location , and famil ybehavior . Fo r presen t purpose s a rang e o f 2- 4 hour s pe r dayspen t outdoor s (and therefor e 20-2 2 hour s spen t indoors ) i s considere d
a reasonabl e averag e (CD , p . 7-42) . 4 . Tim e weighte d ai r lea d concentration s fo r eac hleve l i s estimate d by : [(outdoo r concentratio n xtim e spen t outdoors ) + (indoo r concentratio n
xtim e spen t indoors) ] •* • 2 4 hours . 5 . Th e volum e o f ai r breathe d eac hdayi s dependen t o nage , body size , lun g capacity , altitude , and activit yo f th e child . Fo r instance , ventilator yvolum e ca nincreas e three-fol d durin g strenuou s exercis e (Cotes , 1979) . Ther e ar e fe wdat a fo r youn g childre nand th e estimate s o f 4. 6 m 3 /da y(ICRP , 1975) , 6 m 3 /da y(Nutritio n Foundation , 1982) , and 1 0
m 3 /da y(CD , p . 7-39 ) fo r 2-yea r old s hav e bee n use d t o construc t a rang e o f averag e ventilatio nrates . 6 . Th e rang e o f tota l lea d intak e b yinhalatio n fo r eac hai r lea d leve l i s compute d b

ymultiplyin g bot hth e estimate d uppe r and lowe r boun dB- 3

time-weighte d averag e concentration s o f ai r lea d b yuppe r and lowe r boun d estimate s o f th e volum e o f ai r respire d pe r day . 7 . Respirator ydepositio nand absorption : Onl ya portio no f inhale d lea d i s deposite d i nth e lung s and subsequentl yabsorbe d int o th e bloodstream . Th e depositio nefficienc yo f lea d particle s depend s primaril yo nthei r siz e and th e physiolog yand rat e o f breathin g o f th e individual . I n Appendi xA (Sectio nla) , a respirator ydeposition/absorptio nrat e o f 2 5 t o 50 % i s calculate d fo r youn g childre nlivin g i n typica l urban/rura l areas , whil e
a rat e o f 5 0 t o 75 % i s calculate d fo r thos e livin g nea r poin t sources . 8 . Tota l lea d uptak e fro m th e ai r i s th e produc t o f tota l intak e an d th e lun g deposition/absorptio nfactor . 9 . Averag e dietar ylea d consumption : I nderivin g thes e estimates , i t i s necessar yt o mak e severa l generalize d assumption s tha t d o no t accoun t fo r spatia l and tempora l variation s i nth e additio n o f atmospheri c lea d t o th e diet . Fo r example , wit hth e exceptio no f self-sufficien t households , mos t foo d i s raised , packaged , and consume d i n differen t locations , thereby blendin g th e effect s o f differen t atmospheri c lea d level s fro maroun d th e country . Furthermore , ther e ma yb e a tim e la g betwee n lead' s introductio n int o th e atmospher e and it s incorporatio n into , and ingestio n vi a th e diet . Nevertheless , i t i s clea r fro mth e mos t recen t dat a tha t depositio no nand absorptio nint o crop s b ylea d throughou t th e countr yserve s a s a significan t rout e o f anima l and huma nexposur e t o atmospheri c lea d (CD , Tabl e 7-18) . Th e recen t EP Arevision s t o th e gasolin e lea d conten t phasedow nschedul e (EPA , 1985b ) wherebyth e standar d i s reduce d fro m1.1 0 gram s pe r gallo n o f leade d gasolin e (gplg ) t o 0.1 0 gplg , effectiv e Januar y1 , 1986 , ca n b e expecte d t o eventuall yreduc e dietar ylea d consumptio ni nrelatio n t o reduce dB- 4

atmospheri c lea d depositio nnationwide . Give nth e wid e spatia l distributio no f atmospheri c lea d ove r tim e t o differen t population s vi a th e foo d pathway , i t i s difficul t t o reliabl y estimat e dietar ycontribution s o f lea d unde r alternativ e ai r lea d level s i n th e future . Estimate s o f curren t mea ndietar ylea d intak e level s are , however , provide d i nth e criteri a documen t (CD , Tabl e 7-25) . B yapplyin g FDAdat a o nlea d conten t o f variou s food s bot hbefor e and afte r processing , packaging , and preparation , and o ndietar ypattern s (Beloia nand McDowell , 1981 ; Jelinek , 1982 ; Nationa l Foo d Processor s Association , 1982 , Pennington , 1983 ; Wolni k e t al. , 1983 ; U.S . FDA , 1984) , th e C D estimate s that , o nth e average , 25. 8 pg o f dietar ylea d ar e ingeste d dail yb ya 2-yea r ol d chil d
and tha t 10. 2 pg o f tha t ca nb e attribute d t o atmospheri c depositio no f lea d o nvegetatio no r soi l surfaces . Th e remainin g 15. 6 pg/da yi s attribute d t o lea d solde r and t o undetermine d sources . I t i s likel ytha t furthe r researc hwil l sho wtha t th e lea d estimate d t o b e fro mundetermine d source s i s par t atmospheri c i norigi nan d par t fro mindustria l metal s (CD , p . 7-42) . Becaus e th e U.S . FDA , i nconjunctio nwit hth e Nationa l Foo d Processor s Association , i s activel ypursuin g program s t o furthe r reduc e lea d i nfoods , th e C D estimate s tha t lea d i ncanne d food s shoul d eventuall ydeclin e b y70 % (CD , p . 7-48) . Th e mea nvalu e o f 15. 6 pg/da ycurrentl yattributabl e t o lea d solde r an d undetermine d source s i s therefor e adjuste d b yanintermediat e facto r o f 35 % t o 10. 1 pg/day . Th e remainin g lea d i nth e die t i s apportione d t o atmospheri c lea d deposition . Mos t crop s ar e grown , and mos t animal s ar e raised , i nrura l
area s wher e atmospheri c lea d ha s bee nprimaril yattributabl e t o gasolin e lead . I t i s necessar ytherefor e t o estimat e th e impac t o f th e recen t revision s t o th e lead-in-gasolin e phasedow nschedul e s o tha t dietar ylea d consumptio nB- 5

unde r alternativ e ai r lea d level s ca nb e estimate d t o represen t futur e trends . By1990 , th e averag e maximu m quarterl yvalu e du e onl yt o mobil e sourc e impact s fo r population-oriente d o r neighborhoo d scal e monitorin g site s i s estimate d unde r th e revise d phasedow nprogra mt o b e approximatel y0.0 1 t o 0.0 2 pg/m 3 (Battye , 1985b) . Projecte d remot e o r rura l monitorin g value s wer e no t analyzed . Base d o nth e projection s fo r neighborhoo d scal e monitors , i t i s clea r tha t regardles s o f wha t th e lea d NAAQ S is , th e averag e ai r lea d level s i narea s awa yfro mpoin t source s (wher e foo d i s generall ygrown and raised ) i nth e U.S . wil l b e belo wcurren t rura l ai r lea d levels . Assumin g tha t majo r poin t sourc e emission s hav e predominatel yloca l impacts , i t i s estimate d tha t th e averag e ai r lea d leve l i narea s wher e foo d i s grown and raise d wil l b e approximatel y0.0 1 pg/m 3

. I n comparison , th e CD' s estimate d mea n atmospheri c contributio nt o th e die t o f 10. 2 pg/da yC D i s derive d primaril y fro mdat a o nfood s fro mcrop s growno r animal s raise d i n th e U.S . sinc e 1979 ; durin g thi s period , maximu m quarterl yaverag e ai r lea d level s i n non-urba n area s hav e generall ybee nbelo w0.4 5 pg/m 3 i nnon-urba narea s and belo w1. 0 pg/m 3 i n urba n area s (CD , Tabl e 7a-3 ; EPA , 1984) . I t is , therefore , assume d tha t fo r averag e ai r lea d level s o f 0.25 , 0.50 , 0.75 , and 1. 0 pg/m 3 , th e contributio no f atmospheri c lea d t o th e die t wil l b e reduce d b

yroughl ya facto r o f 1 0 fro mtha t estimate d unde r curren t conditions , i.e. , 10. 2 t o 1. 0 pg/day . Fo r an ai r lead leve l tha t i s constantl ymaintaine d a t 1.25 , 1.5 0 an d 1.7 5 pg/m 3 , i t i s assume d tha t som e non-automotiv e emission s o f lea d wil l
caus e a smal l effec t o ndietar ylea d consumptio n suc htha t th e averag e atmospheri c contributio nwil l b e reduce d approximatel yfive-fold , fro m10. 2 t o 2. 0 pg/day .P.4 9

B- 6 Th e tota l averag e dietar ylea d intak e fo r alternativ e ai r lea d level s ca nthe nb e calculate d b yaddin g th e atmospheri c contributio nt o th e estimate d lea d intak e fro msolde r and undetermine d sources . 10 . Gu t absorption : Onl ya portio no f ingeste d lea d i s absorbe d int o th e bloodstream . A s discusse d i nAppendi xA , th e percentag e o f absorptio n o f lea d varie s greatl ydependin g o nth e content s o f th e gu t and th e nutritiona l statu s o f th e child . Arang e o f absorptio nrate s betwee n4 2 an d 53 % (Ziegle r e t al. , 1978 ; Alexande r e t al. , 1973 ) i s assume d fo r children . 11 . Dail ydietar ylea d uptak e i s obtaine d b ymultiplyin g row s 1 0 and 9 . 12 . and 13 . Dust/soi l concentrations : A s discusse d i nSectio nIV , th e accumulatio no f lea d i nstree t and househol d dust s and soil s appear s t o b e directl yrelate d t o th e volum e o f traffic , and inversel yrelate d t o distanc e fro mneighborhoo d street s and roads , distanc e fro mlea d painte d and bric k house s and buildings , and distanc e fro mlea d smelter s and othe r poin t sources . Despit e thes e observations , ther e i s littl e informatio no nth e relationshi p betwee ndifferen t ai r lea d level s and dus t level s ove r time . Predictin g suc h
a relationshi p woul d requir e th e inclusio no f manycomple xvariable s suc ha s depositio nrates , chemica l and physica l characteristic s o f th e lea d particle s and soils , topographi c and meteorologica l conditions , frequenc yo f stree t washing s and precipitation , backgroun d dus t concentrations , and informatio n o ntranspor t o f dus t and soi l int o home s and buildings . Give ncurren t data , ther e woul d b e a nextremel ylarg e amoun t o f uncertaint ysurroundin g any on e o f thes e variable s fo r differen t locations . I norde r t o predic t outdoo r and indoo r dus t concentration s unde r alternativ e ai r lea d concentrations , relianc e i s place d o navailabl e studie s tha t includ e measurement s o f bot hai r level s and dus t and/o r surfac e soi l concentration s (se e Tabl e B-l) . Thes e dat aB- 7

Tabl e B-l

. Summar

yo fEnvironmenta l Lea d Measurement s fro m Variou s Location s Averag e Ai rLead (pg/m 3 ) 0.2 0 0.4 0 0.2 8 0.3 4 0.4 0 0.6 8 0.8 2 0.95 a 1. 6 - 2. 0 0.2 7 0.25 5 0.27 8 0.1 9 0.3 0 0.4 5 0. 8 3.6 7 Averag e

Outdoo rSoil / Dus tLead (pg'/g ) 43 33 6 51 8 4,88 1 8 1 339 262

_ 1,20 0 63 1 39 8 43 8 8 1 11 2 11 4 46 6 2,56 0 Averag e Indoo r Dus tLead (pg/g ) 70 19 0 565 1,80 3 21 1 30 0 47 9 50 0 11,00 0 41 2 42 4 33 1 8 0

- Location/Referenc e

Variou s Site s i n U.K

. (DOE , 1983 ) Derbyshire , U.K

. (lea d minin g area ) (Barltro p e tal. , 1975 ) Omah a (Angl e an d Mclntire , 1978 )

Ne wHave n (Star k

e tal. , 1982 ) Hartfor d (Lepowe tal. , 1975 ) Nea rnon-ferrou s smelter s in : Bartlesvill e Anacond a Palmerto n Aj o (Hartwel l e tal. , 1983 ) Rura l area , Brussels , an d nea rlea d smelter , Belgiu m (Roel s e tal. , 1978 , 1980 ) 0.4 1 69 0 1,23 9 Nea rArnhei m lea d smelter , Hollan d (Brunkree fe tal. , 1981 ; Dieme l e tal. , 1981 ) 0.8 2 92 4 71 3 Nea rToront o lea d smelter s an d i n 3.0 1 2,41 6 1,55 0 cit y(Robert s e tal. , 1974 ) 1. 3 42 7 1,47 9 Nea rE l Paso lea d smelte r(Mors e 2.7 b 948 f8,623 ce tal. , 1979 ) 1,70 0 Nea rSilve rValle ylea d smelte r 3,90 0 (Yanke l e tal. , 1977 ; Idah o Dept

. 3,40 0 Healt h an d Welfare , 1977 ) 3,30 0 2,40 0 10,40 0 11,70 0 Estimate d fro m SAR0A D monitorin g dat a ^Geometri cannua l mea n o fai rlea d level s measure d withi n 5 k m o fsmelte r
c Geometri cmea

n o fdus tan d soi l lea d level s withi n 6. 4 k m o fsmelte r 0. 5 0. 5 0. 7 3. 0 6. 6 14. 2 16. 8 70 0

337 2,20 0 1,30 0 1,20 0 3,00 0 7,47 4P.5 1

•3- 8
ar e limite d i ntha t sample s wer e collecte d onl yonc e fro ma smal l numbe r o f locations . I t i s assumed , however , tha t bot hth e ai r and dus t measurement s wer e representativ e o f lea d level s i nthos e area s and tha t th e studie s employe d comparabl e samplin g and analytica l techniques . Becaus e o f historica l accumulation s o f relativel ylarg e lea d particle s nea r primar yand secondar ylea d smelter s and othe r poin t sources , outdoo r soi l an d dus t lea d concentrations , and consequentl ypotentia l exposures , ar e significantl ygreate r i nthes e areas , regardles s o f ongoin g emissio n controls . Therefore , separat e exposur e estimate s fo r individual s livin g nea r poin t source s unde r alternativ e ai r lea d level s ar e required . Dat a collecte d nea r lea d smelter s wher e emission s wer e comparabl e t o curren t situation s wil l b e use d t o develo p outdoo r soil/dus t lea d level s fo r poin t source s meetin g differen t ai r lea d concentrations . Thre e o f th e studie s no t use d t o develo p relationship s requir e comment : a ) Barltro p e t al . (1975 ) surveye d a rura l distric t i nEnglan d wit hminima l ai r pollution , bu t wit hhig hnatura l soi l lea d level s a s wel l a s bein g contaminate d b

ynearl y190 0 year s o f minin g activity . Thus , lea d depositio no nsoi l surface s ha d probabl ybee nlo wfo r som e time , i ncontras t t o th e othe r studie s i nwhic hsurfac e contaminatio nwa s ongoin g o r ha d bee n recentl yreduced ; b ) Eigh t o f th e te nhome s sample d b yLepo we t al . (1975 )
wer e buil t prio r t o 194 0 and apparentl yha d significan t source s o f leade d pain t tha t ha d bee n"corrected " fo r previou s t o th e study . I naddition , som e o f th e home s wer e locate d clos e t o heavil ytrafficke d roadways , wher e stree t leve l ai r concentration s range d betwee n2. 2 and 7. 7 pg/m 3 , thu s lendin g uncertaint yt o a dust/ai r relationshi p fro mthi s studybase d o n annua l averag e ai r lea d level s measure d a t centrall ylocate d monitor s distan t fro mth e dus t samplin g sites ; c ) Th e smelte r studie d b yP.5 2

B- 9 Yanke l e t al . (1977 ) operate d fo r severa l year s wit hseverel ylimite d ai r pollutio ncontro l capacit ydu e t o a baghous e fir e i n1973 . Th e ver y hig hsoi l and dus t lea d concentration s measure d nea r th e smelte r the nwoul d
no t b e expecte d toda ywit hnormall ycontrolle d emissions . I naddition , th e hig hindoo r dus t lea d level s measure d b yBrunekree f e t al . (1981 ) and Dieme l e t al . (1981 ) nea r th e Belgia nsmelte r wer e probabl ydue , i npart , t o extremel yhig hlea d conten t (u p t o 40 % b

yweight ) i npeelin g pain t i nol d house s (buil t aroun d 1900 ; th e childre ni nthes e house s wer e exclude d fro m analysi s o f bloo d lea d levels) . Wit hthes e exceptions , th e studie s liste d i nTabl e B- l appea r t o hav e sample d a broa d spectru mo f home s (e.g . bot hlo wand middl e class , ol d and modern , wit hand withou t leade d paint ) an d neighborhood s tha t ca n b e considere d fairl yrepresentativ e o f curren t U.S . condition s i nurba nand poin t sourc e areas . Althoug hfa r fro mconclusive , th e availabl e dat a sugges t th e generalize d relationship s betwee nai r lea d and dus t lea d concentration s presente d i nTabl e B-2 . Th e range s represen t boundarie s tha t encompas s th e majorit yo f observe d and interpolate d value s and ar e use d t o estimat e stree t dust/soi l lea d and indoo r dus t lea d concentration s unde r alternativ e ai r lea d levels . Interpolation s wer e necessar ybecaus e o f th e limite d amoun t o f data . Fo r instance , Angl e and Mclntir e (1978 ) and DO E (1982 ) repor t outdoo r soil / dus t lea d concentration s i nurba narea s wit hanaverag e ai r lea d leve l
o f approximatel y0. 4 pg/m 3 t o b e 8 1 and 33 6 ppm(pg Pb/ g soi l o r dust) , respectively . On e o f th e rura l contro l area s studie d b yRoel s e t al . (1978 ) ha d a noutdoo r soil / dus t lea d concentratio no f 11 4 ppmcorrespondin g t o an ai r lea d leve l o f 0.4 5 pg/m 3

. Th e rang e o f 80-35 0 ppmi s thu s estimate d base d
o nthes e data . Fo r indoo r dust , th e forme r tw o studie s repor t concentration sP.5 3

B-1 0

Tabl e B-2 . Generalize d Relationship s Betwee nLea d Concentration s

i nAi r and i n Dust s and Soil *

A i r Lea d (pg/m 3 ) 

### 0. 2 0. 3 0. 4 0. 5 0. 6 0. 7 0. 8 1. 0 1.2 5 

### 1. 5 1.7 5 Outdoo r

Genera l 40-15 0 60-25 0 80-35 0 100-45 0 200-60 0 250-65 0 300-95 0 500-115 0 600-125 0 700-140 0 775-145 0 Soil/Dus t Lea d (ug/g ) Near Point Sourc e 80-37 5 200-60 0 250-70 0 350-80 0 450-100 0 550-115 0 650-130 0 750-145 0 850-160 0 1000-175 0 1075-195 0 Indoo r Dus t (pg/g )
Genera l 70-10 0 70-15 0 140-20 0 220-30 0 250-50 0 300-62 5 450-70 0 525-87 5 625-100 0 750-115 0 800-120 0 Lea

d

Near Point Sourc e 80-40 0 200-60 0 350-65 0 450-70 0 550-75 0 600-80 0 650-90 0 800-115 0 1050-140 0 1200-170 0 1350-190 0

^Derive d fro menvironmenta l survey s i n Tabl e B-l . Th e range s o f dus t an d soi l concentration s fo r eac hai r lea d leve l reflec t difference s i n emissio n sources , distanc e o f measuremen t site s fro mthes e source s (withi n5 k mfo r poin t sources ) and characteristic s o f th e home s (e.g. , permeability , pain t condition , etc.) , an d othe r variable s assume d t o b e representativ e o f rea l worl d conditions . Value s tha t ar e underline d represen t actua l dat a (rounde d of f wher e necessary ) liste d i n Tabl e B-l , whil e th e remainde r ar e interpolation s usin g th e mos t representativ e and plausibl e dat a i n Tabl e B- l and a n assumptio n tha t ther e i s a directl yproportiona l relationshi p betwee nai r lea d and lea d i n soi l and dus t (bot hindoor s and outdoors) .P.5 4

B-l l

o f 19 0 an d 21 1 ppm ; thes e wer e chose na s anuppe r boun d estimat e fo r 0. 4 pg/m 3 whil e th e lowe r boun d o f 14 0 ppmwa s derive d b ymultiplyin g b

y tw o th e lowe r boun d estimat e fo r a nurban/rura l are a wit hanai r lea d leve l
o f 0. 2 pg/m 3 (7 0 pp mfro mDOE , 1982) . Outdoo r soil/dus t lea d concentration s nea r poin t source s tha t ca nreasonabl yb e associate d wit h0. 4 pg/m 3 wer e derive d fro m

Brunekreef/Dieme l e t al. , 198 1 (69 0 ppm ) an d b yinterpolatin g th e level s measure d b yHartwel l e t al . (1983 ) concurrentl ywit haverag e ai r lea d level s o f aroun d 0.2 5 - 0.2 8 pg/m 3

. Th e resultin g estimat e i s 62 4 t o 63 0 pp m and , whe ncombine d wit hth e Brunekree f value , result s i na nuppe r boun d estimat e o f 70 0 ppm . Th e lowe r boun d estimat e o f 25 0 pp mi s assume d base d o nth e level s o f 8 0 ppmobserve d b yHartwel l e t al . a t 0. 2 pg/m 3 , 46 6 pp msee na t 0. 8 pg/m 3 b yRoel s e t al. , and 33 7 pp msee na t 0. 5 pg/m 3 b y Yanke l e t al . Thi s brie f exampl e a t 0. 4 pg/m 3 onl ysuperficiall yillustrate s th e limitation s o f th e availabl e dat a an d th e judgment s necessar yt o fil l i ngap s usin g variou s assumptions , suc ha s th e assumptio no f a direc t and roughl ylinea r relationshi p betwee nai r lea d and surfac e deposition . I t mus t b e emphasize d tha t ther e i s a grea t dea l o f uncertaint yi nthes e estimates . Fo r instance , assumin g tha t a decreas e i nai r lea d fro m1. 0 t o 0. 8 pg/m 3 woul d resul t i nreduce d soi l an d dus t lea d concentration s ma y overestimat e th e impac t tha t suc ha decreas e i nlea d emission s woul d hav e o nchildren' s exposure , particularl yvi a outdoo r soi l whic htend s t o retai n lea d fo r lon g period s o f time . Dus t lea d level s woul d likel yrespon d relativel ymor e contemporaneousl yt o reduce d ai r emissions , bu t th e necessar y lengt ho f tim e i s difficul t t o estimate . 14 . Tim e weighte d concentration s o f lea d i ndus t and soi l tha t a chil d i s expose d t o i s compute d by : [(outdoo r soil/dus t lea d concentratio nP.5 5

B-1 2
xtim e spen t outdoors ) + (indoo r dus t lea d concentratio nxtim e spen t indoors) ] * 2 4 hours . 15 . Amoun t o f dir t ingested : Han d t o mout hactivit y(e.g. , thumb suckin g and finge r licking ) and immatur e dietar yhabit s (i.e. , th e retrieva l
and subsequen t consumptio no f foo d fro mdust ysurface s o r soil) , whic har e norma l behavoria l characteristic s o f childre nu p t o fiv e year s o f ag e (Lin-Fu , 1972) , mak e soi l and dus t majo r source s o f ingeste d lea d fo r childre n(Charne ye t al. , 1983) . Ther e i s littl e informatio no nth e amoun t o f dir t a chil d eat s i nth e norma l cours e o f a day . Base d o na smal l numbe r o f direc t measurements , Daye t al . (1975 ) estimate d tha t unde r averag e urba ncondition s (and afte r 3 0 minute s o f norma l playgroun d activity) , 5 t o 5 0 mg o f dir t fro ma child' s hand s ca nb e transferre d t o a typica l "stickysweet" . Asmal l chil d playin g i ndir t easil yingest s 1 0 m g o f soil/dus t wit heac hepisod e o f hand t o mout hactivit y(Dril l e t al. , 1979) . Te nhand-mout hactivitie s pe r da y(o r ingestio no f 2 t o 2 0 "sweets" ; Daye t al. , 1975 ) woul d thu s resul t i nth e ingestio no f 1U 0 m g (0. 1 g ) o f dus t and soi l pe r da y(Lepo we t al. , 1975) . Thi s estimat e ha s bee nuse d i nsevera l document s (Dril l e t al. , 1979 ; NAS , 1980 ; CD , Tabl e 7-23 ) an d wil l b e use d her e a s well . Childre nwit hpic a wh o displa ypattern s o f repetitiv e hand-to-mout h activit yo r delibertel yinges t paint , plaster , pape r and othe r non-foo d item s includin g dir t mayb e expose d t o considerabl e amount s o f lea d compare d t o childre nwh o onl yinadvertantl yinges t foreig nsubsances . Futur e reduction s i nairborn e lea d emission s ar e no t likel yt o significantl yalte r thei r exposur e t o lea d ove r th e nex t fe wyears . Regulator yalternative s t o protec t thes e childre nar e discusse d i nSectio nVII . 16 . Lea d intak e fro m dus t and soi l i s compute d b ymultiplyin g th e tim e weighte d concentratio no f indoo r and outdoo r soil/dus t concentration s b y10 0 mg .P.5 6

B-1 3
17 . Gu t absorptio no f dirt : A s discusse d i nAppendi xA , a n absorptio n rat e o f 30 % i s assume d fo r ingeste d lea d i ndus t and soil . 18 . Tota l lea d uptak e fro m dus t and soi l i s obtaine d b ymultiplyin g row s 1 6 and 17 . 19 . Tota l lea d uptak e i s th e sumo f row s 8 , 11 , and 18 .P.5 7

APPENDI XC . UPTAK E AND BLOO D LEAD CONCENTRATIO N Severa l studie s ar e availabl e tha t provid e th e necessar ylinkage s t o relat e th e exposure/uptak e estimate s calculate d unde r differen t ai r lea d level s i n th e integrate d uptak e mode l (Se e Sectio nV.D.I(a) ) t o children' s Pb B levels . Th e result s o f thes e studie s ar e summarize d i nSectio n V.D.l(b ) and ar e discusse d below , a ) Dietar yLea d Ingestio n Studie s i nInfant s Studie s tha t hav e measure d dietar ylea d intak e concurrentl ywit h Pb B level s amon g infant s and toddler s ar e compare d i nth e criteri a documen t (Tabl e 11-49) . Althoug hprecis e estimate s o f dietar ylea d consumptio n ca n no t b e assumed , thes e studie s (U.K . Centra l Directorate , 1982 ; Sherloc k
e t al. , 1982 ; Ry

u e t al. , 1983 ) hav e severa l advantages : 1 ) carefu l contro l
and analysi s o f dietar yintake ; 2 ) minima l lea d exposur e t o source s othe r tha n th e die t a s th e studypopulatio n(infants ) i s relativel yimmobile ; and 3 ) th e impac t o f tota l lea d exposur e (i.e. , fro mal l sources ) o nbloo d lea d
ca nb e estimate d b

yapplyin g intake/bloo d lea d relationship s becaus e trace r studie s (Chamberlai ne t al. , 1978 ; Rabinowit z e t al. , 1976 ) sho wn o difference s i nth e distributio no f lea d t o tissue s whethe r take nu p fro mlun g o r gut . Bot hth e U.K . Centra l Directorat e and th e Sherloc k e t al . studie s involve d infant s wit hrelativel yhighPb B level s and hig hintakes . Becaus e th e Pb B level s ( < 2 0 yg/dl ) and lea d intake s o f th e Ryu infant s ar e mor e relevant , th e criteri a documen t conclude s tha t th e slop e fro mthi s studyi s th e bes t availabl e estimat e (CD , p . 11-126) . Th e relationshi p betwee nlea d intak e and infants ' bloo d lead , derive d b yEPA' s analysi s o f Ryu e t al . (1983 ) is : Pb B = A+ 0.1 6 PbD , wher e "PbD " represent s dietar ylea d intak e and "A " represent s non-dietar ylead . Applyin g th e gastrointestina l absorptio n rate s (42-53% ) use d i n Sectio nV.D. I t o conver t dietar yintak e level sP.5 8

C- 2 int o uptak e and assumin g a backgroun d Pb B o f 4 pg/dl , base d o na studyo f bloo d lea d and lea d intak e i nBosto ninfant s (Rabinowit z e t al. , 1984b) , yield s tw o possibl e lea d uptake/Pb B relationship s dependin g o nth e absorptio n rate . Thes e relationship s ar e illustrate d i nFigur e 5- 1 i nth e summar yo f uptake/Pb B relationships . b ) Applicatio no f Chamberlai nand Hear d Analysi s A nattemp t t o relat e bloo d lea d and absorbe d lea d wa s mad e b yChamberlai n an d Hear d (1981 ) usin g epidemiologica l and clinica l dat a o nadul t me n (William s e t al. , 1969 ; Kehoe , 1961 ; Nordman , 1975 ; Zurl o and Griffini , 1973 ; Fuga s and Saric , 1979) . Tota l dietar yand airborn e lea d uptak e wa s estimate d usin g calculation s simila r t o thos e presente d i nth e integrate d lea d uptak e mode l i nSectio nV.A . Th e resultin g eye-fitte d curv e i s showni n Figur e C-1 . Th e dashe d curv e i s tha t previousl yderive d i na NA S (1972 ) report , Th e straigh t lin e i s th e increas e i nbloo d lea d t o b e expecte d fro ma n increas e i nlea d uptak e base d o nth e assumption s give ni nChamberlai ne t al. , (1978) : a ) a fraction , 0.55 , o f th e uptak e become s attache d t o re d bloo d cells ; b ) th e biologica l half-lif e o f lea d i nbloo d i s 1 8 days ; c ) a factor , 1.3 , i s t o b e allowe d fo r long-ter mresorptio nand re-entr yint o bloo d o f
som e o f th e lea d whic hi s store d i nbone ; and d ) th e mas s o f bloo d i s 540 0 gram s Wit hthes e assumptions : APb B = 0.5 5 x1 8 x1. 3 = 0.3 4 pg/d l pe r pg/da y AUptak e 5 4 x0.69 3 I norde r t o appl ythi s equatio nt o children , severa l adjustment s ar e required . Fo r example , th e mas s o f bloo d i nyoun g childre ni s estimate d t o fal l betwee n80 0 an d 150 0 gram s (Wintrobe , 1979) . I t ha s bee nsuggestee d tha t th e half-lif e o f lea d i nchildren' s bloo d i s shorte r tha ni nadult s (Duggan , 1983 ) althoug hn o direc t measurement s hav e bee ntake nt o allo wa reliabl e estimate .P.5 9



### C- 3

30 0 Uptake . T(pg/d l Figur e G-1 , Relationshi p betwee ndail ylea d uptak e an d bloo d lea d i n

adul t men . Fro mChamberlai nan d Hear d (1931) .P.6 0

C- 4 Becaus e ther e i s n o informatio navailabl e o nappropriat e factor s t o adjus t thi s specifi c equatio nt o children , th e derive d relationshi p fro m adul t dat a illustrate d i nFigur e C- 1 i s illustrate d i nFigur e 5- 1 onl y fo r comparativ e purposes , c ) Lea d Balanc e Studies : Compartmenta l Model s T o demonstrat e a causa l relationshi p betwee nlea d i nth e bodyand a biologica l change , i t woul d b e idea l t o kno wth e amoun t o f lea d presen t a t th e sit e and tim e o f th e effect . Fo r instance , i f lea d i s suspecte d t o induc e neuropsychologica l changes , a measur e o f th e lea d leve l presen t i n nerv e cell s whe nth e chang e occurre d woul d b e desirable . Livin g tissue s ca nrarel yb e sampled , and dat a obtaine d a t necrops ycanno t revea l th e variation s i nexposur e throughou t th e individual' s life . Fo r analytica l simplicity , thes e tissue s ca nb e groupe d togethe r o nth e basi s o f lea d distributio ncharacteristic s and bodyburden s o f lea d represente d a s a limite d numbe r o f distinct , homogenous , and well-mixe d pool s o r physiologica l compartment s wit hsimila r kineti c properties . Mathematica l biokineti c model s hav e bee nfitte d t o dat a obtaine d i nlong-ter mbalanc e studie s and t o lea d isotop e trace r experiment s tha t estimat e th e rate s o f inpu t to , transfe r between , and excretio nfro mth e differen t compartment s (Rabinowit z e t al. , 1976 , 1977 ; Batschele t e t al. , 1979 ; Bernard , 1977 ; Mallo n1983 ; Harle yand Kneip , 1985) . Difference s i nth e predictiv e lea d model s hav e bee ndiscusse d b

yBernar d (1977 ) and Batschele t e t al . (1979) . Tw o model s ar e shownschematicall yi nFigur e C-2 . Compartment s a s define d kineticall yar e no t necessaril ycongruen t wit hspecifi c tissue s o r orga nsystems ; th e thre e poo l mode l o f Rabinowit z e t al . (1976 ) consider s blood , th e mos t labil e sof t tissues , and bon e marro w(M . Rabinowitz , persona l communication ) a s par t o f th e centra l compartmen t wher e exchang e take s plac e continuousl ywit hth e secon d (sof t tissue s and labil e bone ) an d(a )

Excretions Leadin Diet , Soil/Oust , Othe r Source s (e.g. , paint ) Ai r Lead

Lung s

Bon e

- 20Om g 7 nq/da v

~ 7 pg/day "sorptio n ~4 8 pg/day 

# 1 Blood 1. 9 m g ~ 1 5"q/^ y Sof t tissue s 0. 6 mg 2 pg/day "3 6 pg/day Urin e -1 2 pg/day Bile , hair , sweat , etc . (b ) Absorptio n ~35. 2 pg/day o i c n

Har dBon e 6 5 mg Sof t Bon e 2. 7 m g „6. 9 uq/day ,12. 5 ug/day h 9 V 1 ' Bloo d 0.4 2 mg L 5 7 pg/da y

^ *

w Live r 1 3 mg

13 3 pg/day Kidney s 0.7 6 m g Urin e andFece s 3 5 ug/day

Figur e C-2 . Schemati c model s o f lea dmetabolis m

i nadul t me ndescribe db y (a ) kabinowit z e t al. , 197 6 an d(b ) Bernard , 1977 . The amount s o f leadineac hcompartment , exchanyiny dail y betwee n compartments , an

dexcrete ddail y

ar e show

nfo r steady

stat e condition s o f continuou s exposur e t o inhale dan dinyeste dlead . Th e amount s o f leadshow nenterin gth e centra l compartmen t ar e th e amount s tha t wer e assume dt o b e absorbe ddail y int o th e systemi c circulatio nfro

m al l source s (Hammon

de t al. , 1981) .

b >P.6 2

C- 6 thir d (immobil e bon e lead ) pools . Th e five-compartmen t mode l propose d b y Bernar d (1977 ) consist s o f pool s tha t ar e mainl yblood , liver , kidney , and sof t an d har d bone . Th e choic e o f pool s o r leve l o f aggregatio ni na mode l depend s o nth e availabl e experimenta l data , th e appropriat e tim e scale , an d th e pre dictiv e use s o f th e analysis , and i s a compromis e betwee naccurac yand complexity . Fo r example , bloo d ca nb e broke ndow nint o plasm a and erythrocyte s and the nfurthe r int o plasm a protein-boun d lead , diffusibl e lead , extracellula r flui d lead , and erythrocyt e proteins . Sof t tissue s ca nb e broke ndownint o brai n(hippocampus , medulla , etc.) , kidneys , liver , hair , and s o on . Th e har d tissu e pool s ca nb e separate d int o compac t (cortical ) an d cancellou s (trabecular ) bones , and teeth ; withi neac ho f these , separat e component s ma yb e neede d t o mode l distinc t diffusio ntim e scale s (Marcus , 1985) . Becaus e th e skeleta l syste mi nyoun g childre ni s rapidl ydevelopin g and i s bot hlarg e and kineticall yactive , i t i s especiall yimportan t t o mode l bon e lea d i nchildren . Unti l suc hrefinement s ar e furthe r tested , a relativel y simpl e 3- 5 poo l mode l shoul d provid e a framewor k fo r predictin g lea d distribution s i nchildren . Thes e model s ar e helpfu l i npredictin g tota l bodyburde no r equilibriu m level s o f lea d ove r tim e i nanyo f th e presume d kineti c compartment s unde r differen t exposur e conditions . Th e basi c assumptio no f th e model s i s tha t th e mas s o f lea d i neac ho f th e compartment s change s accordin g t o a syste m o f couple d first-orde r linea r differentia l equation s wit hconstan t fractiona l transfe r rates . Suc hmodel s predic t tha t whe nth e lea d intak e change s fro m on e constan t leve l t o another , ther e i s a directl yproportiona l chang e i n th e mas s o f lea d i neac hcompartmen t and th e attainmen t o f a ne wequilibrium .P.6 3

C- 7 Th e rate s and magnitude s o f thes e change s ar e dependen t upo nth e rate s o f lea d fluxi nth e tissue s and ca ntheoreticall yb e calculate d fro ma compartmenta l mode l o f th e appropriat e parameters . Suppor t fo r a firs t orde r kineti c mode l fo r lea d metabolis mi s demonstrate d b ycalculations , usin g firs t orde r model s o f sof t tissu e and bon e concentration s o f lead , and othe r element s (calcium strontium , radium) , tha t fi t huma nmeasurement s a s wel l a s b yusin g mor e comple xone s (Johnso n and Myers , 1981 ; Mallon , 1983) . Pb B level s i nadult s afte r exposur e fo r 5 and 1 9 year s hav e bee n compute r simulate d b yHammon d e t al . (1981 ) base d o nprediction s o f th e Rabinowit z and th e Bernar d models . Th e amoun t o f lea d absorbe d eac hday int o th e systemi c circulatio nwa s entere d int o th e compute r progra ma s a singl e unit . Thi s dail yincremen t wa s allowe d t o b e distribute d and excrete d i naccordanc e wit hth e magnitudes o f th e mode l rat e constants . Tabl e C- 1 give s th e predicte d Pb B level s a t th e end o f th e specifie d exposur e period s expresse d a s function s o f th e tota l amoun t o f lea d absorbe d eac hda yfro m al l sources . I t i s assume d tha t thes e linea r mathematica l model s wit hdistinc t rat e constant s fo r eac hlea d compartmen t are , i ngeneral , vali d fo r relativel y lo wt o moderat e lea d exposure s (CD , p . ll.A-2) . Th e studie s tha t hav e experimentall ydetermine d compartmenta l model s i nhuman s hav e use d a verysmal l numbe r o f subjects , however , al l o f who m wer e adul t males , wit ha limite d rang e o f exposur e conditions . Give n th e physiologica l and metaboli c difference s betwee nchildre nand adults , th e projecte d Pb B level s calculate d i nTabl e C- 1 hav e limite d applicabilit yand ar e use d fo r comparativ e purpose s only . Afour-compartmen t biokineti c mode l o f lea d metabolis mha s bee n develope d fro mdat a obtaine d i ncontrolle d singl e dos e and chroni c lea d exposure s o fC- 8

infan t ( 9 months ) and juvenil e (2 2 months ) baboon s (Mallon , 1983 ; Knei p e t al. , 1983) . Dynami c bloo d measurement s and steadystat e bloo d and orga n lea d measurement s wer e accuratel yfitte d t o predic t concentration s o f lea d i nblood , liver , and kidney , and bon e (th e fou r compartment s i nwhic h95 %
o f tota l bodylea d i s contained ) (Hear d an d Chamberlain , 1984) . Huma n metabolis mand growt hpattern s wer e applie d i na compute r simulatio no f th e mode l tha t wa s the nsuccessfull yvalidate d usin g huma nautops ydata . Th e mode l parameter s wer e revise d usin g measure d metaboli c dat a fo r eac horga n(e.g. , bon e turnove r rates ) fo r childre nand wer e use d t o simulat e lea d orga nburden s and concentration s i nchildre nwit hconstan t lea d exposure s fro mbirt h(Harle yan d Kneip , 1985) . Althoug hcomplet e mode l validatio ni s no t possible , th e revise d mode l i s consisten t wit hexperi

menta l dat a o nbloo d lea d accumulatio nfollowin g dietar ylea d uptak e amon g infant s (Ziegle r e t al. , 1978) , and skeleta l lea d accumulatio nfollowin g controlle d exposure s i nadult s (Hear d and Chamberlain , 1984) , and , give n th e availabl e dat a i t appear s t o provid e th e bes t estimate s o f Pb B level s i nchildre nwit hcontinuou s lea d uptake . Tabl e C- 2 present s Pb B level s predicte d b yth e mode l fo r mal e childre n unde r differen t exposures , o r lea d uptak e levels . N o difference s wer e foun d betwee nth e sexe s excep t a t olde r ames , and predicte d Pb B level s wer e highes t amon g 2- 3 yea r olds , consisten t wit hresult s o f NHANE S I I and th e Ne wYor k Cit yscreenin g progra m(Billic k e t al. , 1979) . Thes e result s ar e applie d t o estimate s o f th e integrate d lea d uptak e mode l i nSectio nVII.C.2(a )
s o tha t children' s Pb B level s ca nb e estimate d unde r alternativ e ai r lea d levels . d ) Empirica l Relationship s Betwee nBloo d Lea d and Lea d i nIndividua l Exposur e Medi a On e o f th e modelin g approache s presente d i nSectio nV , and applie d i nP.6 5

C- 9 Tabl e C-2 . Predicte d Equilibrate d Bloo d Lea d Level s Ove r Tim e Amon g Childre nwit h


### Ag e 

### 1 2 3 4 5 6 7 8 9 1 0 1 0



### 3. 0 4. 0 3. 7 3. 5 3. 6 3. 5 3. 3 2. 5 2. 3 2. 6 2 0



### 5. 9 8. 1 7. 3 7. 0 7. 3 6. 9 6. 5 5. 0 4. 6 5. 2 Constan t Lea

d Upt a Lea d Uptak e 

### 3 0 

### 8. 9 12. 1 11. 0 10. 5 10. 9 10. 4 

### 9. 8 7. 4 6. 9 7. 8 4 0

11. 9 16. 2 14. 6 14. 0 14. 5 13. 8 13. 0 

### 9. 9 9. 3 10. 4 kes a

(yg/day ) 

### 5 0 14. 8 20. 2 18. 3 17. 5 18. 1 17. 3 16. 3 12. 4 11. 6 13. 0 

### 6 0

17. 8 24. 2 22. 0 21. 0 21. 8 20. 7 19. 5 14. 9 13. 9 15. 6 

### 7 0

20. 8 28. 3 25. 6 24. 5 25. 4 24. 2 22. 8 17. 4 16. 2 18. 2 

### 8 0

23. 8 32. 3 29. 3 28. 0 29. 0 27. 6 26. 0 19. 9 18. 5 20. 8

a Fro mHarle yand Knei p (1985) .P.6 6

C-1 0 Sectio nVI I .C.2 , t o estimat e Pb B level s i nchildre nexpose d t o variou s ai r lea d level s i s referre d t o a s th e "disaggregate " model . I nthi s model , fo r eac hexposur e mediu m t o whic hchildre nar e expose d t o airborn e lea d (i.e. , air , dust , soil , diet ) separat e empirica l relationship s derive d fro mcontrolle d experimental , observationa l o f communit ystudies , ar e applie d s o tha t a combine d exposur e functio nca nb e estimate d unde r variou s ai r lea d levels . Th e disaggregat e mode l develope d i nth e C D (Tabl e 13-6 ) and presente d her e i nTabl e 7-1 0 relie s o nth e mos t relevan t and reliabl e o f th e availabl e mathematica l relationships . Th e relationshi p (»1.9 7 pg/d l pe r pg/m^ ) betwee nchildren' s bloo d lea d and inhale d ai r lea d (derive d fro mAngl e and Mclntire , 1979 ; Roel s e t al. , 1980 ; and Yanke l e t al. , 1977 ) ha s already bee ndiscusse d i nSectio nV . Th e studie s use d t o deriv e th e remainin g relationship s i nth e disaggregat e model , betwee nchildren' s bloo d and lea d i ndiet , soil , and dust , ar e summarize d i nth e followin g tables .Tabl e C-3 . STUDIE S RELATIN GBLOO DLEA DLEVELS (ug/dl ) T

ODIETAR

YINTAKES (ug/day )

Stud y Analysi s Mode l R » Estimate dPredicte dbloo dlea d Bloo dcontributio n(ug/dl ) fo

r Mode l lea

dat a give ndietar

y Intak e D.F . 0 H 2 0 P

b(ug/day ) Slop e fro a 10 0 t o 20 0 pg/d. , ug/dl per pg/d .

Sherlocke t al . (1982 ) stud

y of 3 1 adul t woae

n I nAy r Sherloc ke t al . (1982 ) stud

y o f Infant s I

nAy r coablne dwithU.K . Centra l Directorat e Stud y U.K . Centra l Directorat e (1982 ) Stud

y o f Infant s t

n Glasgo w Ry ue t al . (1983 ) stud y o f Infant s Sherloc ke t al . (1982 )

Sherloc ke t al . (1982 )

U.K . Centra l Directorat e o nEnvironmenta l Pollutio

n (1982 ) EP A PB B = -1. 4 • 3. 6 V

PB 0 0.5 2

PB B = 2. 5 • S. OV

PB D

PB B = 17. 1 • .056(PBD ) 0.1 9 PB B = 3. 9 * 4. 6 V

PB D0.4 3

PB B = A • .16P8 0 -1. 4

2. 5

17. 1 3. 9 10 0

16. 7

23. 2 20 0

21. 1

29. 2 30 0

24. 1

33. 5

5. 6 11. 2 16. 8 21. 4 26. 9 30. 8

16. 0 32. 0 48. 0 0.03 4

0.06 0

0.05 6 0.05 3

0.1 6 O

I

Source : CD , Tabl e 11-49

.P.6 8

C-1 2 Tabl e C-4 . ESTIMATE S O F TH E CONTRIBUTIO

N O F SOI L LEA

DT OBLOO DLEA D

Stud y Rang

e of soi l lea dvalue s (pg/g ) Dept ho f Estimate dSampl e sampl e slop e (XlO 3 ) siz e 

### R 2 Angl e an

dMclntire (1982 ) stud

y of childre ni n Omaha , N

E Star ket al . (1982 ) stud

y o f childre

n Ne w Haven , CT Yankel et al . (1977 ) stud

y of childre

n I nKellogg , I

D Galk e e t al . (1975 ) stud y of chllre n1 n Charleston , SC Barltro pe t al . (1975 ) stud y of childre n1 n Englan d Neri et al . (1978 ) stud

y of childre

n 1 nBritish Columbi a 16-479 2

3 0 - 700 0 (ag e 0-1 ) 3 0 - 760 0 (ag e 2-3 ) 5 0 - 24,60 0

789 0

42 0 - 13,96 9 (grou pmeans )

225-180 0 (grou pmeans , ag e 1-3 )
225-180 0 (grou pmeans , ag e 2-3 ) 

### 2 "



## V

3/4 "



### 2 "

2 "

N A

N A 6. 8

1. 5

0. 6

7. 6

4. 6 107 5



### 194

8 2

8 7

103 .19 8



### 2. 2 2. 0 1. 1 15

3 334 86 0 .28 9

.30 0
.66 2

.38 6



### NAN A

N A

"N A means Not Available . Source : CD , Tabl e 11-63 . Tabl e C-5 . ESTIMATE S O F TH E CONTRIBUTIO

N O F HOUSEDUS T T

OBL00 0 LEA

DI N CHILDRE

N

Stud y Angl e an

dMclntlre (1979 ) stud

y 1 n Omaha , N

E Star ket al . (1982 ) stud y 1 nNe w Haven , 

### e t Yanke l e

t al . (1977 ) stud y 1 nKellogg , I D Rang e o f dus t Lea dvalue s (ug/g ) 18-557 1

70-760 0 40-760 0 9-490 0 50-35,60 0 Age rang e 1 nyear s 1-1 8 6-1 8
0- 1 2- 3 4- 7 0- 4 5- 9 Estimate d slop e (XlO 3 ) 7.1 8 3.3 6
4.0 2 1.8 2 0.0 2 0.1 9 0.2 0 Sampl e

Siz e 107 4 83 2
15 3 33 4 43 9 18 5 24 6 

### R

» .19 8 .26 2 .28 9 .30 0 .14 3 .72 1 .62 3

Source : CD , Tabl e 11-64 .P.6 9

APPENDI XD . HEALT H EFFECT S O F LEAD Thi s appendi xdiscusse s and evaluate s th e informatio no nth e variou s huma nhealt heffect s associate d wit hlea d exposure . Th e discussio ni s broke ndownint o th e majo r healt heffect s area s o f primar yconcer nand i s intende d t o suppor t th e assessmen t i nSectio nVII.C(l ) o f healt hrisk s associate d wit hvariou s bloo d lea d (PbB ) level s fo r purpose s o f determinin g anappropriat e lea d NAAQS . 1 . Hem e Biosynthesi s and Relate d Function s Unde r norma l circumstances , hem e biosynthesi s i s a highl yefficien t and coordinate d pathway , whic hproduce s onl ysufficien t amount s o f inter

mediate s and , ultimately , hem e t o servic e requirements fo r hemoglobi n- - th e bloo d pigmen t responsibl e fo r transportin g oxyge nt o th e tissue s - - a s wel l a s a multitud e o f function s mediate d i nmos t cell s b yheme-containin g proteins . Thes e hemoprotein s includ e myoglobin , th e hemoglobi no f muscle , and th e mitochondria l respirator ypigments , cytochromes , responsibl e fo r cellula r energetics . Moderatel yelevate d lea d exposur e ha s bee ndemonstrate d t o distur bth e biosyntheti c sequenc e s o a s t o produc e larg e quantitie s o f redundan t intermediate s tha t mus t the nb e excreted ; mor e sever e lea d intoxicatio nma yresul t i nth e developmen t o f anemia . Lead' s interferenc e a t susceptibl e stage s o f th e biosyntheti c pathwa y(illustrate d i nFigur e D-1 )
ma yhav e importan t implications fo r a multitud e o f organ s and systems , especiall yi nth e growin g child , and i s briefl yreviewe d below . i . Th e initia l ste p o f th e hem e syntheti c pathway , th e formatio n o f delta-aminolevulini c aci d (ALA ) fro msuccinyl-Co Aand glycin e b yth e mitochondria l enzym e delta-aminolevulini c aci d synthetas e (ALA-S) , represent s th e contro l poin t o f th e pathway . Durin g lea d exposure , th e activit yo f thi s rate-limitin g enzym e i s increase d throug hfeedbac kP.7 0

D- 2 MITOCHONDRIA L MEMBRAN E MITOCHONDRIO N HEM E GLYCIN E SUCCINYLCo A FERRO CHELATAS E 

# it P b Fe-PROTOPORPHYRI N d-AL ASYNTHETAS E (INCREASE ) Pb (DIRECTL

YOR B Y DEREPRESSION ) 

# t F e

d-AL A d-AL A DEHYDRAS E (DECREASE) Pb COPROPORPHYRI N (INCREASE ) Pb

PORPHOBILINOGE N (PBG ) Figur e D-1

. Lea d effect s o n hem e biosynthesis,fro m CD , Figur e 6-1

.P.7 1

D- 3

contro l apparentl yi n a n attemp t t o compensat e fo r th e diminishe d productio n o f hem e du e t o lead' s interferenc e (Maxwel l and Meyer , 1976) . ii . I n th e secon d ste p o f th e pathway , th e zinc-requirin g enzym e delta

aminolevulini c aci d dehydras e (ALA-D) , catalyze s th e condensatio n o f tw o molecule s o f AL At o for mporphobilinogen . ALA- D i s inactivate d b ylea d withou t an

yapparen t threshold , and i nerythrocytes , it s activit yappear s t o b e markedl yreduce d a t a Pb B aroun d 1 5 ug/d l i n bot hadult s and childre n (Hernber g and Nikkanen , 1970 ; Wad a e t al. , 1976 ; Nieber g e t al. , 1974 ; Secch i e t al. , 1974 ; Roel s e t al. , 1975b) . Base d o n severa l o f thes e studies , Zielhui s (1975 ) calculate d tha t th e fractio no f childre nwit h40 % reductio no f ALA- D activit yincrease s fro m abou t 1 0 t o abou t 90 % a s Pb B rise s fro m1 0 t o 3 0 yg/dl . Th e combinatio n o f increase d ALA- S and decrease d ALA- D activit yaccount s fo r th e marke d accumulatio no f AL Ai nth e plasm a and bodyfluids , and
exces s excretio no f AL Ai nurine . Th e rat e o f AL Aexcretio n accelerate s abov e a Pb B o f 4 0 ug/d l i nadult s and childre n(Crame r e t al. , 1974 ; Moor e e t al. , 1980 ; O'Flahert ye t al. , 1980) . Severa l studie s indicat e a continuous correlatio n betwee nurinar yAL A(ALA-U ) and Pb B dow nt o level s aroun d 20-2 5 ug/d l (Meredit he t al. , 1978 ; Selande r and Cramer , 1970 ; Lauwery s e t al. , 1974 ; Chisol me t al. , 1976) . I n ligh t o f conflictin g finding s fro mstudie s usin g differen t measuremen t techniques , i t remain s t o b e establishe d whethe r increase s i nALA- Uar e precede d b yelevations i n circulatin g level s o f AL Ai nplasm a a t Pb B level s belo w4 0 ug/d l (Meredit he t al. , 1978 ; O'Flahert ye t al. , 1980) . Th e criteri a documen t conclude s tha t despit e a positiv e bia s i nabsolut e AL Avalue s du e t o measure men t contaminatio n b yaminoketone s no t correlate d wit hbloo d lead , th e relativ e change s i nbloo d AL Adetecte d b yMeredit he t al . (1978 ) "appea rP.7 2



### D- 4

t o provid e th e mos t plausibl e basi s fo r th e observe d correlation s wit hPb B level s a s lo wa s 1 8 ug/dl " (CD , p . 12-19) . Whil e bloo d indicator s o f erythropoieti c effect s o f lea d ma yb e mor e accessible , the yar e no t th e only , no r necessaril yth e mos t sensitiv e indicator s o f hem e biosynthesi s derangemen t i nothe r organ s (CD , p . 12-26) . A t roughl ycomparabl e lea d level s associate d wit hsuc hchange s i nbloo d AL Aand ALA-D , inhibition s o f ALA- D an d elevation s i nAL Aar e observe d i n th e liver , kidneys , and splee no f adul t rat s an d humans , and t o a greate r degre e i nth e developin g brai no f young , compare d t o adul t rodent s (Milla r e t al. , 1970 ; Secch i e t al. , 1974 ; Gerbe r e t al. , 1978 ; Silbergel d e t al. , 1982) . Th e impac t tha t elevate d AL Ama yhav e o nth e neurologica l syste mi s discusse d i nAppendi xD.l(d) . I t i s importan t t o not e tha t becaus e lea d i s preferentiall ydeposite d i nbon e (Appendi xA) , th e concentration s o f lea d i nth e marro wwil l b e significantl ygreate r tha ni nth e bloo d durin g re d bloo d cel l formatio nan d hemoglobi nsynthesi s i nth e bon e marro w(Albahary , 1972) , and th e developin g re d bloo d cell s i nth e marro wwil l b e particularl yaffected . iii . Anothe r effec t o f lea d o nhem e biosynthesi s i s it s interferenc e wit hth e las t ste p o f thi s chain , i.e. , insertio no f iro n int o protoporphyrin . Thi s i s mediate d b

yth e enzym e ferrochelatase , whic hi s locate d i nth e inne r matri xo f th e mitochondri a o f mos t cell s (Moor e e t al. , 1980) . Lea d impair s th e transmitochondria l transpor t o f iro nand instea d o f producin g heme , th e mitochondri a accumulat e it s precursor , protoporphyrin , whic h lack s iro nand i s incapabl e o f performin g it s essentia l respirator yfunction . A s a resul t o f lea d intoxicatio ni nnewl yformin g erythrocytes , protoporphyri n (referre d t o a s erythrocyt e protoporphyri n o r EP ) take s th e plac e o f hem e i nth e specifi c pocke t o f th e hemoglobi nmolecule . A s th e re d bloo d cell sP.7 3

D- 5 remai ni nth e circulation , zin c i s rapidl ychelate d a t th e cente r o f th e molecul e i nth e sit e normall yoccupie d b yiro n(Piomell i e t al. , 1982) . Th e resultin g zin c protoporphyri n (ZPP ) i s tightl yboun d i nth e availabl e hem e pocke t fo r th e lif e o f th e erythrocyte , normall y120-13 0 day s (Lamol a e t al. , 1975) . Thus , th e conten t o f protoporphyri ni ncirculatin g re d bloo d cell s represent s wha t ha s accumulate d durin g re d bloo d cel l maturatio nand consequentl y describe s aneffec t tha t too k plac e i nth e bon e marrow , wit ha tim e la g o f 3- 4 month s (Sass a et.al. , 1973) . Wit hincreasin g bloo d lead , ther e i s a rapi d exponentia l increas e o f protoporphyrin , wit hsignifican t accumulation s ove r baselin e a t Pb B level s o f approximatel y1 5 pg/d l i ninfant s and childre n(Roel s e t al. , 1976 ; Piomell i e t al. , 1977 , 1982 ; Hammon d e t al. , 1984 ; Rabinowit z e t al. , 1985 )
an d 25-3 0 pg/d l i nadult s (Roel s e t a l . , 1975b ; Grandjea nan d Lintrup , 1978 ; Odon e e t al. , 1979 ; Herber , 1980) . Th e populatio ndose-respons e relationshi p betwee nE P and bloo d lea d i nchildre nage d 10-1 5 year s indicate d tha t E P level s wer e significantl yhighe r ( > 2 standar d deviations ) tha nth e referenc e mea ni n50 % o f th e childre na t a Pb B leve l o f 2 5 pg/d l (Roels . e t al. , 1976) . Astudyo f 200 4 childre nfoun d tha t E P level s increase d exponentiall y abov e a Pb B o f 1 8 pg/d l and tha t Pb B level s o f 29. 9 an d 35. 2 pg/d l corresponde d t o E P elevation s o f mor e tha n1 and 2 standar d deviations , respectively , i n50 % o f th e childre nstudie d (Piomell i e t al. , 1982) . Th e healt hsignificanc e o f E P o r ZP P accumulatio ni s attribute d t o th e fac t tha t i t i s evidenc e o f impaire d hem e and hemoprotei n formatio ni n manytissue s tha t result s fro mlead' s entr yint o mitochondri a (CD , p . 12-46) . Beside s it s rol e i nth e erythropoieti c syste mi nformin g hemoglobin , hem e i s activ e i nlive r function , vitami nD metabolism , and th e nervou s system . Thes e interactions , and lead' s impac t o nthem , ar e depicte d back.i n Figur e 7- 1 and discusse d below .P.7 4

D- 6

a ) Effect s o f Lea d o nHem e and Hemoglobi nSynthesi s an d Erythrocyte s Anemi a i s ofte nth e earlies t manifestatio no f chroni c and acut e lea d poisoning . I t i s define d a s a hemoglobi nconcentratio ndepresse d belo w som e clinicall yaccepte d level , usuall yabou t 9.5-11. 0 gram s o f hemoglobi n pe r dl blood . Th e symptom s o f anemi a i nyoun g childre nca ninclud e pallor , sallo wcomplexion , fatigue , irritability , and decrease d pla yactivity . Th e anemi a o f lea d poisonin g i s relate d t o som e combinatio no f decrease d hem e and hemoglobi nproductio nan d increase d rat e o f re d bloo d cel l destruc

tion . I nadditio nt o it s inhibitor yeffect s o nhem e synthesis , lea d disturb s th e biosynthesi s o f globin , th e protei ncomponen t o f hemoglobin , disrupt s enzymati c activitie s necessar yfo r erythrocyt e membran e stabilit yan d ultimately , cellula r surviva l (e.g. , pyrimidin e nucleotidase , ATPase) , and
cause s oxidativ e damag e t o th e re d bloo d cel l membran e (Whit e and Harvey , 1972 ; Dresne r e t al. , 1982 ; Gelma ne t al. , 1978 ; Secch i e t al. , 1973 ; Valentin e and Paglia , 1980 ; Angl e and Mclntire , 1978 ; Moor e e t al. , 1980 ; Levande r e t al. , 1975) . Althoug hthes e effect s o nenzym e activit yand globi nsynthesi s ar e detectabl e a t Pb B level s a s lo wa s 1 0 and 2 0 pg/dl , respectively , thei r role , i f any , i nreduce d hemoglobi nsynthesi s and shortene d erythrocyt e surviva l a t suc hlevel s i s uncertain . I ndeterminin g a Pb B leve l o f concer nfo r anemia , i t i s importan t t o distinguis hth e effect s o f lea d fro miro n deficiency , whic hi s prevalen t i n youn g childre nand coul d increas e anindividual' s sensitivit yt o lea d toxicity . Unfortunately , th e availabl e dat a d o no t provid e sufficien t informatio nt o separat e thi s potentiall yconfoundin g factor . I nchildre n wit hn o obviou s iro n deficiencies , th e incidenc e o f anemi a (define d a s a hemoglobi nconcentratio nbelo w1 1 g/dl ) ros e sharpl ya s th e Pb B level s increase d fro m3 7 t o 10 0 pg/d l (Bett s e t al. , 1973) . A t Pb B level s belo w 3 6 pg/dl , 14 % o f th e childre nwer e anemic , compare d t o 36 % wit hlevel sP.7 5

D- 7 betwee n3 7 an d 6 0 pg/dl . Th e criteri a documen t cite s a threshol d Pb B fo r anemi a i n childre no f 4 0 pg/d l (WHO , 1977 ) an d 5 0 pg/d l i n adult s (CD , p . 12-28) . However , unti l additiona l dose-respons e informatio n o n larg e group s o f childre ni s available , wit happropriat e control s fo r iro n deficiency , thi s "threshold " shoul d no t b e considere d definitive . b ) Hem e Synthesi s and Live r Functio n Amajo rfractio n o fhem e synthesize d i n th e live ri s use d i n th e hemoprotein , cytochrom e P-450

. Thi s hemoprotei n i s th e termina l oxidas e o fth e microsoma l mixe d functio n oxidas e syste m tha ti s involve d i n th e metabolis m o fa variet yo fdrug s an d foreig n toxins , as wel l as endogenou s substrate s suc h a

s steroi d hormone s (Granic k e tal. , 1978)

. Decrease s i n live rcytochrom e P-45 0 conten tan d i n dru g detoxificatio n rate s hav e bee n observe d followin g acut e an d chroni clea d administratio n i n animal s an d i n lead-poisone d childre n an d occupationally-expose d adult s (Scopp a e tal. , 1973 ; Alvare s e tal. , 1975 , 1976 ; Meredit h e tal. , 1977 ; Cho wan d Cornish , 1978)

. Lead-induce d alteration s an d diminishe d cytochrom e P-45 0 functio n ar e als o believe d responsibl e fo rth e decrease d excretio n o f6 Beta-Hydroxy cortiso l (6 , 3-0HF) , a metabolit e o fCortisol , i n youn g childre n wit h moderat e elevation s o fbloo d lea d (4 6 pg/dl)(Saenge re tal. , 1984)

. Becaus e o fchildren' s vulnerabilit yan d exposur e t o drug s an d foreig n chemicals , an d thei rhig h metaboli crates , thes e finding s sugges ttha t i n th e absenc e o fconclusiv e dat a i tshoul d be assumed tha tan yindicatio n o f significantl yaltere d hem e biosynthesi s (e.g. , elevate d EP) ma yals o indicat e a possibl e inhibitio n o flive rdetoxificatio n function

. c ) Hem e an d Vitami n D Metabolis m Rena l 1-hydroxylase , anothe rheme-requirin g cytochrom e P-45 0 mediate d mitochondria l enzym e system , convert s 25-hydroxyvitami n D (whic h i s forme d i n th e live rfro m vitami n D ) t o th e hormona l metabolit e 1 , 25-dihydroxy -P.7 6

D- 8 vitami nD (1,25-(0H) 2 D ) i nth e kidney . 1,25-(0H) 2 D i s th e majo r activ e for mo f vitami nD in : 1 ) orchestratin g th e differentiatio nand turnove r o f cell s i nbon e mineralizatio n(CD , p . 12-41) ; 2 ) stimulatin g intestina l absorptio no f calciu man d phosphorou s (Sorel l e t al. , 1977 ; Rose ne t al. , 1980) ; 3 ) maintainin g extra
- and intra-cellula r calciu mhomeostasi s essentia l fo r cellula r integrit yand functio n(includin g response s t o hormona l and electrica l stimuli , modulatio no f cycli c nucleotid e metabolism , and regulatio n o f severa l enzym e systems ) (Cheung , 1980 ; Rasmusse nand Waisman , 1983 ; Rose n and Chesney , 1983 ; Rosen , 1983) ; 4 ) mediatin g th e activatio no f variou s immunoregulator yprocesse s (Provvedin i e t al. , 1983 ; Bhall a e t al. , 1983 ; Tsouka s e t al. , 1984) ; and 5 ) mediatin g pancreati c functio nan d insuli n secretio n(Clar k e t al. , 1981 ; Kadowsk i and Norman , 1984a,b) . I nadditio nt o it s relianc e upo nheme , th e biosynthesi s o f th e vitami n D hormon e i s controlle d largel yb yth e functiona l integrit yo f th e rena l mitochondria , b yth e ioni c (calcium , phosphorus ) environmen t o f th e exracellula r fluid , and b yth e activ e uptak e o f calciu mb ymitochondri a (CD , p.12-38) . Give nlead' s toxi c effect s o nmitochondria , cellula r energetics , and cytochrom e P-45 0 function , and th e fac t tha t ferrochelatas e activit yi nkidney s i s inhibite d b ylea d jus t a s i t i s i nre d bloo d cell s (Fowle r e t al. , 1980) , i t i s no t surprisin g tha t lowere d 1,25-(0H) 2 D level s occu r a t Pb B level s correspondin g t o thos e associate d wit hth e onse t o f E P accumulatio ni nerythropoieti c tissue . Fo r example , a stron g negativ e correlatio nbetwee nchildre n1,25-(OH)2 D an d Pb B level s wa s foun d ove r a rang e o f 12-12 0 pg/d l (Rose ne t al. , 1980) . I nchildre nwit hPb B level s ove r 3 3 pg/dl , th e reduction s i n1,25-(0H) 2 D wer e comparabl e t o thos e observe d i nchildre nwit hsever e rena l insufficienc ylackin g two-third s o f
norma l rena l function , a s wel l a s i nthos e childre nwit ha variet yo f in-born e metaboli c disorder s suc ha s vitami nD-dependen t rickets , oxalosis , andP.7 7



### D- 9 hypoparathyroidis m(Rose nand Chesney , 1983 ; Chesne ye t al. , 1983) . Severa l othe r point s shoul d b e mad e regardin g th e significanc e o f lead-induce d reduction s i nbloo d serumlevel s o f 1,25-(0H) 2 D : (1 ) Mahaffe y e t al . (1982 ) note d th e possibilit yo f a feedbac k mechanis mb ywhic hlead

induce d reduction s i n1,25-(0H) 2 D interfer e wit hintestina l lea d absorption , o r tha t norma l bon e mineralizatio npermit s lea d t o b e sequestere d i nbone . Recen t experimenta l dat a i nrat s (Smit he t al. , 1981) , however , indicat e that : dietar yintak e o f vitami nD doe s no t affec t bloo d lea d concentration ; lo w1,25-(0H) 2 D level s ca ninhibi t calciu mtranspor t therebyenhancin g lea d absorption ; an d reduce d 1,25-(0H) 2 D level s d o no t protec t targe t organ s (e.g. , kidney ) b ysequesterin g lea d i nbone . (2 ) Althoug hchelatio n o f childre nwit helevate d Pb B level s result s i na rapi d (withi n2 days ) retur nt o norma l 1,25-(0H> 2 D level s (Rose ne t al. , 1980) , th e vitami nD system' s abilit yt o recove r onl yafte r lea d level s ar e reduce d doe s no t necessaril yimpl ytha t th e syste mi s operatin g a s a norma l biologica l feedbac k mechanism . (3 ) Decrease d calciu mlevel s and increase d parathyroi d hormon e (PTH) , alon g wit himpaire d bon e mineralizatio n- - condition s tha t typicallyaccompan ysever e vitami nD deficienc y(a s e.g. , i nrickets ) - - ar e no t eviden t i nchildre nwit hPb B level s belo w6 2 pg/d l (Rose ne t al. , 1980) . However , PT H and serumcalciu mlevel s typicallyar e norma l eve ni n childre nwit hstag e I rickets ; thes e change s ar e therefor e no t meaningfu l indicator s o f th e signifianc e o f reduce d 1 ,25-(OH) 2 D i nchildre n(Rose n and Chesney , 1983) . Th e fac t tha t bon e mineralizatio ni s impaire d i n vitami nD deficienc yricket s bu t no t i nlead-induce d 1,25-(0H) 2 D deficienc y i s als o no t relevan t sinc e vitami nD deficien t childre nma yhav e norma l o r eve nelevate d 1,25-(0H) 2 D levels .P.7 8

D-1 0
Th e varie d biologica l role s o f 1,25-(0H) 2 D i nth e body , includin g extra
- an d intracellula r calciu mhomeostasis , cel l differentiation / maturation , immunoregulator yfunction , and pancreati c function , e.g. , insuli nsecretio n(Kadowsk i an d Norman , 1984a,b, ; Clar k e t al. , 1981 ) ar e becomin g increasingl yevident . Impairmen t o f thes e activitie s tha t result s fro mlead' s depressio no f circulatin g 1,25-(0H) 2 D level s ma yunderli e many o f th e divers e effect s o f lead . Th e criteri a documen t conclude s tha t "I t appear s likel ytha t lead-induce d reduction s i nhem e underli e th e effect s see ni nth e vitami nD-endocrin e system . Thi s origi nwoul d accoun t fo r th e similaritie s i n"thresholds " fo r th e effect s o f lea d o nbot hE P accumulatio n and decrease s i nlevel s o f 1,25-(0H) 2 D . I t als o typifie s a cascad e o f biologica l effect s amon g variou s orga nand physiologica l system s o f th e body , a cascad e tha t ca nultimtel yencompas s th e entir e organism " (CD , p . 12-37 ) and "tha t impaire d productio no f 1,25-(0H) 2 D ca nhav e profoun d and pervasiv e effect s o ntissue s and cell s o f divers e typ e and functio nthroughou t th e body " (CD , p . 12-49) . d ) Hem e Synthesi s and th e Nervou s Syste m Th e nervou s system , bot hcentra l an d peripheral , i s recognized'a s a targe t o f critica l importanc e i nth e toxicit yo f lead . Behavioral , electro

physiological , morphological" , and biochemica l investigation s hav e demonstrate d alteration s i nbrai nfunctio na t relativel ylo wlevel s o f exposure , particularl y whe nexposur e occur s durin g earl ydevelopment . Mechanism s tha t explai nth e neurologica l effect s o f lea d includ e (bu t ar e no t limite d to ) direc t alteratio n o f sodiumand calciu m metabolism , inhibitio no f certai nneurona l enzyme s (Na , K-ATPas e and adeny l cyclase) , and a decreas e i nmitochondria l oxidativ e phosphorylatio n(Silbergel d e t al. , 1982) . Othe r evidenc e suggest s tha t som e aspect s o f lea d neurotoxicit yma yb e mediate d throug hit s inhibitio n o f hem e synthesi s b yth e followin g mechanisms :P.7 9

D-1 1 (i ) Interferenc e wit hneurotransmissio nb yth e hem e precursor , AL A Th e excessiv e accumulatio no f AL Ai s believe d t o b e linke d t o th e clinica l and biochemica l similaritie s (e.g. , paralysis , psychiatri c disturb

ances , nerv e demyelination ) o f lea d intoxicatio nand "porphyria" , condition s i nwhic helevate d tissu e concentration s o f porphyri nprecursor s resul t fro m geneti c o r acquire d deficiencie s (Dag g e t al. , 1965 ; Moor e e t al. , 1980) . Excessiv e AL Alevel s i nth e brai nma yb e responsibl e fo r som e neurologica l dysfunction s associate d wit hmor e mil d lea d exposur e a s well , sinc e lo w level s o f AL Ai nvitr o ca ninterfer e a t th e neuromuscula r junctio no r spina l
cor d wit hnorma l neurotransmissionb yy-aminobuityri c aci d (GABA) , whic h AL Aclosel yresemble s (Nico l 1 , 1976 ; Brenna nan d Cantrill , 1979 ; Silbergel d
e t al . 1980 , 1982) . Interferenc e wit hGABA-ergi c functio nb yexposur e t o lea d i s consisten t wit hsuc hclinica l and experimenta l sign s o f lea d neuro toxicitya s excitability , hyperactivity , hyperreactivity , and i nsever e cases , convulsion s (Silbergel d and Lamon , 1980) . (ii ) Hem e deficienc yand altere d neurochemica l synthesi s Litma n an d Correi a (1983 ) hav e reporte d tha t lea d treatmen t o f rat s wa s associate d wit haninhibitio no f th e hepati c heme-requirin g enzym e system , tryptopha npyrrolase , and resulte d i nsignificantl yelevate d brai n level s o f tryptophan , 5-hydroxyindoleaceti c acid , and th e neurotransmitter , serotonin . Wit hinfusio no f heme , thes e increase s wer e reversed . Elevate d level s o f tryptopha nand it s metabolite s hav e bee nassociate d wit hhuma n hepati c encephalopath yand wit hneurohistologica l and symptomati c change s see ni nvictim s o f acut e porphyri a attack s (e.g. , alteratio no f brai nneurons , axona l wasting , psychomoto r disturbances ) (Litma nand Correia , 1983) . I t remain s t o b e resolved , however , whethe r change s i nthi s heme-dependen t enzym e syste m

alon e ca naccoun t fo r observe d low-leve l lea d neurotoxicity .P.8 0

D-1 2
(iii ) Impairmen t o f hem e availabilit yi nneura l tissu e Hem e biosynthesi s appear s t o b e inhibite d i nnervou s syste mtissue s a t dos e range s comparabl e t o thos e whic har e toxi c i n erythroi d and live r cell s (Whetsel l e t al. , 1978 ; Sass a e t al. , 1979) . Co-administratio n o f hem e and lea d prevente d mos t o f th e neuro-morphologica l effect s cause d b ylea d alone , namel ydestructio no f myeli nand Schwan n cell s and structura l alteration s o f neuron s (Whetsel l and Kappas , 1981 ; Whetsel l e t al. , 1984) . Thes e result s ar e suggestiv e o f heme' s possibl e rol e i n neurotoxicity , bu t again , fir mconclusion s mus t awai t furthe r research , (iv ) Impairmen t o f cytochrom e functio ni n brai n energ ymetabolis m Anothe r possibl e heme-mediate d mechanis m o f lea d neurotoxicit yi s suggeste d b

yfinding s tha t productio nand operatio no f th e electro n transpor t cytochrom e C respirator ychai ni n th e developin g cerebra l corte xar e impaire d whe n neonata l rat s ar e chronicall yexpose d t o lo wlevel s o f lea d (Holtzma n and She nHsu , 1976 ; Bul l e t al. , 1979) . Disruptio n o f energ ymetabolis m ha s bee nimplicate d i ndevelopmenta l delay s i nth e metabolicall yactiv e nervou s syste mo f youn g animal s expose d t o relativel ylo wlevel s o f lea d (McCaule ye t al. , 1979 ; Crofto ne t al. , 1980) . Thes e linkage s betwee nth e biochemica l effect s o f lea d o nhem e synthesi s and neurologica l functio nar e primaril ybase d o n anima l o r i n vitr o experimenta l data . A s such , i t i s difficul t a t thi s tim e t o determin e a lea d exposur e leve l o f concer nfo r heme-relate d neurologica l impairment s i n humans . Nevertheless , th e commo nbiochemica l processe s operatin g acros s neurologica l and hematologica l system s i nmammalia nspecie s sugges t tha t th e abnormalitie s i nhem e synthesi s cause d b ylo wleve l lea d exposur e i n human s ma yals o indicat e som e ris k o f neurobehaviora l impairments .P.8 1

D-1 3
2 . Neurologica l Effect s o f Lea d
a ) Acut e Effect s and Periphera l Nerv e Damag e Th e effect s o f lea d o nth e nervou s syste mar e bot hstructura l and functional , involvin g variou s region s o f th e brai nan d spina l cor d (i.e. , th e centra l nervou s system ) a s wel l a s th e moto r and sensor ynerve s leadin g t o specifi c area s o f th e body(i.e. , th e periphera l nervou s system) . Thes e effect s ca nresul t i ndeterioratio no f intellectual , sensory , neuromuscular , and/o r psychologica l functions . Acut e encephalopathy(degenerativ e brai ndisease ) i s th e mos t sever e consequenc e o f lea d intoxication . Earl yfeature s o f th e syndrom e includ e lethargy , sporadi c vomiting , irritability , los s o f appetite , dizziness , poo r attentio nspan , muscula r tremor , and memor yloss . Thes e sign s ca n abruptl yprogres s t o delirium , convulsions , coma , and ultimatel ydeat h (Cuming s e t al. , 1959) . Acut e encephalopath yi nadult s usuall yi s manifeste d
a t Pb B level s o f approximatel y100-12 0 pg/d l (Chisol mand Harrison , 1956 ; Chisolm , 1965) ; scattere d evidenc e (Gan t e t al. , 1938 ; Smit he t a l ; 1938 ; Bradle ye t al. , 1956 ; Bradle yand Baumgartner , 1958 ; Cumings , 1959 ; Rumm o e t al. , 1979 ) suggest s tha t thi s syndrom e ma yb e associate d wit hPb B level s betwee n8 0 and 10 0 pg/d l i nth e mos t susceptibl e childre n(CD , p . 12-62) . Sever e lea d poisonin g wit ho r withou t encephalopathyha s permanen t effect s o nth e behavio r and intellectua l functionin g o f children , eve ni f subsequen t lea d exposur e i s minimized . Suc hsequela e rang e fro mmenta l retardatio nand cerebra l pals yt o sensorimoto r deficits , shor t attentio n span , and opti c atrophy(Byer s and Lord , 1943 ; Chisol mand Harrison , 1956 ; Perlstei nan d Attala , 1966 ; Chisol mand Barltrop , 1979) .P.8 2

D-1 4 Whil e encephalopathyoccur s primaril yi nchildren , periphera l nerv e damag e (neuropathy ) du e t o hig hlea d exposur e i s mor e commonl yfound i n adult s occupationall yexpose d t o lead . Over t symptom s suc ha s muscl e tremor , pals y(e.g. , "wris t drop" ) o r weakness , muscl e and join t pain , and gastrointestina l complaint s hav e bee nobserve d i nworker s wit hPb B level s exceedin g 4 0 ug/d l (Lili s e t al. , 1977 ; Spive ye t al. , 1979 ; Bake r e t al. , 1979 ; Haennine ne t al. , 1979 ; Zimmerman-Tansell a e t al. , 1983) . Smal l reduction s i n nerv e conductio n velocitie s hav e bee n observe d i n som e apparentl y asymptomati c worker s wit hPb B level s a s lo wa s 30-5 0 ug/d l (Seppalaine n e t al. , 1975 , 1979 ; Arak i and Honma , 1976 ; Melgaar d e t al. , 1976 ; Ashby , 1980 ; Bord o e t al. , 1982 ; Johnso ne t al. , 1980 ; Seppalaine n and Hernberg , 1980 , 1982 ; Singe r e t al. , 1983 ; Triebi g and Nottbohm , 1983) . Thes e observa

tion s wer e primaril yo nperiphera l ar m nerve s tha t ar e responsibl e fo r th e conductio no f tactil e and positiona l information , and informatio nabou t painfu l stimul i and temperature . Overt , lea d induce d periphera l neuropathyha s bee ndocumente d i nchildre n wit hPb B level s abov e 6 0 pg/d l (Erenber g e t al. , 1974) , and i n som e case s possibl ya s lo wa s 4 0 yg/d l (CD , p . 12-95) . Althoug hmor e subtl e sign s o f possibl e advancin g neuropathy(i.e. , slowe d nerv e conductio nvelocities ) hav e bee nobserve d i nchildre nacros s a wid e rang e o f increasin g Pb B levels" , (Landriga n e t al. , 1976) , n o clea r threshol d fo r abnorma l functio nca nb e determine d fro mth e availabl e data . I ninterpretin g th e effect s o f lea d o nth e periphera l nervou s system , i t i s importan t t o not e that : 1 ) Becaus e thes e ar e chroni c effect s and Pb B level s d o no t accuratel yreflec t th e long-ter m accumulatio no f body lead , i t ha s no t bee ndetermine d i f pea k exposure s prio r t o th e tim e o f studyar e responsibl e fo r th e dysfunction , o r th e lengt ho f tim e tha t Pb BP.8 3

D-.1 5

mus t remai nabov e a certai nleve l t o caus e impairment ; 2 ) Th e rang e o f
nerv e conductio nvelocitie s i nhuman s i s great , eve nwhe nmeasure d b ya singl e investigato r and , i nalmos t al l studies , mos t velocitie s amon g individual s ar e wel l withi nth e rang e o f norma l value s (althoug ha statistica l reductio ni na populatio ndoe s indicat e th e nee d fo r reducin g lea d exposure ; Seppalaine ne t al. , 1975) ; and 3 ) Becaus e periphera l nerve s ar e abl e t o regenerate , ther e i s som e disput e a s t o whethe r th e observation s o f slowe d
nerv e conductio nvelocitie s reflec t mild , reversibl e impact s o f lea d (Buchta l
and Behse , 1981 ) o r ar e earl ywarnin g signal s o f progressivel ymor e seriou s periphera l neuropathie s tha t ar e importan t i nth e diagnosi s o f otherwis e unrecognize d toxi c lea d effect s (Feldma ne t al. , 1977 ; Seppalaine nand Hernberg , 1980) . Th e criteri a documen t conclude s "nevertheles s i t i s clea r tha t thes e effect s represen t departure s fro mnorma l neurologi c functionin g and thei r potentia l relationshi p t o othe r mor e seriou s effect s argue s fo r prudenc e i n interpretin g thei r potentia l healt hsignificance. " (CD , p . 12-61 ) b ) Effect s Associate d wit hChroni c Low-Leve l Exposure s Beside s th e sever e pathophysiologica l change s observe d i nth e centra l nervou s syste massociate d wit hchildhoo d lea d intoxication , variou s maladaptiv e behaviors , neuropsychologica l deficits , and neuro-anatomica l change s mayb e associate d wit hchroni c exposure s t o relativel ylo wconcentration s o f lead . Belo wi s a summar yo f th e numerou s biochemical , morphological , and functiona l effect s o f lea d a t lo wdosage s and exposure s tha t hav e bee n foun d i ndevelopin g nervou s systems . N o singl e mechanis mappear s sufficien t t o accoun t fo r th e divers e effect s o f lea d o nneurologica l function , and i t i s mor e likel ytha t lea d act s a t severa l cellula r and sub-cellula r sites . Althoug hneurochemica l change s ma yprecee d observabl eP.8 4

D-1 6

effect s o nelectrophysiology , morphology , and behavio r i nterm s o f dose , the yar e no t separat e fro m functiona l change s a t highe r levels . I n thos e system s tha t hav e bee nexamine d pharmacologicall yi nvitr o (e.g. , inhibitio n o f adeny l cyclase , acetylcholin e release , and Na,K-ATPase) , a continuou s dose-respons e relationshi p i s suggested , bes t fitte d b ysmoot hcurve s wit h eithe r n o threshol d o r threshold s i nth e nanomola r rang e (Silbergeld , 1983) . I t shoul d b e note d tha t th e finding s fro mi nvitr o o r anima l studie s canno t b e directl yextrapolate d t o estimat e Pb B level s associate d wit h change s i npediatri c neurologica l function s because : a ) th e relativel y shor t lifespan s o f experimenta l animal s alter s th e relationshi p betwee n dos e and duratio nassume d fo r humans ; b ) significan t specie s difference s exis t fo r absorption , retention , and interna l compartmentalizatio n o f lead ; and c ) wit hsom e exceptions , th e measurement s o f neurotoxicityar e no t comparabl e t o thos e possibl e i n studie s o f childre n (Silbergel d and Goldberg , 1980 ; Winnek e e t al. , 1982b) . However , i nassessin g th e mor e over t effect s reviewe d i nth e nex t section , i t i s importan t t o not e thi s continuu mo f lea d neurotoxicit ystartin g wit hbiochemica l change s a t th e lowes t observe d dos e levels . 1 ) Brai n Developmen t Lea d readil yenter s th e brai nand appear s t o b e selectivel ydeposite d i nth e hippocampu s and corte xa s wel l a s i nnon-neurona l element s (e.g. , glia l cells , endothelia l cell s o f brai ncapillaries ) tha t ar e importan t i n th e maintenanc e o f "blood-brai n barrier " function s (Fjerdingsta d e t al. , 1974 ; Grandjean , 1978 ; Stump f e t al. , 1980) . Onc e deposited , lea d i s retaine d i nth e brai nfo r lon g period s o f tim e eve nafte r externa l exposur e cease s and Pb B level s declin e (Mykkane ne t al. , 1979 ; Goldstei ne t al. , 1974) . Thes e spatia l and tempora l pattern s o f brai n lea d accumulatio nP.8 5

D-1 7

correspon d t o th e followin g neurobehaviora l and morphologi c abnormalitie s associate d wit hlea d exposure : 1 ) pathologi c studie s o f expose d animal s and encephalopath yhuman s tha t indicat e change s o f a primaril yvascula r (e.g. , endothelia l and glia l cell ) natur e (Michaelso n and Sauerhoff , 1974) ; 2 ) anima l studie s tha t sho weffect s o nneurona l population s i nth e hippocampu s and corte xand behaviora l change s indicativ e o f hippocampa l and cerebella r dysfunctio n(Campbel l e t al. , 1982 ; Peti t and Alfano , 1979 ; Bushnel l and Bowman , 1979) ; and mos t importantl y3 ) electro-physiologica l and behaviora l change s associate d wit hlea d exposur e measure d i n youn g animal s and childre n tha t persis t lon g afte r exposur e i s reduce d o r cease s (Brown , 1975 ; Ott o e t al. , 1982) . Th e sensitivit yo f th e brai ndurin g th e perio d o f maxima l brai ngrowt h
and differentiatio n i nth e firs t 2 year s o f lif e tend s t o magnif yth e severit yo f th e long-ter mconsequence s o f an ytoxi nencountere d durin g tha t perio d (Dobbing , 1974) . Th e immaturit yo f specifi c brai ntissue s (i.e. , hippocampus , cerebellu mand neocortex ) a t birt hand thei r relativel ylat e developmen t suggest s tha t post-nata l lea d exposur e coul d interfer e wit h mitosis , cellula r migration , differentiatio no f dendriti c and axona l processes , synaptogenesis , and myeli nproduction , a s wel l a s exertin g biochemica l and cytotoxi c effect s (Campbel l e t al. , 1982) . Whil e th e developin g nervou s syste mma yposses s considerabl e reserv e fo r functiona l compensatio n (involvin g plasticity , regeneration , and redundanc yo f neura l pathways) , specifi c processe s affecte d b ylea d apparentl yma yno t b e reversed , eithe r becaus e lea d i s no t remove d fro mbrai ncell s (Silbergeld , 1983 ) o r becaus e o f interruptio no r damag e t o neurostructura l components undergoin g rapi d developmen t a t th e tim e o f th e lea d insult .P.8 6

D-1 8

Ra t pup s expose d t o lo wlevel s o f lea d durin g th e pre-nata l o r neonata l perio d sho wretarde d developmen t i ncerebra l energ ymetaboli c pathways , delaye d cerebra l corte xsynaptogenesis , and reduction s i n hippocampa l morphometric , dendritic , and axona l developmen t (Bul l e t al. , 1979 , 1983 ; McCaule ye t al. , 1979 , 1982 ; Peti t and Alfano , 1979 ; Alfan o and Petit , 1982 ; Peti t an d LeBoutillier , 1979 ; Campbel l e t al. , 1982) . Thes e biochemica l
and morphologica l disruption s ar e parallele d b ydelay s i n th e developmen t o f explorator yand locomoto r activity , and b ylearnin g and behaviora l deficit s i nyoung , lead-expose d animal s (Bul l e t al. , 1979 , 1983 ; McCaule y e t al. , 1979 , 1982 ; Brown , 1975 , Overmann , 1977 ; Bushnel l an d Bowman , 1979 ; Ric e and Wille.s , 1979 ; Peti t e t al , 1983) . Th e effect s o f i n uter o o r post-nata l lea d exposure s o n huma n infan t neurologica l developmen t hav e begu nt o b e investigated . Mentall yretarde d childre ni nScotlan d wer e mor e likel yb ya facto r o f 1. 7 t o com e fro mhome s i nwhic hhig hlevel s o f lea d i ndrinkin g wate r ( > 80 0 ppm ) wer e presen t durin g pregnanc ycompare d t o control s (Beatti e e t al. , 1975) . Pb B level s i na sampl e o f thes e childre n a t 2 week s o f ag e wer e 25. 8 +

_ 8. 9 pg/d l compare d t o 20. 9 +

_7. 9 yg/d l i nnorma l childre n(Moor e e t al. , 1977) . Althoug hthes e are

provocativ e findings , thei r quantitativ e valu e i s uncertai n give n tha t th e childre nwer e limite d t o thos e knownt o healt hcar e service s (an d henc e no t necessaril yrepresentative) , th e matchin g wa s imperfect , and th e Pb B level s wer e availabl e fo r onl yabou t 50 % o f th e children . Preliminar yresult s fro m recentl yinitiate d prospectiv e studie s sugges t tha t lo wt o moderat e lea d exposur e (mea nPb B = > 1 5 yg/dl ) durin g th e firs t tw o year s o f lif e ma yhav e a smal l impac t o nearl ysensorimoto r and menta l developmen t (Bellinge r e t al. , 1984 ; Dietriche t al. , 1984) . Assessmen t o fP.8 7

D-1 9

th e medica l significanc e and persistenc e o f thes e effects , i f any , mus t awai t follow-u p testin g and replication s fro mothe r longitudina l studies . 2 ) Moto r Coordinatio nand Reflexe s Pre
- and post-natall ylead-expose d rat s tend t o sho wdevelopmenta l delay s i nthei r abilit yt o orien t properl yand respon d t o selecte d reflexiv e stimul i (Overmann , 1977 ; Overman n e t al. , 1979 , 1981 ; Gran t e t al. , 1980) . Impaire d performanc e wa s observe d i n rat s wit hPb B level s a s lo wa s 3 5 yg/d l
a t 1 1 day s o f ag e althoug hn o significan t effect s hav e bee nfoun d a t highe r exposure s i nsom e studie s usin g somewha t differen t measure s o f moto r coordi

natio nand reflexe s (Overman ne t al. , 1979 ; Zenic k e t al. , 1979 ; Gran t e t al. , 1980) . Thes e contrastin g result s ca nprobabl yb e attribute d t o difference s i nbodyweight , ag e a t testing , and i nth e tes t apparatu s and procedure s (Zenic k e t al. , 1979) . Lead-induce d abnormalitie s i n moto r abilit yma yb e linke d t o preferentia l concentratio n o f lea d i nth e cerebellu mwher e postur e and movemen t i s regulated , o r t o lead' s damagin g effect s o nperiphera l nerve s and a t th e neuromuscula r junctio n(Coope r and Manalis , 1974 ; Silbergel d e t al. , 1974) .

Smal l deficit s i n perceptua l moto r integratio n and fin e moto r coordinatio nhav e bee nreporte d i n childre n wit hPb B level s o f 50-6 0 yg/dl , and possibl ya s lo wa s 30-4 0 yg/d l (d e l a Burd e and Choate , 1972 , 1975 ; Landriga n e t al. , 1975 ; McBrid e e t al. , 1982 ; Needlema n e t al. , 1979 ; Winnek e e t al. , 1982a) , o r lowe r (Winnek e e t al. , 1983) . N o significan t lead-relate d deficit s i npsychomoto r performanc e hav e bee n foun d a t comparabl e Pb B level s (i.e. , 30-6 0 pg/dl ) (Rummo , 1974 ; Rumm o e t al. , 1979 ; Perin o and Ernhart , 1974 ) and a t Pb B level s belo w2 5 yg/d l (Winnek e e t al. , 1984) . N o difference s i nfin e moto r score s wer e foun d i nanothe r study , althoug h th e mea nPb B level s fo r th e contro l group (2 6 yg/dl ) ma yhav e bee n to oP.8 8

D-2 0 hig ht o detec t anyeffec t i nth e expose d grou p (PbB « 3 8 yg/dl ) (Kotok , 1972 ; Koto k e t al. , 1977) . Thes e conflictin g result s ar e analogou s t o thos e foun d i n anima l experiment s i n whic hsomewha t differen t measure s o f moto r coordinatio n and reflexe s wer e als o used . Nevertheless , an ydeficit s i nperceptua l moto r and fin e moto r coordinatio n tha t are , i nfact , relate d t o lea d ma yb e functiona l evidenc e o f lead-induce d decrement s i nmoto r nerv e function . Thi s ha s bee nnote d i nchildre nand i n adult s wh o exhibi t conductio n deficit s i ndistal-extremit ynerve s a t Pb B level s abov e 3 0 yg/d l (Se e Appendi xD.2.a) . Similarly , th e finding s o f perceptua l inaccuracie s associate d wit hlea d exposur e hav e bee n interprete d i nterm s o f lead-induce d attentiona l deficit s whic har e discusse d belo w(Winnek e e t al. , 1983) . 3 ) Hyperactivit yand Othe r Behavioral . Disorder s Sinc e Byer s and Lor d (1943 ) reporte d hyperactivit ya s a possibl e seque l fo r childre nwh o ha d recovere d fro m lea d poisoning , ther e ha s emerge d a larg e and controversia l dat a bas e concernin g possibl e association s betwee nlea d and hyperactivit yan d othe r behaviora l disturbances . Hyper
activit yi s a comple xsyndrom e wit hrespec t t o bot hcaus e and manifesta

tion . Attentio n defici t disorde r i s generall ythough t t o b e th e mos t salien t manifestatio n o f th e conditio n (America n Psychiatri c Association , 1980) . Thi s disorde r occur s wit hand withou t hyperkinesis , whic hrefer s mor e t o inappropriat e and/o r rando mactivit ytha n i t doe s t o an increas e i n activity , althoug hth e latte r i s sometime s see n (Davi d e t al. , 1983) . Othe r symptom s frequentl ypresen t are impulsivity , lo wfrustratio n tolerance , hyperexcitability , and disturbance s i nconduc t (Wender , 1971 ; Davi d e t al. , 1983) . Inconclusiv e finding s o f hyperkinesi s hav e bee n reporte d i n neonatall y lead-expose d rodent s (CD , Tabl e 12-2) . Attempt s t o collat e thes e dat a ar eP.8 9

D-2 1 hampere d b

yvariabilit yi nth e species , dos e o f lead , lengt hand rout e o f exposure , age , th e methodolog yfo r activit ytestin g an d th e presenc e o f growt hretardation . I t ha s bee npropose d tha t a ) th e apparentl ydiscrepan t finding s o nhyperkinesi a ar e consisten t wit hanexplanatio ni nterm s o f lead-induced , situation-specific , emotiona l o r behaviora l over-reactivit y rathe r tha nhyperactivit ype r s e (Hasting s e t al. , 1977 ; Winnek e e t al. , 1982b ; Kish i e t al. , 1983) ; b ) thes e behaviora l disturbance s ar e consisten t wit hpreviousl ydescribe d disruption s i nhippocampa l morpholog yand functio n (Peti t e t al. , 1983) ; and c ) thes e behaviora l effect s ma ycontribut e t o learnin g deficit s observe d i nlead-expose d animal s (se e Appendi xD.2(b)5) . Despit e thes e interestin g analogie s betwee nsom e o f th e change s i n developmenta l anima l behavio r and hyperactiv e abnormalities , i t woul d b e prematur e t o extrapolat e fro msimpl e anima l model s t o thi s comple xclinica l syndrom e i nchildren . Multipl e etiologi c factor s includin g geneti c influences , perinata l complications , cover t cerebra l insult , irregula r brai nmaturation , maldevelopmen t and perhaps , mos t importantly , psychosocia l factor s ca npla y a rol e i nhyperactivit y(Davi d e t al. , 1983) . Som e studie s tha t hav e attempte d t o contro l fo r thes e etiologica l factor s an d pic a (whic h
ma yb e a consequenc e rathe r tha na caus e o f hyperactivity ) hav e foun d consistentl yhighe r lea d level s i nhyperactiv e childre n(Balo he t al. , 1975 ; Davi d e t al. , 1976 ; Gittlema nand Eskenazi , 1983) , whil e othe r studie s hav e no t (Rummo , 1974 ; Mi 1a r e t al. , 1981) . Becaus e o f methodologica l limitations , conclusion s fro mthes e studie s ar e als o limited . I na mor e carefull ycontrolle d study , Davi d e t al . (1983 ) foun d tha t reduction s i nhyperactiv e children' s Pb B level s (fro m29. 3 t o 19. 5 yg/dl )
a s a resul t o f chelatio ntherap ywit hpenicillamin e wer e associate d wit h marke d symptomati c an d behaviora l improvements , a s assesse d b yteachers ,P.9 0

D-2 2

parents , an d treatin g physicians . Hyperactiv e childre ngive na therapeuti c dru g t o trea t th e syndrome , bu t whos e Pb B level s remaine d approximatel yth e same , showe d som e simila r improvement s whil e childre ngive na placeb o exhibite d n o significant change s i nbehavio r rating s o r Pb B levels . Th e criteri a documen t conclude s tha t th e abov e dat a ar e a t bes t qualitativel ysuggestiv e and tha t i f lea d i s indee d causall yinvolve d i n th e etiolog yo r exacerbatio no f th e behaviora l abnormalitie s associate d wit hhyperactivity , i t i s currentl yimpossibl e t o stat e wit hconfidenc e th e levels , duration s o r critica l period s o f lea d exposur e tha t ma yhav e bee nimportan t (CD , p . 12-89) . Ther e i s somewha t mor e convincin g evidenc e tha t lo wPb B level s may contribut e t o som e othe r behaviora l disorder s suc ha s attentiona l deficit s and distractibilit yi nessentiall ynorma l childre nno t diagnose d a s hyper

active . Severa l analyse s o f classroo mbehavio r hav e faile d t o adequatel y accoun t fo r th e influenc e o f socia l clas s althoug hthe yhav e produce d consisten t dose-respons e relationship s i nwhic hteachers ' rating s o n severa l behaviora l measure s (e.g. , "distractability" , "no t persistent" , lo woveral l functioning ) increas e paralle l wit htoot han d Pb B level s (d e l a Burd e and Choate , 1972 ; Needlema ne t al. , 1979 ; Yul e e t al. , 1984) . A s i s th e cas e fo r severa l othe r genera l populatio nstudie s (Landriga ne t al. , 1975 ; Winnek e e t al. , 1983) , hyperactivit ywa s note d i nver yfe w childre nand wa s generall yno t associate d wit hlea d levels . Afte r adjustin g fo r socio-economi c an d othe r potentiall yconfoundin g factors , behaviora l
and attentiona l deficit s a s rate d b yteacher s (e.g. , disordere d classroo m activity , restless , easil ydistracted , no t persistent , doe s no t follo w directions , lo woveral l functioning ) wer e significantl yassociate d wit h children' s toot hand Pb B level s (Winnek e e t al. , 1983) . Th e criteri a documen tP.9 1

D-2 3

ha s interprete d thi s study , whic hals o assesse d lead-induce d deficit s i nI Q and othe r psychometri c tests , a s showin g overal l neurobehaviora l deficit s a t Pb B level s possibl ybelo w3 0 pg/d l (Winnek e e t al. , 1983) . I naddition , lea d level s i nyoun g childre nhav e bee nconsistentl y associated , followin g appropriat e adjustments , wit hdeficit s i nreactio ntim e unde r varyin g intervals , whic hi s aninde xo f attentivenes s (Needlema ne t al. , 1979 ; Winnek e e t al. , 1983 ; Yul e and Landsdown , 1983 ; Hunte r e t al. , 1983) , and wit hreactio nbehavio r (Winnek e e t al. , 1984) . Th e criteri a documen t conclude s tha t thes e finding s appea r t o argu e fo r probabl e effect s o f lea d o nattentio nand vigilanc e function s a t Pb B level s extendin g belo w 3 0 pg/dl , and possibly , dow nt o a s lo wa s 15-2 0 pg/d l (CD , p . 12-84) . 4 ) Auditor yan d Languag e Processin g Centra l nervou s syste mdamag e cause d b ysever e childhoo d lead , poisonin g i s ofte nassociate d wit hmotor-speec hand languag e disorder s (Byer s and Lord , 1943 ; Me l 1in s and Jenkins , 1955) . Ther e i s conflictin g evidenc e o n whethe r subtl e cerebra l injur yassociate d wit hchroni c low-leve l lea d absorptio n i s manifeste d i nimpaire d verba l behavio r and auditor yprocessing . Severa l studie s hav e foun d n o statisticall ysignifican t lead-relate d difference s o n verba l subtest s o f standardize d intelligenc e test s i nchildre nwit hPb B level s acros s a rang e fro m belo w1 0 t o abov e 6 0 pg/d l (d e l a Burd e and Choate , 1975 ; Landriga ne t al. , 1975 ; Koto k e t al. , 1977 ; Yul e and Landsdown , 1983 ; Yul e e t al. , 1984 ; Smit he t al. , 1983 ; Winnek e e t al. , 1982a , 1983 , 1984) , whil e othe r studie s hav e (Kotok , 1972 ; Rumm o e t al. , 1979 ; Needlema ne t al. , 1979 ; Yul e e t al. , 1981) . Significan t associations , however , hav e bee n detecte d betwee nchildren' s lea d level s (possibl ya s lo wa s 30-5 0 pg/d l PbB ) and a mor e extensiv e batter yo f measures , includin g motor-speec h behaviors , languag e comprehension , formulatio nbehavior s (Needlema ne tP.9 2

D-2 4
al. , 1979 ; 1984 ) an d auditor yprocessin g task s (d e l a Burd e and Choate , 1975 ; Needlema ne t al. , 1979) . I nadditio nt o mor e specifi c measure s o f languag e an d auditor yfunction , thes e finding s o f lead-associate d decrement s ma yb e attributabl e t o sample s draw nfro mamon g childre nwit hrelativel y earl yexposure s t o lead . Althoug hn o conclusion s ca nb e draw nfro mthes e findings , i t i s clea r tha t furthe r researc ho nlo wleve l lea d effect s i nchildre nshoul d includ e sensitiv e measure s o f motor-speec hbehavior s an d communicatio nimpairments . Becaus e maturatio no f th e auditor ycortex , whic hplay s a vita l rol e i n languag e processing , and th e onse t o f competenc e i nspeec hand languag e occur s withi nth e secon d yea r o f lif e (Shaheen , 1984) , suc hresearc hshoul d includ e assessment s o f th e effect s o f lea d absorptio ni nchildre nprio r t o thei r secon d birthdays . 5 ) Cognitiv e Functio n I nadditio nt o deficit s i nbehaviora l functions , fin e moto r control , and auditory , languag e and speec hdevelopment , ther e i s evidenc e tha t lo w level s o f lea d ma yb e associate d wit heffect s o nsom e comple xcognitiv e function s includin g learning , visual-perceptio nskills , an d I Q scores . I n studie s no t confounde d b ynutritiona l o r litte r effect s ( a commo nproble m i nbehaviora l assays) , rat s expose d t o lea d i nuter o and/o r throug h earl ydevelopment , resultin g i nPb B level s belo w3 0 yg/d l and a s lo wa s 2 0 yg/dl , displa yalteration s i nlearnin g tas k performance s (visua l discrimination , shoc k avoidance , operan t conditioning ) (Winnek e e t al. , 1977 , 1982b ; Cory-Slecht a an d Thompson , 1979 ; Gross-Selbec k an d Gross-Selbeck , 1981) . Monkey s expose d fo r on e yea r afte r birt ht o achiev e Pb B level s betwee n3 0 and 5 0 yg/d l wer e significantl yretarde d i nthei r abilit yt o lear nspatia l and discriminatio ntask s (Bushnel l and Bowman , 1979 ) an d i nP.9 3



### 0-25 thei r abilit yt o alte r thei r behavio r unde r change d learnin g condition s (Ric e an d Willes , 1979) . Afte r lea d dosin g ceased , th e lea d treate d monkey s a t 2- 3 year s o f ag e (PbB * 2 0 yg/dl ) ha d highe r respons e rate s tha n control s t o reinforce d stimul i (Ric e e t al. , 1979) , and deficit s i nspatia l memor ypersiste d i nthes e monkey s a t 4- 5 year s o f ag e whe nPb B level s ha d stabilize d a t 5 yg/d l (Levi nand Bowman , 1983) . Pb B level s ar e presente d fo r comparativ e purpose s onl yand shoul d no t b e extrapolate d t o huma ndose

respons e relationships . I nconsiderin g thes e effects , i t shoul d b e note d tha t performanc e i na learnin g tas k i s base d o na numbe r o f functiona l processes , suc ha s moto r functions , emotional-motivationa l conditions , sensor yfunctions , and cognitiv e function s (namel ymemor yand/o r learnin g processes , i.e. , th e formatio nand retentio no f stimulus-respons e associations ) (Bornschei ne t al. , 1980 ; Winnek e e t al. , 1982b) . I t ha s bee nsuggeste d tha t th e abov e findings , whic hinclud e "improved " performanc e i nlead-treate d animal s o nsom e learne d task s wher e succes s wa s measure d b

yrapi d response , indicat e a nunderlyin g tendenc yt o respon d excessivel yo r a behaviora l "over-reactivity, " whethe r o r no t suc hrespons e i s appropriat e (Winnek e e t al. , 1982b) . Thi s interpretatio ncorrespond s t o som e exten t t o lead-induce d increase s i nlocomoto r activit yand response disinhibitio n(Overmann , 1977 ; Winnek e e t al. , 1977 ; Schlipkote r and Winneke , 1980) . Take ntogether , thes e dat a indicat e tha t lea d exposur e durin g earl y developmen t i s disruptiv e i nattention-demanding , difficul t discriminatio n learnin g and comple xneuropsychologica l performanc e and reduce s responsivenes s t o contingencie s i nth e environment , bu t thi s exposur e facilitate s activ e avoidanc e and othe r simpl e learnin g task s (Overmann , 1977 ; Winnek e e t al. , 1982b) . Althoug hthes e result s canno t b e quantitativel yextrapolate d t oP.9 4

D-2 6 children , the yar e i nagreemen t wit hfinding s fro mrecen t studie s tha t lea d
a t lo wdose s ma yb e associate d wit ha spectru mo f alteration s i nchildren' s behavioral , academic , and possibl yintellectua l developmen t (se e below) . Thes e studie s onchildre nhav e attracte d controvers ybecaus e o f difficultie s associate d wit hattributin g subtl e deficit s i nchil d developmen t t o lea d ex posur e rathe r tha nt o effect s du e t o genetics , nutrition , medica l history , acces s t o education , and parenta l and socia l influences , al l o f whic hinterac t i npotentiall ycomple xway s t o mol d a nindividua l (Pearso nan d Dietrich , 1985) . Untanglin g thes e differen t source s o f behaviora l varianc e i s complicate d b yth e necessar yfocu s o nchildre nfro mlowe r socioeconomi c area s wher e lea d exposur e i s elevate d and learnin g and caregivin g condition s ofte nar e no t ideal . Othe r difficultie s encountere d i nth e conduc t and interpretatio no f childhoo d lea d studie s include : 1 ) accuratel yclassifyin g exposur e sinc e Pb B i s aninde xo f recent , bu t no t necessaril yhistorical , lea d exposure , and becaus e th e relationshi p betwee ntoot hand Pb B level s i s uncertain ; 2 ) in

appropriat e measuremen t covariate s (e.g. , socia l clas s a s aninde xo f parenta l car e and intellectua l stimulation ) tha t ca nbia s regressio nanalyses ; 3 ) incomplet e assessmen t o f comple xbehaviora l an d intellectua l processes ; an d 4 ) possibl e non-representativenes s o f studysample s sinc e mos t studie s relie d o ninformatio nfro meithe r pre-selecte d clini c group s alon g wit ha selecte d "match " sample , o r volunteer s fro mth e genera l populatio nwh o ma yb e mor e altruistic , interested , o r bette r informe d (Smit he t al. , 1983) . Base d o nfiv e methodologica l criteri a (adequat e marker s o f lea d exposure , sensitiv e measure s o f neurobehaviora l function , appropriat e subjec t selection , contro l o f confoundin g covariates , and appropriat e statistica l analysis) , th e criteri a documen t ha s identifie d a group o f neurobehaviora l studie s tha t "wer e conducte d rigorousl yenoug ht o warran t a t leas t som e consideratio n here " (CD , p . 12-65) .P.9 5

D-2 7 A s wit hothe r parameter s o f neuropsychologica l performance , ther e hav e bee nmixe d finding s regardin g lead' s associatio nwit hchildren' s score s o nstandardize d I Q tests , whic hmeasur e som e combinatio no f literacy , information , academi c capacity , and intelligenc e (Flynn , 1984) . Severa l well-controlle d studie s hav e foun d effect s tha t ar e clearl ystatisticall y significan t wherea s other s hav e foun d "non-significant " bu t borderlin e effects . I t i s importan t t o not e that : 1 ) th e definitio no f "statistica l significance " ( p < 0.05 ) i s somewha t arbitrar yand shoul d no t b e use d t o totall yexclud e result s tha t ma yhav e importan t publi c healthimplications ; an d 2 ) give nth e likel ysubtl e natur e o f th e behaviora l o r neura l effect s probabl e a t lo wlevel s o f lea d exposure , th e differentia l maturatio npattern s and sensitivitie s amon g differen t brai nprocesses , and th e man yothe r factor s tha t pla ya large r rol e i nanindividual' s developmenta l trajectory , on e woul d no t expect t o find strikin g difference s i never ystudy , especiall yi n thos e tha t us e standardize d bu t non-specifi c measure s o f intelligenc e o r academi c capacity . Th e genera l indicatio nfro mth e bette r investigation s i s tha t Pb B level s persistentl yelevate d i nth e rang e o f 50-7 0 yg/d l ten d t o b e associated , o n average , wit habou t a 5 poin t reductio ni nIQ , eve namon g asymptomati c childre n and afte r controllin g fo r potentiall yconfoundin g variable s (d e l a Burd e and Choate , 1972 , 1975 ; Rummo , 1974 ; Rumm o e t al. , 1979) . A5 poin t decreas e i n children' s averag e I Q score , give nth e norma l curv e o f distributio no f intelligence , woul d b e associate d wit ha doublin g i nth e numbe r o f childre n wit hIQ' s belo w7 0 (th e leve l use d t o defin e menta l retardation) , a s wel l a s a reductio ni nth e numbe r o f childre nwit hIQ' s abov e 12 5 (Rutter , 1980) . Thus , whil e anyindividua l child' s I Q scor e ma yfluctuat e ove r time , th e implication s o f a 5 poin t averag e defici t amon g childre nar e serious .P.9 6

DT,2 8 Considerabl e uncertaint yexist s regardin g lead' s impac t o nI Q score s o f childre nwit hPb B level s belo w4 0 pg/dl . Thi s uncertaint ylargel ystem s fro m th e comple xinteractio nbetwee nlea d exposur e ove r time , socia l factors , and intelligenc e scores , and fro mth e statistica l and methodologica l limitation s o f cross-sectiona l studie s t o untangl e thes e variables , and th e rang e o f interpretation s tha t resul t fro mthes e studies . Fo r example , Ernhar t (1983 , 1984 ) reanalyze d previously-publishe d dat a o na group o f childre n whos e averag e Pb B leve l droppe d fro m35. 2 t o 26. 9 pg/d l ove r 5 year s (Perin o an d Ernhart , 1974 ; Ernhar t e t al. , 1981 ) and foun d tha t afte r partiallin g ou t th e effect s o f sex , parenta l IQ , and parenta l educatio n(bu t no t socio-economi c status) , th e proportio no f varianc e explaine d b ylea d wa s n o greate r tha n5 % o nan yon e o f th e I Q measures . Wit hth e exceptio no f Genera l Cognitiv e Inde xand Verba l Scal e scores , th e effect s o f earl ylea d exposur e o nI Q score s appeare d t o b e neithe r statisticall ysignifican t no r persisten t throughou t childhood . I t i s possible , a s wit hothe r studies , tha t b ycontrol

lin g fo r on e variabl e suc ha s parenta l IQ , whic hma yb e affecte d b ylea d exposure , th e effect s o f lea d o nchildren' s I Q i s diminished . Ernhar t (1983 ) conclude d tha t althoug hthes e dat a d o no t suppor t a ninferenc e fo r a n associatio nbetwee nneuropsychologi c deficit s and lea d exposure s a t th e level s experience d b yth e childre ni nthi s study , th e rathe r lo wstatistica l powe r o f th e reanalyse s doe s no t allo wfo r a definitiv e conclusio no f "no
effect" , either . Nevertheless , th e result s fro mthes e analyse s ar e reasonabl y consisten t wit hthos e fro mothe r investigators ; namel ytha t Pb B level s abov e 3 0 pg/dl , compare d t o lowe r levels , sho wa small , bu t significan t associatio n wit hsom e measure s o f I Q afte r controllin g fo r confoundin g variables . Th e criteri a documen t conclude d fro mth e Needlema ne t al . (1979 ) study and subsequen t re-analyse s (Needleman , 1984 ) that , afte r controllin g fo rP.9 7

D-2 9 confoundin g variable s includin g pica , averag e I Q decrement s o f abou t 4 point s appea r t o b e associate d wit hPb B level s i nth e 30-5 0 pg/d l rang e (CD , p . 12-7 4 t o 12-80) . Needlema ne t al . (1982 ) calculate d tha t a 4 poin t decremen t i nth e mea nI Q o f a norma l populatio ndistributio nwoul d b e associate d wit ha three-fol d increas e i nth e numbe r o f childre nwit hsever e deficit s (I Q
< 80 ) alon g wit ha 5 % reductio ni nth e numbe r o f childre nwh o attai nsuperio r functio n(I Q > 125) . I t i s o f interes t t o not e tha t tw o pilo t studie s (Yul e e t al. , 1981 ; Winnek e e t al. , 1982a ) tha t include d childre nwit h Pb B level s belo w30-3 5 pg/d l (Rutter , 1983 ) livin g nea r lea d smelter s i n Europ e foun d I Q deficit s (4. 5 t o 7 points ) simila r t o thos e observe d b y Needlema ne t al . (1979 ) betwee nhig hand lo wexposur e group s afte r correctio nfo r confoundin g variables . However , th e relativel ycrud e control s fo r socia l variable s provide d i nthes e latte r tw o pilo t studie s preven t conclusiv e interpretatio no f th e observe d association s (CD , p . 12-86) . Studie s o f Europea nchildre nwit hlowe r lea d exposure s (mea nPb B « 8

- 1 5 pg/dl ) hav e generall yfoun d onl y1- 2 point , and statisticall ynon-signifi

can t difference s i nvariou s I Q score s a t Pb B level s i nth e 15-3 0 pg/d l rang e afte r controllin g fo r confoundin g variable s (Smit he t al. , 1983 ; Harve y e t al. , 1983 , 1984 ; Yul e e t al. , 1983 ; Yul e and Landsdown , 1983 ; Winnek e e t al. , 1983 , 1984) . Smit he t al . (1983 ) commente d tha t i f difference s exis t i n neuropsychologica l performanc e attributabl e t o lea d a t th e level s the ystudie d (<2 5 pg/dl) , the nth e sensitivit yo f psychologica l test s and othe r currentl y availabl e measure s and statistica l procedure s d o no t allo wthes e difference s t o b e detecte d wit han ydegre e o f certainty . Animportan t findin g fro msevera l o f thes e studie s tha t teste d fo r interactiv e effect s (Yul e and Landsdown , 1983 ; Winnek e e t al. , 1983 ; Harve ye t al. , 1983 ) wa s tha t neurobehaviora l deficit s associate d wit hP.9 8

DT3 0 lea d wer e enhance d in , o r eve nlargel yconfine d to , sociall ydisadvantage d childre ncompare d t o thos e fro m mor e middl e clas s backgrounds . Thes e finding s sugges t tha t lo wleve l lea d exposure , i ncombinatio n wit hothe r factor s associate d wit hlo wsocio-economi c statu s (e.g. , undernutrition ) ma y predispos e a chil d t o psychologica l impairment . Furthe r researc hi s neede d t o investigat e th e possibilit ytha t th e effect s o f lo wlevel s o f lea d (PbB < 3 0 pg/dl ) o nI Q ar e due , no t t o som e "pure " for m o f permanen t damag e t o th e brain , a s muc ha s t o th e effect s o f lea d a s par t o f a mor e comple xse t o f interactin g influence s includin g socia l and nutritiona l factors . 5 ) Electrophysiologica l Effect s A s discusse d earlier , i nadditio n t o it s varie d effect s o n neurona l developmen t and chemically-mediate d synapti c transmission , lea d impair s periphera l nerv e conductio nvelocities , a t level s possibl ya s lo wa s 3 0 pg/d l (Appendi xD.2.a) . Similarly , lea d exposur e affect s brai n morpholog yand metabolism , interfere s wit hneurotransmissio ni n centra l
nervou s syste m

tissu e (e.g. , cerebellum , retina ) (Palme r e t al. , 1981 ; Fo xan d Sillman , 1979 ; Sillma n e t al. , 1982) , and depresse s conductio n velocitie s i n th e visua l pathway s o f rat s accompanie d b ypersisten t decrease s i n visua l acuit yand spatia l resolutio n(Fo xe t al. , 1977 ; Coope r e t al. , 1980 ; Winneke , 1980 ; Impelma n e t al. , 1982 ; Fo xand Wright , 1982) . Consisten t wit hthes e finding s ar e thos e fro mneurologica l assessment s o f childre nand adul t worker s whic hprovid e consisten t finding s indicatin g tha t a wid e rang e o f lea d level s ar e associate d wit himpaire d functio ni n th e visual-moto r and auditor ysystem s (Repko , 1979 ; Haennine ne t al. , 1978 ; Needlema ne t al , 1979 ; Winnek e e t al. , 1983) .P.9 9

D-3 1 I t ha s als o bee ndemonstrate d tha t electrica l activit yi nth e brai n itself , determine d b yelectroencephalogram s (EEG) , i s disrupte d i nanimal s and human s sufferin g fro mlea d intoxicatio n(Coope r e t al. , 1980) . Mor e subtl e abnormalitie s i nEE Gpattern s (increase d delta/decrease d alph a activity ) wer e detecte d i na subse t o f childre nfro mth e Needlema ne t al . (1979 ) studywit hhig htoot hlea d level s (Burchfie l e t al. , 1980) . Th e lowe r amount s o f alph a activit yi nth e hig hlea d childre n(Pb B level s

» 30-5 0 pg/dl ; CD , p . 12-92 ) migh t signif ytha t brai nmaturatio nwa s somewha t delaye d b

ylea d sinc e suc hactivit ytend s t o increas e wit hag e i nchildre n(Beningnu s e t al. , 1981) . Th e brai nwav e pattern s (indexe d b yslo wcortica l potential s elicite d b yclassica l conditioning ) o f 1- 6 yea r ol d childre nvarie d a s a linea r functio no f Pb B (rangin g fro m6-5 9 pg/dl ) wit hn o evidenc e o f a threshold , althoug hth e slop e change d systematicall ywit hag e (Ott o e t al. , 1981) . Slo wwav e voltag e tende d t o b e positiv e i nchildre nles s tha n5 year s ol d
an d negativ e i nchildre nove r 5 years . Neurophysiologica l evidenc e suggest s tha t slo wsurface-positiv e potential s i nver yyoun g childre nma yreflec t axodendriti c inhibitor yprocesse s (Ott o an d Reiter , 1984) . Rostro n(1982 ) ha s speculate d tha t thes e finding s sugges t a decreas e i nattentivenes s wit h increase d Pb B levels , perhap s lendin g suppor t t o finding s o f greate r distractabilit yi nchildre nwit helevate d lea d level s (Needlema ne t al. , 1979 ; Winnek e e t al. , 1983 ; Yul e e t al. , 1984) . Th e relativ e amplitud e o f synchronize d electrica l activit ybetwee nth e lef t and righ t hemisphere s o f th e brai nvarie d a s a cubi c functio no f Pb B level s i nthes e children , wit hinflectio npoint s a t 1 5 pg/d l and 4 0 pg/d l (Beningnu s e t al. , 1981) . Increase d synchron yand relativ e amplitud e o f th e EE Ga t thes e point s coul d indicat e a nincreas e i nth e amoun t o f informatio nbein gD-3 2

processe d and , perhaps , tha t a nincrease d effor t i s require d t o assimilat e thi s informatio n(Rostron , 1982) . I na subsampl e o f thes e childre nassesse d 2 year s later , slow-wav e voltag e durin g sensor yconditionin g agai nvarie d linearl ywit hPb B wit hn o apparen t threshol d ove r a rang e o f 11-3 9 yg/d l (Ott o e t al. , 1982) . Thi s relationshi p wa s constan t whethe r Pb B level s fro mth e initia l o r follow-u p studywer e analyzed , suggestin g a chang e tha t persiste d ove r tim e despit e a substantia l declin e i nmea nPb B fro m32. 5 t o 21. 1 yg/dl . I na five-yea r follow-u p o na subse t o f th e sam e children , significan t association s wer e foun d betwee nPb B level s and increase d latencie s i nbrainste mauditor y evoke d potential s (Ott o e t al. , 1984) . Th e author s state d tha t whil e th e functiona l significanc e o f slo wwav e change s associate d wit hP bexposur e i s uncertain , th e slowin g o f nerv e conductio ni nth e auditor ypathwa yha s bee n unambiguousl yrelate d t o pathologica l lesion s and non-specifi c demyelinatin g disease s suc ha s multipl e sclerosis ; therefor e th e latte r effect s o nbrainste m auditor yevoke d potential s ar e clearl yindicativ e o f neurologica l impairmen t (Ott o e t al. , 1984) . Interpretatio no f thes e dat a mus t b e tempere d b yuncertaintie s regarding : 1 ) th e clinica l and functiona l significanc e o f manyo f th e electrophysiologica l
measure s use d tha t ar e presentl yconsidere d experimental ; 2 ) th e Pb B level s actuall yassociate d wit hth e observe d effects ; 3 ) severa l inconsisten t correlation s betwee nPb B and derive d EE Gmeasure s withi nth e populatio n ove r time ; and 4 ) th e representativenes s o f th e dat a sinc e onl y4 3 childre n wer e initiall ystudied , and 2 8 subsequentl yevaluate d i nth e follow-u p studies . Nevertheless , th e criteri a documen t conclude s tha t thes e finding s "provid e clea r evidenc e o f altere d CN S functionin g associate d wit hrelativel y lo wleve l lea d exposur e a t Pb B level s i nth e 15-3 0 yg/d l range , and