p. 1



# OAR Box 1128 Prepped by Ollie Stewart



### Document

Number: 

# 106)11-1-43 5

Docket Number: 

# A-83-2 2

Printed 4/21/2008 11:07:15 AM Sheet 106 of 198P. 2



# AEPA $-%?>'

Unite d State s Environmenta l Protectio n Agenc y Offic e o f Healt h an d Environmenta l Assessmen t Washingto n D C 2046 0 EPA/600/8-89/045 A Marc h 198 9 Externa l Revie wDraf t
Researc h an d Developmen t 

# Evaluatio n o f th e Potentia l Carcinogenicit y o f Lea d an d Lea d Compounds : Revie w Draf t (D o No t Cit e o rQuote ) 

# 1 I 6 6 B f II
. MA R 3 0 I99 2
EP AAI R DOCKE T 

# n Suppor t o f Reportabl e Quantit y Adjustment s Pursuan t t o CERCL A Sectio n 10 2

NOTIC E Thi s documen t i s a preliminar ydraft

. I t ha s no t bee n formall y release d b yEP A an d shoul d no t a t thi s stag e b e construe d t o represen t Agenc ypolic yi t i s bein g circulate d fo rcommen t o n it s technica l accurac yan d polic yimplication sP. 3

DRAF T EPA/600/8-89/045 A D O NO T QUOT E O RCIT E Marc h198 9 Externa l Revie w

Draf t

EVALUATIO N

O F TH E POTENTIA L CARCINOGENICIT YO F LEAD AN D LEAD COMPOUND S

InSuppor t o f Reportabl e Quantit y Adjustment s Pursuan t t o CERCL A

Sectio n10 2

NOTIC E THI S DOCUMEN T I S A

PRELIMINAR YDRAFT . I t ha s no t bee nformall y release db

y th e U.S . Environmenta l Protectio nAgenc y an dshoul dno t a t thi s stag e b e construe dt o represen t Agenc y policy . I t i s bein g circulate dfo r commen t o n it s technica l accurac y an dpolic y implications .

Offic e o f Healt han

dEnvironmenta l Assessmen t Offic e o f Researc han dDevelopmen t U.S ; Environmenta l Protectio nAgenc y

Washington , D.C .P. 4

DISCLAIME R

Thi s documen t i s a

nexterna l draf t fo r revie w purpose s onl y

an d doe s no t constitut e Agenc y

policy . Mentio no f trad e name s o r commercia l product s doe s

no t constitut e endorsemen t o r recommendatio nfo r use .



### nP. 5

CONTENT S

Table s v Prefac e v i Abstrac t i x Author s and Reviewer s x 1
. WEIGH T O F EVIDENC E
. 1 1.1
. HUMA

NSTUDIE S 1 1.1.1
. Epidemiologi c Studie s 1 1.1.2
. Cas e Report s 1 7 1.1.3
. Discussio n 1 8 1.2
. ANIMA L STUDIE S 2 3 1.2.1
. Lea d Acetat e 2 3 1.2.2
. Lea d Subacetat e 4 6 1.2.3
. Lea d Oxid e 5 5 1.2.4
. Lea d Phosphat e 5 6 1.2.5
. Lea d Nitrat e 5 8 1.2.6.
. Lea d Naphthenat e 5 9 1.2.7
. Lea d Dimethyldithiocarbamat e 5 9 1.2.8
. Tetraethy l Lea d 6 4 1.2.9
. Ambien t lea d 6 4 1.2.10
. Discussio n 6 5 1.3
. SHORT-TER M TEST S 7 8 1.3.1
. Mutagenicit y7 8 1.3.2
. Cel l Transformatio n 7 9 1.4
. TOXICOLOGI C EFFECT S RELEVAN T T O CARCINOGENICIT Y 7 9 1.4.1
. Huma n Studie s 7 9 1.4.2
. Anima l Studie s 8 2 1.5
. PHARMACOKINETI C PROPERTIE S 8 4 1.5.1
. Absorptio n 8 4 1.5.2
. Distributio n an d Retentio n 8 8 1.5.3
. Excretio n 9 2 1.5.4
. Discussio n 9 3



### m

### CONTENT S (continued )

. 1.6 . WEIGHT-OF-EVIDENC E CLASSIFICATIO N 9 4 2 , POTENC Y10 4 2.1 . GENERAL METHODOLOG Y10 4 2.2 . DATA

SELECTIO N

10 6 2.3 . POTENC YESTIMATION AND CHARACTERIZATION

10 7 2.4 . DISCUSSIO N

. Il l 3 . HAZAR D RANKIN

G. 11 8 3.1 . GENERAL METHODOLOG Y11 8 3.2 . . OVERAL L CHARACTERIZATION 11 9 REFERENCE S '. 12 0

i vP. 7

TABLE S

1- 1 Summar y

o f positiv e anima l studies . . 1- 2 Summar y

o f nonpositiv e anima l studie s 2 4 3 2PREFAC E

Thi s repor t summarize s an devaluate s informatio no nth e potentia l carcinogenicit y

o f a hazardou s substanc e define dunde r Sectio n101(14 ) o f th e Comprehensiv e Environmenta l Response , Compensation , an dLiabilit y

Ac t o f 198 0 (CERCLA) . EPA' s Offic e o f Emergenc y an dRemedia l Respons e consider s thi s repor t alon g wit hothe r informatio nwhe nadjustin g reportabl e quantitie s unde r CERCL A Sectio n102 . Th e genera l methodolog y fo r adjustin g reportabl e quantitie s i s describe dinth e Technica l Backgroun dDocumen t t o Suppor t Rulemakin g Pursuan t t o CERCL A Sectio n102 , Volume s 1-3 . Th e specifi c methodolog y

fo r evaluatin g potentia l carcinogenicit y i s describe dinmor e detai l i nth e Methodolog y fo r Evaluatin g Potentia l Carcinogenicit y inSuppor t

o f Reportabl e Quantit y Adjustment s Pursuan t t o CERCL A Sectio n102 . Bot h methodolog y

document s hav e bee nsubjecte dt o publi c revie w an dcommen t a s par t

o f CERCL A

rulemakin g activities . Initia l draft s o f thi s repor t wer e researche dan dwritte nb

y th e staf f o f th e Chemica l Hazar dEvaluatio nProgram a t th e Oa k Ridg e Nationa l Laborator y unde r Interagenc y

Agreemen t No . DW89933015 . Th e discussion s an dconclusion s

o f thi s repor t wer e develope dan dwritte nb

y member s o f th e Huma nHealt h Assessmen t Grou pinEPA' s Offic e o f Healt han dEnvironmenta l Assessment . Pertinen t studie s include dinthi s repor t wer e identifie dthroug h compute r literatur e searche s an dfro m th e referenc e list s o f relevan t publications . Ever y attemp t ha s bee nmad e t o us e primar y source s fo r th e pertinen t cance r studie s instea do f abstract s o r dat a summarie s containe di n secondar y

source s suc ha s revie w articles , surveys , an dmonographs . Compute r searche s wen t a s fa r bac k i ntime a s th e dat a base s woul dallow . Studie s

v iP. 9

appearin g i n on e o f thes e source s u p throug h 198 8 hav e bee n included

. Th e followin g dat a base s wer e used :

CHEMLIN E TOXLI T TOXLIN E Subfiles : EMI C ETI C EPIDE M PESTA P HMT C TOXNE T Subfiles : CCRI S

. HSD B RTEC S Chemica l Abstract s (CA ) BIOSI S Internationa l Pharmaceutica l Abstract s (IPA ) CI S Abstract s

CRIS P NTI S TSCAT S Nationa l Librar yo f Medicin e Nationa l Librar yo f Medicin e Nationa l Librar yo f Medicin e Oa k Ridg e Nationa l Laborator y Oa k Ridg e Nationa l Laborator y Oa k Ridg e Nationa l Laborator y U.S
. Environmenta l Protectio n Agenc y(Pesticid e Abstracts ) Departmen t o f th e Army Nationa l Librar yo f Medicin e Nationa l Cance r Institut e Nationa l Librar yo f Medicin e Nationa l Institut e o f Occupationa l Safet yand Healt h Chemica l Abstract s Servic e Biologica l Abstracts , Inc
.
America n Societ yo f Hospita l Pharmacist s Internationa l Labou r Office , Internationa l Occupationa l Safet yan d Healt h Informatio n Cente r Nationa l Institute s o f Healt h Nationa l Technica l Informatio n Servic e U.S
. Environmenta l Protection^Agenc y(Toxi c Substance s Contro l Ac t Tes t Submissions )

* '" EPA' s Ai r Qualit yCriteri a fo r Lea d (U.S
. EPA , 1986c ) ha s bee n use d

extensivel ya s a reference

. Th e Ai r Qualit yCriteri a fo r Lea d ha s ha d considerabl e pee r review , includin g revie wb yth e Clea n Ai r Scientifi c Advisor yCommitte e o f th e Scienc e Advisor yBoar d i n publi c sessions

. Befor e beginnin g wor k o n thi s report , EP Aconsulte d severa l meta l carcinogenicit yexpert s regardin g th e evidenc e o n th e potentia l carcinogenicit yo f lead

. Th e conclusion s o f thi s repor t ar e consisten t wit h th e recommendation s o f thos e experts
.



### vnTh e conclusion s o f thi s repor t ca nals o be regarde da s a natura l

extensio no f th e conclusion s concernin g th e potentia l carcinogenicit y o f lea d reache db

y th e Internationa l Agenc y fo r Researc honCance r in198 0 an d198 7

an db y th e Nationa l Toxicolog y Program

in1985 . Thi s repor t i s organize dt o reflec t two factors—weigh t o f evidenc e an d potency—tha t th e Agenc y consider s importan t i ncharacterizin g potentia l carcinogens . Sectio n1 deveTop s th e weigh t o f evidenc e (the strengt ho f th e evidenc e tha t a substanc e cause s cancer ) accordin g t o EPA' s Guideline s fo r Carcinoge nRis k Assessment . Informatio nha s bee norganize da s describe di n th e guidelines ; accordingly , fectio n1 ha s subsection s dealin g wit hhuma n studies , long-ter m

anima l studies , short-ter m tests , toxicologi c effect s othe r tha ncarcinogenicit y

tha t ar e relevan t t o th e evaluatio no f carcinogenicity ,
an dpharmacokineti c properties . Sectio n2 discusse s th e potenc y (the strengt h

o f a substanc e t o caus e cancer) . Sectio n3 combine s th e weigh t o f evidenc e

an dth e potenc y

int o a noveral l hazar drankin g fo r potentia l carcinogenicity . Finally , ther e i s a lis t o f reference s cite dinthi s report .



### v mP.1 1

ABSTRAC T

Informatio nonth e potentia l carcinogenicit y o f lea dandlea dcompound s i s summarize dan

devaluate dunde r EPA' s Guideline s fo r Carcinoge nRis k Assessment . Th e huma nstudie s provid e suggestiv e evidenc e o f carcinogenicity , but , becaus e o f confoundin g exposure s t o othe r carcinogen s an dth e lac k o f measurement s o f lea dexposure , ar e inadequat e t o prov e o r disprov e carcinogenicity . Numerou s long-ter m anima l studies , usin g severa l differen t form s o f lea dan

droute s o f exposure , provid e sufficien t evidence . Thi s combinatio no f evidence , togethe r wit h-Informatio nfro m short-ter m

tests , othe r toxi c effects , an dpharmacokineti c properties , yield s a classificatio n

o f lea dan

dlea dcompound s a s probabl e huma ncarcinogens , Grou pB2 . No specifi c cance r potenc y ha s bee nestimate dfo r lead . Man y factor s influenc e lead-induce dcancer , creatin g difficultie s inselectin g a n appropriat e measur e o f dose . Cross-specie s pharmacokineti c model s ar e neede d befor e th e anima l studie s ca nb e use dt o estimat e a huma ncance r potency . Becaus e i t ha s bee nrelativel y hig hconcentration s o f lea dtha t hav e increase d th e incidenc e o f cance r i nanimals , i t seem s appropriat e t o characteriz e th e

cance r potenc y

o f lea da s low , placin g lea dinpotenc y Grou p3 unde r EPA' s Methodolog y

fo r Evaluatin g Potentia l Carcinogenicit y i nSuppor t o f Reportabl e Quantit y Adjustment s Pursuan t t o CERCL A Sectio n102 . Combinin g th e weight-of-evidenc e grou pan dth e potenc y

group , lea dan

d lea dcompound s receiv e a low hazar drankin g amon g potentia l carcinogen s ranke d fo r th e purpos e o f adjustin g CERCL A reportabl e quantities . Th e hazar drankin g shoul db e interprete dno t a s a nabsolut e measur e o f concern , bu t a s a rankin g relativ e t o othe r carcinogens .
ixP.1 2

AUTHOR S AND REVIEWER S

EPA' s Offic e o f Healt han dEnvironmenta l Assessmen t (OHEA ) i s responsibl e fo r thi s report . Th e projec t manager , wit hoveral l responsibilit y fo r coordinatin g an

ddirectin g th e researc han dproductio no f thi s repor t i s

Vincen t Jame s Cogliano , Ph.D . Offic e o f Healt han

dEnvironmenta l Assessmen t U.S . Environmenta l Protectio nAgenc y Washington , D.C .
Initia l draft s o f thi s repor t wer e researche dan dwritte nb

y

Koweth a A . Davidson , Ph.D . Chemica l Hazar dEvaluatio nProgram Oa k Ridg e Nationa l Laborator y Oa k Ridge , Tennesse e

Eac hsectio nwa s reviewe dan dsupplemente db

y OHE A scientists , wh o ar e responsibl e fo r th e fina l draf t an dfo r developin g an

dwritin g th e discussion s

an dconclusions . Eac hscientis t i s wit hOHEA' s Huma nHealt hAssessmen t Grou p inWashington , D.C , unles s otherwis e indicated .

Sectio n1.1 . Aparn a M . Koppikar , M.D. , D.P.H. , D.I.H. , Ph.D .

Srikuma r Menon , M.D. , M.P.H. , Ph.D . Departmen t o f Psychiatr y Alber t Einstei nMedica l Cente r Philadelphia , Pennsylvani a
Sectio n1.2 . Willia m E . Pepelko , Ph.D . Davi dH . Reese , Ph.D . Dharm V . Singh , D.V.M. , Ph.D . Tables . Vincen t Jame s Cogliano , Ph.D .P.1 3

Sectio n1.3 . Vick i L . Dellarco , Ph.D .

Davi dH . Reese , Ph.D .
Sectio n1.4 . Willia m E . Pepelko , Ph.D .
Sectio n1.5 . Jea nC . Parker , Ph.D .

J . Michae l Davis , Ph.D . Environmenta l Criteri a an dAssessmen t Offic e Offic e o f Healt han

dEnvironmenta l Assessmen t U.S . Environmenta l Protectio nAgenc y Researc hTriangl e Park , Nort hCarolin a
Sectio n1.6 . Vincen t Jame s Cogliano , Ph.D .

Charle s H . Ris , M.S. , P.E .
Sectio n2 . Vincen t Jame s Cogliano , Ph.D .
Sectio n3 . Vincen t Jame s Cogliano , Ph.D .
Overal l revie w

o f thi s repor t wa s provide db y

Charle s H . Ris , M.S. , P.E . Deput y Director , Huma nHealt hAssessmen t Grou p Jea nC . Parker , Ph.D . Actin g Associat e Directo r fo r Science , Offic e o f Healt han

dEnvironmenta l Assessmen t Willia m H . Farland , Ph.D . Director , Offic e o f Healt han dEnvironmenta l Assessmen t

x iP.1 4

1 . WEIGH T O F EVIDENC E

1.1 . HUMA

N STUDIE S 1.1.1 . Epidemiologi c Studie s Ove r a doze nepidemiologi c studie s o nlea dexposur e an

dcance r ar e reviewed . Thes e studie s wer e conducte di ndifferen t occupationa l setting s including : a cohor t o f lea dbatter y worker s i nEnglan d(Dingwall-Fordyc e an d Lane , 1963 , whic hwa s expande dan dstudie db

y Malcol m an dBarnett , 1982 , an

d the nb y Fanning , 1988) ; lea dbatter y an dsmelte r worker s (Coope r an dGaffey , 1975 , an dfollowe du

plate r b

y Cooper , 1976 , an

dCoope r e t al. , 1985) ; smelte r worker s (McMichae l an dJohnson , 1982 ; Seleva ne t al. , 1985 ; Gerhardso ne t al. , 1986 ; Ade s an

dKazantzis , 1988) ; chemica l plant s producin g tetraethy l lead (Robinson , 1974 ; Sweene y e t al. , 1986) ; ah

dplumber s an

dpip e fitter s (Canto r

e t al. , 1986) . Tw o othe r studie s wer e designe dt o tes t th e hypothesi s tha t paterna l occupationa l exposur e t o lea dwa s associate dwit ha nincrease dris k

o f Wilms' s tumo r inoffsprin g (Kanto r e t al. , 1979 ; Wilkin s an dSinks , 1984) . I naddition , two cas e report s o f long-tim e lea dworker s havin g cance r ar e reviewed . Th e majo r objectiv e inreviewin g th e epidemiologi c dat a bas e i s t o determin e i f a causa l associatio nbetwee nlea dexposur e an dcance r ca nbe demonstrate do r refuted . Th e presenc e an dabsenc e o f positiv e result s an dth e characterizatio no f th e stud y methodolog y

alon g wit hconfoundin g factor s ultimatel y

provide s th e basi s fo r weighin g th e huma nevidenc e accordin g t o EPA' s Guideline s fo r Carcinoge nRis k Assessmen t (U.S . EPA , 1986a) .P.1 5

1.1.1.1 . Studie s i nLea dBatter y Workers- - 1.1.1.1.1 . Dingwall-Fordvc e an dLane , 1963 . I

nthi s retrospectiv e surve y o f worker s know

nt o hav e bee nexpose dt o lea dinsevera l companie s inEngland , mortalit y

record s fo r 42 5 pensioner s wer e reviewe dan dth e caus e o f deat hwa s obtaine dfro

m deat hcertificates . Th e cohor t wa s define da s al l me nwh o becam e pensioner s betwee n192 6 an d196 0 a t th e ag e o f 6 5 year s wit ha t leas t 2 5 year s o f service . O f th e 42 5 pensioners , 18 4 ha ddie ddurin g th e revie w period . Expecte ddeath s wer e calculate db y applyin g th e deat hrate s fo r al l male s i nEnglan dan

dWale s standardize db y age . Th e mortalit y

experienc e o f

menwh o ha ddie dbetwee n194 6 an d196 1 whil e employe di non e electri c accumulato r company

wa s als o studie dprovidin g 15 3 suc hdeaths . Sinc e th e populatio na t ris k wa s unknow nfo r thi s group , ris k ratio s wer e calculate d usin g a proportiona l mortalit y analysis . Worker s wer e place di non e o f thre e categorie s dependin g o nurin e lea dlevels : (1 ) n o exposur e (grad e A) , (2 ) negligibl e exposur e (grad e B) , an d(3 ) lea di

nurin e betwee n10 0 an d25 0 ug/ L (grad e C) . Th e analysi s demonstrate dincrease dtota l cance r death s amon g pensioner s (standardmortalit y

rati o [SMR ] = 212 ) a s wel l a s amon g employe dme n (proportiona l mortalit y rati o [PMR ] = 157 ) i ngrad e B . I nth e grad e A exposur e group , a

nSM Ro f 12 3 an

da PM Ro f 11 3 wer e observe dinpensioner s an d employe dmen , respectively . Non e o f th e excesse s wer e statisticall y significant . Ther e wa s n o evidenc e o f an y exces s o f death s fro m malignancie s

amon g pensioner s an

demploye dme ningrad e C . Thi s study

i s a t bes t a ver y

explorator y

study wit hmany

limitations . Thes e includ e smal l sampl e size , lac k o f lifetim e occupationa l history , lac kP.1 6

df cause-specifi c deat hanalysis , an dabsenc e of dat a onsmokin g an dothe r confounders . 1.1.1.1.2 . Malcol m

an dBarnett , 1982 . Th e mortalit y experienc e o f 189 8 pensioner s (164 4 me nan d25 4 women ) fro

m fou r lea dan

dbatter y

companie s in England , whic hinclude dth e factorie s use db y Dingwall-Fordyc e andLan e in thei r study , wa s analyze dusin g a retrospectiv e cohor t design . A proportiona l mortalit y

analysi s o f death s amon g 55 3 employee s wh o die dwhil e stil l employe d

wa s als o done . Th e cohor t o f pensioner s wa s define da s long-ter m employee s wh o betwee nJanuar y

1 , 1925 , an

dDecembe r 31 , 1960 , ha da combine dscor e of
ag e a t retiremen t plu s year s of servic e o f 9 0 an d9 5 year s fo r wome nan dmen , respectively . Cause s of death s wer e code dusin g th e eight hrevisio nof th e Internationa l Classificatio nof Death s (ICD) . Expecte ddeath s wer e calculate d b y multiplyin g th e numbe r of individual s expose da t ris k i neac hag e grou pan

d quadrennia l perio db y th e appropriat e nationa l ag e an dcause-specifi c rat e o f mortalit y

fo r th e same period . Principa l occupatio na t wor k wa s use dt o classif y worker s a s havin g no (grou p1) , ligh t (grou p2) , o r hig h(grou p3 ) occupationa l lea dexposure . Th e analysi s showe dn o significan t exces s mortalit y fro m al l cancer s combine dinan

y of th e thre e group s amon g pensioners . Among , me ndyin g i n service , wh o ha dhig hexposur e t o lead , dyin g inservice , a nexces s mortalit y from digestiv e trac t cance r wa s observe d(observe d= 12 , PM R= 167 , p= 0.009) . Mos t of thi s exces s wa s confine dfro m 196 3 t o 1966 . Overall , n o
exces s death s fro

m malignan t disease s wer e foundi nan y othe r groups . Th e absenc e o f a consisten t inde xo f cumulativ e lea dexposur e i s a majo r limitatio no f thi s study . Th e us e o f principa l occupatio na t wor k rathe r tha n

a summar y

measur e of lifetim e occupatio nt o asses s lea dexposur e i s anothe r

3P.1 7

drawbac k o f thi s study . No dat a o nconfoundin g variable s wer e availabl e fo r analysis . 1.1.1.1.3 . Fanning , 1988 . Usin g a case-contro l approach , th e author s o f thi s study reviewe dth e record s o f 86 7 me nwh o die dan dwer e considere dt o hav e hig ho r moderat e lea dexposur e an dcompare di t wit hth e record s o f 120 6 me n wh o die dandwer e identifie da s havin g littl e o r n o lea dexposure . Batter y factorie s use db

y Dingwall-Fordyc e an dLan e (1963 ) an

dMalcol m

an dBarnet t (1982 ) t o dra w

thei r populatio nwer e include dinth e sourc e populatio nfo r thi s study . Th e study populatio nwa s employe dinbatter y factorie s an

dother s producin g plastic s andelectrica l equipment . Th e cas e grou pcomprise dth e cause-specifi c death s o f interest , an dal l othe r death s serve da s th e contro l
group . Scrutin y

o f jo btitle s b

y manager s an

dphysician s categorize dworker s int o hig han

dlow exposur e groups . A s a genera l indicatio no f th e leve l o f lea dexposur e o f thes e two groups , th e rang e o f bloo dlevel s ove r th e pas t 20 year s o f monitorin g (wheneve r carrie dou t periodically ) woul dhav e bee n betwee n4 0 an

d8 0 ug/d L fo r highexposur e whil e les s tha n4 0 ug/d L fo r low exposure . Althoug hth e study

desig nwa s a case-contro l type , th e result s o f th e analysi s wer e presente da s table s o f observe dt o expecte dvalues . Th e author s conclude dtha t n o exces s ris k wa s observe dfo r malignan t neoplasms . Ther e ar e man y

question s relate dt o th e study desig nan

danalysi s tha t hav e no t bee nanswere db y th e authors . Notably , i nth e method s sectio n mentio ni s mad e o f constructin g 2x 2 table s an dderivin g odd s ratio s ina case contro l design , bu t th e result s ar e discusse di nterm s o f observe dan d expecte ddeath s wit hno elaboratio no f how th e expecte ddeath s wer eP.1 8

calculated . On e is , therefore , unabl e t o commen t o nth e conclusion s reache d b y th e authors . 1.1.1.2 . Studie s inBatter y Plan t an

dSmelte r Workers- - 1.1.1.2.1 . Coope r an dGaffey , 1975 ; Cooper , 1976 . Si xlea dproductio nplant s

an d1 0 batter y

plant s wer e selecte dfo r a study o f mortalit y

inworker s wh o ha dbee nemploye da t leas t 1 yea r betwee nJanuar y 1 , 1946 , an

dDecembe r 31 , 1970 . A populatio no f 703 2 (235 2 smelte r worker s an d468 0 batter y

workers )

wa s selecte dfro

m a tota l o f 24,49 4 workers . Betwee n194 7 an d197 0 ther e wer e 135 6 death s (1 9 percen t o f th e study population) , wit h34 2 death s amon g smelte r worker s and101 4 amon g batter y workers . Th e PMR s o f 1 2 selecte d

cause s o f deat hwer e determine dan dcompare dwit hthos e o f U.S . males , an dth e SM Rbase do

nth e numbe r o f observe dan dexpecte ddeath s wa s calculate dusin g th e genera l U.S . mal e populatio na s th e reference . Cause s o f deat hwer e code d accordin g t o th e sevent h(1955 ) revisio no f th e ICD . Urinar y an dbloo dlea d level s wer e availabl e fo r some o f th e workers . Th e averag e urinar y lead concentratio nwa s 173. 2 ug/ L insmelte r worker s an d129. 7 ug/ L inbatter y workers ; th e averag e bloo dlea dconcentratio nwa s 79. 7 ug/d L i nsmelte r worker s and62. 7 ug/d L i nbatter y workers . Becaus e o f th e ver y lo w proportio n

o f decease dworker s wit hknow nvalues , no attemp t wa s mad e t o correlat e th e mortalit y

wit hurinar y

o r bloo dlea dconcentrations . A nonsignifican t exces s indeath s du e t o al l cause s wa s observe damon g smelte r worker s bu t no t amon g batter y workers . Nevertheless , Coope r an d Gaffe y (1975 ) state dtha t thi s wa s a nunfavorabl e finding , becaus e mos t employe dpopulation s show SMR s below

100 . Th e exces s indeath s du e t o al l malignan t neoplasm' s wa s statisticall y significan t amon g smelte r worker s ( p< 0.05 ) bu t no t amon g batter y workers . Th e SMR s fo r malignan t neoplasm s a tP.1 9

specifi c sites , however , wer e no t statisticall y significant . I t shoul dals o be note dtha t th e SMR s fo r "othe r hypertensiv e diseases " (rena l i norigin ) an

d fo r chroni c o r unspecifie dnephriti s wer e increase dinbot hcohort s bu t no t significantly . Th e Internationa l Agenc y fo r Researc ho

nCance r Workin g Grou p (IARC , 1980 ) use dth e Poisso nmetho dt o recalculat e th e dat a presente db y Coope r an

dGaffe y (1975 ) an

dreporte dn o statistica l significanc e base don 9 5 percen t confidenc e limits . Kan g e t al . (1980) , believin g tha t a nerro r wa s involve di nth e statistica l analysi s b y Coope r an

dGaffe y (1975) , analyze dth e dat a usin g th e Chian g metho d(Chiang , 1961 , a s cite di nKan g e t al. , 1980 ) an d th ? Poisso nmetho dan dreporte dstatistica l significanc e fo r exces s death s du e t o al l malignan t neoplasms , neoplasm s o f th e digestiv e organs , an dneoplasm s

o f th e respirator y

system fo r smelte r workers . Fo r batter y workers , the y reporte dstatistica l significanc e fo r exces s death s du e t o neoplasm s o f th e digestiv e organ s an

drespirator y

organ s bu t no t fo r al l malignan t neoplasms . Gaffe y (1980 ) state dtha t th e erro r wa s mad e inth e typin g an dno t inthei r analysis . 1.1.1.2.2 . Coope r e t al. , 1985 . A secondfollow-u pstudy o f th e two cohort s

wa s conducted ; th e observatio nperio dfo r mortalit y wa s extende dt o Decembe r 31 , 1980 . Th e siz e o f th e study population , b

y stric t editin g o f th e dat a base , wa s reduce dfro m 703 2 t o 6819 , wit h230 0 smelte r worker s an d451 9 batter y worker s remainin g ineac hcohort ; 3 5 death s counte dearlie r wer e eliminated . Cause s o f deat hwer e code daccordin g t o th e sevent hrevisio no f th e ICD . Th e same exposur e dat a use dinth e previou s study (Coope r an

d Gaffey , 1975 ) wer e presente di nthi s report . Amon g batter y

workers , ther e wa s a significan t exces s i ndeath s du e t o al l cause s (SM

R= 113 , p< 0.01) . Exces s death s du e t o al l malignan tP.2 0

neoplasm s (SM

R= 114 , p< 0.05) , malignan t neoplasm s o f th e stomach (SM R= 168 , p< 0.01) , respirator y syste m (SM R= 124 , p< 0.05) , an dtrachea , bronchus , an

dlun g (SM

R= 124 , p< 0.05 ) wer e significant . Nonsignifican t

excesse s wer e observe dfo r live r an dlaryngea l cancers , bu t bot hthes e
excesse s wer e base dona smal l numbe r o f deaths . Amon g smelte r workers , ther e

wa s a significan t exces s indeath s du e t o al l cause s (SM R= 107 , p< 0.01 ) an d du e t o al l malignancies . Malignancie s a t specifi c site s wer e note damon g smelte r worker s a t th e same site s a s amon g batter y workers . I t shoul db e note dtha t th e SMR s fo r malignancie s o f th e kidne y wer e les s tha n10 0 i nbot h cohorts , bu t death s du e t o chroni c kidne y disease s wer e significantl y elevate d ( p< 0.01 ) i nbot hcohorts . Mortalit y coul dno t be positivel y relate dt o duratio no f employmen t ineithe r cohort , becaus e ther e wa s a tren dtowar d decreasin g SMR s wit hincreasin g cumulativ e year s o f employment . I nth e origina l study

(Coope r an

dGaffey , 1975 ) an

dth e follow-u p(Coope r e t al. , . 1985) , diseas e incidenc e coul dno t b e relate dt o exposur e du e t o insufficien t number s o f worker s wit hexposur e values . Som e o f th e methodologi c limitation s o f thes e studie s includ e lac k o f dat a onconfoundin g factors , suc ha s smokin g habits , alcoho l consumption , an d
exposur e t o othe r occupationa l chemicals , an dabsenc e o f separat e mortalit y analysi s fo r who m

th e exposur e dat a wer e available . Larg e sampl e siz e an da lon g follow-u pperio dwer e amon g it s strengths . 1.1.1.3 . Studie s i nSmelte r Workers- - 1.1.1.3.1 . McMichae l an dJohnson , 1982 . A

proportiona l mortalit y analysi s

wa s conducte donth e 14 0 death s occurrin g amon g 24 1 mal e lea dsmelte r worker s inNe w Sout hWales , Australia , wh o wer e diagnose da s havin g lea dpoisonin g betwee n192 8 an

d1959 . A t th e time o f diagnosis , eac ho f thes e employee s hadP.2 1

worke da t th e Brake nHil l Associate dSmelter s operatio nfo r 1 t o 3 0 years ; th e earlies t dat e o f hir e wa s aroun d1910 . A lis t o f 24 1 employee s wit hful l

name s an ddate s o f birt hwa s availabl e fro m company record s an

dwa s cross checke dagains t deat hregistratio nrecord s inSout hAustrali a fo r th e year s 193 0 t o 1944 . A

grou po f predominantl y productio nworker s fre e o f know nlea d poisoning , togethe r wit ha smal l numbe r o f offic e workers , totalin g 69 5 worker s comprise dth e compariso ngroup . Standardize dproportiona l mortalit y analysi s wa s don e acros s fou r ag e strata : 30-44 , 45-59 , 60-74 , an d7 5 an d older . Th e expecte dnumbe r o f death s amon g lead-poisone dworker s wa s calculate dfro

m th e mortalit y

experienc e o f othe r workers . Proportiona l mortalit y

rate s wer e als o calculate dusin g th e tota l Australia nmal e populatio na s th e externa l compariso ngroup . Th e analysi s showe dtha t lea dpoisonin g di dno t increas e th e ris k o f

cancer . Th e age-standardize dPM R(SPMR ) wa s 70 . A

modes t exces s o f death s

wa s observe dfrom

chroni c nephriti s (SPM R= 306 ) an

dcerebra l hemorrhag e (SPM R= 199) . Th e majo r limitation s o f proportiona l mortalit y analysi s ar e tha t th e derive dratio s ar e no t tru e measure s o f association s becaus e a ris e i nth e proportio no f death s du e t o a particula r caus e i s alway s dependen t o nth e death s du e t o othe r causes . Th e populatio na t ris k i s no t known , s o i t i s difficul t t o know

whethe r th e observe dincreas e i s a tru e ris e i nth e actua l rat e o f deat ho r a fal l i nth e rat e fro m al l othe r causes . Th e author s als o d o no t provid e an

y definitio no f "lea dpoisoning " o r ho w i t wa s measured , whic hwa s use da s a surrogat e fo r exposure . 1.1.1.3.2 . Seleva ne t al. , 1985 . Seleva ne t al . conducte da cohor t mortalit y study o f 198 7 whit e mal e hourl y workers , wh o hadworke dfo r a t leas t 1 yea r a t

8P.2 2

a primar y

lea dsmelte r i nIdaho , betwee nJanuar y 1 , 1940 , an

dDecembe r 31 , 1965 . Th e follow-u pperio dwas . throug hDecembe r 31 , 1977 . Fro m thi s cohort , tw o neste dsubcohort s wer e selected . Thos e wh o ha dbee nsubjecte dt o mea n airborn e lea dlevel s abov e 20 0 ug/ m o r thos e inwhic h5 0 percen t o r mor e job s examine dha dmea nairborn e lea dexposure s greate r tha ntwic e th e standar d

wer e place dinth e "high-lead " exposur e group . Thos e inth e high-lea dgrou p wh o ha drelativel y

low potentia l exposur e t o th e othe r metal s wer e place di n th e "high-lead/low-others " group . Cause s of deat hwer e code daccordin g t o th e revisio ni neffec t a t th e tim e of death , an dthe nconverte dt o th e sevent h revisio nof th e ICD . SMR s wer e calculate dusin g th e U.S . whit e mal e populatio na s a reference . Statistica l significanc e wa s presente da s 95 - percen t confidenc e intervals . Exces s death s du e respirator y system cancer s i

nth e entir e grou p (observe d= 41 , SM

R= 111 ) an

despeciall y

t o kidne y

cance r inth e entir e grou p (observe d= 6 , SM

R= 204 ) wer e observe dinal l cohorts . Bot hduratio nof
exposur e fo r mor e tha n2 0 year s an dlatenc y

perio dof mor e tha n2 0 year s wer e positivel y

associate dwit hth e cancer s of th e trachea , bronchus , an dlung . Non e of thes e excesse s wer e statisticall y significant . Fo r kidne y cancer , al l bu t on e cas e wa s foun di nbot ho f th e high-lea dsubcohorts . Thi s findin g approache s statistica l significanc e inth e high-lead/low-other s grou p (SM R= 301 , 95-percen t confidenc e interval : 9 8 t o 703) . Th e SM Rfo r chroni c

rena l diseas e wa s highes t inth e high-lea dgroup . Chroni c rena l diseas e wa s als o positivel y

correlate dwit hduratio nof exposure , an dth e majorit y

of

exces s wa s foundafte r 2 0 years ' latency .P.2 3

Thi s study

had fe w

methodologi c limitations , on e o f them bein g lac k o f adjustmen t fo r exposur e t o othe r metal s an d smoking . Inthi s study , cance r in human s wa s observe d fo r th e same site , namel y th e kidney , a s inexperimenta l animals , bu t th e investigator s pointe d ou t tha t th e level s o f exposur e t o animal s fa r exceede d th e maximu m dose s tolerate d b

y humans . 1.1.1.3.3 . Gerhardso ne t al. , 1986 . Thi s i s a retrospectiv e cohor t mortalit y study o f 383 2 mal e Swedis hworker s (cohor t A ) employe d befor e 196 7 a t a coppe r smelte r inNorther nSwede nfo r a t leas t 3 month s an d followed-u p fro

m 195 0 t o 1981 . A subcohor t (B ) o f 43 7 worker s employe d a t wor k site s wit ha t leas t 3 years ' verifie d high-lea d exposur e fro m '95 0 t o 197 4 wa s als o studied . Th e accumulate d lea d exposur e fo r thes e worker s wa s calculate d a s a cumulativ e bloo d lea d dos e obtaine d b y a summatio no f th e annua l mea nbloo d lea d level s fo r eac hworker . Base d o nth e media nvalu e o f th e cumulativ e bloo d lea d dos e (478. 5 ug/dL) , worker s wer e categorize d a s high-exposur e i f th e valu e exceede d th e media nan

d low-exposur e i f th e valu e wa s lower . Thes e subcohort s wer e designate d a s B l (21 8 workers ) an d B 2 (21 9 workers) , respectively . Pea k lea d bloo d value s wer e als o use d t o divid e worker s int o thos e wh o had a t leas t onc e exceede d a bloo d lea d concentratio no f 7 0 ug/d L (hig hpea k value ) an

d thos e wh o had neve r exceede d thi s leve l (lo w pea k value) . Thes e subcohort s wer e calle d B 3 (28 8 workers ) an d B 4 (14 9 workers) , respectively . Cause s o f death s

wer e code d b

y usin g th e eight hrevisio no f th e ICD . Swedis hnationa l an d count y mortalit y

rate s b

y cause , sex , 5-yea r ag e groups , an d calenda r period s

wer e use d t o calculat e expecte d death s an d SMRs , an

d test-base d 95-percen t confidenc e limit s wer e calculate d accordin g t o Miettinen . A nonsignifican t raise d mortalit y fo r lun g cance r (SM R= 160 ) wa s observe d fo r subcohor t B wit hhig hlea d exposure . No consisten t dose-respons e

1 0patter nwa s see nwhe nanalysi s wa s don e b y mea no r pea k bloo dlea dvalues . Analysi s usin g a latenc y perio do f 1 5 year s di dno t provid e additiona l information . Th e mor e precis e assessmen t o f lea dexposur e inthi s study i s on e o f it s majo r strengths . Sinc e smelte r worker s hav e multipl e exposure s t o othe r chemicals , a protectiv e effec t o f some o f them (e.g. , selenium ) canno t b e rule dout . Th e sampl e siz e wa s small , an dn o analysi s b

y smokin g habit s o r othe r chemica l exposure s wa s available . 1.1.1.3.4 . Ade s an

dKazantzis , 1988 . Thi s i s a retrospectiv e cohor t study tha t examine dlun g cance r mortalit y i na cohor t o f 429 3 me nemploye da t a zinc-lead-cadmium

smelte r inGrea t Britain . Th e cohor t include dindividual s wh o wer e bor nprio r t o 1940 , al l hourly-pai dmal e worker s employe da t th e smelte r o

nJanuar y

1 , 1943 , an

dthos e wh o subsequentl y starte dwor k befor e 197 0 an dhadworke dfo r a t leas t 1 year . At th e endo f th e follow-u pdat e o f Decembe r 31 , 1982 , ther e wer e 439 3 men . A nexces s o f lun g cance r wa s observe db y usin g th e compariso npopulatio n

o f Sout hWes t Urba nAggregate s (observe d= 182 , SM R= 124 , p< 0.005) . A significan t linea r tren do f increasin g lun g cance r SMR s wit hincreasin g duratio no f employmen t wa s observe d( p< 0.001) . Th e lun g cance r SMR s fo r th e tota l cohor t wer e 19 0 ( p< 0.005) , 14 2 ( p> 0.05) , an d29 2 ( p< 0.02 ) fo r th e duratio no f employmen t o f 20-29 , 30-39 , an d40 + years , respectively . A matche dcase-contro l analysi s wa s als o performe dt o determin e th e rol e

o f specifi c departments , processes , an dcontaminant s inth e smelte r operatio n i ncausin g cancer . A tota l o f 417 3 mal e smelte r workers , o f whom 17 4 die do f lun g cancer , wer e selecte dfo r analysis . Up . t o 20 control s wer e chose nfo r

eac hlun g cance r case . I nal l ther e wer e 271 7 controls . Th e follow-u pperio d

1 1wa s 1 0 years . Exposur e estimate s wer e obtaine dfo r cadmium , arsenic , lead ,

zinc , sulphu r dioxide , an dtota l dust . Thi s wa s don e b y reducin g th e jo b code s t o te nmajo r categorie s an dassignin g value s o f 0 t o 3 (t o represen t backgroun dt o hig hexposure) . Thes e assessment s wer e mad e b y th e plan t hygienis t withou t knowledg e o f th e vita l statu s o r caus e o f deat ho f th e cohor t members . SMR s wer e calculate d usin g th e Oxfor dperson-year s program ,
an dth e matche dcase-contro l study wa s constructe db

y selectin g control s fro m th e sam e cohor t matche dfo r dat e startin g work , dat e o f birth , an dsurvivin g th e case . Cumulativ e exposure s wer e calculate db y summin g th e year-by-yea r exposur e assessment s ove r th e perio do f employmen t u pt o 3 year s befor e th e

• deat ho f th e cas e t o who m control s wer e matched . Chi-squar e likelihoo drati o statistic s wer e derive db y multipl e logisti c regressio nanalysi s preservin g th e matching . Relativ e risk s wer e estimate dfo r 1 0 year s o f employmen t a t

eac hexposur e leve l independentl y an dadjuste dfo r th e others . Fo r lea dalone , th e chi-squar e likelihoo drati o wa s 6.84 , an dth e relativ e ris k (R.R. ) derive dwa s 1.1 2 pe r level-decad e ( p< 0.01) . Fo r exposur e t o arsenic , th e correspondin g figure s wer e chi-squar e = 6.31 , R.R . = 1.2 2 ( p< 0.025) . A hig hcorrelatio nbetwee nexposur e t o arseni c an d lea dwa s observe d(0.72) , an da mode l yieldin g risk s fo r eac hadjustin g fo r th e effect s o f th e othe r showe dno statistica l significance . Th e investigator s use da four-poin t ratin g scal e t o estimat e exposures , bu t mad e n o effort s t o validat e it , an ddi dno t discus s th e assumption s an d limitation s o f thi s approach . N o dat a o nsmokin g habit s o f th e populatio n

wer e available . Lastly , whil e a nincrease dris k o f lun g cance r wa s observe d fo r lead , i t wa s no t possibl e t o determin e th e contributio no f simultaneou s exposur e t o arseni c an dothe r contaminant s t o thi s risk .

1 21.1.1.4 . Studie s i nTetraethy l Lea dProductio nWorkers- -

1.1.1.4.1 . Robinson . 1974 . Thi s study i s a compariso no f th e mortalit y experienc e o f worker s havin g potentia l exposur e t o tetraethy l lea d(TEL ) wit h thos e havin g n o exposur e ove r a 20-yea r period . Th e TEL-expose dgrou p comprise d59 2 whit e male s (age s 2 0 t o 5 8 years ) wh o wer e activel y employe di

n

a productio nfacilit y a s o f Decembe r 31 , 1947 . Thei r averag e lengt ho f TEL are a servic e wa s 17. 9 years . Th e non-TEL-expose dgrou pconsiste do f al l whit e mal e non-TE L operatin g an dmaintenanc e personne l a t th e same facilit y a t th e
same date . Ther e wer e 66 0 male s inthi s grou prangin g inag e fro m 2 1 t o 6 2 year s an

dwit ha

naverag e lengt ho f servic e o f 20. 3 years . Th e mortalit y statu s o f bot hpopulation s wa s determine da s o f Decembe r 31 , 1967 . Crude an d standardize ddeat hrate s wer e calculate dfro m th e TE L grou pan

dth e non-TE L groups . Standardize ddeat hrate s wer e als o calculate db y applyin g race-sex ag e cause-specifi c deat hrate s t o th e observe ddistribution s o f person-year s

o f experienc e o f th e tw o groups . Th e expecte dnumber s o f death s inth e variou s categorie s o f cause s wer e derived . Th e analysi s showe dtha t bot hth e TE L an dnon-TE L group s ha dn o exces s death s fro

m malignan t neoplasms . Th e absenc e o f specifi c quantitativ e informatio no nTE L exposur e an

d smal l sampl e siz e ar e tw o majo r limitation s o f thi s study . Th e lo w los s t o follow-u prat e an

dlon g follow-u pperio dar e amon g it s strengths . 1.1.1.4.2 . Sweene y

e t al. , 1986 . Thi s study i s a retrospectiv e cohor t mortalit y

study o f 251 0 male s employe da t a neas t Texa s chemica l plan t t o evaluat e a suspecte dincreas e indeath s fro m multipl e myeloma an dbrai n

cancer . Th e plan t wa s opene din195 2 fo r th e productio no f fue l antiknoc k additiv e TEL , an

dth e cohor t wa s define da s al l mal e employee s wh o worke dat

1 3P.2 7

leas t 1 da y

a t th e plan t betwee nJanuar y 1 , 1952 , an

dDecembe r 31 , 1977 . Vita l statu s throug hDecembe r 31 , 1977 , wa s ascertaine dthroug hcompany
source s an

ddeat hcertificate s requeste dfro m Stat e vita l statistic s offices . Th e Nationa l Institut e o f Occupationa l Safet y an dHealt h(NIOSH ) modifie d life-tabl e analysi s system wa s use dt o accumulat e person-year s a t ris k fo r

eac hcohor t member . Vita l statu s a s o f Decembe r 31 , 1977 , wa s ascertaine dfo r 249 3 (99% ) o f th e 251 0 me nwh o comprise dth e cohort , an ddeat hcertificate s

wer e ascertaine dfo r al l bu t 2 o f th e 15 6 deaths . Th e sevent hrevisio no f th e IC D wa s use dt o cod e th e cause s o f deaths . Th e mortalit y fo r al l cause s wa s lowe r tha nth e expecte d(SM R= 74) . Th e SM

Rfo r al l malignan t neoplasm s wa s slightl y elevate d(SM

R= 102 ) du e inpar t t o statisticall y nonsignifican t increase s inmortalit y fro m carcinoma s o f the trachea , bronchus , an dlung (SM R= 122) , laryn x(SM R= 426) , an

dbrai n(SM

R= 186) . Al l thes e excesse s

wer e base do nth e smal l numbers . N o increase dris k o f mortalit y wa s note d wit hincreasin g employment . Th e man y limitation s o f th e stud y includ e lo

w powe r (0.2 7 fo r malignancie s o f specifi c sites) , lac k o f complet e workplac e exposur e dat a on lea dcompound s an

dothe r chemical s suc ha s viny l chlorid e monomers , ethylen e dibromide , ethylen e chloride , an ddyes , an

dth e absenc e o f dat a o nsmokin g an

d othe r lifestyl e confoundin g variables . 1.1.1.5 . Study

inPlumber s an

dPip e Fitters- - 1.1.1.5.1 . Canto r e t al. , 1986 . Thi s i s a proportiona l mortalit y study o f 712 1 member s an

dretiree s o f th e Unite dAssociatio no f Plumber s an dPip e Fitter s i nCaliforni a wh o die dbetwee n196 0 an d1979 . Th e study

populatio n comprise dal l employe dworker s an dretiree s wh o remaine dunio nmember s o f the Unite dAssociatio n(UA) , th e leadin g labo r unio nfo r plumber s an dpip e fitter s

1 4P.2 8

inNort hAmerica . Deat hcertificate s fro m list s o f death s occurrin g betwee n Januar y 1 , 1960 , an

dDecembe r 31 , 1979 , wer e locate dfro m the - CaLiforni c U

A local s an

dStat e vita l statistic s office s an dcode daccordin g t o th e eight h revisio no f th e ICD . Ninety-seve npercen t o f th e deat hcertificate s wer e located . PM

Rwa s calculate dusin g Monson' s softwar e b y 5-yea r ag e an

d5-yea r calenda r periods . Amon g plumbers , th e PMR s fo r al l malignan t neoplasm s (PM R= 124) ; stomac h

cance r (PM

R= 129) ; cance r o f bronchus , trachea , an dlun g (PM

R= 141) ; kidne y
cance r (PM

R= 148) ; brai ncance r (PM R= 150) ; an

dal l lymphopoieti c cance r an d lymphosarcoma/reticulosarcom a (PM R= 124 ) wer e significantl y elevated . Th e pip e fitter s ha da significantl y elevate dPM

Rfo r al l cancer s combined , primaril y

du e t o exces s lung cancer . PMR s fo r lun g cance r wer e consistentl y elevate dwhe nanalysi s wa s don e b y birt hcohor t an

dyea r o f death . Lung

cance r accounte dfo r 18 5 o f th e 33 7 exces s death s fro m al l malignan t neoplasms . Sinc e plumber s an

dpip e fitter s encounte r man y hazardou s material s includin g asbestos , solvents , meta l fume s (leadan dchromium) , an

dgase s fro

m welding , i t i s impossibl e fro m thi s stud

y t o attribut e an

y o f th e exces s malignancie s observe dsolel y t o lea dexposure . N o dat a wer e availabl e t o categoriz e an

danalyz e dat a b

y degre e o f lea dexposure . Th e significantl y elevate dPM

Rfo r kidne y

cance r amon g plumber s onl y (PM R= 1.48 ) an

dth e experimenta l inductio no f rena l tumor s inanimal s i s onl y suggestiv e o f a possibl e associatio ntha t merit s furthe r exploratio ni nstudie s tha t asses s individua l exposure s an dwor k practices .



### 1 5P.2 9

1.1.1.6 . Studie s i

nChildre nwit hPaterna l Occupationa l Lea dExposure- - 1.1.1.6.1 . Kanto r e t al. , 1979 . Thi s study wa s designe d t o tes t th e hypothesi s tha t perinata l exposur e t o carcinogen s ma y be associate dwit hth e subsequen t occurrenc e o f Wilms' s tumor . A case-contro l study

wa s conducte do f 14 9 Connecticut-bor nchildre nwit hWilms' s tumo r reporte dt o th e Connecticu t Tumo r Registr y

durin g th e perio d1935-1973 . Case s range di nag e from th e newbor nt o 1 9 years . Th e 14 9 control s wer e selecte dfro m th e Connecticu t Stat e Healt hDepartmen t file s o f birt hcertificate s an dmatche dfo r sex , race ,
an dyea r o f birth . Sociodemographi c information , includin g paterna l occupation , wa s abstracte dfro m birt hcertificate s an dth e tumo r registr y files . Case-contro l comparison s wer e don e fo r paterna l individua l occupation s

a s wel l a s fo r thos e categorize da s lea dexposur e only , hydrocarbo nexposur e only , an dth e tw o combined . Th e occupation s o f father s o f 2 2 tumo r case s an d6 control s wer e foundt o be lea drelated . Th e resultin g odd s rati o wa s 3. 7 ( p= 0.005) . Case s an d control s wer e foun dt o b e simila r b y mother' s pregnanc y

history , parents ' ag e

an dplac e o f birth , child' s birt hweight , an dlengt ho f gestation . Th e importan t limitation s o f thi s study ar e th e tota l absenc e o f dat a o nmaterna l
exposures , lac k o f validatio no f occupatio nhistor y abstracte dfrom

birt h certificates , lac k o f hereditar y informatio no f Wilms' s tumor , an domissio no f result s o f test s o f an y measur e o f lea dintoxicatio namon g study subjects . 1.1.1.6.2 . Wilkin s an dSinks , 1984 . Thi s i s a nepidemiologi c case-contro l study o f paterna l occupatio nan dWilms' s tumo r i

noffsprin g t o tes t th e hypothesi s tha t lea dexposur e i s a ris k factor . Th e Columbu s Childrens ' Hospita l (CCH ) Tumo r Registr y wa s reviewe dt o identif y childre nwit hWilms' s tumo r betwee nJanuar y 1 , 1950 , an

dOctobe r 31 , 1981 . Fo r eac hcase , two

1 6P.3 0

control s wer e selecte da t random usin g birt hcertificat e file s o f Ohi o resident s a s th e samplin g frame . Bot hcontrol s wer e matche dwit hth e cas e b y age , sex , an

drace , an

don e o f them

wa s als o matche db

y mother' s count y

o f residenc e a t th e tim e o f th e child' s birth . Control s wer e selecte dfro m countie s withi nth e CC H Wilms' s tumo r referra l area . Birt hcertificate s fo r study subject s wer e reviewe dan dinformatio nwa s abstracte don sociodemographi c factors , includin g father' s occupatio na t th e tim e o f child' s birth . Th e occupatio nan dexposur e linkag e syste m develope db

y Hoa r e t al . (1980 ) wa s use dt o identif y job-relate dexposure s o f father s o f stud y subjects . Sixty-tw o case s an dcontrol s wer e availabl e fo r compariso nb y paterna l occupation . Al l form s o f lea dconsidere dtogethe r gav e anodd s rati o

o f 1. 0 (95-percen t confidenc e interva l o f 0.5 , 1.9) . Fo r exposur e t o lea dan d lea dalkyls , th e relativ e odd s wer e 1. 1 an d1.3 , respectively , bu t neithe r wa s statisticall y

significant . Thus , thes e dat a d o no t suppor t th e hypothesi s tha t paterna l exposur e t o lea di s a ris k facto r fo r Wilms' s tumo r i nth e offspring . Th e smal l sampl e size , lac k o f lifetim e paterna l occupationa l historie s

andexposur e misclassification , absenc e o f informatio nonmaterna l exposures ,
an dselectio nbia s inselectin g case s fro m on e hospita l onl y

ar e amon g th e majo r limitation s o f thi s study . 1.1.2 . Cas e Report s 1.1.2.1 . Bake r e t al. , 1980-- A 48-year-ol dmal e wh o ha dworke da t a smelte r fo r 2 2 year s ha delevate dbloo dlea dlevel s o f 6 4 ug/dL . Exposur e t o othe r chemical s wa s no t reported . Clinica l test s indicate drena l damage , an da mas s

wa s foun donth e righ t kidne y whic hwa s remove db y nephrectomy . B

y ligh t microscopy , th e mas s wa s identifie da s a nadenocarcinom a wit ha predominan t

1 7P.3 1

tubula r patter nan

dextensiv e necrosis . Section s o f th e rena l corte xshowe d

some glomerula r sclerosis , swellin g o f proxima l tubula r epithelia l cells , spars e intranuclea r inclusio nbodies , an dfoca l area s o f interstitia l fibrosi s

an dinflammation . Th e concentratio no f lea dwa s 2.4 7 ug/ g tissu e inth e tumor , 1.0 4 ug/ g tissu e inth e rena l cortex , an d0.7 8 ug/ g tissu e i nth e rena l medulla . Norma l value s wer e reporte da s 0.2 7 t o 1.2 7 ug/ g tissue . Th e author s suggeste dtha t a recen t chelatio ntherap y ma y hav e lowere dth e lea d concentratio ni nnorma l rena l tissue . 1.1.2.2 . Lilis , 1981-- A 61-year-ol dmal e wh o hadbee nemploye di na secondar y lea dsmelte r fo r 3 4 year s startin g in193 9 require dfiv e episode s o f chelatio n therap y an dwa s repeatedl y

remove dfro

m hi s wor k becaus e o f excessiv e bloo d lea dconcentrations . Exposur e t o th e othe r chemical s wa s no t discussed . Th e patien t denie dsignifican t alcoho l consumptio nan dha dno t bee nsmokin g fo r a year . Clinica l test s i nFebruar y an dDecembe r 197 3 indicate dtha t th e patien t suffere dfro

m kidne y damage , an

dbloo dlea dconcentration s wer e 8 3 an d 6 0 ug/dL , respectively . A tumo r foundo

nth e righ t kidne y

wa s remove db

y partia l nephrectom

y an dwa s identifie da s a clea r cel l adenocarcinoma . 1.1.3 . Discussio n Epidemiologi c studie s o f worker s i noccupation s wher e th e potentia l fo r lea dexposur e i s usuall y greate r tha ninth e genera l populatio nwer e evaluate d t o ascertai nwhethe r lea di s causall y associate dwit ha

nincreasedoccurrenc e

o f cancer . I

ngeneral , n o attemp t wa s mad e b y an y investigato r t o conside r differen t type s o f lea dcompound s o r predominan t rout e o f exposur e excep t fo r two studie s dealin g wit htetraethy l lead . Al l th e reviewe dstudie s hav e on e o r mor e methodologica l limitation s tha t preclud e th e definitiv e inferenc e o f a causa l associatio nbetwee nlea d

1 8P.3 2

exposur e andth e occurrenc e o f cance r inhumans . Deficiencie s i nexposur e assessments , especiall y th e lac k o f informatio no ncumulativ e lea dexposure ,
ar e a majo r limitatio ninal l th e studies . Becaus e o f th e lac k o f informatio n

onlea dexposur e i t i s difficul t t o tel l whethe r th e entir e populatio nstudie d reall y ha dth e exposur e an ddi dno t show

an y exces s o f cance r o r whethe r th e absenc e o f anexces s i s du e t o th e fac t tha t ther e wa s littl e o r no exposur e t o lea dcompounds . Th e know npresenc e o f othe r potentiall y carcinogeni c agent s i nth e workplace , i nadditio nt o lead , als o make s i t difficul t t o determin e i f th e observe dincrease dris k i s du e t o th e effec t o f lea dalon e o r whethe r thes e excesse s ar e influence db y th e presenc e o f othe r agents . Furthermore , severa l o f th e studie s ar e proportiona l mortalit y studies , whic hb y thei r natur e ca nbe use dt o generat e a hypothesi s abou t causalit y bu t

canno t b e use dt pauthenticat e one . Th e interpretiv e limitation s o f proportiona l mortalit y studie s cove r fiv e areas . First , a proportiona l mortalit y

analysi s i s usuall y use dwhe nth e informatio no nth e populatio na t ris k i s no t available . A proportional mortalit y analysi s use s th e death s fro m

a give nsettin g bu t no t th e populatio nexpose dt o tha t setting ; hence , thi s typ e o f stud y

canno t provid e an

y informatio nabou t th e population' s ris k o f dyin g fro

m an y give ncause . Second , a proportiona l mortalit y analysi s assume s tha t overal l mortalit y i s equa l inth e tw

o population s bein g compared . I f thi s assumptio ni s no t tru e an dth e mortalit y

rat e o f th e study

grou pi s lowe r tha nth e mortalit y

rat e o f th e compariso npopulatio nfo r al l cause s o f deaths , th e proportiona l mortalit y rati o wil l inflat e th e cause-specifi c mortality . Third , proportiona l mortalit y ratio s o f two o r mor e cause s o f deat har e interdependen t rathe r tha nindependent , sinc e th e su m o f th e observe dnumber s

o f death s necessaril y equal s th e su

m o f th e expecte dnumber s (100%) ; hence , a

1 9P.3 3

defici t i non e cause-specifi c mortalit y wil l artificiall y

forc e a

nexces s in anothe r cause-specifi c mortality . Fourth , a proportiona l mortalit y analysi s als o assume s tha t th e classificatio nan dreportin g o f death s inth e stud y populatio nan

dth e compariso npopulatio nar e complet e an dcomparable . Fifth, , whe na proportiona l mortalit y analysi s i s use dt o compil e cause s o f death , i t i s assume dtha t bot hpopulation s ar e comparable . An y violatio no f thes e assumption s ma y

resul t inexcesse s o r deficit s whic har e no t authentic . Tha t said , McMichae l an dJohnso n(1982 ) studie donl y thos e individual s wh o ha d"lea dpoisoning" ; othe r expose dworker s wer e no t include dinth e study . Thi s wa pa proportiona l mortalit y study wit hinheren t limitations . Tw o othe r studie s wer e conducte dinchildre nt o evaluat e th e associatio n

o f Wilms' s tumo r wit hpaterna l occupatio ninth e lea dindustr y (Kanto r e t al. , 1979 ; Wilkin s an

dSinks , 1984) . Whil e neithe r study identifie da statisticall y

significan t association , bot hstudie s hav e limitation s suc ha s a lac k o f informatio no nth e geneti c predispositio no f children , materna l
exposures , an

dsmal l sampl e sizes . Therefore , thes e two studie s ar e unabl e t o provid e eithe r positiv e o r negativ e evidenc e o f transplacenta l carcinogenicit y

o f lea dan

dit s compounds . Tw o studie s wer e conducte damon g worker s expose dt o tetraethy l lea d (Robinson , 1974 ; Sweene y e t al. , 1986) . Bot hstudie s ha dlow powe r du e t o smal l sampl e size s an dconfoundin g b

y othe r exposures , henc e precludin g an y conclusiv e inferenc e fo r th e carcinogenicit y o f tetraethy l lead . Amon g th e remainin g studies , nonsignifican t exces s o f kidne y cance r wa s observe di na cohor t mortalit y study b y Seleva ne t al . (1985) , whil e a borderlin e significan t exces s o f kidne y cance r wa s reporte db y Canto r e t al . (1986) . Thes e tw o studies , togethe r wit htwo cas e report s o f kidne y cance r

2 0P.3 4

amon g lea dworker s (Bake r e t al. , 1980 ; Lilis , 1981) , create dsome interes t i n certai nscientifi c forum s since , kidne y cance r wa s als o observe di nanima l studies . Amon g th e fou r reports , th e nonsignifican t kidne y cance r exces s i n th e Seleva ne t al . (1985 ) study wa s base dononl y

si xcases . Th e Canto r e t • al . (1986 ) study , whic hhadborderlin e significance , i s a proportiona l mortalit y

study , whic hha s inheren t interpretiv e limitations . A s ther e i s no informatio navailabl e abou t th e populatio na t ris k fo r th e two cas e reports , thes e studie s canno t b e use dfo r supportin g o r refutin g an y hypothesis . O n th e othe r hand , deficit s inrena l cancer s wer e observe dinbot hth e batter y

an dsmelte r worke r cohort : o f th e Coope r studies . Therefore , th e reporte d huma nkidne y

cance r excesse s mus t b e viewe dinligh t o f th e varie dresult s an d attendan t interpretiv e consideration s inorde r t o maintai na prope r perspective . Studie s b

y Coope r e t al . (1985 ) inbatter y workers , Ade s an

dKazantzi s (1988 ) i nsmelte r workers , an da reanalysi s b

y Kan g e t al . (1980 ) o f th e Coope r an

dGaffe y (1975 ) dat a insmelte r worker s showe dstatisticall y increase dlun g cance r mortality . I naddition , nonsignifican t excesse s o f lung

cance r mortalit y

amon g smelte r worker s wer e observe db y Gerhardso ne t al . (1986) , Coope r e t al . (1985) , an dSeleva ne t al . (1985) . Significan t increase s instomac hcance r mortalit y wer e als o observe db y Coope r e t al . (1985 ) amon g batter y

worker s an

dinth e reanalysi s b y Kan g e t al . (1980 ) o f th e Coope r an

dGaffe y (1975 ) dat a o

nsmelte r workers . Althoug hincrease dlun g

cance r mortalit y

ha s bee nobserve di nsevera l studies , ther e ar e methodologica l limitation s suc ha s confoundin g exposure s t o othe r agent s i n al l thes e studies . Th e confoundin g include s exposur e t o smokin g an dsome heavy metal s suc ha s arseni c an dchromium , whic hhav e bee nprove nt o b e

2 1P.3 5

pulmonar y

carcinogens . Thi s possibl e confounding , however , doe s no t lesse n th e relevanc e o f exposur e t o lead , whic hma y be contributin g t o th e excesse s i nhuma ncancer , an

dhence , canno t be rule dout . I nconclusion , th e epidemiologi c evidence , althoug hno t stron g enoug ht o be sufficien t o r limite d(i.e. , t o infe r a causa l relationship) , shoul dno t be interprete da s negative . A t thi s tim e th e epidemiologi c evidenc e fo r lea d (an dlea dcompounds ) bein g a huma ncarcinoge ni s considere dinadequat e accordin g t o th e terminolog y o f th e EP

A Guideline s fo r Carcinoge nRis k Assessmen t (U.S . EPA , 1986a) ; nevertheless , i t i s importan t t o not e tha t th e evidenc e i s though t t o be suggestive . I nthi s instanc e "suggestive " mean s tha t althoug hth e availabl e dat a ar e unabl e t o provid e th e evidenc e fo r a
causa l association , the y ar e positiv e enoug ht o rais e a concer nabou t th e huma ncarcinogenicit y o f lead . A

well-designe dan

dwell-conducte dpositiv e study ma y elevat e th e huma nevidenc e t o th e "limited " o r eve nt o th e ^sufficient " category , whil e a simila r study showin g negativ e finding s in human s coul dsuppor t downgradin g th e classification . Additionally , a relativel y larg e bod

y o f informatio ni s availabl e o nthe . frequenc y

o f chromosoma l aberration s inculture dlymphocyte s o f lead-expose d worker s (se e U.S . EPA , 1986c , fo r a revie w an dreferences) . Deficiencie s can b e foun di nbot hth e positiv e an dnegativ e studie s reporte do nlea d(e.g. , exposur e t o othe r chemicals , lac k o f appropriat e controls , smal l numbe r o f worker s evaluated , lac k o f dose-respons e relationships , protoco l inadequacie s i ncytogeneti c analysis , and/o r lac k o f quantitativ e measurement s o f lea d exposure) . Nevertheless , whe nal l o f th e studie s ar e take ntogether , ther e i s

a suggestio ntha t lea di s capabl e o f increasin g th e frequencie s o f chromosoma l aberration s inperiphera l bloo dlymphocyte s o f expose dworkers . Th e positiv e

2 2P.3 6

cytogeneti c studie s inworker s expose dt o lea dlendsuppor t t o th e "suggestive " epidemiologi c cance r evidence .

1.2 . ANIMA L STUDIE S A tota l o f 3 5 experiment s relevan t t o th e carcinogenicit y o f lea din laborator y

animal s i s reviewed . Al l excep t on e ar e laborator y studies . Th e lon e exceptio ni s a populatio nstudy o f free-livin g wil drats . Althoug hlea d acetat e an

dlea dsubacetat e hav e bee ninvestigate dmos t extensively , othe r lea d compound s wer e als o tested , includin g lea doxide , lea dphosphate , lea d naphthenate , lea ddimethyldithiocarbamate , an d tetraethy l lead . Lea dwa s administere dinth e food , b y intraperitonea l injection , subcutaneou s injection , intratrachea l instillation , ski npainting , an dgavage . Lea dsubacetat e wa s evaluate dfo r tumor-promotin g ability , whil e lea dacetat e an dlea doxid e wer e teste d fo r cocarcinogenicity . A t leas t some evidenc e o f th e carcinogenicit y o f lea do r lea dcompound s wa s detecte di n2 4 o f thes e experiments . Summarie s o f th e anima l studie s describe di nthi s sectio nappea r in Table s 1- 1 an

d1-2 . 1.2.1 . Lea dAcetat e (CA S No . 301-04-2 ) 1.2.1.1 . Studie s inRats- - 1.2.1.1.1 . Boylan de t al. , 1962 . Group s o f 2 0 mal e Wista r rat s wer e administere d1 percen t lea dacetat e inth e fee dfo r 1 year . A contro l grou p

wa s no t included . Foo dintak e wa s limite dt o 2 0 g pe r ra t pe r da y durin g th e firs t month , 3 0 g pe r ra t pe r da y durin g th e secon dmonth , an d4 0 g pe r ra t pe r da y durin g th e 1 0 subsequen t months . Th e averag e initia l body weigh t wa s 20 0 g , an

dtermina l body

weight s range dfro

m 60 0 t o 80 0 g . Followin g th e



### 2 3TABL E 1-1
. SUMMAR Y O F POSITIVE ANIMAL STUDIE S

Compoun d Anima l Dos e an d duratio n Tota l lea d Tumo r respons e Referenc e

Lea d acetat e M Wista r ra t 10,00 0 pp mi n feed 3 4 q (1 2 mo ) 15/1 6 rena l tumor s Boyland e t al. , 196 2
Lea d acetat e M Wista r ra t

r o -p .

Lea d acetat e F Wista r ra t

M/ F Wista r ra t Contro l

3 m g i n feed ( 2 mo) , the n 4 m

g (1 6 mo )

Contro l 3 m g i n fee d ( 2 mo) , the n 4 m

g (1 6 mo ) 3 m g i n fee d fo r 60 , 162 , 307 , or

50 4 d 1 g 0/1 9 58/9 4 rena l tumors , 23/9 4 testicula r tumors , 23/9 4 adrena l tumors , 22/9 4 prostat e tumors , 3/9 4 cerebra 1 glioma s

thyroi d tumors ; 10/9 4 cerebra l glioma s Zawirsk a and Medras , 196 8

i g

0.1

- 0. 8 g 0/1 3

14/3 2 rena l tumor s
pituitary , adrenal , lung , renal , prostate
. Zawirsk a and Medras , 197 2

Lea d acetat e M/ F Charle s

Rive r C D ra t 0 , 10 , 50 , 100 , o r

100 0 pp mlea d i n fee d (2 2 mo ) 0.1-1 2 g Tumor s observed , bu t incidenc e no t reporte d API , 197 1

(continue d o n th e followin g page )TAB- E 1-1
. (ce n tinned )

Compoun d Anima l Dos e an d duratio n Tota l lea d Tumo r respons e Referenc e

Lea d acetat e

rv > t n M ra t (strai n no t specified )

F rat (strai n no t specified )

Lea d acetat e M F34 4 rat

Lea d acetat e M Wista r rat 3- 5 pp mlea d i n 1 8 pp mfee d 6 2 pp m(2 4 mo ) 14 1 pp m 54 8 pp m 113 0 pp m 210 2 pp m 3- 5 pp mlea d 1 8 pp m 6 2 pp m 14 1 pp m 54 8 pp m 113 0 pp m 210 2 pp m 0 pp mlea d i n

fee d 10,00 0 pp m(1 2 mo )

0 pp mi n fee d 500 O pp m( 6 mo ) 10,00 0 pp m 0.0 6 0. 2 0. 8 2 7 1 4 2 6
0.0 6 0. 2 0. 8 2

- 7 1. 4 2 6 g

g 0/12 0

0/5 0 0/5 0 0/5 0 5/5 0 10/2 0 16/2 0 0/12 0 0/5 0 0/5 0 0/5 0 0/5 0 0/2 0 7/2 0 rena I tumor s

rena I tumor s Aza r e t al. , 197 3

Non e

, 3 g

— 9 g

. 7 1/ 5 rena l

adenocar c inoma s 0/1 0 0/1 2 9/1 0 rena l tumor s Tanne r an d Lipsky , 1984

Nogueira , 198 7

(continue d o n th e fallowin g page )TABL E 1-1
. (continued )

Compound Anima l Dos e an d duratio n Tota l lea d Tumo r respons e Referenc e

r o Lea d acetat e M Sprague

Dawle yra t

Lea d acetat e F Swis s

mous e 0 pp mlea d i n wate r 260 0 pp m(1 8 mo ) 0 pp mlea d wit h E U an d MaNO j 2 6 pp mlea d wit h E U an d NaNO

260 0 pp mlea d wit h B J an d INaNC ^ 0 pp mlea d i n 5 0 pp mwate r 1.00 0 pp m( 9 mo ) — 3 8 g

— 0. 4 g 3 8

— 0. 1 g 1. 4 0/ 7

13/1 6 rena l tumor s C/ 8 0/ 7 6/1 0 rena l tumor s

24/5 0 Lymphocyti c 34/5 0 leukemi a 38/5 0 Kolle r e t al. , 198 5

Blakley , 198 7

Lea d subacetat e

Lea d subacetat e M Wista r ra t

F Wista r ra t

M Wista r ra t 

## o 100 0 10,00 0
0 100 0 10,00 0
0 10,00 0 pp m

pp m pp m
pp m pp m pp m
pp m pp m i n fee d (2 4 mo )

i n fee d (2 4 mo )

i n fee d (life ) —

1 0 g 9 7

— 1 0 g 9 7

— 9 7 g Man e

5/1 3 rena l tumor s 6/ 7

Non e 6/1 3 rena l tumor s 7/ 9 1/2 0 31/3 4 rena l tumor s Va n Esc h e t al. , 196 2

Ma o an d Molnar , 196 7

(continue d o n th e following page )TABL E 1-1
. (continued )

Compound Anima l Dos e an d duratio n Tota l lea d Tumo r respons e Referenc e

Lea d subacetat e M Charle s

Rive r C D ra t 5000-10,00 0 pp min feed (7-1 7 mo ) wit h ar withou t 2AAF 14-6 9 g Rena l tumor s an d cerebra l glioma s Has s e t a1. , 196 5

Lea d subacetat e M Sprague

Dawle yra t 10,00 0 pp mi n feed (1 8 mo ) with : 0V. calciu

macetat e 0.37
. 17
. 37
. 67
. 7 3 g Kasprza k e t al. , 198 5 .13/2 9 rena l tumor s 21/3 0 18/2 9 22/3 0 22/2 8

r o 37
. calciu macetat e onl y 0/2 9

Me i the r O/3 0

(continue d o n th e following page )



# cTABL E 1-1
. (continued )

Compoun d Anima l Dos e an d duratio n Tota l lea d Tumo r respons e Referenc e

Lea d subacetat e M Wista r ra t

r o co 50 0 pp mEHE Ni n fee d 2 g ( 2 wk) , the n 100 0 pp mlea d subacetat e (2 0 wk) , the n basa l die t (1 0 wk ) 50 0 pp mEHE Nonl y 100 0 pp mEHE Ni n 2 g fee d ( 2 wk) , the n 100 0 pp mlea d subacetat e (2 0 wk) , the n basa l die t (I O wk ) 100 0 pp mEHE Nonl y 100 O pp mlea d 2 g subacetat e onl y Neithe r 10/2 2 rena l tumor s Hias a e t al. , 198 3

0/2 4 17/1 7 rena l tumor s

9/1 8 0/2 4

0/2 4

(continue d o n th e followin g page )TABL E "1-1
. (continued )

Compound Anima l Dos e an d duratio n Tota l lea d Tumo r respons e Referenc e

Lea d subacetat e M F34 4 ra t lOO O pp mEHE Ni n w a te r ( 1 wk) , the n 100 0 pp mlea d subacetat e i f feed (3 5 wk ) 5 g 13/2 5 rena l tumor s Shira i e t al. , 198 4

100 0 pp mEHE Nonl y 5/2 3 100 0 pp mlea d subacetat e onl y 3 g 0/25 , bu t 6/2 5 ha d possibl e preo.I'sor s

r o Lea d subacetat e M Swis s

mous e 0 pp mi n fee d 100 0 pp m(2 4 mo ) 10,00 0 pp

m 2 g

2 2 Non e

6/2 5 rena l tumor s Substantia l mortalit y Va n Esc h an d Kroes , 196 9

Lea d subacetat e F Swis s

mous e

M/ F Strai n A/Stron g mous e O pp min fee d 100 0 pp m(2 4 mo ) 10,00 0 pp

m 1 5 i.p

. injection s totalling 30 , 75 , o r 15 0 mg/k g ( 7 mo ) — 2 g 2 2 0.0009

- 0.004 5 g Non e

2/2 5 rena l tumor s Substantia l mortalit y Lun g tumo r incidenc e an d lun g tumor s pe r mous e Stone r e t a). , 197 6 increase d a t 15 0 mg/kg ; rena l tumor s no t reporte d

(continue d o n th e fallowin g page )

r oTABL E 1-1
. (continued )

Compound Anima l Dos e an d duratio n Tota l lea d Tumo r respons e Referenc e

Lea d oxid e M/ F Syria n

hamste r 1 0 intratrachea l

instillation s o f 1 m g wit h 1 m

g B,a] P (1 4 mo ) 0.00 9 g 10/2 6 lun g tumor s Kobayash i and Okamoto , 197 4

c o o Lea d phosphat e

Lea d phosphat e

Lea d naphthenat e (mixture ) M albin o C B

Wista r rat

Whit e ra t

M albin o Schofiel d mous e Lea d oxid e onl y

B[a] P onl y Neithe r

s.c . or i.p

. injection s ( 8 mo ) tota11ing : 2 9 mg " 14 5 m g 45 0 m g

s.c . injection s totallin g 40-76 0 m g lea d (1 6 mo ) Ski n application s totallin g 6 m L i n 207
. solutio n i n benzen e (1 8 mo ) O.0O 9 g

—

—

0.0 3 g 0. 1 0. 4
0.04

- 0.7 6 g

N.C
. 0/2 0

0/2 7 0/5 7

0/2 3 rena l tumor s 14 /z 3 2/ 3 19/2 9 rena l tumor s

5/5 9 rena l tumor s Ro e e t al. , 196 5

Zol1inger , 195 3

Baldwi n e t al. , 196 4

(continue d o n th e foilowin g page )TABL E 1-1
. (continued )

Compound Anima l Dos e an d duratio n Tota l lea d Tumo r respons e Referenc e

Lea d dimethyl

dithio

carbamat e Tetraethy l lea d M B6C3F 1

mous e

M/ F Swis s ICR/H a mous e 46. 4 mg/kg/ d b y gavag e ( 1 mo) , the n 13 0 pp mi n feed (1 7 mo )

s.c . injection s (1 2 mo ) totalling : 0. 6 m g 0. 2 g

0.000 4 g 5/1 6 reticulu mcel l sarcomas , significan t ove r contro l (12/146 ) BRL , 196 8

5/4 1 1ymphomas , significan t ove r tricapryli n contro l (1/89 ) Epstei n and Mantel , 196 8

C O 1. 2 m g 0.000 8 9Z/

. mortalit y befor e weanin g

. 0 m g 0.001 3 1007
. mortalit y

Tota l lea

d adjust s fo r th e lea d conten t o f eac h compound (lea d acetat e i s 207/37 9 lead ; lead subacetate , 621/807 ; lea

d oxide , 207/223 ; lea d phosphate , 722/812 ; lea d dimethyldithiocarbamate , 207/447 ; tetraethy l lead , 207/323 ; an

d lea d nitrate , 207/331)

. Tota l lea d fro mfoo d o r wr.e r exposur e assume s tha t rat s ea t an d drin k 57
. an d 7.87. , respectively , o f thei r 350- g weigh t eac h day , an d tha t mic e ea t an

d drink 137
. an

d 177. , respectively , o f thei r 30- g weigh t eac h day

. N.C
. - N o calculation

.TABL E 1-2
. 9JMMAR Y O F NONPOSITIV E ANIMAI.
. STUDIE S

Compoun d Anima l Dos e an d duratio n Tota l lea d Comment s Referenc e

Lea d acetat e M/ F Long

- 5 pp mlea d i n wate r 0. 1 g

Evan s rat fo r lif e MT D wa s no t reache d Kanisaw a an d Schroeder , 196 9

Lea d acetat e F Swis s

mous e O
. 50 , 200 , o r

100 O pp mlea d i n wate r fo r 1 5 w k wit h 1 i.p

. injectio n o f uretha n 0.03

- 0. 5 g N o effec t o n urethan

- Blakley ,

induce d pulmonar ytumor s 198 7

C O r o .ead acetat e Beagl e dog s 2 , 16 , 57 , 155 , o r 57 6 pp mi n feed fo r 2 4 m n N.C
. Stud yduratio n i s inadequat e fo r a cance r stud yi n dog s Aza r e t al. , 197 3

Lea d acetat e M/ F Beagl e

dog s O , 10 , 50 , 100 , o r

100 0 pp mi n fee d fo r 2 2 m o N.C. Stud yduratio n i s inadequat e fo r a cance r stud yi n dog s API , 1*77 1

Lea d acetat e M/ F Rhesu s

monkey s 0 , 1.25 , o r

2 5 mg/kg/ d b

ygavag e fo r 2 2 m o N.C
. Stud yduratio n i s inadequat e fo r a cance r stud yi n monkey s API , 197 1

Lea d subacetat e Golde n

hamster s 0 , 1000 , or 50O O pp

m i n fee d fo r 2 4 m o M.C
. Hig h mortality , wit h fe w survivor s afte r 60 O day s Va n Esc h an d Kroes , 196 9

(ccritinue

d o n th e followin g page )TABL E 1-2
. (continued )

Compound Anima l Dos e an d duratio n Tota l lea d Comment s Referenc e

Lea d subacetat e M Rabbit s ( 3

strains )

C O C O Lea d nitrat e

Lea d dimethyl

dithio

carbamat e M Long—Evan s

ra t

M/ F F34 4 ra t 500 0 o r 10,00 0 pp m i n feed fo r 1 8 m o wit h o r withou t 2AAF , 1insee d oi1 , cholesterol , chloroform , carbo n tetrachloride , o r vitami n D 2 5 pp mlea d i n wate r fo r lif e wit h 1 pp

m trivalen t chromiu

m 0 , 25 , or

5 0 pp min fee d fo r 2 4 m o N.C
.

0. 5 g

0. 4 Stud

yduratio n i s inadequat e fo r a cance r stud yi n rabbit s Has s e t a1. , 196 5

MT D wa s no t reache d

N o toxi c signs , thi s indicate s tha t th e MT D wa s no t reached ; rena l lesicn s wer e observe d a t highe r dose s i n th e range-finding study ; 3 glioma s wer e see n Schroede r e t al. , 197 0

NCI , 197 9

Lea d dimethyl

dithio

carbamat e F B6C3F 1

mouse , M/ F B_A<F 1 mous e 46. 4 mg/kg/ d b y gavag e fo r 1 mo , the n 13 0 pp

mi n feed fo r 1 7 m o 0
. N o tumor s observe d a t thi s low dos e BRL , 196 8

(continue d c n tti

e following page )TABL E 1-2
. (continued )

Compound Anima l Dos e an d duratio n Tota l lea d Comment s Referenc e

M/ F B6C3F 1 mouse , M/ F B6AKF 1 mous e On e s.c . injectio n 0.0 2 g

o f 100 0 mg/k g N o tumor s observe d a t thi s lo w dos e

Lea d dimethyl

dithio

carbamat e M/ F B6C3F 1 0 , 25 , o r 5 0 pp mi n 0.04

- mous e fee d fo r 2 4 m o 0.0 8 g N o toxi c signs , thi s indicate s tha t th e MT D wa s no t reached ; rena l lesion s wer e observe d a t highe r dose s i n th e range-findin g study ; 1 glioma wa s see n NCI , 197 9

C O Tota l lea

d adjust s fo r th e lea d conten t o f eac h compound (lea d acetat e i s 207/37 9 lead ; lead subacetate , 621/807 ; lea

d oxide , 207/223 ; lea d phosphate , 722/812 ; lea d dimethyldithiocarbamate , 207/447 ; tetraethy l lead , 207/323 ; an

d lea d nitrate , 207/331)

. Tota l lea d fromfoo d o r wate r exposur e assume s tha t rat s ea t and drin k 57
. an d 7.87. , respectively , o f thei r 350- g weigh t eac h day , an d tha t mic e ea t an d drink 137
. and 17% , respectively , o f thei r 30— g weigh t eac h day

. N.C
. - N o calculation

.



### 3P.4 8

exposur e period , th e animal s wer e kille dwhe nmoribun do r whe npalpabl e tumor s

wer e detected . Rena l lesions , bu t n o tumors , wer e see ni nfou r animal s tha t die dwithi n 6 month s o f th e star t o f exposure . Afte r 6 months , al l rat s develope dchroni c cysti c nephriti s du e t o a cysti c dilatatio no f th e rena l tubule s accompanie db y sligh t interstitia l fibrosis . Th e firs t neoplasti c lesio nwa s detecte dinth e kidne y a t 1 1 months . O f th e 1 6 animal s tha t survived , 1 5 (9 4 percent ) develope drena l tumors . Almos t al l rena l tumor s wer e describe da s bilatera l cuboida l cel l carcinomas . 1.2.1.1.2 . Zawirsk a an dMedras , 1968 . Th e experiment s wer e carrie dou t wit ha tota l o f 12 6 Wista r rat s (9 4 males , 3 2 females) ; a nadditiona l 3 2 rat s serve d

a s control s (1 9 males , 1 3 females) . Th e animal s wer e feda dail y ratio no f 20 g o f fee dcontainin g lea dacetat e fo r 1 8 months . Th e dail y dos e wa s 3 m

g pe r ra t fo r th e firs t 2 months , an dfo r th e remainde r o f th e exposur e perio d (1 6 months ) th e dos e wa s raise dt o 4 m g pe r rat . Assumin g a naverag e body weigh t o f 0.3 5 kg , th e weight-normalize d dos e o f lea dacetat e wa s 8. 6 mg/kg' d fo r th e firs t 2 month s an d11. 4 mg/kg' dthereafter . Th e tota l dos e o f lea d
acetat e wa s 213 1 m

g pe r ra t a t th e en

do f 1 8 month s o f exposure . Control s wer e fe da die t withou t lead . Al l animal s wer e examine donc e pe r week . Th e kidney s

an dothe r organ s inth e abdomina l cavit y a s wel l a s th e teste s o f male s wer e palpated . Al l animal s wer e examine dhistologically . Fort y animal s wer e kille d

a t variou s tim e interval s followin g exposure ; th e remainde r wer e kille da t 2 6 month s fro

m th e star t o f th e experiment . O f 9 4 mal e rats , 8 1 survive d1 8 t o 2 0 months ; o f 3 2 females , 9 survive d1 8 t o 2 0 months .



### 3 5P.4 9

Lea d acetat e induce d numerou s benig nan d malignan t tumor s a t multipl e sites . Th e mai ntarge t organ s wer e th e kidneys , testes , an d othe r endocrin e glands . Mos t o f th e tumor s appeare d betwee nth e 18t han d 20t hmont h(i.e. , afte r cessatio no f treatment) . Th e incidenc e o f rena l adenoma s wa s 4 6 percen t

an d 3 8 percen t inmale s an d females , respectively ; th e incidenc e o f rena l carcinoma s wa s 1 6 percen t an d 6 percen t inmale s an d females , respectively . A s

a resul t o f numerou s cyst s an d tumorou s changes , th e kidney s wer e alway s enlarged . Th e longes t survivin g animal s displaye d fibrou s change s o f th e kidneys . Many

kidne y carcinoma s metastasize d t o th e lungs , lymp hnode s (particularl y

t o thos e locate d inth e peritoneum) , an d live r bu t rarel y

t o th e spleen . Othe r tumor s an

d th e overal l incidenc e base d o n12 6 expose d animal s (male s

an d female s combined ) wer e a s follows : 2 6 unilatera l adenomas , 5 bilatera l adenomas , an

d 1 carcinom a o f th e adrena l gland ; 5 pituitar y adenomas ; 3 adenomas , an

d 2 carcinoma s o f th e liver ; 4 adenoma s an d 1 carcinoma o f th e thyroid ; an

d a nunspecifie d numbe r o f lung adenomas . I nth e male s (9 4 animal s total ) ther e wer e 1 4 unilatera l an d 9 bilatera l tumor s o f th e testes , 2 1 adenoma s an

d 1 carcinoma o f th e prostate , 2 neurinoma s an d 2 carcinoma s o f th e seminiferou s duct , 3 gliomas , an d 2 ski ncarcinomas . Female s (3 2 animal s total ) develope d 1 adenoma an d 2 carcinoma s o f th e mammar y glan d an

d 1 carcinom a o f th e forestomach . Th e percen t respons e i s no t provide d her e becaus e th e numbe r o f affecte d animal s coul d no t b e determine d fro m th e dat a presente d (numbe r o f unilatera l an d bilatera l sites) . Wit hth e exceptio no f

on e adenoma (sit e unspecified ) an d on e mammar y

carcinoma , ther e wer e no tumor s inth e contro l group . Historica l control s develope d no spontaneou s tumor s i n kidneys , othe r organs , o r endocrin e glands . Thi s stud y indicate s that , a t a

3 6P.5 0

relativel y

low dose , lea dacetat e induce s tumor s a t multipl e site s involvin g th e kidney s an

dendocrin e organs . 1.2.1.1.3 . Zawirsk a andMedras , 1972 ; Zawirska , 1981 . A tota l o f 9 4 Wista r rat s (4 7 male s an

d4 7 females ) wer e divide dint o fou r exposur e groups , an da n additiona l 9 4 rat s (4 7 male s an d4 7 females ) serve da s controls . Th e animal s

wer e feda dail y

ratio no f 2 0 g o f fee dpe r da y containin g 3 m

g o f lea d acetate . Assumin g anaverag e body weigh t o f 0.3 5 kg , th e weight-normalize d dos e o f lea dacetat e wa s 8. 6 mg/kg'd . Grou pI (2 0 rats ) wa s give ndietar y lea dacetat e fo r 6 0 days ; si xanimal s (thre e o f eac hsex ) wer e kille d immediatel y

afte r th e exposur e perio dended , an dth e remain.n g rat s wer e lef t t o di e naturally . Grou pI I (2 0 rats ) wa s give ndietar y lea dacetat e fo r 16 2 days ; si xanimal s wer e kille dimmediatel y afte r th e exposur e perio dended ,
andth e remainin g rat s wer e lef t t o di e naturally . Grou pIl a ( 8 rats ) wa s als o give ndietar y

lea dacetat e fo r 16 2 days ; on e wa s kille dwhe nmoribund , an dth e remainin g rat s wer e lef t t o di e naturally . Grou pII I (2 0 rats ) wa s give n dietar y lea dacetat e fo r 30 7 days ; si xanimal s wer e kille dimmediatel y afte r th e exposur e perio dended , an dth e remainin g rat s wer e lef t t o di e naturally . Grou pI V (2 6 rats ) wa s give ndietar y lea dacetat e fo r 50 4 days ; seve nrat s ( 3 female s and4 males).wer e kille dimmediatel y afte r th e exposur e perio dended ,
an dth e remainin g animal s wer e lef t t o di e naturally . Th e surviva l o f th e animal s lef t t o di e naturall y wa s 3 8 t o 50 5 day s fo r grou pI , 9 5 t o 39 8 day s fo r grou pII , 17 8 t o 29 6 day s fo r grou pIla , 4 t o 34 4 day s fo r grou pIII , and32 4 t o 57 2 day s fo r grou pIV . O f th e 9 4 contro l animal s used , si xwer e kille dafte r 6 0 day s an dsi xafte r 16 2 days . Animal s i n group s I an

dI I wer e kille di

nequa l number s a t th e same time . Th e surviva l o f



### 3 7P.5 1

th e remainin g animal s range d fro m 30 0 t o 80 0 days . N o neoplasti c o r nonneoplasti c lesion s wer e found i nan y o f th e contro l animals . Th e incidenc e

o f kidne y

adenoma s inexpose d animal s wa s 1/2 0 ( 5 percent ) ingroup s I an d II , 1/ 8 (1 3 percent ) ingrou p Ila , 3/2 0 (1 5 percent ) ingrou p III , an d 6/2 6 (2 3 percent ) ingrou p IV . Th e overal l incidenc e fo r al l group s combine d wa s 12/9 4 (12. 8 percent) . Th e incidenc e o f glioma s wa s 2/2 0 (1 0 percent ) i ngroup s I , II , an

d III , 0/ 8 ingrou p Ila , an d 4/2 6 (1 5 percent ) i ngrou p IV . Th e overal l incidenc e fo r al l group s combine d wa s 10/9 4 (1 1 percent) . Therefore , inthes e animals , gliomas , whic har e no t ofte nfound inlead-treate d rat s

occurre d a t anincidenc e almos t a s hig ha s tha t o f kidne y tumors , whic har e usuall y foun d inlead-expose d animals . Othe r tumor s an d th e overal l incidenc e base d on9 4 treate d animal s wer e a s follows : 1 5 lung adenoma s (1 6 percent) , 1 7 pituitar y

adenoma s (1 8 percent) , 1 1 thyroi d adenoma s (1 2 percent) , 4 parathyroi d adenoma s ( 4 percent) , 1 5 adenoma s o f th e adrena l cortex/medull a (1 6 percent) , 1 1 prostat e adenoma s (1 2 percent) , 8 mammar y adenoma s ( 9 percent) , 3 reticulosarcoma s ( 3 percent) , an d 1 leukemi a ( 1 percent) . A tota l o f 10 9 tumor s wer e found in9 4 animal s treate d wit hlead . Th e multiplicit y

o f tumo r type s found inthes e animal s i s unusua l fo r animal s treate d wit hdietar y lead . I

non e grou p o f animal s (group I V animal s kille d afte r 50 4 day s o f dietar y lead) , 1 0 differen t type s o f tumor s wer e found in
seve nanimals . Th e lac k o f a detaile d descriptio no f patholog y incurren t contro l animal s (o r historica l controls) , considerin g tha t som e animal s live d a s lon g a s 80 0 days , i s a majo r weaknes s inthi s study . I t i s unlikely tha t 8 2 animal s coul d surviv e a s long a s th e curren t control s (u p t o 80 0 days ) an

d no t develo p

an y reportabl e pathology . Th e absenc e o f thi s informatio nconsiderabl y weaken s

3 8P.5 2

th e valu e place do

nthi s study

(whic hshow s tha t lea dinduce s tumor s a t multipl e site s a t dose s lowe r tha nthos e reporte dinothe r studies ) fo r evaluatin g th e carcinogenicit y o f lead . Th e numbe r o f animal s use dineac h
exposur e grou pi s small ; thus , meaningfu l result s require s poolin g dat a fro m th e variou s groups . 1.2.1.1.4 . America nPetroleu m Institute , 1971 . Chroni c toxicit y studie s wer e conducte dfo r 2 2 month s i nrats . Mal e an

dfemal e Charle s Rive r C D rat s (5 0 pe r grou ppe r sex ) wer e expose dt o lea dacetat e i nthei r diet s a t concentration s o f 0 , 10 , 50 , 100 , o r 100 0 ppm . Th e rat s wer e kille da t th e endo f th e exposur e period . Intranuclea r inclusio nbodie s an dcytomegal y

wer e foun di

nmos t animals . Atypica l nodula r o r adenomatou s rena l epithelial hyperplasi a wa s observe din

on e mal e receivin g 5 0 pp m (numbe r examine dno t reported) , 4/1 4 male s receivin g 10 0 ppm , an

d7/1 5 male s an

d3/1 5 female s receivin g 100 0 ppm . Accordin g t o th e report , rena l neoplasi a o f th e cortica l epithelium wa s observed , bu t incidenc e dat a wer e no t presented . 1.2.1.1.5 . Aza r e t al. , 1973 . Lea dacetat e wa s fe dt o rat s (strai nno t specified ) a t concentration s o f lea dmeasure da t 5 (basa l diet) , 18 , 62 , 141 , 548 , 1130 , o r 210 2 pp m fo r 2 years . Ther e wer e 10 0 rat s o f eac hse xi nth e contro l grou pan

d5 0 rat s o f eac hse xi neac hexposur e grou preceivin g th e fou r lowes t doses . Th e two highes t dose s wer e starte da t a differen t tim e an d consiste do f 2 0 rat s o f eac hsexinth e contro l an dexpose dgroups . Body weights , foo dconsumption , an dlea dconten t inth e blood , urine , feces , an d tissue s wer e measured ; clinica l appearanc e an dbehaviora l change s wer e observed . Al l animal s wer e examine dfo r gros s an dmicroscopi c lesions .



### 3 9N o clinica l toxicit y o r behaviora l change s wer e observe dinrats , eve na t th e highes t concentratio no f lead . Body weigh t gai nwa s reporte dt o b e reduce d i nanimal s receivin g th e two highes t concentrations . Mortalit y wa s increase d i nmal e rat s receivin g 54 8 o r 210 2 ppm , compare dwit hthei r respectiv e controls . Anunexplaine dhig hmortalit y rat e wa s observe di nth e secon dgrou p

o f contro l rats ; consequently , th e mortalit y rat e inmale s receivin g 113 0 pp m

wa s no t increase dsignificantly . Th e mortalit y rat e wa s no t increase di nan y

o f th e femal e groups . Kidne y tumors , mos t o f them adenoma s arisin g from th e tubula r epithelium , wer e induce di nmal e rat s receivin g th e thre e highes t dose s

andinfemal e rat s receivin g th e highes t dos e only . Th e tumo r incidenc e wa s 10 , 50 , an

d8 0 percen t inmale s receivin g 548 , 1130 , an d210 2 ppm , respectively , an

d3 5 percen t i

nfemale s receivin g 210 2 ppm . No tumor s wer e observe di ncontrols . Th e lea dconten t inth e kidne y increase dwit hdos e u pt o 13. 2 an d13.3 7 ug/ g o f tissu e inrat s fed54 8 an d113 0 ppm , respectively , wit h

a sligh t decreas e t o 11.6 0 ug/ g o f tissu e a t 210 2 pp m a t th e endo f 2 4 months . Thus , th e increas e i nth e tumo r incidenc e a t th e highe r dose s di dno t correlat e wit ha simila r increas e inlea dconten t inth e kidney . However , othe r measurements , specifically , urine , liver , an dbon e lea dcontent , continue dt o increas e wit hdose . Lea dconten t wa s highes t inbone , whic hhadlevel s mor e tha n1 0 time s tha t o f othe r tissues , an dit s leve l increase dthroughou t al l dietar y concentrations . Th e numbe r o f stipple dre dbloo dcell s increase da t th e 18-pp

m dos e an

dth e ALA- D wa s decrease da t 6 2 ppm ; th e hemoglobi nand hematocrit , however , wer e no t depresse dinth e rat s unti l the y receive da dos e

o f 113 0 ppm . A t 113 0 an d212 0 pp

m lead , 21-day-ol dweanlin g rat s showe dno tumor s bu t di dshow

histologica l change s i nth e kidne y

comparabl e t o thos e seen i nadul t rat s receivin g 54 8 pp m o r mor e lea dinthei r diet .

4 0P.5 4

Ther e wer e severa l weaknesse s i nthi s study . Th e descriptio no f methodolog y

wa s ver y

scanty . Bod

y weight s an

dfoo dconsumptio ndat a wer e no t presented . Onl y

th e termina l mortalit y rat e wa s presented , an dtim e t o firs t tumo r wa s no t given ; tumo r incidenc e coul dno t b e relate dt o number s o f animal s

a t ris k (numbe r o f survivor s a t latency) . Furthermore , th e dat a wer e no t analyze dstatistically . Th e repor t o f th e study come s fro

m th e proceeding s o f th e Internationa l Symposiu m onth e Environmenta l Healt hEffect s o f Lea d

convene dinAmsterda m i nOctobe r 1972 . Th e proceeding s wer e publishe d7 month s late r i nMa y

1973 . A

telephon e cal l t o th e Haskel l Laborator y inNewark , Delaware , reveale dtha t th e raw dat a fro

m th e study

coul dno t b e locate dan d thu s wa s no t availabl e fo r review . Ther e i s n o evidenc e tha t thi s study ha s undergon e a pee r revie w inth e conventiona l sens e o f bein g publishe dina peer reviewe djournal . Th e strength s o f th e study includ e th e us e o f multipl e dos e levels , th e 2-yea r duratio no f exposure , an dth e number s o f animal s pe r dos e at th e lowe r dos e levels . 1.2.1.1.6 . Tanne r an dLipsky , 1984 . Mal e Fische r 34 4 rat s wer e expose dt o lea dacetat e inthei r diet s a t a concentratio no f 10,00 0 pp m fo r u pt o 5 2 weeks ; control s wer e fe da basa l die t withou t adde dlea dacetate . Survivor s

wer e kille da t 16 , 24 , 36 , o r 5 2 week s fro m th e star t o f exposure . Althoug h5 0 animal s pe r grou pwer e expose da t th e star t o f th e study , a s a resul t o f schedule ddeath s an

dearl y mortality , onl y

5 rat s remaine dafte r 5 2 weeks . Non e o f th e control s develope dtumors . No tumor s wer e foundi nanimal s ( 5 t o 1 0 rat s fo r eac htime period ) kille d

a t 16 , 24 , o r 3 6 weeks . On e expose danimal , o f fiv e surviving , develope da n adenocarcinom a o f th e kidne y a t 5 2 weeks . Nonneoplasti c rena l lesion s wer e als o observed . Karyomegal y (enlarge dnuclei ) wa s th e firs t morphologi c chang e

4 1i nproxima l tubul e epithelia l cells , appearin g a s earl y a s wee k 4 inlead expose danimal s an

dincreasin g fro

m week s 1 6 t o 52 . Hyperplasti c lesion s o f th e kidne y

corte xwer e presen t a t wee k 1 6 i n4/ 8 rat s an di n10/1 0 rat s a t wee k 36 . Accordin g t o th e investigators , ther e wa s n o correlatio nbetwee n karyomegal y

an dth e late r appearanc e o f hyperplasi a o r carcinomas . Th e weaknesse s o f th e study wer e th e us e o f onl y on e dos e leve l an

dth e smal l numbe r o f animal s survivin g t o termination . 1.2.1.1.7 . Noqueira , 1987 . Mal e Wista r rat s wer e administere ddietar y lea d acetat e a t concentration s o f 0. 5 percen t o r 1 percen t fo r 2 4 weeks , o r th e basa l die t withou t lea dacetat e (control) . Th e animal s wer e kille da t th e en d

o f th e 24-wee k exposur e period . Neoplasti c an dnonneoplasti c lesion s wer e identifie db

y microscopi c examination . Al l rat s survive dunti l detectio no f th e firs t tumor . Tw o type s o f rena l tumor s wer e found , thos e compose do f basophili c cell s

an dthos e compose do f chromophobi c cells . Bot htumo r type s wer e claime dt o hav e originate dfro

m th e proxima l tubule . In2/1 0 controls , "oncocytic " change s wer e note dinth e wall s o f th e collectin g duct . Non e o f th e rat s receivin g 0. 5 percen t lea dacetat e develope dtumor s a t an y site , wherea s 2/1 0 rat s receivin g 1 percen t lea dacetat e develope dbasophili c rena l tumor s an d 7/1 0 develope dchromophobi c tumors . Nonneoplasti c rena l tubula r lesion s include dkaryomegaly , yello w cytoplasmi c pigment , an dnuclea r inclusions . Th e limitation s o f thi s study wer e smal l grou psize , shor t duratio no f exposur e an d

o f th e study , an

dus e o f on e se xonly . 1.2.1.1.8 . Kanisaw a an dSchroeder , 1969 . Mal e an dfemal e random-bre d Long-Evan s strai nrat s (5 0 pe r sex ) wer e administere dlea dacetat e a t a concentratio no f 5 pp m ( 5 mg/L ) indrinkin g wate r fo r thei r lifetime . Th e lif e

4 2P.5 6

spa no f th e rat s administere dlea dwa s shortene dcompare dwit hcontrols ; 7 5 percen t mortalit y

wa s observe da t 90 3 an d92 5 day s inexpose dmal e an d femal e rats , respectively , compare dwit h97 9 an d105 0 day s i

ncontro l mal e an

d femal e rats , respectively . Surviva l time , however , wa s considere dt o b e adequate , eve ni f somewha t shortened . Kidne y tumor s wer e no t found , andth e incidenc e o f tumor s a t othe r site s

wa s no t significantl y increase dinth e expose dgroups . Th e dose , however , wa s

ver y low . 1.2.1.1.9 . Kolle r e t al. , 1985 . On e grou po f 1 6 mal e Sprague-Dawle y rat s receive dlea dacetat e alon e a t a concentratio no f 260 0 pp m o f lea dindeionize d drinkin g wate r fo r 7 6 weeks . Othe r group s receive d2 6 o r 260 0 pp m o f lea di n combinatio nwit hethy l ure a an dsodiu m nitrite . Th e control s wer e no t exposed . Th e weight-normalize d highdos e calculate dfro m th e fractio no f th e body weigh t

consume da s wate r (0.07 8 L/kg'day ) (U.S . EPA , 1986b ) wa s 19 5 m g o f lea dpe r k

g pe r day . Th e rat s wer e kille dwhe nmoribun do r immediatel y afte r terminatio no f
exposur e (7 6 weeks) . Tumor s wer e detecte donl y i nth e kidneys . The y

wer e identifie da s tubula r cel l carcinomas . Th e firs t tumo r appeare da t 7 2 week s inrat s receivin g lea d only ; th e incidenc e a t th e endo f th e study wa s 13/1 6 (8 1 percent) . Rena l neoplasm s inthre e rat s metastasize dt o th e lungs , adrena l glands , an d lymphatics . Kidne y

tumor s (6/10 ) als o appeare di nrat s receivin g ethy l ure a

an dsodiu m nitrit e inadditio nt o 260 0 pp m lead , bu t no t i

nrat s receivin g 2 6 pp m o f lea dincombinatio nwit hethy l ure a o r sodiu m nitrite . No tumor s develope dincontrol s a t an y site . Th e result s indicat e tha t lea dacetat e i s carcinogenic , bu t ther e i s n o evidenc e fo r cocarcinogenicit y wit h



### 4 3P.5 7

ethylnitrosoure a precursors . Th e limitation s o f th e study includ e smal l grou p siz e an d us e o f onl y

on e sex . 1.2.1.2 . Studie s i nMice- - 1.2.1.2.1 . Blakley , 1987 . T o study th e effec t o f lea d o nth e developmen t o f urethan-induce d pulmonar y adenomas , lea d acetat e wa s administere d t o 3-week-ol d femal e Swis s mic e (numbe r o f animal s pe r dos e wa s no t given ) inacidifie d drinkin g wate r a t 0 , 50 , 200 , o r 100 0 pp m o f lead fo r 1 5 weeks . Thre e week s afte r initiatin g exposure , th e mic e wer e give na nintraperitonea l (intraperitoneal ) injectio no f uretha n(1. 5 mg/ g body weight) . Th e animal s we^ e kille d immediatel y afte r terminatin g exposure . Neithe r siz e no r numbe r o f tumor s pe r mous e wa s affecte d b y lea d (th e numbe r o f animal s affecte d i s no t reported) . Inanothe r experimen t b y th e sam

e authors , designe d t o study th e effec t o f lea d onth e spontaneou s incidenc e o f lymphocyti c leukemi a o f thymi c origi nin Swis s mice , 8-week-ol d femal e mic e (5 0 animal s pe r dose ) were-administere d lead i ndrinkin g wate r fo r 28 0 day s a t concentration s o f 0 , 50 , o r 100 0 pp m o f lead . Th e incidenc e o f animal s dyin g fro m lymphocyti c leukemi a o f thymi c origi n increase d from

24/5 0 i ncontrol s t o 34/5 0 i nth e low-dos e grou p an d 38/5 0 i n th e high-dos e group . Th e media nsurviva l time wa s reduce d du e t o lymphocyti c leukemi a inmic e expose d t o lead . Measuremen t o f th e lea d conten t i nth e live r

an d kidne y

showe d a

nexposure-relate d increas e intissu e concentration s o f lead , bu t th e magnitud e o f th e respons e betwee nth e tw o exposur e group s di d no t correspon d wit heithe r exposur e concentratio no r tissu e concentration . Th e author s interprete d thes e result s a s indicativ e o f a nimmunosuppressiv e effec t

o f lea d wit hregar d t o th e spontaneou s inductio no f lymphocyti c leukemia , bu t

no t t o th e inductio no f pulmonar y adenoma s b

y urethan .

4 41.2.1.3 . Studie s i nDoqs- -

1.2.1.3.1 . Aza r e t al. , 1973 . Lea dacetat e wa s fedto . beagl e dog s a t measure d concentration s equa l t o 2 (basa l diet) , 16 , 57 , 155 , o r 57 6 pp m o f lea dfo r 2 years . Fou r beagl e dog s o f eac hse xwer e use dfo r eac hgroup . Body weights , foo dconsumption , an

dlea dconten t inblood , urine , feces , an dtissue s wer e measured ; clinica l appearanc e an dbehaviora l change s wer e observed . Al l animal s wer e examine dfo r gros s an dmicroscopi c lesions . Ther e *a s n o gros s o r microscopi c damag e indogs , excep t sligh t rena l damag e i nmal e dog s receivin g 57 6 ppm . Thi s study hadsevera l limitations . Th e grou psiz e wa s small , an dth e 2-yea r exposur e duratio nwa s inadequat e fo r detectin g cance r indog s wit hlif e span s u pt o 1 5 years . Bod

y weight s an

dfoo d consumptio ndat a wer e no t presented . 1.2.1.3.2 . America nPetroleu m Institute , 1971 . Chroni c toxicit y studie s wer e conducte dfo r 2 2 month s i ndogs . Si xmal e an

dsi xfemal e beagl e dog s pe r grou p

wer e administere dlea dacetat e inthei r diet s a t concentration s o f 0 , 10 , 50 , 100 , o r 100 0 ppm . On e mal e an don e femal e wer e kille dafte r 1 year , th e remainde r afte r 2 2 months . No gros s lesion s wer e observed ; mino r microscopi c lesion s characterize da s thickenin g o f th e glomerula r tuft s wer e observe di n female s receivin g 100 0 ppm . Th e lac k o f effect s wa s reflecte db y th e bloo d lea dlevels , whic hwer e onl y slightl y

elevate drelativ e t o controls . Th e stud y duratio nwa s inadequat e t o detec t cance r indogs . 1.2.1.4 . Studie s i nMonkevs- - 1.2.1.4.1 . America nPetroleu m Institute , 1971 . Mal e an dfemal e rhesu s monkey s (tw o pe r se xpe r group ) wer e give nlea dacetat e indistille dwate r b y gavage , 7 day s pe r wee k fo r 2 2 month s a t dos e level s o f 0 , 1.25 , o r 25. 0 mg/kg'day .



### 4 5P.5 9

Th e contro l grou pconsiste do f two mal e an dtwo femal e monkey s intubatedwit h wate r alone . On e mal e fro m th e 25-mg/k g grou pdie dafte r 9 month s du e t o respirator y

disease ; th e res t o f th e animal s wer e kille da t th e en do f th e exposur e period . Intranuclea r inclusio nbodie s an ddegenerativ e lesion s inth e tubula r epithelium

wer e observe dinanimal s receivin g 2 5 mg/kg . Becaus e o f thei r lon g lif e spa n(3 5 years) , th e study duratio ni s considere dt o be inadequat e t o detec t cance r i nrhesu s monkeys . 1.2.2 . Lea dSubacetat e (CA S No . 1335-32-6 ) 1.2.2.1 . Studie s i nRats- - 1.2.2.1.1 . Va nEsc he t al. , 1962 . Mal e an dfemal e Wista r rat s wer e administere deithe r 0. 1 percen t lea dsubacetat e (1 4 mal e an d1 5 femal e contro l rats , 1 6 mal e an

d1 6 femal e treate drats ) inthei r diet s fo r 2 9 month s o r 1 percen t lea dsubacetat e (1 3 mal e an d1 3 femal e contro l rats , 1 3 mal e an d1 1 femal e treate drats ) fo r 2 4 months . Moribun danimal s wer e killed , an dal l survivin g animal s wer e kille dwhe nth e exposur e perio dended . Bod y weight s

wer e measure dweekly , an dhematolog y

test s wer e performe da t 1 4 week s o n animal s receivin g th e 0. 1 percen t die t an da t 3 7 week s o

nanimal s receivin g th e 1 percen t diet . Averag e body

weight s wer e significantl y reduce dafte r 1 0 week s inbot h mal e an dfemal e rat s receivin g th e 1 percen t diet . Th e averag e surviva l time

wa s reduce dinrat s receivin g th e 1 percen t diet ; si xmal e an dtwo femal e rat s die dprio r t o th e appearanc e o f th e firs t tumor , leavin g seve nmale s an dnin e female s a t ris k fo r developin g rena l tumors . Inrat s receivin g 0. 1 percen t lea dacetat e inth e diet , th e earl y mortalit y

rat e wa s lowe r tha ni nth e correspondin g controls ; 3 treate drat s o f eac hse xdie dprio r t o th e appearanc e

o f th e firs t tumor , leavin g 1 3 rat s o f eac hse xa t ris k fo r developin g rena l

4 6P.6 0

tumors . Th e firs t kidney tumo r appeared1 8 t o 2 4 month s afte r initia l exposur e inanimal s receivin g 0. 1 percen t lea dsubacetat e inth e die t an d6 t o 1 2 month s i nfemale s o r 1 2 t o 1 8 month s inmale s receivin g 1 percen t i nth e diet . Th e incidenc e o f kidney

adenoma s an

dcarcinoma s wa s 5/1 3 inmale s an d6/1 3 in female s receivin g 0. 1 percen t lea dsubacetate . Th e incidenc e wa s 6/ 7 i nmale s

and7/ 9 infemale s receivin g 1 percen t lea dacetate . Combinin g th e sexes result s ina

nincidenc e o f 11/2 6 inrat s administere dth e 0. 1 percen t die t an d 13/1 6 i nrat s administere dth e 1 percen t diet . Althoug hth e numbe r o f animal s pe r dos e grou pwa s small , bot hsexe s wer e used , th e duratio no f exposur e wa s a t leas t 2 years , an

dtumo r inductio nwa s dose-related . 1.2.2.1.2 . Ma o an

dMolnar , 1967 . Fort y mal e Wista r rat s wer e administere d 1 percen t lea dsubacetat e i nth e fee dfo r thei r lifetimes . Thirtee nanimal s

wer e kille dbetwee n21 3 an d59 3 day s o f feeding ; th e remainin g animal s die d betwee n16 2 an

d67 7 days . Control s consiste do f 2 0 rat s fedth e basa l die t withou t lea dsubacetate . Th e kidney s o f al l animal s wer e subjecte dt o microscopi c examinatio nfo r detectio no f tumor s no t grossl y visible . Si xanimal s die do r wer e kille dprio r t o th e appearanc e o f th e firs t microscopi c kidney

tumo r o

nda y 30 5 (1 0 months ) o f feeding . Kidne y adenoma s o r carcinoma s wer e foun di n31/3 4 (9 1 percent ) animal s survivin g 30 5 days , 24/2 5 (9 6 percent ) animal s survivin g a t leas t 40 0 days , an d12/1 2 (10 0 percent ) animal s survivin g a t leas t 50 0 days . Th e strength s o f thi s study ar e th e lifetim e duratio no f exposur e an dmicroscopi c examinatio no f th e kidney . 1.2.2.1.3 . Has s e t al. . 1965 . Twenty-fou r mal e Charle s Rive r C D rat s wer e administere ddietar y

lea dsubacetat e plu s indole , linsee doil , o r N-2-fluorenylacetamid e (2AAF ) fo r 3 0 t o 7 4 weeks . Indol e wa s use dt o reduc e th e toxicit y

o f 2AAF , an

dlinsee doi l wa s use da s a carrier . Grou pI receive d

4 7P.6 1

0.0 6 percen t 2AA

F an d 1. 6 percen t indole ; grou p I I receive d 0. 5 t o 1. 0 percen t lea d subacetat e an

d indole ; grou p II I receive d lea d subacetate , indole , an d linsee d oil ; an

d grou p I

V receive d lea d subacetate , indole , linsee d oil , an d 2AAF . A contro l grou p wa s no t included . Al l animal s dyin g spontaneously , kille d whe nmoribund , o r kille d whe nexposur e wa s terminate d wer e processe d fo r gros s an d histopathologi c examination . Th e dat a wer e analyze d base d o ntumo r incidenc e afte r eithe r 3 0 t o 5 2 week s o r 5 ? t o 7 4 week s o f exposure . Rena l tumor s wer e no t reporte d ingrou p I . Amon g grou p I I animal s examine d betwee n3 0 an d 5 2 week s o f exposure , rena l adenoma s wer e foun d in8/1 3 (6 2 percent ) an

d adenocarcinoma s in3/1 3 (2 3 percent) . Amon g thos e examine d betwee n5 2 an

d 7 4 weeks , 11/1 1 animal s (10 0 percent ) had rena l adenoma s an d 8/1 1 (7 3 percent ) had adenocarcinomas . Th e overal l incidenc e wa s 19/2 4 (7 9 percent ) fo r adenoma s an d 11/2 4 (4 6 percent ) fo r carcinomas . Ingrou p II I rats , th e reporte d incidenc e wa s 0/1 1 fo r rena l adenoma s an d 1/1 1 ( 9 percent ) fo r adenocarcinoma s betwee n3 0 an d 5 2 week s an

d 20/3 9 (5 1 percent ) fo r adenoma s

an d 13/3 9 (3 3 percent ) fo r adenocarcinoma s betwee n5 2 an d 7 4 weeks , givin g a n overal l incidenc e o f 20/5 0 (4 0 percent ) fo r adenoma s an d 14/5 0 (2 8 percent ) fo r adenocarcinomas . Ingrou p I V animals , th e incidenc e wa s 10/3 2 (3 1 percent ) fo r

rena l adenoma s an

d 11/3 2 (3 4 percent ) fo r adenocarcinoma s betwee n3 2 an d 5 2 week s an

d 19/4 2 (4 5 percent ) fo r adenoma s an d 14/4 2 (3 3 percent ) fo r adenocarcinoma s betwee n5 2 an d 7 4 weeks , givin g a noveral l incidenc e o f 29/7 4 (3 9 percent ) fo r adenoma s an d 25/7 4 (3 4 percent ) fo r adenocarcinomas . Rena l cystoma s wer e found wit ha noveral l incidenc e o f 0/6 4 amon g grou p I , 22/2 4 (9 2 percent ) amon g grou p II , 30/5 0 (6 0 percent ) amon g grou p III , an d 37/7 4 (5 0 percent ) amon g grou p I V animals . Rena l tumor s induce d b y lea d subacetat e

wer e confine d t o th e cortex ; the y wer e slo

w growin g an

d ha d a lo w tendenc y

t o

4 8metastasize . Thi s study showe dtha t (1 ) rena l adenoma s an dcarcinoma s wer e induce di nrat s give ndietar y lea dsubacetate , (2 ) th e incidenc e o f bot h increase dwit hduratio no f exposure , an d(3 ) 2AAF di dno t potentiat e th e effect . Nonneoplasti c rena l toxicit y wa s show

nb y th e accumulatio no f intracytoplasmi c pigment , cytomegaly , an dintranuclea r inclusio nbodie s in tubula r epithelia l cells . Thes e change s wer e eviden t afte r 2 t o 3 month s o f
exposure . Th e inclusio nbodie s tende dt o decreas e durin g th e lat e phas e o f
exposur e an

dwer e no t foundinrena l tumo r cells . Tumor s wer e als o founda t othe r sites . On e papillom a o f th e rena l pelvi s

wa s foun di ngrou pI I andon e cholangiocarcinom a i ngrou pIII . Cerebra l glioma s wer e reporte dinthes e animal s wit hoveral l incidence s o f 3/6 4 ( 5 percent ) i ngrou pI , 2/2 4 ( 8 percent ) ingrou pII , 4/5 0 ( 8 percent ) ingrou p III , an d8/7 4 (1 1 percent ) i ngrou pIV . Sinc e control s wer e no t include di n th e study , th e statistica l significanc e o f thes e finding s i s uncertain . Inanothe r study , Oyas ue t al . (1970 ) als o reporte dth e incidenc e o f glioma s fro

m dat a collecte dfro

m variou s experiment s usin g rat s administere d 2AAF , lea dsubacetate , o r both . Inanimal s give n1 percen t lea dsubacetat e only , th e incidenc e o f glioma s wa s 2/1 7 (1 2 percent) , compare dwit h3/4 1 ( 7 percent ) inanimal s give nlea dsubacetat e an dindole , an

d6/7 2 ( 8 percent ) whe n2AAF wa s added . Inanimal s give n2AAF withou t lea dsubacetate , th e incidenc e range dfro

m 0 t o 6. 8 percent , wit ha noveral l incidenc e (al l experiment s pooled ) o f 12/48 7 (2. 5 percent) , compare d1/32 5 (0. 3 percent ) among poole dcontrols . Accordin g t o th e authors , th e differenc e i ntumo r incidence s betwee ncontrol s an

danimal s receivin g eithe r 2AAF , lea dsubacetate , o r bot h

wa s statisticall y

significant . Th e significanc e o f th e result s o f thi s stud y

4 9ar e questionabl e fo r a t leas t tw o reasons . First , th e result s reporte dwer e obtaine db

y poolin g th e dat a from severa l experiment s wit hpossibl y differin g protocols . Second , th e averag e surviva l time s fo r th e two group s o f control s

wer e 5 8 an

d6 0 weeks . Th e author s reporte dthat , inrat s administere d2AAF in combinatio nwit hothe r substances , developmen t of glioma s wa s usuall y delaye d unti l afte r 6 0 week s o f age . Consequently , whethe r th e control s die do r wer e killed , i t i s doubtfu l tha t mos t survive dlon g enoug hfo r glioma s t o appear . Ha dthe y live dlonger , th e incidenc e of glioma s incontro l rat s ma y hav e bee n higher . 1.2.2.1.4 . Kasprza k e t al. , 1985 . Mal e Sprague-Dawle y rat s (3 C pe r group )

wer e place dondiet s containin g 1 percen t lea dsubacetate , wit ho r withou t 0.3 , 1 , 3 , o r 6 percen t calcium acetate , fo r 7 9 weeks . Th e animal s wer e weighe d weekly . Al l animal s wer e necropsied . At th e en dof th e study , body weight s

wer e significantl y

reduce di

nal l exposur e groups : b y 1 9 percen t inth e grou p receivin g lea dsubacetat e alone , b y 7 percen t inthos e receivin g calcium acetat e alone , an

db y 2 6 t o 4 6 percen t inthos e receivin g lea dsubacetat e plu s 0. 3 t o 6 percen t calcium acetate . Relativ e weight s of th e kidney s an dlive r

wer e increase dinrat s fe dlea dsubacetat e alone ; th e additio nof calcium acetat e t o th e die t cause dfurthe r increase s i nrelativ e kidne y

weight s bu t no t i nrelativ e live r weights . Mortalit y wa s no t significantl y increased ; 29/3 0 rat s receivin g lea dsubacetat e alon e wer e aliv e whe nth e firs t tumor s appeare d

a t 5 8 weeks , an

d2 3 rat s wer e aliv e a t th e en dof th e study . O f th e animal s receivin g lea dacetat e plu s calcium acetate , 2 8 t o 3 0 wer e aliv e a t 5 8 weeks ,
an d2 6 t o 2 8 wer e aliv e a t th e endof th e study . Amon g animal s expose dt o lea dsubacetat e alone , adenoma s wer e foun din1 1 (3 8 percent ) an

dadenocarcinoma s in2 ( 7 percent) , fo r a noveral l incidenc e o f

5 0P.6 4

13/2 9 (4 5 percent) , compare dwit h0/3 0 i nunexpose danimals . Thi s increas e wa s highl y significan t ( p< 0.001) . Th e incidenc e o f adenocarcinoma s wa s increase d t o 17 , 24 , 23 , o r 2 5 percen t inanimal s receivin g lea dsubacetat e plu s 0.3 , 1 , 3 , o r 6 percen t calcium acetate , respectively . Th e tota l incidenc e o f rena l tumor s (adenoma s plu s adenocarcinomas ) increase dt o 70 , 62 , 73 , an d7 8 percen t respectively , inth e latte r fou r groups . Th e increas e inth e tota l incidenc e

o f rena l tumor s inanimal s give nlea dacetat e plu s 3 o r 6 percen t calcium acetat e wa s statisticall y significan t ( p< 0.0 3 o r p< 0.01 , respectively) , compare dwit hthos e receivin g lea dsubacetat e alone . No othe r tumor s wer e foun dinanimal s give nlea dsubacetat e only , an dno othe r exposure-relate d tumor s wer e foun di nth e othe r groups . Thi s study demonstrate s bot hth e carcinogenicit y

o f lea dsubacetat e an dth e enhancin g effec t o f calciu m acetat e

oncarcinogenesis . Kasprza k e t al . (1985 ) als o measure dth e lea dconten t inth e kidney s a t 7 9 weeks . The y

reporte dtha t inanimal s receivin g lea dsubacetat e alon e th e lea dconten t wa s 57 2 ug/ g o f dr y tissue . Additio no f calcium acetat e resulte d i na significan t decreas e i nth e lea dconten t inth e kidney , t o 16 2 ug/ g o f dry tissu e inanimal s receivin g 6 percen t calciu m acetate . Ther e wa s n o chang e in th e lea dconten t i nth e liver , suggesting , incontras t t o othe r report s (Meredit he t al. , 1977 ; Conra dan dBarton , 1978) , tha t th e decreas e inlea din th e kidne y

wa s no t du e t o a calcium-induce ddecreas e inabsorptio no f lea dfro m th e gastrointestina l tract . Th e decreas e i nlea d conten t inth e kidney , coinciden t wit hanincreas e i nth e incidenc e inrena l tumors , suggest s a n absenc e o f a correlatio nbetwee nth e concentratio no f lea di nth e kidne y

an d th e incidenc e o f rena l tumors .



### 5 11.2.2.1.5 . Hias a e t al. , 1983 . A ninitiation-promotio nstudy wa s carrie dou t i nwhic hmal e Wista r rat s wer e administere d50 0 o r 100 0 pp m o f N-ethyl-N-hydroxyethylnitrosamin e (EHEN ) ( a know ncarcinogen ) i nth e die t fo r 2 weeks , followe db

y 100 0 pp

m o f lea dsubacetat e fo r 2 0 weeks , an da basa l die t fo r a nadditiona l 1 0 weeks . Othe r group s receive dth e basa l diet , 50 0 o r 1000 pp m o f EHE N

alon e fo r 2 weeks , o r 100 0 pp m lea dsubacetat e fo r 2 0 weeks . Survivor s wer e kille d3 2 week s afte r th e star t o f th e study . Th e incidenc e o f rena l tumor s (adenoma s an dadenocarcinomas ) inth e variou s group s wa s a s follows : 0/2 4 inrat s receivin g th e basa l diet , lea d subacetat e alone , o r 50 0 pp m EHEN alone , 9/1 8 inrat s receivin g 100 0 pp m EHE N alone , 10/2 2 i nrat s receivin g 50 0 pp m EHEN an dlea d subacetate , an d17/1 7 i

n rat s receivin g 1000 pp m EHEN an dlea dsubacetate . Th e increas e i nincidenc e o f kidne y tumor s inrat s receivin g lea dsubacetat e an dEHEN wa s significantl y elevate dcompare dwit hanimal s tha t receive dEHEN alone . Kidne y

tumor s found i nrat s receivin g EHE N followe db

y lea dsubacetat e wer e large r tha nthos e found i nrat s receivin g EHEN alone . Th e primar y noncance r patholog y wa s minima l an

d

wa s i nth e form

o f dysplasti c lesions , whic happea r t o be forerunner s o f th e - tumors . Thi s study

indicate s tha t lea dsubacetat e ma y ac t a s a kidne y

tumo r promoter . 1.2.2.1.6 . Shira i e t al. , 1984 . A ninitiation-promotio nstudy wa s carrie dou t i nwhic hmal e Fishe r 34 4 rat s wer e administere d0. 1 percen t EHE N i nthei r drinkin g wate r fo r 1 week , followe db y O. I percen t lea dsubacetat e inth e die t fo r 3 5 weeks . Contro l group s include drat s give n0. 1 percen t EHE N o r 0. 1 percen t lea dsubacetat e only . N o rena l tumor s wer e foundinth e 2 5 rat s receivin g lea dsubacetat e alone , althoug heffect s suggestiv e o f earl y neoplasti c change s wer e observe di n6/2 5

5 2rats . I nrat s receivin g EHEN alon e 5/2 3 (2 2 percent ) develope drena l tumors . Combinatio no f EHEN

plu s lea dacetat e induce drena l tumor s i n13/2 5 (5 2 percent ) o f th e rats . Thes e result s indicat e tha t lea dsubacetat e ca nac t

a s a kidne y

tumo r promote r o r possibl y a s a cocarcinogen , an dconfirm s th e result s o f Hias a e t al . (1983) . 1.2.2.2 . Studie s inMice- - 1.2.2.2.1 . Va nEsc han dKroes , 1969 . Mal e an dfemal e Swis s mic e (2 5 o f eac h

sex ) wer e administere ddiet s containin g 0 percent , 0. 1 percent , o r 1 percen t lea dsubacetat e fo r 2 years . Al l survivin g animal s wer e kille d2 year s afte r initia l exposure . Th e 1 percen t die t wa s reduce dt o 0. 5 percen t o nda y 9 2 fo r male s andda y

11 4 o f feedin g fo r females ; nevertheless , b y thi s time th e surviva l rat e wa s to o lo w (abou t 1 0 femal e an d2 mal e survivors ) fo r a n analysi s o f long-ter m effects . Th e mortalit y rat e inanimal s receivin g th e 0. 1 percen t die' t wa s no t significantl y differen t fro

m controls , wit habou t 8 0 percen t survivin g a t leas t 1 year . No rena l tumor s wer e detecte dincontro l mice . Amon g animal s receivin g 0. 1 percen t lea dsubacetate , kidne y adenoma s wer e foundi non e femal e an dtwo males . Rena l carcinoma s wer e see ninfou r males . Amon g th e survivin g animal s receivin g th e hig hdietar y concentration , a kidne y carcinom a wa s foundi non e female . Whil e th e exposur e duratio nan dinitia l grou psiz e wa s adequate , excessiv e mortalit y

inth e high-dos e grou pan duncertaint y

regardin g th e numbe r

o f animal s a t ris k limite dth e strengt ho f thi s study . 1.2.2.2.2 . Stone r e t al. , 1976 . Strai nA/Stron g mal e an dfemal e mic e (2 0 pe r group ) wer e administere dintraperitonea l injection s o f lea dsubacetat e (dissolve dintricaprylin ) thre e time s pe r wee k fo r 5 weeks . Th e tota l dose s

wer e 15 0 mg/k g (maximu m tolerate ddose) , 7 5 mg/kg , an d3 0 mg/kg ; control s

5 3receive d th e vehicl e tricapryli nthre e time s pe r wee k fo r 8 week s o r wer e lef t

untreated . Al l animal s wer e kille d 3 0 week s afte r initia l exposure . Th e lung s

wer e examine d fo r nodules ; othe r organs , includin g th e kidneys , wer e examine d fo r abnorma l lesions ; an d grossl y

abnorma l tissue s wer e examine d histologically . Th e result s wer e presente d a s th e percentag e o f mic e wit hlung tumor s an

d th e averag e numbe r o f tumor s pe r mouse . Th e respons e inth e differen t group s wa s a s follows : untreate d controls , 6/1 9 (31 . percent) , 0.2 8 + 0.0 7 tumors/mous e (mea n+ standar d error) ; tricapryli ncontrols , 8/1 8 (4 4 percent) , 0.5 0 + 0.1 2 tumors/mouse ; 3 0 mg/kg , 6/1 7 (3 5 percent) , 0.3 5 tumors/mouse ; 7 5 mg/kg , 5/1 2 (4 2 percent) , 0.5 0 ± 0.1 4 tumors/mouse ; 15 0 mg/kg , 11/1 5 (7 3 percent) , 1.4 7 + 0.3 8 tumors/mouse . Th e lun g tumo r respons e wa s significantl y increase d onl y

a t th e highes t dose . Rena l tumor s wer e no t described . I f gros s lesion s wer e no t observed , the nth e kidney s wer e no t examine d fo r microscopi c lesions . Thi s study show s tha t lead subacetat e i s capabl e o f inducin g tumor s a t anothe r sit e an d b y anothe r rout e

o f exposure . Althoug hth e kidney s wer e apparentl y no t examine d microscopically , positiv e response s inthi s orga nwer e unlikel y du e t o th e smal l doses , approximatel y

5 m g pe r mous e a t th e highes t level . 1.2.2.3 . Studie s inHamsters- - 1.2.2.3.1 . Va nEsc han d Kroes , 1969 . Golde nhamster s (4 5 o r 4 6 pe r group , abou t equall y

divide d betwee nsexes ) wer e administere d 0. 5 percen t dietar y lead subacetate , 0. 1 percent , o r a basa l die t withou t lea d subacetat e fo r 2 years . Al l survivin g animal s wer e kille d whe nexposur e wa s terminated . Th e mortalit y rat e wa s increase d inbot hexpose d groups ; approximatel y 5 0 percen t o f th e animal s receivin g th e 0. 1 an d 0. 5 percen t die t survive d a t leas t 40 0 day s an d 30 0 days , respectively , an d a few animal s survive d 60 0 days .
5 4P.6 8

N o rena l tumor s o r earl y indication s o f tumo r growt hwer e foundineithe r expose do r contro l animals . Intranuclea r inclusio nbodie s an dothe r sign s o f

rena l toxicit y

wer e observed . I

naddition , "ova l cel l type " bil e duc t proliferatio nwa s see ni ntwo male s an dtwo female s receivin g th e 0. 1 percen t diet , an dinfou r female s an dthre e male s receivin g th e 0. 5 percen t diet . 1.2.2.4 . Studie s i nRabbits- - 1.2.2.4.1 . Has s e t al. , 1965 . Mal e Ne w Zealan dalbin o rabbit s an dals o a few Germa nChecke r andBelgia nHar e strain s (sexunspecified , 5 t o 3 5 pe r dos e group ) wer e give n0. 5 t o 1 percen t dietar y lea dsubacetat e alone , o r i n combinatio nwit h2AAF , linsee doil , cholesterol , chloroform , carbo n tetrachloride , o r vitami nD fo r 3 t o 7 8 weeks . Rena l tumor s wer e no t foun din

an y rabbit s receivin g lea dsubacetat e eithe r alon e o r i ncombinatio nwit hothe r substances . Cytoplasmi c pigment , cytomegaly , intranuclea r inclusio nbodies , cellula r degeneration , an

danaplasi a wer e see ninth e kidneys . Th e earlies t change s

occurre dabou t 8 t o 1 2 week s afte r initia l exposure ; permanen t damage , whic h becam e eviden t afte r abou t 2 8 t o 3 6 weeks , increase di nseverit y u pt o abou t : 5 5 weeks , the nlevele doff . Mil dt o moderat e hemosiderosi s wa s observe di nth e liver s o f animal s give nlea dsubacetate . Unde r th e condition s o f thi s study , lea dwa s no t show

nt o b e carcinogeni c i nrabbits ; however , th e duratio no f
exposur e wa s probabl y inadequat e fo r detectin g cance r inrabbits , sinc e thi s specie s normall y

live s u

pt o 7 years . 1.2.3 . Lea dOxid e (CA S No . 1317-36-8 ) 1.2.3.1 . Studie s inHamsters- - 1.2.3.1.1 . Kobayash i an dOkamoto . 1974 . Group s o f 1 5 mal e an d1 5 femal e Syria nhamster s wer e administere d1 m g o f lea doxide , 1 m g o f benzo[a]pyrene ,

5 5P.6 9

o r a combinatio no f 1 m g o f eac hsuspende d in0. 2 m L o f 0. 5 percent carboxymethylcellulose-isotoni c salin e solutio nb y intratrachea l instillatio n weekl y fo r 1 0 weeks . Control s wer e administere d th e vehicl e o r wer e untreated . Th e animal s wer e kille d 6 0 week s afte r initiatio no f exposur e o r whe nmoribund . Th e animal s wer e autopsied , an d variou s tissue s wer e processe d fo r microscopi c examination . Bot hcompound s an

d th e combinatio ninduce d alveola r metaplasi a inth e lungs , bu t lea d oxid e wa s th e mos t effective . Neithe r compoun d alon e induce d tumor s inth e lung , bu t th e combinatio ninduce d adenoma s innin e animal s an d a n adenocarcinom a inanother . Th e tumor s wer e locate d inth e periphera l are a o f th e lung , indicatin g bronchiolar-alveola r origin . Untreate d o r vehicl e control s develope d n o tumors . Th e study showe d tha t lead oxid e ma y ac t a s a cocarcinogen . Thi s study provide s some evidenc e fo r th e carcinogenicit y o f anothe r lea d compoun d b y anothe r rout e o f exposure . 1.2.4 . Lea d Phosphat e (CA S No . 7446-17-7 ) 1.2.4.1 . Studie s inRats- - 1.2.4.1.1 . Ro e e t al. , 1965 . Mal e albin o C B Wista r rat s wer e give n subcutaneou s (subcutaneous ) o r intraperitonea l injection s o f technica l grad e lea d orthophosphat e (i nwater ) ove r a perio d o f 3 4 weeks , accordin g t o th e followin g protocols : grou p A receive d a tota l dos e o f 45 0 m g pe r ra t give nin dose s o f 2 5 o r 12. 5 m g each ; grou p B receive d 14 5 m g pe r ra t indose s o f 5 m g each ; grou p C receive d 2 9 m g pe r ra t indose s o f 1 m g each . Becaus e o f insufficien t information , dail y weight-normalize d dose s coul d no t b e calculated . Th e animal s wer e kille d 20 0 day s fro m th e star t o f exposure , whe n moribund , o r whe nwit hobviou s neoplasms . Rena l tumor s originatin g inth e

rena l corte xwer e found i ngroup s A an d B . Ingrou p A , 3/2 4 rat s survive d

5 6P.7 0

20 0 days , wit h2 developin g rena l tumors . I ngrou p B , 23/2 4 rat s survive d 20 0 days , wit h1 4 developin g rena l tumor s ( 7 adenomas , 6 adenocarcinomas , an d 1 undifferentiate d malignan t tumor) . I ngrou p C , 23/2 4 rat s survive d 20 0 days , wit hr;on

e developin g rena l tumors . On e contro l ra t develope d a n undifferentiate d malignan t tumo r inth e kidney , an d anothe r develope d a transitional-cel l carcinom a arisin g inth e rena l pelvis . Additiona l group s o f rat s an d appropriat e control s wer e injecte d wit heithe r testosteron e propionat e

o r xanthopterin , bu t neithe r influence d th e incidenc e o f rena l tumors . Lea d treatmen t wa s no t associate d wit htumor s o f othe r organ s o r tissues . Chroni c nephriti s wa s present i nal l treate d rats , bu t ther e wa s n o correlatio nbetwee n th e severit y

o f th e conditio nan d th e tumo r response . Thi s stud y provide s goo d evidenc e fo r th e carcinogenicit y o f lead phosphate . 1.2.4.1.2 . Zollinger , 1953 . Group s o f 1 0 whit e rat s (27 0 animal s total ; sex

an d strai nno t reported ) wer e administere d subcutaneou s injection s o f 1 m L o f a 2 percent lea d phosphat e suspensio n(2 0 m g lea d phosphate ) onc e pe r wee k fo r u p t o 1 6 months . Accordin g t o th e authors , th e tota l lea d dos e varie d fro m 4 0 t o 76 0 m g pe r anima l dependin g o ntime o f death . Fort y rat s serve d a s controls . Som e o f th e animal s wer e kille d durin g th e exposur e period , other s a t a n unspecifie d time perio d afte r th e exposur e period . Th e rat s wer e autopsied ,
an d th e kidney s o f 11 2 wer e processe d fo r microscopi c examination . Th e mortalit y

wa s high . Rena l cortica l tumor s wer e observe d in2 1 animals . Th e earlies t tumo r wa s found betwee nth e thir d an d fourt hmonth s o f exposure . Amon g animal s survivin g 1 0 month s o r longer , adenomas , papillomas , o r cystadenoma s o f th e rena l corte x

wer e detecte d in19/2 1 animals . Th e majorit y o f th e tumor s coul d be palpated . Carcinoma s wer e observe d inthre e rats , two o f whic hmetastasize d t o th e


### 5 7P.7 1

peritoneum

o r rena l pelvis . Onl y 5/1 8 animal s examine d betwee nth e 15t han d 16t hmonth s o f exposur e wer e tumo r free . Th e lowes t dos e tha t induce d a tumo r

wa s 12 0 mg . A

direc t relationshi p betwee nth e lea d dos e an d tumo r incidenc e coul d not , however , b e established . Th e tumo r incidenc e incontrol s wa s no t reported . Nonneoplasti c change s occurrin g intreate d animal s include d rena l cortica l cyst s o f varie d siz e an d appearanc e inth e earl y phas e o f treatmen t

an d inth e late r phase , atypica l a s wel l a s hyperplasti c change s o f th e tubula r epithelium . Mos t animal s had enlarge d livers . Th e stud y provide s additiona l evidenc e fo r th e carcinogenicit y o f lead phosphate . Weaknesse s o f th e stud y includ e inadequat e reportin g o f th e dos e administered , smal l numbe r o f animal s survivin g t o th e en

d o f th e study , an

d a lac k o f examinatio no f tissue s othe r tha nth e kidne y

t o determin e i f tumor s ma y hav e bee ninduce d a t mor e tha non e site . Th e dat a wer e no t evaluate d statistically . 1.2.5 . Lea d Nitrat e (CA S No . 10099-74-8 ) 1.2.5.1 . Studie s inRats- - 1.2.5.1.1 . Schroede r e t al. , 1970 . A grou p o f 5 2 mal e Long-Evan s rat s wer e expose d t o 2 5 pp

m o f lea d nitrat e inthei r drinkin g water . Th e wate r als o containe d 1 pp

m trivalen t chromiu

m an d othe r metal s a s nutritiona l supplements . ( A previou s study

o f chromium-deficien t rat s give nth e sam e dos e o f lea d showe d earl y mortalit y

an d a shortene d lif e span , whic hwa s correcte d b y chromiu

m supplement s [Schroede r e t al. , 1965]. ) Thi s wa s th e onl y sourc e o f drinkin g wate r fo r th e entir e lifetim e o f th e animals . Control s receive d unsupplemente d water . Th e result s showe d tha t bod y weight s an

d surviva l wer e no t affecte d b y lead . Th e investigator s attribute d thi s observatio nt o th e protectiv e effect s

o f chromium

agains t lea d toxicity . Mea nlea d conten t inkidne y wa s 2.6 5 ug/ g

5 8P.7 2

o f tissu e i ntreate danimal s compare dwit h0.5 0 ug/ g o f tissu e incontrols . Accordin g t o th e authors , lea dnitrat e wa s "no t tumorigeni c a s evidence db y visibl e tumor s a t necropsy. " Microscopi c examinatio no f th e kidney s wa s no t performed . Furthermore , th e dos e o f lea dwa s low . 1.2.6 . Lea dNaphthenat e (CA S No . 61790-14-5 ) 1.2.6.1 . Studie s inMice- - 1.2.6.1.1 . Baldwi ne t al. . 1964 . Th e lea dnaphthenat e fractio no f a nengin e oi l fractio nwa s teste dfo " carcinogeni c activit y inth e ski no f mal e albin o (Schofiel dstrain ) mice . Th e fraction , whic hwa s use da s a 2 0 percen t (b y volume ) solutio ninbenzene , wa s applie dt o th e dorsa l ski no f th e mic e onc e o r twic e pe r wee k fo r 1 2 months . Th e tota l dos e o f lea dnaphthenat e administere d

wa s equa l t o 6 mL . Th e animal s wer e kille da t 1 8 months . Ski ntumor s wer e observe di nonl y

2 o f 5 0 animal s treate dwit hlea dnaphthenate , bu t extensiv e

rena l damag e alon g wit hth e presenc e o f fou r rena l adenoma s an don e rena l carcinom a wa s reported . A solven t contro l wa s no t include dinthi s study ; therefore , th e carcinogeni c o r potentiatin g effec t o f benzen e coul dno t be assessed . A

statistica l analysi s wa s no t performed . Nevertheless , sinc e kidne y lesion s induce db

y lea dnaphthenat e wer e identica l t o thos e induce db y othe r lea dcompound s administere dorally , an dsinc e th e critica l targe t orga n fo r benzen e i s no t th e kidney , th e result s ar e strongl y suggestiv e o f a carcinogeni c effect . 1.2.7 . Lea dDimethyldithiocarbamat e (CA S No . 19010-66-3 ) 1.2.7.1 . Studie s inRats- - 1.2.7.1.1 . Nationa l Cance r Institute , 1979 . A comprehensiv e 2-yea r carcinogenicit y

study o f lea ddimethyldithiocarbamat e (als o know na s ledate )

wa s conducte dinmal e an dfemal e Fische r 34 4 rats . Th e compoun dwa s 9 8 percen t

5 9pur e andcontaine d4 5 percen t lead . Th e concentratio no f lea duse di nth e

stud y wa s estimate dfrom

a 7-wee k range-findin g study i nwhic hrat s wer e give n dietar y lea ddimethyldithio - carbamat e a t dose s rangin g upt o 50 0 pp m (th e lowe r dos e rang e wa s no t reported) . Toxicit y wa s assesse db

y relevan t histopathologi c findings . Nephrotoxicit y wa s see na s hypertroph y o f th e epithelium

o f th e proxima l tubule s accompanie db y nuclea r swellin g andth e presenc e o f eosinophili c nuclea r inclusio nbodies . Thes e lesion s wer e moderat e i nrat s a t 50 0 ppm , sligh t t o moderat e a t 25 0 ppm , mil da t 12 5 ppm , minima l a t 6 2 ppm , andabsen t a t lowe r doses . Hematopoieti c change s wer e sligh t t o mil d i nrat s give n12 5 t o 50 0 ppm . Base donthes e results , 2 5 an d5 0 pp m wer e selecte da s th e lo w andhig h dose s fo r th e chroni c studies . Al l expose dgroup s wer e compose do f 5 0 animal s

o f eac hsex , an

dage-matche dcontro l group s wer e compose do f 2 0 animal s pe r
sex . Th e rat s remaine donth e diet s fo r 10 4 weeks . Body weight s an

dclinica l examination s wer e performe da t regula r intervals ; gros s an dhistopathologi c examination s wer e performe donal l animals . Mortalit y an dtumo r incidenc e dat a

wer e analyze dstatistically . Body weigh t gai nwa s no t significantl y affected ,
and2-yea r surviva l wa s equa l t o o r greate r tha n7 0 percen t i nmale s and female s a t bot hdoses . Therefore , surviva l rate s wer e sufficien t fo r analysi s

o f late-developin g lesions . Neoplasm s foun dinthes e animal s occurre dinequa l frequenc y inbot h
expose dan

dcontro l animals . N o rena l tumor s occurre dineithe r expose do r contro l animals . Glioma s wer e foun dinon e high-dos e femal e an di non e high andon e low-dos e mal e rat . Nonneoplasti c rena l lesion s wer e no t induce dan d intranuclea r inclusio nbodie s wer e no t seen . Hyperplasi a o f th e rena l pelvi c epithelium

wa s see ni non e low-dos e male .
6 0Thi s study wa s generall y

wel l designed , althoug hdat a o nfoo d consumptio n

wa s lacking , an

d lea d conten t inselecte d tissue s wa s no t analyzed . Th e weight-normalize d dose s wit hrespec t t o th e amoun t o f lead , however , wer e ver y low compare d wit hothe r studie s showin g nephrotoxicit y an d carcinogenicity . Nevertheless , th e appearanc e o f rena l lesion s inrat s give nhighe r dose s inth e range-findin g study

show s that , lik e othe r carcinogeni c lea d compounds , lea d dimethyldithiocarbamat e i s capabl e o f inducin g nephrotoxicity , an d highe r dose s

ma y hav e elicite d a carcinogeni c response . Th e author s conclude d tha t th e absenc e o f an

y toxi c sign s i nth e expose d animal s a s wel l a s th e lac k o f significan t mortalit y an d weigh t depressio nsuggeste d tha t th e animal s ma y hav e tolerate d highe r doses , tha t is , th e maximu m tolerate d dos e (MTD ) wa s no t reached . Therefore , thi s study i s considere d t o b e inadequat e fo r definitivel y evaluatin g th e potentia l carcinogenicit y o f lead dimethyldithiocarbamate . 1.2.7.2 . Studie s inMice- - 1.2.7.2.1 . Bionetic s Researc hLabs , Inc. , 1968 . A nevaluatio no f th e potentia l carcinogenicit y o f lea d dimethyldithiocarbamat e wa s performe d intw o strain s o f mice , B6C3F 1 an d B6AKF1 , administere d th e tes t compoun d eithe r b y subcutaneou s injectio no r orally . Inth e ora l study , lea d dimethyldithiocarbamat e suspende d in0. 5 percen t gelati nwa s administere d t o th e mic e dail y

fro m 7 t o 2 8 day s o f age , vi a gavage , a t a dos e o f 46. 4 mg/kg'd . Dosin g wa s continue d afte r da y 2 8 b y administerin g th e compound inth e die t a t 13 0 ppm . Th e animal s wer e expose d unti l the y wer e 1 8 month s o f
ag e a t whic htime the y wer e kille d an

d necropsied , an

d selecte d tissue s wer e processe d fo r histopathologi c examination . Animal s expose d subcutaneousl y wer e injecte d onc e a t 2 8 day s o f ag e wit h100 0 mg/k g o f lead dimethyldithiocarbamat e



### 6 1suspende d in0. 5 percen t gelatin . Thes e animal s wer e als o kille d whe nthe y

wer e 1 8 month s o f age ; the y wer e necropsie d an

d th e tissue s wer e processe d fo r histopathologi c examination . Vehicl e an d untreate d contro l group s wer e forme d b y poolin g th e control s fro m al l othe r chemical s teste d a t th e same time . Th e combine d control s fo r al l tes t compound s give norall y wer e a s follows : 14 6 mal e an d 17 1 femal e B6C3F 1 mic e an d 17 5 mal e an

d 16 6 femal e B6AKF 1 mice . Amon g orally-treate d mal e B6C3F 1 mice , 5 o f 1 6 animal s (3 1 percent ) survivin g t o 1 8 month s develope d typ e A reticulu

m cel l sarcomas , wherea s onl y 1 2 o f 14 6 control s (8. 2 percent ) develope d th e same tumor . No othe r neoplasm s occurre d inmor e tha non e o r tw o animal s give nth e compoun d orally . Th e tota l numbe r o f control s fo r tes t compound s injecte d subcutaneousl y wa s a s follows : 5 4 mal e

an d 6 2 femal e B6C3F 1 mic e an d 5 6 mal e an

d 6 0 femal e B6AKF 1 mice . Amon g animal s injecte d subcutaneousl y wit hlea d dimethyldithiocarbamate , n o exposure-relate d neoplasm s wer e found . Onl y 1 o f 1 5 ( 7 percent ) expose d an d 5/5 4 ( 9 percent ) contro l B6C3F 1 male s survivin g t o 1 8 month s develope d typ e A reticulu

m cel l

sarcomas . Th e onl y

othe r tumor s found wer e pulmonar y adenoma s intw

o mal e an

d two femal e B6C3F 1 mic e an d on e mal e an

d on e femal e B6AKF 1 mouse . Thi s study , show s tha t lea d dimethyldithiocarbamat e administere d orall y ma y als o induc e reticulum

cel l sarcoma s i nmice . Sinc e th e grou p siz e wa s smal l an d effect s

wer e no t see ninfemale s o r inmic e expose d subcutaneously , th e result s ar e considere d t o b e onl y suggestive . 1.2.7.2.2 . Nationa l Cance r Institut e (NCI) , 1979 . A comprehensiv e 2-yea r carcinogenicit y

stud y o f lea d dimethyldithiocarbamat e wa s conducte d inmal e an d femal e B6C3F 1 mice . Th e compoun d wa s 9 8 percen t pur e an d containe d 45. 2 percen t lead . Th e concentratio no f lead use d inth e study wa s estimate d fro m a 7-wee k range-findin g stud y inwhic hrat s an

d mic e wer e give ndietar y

6 2P.7 6

lea ddimethyldithiocarbamat e a t dose s rangin g u pt o 50 0 pp

m (th e lowe r dos e rang e wa s no t reported) . Toxicit y wa s assesse db

y histopathologi c findings . Intranuclea r inclusio nbodie s an dvacuola r degeneratio no f th e proxima l tubula r epithelium

wer e observed . Thes e lesion s wer e sligh t t o moderat e a t 25 0 pp m an d sligh t a t 6 2 an

d12 5 ppm . Base donthes e results , 2 5 an d5 0 pp m wer e selecte da s th e low an dhig h dose s fo r th e chroni c studies . Al l expose dgroup s wer e compose do f 5 0 animal s

o f eac hse xan

dage-matche dcontro l group s wer e compose do f 2 0 animal s pe r sex . Th e mic e remaine donth e diet s fo r 10 5 weeks . Body weight s an

dclinica l examination s wer e performe da t regula r intervals ; gros s an dhistopathologi c examination s wer e performe do nal l animal s tha t die do r wer e kille dwhe n moribun do r a t termination . Mortalit y an dtumo r incidenc e dat a wer e analyze d statistically . Body

weigh t gai nwa s no t significantl y affected , an

dsurviva l

wa s equa l t o o r greate r tha n7 5 percen t fo r al l dos e groups . Therefore , surviva l rate s wer e sufficien t fo r analysi s o f late-developin g lesions . Neoplasm s foun dinthes e animal s occurre dwit happroximatel y equa l frequenc y

i nexpose dan

dcontro l animals ; n o rena l tumor s wer e foun dinany .... . group . On e gliom a appeare dinon e mal e give nth e low dose . Othe r neoplasti c lesion s wer e o f singl e o r low occurrence . Nonneoplasti c rena l lesion s o r intranuclea r inclusionbodie s wer e no t reported . Thi s study

satisfie dalmos t al l th e requirement s use dt o evaluat e studie s fo r carcinoge nris k assessment , wit hth e exceptio no f adequat e doses . I t appear s tha t th e MT D wa s no t reached , becaus e th e dose s o f lea d dimethyldithiocarbamat e di dno t resul t i nsignifican t weigh t depression , mortality , o r pathology . Dose s wer e als o les s tha nthos e use dinth e ora l BR L (1968 ) study . Therefore , thi s study i s considere dt o b e inadequat e fo r

6 3definitivel y evaluatin g th e potentia l carcinogenicit y o f lea d dimethyldithiocarbamate . 1.2.8 . Tetraethy l Lea d(CA S No . 78-00-2 ) 1.2.8.1 . Studie s i nMice- - 1.2.8.1.1 . Epstei nan dMantel , 1968 . Mal e an dfemal e random-bre dSwis s mic e (ICR/Ha ) wer e administere dsubcutaneou s injection s o f tetraethy l lea ddissolve d i ntricaprylin . Th e mic e wer e injecte daccordin g t o th e followin g protocol : grou p1 (12 4 mice ) receive dtricapryli nalone ; grou p2 (6 9 mice ) receive don e injectio no f 2. 0 m

g o f tetraethy l lea do nda y 1 afte r birth ; grou p3 (9 2 mice ) receive d0. 2 m

g o nday s 1 an

d7 , an d0. 4 m g onday s 1 4 and21 ; grou p4 (10 9 mice ) receive d0. 1 m g onday s 1 an

d7 , an d0. 2 m g o nday s 1 4 an

d21 . Th e study

wa s terminate dafte r 4 9 t o 5 1 weeks . Mortalit y wa s yery

highwit h100 , 92 , an d 2 0 percen t o f th e animal s ingroup s 2 , 3 , an d4 , respectively , dyin g prio r t o weaning . Lymphoma s wer e observe dinfemal e mic e ingroup.4 , wit ha nincidenc e o f 5/4 1 (compare dwit h1/8 9 amon g controls , p< 0.02 ) a t 3 6 weeks . Unlik e othe r lea dcompounds , tetraethy l lea ddi dno t induc e nephrotoxi c lesion s o r rena l -.%
tumors . A

limitatio no f thi s study wa s th e hig hearl y

mortalit y

rate , leavin g

ver y fe w animals , o r none , fo r detectio no f lat e lesions . Whil e rena l tumor s

wer e no t detected , th e duratio no f thi s study ma y hav e bee ninadequate . Thi s stud y di dshow

tha t tetraethy l lea dca ninduc e lymphoma s inmice . 1.2.9 . Ambien t Lea d Kilha m e t al . (1962 ) studie dtissue s o f wil dNorwa y rat s trappe da t a tras hdump . Thi s dum pburne do r smoldere dcontinuously . A s a result , th e animal s a t thi s locatio nlive dunde r a constan t pal l o f smoke . Th e author s considere dtha t a majo r portio no f th e exposur e t o an y toxicant s presen t wa s

6 4P.7 8

th e resul t o f smok e inhalation . Intak e o f toxicant s vi a contaminate dgroun d water , however , canno t b e rule dout . A variet y o f pathologica l effect s wa s see ninth e kidney s o f al l 6 2 adul t rat s examine dupo ncapture . Thes e include dth e presenc e o f nuclea r inclusio n bodies , cellula r destruction , an dfoca l hyperplasi a inth e proxima l convolute d tubule s o f th e kidneys . Additionally , kidne y carcinoma s wer e foun di nabou t 5 percen t o f th e rats . Thes e tumor s wer e histologicall y an dbiologicall y malignant . The y

ofte ninvade dextensively , destroyin g adjacen t rena l tissue . Severa l line s o f evidenc e indicate dtha t th e toxican t responsibl e fo r thes e effect s wa s lead . Firs t o f all , lea dwa s presen t inmuc ho f th e refus e insuc hlandfill s (fo r example , storag e batteries) . Secondly , th e natur e o f th e pathologica l effects , especiall y th e presenc e o f nuclea r inclusio nbodies , i s typica l o f lea dexposure . Thes e response s wer e als o show nt o b e relate dt o exposur e intha t first-generatio noffsprin g o f thes e rats , whic hwer e maintaine di nclea nair , di dno t hav e inclusio nbodies . Finally , kidne y lea d level s wer e greatl y

increase dinrat s examine dsoo nafte r trapping . 1.2.10 . Discussio n Thirtee nstudie s wer e reporte dinwhic hth e carcinogenicit y o f lea d acetat e wa s tested . Inseve no f thes e studie s th e lea dacetat e wa s administere dt o rat s inth e feed . Th e cumulativ e dos e o f lea dadministere di n thes e set s o f experiment s range dfro m les s tha n0. 1 g t o abou t 6 3 g . Increase s i nkidne y

tumo r incidence s wer e generall y detecte da t lifetim e dose s inexces s

o f 7 g o r more . Inth e studie s conducte db y AP I (1971 ) th e dos e leve l inducin g tumor s wa s no t reported , bu t base do npathology , probabl y occurre di nth e high dos e grou preceivin g a lifetim e dos e o f 6 g . Inth e Zawirsk a an dMedra s (1972 ) studies , kidne y

tumor s wer e reporte da t cumulativ e dose s o f slightl y les s tha n

6 5P.7 9

1 g . Inthi s study , however , th e significanc e o f th e result s ar e rendere d somewha t uncertai nb y a lac k o f contro l data . Positiv e result s wer e reporte d i non e o f two experiment s wit hrat s expose d t o lea d acetat e vi a drinkin g water . I nth e positiv e study

(Kolle r e t al. , 1985 ) th e cumulativ e lea d dos e wa s ove r 3 0 g , compare d wit honl y 0.0 5 g inthe negativ e study

(Kanisawa an

d Schroeder , 1969) . Possibl e inductio no f lymphocyti c leukemi a occurre d inmic e dose d wit ha s littl e a s 0. 1 g o f lead vi a th e drinkin g wate r (Blakley , 1987) . Negativ e result s inmonkey s an d dog s wer e likel y du e t o inadequat e exposur e duration s (Aza r e t al. , 1973 ; API , 1971) . Amon g th e lea d acetat e studies , th e mos t rigorou s on e wa s conducte d b y Aza r e t al . (1973) . Fift y rat s pe r se xwer e expose d t o si xdifferen t lea d concentration s inth e feed , resultin g incumulativ e dose s o f 0. 1 t o 1 4 g . Th e investigator s observe d clinica l appearanc e an d behavior ; recorde d foo d consumption , growt han d mortality ; assesse d reproduction ; an d analyze d bloo d specimen s fo r re d cel l counts , hemoglobin , hematocrit , stipple d cel l count , prothrombi ntime , alkalin e phosphatase , ure a nitrogen , glutamic-pyruvat e transaminase , an

d albumin-to-globulin-ratio . Th e activit y o f th e enzyme delta aminolevulini c aci d dehydras e (ALA-D ) inth e bloo d an d th e excretio no f it s substrat e delta-aminolevulini c aci d (d-ALA ) inth e urin e wer e als o determined . A thoroug hnecropsy , includin g bot hgros s an d histologi c examination , wa s performe d onal l animals . Reproductio nwa s als o assessed . I nthi s study tumorigeni c response s wer e see na t cumulativ e dose s o f 7 g o r more . Th e carcinogenicit y

o f lea d subacetat e wa s teste d in1 0 separat e experiments . O f th e si xra t studie s inwhic hth e agen t wa s administere d inth e feed , fou r wer e positive ; th e othe r two teste d positiv e fo r tumo r promotion , bu t wer e negativ e fo r direc t inductio no f tumor s in3 2 t o 3 5 weeks . I nth e

6 6P.8 0

latte r tw

o studie s (Hias a e t al. , 1983 ; Shira i e t al. , 1984) , cumulativ e dose s

o f 2 t o 3 g wer e use dcompare dwit h1 0 g o r mor e inth e othe r fou r positiv e studies . Significan t increase s inkidne y tumo r incidence s wer e reporte dfo r mic e administere dcumulativ e dose s o f lea dsubacetat e o f 2 g o r mor e i nth e fee d(VanEsc han

dKroes , 1969) , bu t muc hlowe r dose s wer e successfu l whe nmic e

wer e administere dth e agen t b y intraperitonea l injectio n(Stone r e t al. , 1976) . Tumo r inductio nwa s no t reporte di nhamster s administere dlea dsubacetat e in th e fee da t a lifetim e dos e o f abou t 4 g (VanEsc han dKroes , 1969) . Negativ e result s wer e reporte di na 78-wee k rabbi t study a t concentration s o f upt o 1 percen t i nth e die t (Has s e t al. , 1965) . Sinc e rabbit s ma y liv e fo r 6 t o 7 years , however , th e exposur e duratio nwa s considere dinadequat e fo r evaluatin g th e effect s o f lifetim e exposure . Amon g th e lea dacetat e o r subacetat e studie s inrats , th e lifetim e dose s inducin g detectabl e increase s intumo r incidences , wit hth e exceptio no f th e Zawirsk a an

dMedra s (1972 ) study , range dfro m 7 g t o mor e tha n6 0 g . A t a cumulativ e dos e o f 2 t o 3 g , evidenc e fo r tumo r promotio nwa s als o see ninrat s treate dwit hlea dsubacetate . I ntw o o f thre e studie s wit hmic e dose dorally , th e effectiv e level s di dno t diffe r greatl y fro m tha t o f rat s i f difference s i n body weigh t ar e take nint o account . Inth e Stone r e t al . (1976 ) study , in whic heffectiv e dose s wer e ver y small , no t onl y

wa s a geneticall y

susceptibl e strai nused , bu t th e agen t wa s administere dvi a intraperitonea l injection , wit h possibl y mor e efficien t uptake . Th e lac k o f respons e i nhamster s give na tota l dos e o f abou t 4 g , a n

amoun t a s larg e o r large r ona mg/k g body weigh t basi s t o tha t use dinman y o f th e positiv e ra t studies , suggest s tha t th e hamste r ma y b e les s sensitiv e tha n rat s o r mic e t o th e carcinogeni c effect s o f lead . However , i t shoul db e note d

6 7P.8 1

tha t hamster s wer e teste dmuc hles s extensivel y tha nrats . I t shoul dals o b e emphasize dtha t a lac k o f detectabl e response s a t lowe r lifetim e dose s i s no t proo f o f noncarcinogenicit y a t thes e levels , o r a basi s t o demonstrat e a threshold , bu t merel y suggest s tha t th e study ma y lac k th e sensitivit y fo r detectio no f positiv e response s (e.g. , th e likel y cas e fo r a low

potenc y carcinogen) . A variet y o f othe r lea dcompounds , whil e les s extensivel y tested , hav e als o bee nshow

nt o induc e tumor s inlaborator y animals . Thes e includ e lea d phosphat e administere dvi a subcutaneou s o r intraperitonea l injectio ni nrat s a t cumulativ e dose s o f les s tha n1 g (Ro e e t al. , 1965 ; Zollinger , 1953) , lea d naphthenat e vi a ski npaintin g i nmice , tota l lea ddos e unknown(Baldwi ne t al. , 1964) , tetraethy l lea dvi a subcutaneou s injectio ni nmic e a t cumulativ e dose s

a s low a s 0. 4 m

g (Epstei nan

dMantel , 1968) , an

di nmic e treate dorall y wit h lea ddimethyldithiocarbamat e a t a cumulativ e dos e o f abou t 0. 2 g (BRL , 1968) . Lea doxide , abou t 0.0 1 g , als o acte da s a cocarcinoge nwit hbenzo[a]pyren e in th e inductio no f lun g tumor s inSyria nhamster s (Kobayash i an dOkamoto , 1974) . Som e o f thes e othe r lea dcompound s wer e successfu l ininducin g cance r a t lowe r dose s tha nlea dacetat e o r subacetate . I nsevera l o f th e studie s administratio nwa s carried.ou t b y injectio no f lea dphosphate , tetraethy l lead ,
o r lea doxide . I t i s likel y tha t th e effectivenes s o f th e lowe r dose s wa s du e t o a greate r absorbe dfraction , sinc e a s wil l b e discusse dlater , absorptio no f lea di s fairl y

lo w vi a th e ingestio nroute . Sinc e neithe r lea dacetat e no r lea dsubacetat e hav e bee nteste db y injection , i t i s uncertai ni f th e effectivenes s o f thes e compound s a t lowe r dose s i s du e t o mor e efficien t uptak e b y th e injectio nroutes , i f compound s suc ha s lea dphosphate , lea doxide , o r tetraethy l lea dar e mor e solubl e an dthu s mor e efficientl y take nu

pb y an y

6 8P.8 2

route , o r i f thes e compound s ar e inherentl y mor e poten t tha nlea dacetat e o r leadsubacetate . Althoug hinhalatio nca nb e a majo r route ^ o f huma nexposur e t o lea d compounds , non e o f th e anima l cance r bioassay s wer e conducte dusin g thi s exposur e route . Dat a fro m a variet y

o f relate dstudies , however , indicat e tha t lea di s likel y

t o b e a s effectiv e a t equa l o r lowe r dose s b y inhalatio na s b

y ingestio ninfoo do r drinkin g water . Depositio no f lea dparticle s o f varyin g size s i nth e huma nrespirator y trac t ha s bee nshow nt o rang e from

2 3 percen t t o

a s hig ha s 8 0 percen t (Chamberlai ne t al. , 1978 ; Gross , 1981 ; Morro w e t al. , 1980 ; Mehani , 1966 ; Nozaki , 1966) . O f th e amoun t deposite di nth e dee plung ,
mor e tha n9 0 percen t wa s absorbe dregardles s o f th e chemica l form o f lead . Moreover , lea dwa s no t accumulate dinth e lungs , indicatin g tha t i t wa s take n

upint o th e bloodstrea m an dtransporte dt o distan t targe t site s followin g absorptio n(Chamberlai ne t al. , 1978 ; Morro w e t al. , 1980) . I

ncontrast , absorptio nfro

m th e gastrointestina l trac t i nnonfastin g adult s wa s show nt o

var y fro m 6 t o 1 5 percen t (Chamberlai ne t al. , 1978 ; Rabinowit z e t al. , 1974 , 1980 ; Kehoe , 1961a,b,c) . Finally , th e increas e i nbloo dlea dconcentratio n wit hdos e inhuman s appear s t o b e greate r followin g exposur e vi a inhalatio n tha nfollowin g ingestio n(U.S . EPA , 1986c) . Th e likelihoo dtha t th e bioavailabilit y o f lea db

y th e inhalatio nrout e o f
exposur e i s hig hcompare dwit hingestio ni s supporte db y th e onl y

inhalatio n toxicolog y

study reporte dt o date . Prigg e an dGrev e (1977 ) foun dtha t in pregnan t rat s expose ddurin g gestatio nt o yery low dose s o f lea daeroso l ( 2 t o abou t 20 mg) , feta l weight s an dhematocrit s wer e reduce dinth e high-dos e groups , whil e inhibitio no f aminolevulini c dehydrogenas e activit y i nbot hdam s

an dfetuse s occurre dina dose-relate dmanner . Kilha m e t al . (1962 ) claime d

6 9tha t kidne y patholog y

an dkidne y cance r i

nwil drat s trappe da t a tras hdum p

wer e induce db

y inhalatio no f lead-containin g smoke . I f true , i t woul dshow tha t inhalatio no f lea dca nresul t i ncarcinogeni c effect s eve nunde r ambien t conditions , albei t unde r extremel y pollute dambien t conditions . However , intak e o f lea dincontaminate dgroun dwate r o r th e possibilit y o f othe r contaminant s inducin g simila r effect s canno t be rule dout . Whil e th e kidne y

i s a primar y

targe t orga nfo r carcinogenesi s i nth e rat , tumo r inductio nwa s als o note da t othe r sites . Fo r example , i nth e study

b y Zawirsk a an

dMedra s (1968) , a

napparen t increas e inadrenal , testicular , an d prostat e tumor s occurred . Increase dtumo r incidence s a t multipl e site s wer e als o reporte di na late r ra t study b y Zawirsk a (1981) . Increasednumber s o f glioma s inrat s wer e reporte db y Has s e t al . (1965 ) an dOyas ue t al . (1970) . Lun g tumor s wer e significantl y increase di nStrai nA mic e injecte dwit hlea d subacetat e (Stoner , 1976 ) an dinhamster s injecte dwit hbenzo[a]pyren e plu s lea doxid e compare dwit hbenzo[a]pyren e alon e (Kobayash i an dOkamoto , 1974) . Increase s i nlymphocyti c leukemi a wer e reporte dinmic e administere dlea d acetat e (Blakley , 1987 ) o r tetraethy l lea d(Epstei nan dMantel , 1968) . Significan t increases-i nreticulu m cel l sarcoma s wer e reporte dinmic e expose d t o lea ddimethyldithiocarbamat e (BRL , 1968) . Th e evidenc e fo r tumor s a t othe r site s i s weake r tha nfo r kidne y tumors . Fo r example , inth e studie s b y Zawirsk a (1981) , contro l incidence s wer e no t reported . Th e significanc e o f result s reporte db y Has s e t al . (1965 ) an dOyas u

e t al . (1970 ) ar e als o rendere dles s clear-cu t b y factor s suc ha s a lac k o f control s an

dpoolin g o f result s o f severa l experiment s wit hpossibl y differin g protocols . Inth e Blakle y (1987 ) study

usin g lea dacetate , th e increase s in leukemi a occurre dagains t a nalread y

hig hbackground , suggestin g tha t lea dma y

7 0b e merel y potentiatin g a

nongoin g process . Inth e BR L (1968 ) study , th e grou p siz e wa s small . Increase s i nreticulu m cel l sarcoma s wer e see nonl y infemale s

an dwit horal , bu t no t subcutaneous , dosing . Thus , whil e i t appear s tha t lea d compound s ar e capabl e o f inducin g tumor s a t site s othe r tha nth e kidney , th e presenc e o f confoundin g factor s increase s th e uncertaint y somewhat . Th e relationshi pbetwee npathologica l change s i nth e kidney s o f animal s expose dt o lea dcompound s an dtumo r inductio ni s uncertain , despit e considerabl e speculation . Som e o f th e effect s commonly see ninclud e proxima l tubul e cel l cytomegal y an dswolle nmitochondri a wit hincrease dnumber s o f lysozome s (Fowle r e t al. , 198C; . Spi t e t al. , 1981 ) an dinterstitia l fibrosi s (Has s e t al. , 1964 ; Goyer , 1971) . Th e primar y localizatio no f effect s inth e straigh t (S 3 ) segment s o f th e proxima l tubul e indicate s tha t no t al l cel l type s o f th e kidne y

ar e equall y

involve dinth e toxicolog y o f lea d(Has s e t al. , 1964 ; White , 1977 ; Fowle r e t al. , 1980) . Althoug hNogueir a (1987 ) ha s claime dtha t th e kidne y tumor s aris e fro

m th e same segment s o f th e proxima l tubules , thi s conclusio nrequire s independen t confirmation , sinc e h e di dno t establis hquantitativ e tempora l an dspatia l relationship s betwee ndos e an d
response . Sinc e man y

o f th e cance r bioassay s wer e carrie dou t usin g larg e doses , th e threshol dfo r pathologica l effect s coul dseldo m b e determined . Amon g th e multidos e studies , i nwhic hlowe r dose s wer e tested , AP I (1971 ) reporte d hyperplasi a i na fe w animal s a t concentration s i nth e foo da s low a s 10 0 ppm . NC I (1979 ) reporte dmil dnecrosi s i nrat s subchronicall y expose dt o 12 5 bu t no t 6 2 ppm . Aza r e t al . (1973 ) note dpathologica l change s a t 50 0 ppm , bu t no t 10 0 ppm . Tumor s wer e generall y no t detecte da t thes e levels . Pathologica l



### 7 1P.8 5

effects , however , wer e frequentl y describe dinanimal s administere d100 0 t o 10,00 0 pp

m inth e food , th e same concentration s show nt o induc e kidne y

cancer . Anothe r pathologica l endpoin t see ninmos t lea dexposur e studie s i s th e presenc e o f lea dinclusio nbodies . Inclusio nbodie s ar e commonl y foun din cell s o f th e kidney , liver , bone , an dbrai no f lead-expose danimals . I nth e kidne y the y occu r mos t frequentl y inth e proxima l portio no f th e tubule s (par s recta ) an

dappea r a s dens e spherica l homogeneou s eosinophili c bodies . The y ca n b e differentiate dfro m vira l inclusion s b

y bein g acid-fas t whe nstaine dwit h th e Zieh l Nielson' s technique . Ultrastructurally , th e bodie s hav e a dens e centra l cor e an

doute r fibrillar y

region . Th e bodie s ar e compose do f non histon e acidi c protein , ric hi nglutami c an dasparti c acids , glycin e an dlittl e cystine . Th e lea dbind s loosel y t o carboxy l group s o f th e acidi c amin o acids . Th e formatio no f inclusio nbodie s appear s t o b e a universa l respons e t o th e presenc e o f intracellula r lea dan di s probabl y

a nattemp t t o immobiliz e it . Nuclea r inclusio nbodie s occu r no t onl y inanimal s bu t als o i nplant s tha t ar e toleran t o f lead . Fo r example , the y hav e bee nobserve di nth e nucle i o f th e lea f cell s o f mos s growninsoi l containin g lead . Inclusion-bearin g cell s hav e als o bee nfoun dinth e rena l tubula r epithelium o f worker s expose d occupationall y

t o lead . (Fo r furthe r detail s se e Goyer , 1971 , 1983. ) Whil e th e pathologica l effect s o f lea dexposur e wer e reporte dt o occu r a t relativel y

larg e doses , th e presenc e o f nuclea r inclusion s i s on e o f th e earlie r sign s o f lea dtoxicit y an doccur s a t considerabl y lowe r exposures . Fo r example , Choi e e t al . (1975 ) reporte dth e presenc e o f nuclea r inclusio nbodie s i nmic e 8 hour s afte r injectio nwit ha s littl e a s 15 0 ug o f lead . Althoug hth e mechanism(s ) o f cance r inductio nb y lea di s currentl y unknown , th e presenc e o f nuclea r inclusio nbodie s inth e kidney s ma y b e

7 2P.8 6

involved , eve nthoug hthei r formatio ni s considere dt o b e a mechanis m t o immobiliz e lea dan

dtherefor e t o protec t th e cell . Th e interactio no f lea d wit hkey nonhiston e chromosoma l protein s i nth e nucleu s t o for

m th e inclusio n bodies , o r th e mer e presenc e o f inclusio nbodie s inth e nucleus , ma y sufficientl y

alte r geneti c functio nt o caus e cel l transformation . Whil e suc ha hypothesi s i s interesting , i t i s stil l speculative . Anothe r particularl y

interestin g mechanism , whic hha s th e potentia l fo r providin g a

nexplanatio nfo r th e carcinogeni c propertie s o f lea dcompounds , involve s activatio no f th e enzym e protei nkinas e C (PKC) . Markova c and Goldstei n(1988 ) hav e show nrecentl y

tha t picomola r concentration s o f lea d acetat e ca nactivat e partially-purifie dPK C fro m ra t brai nt o enzym e level s whic hnormall y

requir e micromola r concentration s o f calcium , th e norma l activato r o f th e enzyme . I f thi s very recen t observatio nca nb e corroborated , the nthi s uniqu e effec t o f lea do nPK C become s highl y

significan t i nvie w o f th e know npropertie s o f th e enzym e an dit s putativ e function . PK C i s a calcium - an

dphospholipid-dependen t enzym e whic hi s foun dwidel y distribute di ntissue s an dorgans . Th e highes t concentration s o f th e enzym e - hav e bee nreporte di nbrai ntissue . Inadditio nt o calciu m an dphospholipi d (probabl y

exclusivel y

phosphatidylserine) , th e plasm a memoran e lipid , diacylglyceol , als o play s a nimportan t rol e inactivatin g PKC . By significantl y

increasin g th e affinit y o f th e enzym e fo r calcium , diacylglycero l

cause s PK C t o b e full y activate dwithou t a ne t increas e i nfre e calcium abov e th e norma l cellula r concentratio n(Nishizuk a 1986 ; Kikkaw a an dNishizuka , 1986) . Presumably , th e concentratio no f fre e calcium availabl e inmos t restin g cell s i s inadequat e fo r PK C activatio ni nth e absenc e o f diacylglycero l whic h exist s onl y

transientl y

inth e plasma membrane . Th e enzyme , therefore , i s

7 3tightl y

regulate db

y th e availabilit y

o f bot hcalcium

an ddiacylglycerol . Tumo r promotor s suc ha s phorbo l esters , mezerein , teleocidin , an dAplasi a toxi n

ca nsubstitut e fo r diacylglycero l inactivatin g PKC . A t leas t i nth e cas e o f th e phorbo l esters , tumo r promotor s perform th e same functio na s diacylglycerol , i.e. , the y increas e th e affinit y o f PK C fo r calcium . PK C i s

no w considere dt o b e th e primar y cellula r targe t fo r th e phorbo l ester s (Castagn a e t al. , 1982 ; Kikkaw a an dNishizuka , 1986) . Onc e activated , PK C i s capabl e o f phosphorylatin g a numbe r o f cellula r protei nsubstrate s includin g growt hfacto r receptor s andproto-oncogenes . Throug hprotei nphosphorylation , PK C i s though t t o pla y a pivota l rol e i

nbot hth e transductio no f externa l signal s whic har e essentia l fo r activatin g variou s norma l cellula r functions , includin g th e contro l o f cel l proliferation , an dinmediatin g th e effect s o f tumo r promotor s (Nishizuk a 1986 ; Kikkaw a an dNishizuk a 1986) . Becaus e PK C appear s t o pla y suc ha nimportan t rol e inmediatin g th e comple xsequenc e o f event s associate dwit htumo r promotion , th e unusuall y highe r sensitivit y

o f th e enzym e fo r activatio nb y lea dstrongl y

suggest s that th e carcinogeni c effect s o f lea dcompound s demonstrate dinth e anima l studies ,
ma y b e mediated , a t leas t inpart , throug hPKC . Th e positiv e evidenc e fro m anima l studie s indicatin g tha t some lea dcompound s hav e tumo r promotin g o r cocarcinogeni c activit y (Hias a e t al , 1983 ; Shira i e t al , 1984 ; Kobiyash i an d Okamato , 1974 ) an

dth e study

b y Choi e an

dRichte r (1974 ) showin g tha t singl e injecte ddose s o f lea dacetat e a s low a s 1 ug/ g bod y

weigh t ca ncaus e a significan t increas e i nkidne y cel l proliferatio ninth e mous e ar e certainl y consisten t wit hth e PK C mechanis m an dsugges t th e possibilit y that lea deithe r function s a s a promoto r o r facilitate s promotion . I t i s possible , fo r example , that th e hig haffinit y o f PK C fo r lea d(compare dt o tha t o f calcium ) cause s th e

7 4P.8 8

requiremen t fo r endogenou s diacylglycero l and/o r environmenta l promotor s t o b e lowere dsuc htha t PK C become s inappropriatel y activated . On e resul t o f thi s activatio nwoul db e th e initiatio no f cel l proliferatio ni ncell s no t normall y schedule dfo r replication . Lea dcompound s ar e capabl e o f stimulatin g proliferatio ninrena l tubula r epithelia l cell s an dar e considere dt o b e poten t mitogens . I t wa s state dinth e 198 6 Ai r Qualit y Criteri a fo r Lea d(U.S . EPA , 1986c ) tha t th e ".. . evidenc e i s accumulatin g t o sugges t tha t lea dan dit s compound s

ar e complet e carcinogen s possessin g bot hinitiatin g an dpromotin g activity. " Wit hth e new

evidenc e fo r th e involvemen t o f lea da s a nactivato r o f PKC , th e abov e quot e take s ona nadde dsignificance . I t shoul db e note dtha t inadditio nt o it s possibl e involvemen t wit hPK C i ncarcinogenesis , lea dma y als o functio nthroug hPK C t o caus e some o f th e neurotoxicologica l effects . PK C i s foundi nhig hconcentration s inth e brain , localize dt o a larg e exten t inth e presynapti c membranes , an di s though t t o pla y a majo r rol e throug hprotei nphosphorylatio ninpresynapti c functio n (Kikkaw a an

dNishizuka , 1986) . Th e inappropriat e activatio no f PK C b y lea din th e nervou s syste m

ma y hav e seriou s consequence s fo r norma l neura l function . Despit e th e uncertaint y regardin g mechanism s o f action , th e evidenc e t o date , whil e no t conclusive , indicate s tha t th e lea dmoiet y i s th e mos t likel y
commo nelemen t responsibl e fo r tumo r induction . Fo r example , fou r differen t lea dcompounds , lea dacetate , lea dsubacetate , lea dphosphate , an dlea d naphthenat e hav e bee nshow nt o induc e simila r type s o f tumor s i nth e same targe t organ , th e kidney , ineithe r rat s o r mice . Th e non-oncogeni c patholog y

wa s als o simila r amon g thes e fou r compound s (Baldwi ne t al. , 1964 ; Zollinger , 1953) . Finally , NC I (1979 ) als o observe dth e sam e typ e o f rena l patholog y

7 5P.8 9

alon g wit hnuclea r inclusio nbodie s i nmic e o r rat s expose d subchronicall y t o lea d dimethyldithiocarbamate , eve nthoug hth e chroni c bioassays , conducte d a t very lo w doses , wer e negativ e fo r carcinogenesis . Whil e th e typ e o f nephropath y

reporte d canno t presentl y be linke d t o th e carcinogeni c process , th e fac t tha t a variet y o f lea d compound s caninduc e simila r oncogeni c a s wel l

a s non-oncogeni c pathologica l change s suggest s tha t th e lea d itsel f i s th e activ e agent . Insummary , lea d acetat e wa s show nt o be carcinogenic , followin g ora l dosin g inseve no f nin e studie s wit hrat s an d inon e o f tw

o studie s wit hmice . A lac k o f detectabl e tumorigeni c response s indog s an d monkey s i s considere d t o b e du e t o inadequat e duratio no f th e experiments . Lea d subacetat e wa s show nt o b e carcinogeni c insi xo f te nstudie s includin g fou r wit hrat s an d tw o wit h mice . Tw o othe r studie s wer e positiv e fo r tumo r promotio nonly . Wit hth e exceptio no f a chroni c bioassa y wit hhamsters , whic hma y b e les s sensitiv e tha n rats , th e negativ e result s occurre d inexperiment s usin g eithe r lo w dose s o r shor t exposur e durations . Severa l othe r lea d compound s wer e als o show nt o induc e carcinogeni c effect s includin g lea d phosphate , lea d naphthenate , lea d v dimethyldithiocarbamate , an d tetraethy l lead . Lea d subacetat e teste d positivel y

fo r tumo r promotion , whil e lea d oxid e wa s cocarcinogeni c wit h benzo[a]pyrene . Base d onthes e results , i t i s conclude d tha t th e evidenc e fo r carcinogenicit y

o f lea d inanimal s i s adequate , althoug hpositiv e response s

wer e generall y

see nonl y

a t hig hdose s (generall y inexces s o f a cumulativ e dos e o f 1 g) . I t shoul d b e noted , though , tha t insome studie s wher e administratio nwa s b y injection , tumo r inductio noccurre d a t lowe r dose s indicatin g absorptio nefficienc y ma y b e a nimportan t facto r inpotency .



### 7 6P.9 0

Th e mechanis m

o f actio no f lea do r lea dcompound s i s a s ye t unknown , althoug hi t ha s bee nhypothesize dinth e literatur e tha t lea dinclusio nbodie s

o r protei nkinas e C ar e involved . Th e evidenc e t o date , however , suggest s tha t th e lea dmoiet y

itsel f i s responsibl e fo r th e tumorigeni c responses . Fo r example , lea dinclusio nbodie s ar e see nfollowin g exposur e t o mos t lea d compounds , includin g organi c a s wel l a s inorgani c ones . Non-oncogeni c pathologica l response s ar e simila r fo r mos t lea dcompound s teste dt o date . Severa l differen t lea dcompounds , includin g organi c an dinorgani c compounds , hav e bee nshow

nt o b e capabl e o f inducin g kidne y cancer . Al l lea dcompound s teste dhav e bee nshow nt o b e capabl e o f increasin g th e body burde no f lead . From a qualitativ e weight-of-evidenc e perspective , therefore , al l lea d compound s ar e considere dt o b e potentiall y carcinogenic . Althoug hlea dwa s mos t commonl y administere dinth e food , positiv e result s

wer e als o see nfollowin g administratio nvi a drinkin g water , intraperitonea l injection , subcutaneou s injection , an dski npainting . Whil e n o inhalatio n

cance r bioassay s ar e available , ther e i s ampl e supplementa l evidenc e fo r th e bioavailabilit y

o f lea dfollowin g exposur e b y thi s route . Lea dis , therefore, , considere dt o b e potentiall y carcinogeni c b

y an y route . I nth e majorit y

o f case s th e critica l targe t orga nfo r oncogeni c effect s

wa s th e kidney . Whil e tumor s hav e bee nreporte dinlea dexpose danimal s a t a variet y o f othe r targe t sites , du e t o weaknesse s inexperimenta l design , uncertaintie s inreporting , etc. , th e evidenc e fo r tumo r inductio na t thes e othe r site s i s considere dt o b e les s certain , bu t woul dstil l contribut e t o
some degre e t o th e weigh t o f evidence .



### 7 7P.9 1

1.3 . SHORT-TER M

TEST S 1.3.1 . Mutagenicit y Th e genotoxicit y

o f lea dha s alread y bee nevaluate di

ndept hinth e Ai r Qualit y Criteri a fo r Lea d(U.S . EPA , 1986c). 1 Th e curren t repor t doe s no t attemp t t o conduc t a ne w evaluation ; rather , i t summarize s th e Ai r Qualit y Criteri a fo r Lea dan ddiscusse s recen t informatio npublishe dsinc e th e 198 6 report . I t shoul db e note dtha t recen t studie s lendsuppor t t o th e conclusion s reache di

nth e Ai r Qualit y

Criteri a fo r Lead . Thi s documen t conclude dtha t lea dha s "genotoxi c properties. "
Lea dha s bee nevaluate dfo r it s abilit y t o produc e bot hgen e mutation s an d chromosoma l anomalies . Briefly , studie s fo r poin t mutation s inbacteri a hav e bee nnegativ e (se e U.S . EPA , 1986c, an dIARC , 1987 , fo r a review) . However , bacteria l system s generall y ar e regardeda s inappropriat e fo r assayin g meta l ions . Wit hth e exceptio no f a recen t study onV7 9 cell s (Zelikof f e t al. , 1988) , lead-induce dgen e mutation s i nculture dmammalia ncell s hav e bee n observe donl y

a t toxi c concentration s (Hsi e e t al. , 1980 ; Oberl y e t al. , 1982) . Bot hpositiv e an

dnegativ e response s hav e bee nreporte dfo r chromosom e aberration s i nhighe r organism s (Sharm a an dTalukder , 1987 ; U.S . EPA , 1986c) . Th e positiv e responses , however , appea r t o depen donfactor s suc ha s harves t tim e followin g exposure , duratio nandrout e o f exposure , andtes t system . Furthermore , th e i nviv o chromosom e breakin g activit y o f lea di s als o affecte d b y diet . I t ha s bee nshow ntha t lead-expose danimal s oncalcium-deficien t diet s exhibi t a highe r incidenc e o f chromosoma l aberration s tha nd o lead -

^ h e Ai r Qualit y

Criteri a fo r Lea d(U.S . EPA , 1986c ) ha s ha dconsiderabl e pee r review , includin g revie w b y th e Clea nAi r Scientifi c Advisor y Committe e o f th e Scienc e Advisor y

Boar di npubli c sessions . 7 8P.9 2

expose danimal s o

nstandar ddiet s (O'Riorda nan dEvans , 1974 ; Deknud t e t al. , 1977b) . Th e mechanism(s ) b

y whic hlea dinduce s chromosoma l aberration s an d mutation s i s unknown . Th e patter no f response s (e.g. , lac k o f clea r dos e response s incertai nstudies , concentration s require dt o elici t a response , an d cultur e conditions ) observe d i nth e variou s genotoxicit y studie s suggest , however , tha t lea dcompound s ma y no t directl y

damag e th e geneti c materia l bu t rathe r ma y

ac t b y a nindirec t mechanism(s) . Fo r example , lea dha s bee nshow n t o distur bo r inhibi t enzyme function s importan t fo r DN A replicatio nan

drepai r (Popeno e an

dSchmaeler , 1979 ; fo r a revie w se e U.S . EPA , 1986c) . Review s an d additiona l reference s o nth e mutagenicit y

o f lea dca nb e foun di nth e U.S . EPA Ai r Qualit y

Criteri a fo r Lead(U.S . EPA , 1986c ) an dinth e Internationa l Agenc y fo r Researc ho

nCance r monograp h(IARC , 1987) . 1.3.2 . Cel l Transformatio n Lea dcompound s hav e bee nreporte dt o induc e cel l transformatio ni n Balb/3T 3 mous e cell s an dFische r 34 4 ra t embry o cell s infecte dwit hth e Rausche r murin e leukemi a viru s (Dunke l e t al. , 1981) . I nstudie s onSyria n hamste r embry o cells , bot hpositiv e (Zelikof f e t al. , 1988 ; DiPaol o e t al. , 1978 ) an dequivoca l (Dunke l e t al. , 1981 ) result s hav e bee nobtained . Lea d compound s hav e als o bee nreporte dt o enhanc e th e vira l transformatio no f Syria n hamste r embry o cell s (Cast o e t al. , 1979) .

1.4 . TOXICOLOGI C EFFECT S RELEVAN T T O CARCINOGENICIT Y 1.4.1 . Huma nStudie s Th e nonneoplasti c effect s du e t o overexposur e t o lea dhav e bee n extensivel y

reviewe db

y th e U.S . EPA

(1986c) . Som e o f th e effect s discusse din

7 9P.9 3

thi s documen t includ e th e following : subcellula r effects , effect s o nheme biosynthesi s an

derythropoiesis/erythrocyt e physiology , neurotoxicity , nephrotoxicity , reproductiv e an ddevelopmenta l toxicity , immunotoxicity , an d toxi c effect s onth e cardiovascular , hepatic , gastrointestinal , an dendocrin e systems . Th e rena l effect s (lea dnephropathy ) o f lead , however , ar e o f particula r interest , becaus e o f a possible , althoug hno t established , correlatio nwit hrena l carcinogenicity . Goye r (1985 ) discusse dtw o type s o f lea dnephropathy , acut e (earl y nephropathy ) an

dchroni c (lat e nephropathy) . Th e characteristi c feature s o f acute nephropath y ar e a s follows : (1 ) th e proxima l tubula r epithelium a s th e focu s o f injury ; (2 ) structura l feature s includin g formatio no f nuclea r inclusio nbodies , ultrastructura l change s in mitochondria , an

dcytomegaly ; (3 ) functio nchanges , suc ha s increase d aminoaciduria , glucosuria , phosphaturia , an dincrease dsodiu

m an ddecrease d uri c aci dexcretion ; (4 ) absenc e o f minima l glomerula r effects ; an d (5 ) reversibilit y

o f th e abov e effects . Chroni c nephropath y o r lat e lea d nephropath y

i s see na s nephrosclerosi s o r chroni c interstitia l nephritis . Th e characteristi c o f chroni c nephropathy ar e a s follows : (1 ) morphologi c feature s includin g progressiv e interstitia l fibrosis , dilatatio no f tubules , atrophy o r hyperplasi a of,tubula r epithelia l cells ; (2 ) clinica l feature s includin g reductio ninglomerula r filtratio nrat e an dazotemia , tubula r disfunctio n disproportionatel y

greate r tha nindicate db y th e decreas e inglomerula r filtratio nrat e followe db y absenc e o f tubula r dysfunctio na t late r stages ; an d (3 ) absen t o r spars e nuclea r inclusio nbodies . Accordin g t o Goye r (1985) , i t i s difficul t t o attribut e th e etiologi c facto r o f chroni c lea dnephropath y t o lea ditsel f becaus e o f th e absenc e o f th e inclusio nbodies . Consequently , th e associatio no f lea dwit hchroni c nephropath y i s base doncircumstantia l

8 0P.9 4

evidence . I

nhumans , th e absenc e o f nuclea r inclusio nbodie s ma y b e du e t o th e

us e o f chelatio ntherapy , whic hcoul dmobiliz e th e lea dsequestere di n inclusio nbodies , thereby eliminatin g evidenc e o f thei r presenc e b y ligh t microscopy . Anima l studie s hav e show ntha t EDTA

ca nmobiliz e rena l lea d (Goyer , 1985) . Bloo dlea dlevel s ar e use da s a nindicato r o f lea dintoxication . Goye r (1985 ) suggeste dtha t bloo dlevel s i nexces s o f 7 0 ug/d L ar e require dfo r inductio no f nephropathy , andBuche t e t al . (1980 , a s cite di nGoyer , 1985 ) foun dtha t bloo dlevel s no t exceedin g 6 2 ug/d L an da naverag e duratio no f
exposur e o f 1 3 year s d o no t influenc e rena l function . Wedee ne t al . (1975 , 1979 , a s cite di nGoyer , 1985 ) foundtha t bloo dlea dlevel s correlate dpoorl y wit hth e degre e o f rena l toxicity . Th e U.S . EP A (1986c ) conclude dtha t

. . . i t i s possibl e t o estimat e a t leas t roughl y th e rang e o f lea d exposur e associate dwit hdetectabl e rena l dysfunctio ninbot hhuma n adult s an

dchildren . Numerou s studie s o f occupationall y expose d worker s hav e providedevidenc e fo r lead-induce dchroni c nephropath y bein g associate dwit hbloo dlea dlevel s rangin g from 4 0 t o mor e tha n 10 0 ug/dL , an

dsome [studies ] ar e suggestiv e o f rena l effect s possibl y occurrin g eve na t level s a s low a s 3 0 ug/dL . I

nchildren , th e relativel y

spars e evidenc e availabl e point s t o th e manifestatio n o f rena l dysfunctio nonl y a t quit e hig hbloo dlea dlevel s (usuall y exceedin g 12 0 ug/dL) . (p . 12-190 ) Bloo dlea dlevels , however , ma y no t reflec t th e degre e o f rena l toxicity , an d urinar y lea dlevel s i nrespons e t o EDT A chelatio ntherapy , whic hmeasure s pas t lea dexposure , ma y

b e a bette r indicato r o f th e potentia l fo r rena l toxicity . Th e U.S . EP A

(1986c ) furthe r conclude dthat .

. . . th e EDT A

lead-mobilizatio ntes t i s th e mos t reliabl e techniqu e fo r detectin g person s a t ris k fo r chroni c nephropathy ; bloo dlea dmeasurement s ar e a les s satisfactor y indicato r becaus e the y ma y no t accuratel y

reflec t cumulativ e absorptio nsome time afte r exposur e t o lea dha s terminated , (p . 12-191 )



### 8 1Wit hregar dt o th e genera l relationshi pbetwee ninterna l lea dlevel s an d advers e effects , th e U.S . EPA (1986c ) conclude dthat . I nlivin g huma nsubjects , direc t determinatio no f tissu e lea dburden s o r ho w thes e relat e t o advers e effect s intarge t tissue s i s no t possible . Som e accessibl e indicato r (e.g. , lea dina medium suc ha s bloo do r a biochemica l surrogat e o f lea dsuc ha s erythrocyt e protoporphyrin) , mus t b e employed . Whil e bloo dlea dstil l remain s th e onl y practica l measur e o f excessiv e lea dexposur e an dhealt h risk , evidenc e continue s t o accumulat e tha t suc ha ninde xha s some limitation s ineithe r reflectin g tissu e lea dburden s o r change s i n suc htissue s wit hchange s i nexposure , (p . 10-69 )
A t present , th e measuremen t o f plumburesi s [lea dexcrete dinurine ] associate dwit hchalleng e b y a singl e dos e o f a lead-chelatin g agen t suc ha s CaNa 2 EDT A

i s considere dth e bes t indicato r o f th e mobile , potentiall y

toxi c fractio no f body lead . Chelatabl e lea di s logarithmicall y

relate dt o bloo dlead , suc htha t a nincrementa l increas e i nbloo dlea di s associate dwit ha nincreasingl y

large r incremen t o f mobilizabl e lead . (p . 10-70 ) Therefore , althoug hbloo dlea dma y no t be th e bes t indicato r o f advers e effect s includin g nephropathy , i t ca nb e correlate dwit hothe r indicator s o f lea d toxicity , whic hi

ntur nca nb e correlate dwit hnephropathy . 1.4.2 . Anima l Studie s A numbe r o f anima l studie s hav e show ntha t nephrotoxicit y ca nb e induce d wit hvariou s lea dcompound s administere deithe r orall y o r topically . Thes e includ e lea dacetat e (Boylan de t al. , 1962 ; API , 1971 ; Tanne r an dLipsky , 1984 ; Nogueira , 1987) , lea dsubacetat e (Has s e t al. , 1965 ; Va nEsc han dKroes , 1969 ; Oyas ue t al. , 1970 ; Kasprza k e t al. , 1985) , lea dnaphthenat e (Baldwi ne t al. , 1964) , an

dlea ddimethyldithiocarbamat e (NCI , 1979) . Mos t o f thes e studie s

wer e conducte di nrat s an dmice , bu t lea dcompound s hav e als o bee nshow nt o induc e nonneoplasti c rena l lesion s inhamster s (VanEsc handKroes , 1969) , rabbit s (Has s e t al. , 1965) , dog s an dmonkey s (API , 1971) .



### 8 2P.9 6

Lea dcompound s ar e capabl e o f stimulatin g proliferatio ninrena l tubula r epithelia l cell s an

dar e considere dt o b e poten t mitogen s (Choi e an dRichter , 1980) . A

singl e intraperitonea l injectio no f 4 0 u g o f lea dpe r g body weigh t stimulate da 40-fol dincreas e incel l proliferatio ninrat s a s measure db y autoradiography , o r whe ncombine dwit hunilatera l nephrectomy , a 65-fol d increas e (Choi e an

dRichter , 1972b , a s cite dinChoi e an dRichter , 1980) . A singl e intracardia c injectio no f lea dacetat e give na t variou s dose s rangin g fro m 0.0 1 t o 10 0 u

g o f lea dpe r g stimulate dDN A synthesi s i

nmous e kidney s a s

measure db

y incorporatio no f H-thymidin e int o DN A (Choi e an

dRichter , 1974) . DN A synthesis , whic hpeake da t 3 3 hours , wa s followe db y a pea k i

nth e mitoti c inde xa t 3 9 hours ; eac hfel l t o contro l level s b y 2 an d4 days , respectively . Maximum DN A synthesi s wa s elevate d15-fol dove r controls , an dth e maximum mitoti c inde xwa s 45-fol dgreate r tha ncontrols . Th e author s conclude dtha t th e stimulatio nincel l proliferatio nwa s no t du e t o a regenerativ e response , becaus e tubula r necrosi s wa s no t see nb y ligh t microscopy . Prolonge dtreatmen t wit hlea dfo r 6 month s als o stimulate dcel l proliferatio nandfoca l hyperplasi a

o f tubula r cells . Th e magnitud e o f th e proliferativ e respons e wa s les s after s 6 month s tha nafte r a singl e treatmen t (Choi e an dRichter , 1972a , a s cite din Choi e an dRichter , 1980) . Simila r effect s oncel l proliferatio nan d hyperplasi a wer e see ni nth e live r o f rat s give na singl e intravenou s injectio n

o f lea dnitrat e (Columban o e t al. , 1983 , 1984 ) o r repeate dinjection s ove r a 30-da y (fou r injections ) o r 80-da y perio d(nin e injections ) (Ledda-Columban o e t al. , 1983) . Afte r a singl e injection , th e pea k inDN A synthesi s (incorporatio n

o f H-thymidin e int o DNA ) occurre d3 6 hour s afte r administratio no f lea dan d th e pea k inth e numbe r o f cell s enterin g mitosi s occurre d4 8 hour s afte r



### 8 3administratio no f lead . Th e absenc e o f necroti c cell s a s see nb y ligh t microscop y

prompte dth e investigator s t o conclud e tha t th e stimulatio ni ncel l proliferatio nwa s a mitogeni c respons e rathe r tha na regenerativ e respons e (Columban o e t al. , 1983) . Th e magnitud e o f th e proliferativ e respons e afte r repeate dadministratio no f lea dshowe da progressiv e decrease , suc htha t th e increas e wa s 16- , 6- , o r 4-fol dafte r 1 , 4 , o r 9 injections , respectivel y (Ledda-Columban o e t al. , 1983) . Additiona l studie s showe dtha t th e mitogeni c effec t o f lea dwa s ineffectiv e ininitiatin g hepatocarcinogenesis , a s determine db

y th e inductio no f enzyme-altere dfoc i inth e live r (Columban o e t al. , 1987a , b) . Room i e t al . (1986 ) demonstrate dtha t lea dnitrat e induce d biochemica l change s (drug-metabolizin g enzymes ) characteristi c o f live r nodule s (foci) . Th e significanc e o f thi s observatio ni s unclear , considerin g tha t lead

wa s show

nno t t o induc e live r foci .

1.5 . PHARMACOKINETI C PROPERTIE S Th e pharmacokinetic s o f lea dhav e alread y bee nreviewe di ngrea t dept hin th e Ai r Qualit y

Criteri a fo r Lea d(U.S . EPA , 1986c, Volum e III) . Th e current , repor t doe s no t attemp t t o conduc t a ne w evaluation ; rather , i t quote s extensivel y

fro m th e Ai r Qualit y

Criteri a fo r Lea da s th e primar y authorit y

o n th e subject . Thi s referenc e ha s hadconsiderabl e pee r review , includin g revie w b y th e Clea nAi r Scientifi c Advisor y Committe e o f th e Scienc e Advisor y Boa^ d in publi c sessions . 1.5.1 . Absorptio n 1.5.1.1 . Huma nStudie s — Lea di s absorbe dint o th e body followin g inhalatio no r ingestio nexposure : derma l exposur e t o certai nlea dcompound s ca nals o resul t



### 84P.9 8

i nnotabl e absorption . Gastrointestina l absorptio no f ingeste dlea di s influence db

y severa l factor s includin g ag e an ddietar y

factors . Th e rol e o f nutrient s i nlea dabsorptio nha s bee nreporte di nsevera l metaboli c balanc e studie s fo r bot hadult s an dchildren . .. . A

numbe r o f report s hav e documente dth e associatio no f lea dabsorptio nwit hsuboptima l nutritiona l state s fo r ironan dcalcium , wit hreduce dintak e bein g associate dwit hincrease dlea dabsorption . . . . Variou s survey s hav e indicate dtha t iron , calcium , zinc , an dvitami ndeficiencie s ar e widesprea damon g [children] , particularl y th e poor . (U.S . EPA , 1986c, pp . 1-76 , 10-43 )
I nadul t humans , th e absorptio no f ingeste dlea dha s bee nestimate dt o rang e fro m 1 0 t o 1 5 percent , bu t fastin g human s ma y absor b2 1 percen t t o abou t 6 3 percent . Severa l studie s hav e focuse do ndifference s ingastrointestina l absorptio nrate s betwee nadult s an dchildren . Experimenta l studie s o f childre n
measure da

naverag e absorptio nrat e o f approximatel y 5 0 percen t fo r ingeste d lea da s compare dt o th e 1 0 t o 1 5 percen t see ninadults . Accordin g t o a revie w

o f th e availabl e literatur e o nhuman s (U.S . EPA , 1986c) , th e absorptio nrate s

o f differen t chemica l farm s o f ingeste dlea dappea r t o b e abou t equal . Amon g th e primar y

determinant s o f th e rat e o f absorptio nar e th e condition s unde r whic hlea di s ingested . A s state dabove , lea dtake ni na fastin g stat e i s generall y

mor e readil y

absorbedtha nlea dtake nwit hfood . Also , th e presenc e

o f mineral s o r othe r substance s i nth e foo dma y reduc e th e absorptio no f ingeste dlead . Unde r ambien t conditions , th e fractio no f inhale dlea dparticle s deposite d i nth e lung s i s abou t 3 0 t o 5 0 percen t (depositio no f lea dpartir.le s o f variou s size s range s fro

m 2 3 t o 8 0 percent ; se e sectio n1.2.10.) , dependin g onparticl e siz e an dventilatio nrate . Th e absorptio no f lea ddeposite dinth e lowe r respirator y

tract , whic happear s t o b e greate r tha n9 0 percent , i s apparentl y
no t markedl y

influence db

y th e chemica l for

m o f lea dcompounds ; therefore , th e



### 8 5P.9 9

overal l pulmonar y

lea d uptak e i s governe d b y th e concentratio no f lea d i nth e air , th e ventilatio nrate , an d th e fractio ndeposited . However , regiona l depositio nfactor s suc ha s lun g clearanc e inth e uppe r respirator y trac t mus t als o be considere d whe nassessin g absorptio no f inhale d lead . Th e rat e o f absorptio no f lea d throug hth e ski ni s generall y muc hlowe r tha nabsorptio nvi a th e gastrointestina l an d respirator y

tracts , althoug h derma l exposur e t o alky l leads , lea d soaps , an d certai nothe r lea d compound s

ca nresul t i nsignifican t absorption . 1.5.1.2 . Anima l studies—Anima l studie s ad d suppor t t o huma ndata . Whil e experimenta l anima l dat a fo r quantitativ e assessmen t o f lea d depositio nan

d absorptio nfro

m th e lung an

d uppe r respirator y

trac t ar e limited , availabl e informatio nfro m th e rat , rabbit , dog , an d nonhuma n primate s support s th e finding s tha t respire d lea d i nhuman s i s extensivel y an d rapidl y

absorbed . (U.S . EPA , 1986c , p . 10-61 )
Youn g developin g animal s absor ba muc hhighe r percentag e o f lea d fro m th e gu t tha nadul t animals , althoug hth e percen t absorptio namon g anima l specie s varie s somewhat . Inlaborator y anima l experiments , lea d absorptio nfro m th e gu t generall y

resemble s tha t o f humans . Fo r example , i nmal e albin o Wista r rats , a comprehensiv e study

o f factor s tha t affec t th e absorptio nan d excretio no f lead

wa s conducte d usin g radioactiv e lead acetat e o r lea d nitrat e a s tracer s an d lea d chlorid e a s a carrie r indistille d wate r (Conra d an d Barton , 1978) . Fou r hour s afte r dosin g wit h0.00 1 an d 1 0 u g o f lea d chlorid e (b y gavage ) th e absorptio nrat e wa s 4 t o 5. 5 percen t o f administere d dose ; th e rat e decrease d t o abou t 1 o r 2 percen t a t dose s o f 10 0 an d 100 0 ug . Likewise , i nothe r anima l studie s lea d absorptio na s a percentag e o f dos e decreased , suggestin g a saturatio nphenomeno nfo r lea d transpor t acros s th e gu t wal l (U.S . EPA , 1986c) . Mos t o f th e lea d wa s absorbe d fro m th e duodena l regio no f th e smal l intestine . Factor s tha t affecte d absorptio nwer e age , an d nutritiona l an

d othe r dietar y

8 6p. 1

factors . Absorptio nwa s maxima l i nyoun g animal s whe ngrowt hwa s rapid ; absorptiondecrease d a s animal s age d an d gaine d weight . Fastin g fo r a t leas t 3 day s had no effec t o nabsorptio no f lead , bu t fastin g fo r 5 day s significantl y

decrease d absorption . However , othe r studie s indicat e tha t fastin g markedl y

enhance d gu t uptak e o f lead inrat s (U.S . EPA , 1986c) . A n iron-deficien t die t significantl y increase d absorption , wherea s iron supplements , a s wel l a s zin c an d calcium , decrease d th e rat e o f absorption , presumabl y

b y competin g fo r lea d absorptionsite s inth e intestina l mucosa . Dietar y substance s tha t enhance d th e solubilit y o f lea d (cystine , cysteine , methionine , tyrosine , arginine , an d ascorbi c acid ) als o enhance d th e absorption

o f lead , probabl y

b y maintainin g mor e lea d ina physica l stat e capabl e o f absorptio n(Conra d an d Barton , 1978) . Bioavailabilit y

o f differen t chemica l an d physica l form s o f lead invarie d die t matrice s ha s bee nreported . Barltro p an d Mee k (1975 ) evaluate d eigh t inorgani c an

d fou r organi c lea d compound s t o determin e th e relativ e absorption inth e ra t followin g dietar y exposur e t o 0.07 5 percent o f lea d ove r a 48-hou r period . Absorptio nwa s compare d t o tha t o f lea d acetate . A relativ e absorptio ninde xwa s determine d fo r th e differen t compound s b y comparin g th e lea d level s inth e blood , bone , an d kidney . A

nabsolut e tota l absorptio nwa s

no t determined . Basi c lea d carbonat e (16 4 percent o f lea d acetate ) an d tallat e (12 1 percent) , wer e th e mos t efficientl y absorbe d compounds , followe d b y lea d sulfid e (6 7 percent) , lea d naphthenat e (6 4 percent) , lea d octoat e (6 2 percent) , lea d chromat e (4 4 percent) , an d metalli c lead (1 4 percent) , whic hwa s th e leas t efficientl y

absorbed . However , particl e siz e an d dietar y

factor s wer e found.t o influenc e th e uptak e fro m th e gut : fo r example , a nincreas e indietar y fa t resulte d ina

nincreas e inlea d absorption . Othe r report s showe d tha t lea d

8 7P. 2

sulfid e (Karhausen , 1973 ) an dlea dnaphthenat e (vanPeteghe m an dd e Vos , 1974 )

ar e readil y

absorbed , becaus e unde r acidi c condition s i nth e gastrointestina l tract , the y

ar e converte dt o lea dchloride , whic hi s readil y absorbe d (Karhausen , 1973) . Lea doxid e an dtetraethy l lea dar e als o readil y absorbe d (Karhausen , 1973) . Alky l lea dcompounds , especiall y tetraethy l lead , ar e expecte dt o b e mor e efficientl y absorbe dfro

m th e gastrointestina l trac t tha n inorgani c lea dcompounds , becaus e o f thei r conversio nt o trialky l lea dunde r gastri c acidi c condition s (Jensen , 1983) . Th e cance r potenc y

o f differen t lea dcompound s ma y var y considerabl y simpl y du e t o absorption , whic hi ntur ni s influence db y a numbe r o f factor s tha t may hel pt o explai ndifference s i nresult s amon g anima l studies . Also , i n interpretin g thes e result s fo r huma nris k assessment , i t i s importan t t o recogniz e tha t no t al l lea dcompound s ar e equall y prevalen t i nth e environment . 1.5.2 . Distributio nan dRetentio n 1.5.2.1 . Huma nstudies—Th e fractio no f absorbe dlea dretaine di nth e body range s fro

m 1 t o 5 percen t inadult s an dfro m 3 2 t o 3 4 percen t inyoun g children . Absorbe dlea di s transporte db y th e systemi c circulatio nan d distribute di nvariou s organ s an dtissues . Th e lea di s the ngraduall y redistribute dt o organ s an dsystem s accordin g t o relativ e affinity . A numbe r

o f bod y compartment s exis t fo r lead , an dth e separat e kineti c pool s hav e differen t rate s o f turnover . Th e greates t fractio no f retaine dlea d accumulate s inth e bone : lea dina larg e an drelativel y

iner t bon e compartmen t ha s a half-lif e greate r tha n2 0 years . Ther e i s als o a fractio no f lea di n bon e tha t i s inequilibrium wit hlea dinothe r tissues . Lea di ncalcifie d tissue s generall y

build s upthroughou t lif e unti l ol dage . Bloo dlea dlevel s indicat e recen t exposur e an dvar y somewha t wit hag e andsex . Lea di nbloo d

8 8P. 3

reside s insevera l distinc t pool s wit hmos t o f th e bloo dlea dinhuman s bein g associate dwit hth e erythrocyte . Th e smal l diffusibl e fractio no f lea din plasm a andserum

i s i nequilibrium

wit hsof t tissu e o r endorgans . Othe r majo r organ s tha t tak e u

plea dar e th e live r andkidneys , wit hamount s als o foun din muscl e andbrain . Inth e brai nth e highes t concentration s o f lea dar e foun di n th e hippocampus , followe db y th e cerebellum , cerebra l cortex , an dmedulla . Lea dconten t i nth e kidne y corte xincrease s wit hag e andma y b e relate dt o th e observatio no f nuclea r inclusio nbodies . Lea ddoe s no t accumulat e inth e lung . U.S . EP A (1986c ) conclude dtha t "Mobil e lea dinorgan s andsystem s i s potentiall y

mor e activ e toxicologicall y interm s o f bein g availabl e t o biologica l site s o f action . Hence , thi s fractio no f tota l bod y lea dburde ni s

a mor e significan t predicto r o f imminen t toxicity " (p . 10-65) . However , thi s mobil e lea dfractio ninorgan s an dsystem s canno t b e measure ddirectly . Althoug hth e bloo dlea dleve l i s a reasonabl e indicato r o f recen t exposure , us e

o f bloo dlea da s aneffectiv e dos e o r a s a measur e o f tota l bod y burde no r impairmen t "ca nhav e limitation s i nreflectin g bot hth e amount s o f lea di n targe t tissu e andth e tempora l change s i ntissu e lea dwit hchange s i nexposure " (p . 10-54) . Chelatabl e lead , usin g calcium disodium

ethylenediaminetetraaceti c aci d(CaNa,"EDTA) , i s viewe da s th e mos t usefu l reflectio no f lea dbod y burden . Th e chelatabl e urinar y lead , e.g. , th e fractio no f lea dtha t i s chelatabl e from

variou s body

compartments , i s though t t o includ e " a labil e lea d compartmen t withi nbon e a s wel l a s withi nsof t tissues " (U.S . EPA , 1986c , p . 10-65) . Placenta l transfe r o f lead , followe db y distributio ni nth e fetus , occur s i nhumans , wit hlea dlevel s i nnewbor ninfant s bein g simila r t o materna l levels . 

### 8 9P. 4

1.5.2.2 . Anima l studies—Anima l studie s hav e helpe dt o sor t ou t som e of th e relationship s of lea dexposur e t o i nviv o distributio no f th e element , particularl y

th e impac t of skeleta l lea donwhole-bod y retention . Inrats , lea ddosin g result s ina ninitia l increas e of lea dlevel s insof t tissue s followe db

y los s o f lea dfro

m sof t tissu e vi a excretio nan dtransfe r t o bone . Lea ddistributio nappear s t o b e relativel y independen t of dose . Othe r studie s hav e show

ntha t lea dlos s fro m organ s follow s first-orde r kinetic s excep t fo r los s fro m bone , an

dtha t th e skeleta l syste m inrat s an

dmic e i s th e kineticall y

rate-limitin g ste pi nwhole-bod y

clearanc e (U.S . EPA , 1986c) . Th e neonatal anima l seem s t o retai nproportionall y highe r level s o f tissu e lea dcompare dt o th e adul t an dmanifest s slow

deca y of brai nlea dlevel s whil e showin g a significan t declin e ove r tim e inothe r tissues . Thi s deca y appear s t o resul t from

enhance dlea dentr y t o th e brai nbecaus e o f a poorl y develope d brai nbarrie r syste m

a s wel l a s from

enhance dbody

retentio no f lea db y youn g animal s (U.S . EPA , 1986c) . Th e effect s o f suc hchange s a s metaboli c stres s andnutritiona l statu s on bod y redistributio no f lea dhav e bee nnoted . Lactatin g mice , fo r example , ar e know nt o demonstrat e tissu e redistributio nof lead , specificall y bon e lea d resorptio nWit hsubsequen t transfe r o f bot hlea dan dcalcium

fro m mothe r t o pu p (U.S . EPA , 1986c) . Essentia l nutrient s hav e a ninfluenc e ove r th e body' s treatmen t of lead . Certai nnutritiona l factor s suc ha s low calcium , phosphat e or vitami nD , an d iron , copper , or zin c deficiency , ca nenhanc e lea dabsorptio nor decreas e rena l excretion . Fo r example , calcium ha s bee nshow

nt o affec t th e absorptio nan d tissu e distributio no f lead . Whole-bod y retentio no f lea d(lea dchlorid e give n b y gavage ) andtissu e distributio nwer e reduce dinrat s give na calcium

9 0P. 5

supplemen t t o rais e th e dietar y leve l t o 35 0 mmo l o f calcium pe r k g o f die t (Meredit he t al. , 1977) , an dth e lea dconten t inth e kidne y an dfemu r wa s increase di

nrat s place do

nlo w calciu m diet s (Mahaffey

e t al. , 1975) . Lo

w dietar y calcium

enhance s toxi c effect s o f lea dan dincrease s chromosom e aberration s i

nbon e marro w

cell s i

nmic e (Deknud t an

dGerber , 1979 ) an

d periphera l lymphocyte s i nmonkey s (Deknud t e t al. , 1977a) . Dietar y calcium supplement s betwee n0. 3 an d6 percen t wer e show nt o caus e a decreas e i nlea d conten t i nth e kidney , bu t no t i nth e live r (Kasprza k e t al. , 1985) , wit ha surprisin g increas e i nrena l toxicit y

an drena l tumo r formation . Lea dnaphthenate , a compoun dtha t i s wel l absorbe dthroug hth e skin , i s distribute dt o th e same tissue s a s lea dcompound s absorbe dfro m th e gastrointestina l tract , wit hth e highes t level s foundinkidneys . Selenium a t 5 an d1 0 pp m indrinkin g wate r administere dsimultaneousl y wit htopica l application s o f lea dnaphthenat e resulte di na dose-relate dincreas e inth e conten t o f lea dinkidney s an dblood , bu t no t inbrai nan dlive r (Rastog i e t al. , 1976) . Mos t o f th e absorbe dlea dfro m alky l lea di s foun dinliver , kidney , and . brain ; ver y

littl e i s foun di nbon e (Jensen , 1983) . Tetraethy l andtetramethy l lea dar e metabolize dt o thei r respectiv e trialky l metabolite s b y oxidativ e dealkylatio nb

y a microsoma l cytochrom e P450-dependen t monooxygenase . Th e trialky l metabolite s ma y b e furthe r converte dt o dialky l metabolite s and finall y t o inorgani c lead . Th e formatio no f inorgani c lea dha s bee nobserve d i nvariou s specie s treate dwit halky l lead , althoug hdifferen t proportion s o f lea dchemica l form s ar e see nacros s th e anima l specie s followin g alky l lea d
exposure .



### 9 1P. 6

1.5.3 . Excretio n 1.5.3.1 . Huma nstudies--U.S . EP A (1986c ) conclude dtha t Dietar y lea di nhuman s andanimal s tha t i s no t absorbe dpasse s throug hth e G I [gastrointestinal ] trac t an di s eliminate dwit hfeces , a s i s th e fractio no f ai r lea dtha t i s swallowe dandno t absorbed . Lea denterin g th e bloodstrea m

an dno t retaine di s excrete dthroug hth e rena l andG I [gastrointestinal ] tracts , th e latte r vi a biliar y clearance . Th e amount s excrete dthroug hthes e route s ar e a functio no f suc hfactor s a s species , age , an dexposur e characteristics , (p . 10-66 )
Jense n(1983) , ina revie w article , indicate dtha t fo r inorgani c lea dabou t three-fourth s i s excrete di nth e urin e an dles s tha none-fourt hinth e feces , wherea s fo r organi c lea d(e.g. , alky l lea dcompounds ) th e patter ni s 'reversed , wit hles s tha na thir dinth e urin e an dth e majorit y

i nth e feces . Lea dca n als o b e excrete di nbreas t mil k andthu s becom e a sourc e o f exposur e fo r nursin g infants . 1.5.3.2 . Anima l Studies--I nexperimenta l animals , bot hurinar y an dfeca l excretio nar e importan t route s o f elimination , althoug hth e relativ e amount s betwee nth e two route s i s dependen t o norgani c versu s inorgani c lead , anima l species , an

ddos e level . Wit hregar dt o specie s differences , biliar y clearanc e o f lea dinth e do g i s bu t 2 percen t o f tha t fo r th e rat , whil e suc hexcretio ni nth e rabbi t i s 5 0 percen t tha t o f th e rat . Lea dmovemen t fro

m laborator y

animal s t o thei r offsprin g vi a mil k constituent s i s a rout e o f excretio nfo r th e mothe r a s wel l a s a rout e o f exposur e fo r th e young . (U.S . EPA , 1986c , p . 10-67 ) A s see ninth e huma nstudies , alky l lea dcompound s ar e excrete dprimaril y i nfeces ; inorgani c lead , whic hi s converte dfro m dialky l lea dinth e intestine , dominates . Th e secondar y rout e o f excretio ni s vi a urine , wit hth e dialky l lea dspecie s dominatin g (Jensen , 1983) . Th e proportio no f chemica l form s excrete dappear s t o b e anima l specie s dependent .



### 9 2P. 7

1.5.4 . Discussio n Th e availabl e evidenc e indicate s tha t lea dan dlea dcompound s ca nb e absorbedint o th e systemi c circulatio nfro m th e respirator y

trac t followin g inhalatio nexposur e an dfro m th e gastrointestina l trac t followin g ingestion . Consequently , variou s compound s o f lea dcontribut e to . th e bloo dlea dleve l and thu s hav e th e potentia l t o ultimatel y caus e advers e effect s upo ndistributio n t o th e variou s targe t organ s an dtissues . Likewise , limite dinformatio nshow s tha t certai nlea dcompound s ca nb e absorbedint o th e systemi c circulatio nan d distribute dfollowin g derma l absorption . Absorptio no f lea di s influence db y a numbe r o f factor s suc ha s particl e size , ag e o f subject , an ddietar y considerations . Eve nunde r identica l conditions , ther e ma y als o be difference s i nth e bioavailabilit y o f differen t form s o f lea ddu e t o th e unequa l rat e an d exten t o f absorptio no f individua l compounds . However , eac ho f th e variou s form s o f lea di s absorbe dt o som e extent , contributin g t o th e bloo dlea dleve l

andthu s t o th e body

burden . Th e evidenc e tha t man y differen t lea dcompound s teste dincance r assay s induc e rena l tumor s an dnonneoplasti c rena l lesion s o r induc e tumor s i nothe r organ s clearl y indicate s tha t the y ar e absorbe dint o th e body an ddistribute dt o dista l targe t organs . I t i s reasonabl e t o assum e tha t al l lea dan

dlea dcompound s ca ncontribut e t o advers e effects , includin g cancer-causin g activities , becaus e the y ar e absorbedint o th e systemi c circulation , contribut e t o lea dbody burden , an

dthu s ar e distribute dt o targe t organ s andtissue s throughou t th e body . Th e potenc y o f differen t chemica l an d physica l form s o f lea dma y vary , however , du e t o absorptio nfactor s a s wel l a s othe r bioavailabilit y pharmacokineti c considerations . I t i s interestin g t o not e tha t certai nra t chow s ar e s o suppressiv e o f lea dabsorptio ntha t uptak e



### 9 3

.P. 8

i s les s tha n1 percen t (U.S . EPA , 1986c , p . 10-12) . Thi s ma y hel pt o explai n

some o f th e differen t result s observe di nth e anima l carcinogenicit y studies . A t th e presen t time , know npharmacokineti c differences , fo r example , uptak e an

ddistributio ndifference s betwee nrodent s an dhumans , disallow s extrapolatio no f effectiv e targe t dos e fo r developmen t o f a cance r ris k estimat e fo r human s base do nth e anima l data . Recentl y availabl e informatio n indicate s tha t distributio no f lea dinth e body , inth e bone , fo r example , i s considerabl y

eve nmor e comple xtha nonc e believed . However , ongoin g developmen t o f pharmacokineti c models , particularl y inanimal s bu t als o improve dmodel s inhumans , make s th e possibilit y o f relevan t species-to-specie s extrapolatio npromisin g fo r th e future .

1.6 . WEIGHT-OF-EVIDENC E CLASSIFICATIO N Althoug hth e primar y concer nabou t lea dha s focuse donit s advers e healt h effect s othe r tha ncancer , many investigator s hav e studie dth e potentia l associatio nbetwee nlea dexposur e an dcancer . Th e evidenc e pertainin g t o

cance r include s huma nstudies , long-term anima l studies , short-ter m tests , an

d

numerou s relevan t biochemica l data . Lookin g firs t a t th e huma nevidence , ther e ar e ove r a doze nepidemiologi c studie s o nlea dexposur e an dcancer . The y

wer e conducte di nvariou s occupationa l setting s involvin g potentia l lea dexposure , includin g lea dbatter y manufactur e an

drecovery , lea dsmelte r operations , tetraethy l lea dproduction ,
an damon g plumber s an

dpip e fitters . On e cohor t study an don e proportiona l mortalit y

study show excesse s i nkidne y

cancer , albei t no t statisticall y significant , whil e deficit s o f kidne y cance r wer e observe di ntw o othe r cohorts , leadin g t o equivoca l epidemiologi c evidenc e fo r kidne y cancer .
9 4P. 9

Nevertheless , thi s circumstanc e i s wort hnotin g sinc e kidne y cance r is , b

y far , th e mos t commo nform

o f cance r see ni

nthe-anima l studies . Severa l cohor t studie s show

a nincrease dincidenc e o f lun g cancer ; thre e ar e statisticall y significant , two ar e not . Al l hav e som e typ e o f shortcomin g tha t preclude s th e drawin g o f a causa l inferenc e betwee nleadexposur e an dcancer . Collectively , th e huma nstudie s sugges t tha t lea dma y caus e cance r i n humans , bu t becaus e eac hstud y ha s methodologica l limitations , the y fal l shor t

o f providin g a causa l lin k betwee nleadexposur e an dcancer . Th e lac k o f a
measur e o f lea dexposur e i s a majo r problem wit hal l th e studies . Th e presenc e

o f othe r carcinogen s i nsome o f th e occupationa l setting s als o make s i t impossibl e t o determin e i f th e observe dincrease s i ncance r ar e du e t o lea d alone , t o th e combinatio no f lea dwit hothe r substances , o r t o th e othe r substance s solely . Fo r thes e reasons , th e evidenc e o f carcinogenicit y fro m huma nstudie s must , a t thi s time , b e considere d"inadequate" ' accordin g t o EPA' s Guideline s fo r Carcinoge nRis k Assessmen t (U.S . EPA , 1986a) . Note , however , tha t th e rol e o f lea dinth e occurrenc e o f huma ncance r canno t b e rule dout , give nth e inferenc e tha t th e positiv e association s see ninth e huma nstudies, - whil e no t adequat e fo r a "limited " o r a "sufficient " classification , ar e characterize da s suggestiv e ( a descripto r no t foundinth e guidelines) . Th e suggestiv e circumstanc e raise s a concer nabou t th e potentia l carcinogenicit y o f lea di nhumans . Thi s concer ni s supporte db y th e suggestio no f genotoxi c effect s i nlead-expose dworkers . Turning , then , t o th e long-ter m anima l evidence , ther e i s stron g evidenc e

o f carcinogenicit y

fro m ove r two doze nstudies . Man y o f thes e studie s involv e th e ingestio no f solubl e lea dsalt s that , presumably , wer e selecte do nth e basi s o f eas e o f administration . In1 2 separat e studies , involvin g fou r ra t

9 5P.1 0

strain s an

don e mous e strai nan dinvolvin g bot hsexe s wheneve r bot hsexe s wer e tested , th e ingestio no f lea dacetat e o r lea dsubacetat e ha s bee nshow nt o induc e kidne y

tumors . Tumo r incidence s i nanimal s ingestin g maximall y tolerate ddose s o f lea dwer e ofte nunusuall y high , almos t 10 0 percent , an dth e . incidence s wer e dose-relate di nstudie s usin g mor e tha non e dose . Othe r long-ter m

anima l studie s an

dsupplementar y

informatio nprovid e evidenc e tha t thes e observation s shoul dno t be viewe da s a phenomeno nspecifi c t o th e ingestio nrout e o f exposure , t o lea dacetat e o r lea dsubacetat e only , o r t o th e kidne y

inparticular . ' A

variet y o f lea dcompound s ha s bee nshow nt o induc e tumor s b

y differen t route s o f exposure : lea dsubacetat e cause dlung tumor s b y intraperitonea l injection ; lea dphosphat e cause dkidne y tumor s b

y subcutaneou s o r intraperitonea l injection ; lea dnaphthenat e cause dkidne y tumor s b y topica l application ; lea ddimethyldithiocarbamat e cause dreticulu m cel l sarcoma s b

y ingestion ; an

dtetraethy l lea dcause dlymphoma s b y subcutaneou s injection . Lea doxid e ha s bee nshow nt o hav e cocarcinogeni c propertie s wit hbenzo[a]pyren e i ncausin g lun g carcinoma s b y intratrachea l instillation , an

dlea dsubacetat e ha s bee nshow nt o promot e kidne y

tumor s by- . ingestio nafte r initiatio nwit hN-ethyl-N-hydroxyethylnitrosamine . I n addition , lea dacetat e ha s cause dtesticula r tumor s an dlymphocyti c leukemi a b y ingestion , an

dbot hlea dacetat e an dlea dsubacetat e hav e cause dcerebra l glioma s b

y ingestion . Althoug hther e ar e severa l nonpositiv e anima l studies , the y d o no t weake n th e patter no f positiv e evidence . Severa l nonpositiv e studie s wer e conducte d fo r duration s wel l shor t o f th e minimu m accepte dduratio nfo r a cance r study . N o tumo r respons e i s expecte di nthi s case , becaus e th e study duratio nma y

no t hav e exceede dth e laten t perio dtha t mus t pas s befor e tumor s ca nb e detected .
9 6P.1 1

Th e othe r nonpositiv e studie s wer e conducte da t dose s wel l belo w th e maximum tolerate ddose . Again , no tumo r respons e i s expected , base dona linea r extrapolatio no f th e positiv e respons e see na t highe r doses . I nfact , studie s tha t ar e clearl y

positiv e a t highe r dose s sho w n o tumo r respons e a t thes e lowe r doses . (Sectio n2. 3 discusse s thi s point , showin g why n o tumor s ar e expecte d

a t th e lowe r dose s an dexplainin g why

thi s i s consisten t wit hth e positiv e respons e see na t highe r doses. ) Non e o f th e positiv e studie s ha s bee nprecede d

o r followe db

y a tru e replicat e negativ e study . Th e dose s tha t induc e tumor s d o s o instudy

afte r study . Th e nonpositiv e studie s cannot , therefore , b e use d t o discoun t th e positiv e evidence . Lookin g a t thes e result s acros s th e differen t form s o f lead , severa l lea d compound s hav e bee nshow nt o b e carcinogenic . Supplementar y informatio nha s show nsevera l othe r form s o f lea dt o b e bioavailabl e and , therefore , highl y likel y t o b e carcinogeni c a t some dose . Considerin g tha t n o lea dcompoun dca n b e calle dnegativ e fo r eithe r carcinogenicit y o r bioavailability , ther e appear s t o b e no evidenc e a t thi s time t o rul e ou t an y form o f lea da s a potentia l carcinogen . Alternatively , lookin g a t thes e result s acros s th e differen t route s o f
exposure , severa l route s hav e bee nshow nt o induc e tumor s a t dista l sites . Fo r example , kidne y

tumor s hav e resulte dfro m exposur e t o lea di nfood , i ndrinkin g water , b

y topica l application , b y subcutaneou s injection , an db y intraperitonea l injection . Supplementar y informatio nha s show nthat inhalatio ni s a

nefficien t rout e o f systemi c absorptio no f lead , contributin g t o th e body

burde no f lea dand , therefore , als o highl y likel y t o provid e th e circumstance s fo r carcinogeni c activity . Considerin g tha t al l route s o f



### 97P.1 2

exposur e ca nresul t insystemi c absorption , ther e appear s t o b e no evidenc e a t thi s tim e t o rul e ou t an y rout e o f exposur e a s potentiall y carcinogenic . I t i s noteworth y

tha t th e injectio nstudie s show tumor s a t lowe r tota l dose s tha nth e ingestio nstudies . Thi s support s th e positio ntha t lea dma y b e carcinogeni c t o th e degre e tha t i t i s bioavailabl e fo r absorptio nint o th e body

andcirculatio nt o targe t tissues . Inhalationstudie s hav e show ntha t deposite dlea ddoe s no t accumulat e i nth e lung , indicatin g tha t i s take nup int o th e bloodstrea m

an dcirculate dt o dista l targe t sites . Ingestio nstudie s hav e show

ntha t ther e i s absorption--a t differen t relativ e rates--o f lea dan da variet y o f lea dcompounds , includin g lea dacetate , lea dcarbonate , lea d tallate , lea dsulfide , lea dnaphthenate , lea doctoate , lea dchromate , lea d chloride , lea doxide , an dtetraethy l lead . Acidi c condition s facilitat e th e absorptio no f inorgani c lea dcompounds , some o f whic hotherwis e woul db e relativel y

insolubl e .i

nstandardreferenc e wate r solutions , throug hconversio n t o mor e soluble , an

dhenc e mor e bioavailable , compound s suc ha s lea dchloride . Tetraalky l lea dcompound s ar e metabolize d t o trialky l lead , whic hintur ni s metabolize dt o dialky l lead , whic hi s finall y converte dt o inorgani c lea d in, th e intestine . Th e formatio no f inorgani c lea dha s bee nobserve di nsevera l anima l specie s expose dt o alky l lead . Thus , ther e appear s t o b e n o evidenc e t o rul e ou t th e potentia l fo r bioavailabilit y o f any lea dcompoun dt o som e degree . I t i s als o interestin g t o not e tha t th e ingestio nstudif s i nwhic hlea d induce dcerebra l gliomas , testicula r tumors , reticulum cel l sarcomas , o r variou s othe r tumor s wer e al l conducte da t exposur e level s wel l belo w th e maximum tolerate ddose . Thi s suggest s tha t lea dma y ac t t o induc e cance r a t a variet y o f sites , a t lowe r exposur e level s tha nthos e tha t clearl y caus e kidne y tumors . Th e inductio no f cance r a t othe r site s i s consisten t wit hth e

9 8P.1 3

pharmacokinetic s o f lead , whic hindicat e tha t lea di s distribute dt o many site s i nth e body , includin g th e site s o f some o f thes e tumors . Th e inductio no f

cance r a t lowe r exposur e level s i s consisten t wit hth e abilit y o f lea dt o caus e othe r advers e healt heffect s a t lowe r exposur e level s an dwit hth e recen t study showin g tha t lea dstimulate s protei nkinas e C a t picomola r concentrations . Th e evidenc e fo r thes e othe r tumors , however , i s les s robus t tha ntha t fo r kidne y tumors . Take ntogether , th e long-term anima l studie s for

m a compellin g patter no f evidence . Lea dcause s cance r b y severa l route s o f exposur e anda t a numbe r o f sites . Thes e finding s hav e bee ndemonstrate dina larg e numbe r o f roden t studies , i nsevera l specie s an dstrains , an

dinbot hsexes . A

dose-respons e tren dha s bee ndemonstrated , a s tumo r incidence s increas e wit hexposur e t o

reac hver y

hig hproportion s a t th e highes t exposur e level s tested . Althoug h th e studie s hav e limitation s indesig no r conduc t whe nconsidere dseparately , th e limitation s d o no t outweig hth e positiv e evidenc e fro m thes e studie s considere da s a whole . Th e evidenc e o f carcinogenicit y fro m long-ter m

anima l studie s is , therefore , considere dt o b e "sufficient " accordin g t o EPA' s Guideline s fo r Carcinoge nRis k Assessmen t (U.S . EPA , 1986a) . Evidenc e fro

m short-ter m

test s suggest s tha t lea dcompound s ar e genotoxic . Briefly , lea dcompound s hav e teste dnegativ e fo r poin t mutation s i nbacteria , bu t hav e teste dpositiv e fo r induce dgen e mutation ? inculture dmammalia n cells . Bot hpositiv e an dnegativ e result s hav e bee nobserve dfo r chromosom e aberration s i nhighe r organisms . I ngeneral , th e positiv e response s fo r genotoxicit y

appea r t o depen do

nfactor s suc ha s th e tes t system , th e duratio n

an drout e o f exposure , an dth e harves t tim e followin g exposure . Althoug hth e mechanis m

throug hwhic hlea dinduce s chromosoma l aberration s an dmutation s i s

9 9p.1 *

unknown , th e patter no f response s suggest s tha t lea d compound s ma y no t directl y damag e th e geneti c material , bu t rathe r ma y ac t throug ha

nindirec t mechanism . Nevertheless , th e result s o f th e genotoxicit y studie s collectivel y lend suppor t t o th e huma nan

d anima l evidenc e fo r carcinogenicity . Lea d compound s hav e induce d cel l transformation s inroden t tissu e cultur e cells . Lea d ha s recentl y bee nshow

nt o activat e th e enzyme , protei nkinas e C , th e putativ e cellula r recepto r fo r tumor-promotin g phorbo l esters . Lea d ca n activat e th e enzym e t o level s tha t normall y requir e a m

i 11ionfol d greate r concentratio no f th e norma l endogenou s activator , calcium . Anima l studie s hav e show ntha t some lea d compound s hav e tumo r promotin g potentia l o r cocarcinogeni c activity . Lea d compound s hav e als o bee nshow nt o stimulat e proliferatio nin

rena l tubula r epithelia l cell s an d ar e considere d t o b e poten t mitogens . Th e questio no f lead' s mechanis m o f actio nan

d th e presenc e o r absenc e o f

a practica l dose-respons e threshol d ha s no t bee ndemonstrate d b y dedicate d scientifi c studie s an d thu s i s a matte r fo r speculatio na t thi s time . Suc h uncertaintie s d o no t provid e a basi s t o alte r th e weigh t o f evidenc e fo r huma n carcinogenicity . Th e evidenc e ontoxi c effect s othe r tha ncance r show s tha t th e noncance r patholog y i s simila r fo r fou r compound s (lead acetate , lea d subacetate , lea d phosphate , an d lead naphthenate ) tha t induc e simila r type s o f kidne y tumors . Th e same kidne y pathology , alon g wit hth e presenc e o f nuclea r inclusio nbodie s followin g thes e exposures , ha s bee nobserve d inrat s an d mic e wit hsubchroni c exposur e t o highe r dose s o f lea d dimethyldithiocarbamate , eve n thoug hchroni c exposur e t o lowe r dose s di d no t induc e cancer . Th e presenc e o f nuclea r inclusio nbodie s inth e kidne y ma y be relate d t o th e carcinogeni c effect s o f lead . Althoug hth e kidne y patholog y

tha t ha s bee nreporte d ha s no t bee ndefinitivel y

linke d t o kidne y

cancer , th e fac t tha t a variet y o f lea d

10 0P.1 5

compound s induc e simila r oncogeni c an dnononcogeni c pathologi c change s suggest s tha t lea ditsel f i s likel y t o b e th e activ e agent . Integratin g al l source s o f informatio nint o a noveral l weigh t o f evidenc e fo r carcinogenicity , th e combinatio no f "sufficient " evidenc e fro m anima l studie s and"inadequate " evidenc e fro m huma nstudies , alon g wit hth e relevan t supportiv e informatio nfro m short-ter m

tests , othe r toxi c effects , an d pharmacokineti c properties , yield s a nassignmen t t o weight-of-evidenc e Grou pB 2 unde r EPA' s Guideline s fo r Carcinoge nRis k Assessmen t (U.S . EPA , 1986a) . Th e overal l classificatio nreflect s th e evidenc e tha t lea dcause s cance r b y severa l route s o f exposur e an da t a numbe r o f sites ; tha t thes e finding s hav e bee n demonstrate dina larg e numbe r o f studies , insevera l specie s an dstrain s o f rodents , andi nbot hsexes ; tha t a dose-respons e tren dha s bee ndemonstrated ,
a s tumo r incidence s increas e wit hexposur e t o reac hver y hig hproportion s a t th e highes t exposur e level s tested ; an dtha t th e pharmacokinetic s o f lea d
suppor t th e consideratio no f lea dan dit s compound s togethe r i nanevaluatio n

o f potentia l carcinogenicity . Base do nthi s overal l evaluation , lea dan dlea d compound s ar e considere dt o b e probabl e huma ncarcinogens . Thes e conclusion s ca nb e pu t int o perspectiv e b y reviewin g th e historica l conclusion s reache db y othe r well-respecte d cance r organizations . I n1980 , th e Internationa l Agenc y

fo r Researc ho

nCance r (IARC , 1980 ) classifie dlea d subacetate , lea dacetate , an dlea dphosphat e inGrou p2B . IARC' s Grou p2 B i s simila r t o EPA' s Grou pB 2 i ntha t bot hclassification s requir e "sufficient " evidenc e fro

m anima l studie s an

d"inadequate " evidenc e fro m huma nstudies . I

n

a subsequen t supplement , IARC (1987 ) extende dthi s classificatio nt o includ e lea dandal l inorgani c lea dcompounds . Organi c lea dcompound s wer e determine d

no t t o hav e a

nadequat e dat a bas e fo r classificatio nunde r th e IAR C scheme .

10 1P.1 6

Meanwhile , th e Nationa l Toxicolog y Program

(NTP , 1985) , i nit s Fourt hAnnua l Repor t onCarcinogens , discusse dlea dan dconclude dtha t Th e toxicologi c (an

dcarcinogenic ) ris k fro m a meta l i s ofte na propert y les s o f th e for

m o f th e meta l administere dtha no f th e meta l pe r se . Th e anio no r ligan do f th e meta l ca ndetermin e th e physico chemica l propertie s whic hthe naffec t characteristic s suc ha s solubility , absorption , distributio nt o site s believe dt o b e involve d i ncarcinogenesis , etc . Thus , i f an y lea dcompound s ar e carcinogenic , the nal l compound s containin g lea dar e potentiall y carcinogenic . Thi s als o applie s t o th e elementa l metal , give nth e propert y o f mos t tissue s o f bein g abl e t o solubiliz e mos t metal s t o some degree . Th e conclusion s reache di nthi s repor t ar e consisten t wit han dare , infact , a natura l extensio no f th e conclusion s reache db y IARC an

dNTP . EPA' s conclusion s ca nb e viewe da s takin g IARC' s classificatio no f lea dan dal l inorgani c lea dcompound s i nGrou p2B , andextendin g i t a s suggeste db y NT P t o includ e lea dandal l lea dcompounds . Thes e conclusion s follo w from th e simultaneou s consideratio no f th e cance r studies , whic hshow tha t severa l lea d compound s induc e cancer , an dth e pharmacokineti c evidenc e o nlead , whic h indicat e tha t thes e finding s appl y t o lea dan

dothe r lea dcompound s a s well . A s a fina l note , befor e beginnin g wor k o nthi s report , EPA

consulte d

severa l meta l carcinogenicit y expert s regardin g th e weigh t o f evidenc e and

cance r potenc y

o f lea dandinorgani c lea dcompounds . InApri l 1986 , a pane l o f expert s (Ro

y E . Albert , M.D. , Universit y o f Cincinnat i Medica l Center ; Pau l Hammond , D.V.M. , Ph.D. , Universit y o f Cincinnat i Medica l Center ; Ma xCosta , Ph.D. , Ne w Yor k Universit y

Medica l Center ; an

dRober t P . Beliles , Ph.D. , D.A.B.T. , U.S . Environmenta l Protectio nAgency ) reviewe devidenc e onth e carcinogenicit y

o f lea dan

dinorgani c lea dcompounds . Th e pane l conclude dtha t th e evidenc e fo r inorgani c lea dcompound s satisfie s th e criteri a fo r a weight of-evidenc e Grou pB

_classification , andraise da concer nfo r any form o f lea d



### 10 2P.1 7

tha t coul d add t o th e overal l bodyburden

. Th e pane l furthe r recommende d tha t comparativ e cross-specie s pharmacokineti c model s b e develope d t o provid e a n appropriat e basi s fo r extrapolatin g th e cance r potenc yt o humans , i f suc h an extrapolatio n i s t o b e attempted

.



### 10 32 . POTENC Y

2.1 . GENERA L METHODOLOG Y Onc e a substanc e ha s bee ndetermine d t o b e a potentia l carcinogen , i t i s natura l t o tr y

t o describ e it s potency , whic hmeasure s th e strengt ho f th e substanc e t o caus e cancer . Potency , fo r toxi c effect s ingeneral , i s measure d b y th e dos e require d t o caus e a particula r effec t o r leve l o f effect . Ondifferen t occasion s wit hdifferen t objectives , EPA ha s use d two differen t approache s t o characteriz e th e potenc y o f carcinogens . On e approac h i s t o obtai na plausibl e uppe r bound onth e increase d cance r ris k resultin g fro m low-leve l exposures . Thi s approac hassume s tha t ther e ma y b e a linea r relationshi p betwee nth e leve l o f exposur e t o a carcinoge nan d th e resultin g increas e inth e ris k o f some for m o f cancer . Th e strengt ho f a carcinoge ni s characterize d b

y th e slop e o f thi s linea r relationship . Unde r thi s approach , a mathematica l mode l i s fitte d t o th e dose-respons e dat a an d use d t o extrapolat e dow nt o low

doses . Becaus e th e slop e a t low dose s ca nb e extremel y sensitiv e t o smal l change s inth e observe d data , a nuppe r bound o

nth e slop e i s estimated . Thi s uppe r boun d ca nb e viewe d a s th e steepest slop e tha t i s stil l consisten t wit hth e observe d dose-respons e data . Thi s approac hi s mos t completel y

describe d inU.S . EPA , 1980 . Some strength s an d limitation s o f thi s approac har e discusse d i nEPA' s Guideline s fo r Carcinoge nRis k Assessmen t (U.S . EPA , 1986a) . Thi s approac hi s mentione d her e onl y fo r perspective , an d i s neithe r use d no r discusse d furthe r inthi s report . EP A ha s chose na

nalternativ e approac hfo r makin g reportabl e quantit y adjustment s pursuan t t o CERCL A Sectio n10 2 (U.S . EPA , 1986b) . Unde r thi s alternativ e approach , th e measur e o f potenc y i s th e dos e associate d wit han

10 4P.1 9

increase dcance r incidenc e o f 1 0 percent . A mathematica l mode l i s fitte dt o th e dose-respons e dat a an duse dt o estimat e th e equivalen t huma ndos e associate dwit ha

nincrease dcance r incidenc e o f 1 0 percent . Th e 10-percen t leve l ha s bee nchose nbecaus e mos t anima l studie s tha t show a nincreas e in

cance r includ e a dos e wher e th e increase dincidenc e i s nea r 1 0 percent . Thi s approac hha s severa l advantages :

a . I t doe s no t requir e extrapolatio nbeyon dth e observe ddos e range . b . I t i s relativel y

insensitiv e t o th e choic e o f a mathematica l dose respons e model , becaus e al l model s tha t fi t agre e quit e wel l acros s th e observe ddos e range .
c . I t doe s no t introduc e th e us e o f statistica l uppe r bounds , whic hca n distor t comparison s an drelativ e rankings . d . I t matche s th e availabl e dat a i nit s relativ e leve l o f sophisticatio n—

th e mathematic s d o no t outstri pth e informatio n containe di nth e dose-respons e data . Th e disadvantage s o f thi s approac hare :
a . I t estimate s th e potenc y "a t anincrease dcance r incidenc e o f 1 0 percen t and , therefore , doe s no t necessaril y reflec t pharmacokineti c propertie s o r cellula r mechanism s tha t ma y operat e a t lowe r doses . b . I t i s no t a low-dos e extrapolatio nand , therefore , shoul dno t b e use d t o mak e inference s abou t cance r risk s tha t ma y resul t from

dose s tha t

ar e severa l order s o f magnitud e belo w th e observe ddos e range . Th e dos e associate dwit ha nincrease dcance r incidenc e o f 1 0 percen t ca n b e use dt o qualitativel y characteriz e th e potenc y o f a carcinoge na s high ,



### 10 5medium , o r low , relativ e t o othe r carcinogens . Th e distinction s ar e mad e a s

follows : Grou p 1 . Highpotency . Th e dos e i s below 0.0 1 mg/kg*d . Grou p 2 . Mediu

m potency . Th e dos e i s betwee n0.0 1 an d 1 mg/kg*d . Grou p 3 . Lo

w potency . Th e dos e i s abov e 1 mg/kg'd . Abou t a quarte r o f th e potentia l carcinogen s evaluate d t o dat e ar e inpotenc y Group s 1 an

d 3 , an d abou t hal f ar e inpotenc y Grou p 2 .

2.2 . DAT A

SELECTIO N Lea d i s certainl y

on e o f th e mor e extensivel y studie d toxi c substances , qualitatively , i f no t quantitatively . Muc hi s know nabou t wha t happen s whe n human s ar e expose d t o lead , an d many o f th e advers e healt heffect s o f lea d hav e bee nwel l documented . Base d o nhuma nstudies , dose-respons e relationship s hav e bee ndescribe d fo r severa l advers e healt heffects . Fo r cancer , however , th e huma nstudie s canno t b e use d t o describ e a dose-respons e relationship , becaus e

o f th e lac k o f a measur e o f lea d exposur e an d becaus e o f confoundin g exposure s t o othe r carcinogens . Therefore , a descriptio no f th e dose-respons e relationshi p fo r cance r o r a nestimat e o f th e cance r potenc y o f lea d must , a t thi s time , conside r th e anima l studies . A nexaminatio no f th e anima l studie s summarize d inTabl e 1- 1 indicate s tha t a respons e o f obviou s concern , a s wel l a s th e mos t sensitiv e response , i s th e inductio no f kidne y tumor s b

y lead . Thi s i s als o th e mos t extensivel y studie d cance r respons e inanimals . Th e huma nstudie s ar e somewha t supportiv e

o f th e choic e o f thi s response , wit hsuggestiv e evidenc e o f a nassociatio n betwee nlea d and kidne y cancer . Huma nexposur e t o hig hlevel s o f lea d ha s als o



### 10 6P.2 1

bee nreflectedb

y kidne y toxicit y

an db y hig hlevel s o f lea di nth e kidney . Lung cancer , whic hha s als o bee nsuggeste db y th e huma nstudies , ha s bee n induce di

nanimal s b

y bot hintraperitonea l injectio nan dintratrachea l instillation . A t thi s time , however , ther e i s no accepte dmethodolog y fo r usin g thes e route s o f exposur e t o estimat e th e cance r potenc y fo r route s o f environmenta l exposure , an dthu s th e lung tumo r respons e canno t b e quantitativel y

assessed . Fo r characterizin g th e cance r potenc y b y environmenta l exposure , studie s b y a rout e correspondin g t o environmenta l exposur e ar e preferred . Becaus e ther e ar e n o cance r studie s o nth e inhalatio no f lead , thi s leave s onl y ingestio nb

y foo do r drinkin g water . Althoug hlea dha s cause dkidne y cance r b

y topica l application , a t thi s time , ther e i s n o wa y t o determin e th e exten t t o whic hth e absorptio no f lea dthroug hth e ski nwa s enhance db y th e us e o f a benzen e solution . Althoug hlea dha s cause dkidne y cance r b

y subcutaneou s o r intraperitonea l injection , a t thi s time , ther e i s no wa y o f inferrin g th e environmenta l exposure s tha t woul dbe equivalen t t o th e directl y injecte d doses .

2.3 . POTENC YESTIMATIO N AN D CHARACTERIZATIO N Th e dose-respons e informatio ncompile dinTable s 1- 1 an d1- 2 reveal s that , wit hon e exception , al l group s o f rat s ingestin g a tota l o f a t leas t 1 0 g o f lea dhada

nincrease dcance r incidenc e o f a t leas t 1 0 percent . Th e exception , th e femal e rat s ingestin g a tota l o f 1 4 g o f lea dinth e Aza r e t al . (1973 ) study , i s balance db

y th e mal e rats , whic hhada 5 0 percen t incidenc e o f kidne y tumor s a t th e same dos e an da 1 0 percen t incidenc e a t a tota l dos e o f 7 g . Animal s ingestin g n o mor e tha n1 g o f lea dshowe dn o kidne y cance r respons e

10 7P.2 2

(althoug hvariou s othe r tumor s sometime s develope d a t tota l lea d dose s belo w 1 g , an d kidne y

tumor s wer e repeatedl y induce d b

y injection s o f lea d totallin g les s tha n1 g) . Therefore , th e tota l ingeste d lea d dos e associate d wit ha n increase d cance r incidenc e o f 1 0 percen t appear s t o b e betwee n1 an d 1 0 g fo r th e rats . Fo r compariso nwit hothe r potentia l carcinogens , thi s dos e i s expresse d i n unit s o f milligram s o f lea d pe r kilogram o f body

weigh t pe r da y

(mg/kg'd) . Assumin g tha t rat s weig h0.35 0 kg , a tota l lead dos e o f 1-1 0 g i s approximatel y equa l t o 3000-30,00 0 mg/k g ove r th e duratio no f th e studies . (Som e rat s weighe d more , whic hwoul d resul t i nproportionall y

lowe r doses. ) A s th e studie s generall y

laste d u

p t o 2 4 months , o

na dail y

basi s thi s i s approximatel y

equa l t o 4-4 0 mg/kg' d fo r th e rats . Thi s appear s t o b e a relativel y

highdail y

dose . Analyzin g th e mous e studie s i na simila r manner , th e informatio ni s sketchy , bu t th e patter ni s similar . Mic e ingestin g a tota l o f a t leas t 2 g o f lea d ha d a

nincrease d cance r incidenc e o f approximatel y 1 0 percen t o r more . Mic e ingestin g n o mor e tha n0. 2 g o f lea d showe d n o kidne y cance r respons e (althoug hothe r tumor s sometime s develope d a t lowe r tota l lea d doses) . Therefore , th e tota l ingeste d lea d dos e associate d wit ha nincrease d cance r incidenc e o f 1 0 percen t appear s t o b e betwee n0. 2 an d 2 g . Assumin g tha t mic e weig h0.03 0 kg , a tota l lea d dos e o f 0.2- 2 g i s approximatel y equa l t o 7000 - 70,00 0 mg/k g ove r th e duratio no f th e studies . A s th e studie s generall y laste d

up t o 2 4 months , o na dail y basi s thi s i s approximatel y equa l t o 9-9 0 mg/kg' d fo r th e mice .



### 10 8P.2 3

I nth e absenc e o f comparativ e toxicologic , physiologic , metabolic , an d pharmacokineti c information , EPA' s Guideline s fo r Carcinoge nRis k Assessmen t (U.S . EPA , 1986a ) cal l fo r makin g cross-specie s extrapolation s base do na surface-are a adjustment . Fo r reason s tha t wil l be mor e full y discusse di

n Sectio n2.4 , th e pharmacokineti c informatio ncurrentl y availabl e indicate s tha t

a surface-are a adjustmen t woul dprobabl y be misleading , althoug hth e informatio ni s no t adequat e fo r validatin g an y alternativ e adjustment . A substantia l bod

y o f accumulate dinformatio nindicate s tha t a variet y o f factors , some o f whic hma y be uniqu e t o lead , ar e involve dinlead-induce d

cancer . O f foremos t concer nar e th e potentia l difference s inpharmacokinetic s betwee nanimal s an

dhumans , s o tha t a cross-specie s extrapolatio nfro m anima l studie s t o estimat e th e cance r potenc y fo r human s canno t credibl y be base do

n anima l dat a alone , bu t shoul dinclud e cross-specie s pharmacokineti c modeling . Therefore , no cross-specie s extrapolatio no r quantitativ e cance r potenc y estimat e i s bein g mad e fo r lea da t thi s time . Nevertheless , becaus e o f th e consisten t patter no f result s fro m a larg e numbe r o f studies , i nwhic hi t ha s bee nrelativel y hig hconcentration s o f lea d

I f dose s ar e equivalen t whe nexpresse dona surface-are a basis , the n 2/ 3 2/ 3 m g human /kg huma n = mg animal /kg anima l Algebrai c manipulatio nyield s 1/ 3

m g human /kg huma n = mg animal /kg anima l x(kg animal /kg human ) Assumin g human s weig h7 0 k g an drat s weig h0.35 0 kg , thi s i s approximatel y

m g human/ k g huma n = mg animal /kg anima l x(1/6 ) Assumin g mic e weig h0.03 0 kg , thi s i s approximatel y

m g human/ k g huma n = mg animal /kg anima l x(1/13 > 10 9P.2 4

tha t hav e increase dth e incidenc e o f kidne y cance r i nanimals , i t seem s appropriat e a t thi s time t o qualitativel y characteriz e th e cance r potenc y o f lea da s low , relativ e t o othe r carcinogens . Thi s characterizatio nwoul dplac e lea di npotenc y

Grou p3 , a s define dearlie r inth e sectio nongenera l methodolog y

fo r adjustin g CERCL A reportabl e quantities . Thi s characterizatio nreaffirm s th e positio ntha t EPA ha s previousl y taken . Th e Ai r Qualit y Criteri a fo r Lea d(U.S . EPA , 1986c ) conclude d

. . . lea dha s bee nobserve dt o increas e tumorigenesi s rate s in animal s onl y

a t relativel y

hig hconcentrations , an dtherefor e i t doe s no t appea r t o b e a poten t carcinogen . . . . J_ nvitr o studie s furthe r suppor t th e genotoxi c an dcarcinogeni c rol e o f lead , bu t als o indicat e tha t lea di s no t poten t inthes e system s either . Befor e proceedin g wit hth e discussio ninth e nex t section , some observation s shoul db e mad e abou t th e apparen t absenc e o f kidne y tumor s a t lowe r doses . Thi s absenc e o f tumor s doe s no t demonstrat e a threshol dfo r lead induce dcancer . A s ha s bee nnote dearlier , othe r tumor s sometime s develope da t tota l lea ddose s belo w 1 gram , an

dkidne y tumor s wer e repeatedl y induce db

y injection s o f lea dtotallin g les s tha n1 gram . Additiona l informatio nca nb e develope dfrom

th e Aza r e t al . (1973 ) study , which , wit hseve ndifferen t lea d concentrations , i s th e mos t comprehensiv e stud y o f lea dingestio na t lowe r doses . Th e study

include s th e highes t tota l lea ddose s a t whic hn o tumor s wer e reported . Th e linearize dmultistag e mode l (U.S . EPA , 1980 ) ca nb e use dt o estimat e how

man y rat s woul db e expecte dt o develo pkidne y tumor s - f th e dose respons e relationshi pi s trul y linea r a t lo

w doses . A s th e followin g tabl e indicates , th e observe dresult s ar e virtuall y identica l t o th e result s expecte d wit ha linea r model . Non e o f th e smal l difference s ar e statisticall y significan t ( p> 0.10) . Thi s indicate s tha t th e anima l studie s di dnot , i n general , hav e adequat e powe r t o detec t a nincreas e i nkidne y

cance r a t lowe r

11 0doses

. Thi s analysis , therefore , demonstrate s tha t th e result s o f th e anima l

studie s ar e no t inconsisten t wit h a linea r dose-respons e relationship , eve n a t th e lowes t dose s tested

. I t shoul d b e noted, however , tha t thi s inferenc e doe s

no t rul e ou t a threshol d response , and tha t th e dat a ar e als o no t inconsisten t wit h suc h a n inference

.

Compariso n o f th e Aza r e t al

. (1973 ) stud yan d a linea r mode l

Lea d acetat e concentratio n (pp min food )

Mal e rat s 5



### 1 8 6 2 

### 141 54 8 113 0 210 2 Numbe r exoecte d = (1.14xl0" 4 x Con e +

Femal e rat s 5



### 1 8 6 2 

### 14 1 54 8 113 0 210 2 Numbe r expecte d = (2.23xl0" 5 x Con e Numbe r

2.07x 1

Numbe r + 4.3 0 Numbe r

o f rat s teste d



### 12 0 5 0 5 0 5 0 5 0 2 0 2 0
teste d x 0"" 7 x Cone


### 12 0 5 0 5 0 5 0 5 0 2 0 2 0 Numbe r

observe d wit h tumor s


### 0 0 0 0 5 1 0 1 6

2 + 6.62x10 "



### 0 0 0 0 0 0 7
teste d x xlO" 2 1 x Cone 6 Numbe r expecte d fro mmode l


### 0. 1 0. 1 0. 4 1. 0 6. 8 9. 8 N.C
.

1 1 x Cone 3

.


### 0. 0 0. 0 0. 1 0. 2 0. 6 0. 7 8. 4

2.4
. DISCUSSIO N Th e calculation s i n th e precedin g sectio n ar e somewha t simplistic

. A variet yo f complicatin g factors , som e o f whic h ma yb e uniqu e t o lead , ar e



### 11 1involve d i nlead-induce d cancer . O f foremos t concer nar e th e difference s in pharmacokinetic s betwee nanimal s an d humans , s o tha t a cross-specie s extrapolatio nfro

m anima l studie s t o estimat e th e cance r potenc y fo r human s

canno t credibl y

b e base d o

nanima l dat a alone , bu t shoul d includ e cross-specie s pharmacokineti c modeling . Whil e suc hstudie s ar e now unde r way , the y

ar e no t ye t availabl e fo r use . Thes e an d othe r consideration s ar e discusse d below . Th e injectio nstudie s sho w cance r a t lowe r tota l dose s tha nth e ingestio nstudies . Thi s suggest s tha t less-than-complet e absorptio nb y ingestion , a s wel l a s b y othe r route s o f exposure , ma y mitigat e th e carcinogeni c respons e t o som e extent . I

naddition , th e injectio nan d ingestio n route s o f exposur e induc e tumor s a t a commo nsite . Thi s suggest s tha t lea d i s distribute d t o th e same targe t sites , despit e difference s i nth e rout e o f
exposure . Althoug hi t appear s tha t al l route s o f exposur e ca nresul t in absorptio no f lea d t o some extent , th e rout e o f exposur e affect s th e degre e o f absorption . Th e absorptio no f inhale d lea d furthe r depend s onparticl e siz e

an d ventilatio nrate . Becaus e th e characterizatio no f lea d a s bein g o f low potency , relativ e t o othe r carcinogens , i s base d oningestio nstudies , th e potenc y b y othe r route s o f exposur e coul d b e eithe r highe r o r lower . Similarly , althoug hi t appear s tha t al l lea d compound s ca nbe absorbe d t o some extent , severa l studie s hav e show ntha t th e specifi c for m o f lea d affect s th e degre e o f absorptio nsomewhat . Becaus e th e characterizatio no f lea d a s bein g o f low

potency , relativ e t o othe r carcinogens , i s base d on studie s usin g lea d acetat e o r lea d subacetate , th e potenc y o f othe r lea d compound s coul d b e eithe r highe r o r lower , dependin g o nth e exten t tha t th e nonlea d moiet y

o f a lea d compoun d affect s it s absorption .



### 11 2P.2 7

I ncertai nenvironments , th e absorptio no r metabolis m o f lea di s facilitate db

y chemica l conversion , whic hmake s th e lea dmor e bioavailable . Unde r acidi c conditions, - severa l lea dcompound s ar e converte dt o compound s suc h

a s lea dchloride , whic hi s mor e readil y absorbe dtha nth e paren t compound . Tetraalky l lea dcompound s ar e metabolize dt o trialky l lead , whic hintur ni s metabolize dt o dialky l lead , whic hi s finall y converte dt o inorgani c lea di n th e intestine . Th e formatio no f inorgani c lea dha s bee nobserve di nsevera l anima l specie s expose dt o alky l lead . Th e absorptio no f lea dha s als o bee nshow nt o depen dsomewha t o hth e dose . Absorptio ni

nrat s 4 hour s afte r gavag e administratio no f lea di s abou t 5 percen t ove r a wid e rang e o f dose s fro m 1 ng t o 1 0 ug , bu t fall s of f t o 1 percen t a t a dos e o f 1 mg . Th e precedin g factor s ar e no t surprisin g and , infact , ar e commo nt o othe r familie s o f compounds . Ther e are , however , severa l additiona l an d complicatin g factor s tha t seem t o b e specifi c t o lead . A s ha s bee nmentione dalready , th e pharmacokinetic s o f lea ddiffe r bot h withi nan

dacros s anima l species . Lea dabsorption , metabolism , distributio n, v patterns , an

dexcretio nthroug hth e rena l an dgastrointestina l tract s hav e al l bee nshow

nt o var y

acros s anima l species . Fo r example , th e structur e and dimension s o f th e respirator y trac t affec t th e depositio nan dabsorptio no f inhale dlead . I

ncase s wher e th e rang e o f cross-specie s difference s in absorption , metabolism , distribution , o r excretio nha s bee nquantified , th e result s indicat e th e importanc e o f cross-specie s modeling . Fo r example , biliar y clearanc e o f lea di nrabbit s i s 5 0 percen t o f tha t inrats ; indogs , th e relativ e clearanc e i s onl y 2 percen t o f tha t inrats . I nanothe r example , th e absorptio no f ingeste dlea dtypicall y range s betwee n1 0 an d1 5 percen t in

11 3adul t humans , an dabou t 5 0 percen t inchildren , bu t inrat s ma y b e n o highe r tha n5 percent . Thi s show s tha t withou t cross-specie s pharmacokineti c modeling , cance r potenc y estimate s base do

nra t studie s ma y

underestimat e huma n risks , perhap s substantiall y inth e cas e o f children . Althoug habsorption , metabolism , distribution , an dexcretio nals o var y acros s route s o f exposur e an d form s o f lead , i t i s th e difference s acros s anima l specie s tha t hav e th e mos t profoun dimplication s fo r th e extrapolatio no f anima l studie s t o projec t huma n

cance r risks . Th e relationshi pbetwee nlea dan dnutritio ni s rathe r complicated . Deficiencie s i ncertai nessentia l nutrients , suc ha s low level s o f calcium , phosphate , vitami nD , iron , copper , o r zinc , ca nenhanc e lea dabsorption , influenc e distribution , o r decreas e excretion . Somewha t surprisingly , however , th e Kasprza k e t al . (1985 ) study show s tha t th e additio no f calcium t o a die t containin g lea dca nsimultaneousl y increas e th e incidenc e o f kidne y tumor s an

d decreas e kidne y

lea dconcentration s inrats . Anothe r exampl e o f th e complicate drelationshi pbetwee nlea dan dnutritio nconcern s fasting . Th e absorptio no f ingeste dlea dtypicall y range s betwee n1 0 an d1 5 percen t i nadul t humans , bu t ma y

increas e t o betwee n2 1 an d6 3 percen t whe nfasting . Som e studie s inrat s als o indicat e tha t fastin g enhance s lea dabsorption . Onth e othe r hand , on e study show s tha t i nyoun g animal s absorptio ni s maxima l whe n growt hi s rapid , bu t absorptio ni s significantl y decrease dafte r fastin g fo r 5 days . Ag e ha s othe r pronounce deffects . Childre nabsor bapproximatel y 5 0 percen t o f ingeste dlead , compare dt o betwee n1 0 an d1 5 percen t fo r adults . Th e fractio no f absorbe dlea dretaine di nth e body range s from

betwee n1 an

d 5 percen t i nadult s t o betwee n3 2 an d3 4 percen t i nyoun g children . I t i s no t

11 4clea r how lifetime-exposur e studie s ca nbe use dt o mak e inference s abou t cance r risk s arisin g fro

m childhoo dexposure . I t appear s fro

m th e Aza r e t al . (1973 ) study an dth e Zawirsk a an

d Medra s (1968 ) study

tha t mal e Wista r rat s ar e mor e sensitiv e t o lead-induce d kidne y tumor s tha nar e femal e rats . I nth e Va nEsc he t al . (1962 ) study , however , mal e an

dfemal e Wista r rat s appea r t o b e abou t equall y sensitive . I t i s no t know

nwhethe r pharmacokineti c difference s pla y a rol e i nth e apparen t differenc e betwee nth e sexes . A few studie s conducte da t dose s wel l below th e maximu

m tolerate ddos e sugges t tha t lea dma y als o induc e cerebra l gliomas , testicula r tumors , reticulu m cel l sarcomas , an

dvariou s othe r tumors . Th e evidenc e fo r thes e othe r tumors , however , i s muc hweake r tha ntha t fo r kidne y tumors . Althoug h thes e effect s lac k th e robustnes s o f th e kidne y response , thes e studie s nevertheles s sugges t tha t lea dma y ac t t o induc e cance r a t a variet y o f sites ,
a t lowe r exposur e level s tha nthos e tha t clearl y caus e kidne y

tumors . Thi s ha s implication s fo r low-dos e extrapolation , a s i t raise s th e possibilit y o f mor e tha non e cance r response . Measuremen t o f tissu e concentration s an dsome understandin g o f cellula r mechanism s woul dai dinth e prope r interpretatio no f thes e possibl e responses . Fro m th e abov e discussio ni t i s clea r tha t man y factor s influenc e lead induce dcancer . Th e relativel y profoun dknowledg e o f lea dchemistr y indicate s th e difficultie s inselectin g a nappropriat e measur e o f dos e an dscalin g equivalen t dose s acros s anima l species . Althoug hpharmacokineti c model s hav e bee ndevelope dt o hel pexplai nsome o f th e advers e healt heffect s observe din humans , comparativ e pharmacokineti c model s acros s specie s ar e neede dfo r th e extrapolatio nfro

m high-dos e anima l studie s t o projec t huma ncance r risk s a t

11 5environmenta l exposures . Whil e suc hstudie s ar e now unde r way , the y

ar e no t ye t availabl e fo r use . I nth e meantime , an

y mode l o r cance r potenc y estimat e tha t doe s no t tak e factor s suc ha s nutritio nan dag e int o consideratio nwoul d b e highl y

unrepresentativ e fo r larg e segment s o f th e population . Fo r thes e
reasons , a specifi c cance r potenc y estimat e fo r lea dha s no t bee ncalculate da t thi s time . I t is , admittedly , a fin e distinctio nt o sa y tha t th e informatio n currentl y

availabl e i s adequat e t o qualitativel y characteriz e th e cance r potenc y bu t no t t o quantitativel y estimat e it . T o understan dthi s distinction , i t i s usefu l t o recal l tha t th e qualitativ e characterizatio ni s base donth e dos e associate dwit ha nincrease dcance r incidenc e o f 1 0 percent , an ddoe s no t necessaril y

reflec t pharmacokineti c propertie s o r cellula r mechanism s tha t ma y operat e a t lowe r doses . A credibl e quantitativ e cance r potenc y estimate , however , shoul db e base do ncross-specie s pharmacokineti c modeling . Nevertheless , th e distinctio ni s somewha t ambiguous , an dpharmacokineti c propertie s ca ninfluenc e th e qualitativ e characterizatio na s well . Lead induce dcance r ca nreasonabl y be expecte dt o depen do nth e for

m o f lead , rout e

o f exposure , anima l species , an dtarge t site . Becaus e ther e may b e a form

o f lea dmor e poten t tha nlea dacetate , a rout e o f exposur e mor e poten t tha n ingestion , ananima l specie s mor e sensitiv e tha nth e rat , o r a targe t sit e mor e sensitiv e tha nth e kidney , th e currentl y availabl e informatio ncanno t rul e ou t tha t th e potenc y

o f lea dmay

be highe r insom

e exposur e circumstance s or fo r
some sensitiv e group s inth e population . Althoug hth e Agenc y

believe s tha t adequat e informatio ni s no t currentl y availabl e fo r a credibl e quantitativ e assessmen t o f th e cance r potenc y o f lead , ther e i s hop e tha t suc hestimate s ma y b e mad e inth e future . Th e Agenc y i s

11 6P.3 1

awar e o f ongoin g researc ht o develo ppharmacokineti c model s fo r rats . Suc h effort s ar e importan t an dar e t o be encouraged , becaus e the y wil l mak e a significan t advanc e i na proces s tha t wil l eventuall y mak e possibl e cross specie s pharmacokineti c model s fo r lead .



### 11 73 . HAZAR D RANKING

3.1 . GENERA L METHODOLOG Y Th e hazar d rankin g i s a relativ e measur e o f overal l concer nabou t a potentia l carcinogen . I t combine s tw o factors—weigh t o f evidenc e an d potency—tha t th e Agenc y consider s importan t i ncharacterizin g a potentia l carcinogen . Weigh t o f evidenc e refer s t o th e strenqt ho f th e evidenc e tha t th e substanc e cause s cancer . Substance s ar e classifie d int o fiv e weight-of evidenc e groups :

Grou p A . Huma ncarcinoge n Grou p B . Probabl e huma ncarcinoge n Grou p C . Possibl e huma ncarcinoge n Grou p D . No t classifiabl e Grou p E . Evidenc e o f noncarcinogenicit y

Potenc y refer s t o th e strenqt ho f th e substanc e t o caus e cancer . Potentia l carcinogen s ar e classifie d int o thre e potenc y groups :

Grou p 1 . Hig hpotenc y (relativ e t o othe r potentia l carcinogens ) Grou p 2 . Mediu

m potenc y Grou p 3 . Lo

w potenc y
Combinin g th e weigh t o f evidenc e an d th e potency , potentia l carcinogen s receiv e a hazar d rankin g o f eithe r high , medium , o r low , relativ e t o othe r carcinogens . Thes e adjective s shoul d be interprete d no t a s a nabsolut e measur e

o f concern , bu t a s a rankin g relativ e t o othe r carcinogens . Tha t is , a carcinoge nwit ha low hazar d rankin g may , infact , b e a seriou s problem ; i t i s considere d low

onl y whe ncompare d wit hothe r carcinogens . Th e hazar d rankin g increase s a s eithe r th e weigh t o f evidenc e o r th e potenc y increases , accordin g t o th e followin g table :

11 8P.3 3

Weight-of Evidenc e Grou p A

B C D E Potenc y

Grou p 1 2 3 Hig h Hig h Mediu m Hig h Medium 

### Lo w Medium 

### Lo w Lo w No hazar drankin g No hazar drankin g

3.2 . OVERAL L CHARACTERIZATIO N Base donthei r classificatio nint o weight-of-evidenc e Grou pB 2 an dpotenc y Grou p3 , lea dan

dlea dcompound s receiv e a low hazar drankin g amon g potentia l carcinogens .



### 11 9P.3 4

REFERENCE S

Ades , A.E. ; Kazantzis , G . (1988 ) Lung cance r i na non-ferrou s smelter : th e rol e o f cadmium . Br . J . Ind . Med . 45:435-442 . America nPetroleu

m Institut e (API) . (1971 ) Th e chroni c toxicit y o f lead . Medica l Researc hRepor t #EA7102 . Washington , DC . Azar , A. ; Trochimowicz , H.J. ; Maxfield , M.E . (1973 ) Revie w o f lea d studie s in animal s carrie d ou t a t Haskel l Laboratory : two-yea r feedin g stud y an d respons e t o hemorrhag e study . In : Environmenta l Healt hAspect s o f Lead . Proceeding s o f a

nInternationa l Symposium ; Octobe r 2-6 , 1972 ; Amsterdam . Luxembourg : Commissio no f th e Europea nCommunitie s Directorat e Genera l fo r Disseminatio no f Knowledg e Cente r fo r Informatio nan d Documentation , pp . 199-210 . Baker , E.L. ; Goyer , R.A. ; Fowler , B.A. ; e t al . (1980 ) Occupationa l lea d exposure , nephropathy , an d rena l cancer . A

m J . Ind . Med . 1:139-148 . Baldwin , R.W. ; Cunningham , G.J. ; Pratt , D . (1964 ) Carcinogeni c actio no f moto r engin e oi l additives . Br . J . Cance r 18(3):503-507 . Barltrop , D. ; Meek , F . (1975 ) Absorptio no f differen t lea d compounds . Postgrad . Med . J . 51:805-809 . Bionetic s Researc hLabs , Inc . (BRL) . (1968 ) Evaluatio no f carcinogenic , teratogenic , an

d mutageni c activitie s o f selecte d pesticide s an d industria l chemicals . Volum e I . Carcinogeni c study . Repor t No . NCI DCCP-CG-1973-1-1 . Bethesda , MD . Availabl e from : NTIS , Springfield , VA , P B 22 3 159 . . Blakley , B.R . (1987 ) Th e effec t o f lea d onchemical - an d viral-induce d tumo r productio ninmice . J . Appl . Toxicol . 7:167-172 . Boyland , E. ; Dukes , C.E. ; Grover , P.L. ; Mitchley , B.C.V . (1962 ) Th e inductio n o f rena l tumor s b

y feedin g lea d acetat e t o rats . Br . J . Cance r 16:283 - 288 . Buchet , J.P. ; Roels , H. ; Bernard , A. ; Lauwerys , R . (1980 ) Assessmen t o f rena l functio no f worker s expose d t o inorgani c lead , cadmium , o r mercur y vapor . J . Occup . Med . 22:741-750 . [As cite d inGoyer , 1985] , Cantor , K.P. ; Sontag , J.M. ; Held , M.F . (1986 ) Pattern s o f mortalit y amon g plumber s an

d pipefitters . Am . J . Ind . Med . 10:73-89 . Castagna , . ; e t al . (1982 ) Direc t activatio no f calcium-activated , phospholipid-dependen t protei nkinas e b y tumor-promotin g phorbo l esters . J . Biol . Chem . 257:7847-7851 .



### 12 0P.3 5

Casto , B.C. ; Meyers , J. ; DiPaolo , F.A . (1979 ) Enhancemen t o f vira l transformatio nfo r evaluatio no f th e carcinogeni c potentia l o f inorgani c lead . Cance r Res . 39:193-197 . Chamberlain , A.C ; Heard , M.J. ; Little , P. ; Newton , D. ; Wells , A.C ; Wiffen , R.D . (1978 ) Investigation s int o lea dfro m moto r vehicles . Harwell , Unite dKingdom : Unite dKingdom Atomi c Energ y

Authority ; repor t no . AERE R9198 . Chiang , C.L . (1961 ) Vita l Statistic s Spec . Rep . 47:275 . [As cite dinKan g e t al. , 1980] . Choie , D.D. ; Richter , G.W . (1972a ) Cel l proliferatio ni nra t kidney s afte r prolonge dtreatmen t wit hlead . Am . J . Pathol . 68:359-370 . [As cite di n Choi e an dRichter , 1980] . Choie , D.D. ; Richter , G.W . (1972b ) Cel l proliferatio ninra t kidne y induce d b y lea dacetat e an

deffect s o f uninephrectom y onth e proliferation . Am . J . Pathol . 66:265-275 . [As cite di nChoi e an

dRichter , 1980] . Choie , D.D. ; Richter , G.W . (1974 ) Cel l proliferatio ni nmous e kidne y

induce d b y lead . I . Synthesi s o f deoxyribonuclei c acid . Lab . Invest . 30:647-651 . Choie , D.D. ; Richter , G.W . (1980 ) Effec t o f lea do nth e kidney . In : Singhal , R.L. ; Thomas , J.A. , eds . Lea dtoxicity . Baltimore , MD : Urba nand Schwarzenberg , pp . 187-312 . Choie , D.D. ; Richter , G.W. ; Young , L.B . (1975 ) Biogenesi s o f intranuclea r lead-protei ninclusion s i nmous e kidney . Beitr . Pathol . 155:197-203 . Columbano , A ; Ledda , G.M. ; Sirigu , P ; Perra , T. ; Pani , P . (1983 ) Live r cel l proliferatio ninduce db y a singl e dos e o f lea dnitrate . Am . J . Pathol . 110:83-88 . Columbano , A. ; Ledda-Columbano , G.M. ; Coni , P.P. ; e t al . (1984 ) Live r hyperplasi a an

dregressio nafte r lea dnitrat e administration . Toxicol . Pathol . 12:89-95 . Columbano , A ; Ledda-Columbano , G.M. ; Coni , P. ; Pani , P . (1987a ) Failur e o f mitogen-induce d cel l proliferatio nt o achiev e initiatio no f ra t live r carcinogenesis . Carcinogenesi s 8:345-347 . Columbano , A. ; Ledda-Columbano , G.M. ; Lee , G. ; Rajalakshmi , S. ; Sarma , D.S.R . (1987b ) Inabilit y

o f mitogen-induce d live r hyperplasi a t o suppor t th e inductio no f enzyme-altere disland s induce db y live r carcinogens . Cance r Res . 47:5557-5559 . Conrad , M.E. ; Barton , J. C (1978 ) Factor s affectin g th e absorptio nand excretio no f lea di nth e rat . Gastroenterolog y 74:731-740 . Cooper , W.C . (1976) . Cance r mortalit y pattern s i nth e lea dindustry . Ann . N.Y . Acad . Sci . 271:250-259 . 12 1P.3 6

Cooper , C.W. ; Gaffey , W.R . (1975 ) Mortalit y o f lea d workers . J . Occup . Med . 17(2):100-107 . Cooper , W.C ; Wong , 0. ; Kheifets , L . (1985 ) Mortalit y amon g employee s o f lead batter y plant s an

d lead-producin g plants , 1947-1980 . Scand . J . Wor k Environ . Healt h11:331-345 . Deknudt , Gh. ; Gerber , G.B . (1979 ) Chromosoma l aberration s inbone-marro w cell s o f mic e give na norma l o r a calcium-deficien t die t supplemente d wit h variou s heav

y metals . Mutat . Res . 68:163-168 . Deknudt , Gh. ; Leonard , A. ; Ivanov , B . (1973 ) Chromosom e aberration s observe d i nmal e worker s occupationall y expose d t o lead . Environ . Physiol . Biochem . 3:132-138 . Deknudt , Gh. ; Colle , A ; Gerber , G.B . (1977a ) Chromosoma l abnormalitie s in lymphocyte s fro

m monkey s poisone d wit hlead . Mutat . Res . 45:77-83 . Deknudt , Gh. ; Manuel , Y ; Gerber , G.B . (1977b ) Chromosoma l aberration s i n worker s professionall y expose d t o lead . J . Toxicol . Environ . Healt h 3:885-891 . Dingwall-Fordyce , I. ; Lane , R.E . (1963 ) A follow-u p stud

y o f lea d workers . Br . J . Ind . Med . 20:313-315 . Dunkel , V.C ; Pienta , R.J. ; Sivak , A. ; Traul , K.A . (1981 ) Comparativ e neoplasti c transformatio nresponse s o f Balb/3T 3 cells , Syria nhamste r embry o cells , an

d Rausche r murin e leukemi a virus-infecte d Fische r 34 4 ra t embry o cell s t o chemica l carcinogens . J . Natl . Cance r Inst . 67(6) : 1303 - 1315 . Epstein , S.S. ; Mantel , N . (1968 ) Carcinogenicit y o f tetraethy l lead . Experienti a 24:580-581 . Fanning , D . (1988 ) A mortalit y

stud y o f lead workers , 1926-1985 . Arch . Environ . Healt h43:247-251 . Fowler , B.A. ; Kimmel , C.A. ; Woods , J.S. ; McConnell , E.E. ; Grant , L.D . (1980 ) Chroni c low-leve l lead toxicit y i nth e rat : III . a

nintegrate d assessmen t o f long-term

toxicit y

wit hspecia l referenc e t o th e kidney . Toxicol . Appl . Pharmacol . 56:59-77 . Gaffey , W.R . (1980 ) Occupationa l lead exposure : wha t ar e th e risks ? Scienc e 208:130-131 . Gerhardson , L ; Lundstrom , N-G. ; Nordberg , G ; Wall , S . (1986 ) Mortalit y an d lea d exposure : a retrospectiv e cohor t stud y o f Swedis hsmelte r workers . Br . J . Ind . Med . 43:707-712 . Goyer , R.A . (1971 ) Lead toxicity : A problem i nenvironmenta l pathology . Am . J . Pathol . 64:167-181 .


### 12 2P.3 7

Goyer , R.A . (1983 ) Intracellula r site s o f toxi c metals . Neurotox . 4:147-156 . Goyer , R.A . (1985 ) Rena l change s associate dwit hlea dexposure . Dietar y an d environmenta l lead : huma nhealt heffects . Ne w York , NY : Elsevier , pp . 315-338 . Gross , S.B . (1981 ) Huma nora l an dinhalatio nexposure s t o lead : summar y o f Keho e balanc e experiments . J . Toxicol . Environ . Healt h8:333-377 . Hass , G.M. ; Brown , D.V.L. ; Einsenstein , R. ; Hemmens , A . (1964 ) Relation s betwee nlea dpoinsonin g inrabbi t an dman . Am . J . Pathol . 45:691-727 . Hass , G.M. ; McDonald , J.H. ; Oyasu , R. ; Battifora , H.A. ; Paloucek , J.T . (1965 ) Rena l neoplasi a induce db y combination s o f dietar y lea dsubacetat e an

dN 2-fluorenylacetamide . Proceeding s o f a nInternationa l Symposiu m onRena l Neoplasia ; ; Brasilia , pp . 377-412 . Hiasa , Y. ; Ohshima , M. ; Kitahori , Y. ; Fujita , J. ; Yuasa , T. ; Myashiro , H . (1983 ) Basi c lea dacetate : promotin g effect s o nth e developmen t o f rena l tubula r cel l tumor s i nrat s treate dwit hN-ethyl-N hydroxyethylnitrosamine . J . Natl . Cance r Inst . 70(4):761-765 . Hoar , S.K. ; Morrison , A.S. ; Cole , P. ; e t al . (1980 ) A noccupatio nan

d exposur e linkag e system fo r th e stud

y o f occupationa l carcinogenesis . J . Occup . Med . 22:722-726 . Hsie , A. ; Johnson , N . Couch , B . O'Neil , P. ; Forbes , N . (1980 ) Quantitativ e mammalia ncel l mutagenesi s an da preliminar y

study o f th e mutageni c potentia l o f metals . In : Kharasch , N. , ed . Trac e metal s inhealt han d disease . New

York , NY : Rave nPress , pp . 55-69 . Internationa l Agenc y

fo r Researc ho nCance r (IARC) . (1980 ) IAR C monograph s o nth e evaluatio no f th e carcinogeni c ris k o f chemical s t o humans : Some metal s an

dmetalli c compounds . Lyon , France , pp . 325-415 . Internationa l Agenc y

fo r Researc ho

nCance r (IARC) . (1987 ) IARC monograph s o n th e evaluatio no f carcinogeni c risk s t o humans : Overal l evaluation s o f carcinogenicity : A

nupdatin g o f IARC monograph s volume s 1 t o 42 . Lyon , France . 7:230-232 . Jensen , A.A . (1983 ) Metabolis m an dtoxicokinetics . In : Grandjean , P. ; Grandjean , E.C , eds . Biologica l effect s o f organolea dcompounds . Boc a Raton , FL : CR C Press , pp . 97-115 . Kang , H.K. ; Infante , P.F. ; Carra , J.S . (1980 ) Occupationa l lea dexposur e an d cancer . Scienc e 207:935-936 . Kanisawa , M. ; Schroeder , H.A . (1969 ) Lif e term studie s o nth e effec t o f trac e element s onspontaneou s tumor s inmic e an drats . Cance r Res . 29:892-895 .



### 12 3P.3 8

Kantor , A.F. ; Curnen , M.G . McC ; Meigs , J.W. ; Flannery , J.T . (1979 ) Occupation s o f father s o f patient s wit hWilms' s tumour . J . Epidemiol . Communit y

Healt h33:253-256 . Karhausen , L . (1973 ) Intestina l lea d absorption . Proceeding s o f a n Internationa l Symposium : Environmenta l Healt hAspect s o f Lead ; Octobe r 2 - 6 , 1972 ; Amsterdam . Luxembourg : Commissio no f th e Europea nCummunitie s Directorat e Genera l fo r Disseminatio no f Knowledg e Cente r fo r Informatio n an d Documentation , pp . 427-437 . Kasprzak , K.S. ; Hoover , K.L. ; Poirier , L.A . (1985 ) Effect s o f dietar y calciu m acetat e onlea d subacetat e carcinogenicit y i nkidney s o f mal e Sprague Dawle y rats . Carcinogenesi s 6(2):279-282 . Kehoe , R.A . (1961a ) Th e metabolis m o f lea d inma ninhealt han d disease : th e norma l metabolis m

o f lead . (The Harbe nlectures , 1960) . J.R . Inst . Publi c Healt hHyg . 24:81-97 . Kehoe , R.A . (1961b ) Th e metabolis m o f lea d inma ni

nhealt han

d disease : th e metabolis m

o f lea d unde r abnorma l conditions . (Th e Harbe nlectures , 1960) . J.R . Inst . Publi c Helt hHyg . 24:129-143 . Kehoe , J.R . (1961c ) Th e metabolis m o f lea d inma ninhealt han d disease : present hygieni c pborlem s relatin g t o th e absorptio no f lead . (The Harbe n lectures , 1969) . J.R . Inst . Publi c Healt hHyg . 24:177-203 . Kikkawa , U. ; Nishizuka , Y . (1986 ) Th e rol e o f protei nkinas e C in transmembran e signalling . Ann . Rev . Cel l Biol . 2:149-178 . Kilham , L. ; Low , R.J. ; Conti , S.F. ; Dallenbach , F.D . (1962 ) Intranuclea r inclusion s an

d neoplasm s inth e kidney s o f wil d rats . Kobayashi , N. ; Okamoto , T . (1974 ) Effect s o f lea d oxid e onth e inductio nof . lun g tumor s inSyria nhamsters . J . Natl . Cance r Inst . 52:1605-1610 . Koller , L.D. ; Kerkvliet , N.I. ; Exon , J.H . (1985 ) Neoplasi a induce d inmal e rat s fe d lea d acetate , ethy l urea , an d sodiu m nitrite . Toxicol . Pathol . 13(l):50-57 . Ledda-Columbano , G.M. ; Columbano , A. ; Pani , P . (1983 ) Lea d an d live r cel l proliferation . Effec t o f repeate d administrations . Am . J . Pathol . 113:315-320 . Lilis , R . (1981 ) Long-ter m occupationa l lea d exposure , chroni c nephropathy , an d rena l cancer : a cas e report . Am . J . Ind . Med . 2:293-297 . Mahaffey , K.R. ; Banks , T.A. ; Stone , C.L. ; e t al . (1975 ) Effec t o f varyin g level s o f dietar y

calciu m onsusceptibilit y

t o lea d toxicity . Proc . Int . Conf . Heavy

Metal s Environ. , Vol . III . Octobe r 25-31 ; Toronto , Ontario , Canada , pp . 155-164 .



### 12 4P.3 9

Malcolm , D. ; Barnett , H.A.R . (1982 ) A mortalit y

stud y o f lea d worker s 1925 - 1976 . Br . J . Ind . Med . 39:404-410 . Mao , P. ; Molnar , J.J . (1967 ) Th e fin e structur e an d histochemistr y

o f lead induce d rena l tumor s inrats . Am . J . Pathol . 50:571-603 . Markovac , J. ; Goldstein , G.W . (1988 ) Picomola r concentration s o f lea d stimulat e brai nprotei nkinas e C Natur e 334:71-73 . McMichael , A.J. ; Johnson , H.M . (1982 ) Long-term mortalit y

profil e o f heavily expose d lea d smelte r workers . J . Occup . Med . 24(5):375-378 . Mehani , S . (1966 ) Lead retentio nb y th e lung s o f lead-expose d workers . Ann . Occup . Hyg . 9:165-171 . Meredith , P.A. ; Moore , M.R. ; Goldberg , A . (1977 ) Th e effec t o f calciu m on lea d absorptio ni nrats . Biochem . J . 166:531-537 . Morrow, . P.E. ; Beiter , H. ; Amato , F. ; Gibb , F.R . (1980 ) Pulmonar y retentio no f lead : a nexperimenta l study

i nman . Environ . Res . 21:373-384 . Nationa l Cance r Institut e (NCI) . (1979 ) Bioassa y o f lea d dimethyl dithiocarbamat e fo r possibl e carcinogenicity . Technica l Repor t Serie s No . 151 . Carcinogenesi s Testin g Program , Division-o f Cance r Caus e an d Prevention , Nationa l Institute s o f Health . Bethesda , MD . Nationa l Toxicolog y

Program

(NTP) . (1985 ) Fourt hannua l repor t o n carcinogens . U.S . Departmen t o f Healt han d Huma nServices , Publi c Healt h Service . Availabl e from : NTIS , Springfield , VA , PB-85-134663 . Nishizuka , Y . (1986 ) Studie s an d perspective s o f protei nkinas e C Scienc e 233:306-321 . Nogueira , E . (1987 ) Ra t rena l carcinogenesi s afte r chroni c simultaneou s exposur e t o lea d acetat e an d N-nitrosodiethy l amine . Virch . Arch . B 53:365-374 . Nozaki , K . (1966 ) Metho d fo r studie s o f inhale d particle s inhuma n respirator y

system an d retentio no f lead fume . Ind . Healt h4:118-128 . Oberly , T.J. ; Piper , C.E. ; McDonald , D.S . (1982 ) Mutagenicit y o f meta l salt s inth e L5178 Ymous e lymphom a assay . J . Toxicol . Environ . Healt h9:367 - 376 . O'Riordan , M.L. ; Evans , H.J . (1974 ) Absenc e o f significan t chromosom e damag e i nmale s occupationall y expose d t o lead . Natur e 247:50-53 . Oyasu , R. ; Battifora , H.A. ; Clasen , R.A. ; McDonald , J.H. ; Hass , G.M . (1970 ) Inductio no f cerebra l glioma s i nrat s wit hdietar y lea d subacetat e an

d 2-acetylaminofluorene . Cance r Res . ^0:1248-1261 .



### 12 5Popenoe , E.A. ; Schmaeler , M.A . (1979 ) Interactio no f huma nDN A polymeras e B wit hion s o f copper , lead , an d cadmium . Arch . Biochem . Biophys . 106:109 - 120 . Prigge , E. ; Greve , J . (1977 ) Effect s o f lead inhalatio nexposure s alon e an d incombinatio nwit hcarbo nmonoxid e innonpregnan t an d pregnan t rat s an

d fetuses : II . Effect s ondelta-aminolevulini c aci d dehydratas e activity , hematocri t an

d bod y weight . Zentrabl . Bacteriol . Parasitendkd . Infektionskr . Hyg . Abt . 1 : Orig . Reih e B 165:294-304 . Rabinowitz , M.B. ; Wetherill , G.W. ; Kopple , J.D . (1974 ) Studie s o f huma nlea d metabolis m

b y us e o f stabl e isotop e tracers . Environ . Healt hPerspect . 7:145-153 . Rabinowitz , M.B. ; Kopple , J.D. ; Wetherill , G.W . (1980 ) Effec t o f food intak e an d fastin g ongastrointestina l lea d absorptio ninhumans . Am . J . Clin . Nutr . 33:1784-1788. . Rastogi , S.C ; Clausen , J ; Srivastava , K.C . (1976 ) Seleniu m an d lead : mutua l detoxifyin g effects . Toxicolog y 6:377-388 . Robinson , T.R . (1974 ) 20-Yea r mortalit y o f tetraethy l lea d workers . J . Occup . Med . 16(9):601-605 . Roe , F.J.C ; Boyland , E. ; Dukes , C.E. ; Mitchley , B.C.V . (1965 ) Failur e o f testosteron e o r xanthopteri nt o influenc e th e inductio no f rena l neoplasm s b y lea d i nrats . Br . J . Cance r 19:860-866 . Roomi , M.W. ; Columbano , A. ; Ledda-Columbano , G.M. ; Sarma , D.S.R . (1986 ) Lea d nitrat e induce s certai nbiochemica l propertie s characteristi c o f hepatocyt e nodules . Carcinogenesi s 7:1643-1646 . Schroeder , H.A. ; Balassa , J.J. ; Vinton , Jr. , W.H . (1965 ) Chromium , cadmiu m : an d lea d inrats : effect s o f lif e span , tumor s an d tissu e levels . J . Nutr . 86:51-66 . Schroeder , H.A. ; Mitchener , M. ; Nason , A.P . (1970 ) Zirconium , niobium , antimony , vanadiu

m an d lea d inrats : Lif e term studies . J . Nutr . 100:59-68 . Selevan , S.G. ; Landrigan , P.J . Stern , F.B. ; Jones , J.H . (1985 ) Mortalit y o f lea d smelte r workers . Am . J . Epidemiol . 122:673-683 . Sharma , A. ; Talukder , G . (1987 ) Effect s o f metal s onchromosome s o f highe r organisms . Environ . Mutagen . 9:191-226 . Shirai , T. ; Ohshima , M. ; Masuda , A. ; Tamario , S. ; Ito , N . (1984 ) Promotio no f 2-(ethylnitrosamino)ethanol-induce d rena l carcinogenesi s inrat s b y nephrotoxi c compounds : Positiv e response s wit hfoli c acid , basi c lea d acetate , an

d N-(3,5-dichlo.*ophenyl)succinimid e bu t no t wit h2,3-dibromo-l propano l phosphate . J . Natl . Cance r Inst . 71(2):477-482 .
12 6P.4 1

Spit , B.J. ; Wibowo , A.A.E. ; Feron , V.J. ; Zielhuis , R.L . (1981 ) Ultrastructura l change s inth e kidney s o f rabbit s treate d wit hlea d acetate . Arch . Toxicol . 49:85-91 . Stoner , G.D. ; Shimkin , M.B. ; Troxell , M.C ; Thompson , T.L. ; Terry , L.S . (1976 ) Tes t fo r carcinogenicit y o f metalli c compound s b y th e pulmonar y

tumo r respons e inStrai nA

mice . Cance r Res . 36:1744-1747 . Sweeney , M.H. ; Beaumont , J.J. ; Waxweiler , R.J. ; Halperin , W.E . (1986 ) A n investigatio no f mortalit y fro m cance r an

d othe r cause s o f deat hamon g worker s employe d a t a nEas t Texa s chemica l plant . Arch . Environ . Healt h 41:23-28 . Tanner , D.C ; Lipsky , M.M . (1984 ) Effec t o f lea d acetat e onN-(4'-fluoro-4 - biphenyl)acetamide-induce d rena l carcinogenesi s inth e rat . Carcinogenesi s 5:1109-1113 . U.S . Environmenta l Protectio nAgency . (1980 , November ) Wate r qualit y criteri a documents ; Availability : Appendi xC - Guideline s an d methodolog y

use d in th e preparatio no f healt heffec t assessmen t chapter s o f th e consen t decre e wate r criteri a documents . Federa l Registe r 45(231):79318-79379 . U.S . Environmenta l Protectio nAgency . (1986a ) Guideline s fo r carcinoge nris k assessment . Federa l Registe r 51:33992-34003 . U.S . Environmenta l Protectio nAgency . (1986b , December ) Methodolog y fo r evaluatin g potentia l carcinogenicit y insuppor t o f reportabl e quantit y adjustment s pursuan t t o CERCL A Sectio n102 , 0HEA-C-173 . (Draft ) U.S . Environmenta l Protectio nAgency . (1986c ) Ai r qualit y criteri a fo r lead , Vols . I-IV . Environmenta l Criteri a an d Assessmen t Office , Researc h Triangl e Park , NC . EPA-600/8-83/028aF , bF , cF , dF . Availabl e from : NTIS , Springfield , VA , PB87-142378 . Va nEsch , G.J. ; Kroes , R . (1969 ) Th e inductio no f rena l tumor s b y feedin g basi c lea d acetat e t o mic e an d hamsters . Br . J . Cance r 23:765-771 . Va nEsch , G.J. ; Va nGenderen , H ; Vink , H.H . (1962 ) Th e inductio no f rena l tumor s b y feedin g o f basi c lea d acetat e t o rats . Br . J . Cance r 16:289 - 297 .
va nPeteghem , T. ; d e Vos , H . (1974 ) Toxicit y stud y o f lea d naphthenate . Br . J . Ind . Med . 31:233-238 . Wedeen , R.P. ; Maesaka , J.K. ; Weiner , B. ; e t al . (1975 ) Occupationa l lea d nephropathy . Am . J . Med . 59:630-641 . [As cite d inGoyer , 1985] . Wedeen , R.P. ; Mallik , D.K. ; Batuman , V . (1979 ) Detectio nan d treatmen t o f occupationa l lea d nephropathy . Arch . Intern . Med . 139:53-57 . [As cite d inGoyer , 1985] .



### 12 7P.4 2

White , D.J . (1977 ) Histochemica l an d histologica l effect s o f lea d onth e live r an d kidne y

o f th e dog . Br . J . Exp . Pathol . 58:101-112 . Wilkins , J.R. ; Sinks , T.H . (1984 ) childre nwit hWilms' s tumor . Occupationa l exposure s amon g father s o f J . Occup . Med . 26(2):427-435 . Zawirska , B . (1981 ) Th e rol e o f th e kidney s i ndisorder s o f porphyri n metabolis m

durin g carcinogenesi s induce d wit hlea d acetate . Environ . Res , 24:391-408 . Zawirska , B. ; Medras , K . (1968 ) Tumor s an d disturbance s o f porphyri nmetabo lis m inrat s resultin g fro m chroni c experimenta l lea d intoxication . I . Morphologica l studies . Zentralblat t Allgem . Pathol . Anatomi e 111:1-12 . Zawirska , B. ; Medras , K . (1972 ) Th e rol e o f th e kidney s i ndisorder s o f porphyri nmetabolis m

durin g carcinogenesi s induce d wit hlea d acetate .

. Arch . Immunol . Ther . Exp . 20:257-272 . Zelikoff , J , (1988 ) T. ; Li , J.H. ; Hartwig , A. ; Wang , X.W. ; Costa , M. ; Rossman , T.G . Geneti c toxicolog y

o f lea d compounds . Carcinogenesi s 9:1727-1732 , Zollinger , H.U . (1953 ) Durc hchronisch e Bleivergiftun g erzeugt e Nierenadenom e und-carcinom e be i Ratte nun d ihr e Beziehunge nz u de nentsprechende n Neubildunge nde s Menschen . Virch . Arch . Bd . 323:694-710 .



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