# OAR Box 1830

Prepped by Ollie Stewart



### Document

Number: 

# 7 ) IV-B-3

Docket Number: 

# A-87-1 1

Printed 11/13/20087:20:51 AM Sheet 7 of 232 p. 1P. 2

lg afj m \ UNITE D STATE S ENVIRONMENTA L PROTECTIO N AGENC Y I^W^Z ? WASHINGTON , D.C

. 2046 0

DE C 2 ? ,rr " rOFFIC E O F fc W : ^ ' RESEARC H AN D DEVELOPMEN T

MEMORANDUM
SUBJECT : Revie w

o f MVM A comment s o

n Gasolin e Vapo r Ris k Assessmen t
FROM : Willia m

Pepelko , Ph.D . 'Jv*'-'->-• - ,J f- c J; " Toxicologis t Carcinoge nAssessmen t Grou p(RD-689 )
TO : Charle s L . Gray , Jr .

Directo r Emissio nContro l Technolog y Divisio n An nArbor , Michiga n
THRU : Willia m

H . Farland , Ph.D . Actin g Directo r Offic e o f Healt hand Environmenta l Assessmen t (RD-689 )

I hav e reviewe dth e Jul y 6 , 198 7 lette r from th e Moto r Vehicl e Manufacturer s Associatio nconcernin g th e EP A Healt hRis k Assessmen t o f Gasolin e Vapors . The y pointe dou t tha t kidne y cel l proliferatio ni n th e mal e ra t i s induce donl y b y a hig hconcentratio no f wholl y vaporize dgasoline , tha t th e degre e o f prolifera tio ncorrelate s wel l wit hth e inductio no f rena l tumors , tha t th e proliferativ e repons e i s causall y

relate dt o th e presenc e o f specifi c hydrocarbon s i n gaso line , and tha t th e cel l proliferatio nand increase dDN A synthesi s cause db

y thes e compound s i s th e resul t o f bindin g t o a specifi c protei nonl y foun dt o dat e i n th e mal e rat . Thi s protei n(alpha-2-microglobulin ) i s filtere d throug hth e glomerulu s o f th e kidney , absorbe db y th e proxima l tubul e cell s an dmetabolized . Bindin g o f th e hydrocarbon s t o th e protei nevidentl y inhibit s catabolism , resultin g i n accumulatio ni n th e tubula r cell s a s hyalin e droplets , leadin g t o cellula r deat han d subsequen t regeneration . Sinc e onl y th e mal e ra t ha s bee nshow

nt o produc e th e specifi c protei nlinke dt o th e histopathologi c response , th e MVM

A feel s tha t th e ra t i s a uniquel y sensitiv e an d therefor e in appropriat e mode l fo r assessin g th e earcinogenicit y o f gasolin e vapor s i n humans . I nsuppor t o f thi s argumen t i s evidenc e tha t a variet y o f othe r organi c chemical s als o induc e kidne y patholog y

t o a significan t degre e onl y i n th e mal e rat . Thre e o f thes e hydrocarbons , hydrogenate ddimer s o f norbornadiene , extra tetrahydr o (cyclopentadiene ) an d para-dichlorobenzene , hav e bee nteste di n lon g ter m bioassay s and hav e als o bee nshow nt o induc e kidne y

tumor s i n mal e rats .P. 3

ENVIRONMENTA L PROTECTIO N

AOFwr. v 

### AP R

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### 198 8 CENTRA L DOCKE T SECTIO NP. 4

I f th e mal e ra t i s determine dt o b e inappropriat e fo r assessin g th e carcino geni c ris k o f exposur e t o gasolin e vapors , the nth e onl y biologicall y

an dstatisti ' call y significan t tumorigeni c respons e foun di nanimal s i s anincreas e i nlive r tumor s i nmice . I f thi s wer e th e cas e the na stron g argumen t coul db e mad e fo r downgradin g th e qualitativ e assessmen t o f carcinogenicit y fo r unleade dgasolin e from categor y

B 2 t o C . Althoug hth e lette r doe s no t mentio nquantitativ e analysi s o f cance r risk , tha t woul dals o requir e chang e i f th e premis e o f th e lette r wer e accepted . I f th e nephrotoxicity , originatin g a s describe dabove , i s a precurso r o f tumon'genicity , the nth e tumo r inductio nca nb e considere d th e resul t o f onl y

th e C6-C 9 branche dchai nhydrocarbo ncomponent s o f th e vapor , whic har e presen t a t onl y abou t 1/ 5 o f thei r concentratio ni nth e aerosolize dgasolin e use di nth e anima l experiments . Secondly , i t ha s bee nhypothesize dtha t th e tumorigenicit y i nrat s i s th e resul t o f promot ing action . I

nthi s hypothesi s lysozym e leakag e i ncell s overloade dwit h hyalin e droplet s ma y

caus e physica l damag e t o chromosomes . Thes e effect s woul db e enhance db

y a muc hmor e rapi drat e o f cel l turnover . Implici t i n thi s hypothesi s i s th e presenc e o f a threshold , renderin g a linea r non threshol dmode l inappropriate .
W e agre e tha t consideratio no f th e newe r dat a doe s strengthe nth e argumen t tha t th e mal e ra t ma y b e uniqu e i nit s respons e t o gasolin e vapors . Nevertheless , w e fee l th e evidenc e i s no t conclusiv e an dtha t a cautiou s approac hi s prudent . Som e of th e reason s fo r th e continuin g uncertaint y

regardin g th e uniquenes s o f th e ra t tumorigeni c respons e ar e liste d below . Firs t o f all , whil e th e tumor s occu r i nth e genera l are a o f nephropathy , th e exac t sit e o f tumorigenesi s ha s no t bee ndefined . Thus , i t i s no t know n fo r certai ni f th e tumor s aris e from th e proxima l tubul e cell.s , th e sit e o f cel l turnover . Secondly , ol drat s normall y develo pkidne y

nephropathy , ye t kidne y tumor s ar e ver y

rar e i nuntreate danimals . Finally , i nth e onl y chroni c study

carrie dou t t o dat e usin g animal s expose dt o aerosolize d whol e unleade dgasoline , a rena l sarcom a wa s reporte di na femal e rat , whil e a nadenom a an da carcinom a wer e reporte dt o hav e occurre di nth e kidney s o f tw o mice . Althoug hthes e wer e no t statisticall y significan t effects , suc htumor s ar e onl y rarel y see ni nunexpose danimals . Take n together , thi s evidenc e tend s t o cas t som e doub t onth e hypothesi s linkin g kidne y

tumo r inductio nt o chroni c nephropathy . I na study

recentl y

publishe d(Toxicolog y an dApplie dPharmacology , 90 : 43-51 , 1987 ) study ^ Olson , e t al . foun dtha t ther e i s no t a one-to-on e correspondenc e betwee ncell s wit hhyalin e droplet s an dcell s stainin g fo r alpha-2-microglobulin . Som e cell s wit hhyalin e droplet s di dno t hav e alpha-2-microglobulin , an dthe y state dtha t i t i s no t knownwhethe r th e accumulatio no f thi s protei ni nth e proxima l tubul e cell s wa s th e caus eP. 5

•* i ,M

o r th e resul t o f th e nephropathy . Thei r finding s leav e ope nth e possibilit y tha t othe r protein s whic har e no t necessaril y uniqu e t o mal e F 34 4 rat s coul d caus e hyalin e drople t formatio nan dsubsequen t nephrotoxicity . Therefore , eve ni f th e hypothesi s linkin g kidne y cance r t o th e developmen t o f nephro toxicit y i s accepted , i t i s possibl e tha t kidne y tumor s coul db e induce db y gasolin e vapor s i nothe r species . Significan t increase s i ncance r incidenc e hav e bee nreporte di nsevera l huma nepidemiolog y

studie s o f occupationa l exposur e t o gasolin e vapor s an d othe r refiner y

products . Becaus e o f weaknesse s i nth e desig no f thes e studie s an duncertaint y regardin g th e natur e o f exposure , thes e studie s ar e generall y

considere dinadequat e t o mak e conclusion s regardin g th e carcinogenicit y

o f gasolin e alon e i nhumans . Collectively , however , the y d o provide , a t least , some suggestiv e evidenc e tha t gasolin e ando r relate dhydrocarbon s ma y be carcinogeni c inhumans . Continuin g uncertainty , regardin g th e relationshi pbetwee nkidne y nephropath y

andtumo r induction , th e possibilit y tha t hydrocarbo n nephropath y

ma y b e induce dinothe r species , th e significan t increas e o f live r tumor s i nfemal e mice , andth e suggestiv e evidenc e fo r a carcinogeni c effect s o f gasolin e and/o r refiner y product s i nhumans , collectivel y

indicat e a concer ntha t gasolin e vapor s coul db e carcino genic . Fo r thi s reaso nw e prefe r t o maintai na conservativ e stanc e and retai nth e B 2 classification . W e recognize , however , th e evidenc e i s no t clearcu t andtha t new dat a ma y

resul t i na reconsideratio no f th e classification .