P. 1


# OAR Box 1856 Prepped byKeeia Richards



### Document

Number: 

# 66 ) ll-A-03 Docket Number: 

# A-87-1 1

Printed 11/24/200812:41:50PM Sheet 66 of 82P. 2

i t 

# EP A Unite d State s Environmen t Protectio n Agency 

# Researc h an d Developmen t

INTERI MQUANTITATIV E CANCE RUNI T RIS K ESTIMATE S DU E T O INHALATIO NO F BENZEN E EPA-600/X-85-02 2 Februar y15 , 198 5 INTERNA L REPOR T



## 00420 0



# Prepare d fo r OFFIC E O F AI RQUALIT YPLANNIN GAN D STANDARD S



# Prepare d by CARCINOGE N ASSESSMEN TGROU P 

### Offic e ofHealt h an d Environmenta l Assessmen t Washingto n D

C 2046 0P. 3

NOTIC E

ihi s documen t i s intende d fo r interna l Agenc yus e only . Mentio n o f trad e name s o r commercia l product s doe s no t constitut e endorsemen t o r recommendatio n fo r use .P. 4

PREFAC E

Thi s documen t wa s prepare dfo r th e Offic e o f Ai r Qualit y Plannin gand Standard s (OAQPS ) b

y th e Offic e o f Healt handEnvironmenta l Assessmen t (OHEA ) Dr . Tod dThorslund , Carcinoge nAssessmen t Group , OHEA , i s th e author . Th e documen t na s bee nreviewe dwithi nOHE A andOAQPS .



### nP. 5



## ':;::::.:: : QUANTITATIV E CANCE RUNI T RIS KESTIMATE S DU E T OINHALATION O F BENZEN E

Ir. f ejectio n I nth e "Carcinoge nAssessmen t Group' s Fina l Repor t o nPopulatio nRis kt o Ambien t Benzen e Exposures " date dJanuar y 10 , 1979 , a "uni t risk " du e t o inha I.*J. » ~£

k, nzen e wa s derived . Thi s uni t ris kwa s obtaine dfrom th e geometri c mea no f estimate s o f ris kfro m thre e independen t epidemiologi c studies . Thi s wa s th e firs t tim e tha t th e U.S . Environmenta l Protectio nAgenc y (EPA ) obtaine d cance r ris kestimate s du e t o a chemica l exposur e base donhuma nepidemiologi c data . Sinc e tha t origina l report , extensiv e new informatio nrelatin g t o th e car cinogeni c potenc y

o f benzen e ha s becom e available . I naddition , animprove d methodolog y

fo r estimatin gcance r ris kha s bee ndevelope dove r time . Th e Carcinoge nAssessmen t Grou p(CAG ) i s presentl y evaluatin g thi s new informatio nandpreparin ganextensiv e repor t coverin g eac hanima l toxicologi c study andepidemiologi c study . Thi s repor t wil l suppl y th e informatio nfrom whic ha current , state-of-the-art , quantitativ e cance r ris kassessmen t fo r benzen e wil l be " derived . A s new informatio nbecam e available , th e CAGwa s aske donsevera l occasion s whethe r o r no t i t woul dmarkedl y chang e it s uni t ris kestimat e du e t o th e new data . O

neac hoccasion , upo na preliminar y evaluation , i t wa s apparen t inou r judgmen t tha t onl y

relativel y

mino r "numerical " alteration s woul dresul t i nth e join t uni t ris kestimat e from incorporatin g th e new information . Wit hthi s assurance , th e EPA

program

office s continue dt o bas e thei r decision s o nthe ' origina l report . Thi s wa s don e i norde r t o stay ona mandate dregulator y schedule . Tn e schedul e woul dbe disrupte di f the y wer e force dt o wai t fo r a current , state-of-the-ar t ris kassessmen t fo r benzen e t o be complete dbefor e 1P. 6

proceeding . I na petitio nt o th e Administrato r o f th e EPA , th e Natura l Resource s Defens e Counci l (NRDC ) take s exceptio nt o thi s approach . Th e NRD C make s th e conjectur e tha t th e informatio nfoun di nth e followin gsource s indicate s tha t EP A ha s seriousl y

underestimate dth e uni t risk : o anepidemiologi c study o f Ohi o rubbe r worker s (Rinks y e t al. , 1981 ) (updatin gInfant e e t al. , 1977) , o anepidemiologica l study o f chemica l worker s submitte dt o EP A b y th e Chemica l Manufacturer s Associatio n(Wonge t al. , 1983) , o th e anima l bioassa y conducte db

y th e Nationa l Toxicologica l Pro gram (NTP , 1984) , o a furthe r updat e throug h198 3 o f th e rubbe r worker s study b y Rin sk y e t al. , and o a review

o f th e healt heffect s literatur e anda quantitativ e ris k assessmen t publishe db y th e Californi a Departmen t o f Healt hSer - . vice s (DHS , 1984) . Th e tim e schedul e fo r answerin gth e NRD C petitio ndoe s no t allow fo r a comple tio no f EPA' s update dris kassessment . Fortunately , a Ma y 198 4 repor t enti tle d"Quantitativ e Estimate s o f Ris ko f Leukemi a from Occupationa l Exposur e t o Benzene, " prepare db y Crum pandAlle nfo r th e Occupationa l Safet y andHealt h Administration , use dth e informatio ncite db y th e NRD C t o mak e ris kassessments , Thi s repor t use s methodolog y i nobtainin gris kestimate s tha t i s consisten t i n mos t respect s t o tha t employe db y EPA , andi t contain s muc hbette r huma nexpo sur e estimate s i nth e epidemiologi c studie s tha nha s bee npreviousl y available . Th e approac ht o b e take nher e i s t o us e thi s secondar y sourc e t o mak e in teri m quantitativ e uni t ris kestimate s tha t wil l b e use dunti l th e mor e exten siv e estimate s ar e completed . However , i t mus t be realize dtha t th e new esti -P. 7

.-nate s d o no t represen t th e optimum us e o f th e informatio nEP A presentl y

ha s at hand . Eve nso , du e t o th e structura l natur e o f th e typ e o f model s use dt o estimat e risk , i t i s no t anticipate dtha t th e resultin gfina l estimate s wil l diffe r b

y anappreciabl e amoun t from th e interi m

estimat e develope dhere . Th e mai nadvantag e o f th e new estimate s wil l b e thei r scientifi c credibility . I. . ti u . c nex t tw o sections , uni t risk s base dupo nepidemiologi c studie s an d anima l studie s wil l b e develope dusin gparameter s calculate db y Crum pand Allen , Th e thir dsectio ndiscusse s thes e results . Th e fourt hsectio ndevelop s andgive s CAGrecommendation s fo r a singl e composit e unit ris kestimate , and discusse s alternativ e approaches . Th e fina l sectio nsummarize s th e result s an d conclusion s o f thi s investigation . Uni t Ris kEstimate s Base donEpidemiologi c Studie s Crum pandAlle n(1984 ) estimate dth e lifetim e ris kdu e t o differen t dura tion s andlevel s o f exposur e t o benzen e i nth e wor kplace . Th e epidemiologi c dat a set s use dt o estimat e thes e risk s wer e obtaine d fro m a reorganizin g o f th e dat a collecte db y Rinsky

e t al . (1981) , Uon g e t al . (1983) , andOt t e t al . (1978 ) i nthre e separat e investigations . Othe r studies , mos t notabl y

thos e o f Asko y

e t al . (1979 ) andAsko y (1978) , whic hdeal t wit h Turkis hsho e workers , indicate danassociatio no f leukemi a wit hbenzene . However , w e agre e wit hCrum ptha t th e exposur e informatio ncompare dwit hth e studie s use di s s o imprecis e that the y ar e no t suitabl e fo r quantitativ e esti mation . A compute r tap e containin gfollow-u pinformatio nthroug h1978 , whic hi s anupdate dversio no f th e cohor t discusse db y Rinsk y e t al . (1981) , wa s used . Thi s i s th e mos t recen t informatio npresentl y availabl e onth e cohort . Th e NRD C implie s that anupdat e throug h198 3 o f th e rubbe r worker s studie d b y Rinsk y e t al . (1981 ) exists . However , th e CAGha s no t bee nabl e t o locat e 3P. 8

"-:'- 1 * ? dat a base , and , give nth e usua l lagtim e require dfo r epidemiologi c investigations , a study tha t curren t i s no t very likely . Th e informatio ncontaine di nWon ge t al . (1983) , whic hinvolve s th e mor talit y experienc e o f mal e chemica l worker s occupationall y expose dt o benzene , wa s use dindependentl y an dinconjunctio nwit hothe r studie s t o estimat e unit '

r i ele c Th e study

conducte db

y Ot t e t al . (1978 ) wa s als o use dincombinatio nwit h th e othe r studie s t o estimat e risk , bu t les s emphasi s wa s place doni t du e t o a lac ko f a clea r dose-respons e relationship . Crum pan dAlle n(1984 ) wer e abl e t o relat e observe dandexpecte dnumber s o f case s o f leukemi a t o grouping s o f variou s exposur e parameter s fo r th e thre e studies . Thes e dat a ar e show ninTable s 1- 3 an

d6-1 1 o f th e Crum

pandAlle n (1984 ) report , include dher e ir i Appendi xA . Th e exposur e categorie s use dwer e denote da s cumulativ e dose , weighte d cumulativ e dose , andwindo w dose . Th e "slope " paramete r bandit s 95 % statis tica l confidenc e interva l wer e estimate dfo r variou s assumption s an dcombina tion s o f dat a anddos e parameter s usin gtechnique s describe db y Crump " andAlle n (1984) . Thes e estimate dparameter s andconfidenc e interval s ar e show ni n Table s 12-1 7 o f th e Crum pandAlle n(1984 ) report , an dar e als o reproduce din Appendi xA . Onc e anestimat e o f th e slop e paramete r bi s obtained , i t ca nb e trans late dint o a uni t ris kb y a straightforwar dmathematica l manipulation . Th e transformatio ndepend s upo nwhethe r th e mode l i s o f absolut e o r relativ e risk , th e typ e o f exposur e paramete r used , an dth e environmentall y expose dpopula tion' s assume dtota l andleukemi a age-specifi c deat hrate . Mathematically , th e ris kdu e t o a constan t lifetim e exposur e o f xpp m in th e ai r may

be expresse da sP. 9

t

- / [h 2 (x,v ) + hi(v)]dv P(x ) = / {h 2 (x,t) e 0 }d t

0

wher e h 2 (x,t ) i s th e age-specifi c deat hrat e a t ag e t du e t o a constan t life time exposur e a t leve l x , an dh^(t ) i s th e age-specifi c deat hrat e fo r al l othe r causes . Se e Gai l (1975 ) fo r a derivatio no f thi s result . Inth e presen t situatio n

h 2 (x,t ) = $(t) 5 r(x,t )

wher e

•1 i fa relativ e ris k mode l 6 = 0 i fan absolut e ris k mode l *(t ) i s th e backgroun d age-specifi cleukemi a deat h rat e o fth e environmentall y expose d populatio n an d
0 t < 2. 5

r(x,t ) = b*x(t-2.5 ) 2. 5 < t

fo r th e cumulativ e exposur e model , an d
0 t < 5 r(x,t ) = b*x(t-5 ) 5 <

_t < 1 0 5 b* x+ bji(t-lO ) 1 0 <

_t < 1 5 3 2 0 b* x+ b_\(t-15 ) 1 5 <

_t 3 6P.1 0

fo r th e weighte dcumulativ e exposur e model , and

0 t < 5 r(x,t ) = b*x(t-5 ) 5 <

_t < 1 5 1 0 b* x1 5 £ t

fo r th e windo w

exposur e model . The term b * = b/(8/24 ) x(240/365 ) = 4.56 b simpl y translate s th e 8 hours/da y 24 0 days/yea r exposur e inth e industria l settin g use db

y Crum pan dAlle n(1984 ) int o a continuou s lifetim e exposur e fo r th e U.S . environmenta l case . Sinc e ther e i s n o informatio nt o sugges t tha t th e backgroun dleukemi a an d tota l age-specifi c deat hrate s fo r thos e expose dt o benzen e inth e environmen t woul ddiffe r from

th e U.S . norm , th e tota l U.S . rate s take nfro m 197 8 (th e mos t curren t yea r available ) ar e use dfo r *(t) . Base dupo nthes e conventions , th e ris kdu e t o 1 pp m constan t exposur e t o benzen e i s calculate dfo r eac ho f th e bvalue s andthei r confidenc e bounds , a s give ninTable s 12-1 7 o f Crum pan dAlle n(1984 ) reproduce di nAppendi xA . Thes e result s ar e showni nTable s 1-6 . A compariso no f thes e result s wit h thos e derive di nth e origina l CA Gdocumen t an

dthos e obtaine dfrom anima l experiments , a s wel l a s a discussio no f thei r relevance , wil l be th e subjec t o f a subsequen t section . Uni t Ris kEstimate s Base do nAnima l Studie s At th e tim e th e CA

Goriginall y

evaluate dth e carcinogeni c potenc y o f ben zene , no anima l studie s existe ddemonstratin g a carcinogeni c response . Benzen e an darseni c wer e pointe dou t t o b e th e onl y compound s wher e huma nevidenc e wa s positiv e andanima l evidenc e negative . Some individual s argue dtha t thi s cas t seriou s doub t o nth e possibilit yP.1 1

TABL E 1 . RESULT S FO RRELATIV E RIS KMODE L USINGCUMULATIV E DOS E

Dat a se t 95 % lowe r bound Uni t ris kestimat e



### ML E 95 % uppe r

bound

- 2 Rinskye t al
. 1.65x1 0 (fcllow-u p fro m 1950 , Tabl e 6) a I I Rinsky e t al . 1.53x10- 2 (follow-u pfrom

1940 , Tabl e 2 ) II I Rinsky e t al . (revise d1.78xlO - 2 exposures , Tabl e 7 ) I V Rinsky e t al . (Tabl e 6 ) 7.78x10- 3 an dOt t e t al . (Tabl e 1 ) 5.10xl0- 2 1.08X10" 1

5.10x10- 2 1.13X10- 1

6.43x10- 2 1.44X10" 1

2.89x10- 2 6.87x10- 2

Same a s I

V excep t two questionabl e case s adde d 4.45X10" 3 2.04x10- 2 5.10x10- 2

VI Won g e t al . (Tabl e 3 , 8.76xl0" 4 SMR=5 0 assume d fo r unexposed ) VI I Rinsky e t al . (Tabl e 6 ) 2.67xl0" 2 Ot t e t al . (Tabl e 1 ) an dWon g e t al . (Tabl e 3 ) VII I Same a s VI I excep t 1.56xl0" 2 SMR=10 0 assume d fo r unexpose d 1.04x10* 1 2.42X10' 1

7.32x10- 2 1.60X10' 1

3.55x10- 2 6.43x10- 2

a Th e table s referre dt o ar e thos e give ninCrum pan dAlle n(1984) , an

dar e reproduce di nAppendi xA .P.1 2

TABL E 2 . RESULT S FO RABSOLUT E RIS KMODE L USINGCUMULATIV E DOS E

Dat a se t Uni t ris kestimat e 95 % lowe r bound 

### ML

E 95 % uppe r

bound
I Rinsky e t al . 1.02x10- 2 (follow-u pfro

m 1950 , Tabl e 6) a I I Rinsky e t al . 9.31xl0" 3 (follow-u pfro

m 1940 , Tabl e 2 ) II I Rinsky e t al . 1.22x10- 2 (revise dexposures , Tabl e 7 ) I V Rinsky e t al . (Tabl e 6 ) 7.23xl0" 3 an dOt t e t al . (Tabl e 1 ) 2.45x10- 2 4.77x10- 2

2.20x10- 2 4.40x10- 2

3.06x10- 2 5.99x10- 2

1.96x10- 2 3.79x10- 2

Same a s I

V excep t two questionabl e case s adde d 7.11x10- 3 2.08x10- 2 4.04x10- 2

a Th e table s referre dt o ar e thos e give ni nCrum pan dAlle n(1984) , andar e reproduce dinAppendi xA .P.1 3



### TABL E 3 . RESULT S FO

RRELATIV E RIS KMODE L USINGWEIGHTE DCUMULATIV E DOS E

Uni t ris kestimat e 95 % lowe r 95 % uppe r Dat a se t boundML E bound l 

### Rinsky e t al . 1.30xl0" 2 

### 4.10xl0- 2 

### 8.79xl0" 2 

### Tabl e 8) a 

### I I Kinsky e t al . 7.29xl0" 3 

### 2.49xl0" 2 

### 5.59X10" 2 

### (Tabl e 8 ) an

d Ot t e t al . (Tabl e 10 )

a 

### Th e table s referre dt o ar e thos e give ni nCrum pan dAlle n(1984) , an

dar e reproduce di nAppendi xA .

TABL E 4 . RESULT S FORABSOLUT E RIS KMODE L USINGWEIGHTE DCUMULATIV E DOS E
Uni t ris kestimat e 95 % lowe r 95 % uppe r Dat a se t boundML E bound I Rinsk ye t al. , 7.47x10- 3 1.76xl0" 2 3.36xl0" 2 1940-197 0 follow-u p (Tabl e 8) a 

### II Rinsk ye t al
. 5.43xl0" 3 1.40xl0" 2 2.71xl0" 2 (Tabl e 8 ) an d Ot t e t al
. " (Tabl e 10 )

a Th e table s referre d t o ar e thos e give n i n Crum p an d Alle n (1984) , an d ar e reproduce d i n Appendi xA
.P.14 ,

TABL E 5 . RESULT S FORRELATIV E RIS KMODE L USING"WINDOW " DOS E
Uni t ris kestimat e 95 % lowe r 95 % uppe r Dat a se t boundML E bound

i Rinsky e t al . 5.56xl0" 3 1.67xl0" 2 2.48x10- 2 (Tabl e 9) a I I Rinsky e t al . 3.60xl0" 3 1.15xl0" 2 2.48x10- 2 (Tabl e 9 ) an

d Ot t e t al . (Tabl e 11 )

a Th e table s referre dt o ar e thos e give ni nCrum pan dAlle n(1984) , andar e reproduce di nAppendi xA .

TABL E 6 . RESULT S FORABSOLUT E RIS KMODE L USING"WINDOW " DOS E
Uni t ris kestimat e 95 % lowe r 95 % uppe r Dat a se t boundML E bound
I Rinsky e t al . 4.34xl0" 3 l.lOxlO" 2 .-2.17xl0" 2 (Tabl e 9) a I I Rinsky e t al . 3.48x10- 3 8.98xl0" 3 2.52xl0" 2 . (Tabl e 9 ) an

d Ot t e t al . • (Tabl e 11 )

a Th e table s referre dt o ar e thos e give ninCrum pan dAlle n(1984) , andar e reproduce di nAppendi xA . 

### 1 0PJ 5

L-nat . uenzen e wa s a carcinogen . Other s argue dtha t i t simpl y mean t tha t th e correc t exposur e route-anima l strain-specie s mode l hadno t bee nadequatel y tested . Subsequen t event s hav e prove dth e latte r view t o b e correct . Goldstei ne t al . (1980 ) an dMalton i e t al . (1983 ) hav e show nbenzen e t o be carcinogeni c fo r variou s strain s o f rat s andmic e vi a th e inhalatio nroute . I: , u-iiiun , Malton i e t al . (1983 ) andth e Nationa l Toxicolog y Program

(NTP ) (Jul y 1984 , unpublished ) hav e demonstrate dtha t benzen e i s als o carcinogeni c vi a gavag e exposure . Crum pandAlle n(1984 ) evaluate dthes e studie s an dselecte dwha t the y considere dt o b e th e mos t relevan t endpoint s upo nwhic ht o bas e ris kextrapo latio nmodels . Lackin ganindependen t EPA evaluatio no f thes e studies , th e approac htake nher e i s simpl y t o adop t Crum

pan dAllen' s selectio no f end points . Thi s dat a ba.s e i s als o reproduce danddisplaye di nAppendi xA o f thi s report . Usin g thes e 2 3 selecte dendpoints , Crum pandAlle n(1984 ) estimate dth e dose s correspondin g t o anincrease dris ko f 10" ^ usin g th e multistag e mode l and , wher e time-to-tumo r dat a existed , th e multistage-Weibul l model . Thes e result s wer e summarize di nthei r Table s 2 3 an d24 , whic har e als o include din Appendi xA . Th e dos e correspondin gt o a nincrease dris ko f 10" 6 inananima l experi men t ma y

b e converte dt o th e ris kfo r a huma ndu e t o a lifetim e exposur e o f 1 pp m benzen e i nth e ai r i nth e followin g manner . Le t th e dos e correspondin g t o a nincrease dris ko f IO" 6 be denote da s x . Assumin g tha t pp

m exposure s ar e equivalen t betwee nspecies , ou r uni t ris kin inhalatio nexperiment s i s simpl y



### 1 1P.1 6

XO D X

wher e (10"** ) i s th e slop e o f a linea r mode l require dt o giv e a ris ko f IO' 6 du e

x t o 8 hours/da y

o f exposur e fo r 5 days/wee kand(24 ) t]\ translat e th e slop e 8 5 from a 4 0 hours/wee kindustria l exposur e t o correspon dt o a constan t exposure . Usin gthi s formul a andth e value s o f xgive ni nTabl e 23 , Appendi xA , th e uni t risk s base dupo nanima l inhalatio nstudie s ar e obtained . Thes e ar e repro duce di nTabl e 7 . T o obtai nth e uni t ris kestimate s fo r anima l gavag e experiments , th e stan dar dassumptio nuse db y EP A o f equivalenc e betwee nspecie s onth e basi s o f mg/surfac e are a i s used . Thi s i s a t varianc e wit hth e Crum pandAlle n(1984 ) equivalenc e assumptio no f mg/k gbetwee nspecies . W e tak e th e uni t ris kestimat e t o be 

# <¥H>

#'l"' 1 

# ^ '

wher e xi s th e dos e correspondin gt o a IO" 6 risk , L/L e i s th e fractio no f th e lifespa nth e anima l wa s exposed , di s th e days/wee kth e anima l wa s exposed , W a i s th e weigh t o f th e anima l i nkg , and3.1 9 x20/7 0 i s th e estimate ddos e i n mg/k gdu e t o a constan t exposur e o f 1 pp m benzen e i nth e air , assumin g2 0 m 3 breathe dpe r day , a 70-k gindividual , andth e weigh t o f 3.1 9 m g o f benzen e i non e m 3 o f ai r fo r eac hppm . Th e value s fo r xar e obtaine dfrom Tabl e 24 , Appendi xA , andsubstitute d int o th e abov e formul a t o obtai nth e estimate s showni nTabl e 8 . A compariso no f thes e result s wit hth e huma nestimates , an da discussio n o f thei r relevance , i s th e subjec t o f th e nex t section . 1 2P.1 7

TABL E 7 . UNI T RIS KESTIMATE S BASE DUPON RODEN T INHALATION

STUDIE S
Multistag e mode l Dat a set s ML E 95 % uppe r limi t
Goldstei ne t al . (1980 ) Leukemia , mal e rat s — 1.1 1 xIO - 3 Leukemia , mal e mic e 2.0 6 xIO - 6 5.4 1 xIO" 4 Bioassay s from Malton i e t al . (1983 ) Leukemia , bot h sexes , rat s 1.3 4 xIO" 4 4.4 0 xIO" 4 Zymba l glando r nasa l cavit y carcinoma o r leukemia , bot hsexes , rat s 1.1 2 xIO" 3 1.8 0 xIO" 3



### 1 3TABL E 8 . UNI T RIS KESTIMATE S BASE DUPON RODEN T GAVAG E STUDIE S

Dat a set s Mode l Multistag e 

### ML E 95 % uppe r limi t Multistage-Weibul l 

### ML E 95 % uppe r limi t
NT P bioassay s Zymba l glandcarcinoma , mal e rat s Al l squamou s cel l carcinomas , mal e rat s Zymba l glan

dcarcinoma , femal e rat s Al l squamou s cel l carcinomas , femal e rat s Squamou s cel l carcinom a o f preputia l gland , mal e mic e Al l squamou s cel l carcinomas , mal e mic e Alveolar/bronchiola r carcinoma , mal e mic e Lymphoma , NOS , mal e mic e Al l squamous cel l carcinoma. , femal e mic e 1.3 3
1.7 3
2.2 0
9.6 1
5.1 9
1.6 1
3.6 1 2.0 8
8.1 8 

### x

X

X

X

X

X

X X

X IO" 2
IO" 2
IO" 2
10- 3
10- 2
IO" 2
10- 2 10- 2
10- 6 2.0 0

2.2 6
3.2 2
1.6 0
1.2 5
1.1. 9
6.4 8 4.3 2
1.1 7 X

X

X

X

X

X

X X

X 10- 2
10- 2
10- 2
10- 2
10- 1
io- i
10- 2 10- 2
10- 2 1.3 8

1.9 4
2.3 0
9.5 3
1.3 6
2.3 3
4.5 6 2.9 2
8.9 8 X

X

X

X

X

X

X X

X 10- 2
10- 2
10- 2
IO" 3
10- 2
10~ 4
10- 2 10- 2
IO" 6 2.2 5 x

2.5 5 x
3.5 5 x
1.7 8 x
1.6 1 x
1.5 0 x
8.2 9 x 6.7 9 x
1.4 4 x IO" 2

10- 2
10- 2
IO" 2
io- i
io- i
10- 2 10- 2
IO- 2


### 1 4TABL E 8 . (continued )

Data set s Mode l Multistag e 

### ML E 95 % uppe r limi t Multistage-Weibul l 

### ML E 95 % uppe r limi t
NTP bioassay s (continued ) Mammar y glan dcarcinoma , femal e mic e Alveolar/bronchiola r carcinoma , femal e mic e Lymphoma , femal e mic e 3.4 9 xIO' 2
2.8 3 xIO" 2 9.2 3 xIO" 3 Bioassay s fro

m Malton i et al . (1983 ) Leukemia , mal e rat s Al l tumors , mal e rat s Zymba l glan

dcarcinoma , femal e rat s Leukemia , femal e rat s Al l tumors , femal e rat s Leukemia , bothsexes , r.t s Al l tumoi . , bothsexes , rat s 2.4 0 xIO" 5 3.2 0 x10~ 5
2.0 2 xIO" 2

5.7 6 xIO' 2 4.2 6 xIO" 3 1.8 8 xIO" 2 5.7 1 xIO" 2

4.2 1 xIO" 2 5.6 9 xIO" 2

1.3 3 xIO" 2 2.3 1 xIO" 2
3.2 8 xIO" 2 6.3 2 xIO" 3 8.9 5 xIO" 2 9.5 5 xIO" 3 4.4 0 xIO" 2 4.5 5 xIO" 2
4.6 3 xIO" 2 6.7 9 xIO" 2
7.2 4 xIO" 2 3.8 4 xIO" 2



### 15 Tl C OP.2 0

uiacussio no f Result s Employin gth e si xmodel s an dvariou s combination s o f dat a set s an dassump tions , a tota l o f 2 1 uni t ris kestimates , wit hthei r 95 % statistica l confidenc e bounds , wa s obtaine dusin gepidemiologi c data . Thes e estimate s ar e show ni n Table s 1 throug h6 . Th e MLE s rang e fro m 8.9 8 xIO - 3 t o 1.0 4 x10 - 1 , o r slightl y liw i c u.ia non e orde r o f magnitude . Th e effect s o f th e mode l assumption s o nth e uni t ris kestimate s ar e illustrate db y th e result s show

ni nTabl e 9 . Al l o f th e si xmodel s hav e bee nfitte dt o th e Rinsk y e t al . cohor t tha t wa s followe d from 1940 t o 1978 , an

duni t ris kestimate s hav e bee nobtained . Fo r th e sak e o f comparison , th e risk s calculate db y Crum pan dAlle n(1984 ) fo r a whit e mal e expose d8 hour s pe r workin g day fro m ag e 2 0 t o ag e 6 0 ar e als o given . W e not e a dro pi nris kgoin g from cumulativ e t o weighte dcumulativ e t o windo w dose , a s wel l a s from

relativ e t o absolute , wit hth e rati o o f i:h e maximum

t o th e minimum ris kestimat e bein g les s tha na facto r o f five . Al l o f th e model s ar e statisticall y consisten t wit hth e observe ddata , s o tha t a selectio no f on e mode l ove r anothe r i s a matte r o f judgment . Th e us e o f informatio nconcernin g leukemi a response s i nothe r studie s migh t suggest.th e appropriat e model . Wit hregar dt o th e dos e parameters , Crum pan dAlle n(1984 ) argu e tha t th e weighte dcumulativ e dos e i s t o b e preferred , sinc e th e tempora l leukemi a respons e i s base dupo ntha t observe dinth e survivor s expose dt o th e atomi c bom

bi nHiroshim a andNagasaki . They als o argu e tha t th e cumulativ e dos e i s acceptabl e bu t tha t th e windo w dos e ha s a considerabl y smalle r credi bility . Wit hregar dt o th e structura l form o f th e model , littl e informatio n exists . I f al l leukemi a result s from th e same mechanism , andbenzen e affect s a stag e i nthi s mechanism , the nth e relativ e ris kmode l woul dhold . Crum pan d Alle n(1984 ) hav e a sligh t preferenc e fo r thi s form o f th e model , althoug hno rational e i s given . O nth e othe r hand , i f th e actio no f benzen e i s differen t

1 6P.2 1

TABL E 9 . RISK S DU E T O 1 PPM BENZEN E EXPOSUR E BASE DUPON

RINSKYE T AL . COHORT , FOLLOW-U P FRO M 194 0 T O 197 8

Exposur e paramete r Cumulativ e

Weighte d cumulativ e

Window Exposur e duratio n Lifetime 4 0 workin g years 3
Lifetime 40 workin g year s Lifetim e 4 0 workin g year s Mode l for m Relativ e Absolut e 5.1 0 xIO" 2
6.6 2 xIO" 3
4.4 0 xIO" 2
4.9 4 x10~ 3
1.6 7 xIO" 2
1.7 5 xIO" 3 2.2 0 xIO" 2

2.2 1 xIO" 3
1.7 6 xIO' 2
1.9 0 xIO" 3
1.1 0 x10- 2
1.3 5 xIO" 3

a 8 hours/da y

5 days/wee kexposur e t o 1 pp m fro m ag e 2 0 t o ag e 60 .



### 1 7P.2 2

fro m othe r factor s producin g leukemia , a nabsolut e ris kmode l ma y b e mor e ?nnrnr.r-iate . Inprinciple , we woul dprefe r t o bas e ou r estimat e onth e mos t extensiv e andinclusiv e body o f dat a availabl e tha t i s o f acceptabl e quality . Thi s argue s fo r makin gus e o f al l thre e epidemiologi c studies , bu t require s some adaptatio nsince , du e t o th e availabilit y o f information , th e Won g e t al . study ca nonl y

b e analyze dinon e form . Ingeneral , th e studie s i nwhic hth e specie s an drout e o f exposur e mos t closel y correspon dt o th e environmentall y expose dpopulatio nar e give nth e mos t weigh t indevelopin g uni t ris kestimates . Also , th e rout e o f exposur e i nth e epidemiologi c studie s andth e environmen t ar e bot hb y inhalation . A s a result , w e woul dplac e mos t o f ou r emphasi s o nth e uni t ris kestimate s develope dfrom th e epidemiologi c studies . Eve nso , anima l studie s ca nsuppl y valuabl e confir mator y information . However , a numbe r o f factor s strongl y sugges t tha t anima l studie s ar e les s reliabl e tha nthos e base dupo nhuma nresponse . Amon gth e mor e importan t factor s fo r benzen e ar e th e following :
• Equivalen t exposure s wer e highe r inth e anima l tha ni nth e epide miologi c studies , resultin g i na greate r extrapolatio ndistanc e t o th e uni t risk .
• Th e possibilit y

alway s exist s tha t some unknownqualitativ e dif ferenc e betwee nma nandroden t coul dresul t ina majo r differenc e i nsensitivit y

t o benzene . § Th e ris kestimate s ar e upper-boun dinnature , an dcoul db e con siderabl y

abov e th e tru e risks . Whe nestimatin g inhalatio nrisk s fro m gavag e studies , th e followin g impor tan t consideration s als o arise :
• A nimplici t assumptio ni s mad e tha t th e fractio no f benzen e delivere dt o th e targe t orga nvi a gavag e i nrodent s i s equa l
1 8P.2 3

co th e fractio no f th e benzen e delivere dt o th e targe t orga n from th e tida l volum e o f ai r b y man . Suc ha

nassumptio ni s highl y speculative .
• Th e approximat e surfac e are a correctio ni s employed— a usag e which , althoug hstandard , i s somewha t controversial . i\t Ch .i" 9 thes e factor s i nmind , w e loo ka t th e anima l results : I nTabl e 10 , al l o f th e anima l response s relate dt o leukemi a ar e presen ted . We not e that , wit hth e exceptio no f th e NT P gavag e study fo r mal e mice , thes e response s ar e al l belo w th e huma nestimates—whic hi s reassuring . I n general , th e larges t estimate s o f th e uni t ris kar e associate dwit hth e gavag e studies . InTabl e 11 , th e effect s o f varyin g some o f th e assumption s i nth e uni t ris kestimat e ar e explore dfo r th e mos t sensitiv e endpoin t preputia l glan d carcinoma s i nB6C3F 1 mal e mic e obtaine dina gavag e study . We not e a chang e o f on e orde r o f magnitud e du e t o th e differenc e betwee nth e surfac e are a and weigh t equivalenc e assumptions . Anothe r chang e o f on e orde r o f magnitud e result s from

usin ga 95 % upper-boun drathe r tha na non-zer o maximum likelihoo d poin t estimat e o f th e linea r term . Thus , thes e tw o source s o f uncertainty , take ntogether , chang e th e estimat e b y mor e tha ntwo order s o f magnitude . Also , i t shoul db e note dtha t th e Zymba l glan dandpreputia l glan dar e foundonl y

inrodent s andno t i nman . Whil e tumor s inthes e organ s ar e a definit e indicatio no f carcinogenicity , the y involv e anadditiona l extrapo latio nassumptio nwhe nattemptin gt o linkthe m quantitativel y

t o tumor s in humans . Considerin gth e point s raise dandth e genera l guideline s previousl y dis cussed , a "bes t judgment " singl e uni t ris knumbe r wil l be develope db y th e CA G a s requeste db

y OAQP S i nth e nex t section . 1 9P.2 4

TABL E 10 . ANIMAL-DERIVE DESTIMATE S OF UNI T RIS K BASE DUPON

LEUKEMI A

O RLYMPHOM

A RESPONS E
Investigato r Goldstei n e t al
. Goldstei n e t al
. Maiton i e t al
. Malton i e t al
. Malton i e t al
. NT P Exposure rout e Inhalatio n Inhalatio n Inhalatio n Gavage Gavage Gavage Species-se x Mal e rat s Mal e mic e Mal e an d femal e rat s Mal e rat s Femal e rat s Femal e mic e Uni t ris k estimat e 1.1 1 xIO" 3 5.4 8 xIO" 4
4.4 1 xIO" 4 1.3 3 x10- 2 6.3 2 x10~ 3 5.6 9 xIO" 2

2 0TABL E 11 . UNI T RIS KESTIMATE S USINGTH E MOS T SENSITIV E ENDPOINT--PREPUTU L GLAN DRESPO r E I N B6C3F 1 MAL E MIC E UNDE RVARIOU S ASSUMPTION S
Mode l an

dstatisti c use d

Cas e numbe r Multistag e

ML E 95

% uppe rboun d Mortalit ycorrecte d Multistage-Weibul l 

### ML E 95 % uppe r bound Exposur e equivalanc e mg/k g mg/m ' Uni t ris k estimat e 1 2 3 4 5 6 7 8 X

X X

X X

X X

X X X X X X

X X X 1.6 1

1.3 6 1.2 5 3.0 2 1.3 4 1.1 3 1.0 4 2.5 1 x10- 1 xIO" 2
x10- 1 xIO" 2
xIO' 2
xIO" 3
xIO" 2
xIO" 3



### 2 1P.26 .

Composit e Uni t Ris kEstimat e Considerin g th e informatio npresented , w e fee l quit e confiden t tha t i f low-dos e linearit y

holds , th e tru e uni t ris klie s somewher e betwee n1 x10~ 2 an d1 x10*1 . Producin g a singl e numbe r from th e variou s estimate s presente d i s a highl y

subjectiv e undertakin g tha t i s ope nt o criticism , n o matte r wha t approac hi s taken . Applyin gou r bes t judgment , we believ e tha t th e join t uni t ris kestimat e should : t b e base dupo nepidemiologi c studie s only ;
• us e th e mos t extensiv e dat a bas e available ; t giv e equa l weigh t t o th e cumulativ e dos e andweighte dcumulativ e dose , a s wel l a s relativ e andabsolut e forms ; and

• us e th e ML poin t estimates . I nTabl e 12 , th e ML E o f uni t ris ki s give nfo r eac ho f th e fou r mode l types , base do nth e mos t complet e dat a se t tha t i s commo nt o al l models . No t havin g an

y rational e fo r preferrin gon e mode l ove r another , we tak e th e geo metri c mea nt o obtai na poole dmode l average . Thi s result s i nth e estimat e 2.1 1 x10*2 . Thi s estimate , unfortunately , doe s no t tak e int o accoun t th e result s o f th e Won ge t al . study . A somewha t ad-ho c bu t reasonabl e adjustmen t woul db e t o assum e tha t th e rati o o f th e Rinsky-Ott-Won g studie s t o Rinsky-Ot t fo r th e relativ e ris kcumulativ e dos e mode l wa s th e same a s fo r othe r models . Unde r thi s assumption , th e compute drati o woul db e multiplie db y th e poole d mode l averag e t o obtai na singl e composit e estimate . Takin gth e SM

R= 10 0 fo r th e unexpose dgroup , andusin g th e poole dinfor matio ni nth e Rinsky-Ott-Won g studie s i s a reasonabl e approac ht o obtainin ga join t estimat e fo r cumulativ e doses . Thi s give s a resul t o f 3.5 5 x10~2 , whic h i s ootaine dfrom

dat a se t VII I an

di s show

ni nTabl e 1 . Usin g thi s approach , 2 2P.2 7

TABL E 12 . RISK S DU E T OLIFETIM E 1 PPM BENZEN E EXPOSUR E BASE DUPON

COMBINE DOT T E T AL . ANDRINSKYE T AL . COHORTS , FOLLOWE DFROM

194 0 T O197 8

Mode l form Exposur e paramete r Relativ e Absolut e Cumulativ e Weighte dcumulativ e 2.8 9 xIO" 2 2.4 9 xIO' 2 . 1.9 6 xIO" 2 1.4 0 xIO" 2 Geometri c mea n= (2.8 9 x2.4 9 x1.9 6 x1.4)1/ 4 xIO" 2 = 2.1 1 xIO" 2 .

ou r correctio nrati o i s estimate dt o be

R= 3.5 5 xIO" 2 T 2.8 9 xIO" 2 = 1.2 3

Th e "corrected " join t uni t ris kestimat e i s thu s

u= 2.1 1 xIO" 2 x1.2 3 = 2.6 0 xIO" 2

whic hwe recommen da s ou r singl e bes t judgmen t uni t ris kestimate . However , a numbe r o f othe r approache s ar e possible . On e approac hmigh t b e t o tak e th e geometri c mean , 2.6 6 xIO" 2 , o f th e 2 1 estimates . However , sinc e th e estimate s ar e no t random sample s fro

m some well define dpopulation , th e rational e fo r suc ha napproac hi s no t clear . Anothe r approac htha t i s regarde da s "safe " i s t o tak e th e highes t esti mate , regardles s o f th e qualit y o f th e informatio no nwhic hi t i s based . A s see ninTabl e 1 , th e Won g e t al . stud y give s th e highes t estimat e o f risk , 1.0 4 x10"1 , wit ha 95 % upper boundo f 2.4 2 x10-1 . However , muc ho f th e 2 3potenc y

associate dwit hthi s estimat e ca nb e attribute dt o th e fac t tha t th e non-expose dgrou pha dn o case s o f leukemia . A s a result , th e increas e o f ris k ove r control s ma y

b e du e t o anartifac t i nth e dat a rathe r tha nt o a tru e carcinogeni c response . Anothe r approac htha t ha s bee nsuggeste di s t o us e a s a nestimat e th e sin - ^ e d?t a . se t mode l tha t ha s th e mos t credibilit y associate dwit hit . I ncu r opinion , thi s woul db e th e estimat e take nfrom dat a se t I , Tabl e 3 , whic hi s th e Rinsk y

e t al . study

- weighte dcumulativ e dos e relativ e ris kmodel . Thi s give s a resul t o f 4.1 0 xIO" 2 . I t i s apparen t tha t regardles s o f th e metho duse dt o obtai nth e join t uni t risk , th e resultin g answer s ar e relativel y consistent , andar e clos e t o th e origina l estimat e o f 2.4 1 xIO" 2 . Summ a r y From th e slop e parameter s estimate db y Crum pandAllen , th e uni t ris kfo r leukemi a du e t o a lifetim e exposur e o f 1 pp m benzen e i nth e ai r ha s bee nesti mated . Usin gvariou s model s andcombination s o f assumption s andepidemiologi c studies , 2 1 uni t ris kestimates , rangin gfro m 0. 9 x10" 2 t o 1 . x10" 1 , wer e obtained . Base dupo nth e criteri a o f usin g th e dat a from al l epidemiologi c studie s wit hreasonabl e exposur e informatio nandanaverag e valu e ove r al l th e mathematica l model s believe dt o b e plausible , a combine duni t ris kestimat e o f 2. 6 x10~ 2 wa s derived . Thi s i s take nt o b e th e CAG' s best-judgmen t uni t risk , andi s onl y

slightl y

large r tha nth e origina l estimat e o f 2. 4 x10^2 , whic hi s base dupo nfa r les s reliabl e data . Uni t risk s wer e als o obtaine dfrom anima l studies . However , the y ar e considere dt o b e confirmator y i nnatur e andintrinsicall y les s reliabl e tha n thos e base dupo nth e huma nresponse . Th e inhalatio nstudie s tha t woul dbe preferre ddu e t o rout e similarit y ten dt o giv e estimate s tha t ar e anorde r o f
2 4P.2 9

ma-anitude lower . Gavag e studies , althoug htendin g t o giv e highe r estimate s tha nhuman , u

pt o abou t fiv e time s i nth e extreme , ar e dependen t upo na larg e serie s O T unverifiabl e assumptions . Thus , whil e the y ma y b e a vali duppe r bound , the y

ar e judge dt o b e overl y conservative , base dupo nth e huma ndata . A mor e detaile danddirec t compariso no f th e huma nandanima l dat a wil l b e possibl e i nth e CAG' s fina l report .



### 2 5P.3 0

REFERENCE S
Aksoy , M. ; Erdem , S. ; Dincol , G . (1974 ) Leukemi a i nshoe-worker s expose d chronicall y

t o benzene . Bloo d44(6):837-841 . Aksoy , M . (1978 ) Benzen e andleukemia . Lance t i:441 . Californi a Departmen t o f Healt hServices . (1984 , September ) Repor t t o th e Scientifi c Revie w

Pane l o

nbenzene . Prepare db y th e staff s o f th e Ai r Resource s Boar dan

dth e Departmen t o f Healt hServices . Carcinoge nAssessmen t Group , U.S . Environmenta l Protectio nAgency . (1979 , Januar y 10 ) Fina l repor t o npopulatio nris kt o ambien t benzen e expo sures . Availabl e from : NTIS , Springfield , VA . PB82-227372 . Crump , K.S. ; Allen , B.C . (1984 , May ) Quantitativ e estimate s o f ris ko f leukemi a from

occupationa l exposur e t o benzene . Prepare dfo r th e Occupationa l Safet y

an dHealt hAdministration . Gail , M . (1975 ) Measurin gth e benefi t o f reduce dexposur e t o environmenta l carcinogens . J . Chroni c Dis . 28:135-147 . Goldstein , B.D. ; Snyder , C.A. ; Laskin , S. ; Bromberg , I. ; Albert , R.E. ; Nelson , N . (1980 ) Myelogenou s leukemi a inrodent s inhalin g benzene . Unpublishe ddata . Infante , P.F. ; Rinsky , R.A. ; Wagoner , J.K. ; Young , R.J . (1977 ) Leukemi a • i nbenzen e workers . Lance t Jul y 19:76-78 . Maltoni , C ; Conti , B. ; Cotti , G . (1983 ) Benzene : a multipotentia l car cinogen . Am . J . Ind . Med . 4:589-630 . Nationa l Toxicolog y

Program

(NTP) . (1984 , July ) NT P technica l repor t o n th e toxicolog y

andcarcinogenesi s studie s o f benzen e (CAS No . 71-43-2 ) i nF344/ N

rat s an

dB6C3F 1 mic e (gavag e studies) . NI HPublicatio nNo . 84-2545 , NTP-84-072 . Unpublished . Ott , M.G. ; Townsend , J.C ; Fishbeck , W.A. ; Langner , R.A . (1978 ) Mortalit y amon g individual s occupationall y expose dt o benzene . Arch . Environ . Healt h33:3-10 . Rinsky , R.A. ; Young , R.J. ; Smith , A.B . (1981 ) Leukemi a inbenzen e workers . Am . J . Ind . Med . 2:217-245 . Wong , 0. ; Morgan , R.W. ; Whorton , M.D . (1983 , Augus t 31 ) Comment s o nth e NIOS Hstudy

o f leukemi a inbenzen e workers . Technica l repor t submitte d t o Gul f Canada , Ltd . b y Environmenta l Healt hAssociates .



### 2 6P.3 1

APPENDI XA

NOTE : Table s referre dt o i nCrum pandAlle n(1984 ) hav e bee nreproduce dexactly . Table s 4 , 5 , 18 , 19 , 20 , 21 , and2 2 ar e no t include dherein ,Tabl e 1 Observe dan dExpecte

dNumber o f Deaths i n Ot t et al_ . Cohor t b y Cumulativ

e Dos e

Caus e 0- 5 ppm-y r (1.48) * 353 3 p- y SM R 

# W E 5-2 0 ppm-y r (10.9 ) 296 1 p- y 

### 0/ E m 20-8 0 ppm-y r 80-20 0 ppm-y

r 200 + ppm-y

r (44.8 ) (125.9 ) (352.9 ) 375 8 p- y

179 0 p-y

122 9 p-y 0/ E SM R0/ E SM

R0/ E SM

R Total

(160.04 ) 1327 1 p-y 0/ E SM

R
Al l Cause s 11/2 2 5 0 19/2 7 7 0 34/39. 8 8 5 21/1 9 11 1 17/1 9 8 9 102/12 7 8 0
Al l Malignant Neoplasm

s 2/3. 5 5 7 9/4. 6 19 6 10/7. 4 13 5 7/3. 6 19 4 3/3. 4 8 8 31/22. 5 13 8 Malignant Neoplasm

s o f Digestiv

e Organ s an dPeritoneu

m 0/1.0 4 3/1. 4 21 4 3/2. 2 13 6 3/1.0 3 29 1 0/.9 8 0 9/6. 7 13 4 Malignant Neoplasm

s o f Respirator

y Syste m i/1.0 7 9 3 2/1. 3 15 4 4/2. 4 16 7 3/1. 2 25 0 1/1. 2 8 3 11/7. 2 15 3 Leukemi a l/r 18 55 6 0/.20 2 1/.3 1 32 3 0/.1 4 0/.1 3 0 2/.9 6 20 8
Othe r Neoplasm

s o f Lymphati c an

d Hematopoieti c Tissue s 0/.2 8 1/.30 4 32 9 1/.4 7 21 3 0/.2 3 0 O/.20 2 0 2/1. 5 13 3 Aveng e exposur

e I nppm-year sP.3 3

Tabl e 6 Observe dan

dExpecte dLeukemla s 1 nRinsky

e t al . Cohor t b

y Cumulativ e Exposure;~T950-197 8 Followup

UWJUfrv e 

### Exposur e 1 nppm-year

s (average ) 0- 5 (1.29 ) 5-2 0 (U.O ) 20-8 0 (42.2 ) 80-20 0 (129.0 ) 200-1000 (421 ) 1000 + (1489 ) Observe d 2 0 " 0 0 5 * 1 Expecte

d 1.1 1 0.5 2 0.5 0 0.3 1 0.3 2 0.04 9 SM

R 18 0 0 0 0 156 0 204 0 person-years

' 1689 0 709 2 659 1 355 7 307 5 39 6 sP.3 4

• Tabl e 7 Observe dan

dExpectedleukemla s 1nRinsk y e t a KCohor t b

y Cumulative Exposur e Using Revised^xposur e Estimates * 1950-197 8 Followup Curylatlve Exposur e 1nppm-year s (average ) 0- 5 (1.32 ) 5-2 0 (11.2 ) 20-8 0 (42.3 ) 80-20 0 (129 ) , 200-100 0 (393 ) 1000 + (1142 ) Observe d



### 2 0 0 1

• 4 

### 1 Expected

1.1 3 0.5 4 0.5 1 0.3 0 0.3 4 0.01 5 

### SM

R 17 7 0 0 33 3
118 0 667 0 person-year s

1717 0 766 7 •673 2 333 5 308 7 

### 12 0P.3 5

Tabl e 8 Observe dan

dExpecte dLeukemia s 1nRinsk y e t al_ . Cohor t b

y Weighte d CumulativeTJose ; 1940-197 8 Followup

We 1 anted Cumulativ e Exposur e Inppm-year s (averaqe ) 0- 3 (0.54 ) 3-1 0 (5.9 ) 10-3 0 (17.7 ) 30-10 0 (56.6 ) 100-30 0 (163.5 ) 300 + (554.8 ) Observe d



### 2 0 0 1 3 2 Expecte d

1.5 5 0.4 6 0.3 6 0.3 3 0.20 4 0.04 7 

### SM

R 12 9 0 0 30 5 147 0 425 0 person-year s

2463 3 584 3 454 4 394 7 228 6 

### 63 3P.3 6

Tabl e 9 Observe dan

dExpecte dLeukemia s InRinsk y e t al . Cohor t b

y Exposur e in Ten-YearUimlow ; 1940-197 8 Followup

ppm-year s xmrmulate d 12. 5 t o 2. 5 year s prio r t o ag e category (average ) 0- 2 (0.15 ) 2- 5 (3.2 ) 5-1 0 (7.3 ) 10-5 0 (23.6 ) 50-20 0 (104.5 ) 200 + (471.1 ) •

Observe d 

### 3 0 0 0 1 4 Expecte d

2.02 5 0.14 5 0.13 1 0.30 9 0.24 9 0.10 3 

### SM

R 14 8 0 0 0 40 1 388 0 person-year s

2710 6 247 4 217 8 493 9 367 1 151 8P.3 7

Tabl e 1 0 Observe o *n

d Expecte d Leukemia s 1n Ot t e t a hCohor t b

yWeighte d Cumulativ e Exposur e
Wlighte d Exposur e 1nppm-year s (average ) 0- 3 (.635 ) 3-1 0 (5.94 ) 10-3 0 (18.8 ) 30-10 0 (51.8 ) 100 + (153 ) Observe d



### 1 0 1 0 0 Expecte d SM R person-year s .3 1 32 1 541 6 .19 9 0 221 8 .1 9 51 8 253 3 .1 7 0 205 6 .08 9 0 105 4P.3 8

Tabl e 1 1 Observe dan

dExpecte dLeukemia s 1n Ot t e_ t a_ L Cohor t b

y Exposur e 1nTen-Yea r Window

oom-year s accumulate d 12. 5 t o 2. 5 year s prio r t o ag e categor y (averaqe ) 0- 2 (.115 ) 2- 5 (3.42 ) - 5-1 0 (7.18 ) 10-5 0 (25.3 ) 50-20 0 (101 ) 200 + (263 ) Observe d



### 1 0 0 1 0 0 Expecte d



### .4 4
.05 2 .06 6 

### .2 1 .1 7 .03 2 

### SM

R 22 9 0 0 48 8 0 0 person-year s

619 2 

### 800 882 290 3 210 5 

### 39 5Tabl e 1 2 Result s o f Fitting Relativ e Ris kMode l Using Cumulative Dos e P.3 9

Dat a Se t I Rinsk y e t al . (followup7rom

195 0 Tabl e 6 ) Paramete r Estimate s i b [back - (Slop e o f Oos e Response ) [ground ) (ppm-years )

95 % 95T "



### .8 7 6oodnes s o f Fi t ML E Lowe r ML E Uppe r Ch1-sq . o*. ^ p-valu e

.007 4 .02 3 .05 1 5. 0 4 

### .2 9 I I Rinsk y e t al. , (followup7rom

1940 , Tabl e 2 ) .8 2 II I Rinsk y e t al_ . (reYlseH'exposures , Tabl e 7 ) .8 8 I V Rinsk y e t al . (Tabl e B T an

d Ot t e t al . (TabT e T J1. 2 .006 9 .02 3 .05 1

.008 0 .02 9 .06 5

.003 5 .01 3 .03 1 5. 0 4

3. 3 4

4. 8 4 

### .2

9

.5 0

.3 1
Sam e a s I V excep t tw o questionabl e case s added 

### 1. 7 .002 0 .009 2 .02 3 2. 6 4 

### .6 3 V I Uon g (Tabl e 3 SMR»5 0 assume d fo r unexposed ) VI I Rinsk y e t al . (Tabl e F T ~ ~ Ot t e t al . (TabT I T J an dWong (Tabl e 3 ) 

### 0. 5

.5 7 .0003 9 .04 7 .1 1

.01 2 .03 3 .07 2 2. 4 2

11. 7 8 

### ,3

0

.1 6
VII ! sam e a s VI I excep t SMR-10 0 assume d fo r unexpose d 

### 1. 0 .007 0 .01 6 .02 9 9. 5 9 

### .4 9P.4 0



### Tabl e 1 3 Result s o f Fitting Absolut e Ris k Mode l Usin g Cumulativ e Dos e
Paramete r Estimate s a b (back - (Slop e o f Dos e Response ) ground ) (ppm-years) " 6oodnes s o f Fi t

95 1 9TS ~ Dat a Se t ML E Lowe r ML E Uppe r Ch1-sq . d.f . p-valu e I Rinskye t al . (followup fro m1950 , , 7 

### - , Tabl e 6 ) 5.9x10* ° 8.3x10" ' 2.0x10" ° 3.9x10" ° 5. 2 4 .2 7 I I Rinskye t al . (followup 7ro m1940 , fi 

### inc
. Tabl e 2 ) 7.9x10" ° 7.6x10" ' 1.8x10" ° 3.6x10" ° 5. 1 4 .2 8 II I Rinskye* : al_ . (revisecTexposures , fi 

### - - , Tabl e 7 ) 6.0x10" ° 1.0x10" ° 2.5x10" ° 4.9x10" ° 4. 0 4 .4 1 I V Rinskye t al . (Tabl e 6 j " ~ an d Ot t e t al . c 7 fi 

### c (TabT e T J 1.4x10' ° 5.9x10 " '.^io" ° 3.1x10" ° 5. 1 4 .2 8 V Sam e a s I V excep t tw o questionabl e c 7 « * case s adde d4.5x10" ° 5.8x10'" ' 1.7x10" ° 3.3x10" ° 2. 8 4 .5 9P.4 1



### Tabl e 1 4 Result s o f Fitting Relativ e Ris k Mode l Usin g Weighte d Cumulativ e Dos e
Paramete r Estimate s a b (back

- (Slop e o f Dos e Response ) ground ) (ppm-years) " 6oodnes s o f Fi t



## 95 * 9T T Dat a Se t ML E Lowe r ML E Uppe r Ch1-sq . d.f . p-valu e I Rinsk y e t al . (Tabl e t T ~ ~ .18 0 .02 5 .07 9 .1 7 2. 0 4 .7 4

I I Rinskye t al . (Tabl e f T " ~ an d Ot t e t al . (TabT e TC ) 1.0 5 .01 4 .04 8 - .10 8 6. 3 9 .7 1Tabl e 1 5 Result s o f Fitting Absolut e Ris kMode l Using Weighte dCumulative Dos e P.4 2

Dat a Se t I Rinsk y e t al . 1940-197 3 ~ followup (Tabl e 8 ) a

(back ground ) ML E Paramete r Estimate s

9.0x1 0 (Slop e o f Dos e Response ) (ppm-years) " IF ? —55 T Lowe r

2.2x1 0 Goodnes u o fFi t

MLE Uppe rCh1-sq
. d.f
. p-valu e



### 5.2xl0' 6

### 9.9xl0" 6

### 2. 1 .7 2



### II Rinsk ye t al
. (Tabl e B J an d Ot t e t al
. (Tabl e TU ) 9.1x1 0 1.6x1 0 4.1x1 0 8.0x1 0 6. 0 .7 4P.4 3

Tabl e 1 6 ResuU s o f Fitting Relative Ris kMode l

Using "Window " Dos e

Dat a Se t 

## I Rinsk y e t (Tabl e 9 j 

## il a

(back ground )

ML E

1.1 1 Paramete r Estimate s b (Slop e o f Dos e Resgi (ppm-years ) ' 95 % Lowe r ML E

.01 7 .05 1 jnse )



## 95i ' Uppe r

.10 7 Goodnes s o f Fi t Chi-sq . d.f . p-valu e

2. 2 4 .7 0

I I Rinsk y e t al . (Tabl e 5 7 ~ " an d Ot t e t al . (TabT e TT ) 1. 3 .01 1 .03 5 .07 6 5. 1 1 0 .8 8P.4 4

Tabl e 1 7 Result s o f Fitting Absolut e Ris kMode l

Using "Window " Dos e

Paramete r Estimate s a b (back - (Slope o f Dos e Response ) ground ) (ppm-years) " Goodnes s o f Fi t



### 55 ? 55? " Dat a Se t ML E Lowe r ML E Uppe r Ch1-sq . d.f . p-valu e I Rinsky e t al . - * , , . (Tabl e 9 7 ~ 4.5x10" ° 1.5x10" ° 3.8x10" ° 7.5x10' ° 2. 3 4 .6 8

I I Rinsky e t al . 

### ' (Tabl e f j " " and
_ Ot te t a h c c c

c 

### (Table11 ) 1.7x1 0 D 

### 1.2x10" ° 3.1x10" ° 8.7x10" ° 5. 0 1 0 .8 9P.4 5

Tabl e 2 3 Dose s Correspondin g t o Increase dRis ko f 10 " I nRoden t Inhalatio nStudie s Multistag e Mode l Dat a Set s • ML E 95 S Lowe r LlmT T Bioassay s fro

m Goldstei ne t a1_ . (1980 ) (Dos e unit s • ppm/ 8 hr day ) Leukemia , mal e rat s Inf . .379E-2 * Leukemia , mal e mic e 2.04 1 .776E- 2
Bioassay s fro

m Malton i e t aj_ . (1983 ) (Dos e unit s • ppm/ 8 hr day ) Leukemia , bot hsexes , rat s .314E- 1 .955E- 2 Zymba l glando r nasa l cavit y carcinom a o r leukemia , bot hsexes , rat s .375E- 2 .233E- 2

a .379E- 2 mean s .37 9 x10" ZP.4 6



### Table2 4 Dose s Correspondin

gt o Increase d Ris

k of 1 0 i nRoden

tGavag eStudie s

____ ^ Mode l Multistag e Multistage-Weibull " 

## 95 i 55 X

_Dat a Set s ML E Lowe r Limi t ML E Lowe r Limi t NT P Bioassay s (Dos e unit s • mg/k gbod y wt. ) Zymba l glandcarcinoma , •al e rat s Al l squamou s cel l carcinomas , mal e rat s Zymba l glandcar dnoma , femal e rat s Al l squamou s cel l carcinomas , femal e rat s Squamou s cel l carcinoma o f preputia l gland , mal e mic e Al l squamou s cel l carcinomas , mal e mic e Alveolar/bronchiola r carcinoma , mal e mic e Lymphoma , NOS , mal e mic e Al l squamou s cel l carcinomas , femal e mic e Mammar y gl: : . o carcinoma , NOS rfe n' , i . ice Alveolar/bronch1ola r carcinoma , femal e mic e Lymphoma , femal e mic e .576E-3 * .444E- 3 .348E- 3 .797E- 3 .297E- 3

.690E- 3 .427E- 3 .742E- 3 1.88 3 .442E- 3 .545E- 3 .167E- 2 .383E- 3

.339E- 3 .238E- 3 .479E- 3 .123E- 3

d29E- 3 •238E- 3 .357E- 3 .132E- 2 .270E- 3 .366E- 3 .271E- 3 .555E- 3

.394E- 3 .333E- 3 .804E- 3 .113E- 2

.660E- 1 .338E- 3 .527E- 3 1.71 6 •329E- 3 .333E- 3
INF . .341E- ?

.300E- 3 -216E- 3 .430E- 3 .955E- 4

.103E- 3 .186E- 3 -227E- 3 .107E- 2 .227E- 3 •.213E- 3 .401E- 3 Bioassay s fro

m Malton i e t al

_ Leukemia , mal e rat s Al l tumors , mal e rat s Zymba l glandcarcinoma . femal e rat s Leukemia , femal e rat s Al l tumors , femal e rat s Leukemia , bot hsexes , rat s Al l tumors , bot hsexes . rat s (1983 ) .70 8 .53 2 .840E- 3 INF . .295E- 3 .399E- 2 .905E- 3 (Dos e unit s

.128E- 2 .736E- 3 .519E- 3 .269E- 2 .190E- 3 .178E- 2 .386E- 3 • mg/k g bod

y wt. ) "

K7r>r_- ) MMXI C C7 A « in' 3P.4 7

CRIM3 - APPENDI XA ' DATA AN OMODE L PARAMETER S FO RANIMA L STUDIE S
Thi s appendi xsummarize s the dat a an dmodel s usedt o estimat e cance r risk s fro

m thre e long-ter

m roden t bioassays : Goldstei ne t a h (1980) , Malton i e t a h(1983) , an dNT P (1983) . Fo r the time-to-respons e r.^t^tcge-Weibul l mode l applie dt o the NT P dat a (page s A24-A35) , tim e 1 s measure d1nweek s an dthe tumo r Indicato r variabl e ha s th e followir j Interpretation :

1 : Deat hwithou t carcinogeni c respons e o f interest ; 2 : Deat hwit hcarcinogeni c respons e o f Interest .



### A OP.4 8

Dat a fro m Goldstei ne_

t a h(1980 ) Spede s an

dSex : Sprague-Dawle y rats , mal e Endpoint : Leukemi a Exposur e Route : Inhalatio n

Dose s 0 7 5 22 5 (ppm/ 8 hr day ) # affecte d0 1 0 # a t ris k6 7 4 0 4 5 Multistag e Mode l - Chi-squar e Goodness-of-Fi t Statistic : 2.81 9 Degree s o f Freedom : 2 p-value : .241 9
Maximu m Likelihoo dParamete r Estimates : q Q• .660E- 2
Linea r ter

m correspondin g t o 95 5 uppe r limi t onrisk , (q/) ; .264E- 3



### A lP.4 9

Dat a fro m Goldstei ne t o h(1980 ) Spede s an

dSex : AKR , C57BL , an dCD- I mice , mal e Endpoint : Leukemi a Exoonr e Route : Inhalation

Dose s 0 (ppm/ 8 h r day ) # affecte d0 # a t ris k21 0 

### 7

5
0 5 0 22 5
2 16 0

/ Multistag e Mode l - Ch1-squar e Goodness-of-F1 t Statistic : .699E- 1 Degree s o f Freedom : 2 p-value : .966 1
Maximu m Likelihoo dParamete r Estimates : 

## Q0" ° 1 q : - 0 q 2 » .240E- 6 L1r._r. ; '.sr

m correspondin gt o 95 S uppe r limi t onris k(q^) : .129E- 3



### A 2P.5 0

Dat a fro m Malton i e t a_

h(1983 ) Spede s an

dSex : Sprague-Dawle y rats , mal e an

dfemal e Endpoint : Leukemi a Exposur e Route : Inhalatio n

Dose s 0 24 1 (ppm/ 8 h r day ) # affecte d1 2 # a t ris k36 5 19 3 Multistag e Mode l - Ch1-squar e Goodness-of-F1 t Statistic : - Degree s o f Freedom : * p-value : -
Maximu m Likelihoo dParamete r Estimates : q 0 ' -274E- 2 , q x- .318E- 4 Linea r ter

m correspondin g t o 95 1 uppe r limi t o nris kIn*):

.I05E- 3

\ A 3P.5 1

uat a fro m Malton i e t a_

h(1983 ) Spede s an

dSex : Sprague-Dawle y rats , mal e an

dfemal e Endpdnt : Zymba l glandor nasa l cavit y carcinoma s o r leukemi a Exposur e Route : Inhalation

Dose s 0 . 24 1 (ppm/ 8 h r day ) # affecte d4 1 4 # a t ris k36 5 19 3 Multistag e Mode l - Ch1-squar

e Goodness-of-Fi t Statistic : - Degree s o f Freedom : - p-value : -
Maximu m Likelihoo dParamete r Estimates : q 0 - .110E- 1 q x• .267E- 3 Linea r ter

m correspondin gt o 95 Xuppe r limi t

. onris k(o^*) . .42EE- 3



### K 4Dat a fro m Malton i e t a h(1983 ) Spede s an

dSex : Sprague-Dawley rats , mal e Endpoint : Leukemi a Exposur e Route : Gavag e

Dose s 0 (mg/kgbod

y wt ) I affecte d0 # a t ris k2 8 

### 5

0
0 2 8 25 0
4 3 3
Multistag e Mode l - Ch1-squar e Goodness-of-Fi t Statistic : .14 5 Degree s o f Freedom : 2 p-value : .930 4
Maximu m Likelihoo dParamete r Estimates : 

## q 0 

## " 

## ° q x• 0 q 2 » .200E- 5 io• er m corresponding onris k(q . ) : .783E- 3 t o 95 X uppe r 1 imi t



### A 5P.5 3



### uat a fr& nMalton i e t a h(1983 ) Spede s an

dSex : Sprague-Dawle y

rats , mal e Endpoint : Al l tumor s Exposur e Route : Gavag e

Dose s 0 (mg/kgbod

y wt ) # affecte d2 # a t ris k2 8 

### 5

0
1 2 8 25 0
8 3 3 Multistag e Mode l - Ch1-square Goodness-of-F1 t Statistic : .51 9 

### Degree s o f Freedom : 1 p-value : .471 3
Maximu m Likelihoo dParamete r Estimates : q 0 

### - .529E- 1 q x• 0 q 2 - .353E- 5 L1n<« rterr a correspondin g t o %% upw? . limi t o n ris k (t\*): .136E- 2 •

A 6P.5 4

Dat a fro m Malton i e t a_

h(1983 ) Spede s an

dSex : Sprague-Dawle y rats , femal e Endpoint : Leukemi a Exposur e Route : Gavag e

Dose s 0 (mg/kgbod

y wt ) # affecte d1 # a t ris k3 0 

### 5

0
2 3 0 25 0
1 3 2
Multistag e Mode l - Ch1-squar e Goodness-of-F1 t Statistic : .57 7 Degree s o f Freedom : 2 p-value : .748 4
Maximu m Likelihoo dParamete r Estimates : q 0 • .445E- 1 Linea r ter

m correspondin g t o 95 5 uppe r limi t onris k(q,*) : .372E- 3



### A 7P.5 5

Dat a fro m Malton i e t a h(1983 ) Spede s an

dSex : Sprague-Dawle y rats , femal e Endpolnt : Zymba l glandcarcinom a Exposur e Route : Gavag e

Dose s 0 (mg/kg bod

y wt ) # affecte d0 # a t ris k3 0 

### 5

0
2 3 0 25 0
8 3 2 Multistag e Mode l - Ch1-squar e Goodriess-of-F1 t Statistic : .527E- 1 Degree s o f Freedom : 2 p-value : .973 9
Maximu m Likelihoo dParamete r Estimates : 

# % 

# " ° ' q x- .119E- 2 ..ea r ter m correspondin gt o 95 1 uppe r limi t i i ris k(q^) : .192E- 2



### A SP.5 6

Dat a fro m Malton i e t aj . (1983 ) Spede s an

dSex : Sprague-Dawle y rats , femal e Endpoint : Al l tumor s Exposur e Route : Gavag e

Dose s 0 (mg/kg bod

y wt ) # affecte d6 # a t ris k3 0 

### 5

0
1 0 3 0 25 0
2 1 3 2
Multistag e Mode l - Ch1-squar e Goodness-of-F1 t Statistic : .741E- 2 Degree s o f Freedom : 1 p-value : .931 5
Maximu m Likelihoo dParamete r Estimates : q 0 - .22 7 q 1 » .339E- 2 Linea r ter

m correspondin gt o 95 1 uppe r limi t onris k(q x *) : .526E- 2



### A 9P.5 7

uat a fro m Malton i e t a h(1983 ) Spede s andSex : Sprague-Dawle y rats , mal e an

dfemal e Endpolnt : Leukemi a Exposur e Route : Gavag e

Dose s 0 (mg/kgbod

y wt ) # affecte d1 # a t ris k5 8 

### 5

0
2 5 8 25 0
5 6 5 Multistag e Mode l - Ch1-squar

e Goodness-of-Fi t Statistic : .326E- 1 Degree s o f Freedom : 1 p-value : .856 2
Maximu m Likelihoo dParamete r Estimates : q 0 - .191E- 1 q x- .251E- 3 Linea r ter

m correspondin g t o 95 5 uppe r limi t onris k(tjj*) : .561E- 3



### A1 0P.5 8

Dat a fro m Malton i e t a h(1983 ) Spede s andSex : Sprague-Dawle y rats , mal e andfemal e Endpoint : Al l tumor s Exposur e Route : Gavag e

Dose s 0 5 0 (mg/kg body

wt ) # affecte d8 1 1 # a t ris k5 8 5 8 Multistag e Mode l - Chl-squar e Goodness-of Degree s o f Freedom : - p-value : - 

### 25 0
2 9 6 5

Fi t Statistic : -

Maximu m Likelihoo dParamete r Estimates : q 0 " -14 8 q x- .110E- 2 q 2 - .266E- 5 Lljie r 'in ncorrespondin g t o 95 5 uppe r limi t onris k{q*): .259E- 2



### Al lP.5 9

Dat a fro m NT P (1983 ) Spede s an

dSex : F344/ N

rats , mal e Endpoint : Zymba l glan dcarcinom

a Exposur e Route : Gavag e

Dose s
# affecte d # a t ris k 

### 0

2 5 0 5 0
6 5 0 10 0
1 0 5 0 200
1 7 5 0
Multistag e Mode l - Ch1-squar

e Goodness-of-Fi t Statistic : .144E-2 Degree s o f Freedom : 1 p-value : .970 6
Maximu m Likelihoo dParamete r Estimates : q 0 - .407E- 1 q 2 » .174E- 2 q 2 - .712E- 6 Linea r ter

m correspondin gt c 95 5 uppe r limi t onris k(g^) : .26 1 E- 2



### A1 2P.6 0

**• » fro m

NT P (1983 ) Spede s an

dSex : F344/ Nrats , mal e Endpoint : Al l squamou s cel l carcinoma s Exposur e Route : Gavag e

Dose s
# affecte d # a t ris k 

### 0

0 5 0 5 0
1 0 5 0 

### 10 0


### 8 5 0 

### 20 0
16 5 0 Multistag e Mode l - Chi-squar e Goodness-of-F1 t Statistic : 5.53 0 Degree s o f Freedom : 3 p-value : .149 3
Maximum Likelihoo d Paramete r Estimates : q 0 ' 0 q x- .225E- 2 Linea r term

correspondin g t o 95 5 uppe r limi t o n rU k {q*):

.295E- 2



### A1 3P.6 1

Dat a fro m NT P (1983 ) Spede s an

dSex : F344/ N

rats , femal e Endpoint : Zymba l glan dcarcinom

a Exoosur e Route : Gavag e

Dose s 0 2 5 5 0 10 0
# affecte d0 5 5 1 4 # a t ris k5 0 5 0 5 0 5 0
Multistag e Mode l - Ch1-squar e Goodness-of-F1 t Statistic : 1.30 2 Degree s o f Freedom : 2 p-value : .522 0
Maximu m Likelihoo dParamete r Estimates : 

# %' ° q : - .287E- 2 

## q 2 

## * o ^ q 3 - .310E- 7 Linea r ter

m correspondin g t o 95 5 uppe r limi t onris k(q^) : .421E- 2



### A1 4P.6 2

Dat a fro m NT P (1983 ) Spede s andSex : F344/ N rats , femal e Endpoint : Al l squamou s cel l carcinoma s Exposur e Route : Gavag e


### Dose s # affecte d # a t ris k 

### 0

0 5 0 2 5
1 5 0 5 0
4 5 0 10 0
6 5 0
Multistag e Mode l - Chi-square'Goodness-of-Fi t Statistic : .47 8 Degree s o f Freedom : 1 p-value : .489 0
Maximu m Likelihoo dParamete r Estimates : q 0 • .444E-2 5 q x• ,125Er 2 q 2 - .P93E- 6 Linea r ter

m correspondin g t o 95 5 uppe r limi t onris k{q^): .209E- 2 •



### A1 5P.6 3

Dat a fro m NT P (1983 ) Specie s an

dSex : B6C3F , mice , mal e Endpoint : Squamou s cel l carcinom a o f the preputia l gland exposur e Route : Gavag e

Dose s 0 2 5 5 0 10 0
# affecte d0 3 1 8 2 8 # a t ris k5 0 5 0 5 0 5 0
Multistag e Mode l - Chi-squar e Goodness-of-Fi t Statistic : 3.87 4 Degree s o f Freedom : 2 p-value : .144 6
Maximu m Likelihoo dParamete r Estimates :

q : - .337E- 2 q= .567E- 4 Linear : teni i . .responding t o 95 5 uppe r limi t onris k{q^):

.811E- 2



### A1 6P.6 4

Dat a fro m NT P (1983 ) Spede s an

dSex : B6C3F . mice , mal e Endpoint : Al l squamou s cel l carcinoma s Exposur e Route : Gavag e

Dose s
# affecte d # a t ris k 

### 0

0 5 0 2 5
4 5 0 5 0
2 0 5 0 10 0
3 7 5 0
Multistag e Mode l - Ch1-squar e Goodness-of-F1 t Statistic : 1.81 4 Degree s o f Freedom : 2 p-value : .404 6
Maximu m Likelihoo dParamete r Estimates : q 0 » 0 q x- .145E- 2 q 2 • .131E- 3 Linea r ter

m correspondin g t o 95 5 uppe r limi t onris k(q^) : .773E- 2



### A1 7P.6 5

Oat a from

NT P (19.83 ) Spede s andSex : B6C3F , mice , mal e tnopoint : Alveolar/Bronchiola r carcinom a Exposur e Route : Gavag e

Dose s
# affecte d # a t ris k 

### 0

5 5 0 2 5
1 1 5 0 5 0
1 2 5 0 10 0


# w 5 0
Multistag e Mode l - Ch1-squar

e Goodness-of-Fi t Statistic : 1.25 0 Degree s o f Freedom : 2 p-value : .535 4
Maximu m Likelihoo dParamete r Estimates : q 0 - .13 7 q x• .234E- 2 Linea r ter

m correspondin g t o 95 5 uppe r limi t onris k(q x * ) : .421E- 2



### A1 8P.6 6

Dat a fro m NT P (1983 ) Spede s an

dSex : B6C3F } mice , mal e Endpoint : Lymphoma , NO S Exposur e Route : Gavag e

Dose s 0 2 5 5 0 10 0

I affecte d3 5 6 1 0 # a t ris k5 0 5 0 5 0 5 0
Multistag e Mode l - Ch1-squar e Goodness-of-Fi t Statistic : .440E- 1 Degree s o f Freedom : 1 p-value : .834 1
Maximu m Likelihoo d Paramete r Estimates : q 0 - .639E- 1 ....q , 135E- 2 q 2 • o q 3 • .234E- 7 Linea r termcorrespondin g t o 95 5 uppe r limi t onris k {q*)\

.280E- 2



### A1 9P.6 7



### Data , fro m NT P (1983 ) Spede s an

dSex : B6C3F , mice , femal e r 

### . m 

### ±-z*.?.ii Al l squamou s cel l carcinoma s Exposur e Route : Gavag e
Dose s 0 2 5 5 0 10 0
# affecte d0 0 1 7 # a t ris k5 0 5 0 5 0 5 0 ' Multistag e Mode l - Chi-squar e 6oodness-of-F1 t Statistic : .12 3 Degree s o f Freedom : 3 p-value : .989 0
Maximu m Likelihoo d Paramete rEstimates : q 0 •0 •qx- 0 q 2 •0 q 3 » .150E- 6 Linea rter m correspondin g t o 95 5 uppe rlimi t o n ris k (qj*) : .760E- 3

A2 0P.6 8

Dat a fro m NT P (1983 ) Swede s an

dSex : B6C3F . mice , femal e tndpolnt : Mammary

glan dcarcinoma , NO S Exposur e Route : Gavag e

Dose s
# affecte d # a t ris k 

### 0

0 42 2 5
2 3 1 5 0
5 4 8 10 0
8 3 4
Multistag e Mode l - Ch1-squar e Goodness-of-F1 t Statistic : .730E- 1 Degree s o f Freedom : 2 p-value : .964 2
Maximu m Likelihoo d Paramete r Estimates : q 0 » 0 q 1 « .226E- 2 q 2 - 0 q 3 - .391E- 7 Linea r ter mcorrespondin g t o 95 5 uppe r limi t o nris k{q^):

.370E- 2



### A2 1P.6 9

Dat a fro mNT P (1983 ) Spede s an

dSex : B6C3F , mice , femal e Endpoint : Alveolar/Bronchiola r carcinoma Exposur e Route : Gavag e

Dose s 0 2 5 5 0 10 0
# affecte d 0 3 6 6 I a t ris k 5 0 4 7 5 0 5 0 Multistag e Mode l - Ch1-squar e Goodness-of-F1 t Statistic : 1.86 3 Degree s o f Freedom : 3 p-value : .602 0
Maximum Likelihoo d Paramete r Estimates : q 0 • 0 q' j - Jcl v- 2 Linea r terr

a com::poddin g t o 95 5 uppe r limi t o n ris k (q*):

.273E- 2



### A2 2P.7 0

Dat a fro m NT P (1983 ) Spede s andSex : B6C3F . mice , femal e Endpoint : Malignan t lymphom a Exposur e Route : Gavag e

Dose s 0 2 5 5 0 10 0
# affecte d1 5 2 4 2 4 1 9 # a t ris' . 4 9 4 5 5 0 4 9
Multistag e Mode l - Ch1-squar e Goodness-of-F1 t Statistic : 5.8 1 Degree s o f Freedom : 2 p-value : .054 8
Maximu m Likelihoo dParamete r Estimates: q Q- .52 7 q 2 - .H:3E- 3 Linea r ter

m correspondin g to 95 5 uppe r limi t onris k(q x * ) : .369E- 2



### A2 3P.7 1

Dat a fro m NT P (1983 ) Specie s an

dFex : F344/ N

rats , mal e r --?o1nt : Zymba l glandcarcinoma Exposur e Route : Gavag e TH E 1 7 rBSFRVATICN i A TLEVE L t WfT H AOCS F r r0.000QC0CO 0 tTI«C t riJMQr . INJICATC R (NUMBE R » ) 

### 12. 0 35. 0 t l J • V J 

### 104. 0 1 1 1 1 4 1 l ( 1 ) 1 ) At 1 31 ) 

### 25. 0 41. 0 87. 0 104. 0 I t l ( l ( 2 1 1 ) 1 1 l l 

### t ) 29. 0 59. 0 83. 0 

### t t 1 ( 2 1 • 1 ) 2 ) 1 ) 

### 31. 0 68. 0 96. 0 l ( 

### I t 1 ( 1 ) 1 ) I ) 

### 32. 0 I t 

### 74. 0 I t 

### 101. 0 U 1 )

I ) 2 ) TH E 2 0 OBSERVATION S A TLEVE L 2 WIT H AOPS E C F 50.000 0 ITI*E,TUMP » INTICATC R tNUM^ER) ) 35. 0 63. 0 89. 0 100. 3 TH E 51. 0 J3. 0 83. 0 93. 0 98. 0 TH E 51. 0 83. 0 87. J 91. 0 95. 0 102. 0 1 1

I t I t I t 2 4
I t H 2 ( I t 2 t 2 8
l l 2 ( l l I t I t I t 1 1 1 ) 1 ) 1 ) 49. 0 l l

65. 0 I t 

### *n. o 

## l l 101. 0 1 1 OBSFRVATIOM S * T
I ) 

# 1 ! I I 1 ) ITMC,TV*fV >

57. 0 l l 77.0 I t 116. 0 1 1 °1. 0 ?i 100. 0 l l OBSERVATION j A

T
1 ) I ) I ) I ) 3 ) 2 ) ITIHL,TUMO R

64. 0 I t *4. 0 I t 8 7. 0 t'A 91. 0 ?i 97. 0 ? ( 104. 0 l ( I ) 50. 0 I t

l l 71. 0 2 1 " t ) 9«. 0 2 1 

## n u;. o 

## i t LEVT L 3 WIT H A 1 ) 1 1 1 1 2 ) OCS F INTICATP R INUMRERJ J l l 69. 0 2 t 1 ) 80. 0 2 1 I ) 87. 0 l l I ) 94. 0 I t 1 ) 104. 0 I t LEVF L 4 WIT H A I ) I ) I ) 

### n 23 ) 

### ons e INJICATC R INUMQER U l l 7P. Tl l I ) "S. 3 l l -' ) 3B. 0 ?i "! » «?. J 1 ( I ) ,J B. 0 U i n J l.K. O 2 1 i ) • 2 ) 1 1 I ) ! ) r 0 55. 0 2 1

80. 0 I t 96. 0 I t 104. 0 I t c r100.00 0
70. 0 l l Rl. O l l 88. 0 1 1 94. 0 2 1 104. 0 2 1 T F 200.00 0 • 7«5. 0 1 1 H6. 0 1 1 fW. O l l 94. 0 l l 99. 0 2 1 I )

1 ) 1 ) 27 )

1 ) I ) 2 ) 1 ) 2 )

I ) I ) I ) 1 ) 2 ) 59. 0

80. 0 99. 0 104. 0

72. 0 83. 0 92. 0 97. 0

* 83. 0 86. 0 90. 0 94. 0 100. 0 2 (

I t I t 2 <

i l 1 1 2 ( I t

I t 2 1 1 1 2 1 H 1 ) 1 ) 1 ) 2 )

2 ) 1 ) 2 ) 1 )

•H E MAXI^f M L IKSLlHnn ) EST'^ATIQ., ' ) F JOS E COEFFICItN " O C 0!«.4591678931740-0 3 Q (I)-.17337191*2280-0 4 0 1 2J«.1656627949150-0 7 0 1 3)>.0C000OO0OO0OD»0 0 TH E MAXIKJ M LIKELIHOO D ESTIMATIO N O F TIM E FUNCTIO N CT-.oo&oconoonooo-rO o I «*i . o o ooooooooo 

### A2

4P.7 2

Dat a fro

m NT P (1983 ) Spede s an

dSex : F344/ N

rats , mal e

. . . Endpoint : Al l squamou s cel l carcinoma s

Exposur e Route : Gavag e TK E 1 6 CPSERViTION S » TLEVE L I WIT H AOCSE C F C.CCCCCCOC C UtKEiTU^C R INClC«rC R UUMEERI I JL2JL0_U
_ 35. 0 I t 83. 0 I t 104. 0 I I 'TH E 22 35. 0 I t 63. 0 2 1 89. 0 2 1 10 0 . 0 I t L04-_0„l. t . m 2 2 51. 0 I t 72. 0 2 1 83. 0 I t .93. 0 I t 104. 0 i t TH E 2 6 51. 0 2 1 14. 0 I t 89. 0 2 H "9*. 0 lt ~ 98. C I t t04o C 2<" " .1 1

1 1 2 ) 32 ) 25. 0 I t

41. 0 I t €7. 0 I t DBSERVAMON S A

T I ) I ) 1 ) 2 ) .26 ) tUME.TUWC R

47. 0 I t 65. 0 I t ' C C l ( 

### ico. o 2t 104. 0 2( CeSERV'TION S * T I ) 1 ) 2 ) 2 ) ITlfE.TUMC P 57. 0 t t 73. 0 I t 66. 0 2 t 94. 0 I f 23 ) IC4. 0 2 ( CBSERVATtCN S I T t ) 1 1 

### n " l i 1 1 6 ) fTIME , TUTJ R 64. 0 I t (5. 0 I t 9 0 r O 2 1 94. 0 2 1 99.. 0 li ; 1 )

1 ) 1 1 LEVE L 29. 0 l l

59. 0 i t CE. O i t 2 W I T H A 1 1 2 ) I ) CC! E INCICITC R (NUMBE R ) l t l !C. Q 2 1 l l 1 ) I ) 1 ) 3 ) LEVE L 71. 0 1 (

95. 0 I t ICJ. O l l 3 WIT H a 1 )

I ) 1 ) OCSE INCICITC R IMJMBERI I 

### n i ) n 2 ) 2 ) • LEVE L 69. 0 i t

77. 0 I t C7. 0 2 ( 57. 0 2 1
4 WIT» - a 

### n

i i 

### n i i
COSE ' INDICATC R INLMBER) ) 1 ) 79. 0 I 1 I ) 2 ) l l \ 86. n i i 91. 0 l l 9 5. 0 I t iCf. O l- ; 2 1

2 ) I ) 

### w 3 1 . C 1 1 6f. O i t 96. C i t C F 50.COC O 55. 0 I t 80. 0 I t 96. 0 I t 1C2. C I f C F iCC.CC C 7C. 0 i f 89. 0 I t et. o i t se. o i t O F 2CC.C0 0 ?!. C 1 1 87. 0 l l 51. C 2 ( 95. 0 2 t 102. 0 2 I )

1 ) I )

1 } 1 ) 1 ) 1 )

I ) 1 ) 2 ) 1 )

1 ) 3 ) I ) 2 ) i) 32. 0 7«. 0 101. 0

59. 0 8C. 0 99. 0 IC2. 0

72. 0 81. 0 92. 0 1C0. 0

(3. 0 88. 0 92. 0 97. 0 104. 0 I t i t I f

I f 2 ( 2 1 2 1

I t 2 1 i f 2 (

i t I t I t 1 1 l l 1 

### l ; 2

1 1 1 I 1

_. .

1 ] i i 2 I J

2 ] 1 1 1 I . 9
TK E •'AXtni M LlKELfHOO O ESTIMATIO N O F DOS E COEFFICIENT ! 

### Q I o>-.oceccccccoooo»c c 0 1 11*.2443073818240-0 4 0 1 2)-.C(fCCCCCCCC0DrC C Q t 31-.000000000000 0 i0 0 TH E rfcXllHJM LIKELIMOO O ESTIMATIO N OF 1 1 P» e FI.KTIC * 

### {r-.oooococoooooo*ooM*i.eeccccacca eP.7 3

Dat a fro m NT

P (1983 )
. «•-"••»•£an d Sex : F344/ N rats , femal e Endpoint : Zymba l glan d c a cinom a Exposur e Route : Gavag e

TH E 5 OnSCRVlTICN S A TLEVE L1 WIT H APCSF
. P F O.0000O0C*0 0 tTlMF,TU»«p o INTICATQ P t NUMBER) ) 33. 0 i t 1 ) 93. 0 I t 1 ) 97. 0 I t 1 ) 103. 0 i t i ) 104. 0 i t 46 ) TH E 1 3 OBSERVATION" , A TLEVE L?. WIT H ADOS E n r25.000 0 ITIMEtTUMrj F INOICATfl R tNUMPEP) ) 48. 0 *8. 0 103. 0 TH E 45. 0 75. 0 96. 0 104. 0 TH E

• • 2 . 0 64. 0 83. 0 97. 0 103. 0 I t

i t IK 1 6
I t i t I t 2 ( 2 3 i t 1 1 2 1 2 1 i t I ) 1 ) I ) nns *
1 ) 2 ) I ) 3 ) AO. O

Ri. O 104. 0 SVATUM * I t

I t 1 1 ; A T IMMEiTUMO P 52. 0 T2. 0 101. 0 riRSFRVATtflN !
1 ) I ) I ) I ) I ) 1 1

2 ( I t

. A T t TVMEtTUHO C 9 . 0 60. 0 R7.. 1 T3. 0 104. 0 l l

" M l l l l l l I ) l l ?5 ) LEVE L 73. 0

9 I. P 104. 0 2 1

I t 2 ( 3 WIT H A INDICATO R ( I ) I ) 1 ) LFVE L 69. 0

8A. 0 102. 0 I )

1 ) 3 ) OCS F INUMRF.P) ) 1 1 i t I t 4 WIT H A iNntCATri R 1 1 l l ' I ) ? ) 17 ) 32. 0

7«>. 0 13. 0 100. 0 I 14. 0 1 )

1 ) 2 )
OOS E (NUMBER) ) I t I t 1 1 I ( 7.1 I ) 1 ) I ) 1 ) R ) « 0 9 7 ri p 7 1 * 9 10 3 O F 5 7 7 ? oc , 1 0 I . 0

. 0
•50 ,

. 0

. 0

. 0 1 1 . 1 1
oooo 2 t I t i t 100.00 0

. 0

. 0 •0

. 0 1 1 2 1 1 1 l l 2 ) 1 )

1 ) 1 ) 1 )

1 ) 1 ) I ) 2 ) 8 1 . 103 .

7 2 9 6 . 104 .

62 . 83 . 97 , 10 2 0 0

, 0

. 0

. 0

. 0

. 0

. 0

. 0 1 1 I t

l l 1 1 I t

•- 2 ( 1 1 l l 2 1 1 ) 1 )

I ) 1 ) 31 1

— 1 1 i ; 3 1 i ;
'•H E MAXIMU M LIKELIHOO D ESTIMATIO N OF OOSE COEFFICIENT S Q l 0)".0000000000000*0 0 O t l»«.2*R < >37l79396D-0 4 .Q l 2)«.0000000000000*0 0 Q l 3)».60029«942l060-0 9 ._.TH E MAXIMU M LIKELIHOO D ESTIMATIO N O F TIM E FUNCTIO N IT-.0000000000000*00)**1.0000000000 0

A26P.7 4

Oat a fro m NT

P (1983 ) Spede s an d Sex : F344/ N rats , female s Endpoint : Al l squamou s cel l carcinoma s Exposur e Route : Gavag

e

TH E 5 OBSERVATION S A TLEVE L I WIT H AOC! E C F C.OCC0O0C»0 O

_tTIMEiTUMO R CNCICATO R tNUM8.ER) l 

### 33. 0 

### 1 1 ._THE_.l 2 

### TeToHif" " 88. 0 I t 1C3. 0 2 1 "TH E 1 6 .— 45. 0 I t 72. 0 i f 96. 0 2 1 104. 0 I f TH E 2 1 2. 0 i t 64. 0 I f 93. 0 I f 101. 0 i t IC4. 0 2 1 I ) 93. 0 I f1 1 <7. Q 1 1 1 1 ••» CBSERVATICN S A

TLEVE L 2 WIT H A CCS E (TIME.TUMO R IS O I C A TO R (NLM8ER) ) "l l 69. 0 i fI ) 73. 0 I I 1 ) 1 ) 89. 0 1 1 I ) 5!. 0 I t 1 ) 1 1 104. 0 I f38 ) CeSERV-MON S A

TLEVE L 3 k l T

H A OCSE tTIf»E,TUMC P INCICITC P IKUM8ERJ ) I ) 52. 0 I t 1 ) "C O I f1 1 1 ) 75. 0 I t 2 ) 82. 0 I t 1 ) 1 ) 101. 0 2 1 I ) IC2. 0 I t I ) 3 4 1 OBSERVATION S A

TLEVE L 4 WIT H A CCSE ITI^EtTUPO R INCICATC R tNUMBER) ) t l 9. 0 I t 1 ) 32. 0 I t I ) l l 69. 0 l l l l 75. 0 I t 2 ) I ) 94. 0 I t 1 ) 57. 0 I f4 ) t ) 101. 0 2 (1 ) 102. 0 l l 1 1 I ) IC3. 0 I f CF 25.000 0 80.1 3 I f 51. C 1 1 C F 5C.CCC C 65. Q 2 ( 85. 0 i f 102. 0 2 t C F 100.OC O 57. 0 I t 83. 0 I t 98. 0 2 1 IC3. C I f l l

2 1 1 1

1 1 1 ) 1 )

l l 2 ) 2 1 1 ) 104. 0

81. 0 1C3. 0

71. 0 96. 0 103. 0

62. 0 87. 0 100. 0 104. 0 I t

I f i t

I f i t I f

i f 2 ( 2 ( i f ..•6 1

l i 1 1

1 1 I J 1 1

l i l i I 24 ;
TH E MAXIfU * UKEI.IHCC C ESTIMfT'C N O F HOS E COEFFICIENT S C t 0)«.0030000000000*0 0 "O fIl«.l2l931«7f7"^880-C 4 Q t 2H.2931336872990-C 7 Q t 3)".CCCCCOCOOOOOO-O O TH E MAXlinj " L1XEL1H0C C ESTIMITIO N O F TIM E FUNCTIO N fT- 2 .0000000000 6 T«fT.fl3fffiO"flfiCC0C ~Sat a fro m NT P (1983 ) .Spede s andSex : B6C3F i mice , mal e Fnrfnolnt : Squamou s cel l carcinom a o f the preputia l gland i^ H u»ur e Route : Gavag e TH E I B CBSEPVATICN S A TLEVE L 1 WIT H ACOSE O F C.CCCCCCD*0 C I TIME,TUMO R INOICATC R tNLMEERI ) 

### 3. 9 

### U 77. 0 I f 8 J . 0 1 t U2. 0 1 1 

## "Trl'Fv " 0. 0 1 1 44. 0 i t 83. 0 I f 94. 0 i t 102. 0 I f l l
_36. 0 I t

M 81. 0 I t 1 ) 92. 0 I t 3 ) 103. 0 I f C!SERV«TION S A

T tTIME.TUMC F 1 ) 1. 0 u 1 ) 68. 0 I f l l E4. 0 I f I ) 96. 0 l l 2 ) IC3. 0 I t 1 ) 4 1. 0 I t 2 ) I ) 82. 0 I fI ) I ) 53. 0 1 1 1 ) 2 1 104. 0 I f28 1 LEVE L 2 WIT H AOOS E INOICATC R _tMJMeE P I I l l 26. 0 I f1 1 l l 74. 0 I fI I t ) U. O l l l l l l 9 7. 0 I t l l 2 ) 104. 0 I f20 ) 43. 0 85. 0 S7. C OF 25 . 3E. C 79. 0 86. 0 10C. 0 104. 0 

### I t I f I f CCC C I f i t i f 1 1 2 1 1 ) 

### l l 1 1

1 1 1 ) 2 ) 1 ) 3 ) 55. 0 86. 0 99. 0

39. 0 8 1. 0 90. 0 ICl. C 

### I t i f i t

i f 1 1 i f i t 

### _l l 1 2 1

1 1 l i 2 2 1 __TH E 2 8 CeSERVATICN S A TLEVE L 3 «IT H AOOSE O F 5C.CCC 0 (TIME , TUMO

R INOICATC R fNUMEERI I 

### "297 6 i t 71. 0 i t 85. 0 i f 93. 0 I f 99. 0 I f 

### .1 ; "-'A.. 1 <. . TH E 3 0 3. 0 I t 76. 0 2 1 87. 0 I f 93. 0 2 t 47. 0 2 ! 101. 0 2 1 1 )

I ) l l 1 1 1 1 2 1 43. 0 I t 77. 0 1 1 87. 0 I t 94. 0 I t 100. 0 t t 104. 0 I t OBSERVATION S A

T ITIME,TUMO R 1 ) 7. 0 I t 1 ) I I 2 ) 4 ) 1 ) 78. 0 I t ee. o 2 t 95. 0 I t 98.0*21 * 102. 0 a il

I ) 1 ) 2 1 2 ) 4 1 64. 0 I f 78. 0 I t 

### ee. o K 94. 0 2 f ICC. O 2 ( 104. 0 2 ( 1 )

1 ) 1 1 I I l l 14 ) LEVE L 4 WIT H AOCSE INCICATC R fNUMBER) ) I ) 2<. 0 I t 1 ) I ) 2 ) 3 ) I ) 1 ) 8 1. 0 I I 89. 0 I t 9'. 0 2 1 99. 0 , 2 1 1C2 . 0 2 ( 2 )

l l 2 ) 2 ) 4 ) 6C. 0 I f 83. 0 I f 85. 0 I f 95. 0 I t 101. 0 2 1 C F IOC.CO O 54. C I f 81. 0 2 1 9C. 0 I t Sc. C I t 100. 0 2 ( 104. 0 I f 1 )

1 ) 

### 1 1 t l 1 )

1 ) 1 ) 1 ) 1 1 2) 3 ) 65. 0 84. 0 91. 0 97. 0 102. 0

74. 0 82. 0 90. 0 96. 0 " T/OI. O 104. 0 i f I t I t I t I f

I f 1 1 2 1 2 1 I t " 2 ( 1 . 1 2 1 2 1 2

2 i ; l 

## n t.i 4 TH E MAXIMU M LIKELIHOO O ESTIMATIC KOF COSE COEFFICIENT S Of0)«.CCCCCC0000C0O»C C Qt if".3460089365780-2 0 Q t 2I« . 1286267493160-2 0 ~Q I 3}-".~OCCC000COOC0O+0 0 Tr" E MAXIMU M LIKELIHOO O ESTIMTIC N H F 1IP E FUSTIC * IT-.CC:CCeCCCCCCO*OCI«*e.3330C3 6 824 4P.7 6

Dat a fro

m NT P (1983 ) Spede s an

dSex : B6C3F] . mice , mal e Endpoint : Al l squamou s cel l carcinoma s Exposur e Route : Gavage. . TH E 1 8 OBSERVATION S A T LEVE L f'"U*£T

H A DolE* " d

F O.OOOOOOD+O O (TIME.TUMO

RINDICATO

R(NUMBER) ) ? • rt1 f 

## 77-.crrr 87. 0 K 02. 0 1 ( TH E 

### 24 0 . 0 1 ( 44. 0 I C 63. 0 K 94. 0 2 ( 02. 0 1 ( TH E 3 0 29. 0 1 ( 7J..0 . l.(.
_ 85. 0 1 ( 91. 0 2 ( 97. 0 1 ( 02. 0 1 ( TH E 2 7 3 . 0 1 ( 76. 0 2 ( 87. 0 2 < 95. 0 1 ( 9 8 ."6 2 < C2. 0 2 ( TH E MA X 1 ) 36. 0 1 ( 1 ) 41. 0 "i f 2 ) 43. 0 1 < 1 ) 81. 0 1 < 1 ) 82. 0 1 ( 1 > 85."0~1 ( 1 ) 92. 0 1 < 1 ) 93. 0 1 < 1 ) 97. 0 1 ( 3 ) 103. 0 1 ( 2 ) 104. 0 i < 28 ) ~ OBSERVATION S A

T LEVE L 2 "WT'T

HA T>C*sr*3*

F 55.000 0 (TIME.TUMO RINDICATO R(NUMBER) ) 1 ) 1. 0 t ( 1 ) 28. 0 1 ( 1 ) 38. 0 1 ( 1 ) 68. 0 1 ( 1 ) 74. 0 1 ( 1 ) 79. 0 1 ( 1 ) 84. 0 1 ( 1 ) 85. 0 1 ( .1 ) 86. 0 1 ( 1 ) 96. 0 1 ( 1 ) 97, 0 1 ( 1 ) 100. 0 1 (

. 2 ) 103. 0 1 ( 2 ) 104. 0 1 ( £0 > 104, 0 2 ( OBSERVATION S A

T LEVE L 3 WIT

HA DOS

E O F 50.000 0 (TTMEfTUMO

RINDICATO R(NUMBER) ) 1 ) 43. 0 1 ( 1 ) 647b " I f 1) ~ 66. 0 l" ( 1 ) 77. 0 1 ( 1 ) . 78...0_1 C L > 83.0_1(_ . 1 ) 87. 0 1 ( 1 ) 88. 0 1 ( 1 ) 89. 0 1 ( 1 ) 93. 0 1 ( 1 ) 94. 0 1 ( 2 ) 94. 0 2 ( 2 ) 99. 0 1 ( 1 ) 100. 0 1 ( 2 ) ' 100. 0 2 ( 2 ) 103. 0 1 ( 1 ) 103. 0 2 ( 1 ) 104. 0 1 ( OBSERVATION S A

T LF'.T L 4 WIT

HA DOS

E O F 100.00 0 (TIMF » TUMO

RINlUCnrO RtNUMBER> > 1 ) 7. 0 1 ( 1 ) 24. 0 l< 1 ) 54. 0 1 ( 1 ) 78. 0 2 ( 1 ) 81. 0 1 ( 2)... . 81. 0 2 (
_ 1 ) 88. 0 2< 2 ) 89. 0 1 ( 1 ) 90. 0 2 ( 1 ) 95. 0 2 ( 4 ) 96. 0 1 ( 1 ) 96. 0 2 ( 1 ) 99. 0 2 ( 2 ) iOO. O 2 < ?.) 101. 0 I t . 5 ) 104. 0 2 ( 7 )
_ IMU M LIKELIHOO D ESTIMATION~~d" F TJOS E ToTFFfCIENTS~ " 1 ) - 1 ) 1 )

1 ) 1 > 2 ) 1 ) .3)... .

. ___ . 

### .U - . 1 ) 1 ) 1 ) 3 )

1)" " 1 )
_ 2 ) 1 ) 1 > 59. 0 1 ( 86. 0 1 < 99. 0 1^
_

. 39.0.1 ( 81.01~ f .90. 0 IC . 101. 0 1 (

. .... . — 69. 0 1 ( 

### 84^o_ic ; 91. 0 1 ( 95. 0 1 ( 101. 0 2 ( 104. 0 2_(.

_

74. 0 1 ( ...82j0..1t . 93. 0 2 ( 97. 0 2 ( iOi. O 2 < 1 )

1 ) _2 )

_ 1 ) 

## ~f )

. 2 ) . . 2 )

- — 1 ) 1 > 1 ) 1 ) 1 ) .15. )

2 ) 2 ) 4 > O • 1 ) V

Q ( O)-.0O0OOOOOOOO0D+O O 0("l)=.0000000000000+0 0 Q ( 2)-.387387062466D-2 2 0("3)=.426343280969D-2 4 _JHE_MAXIMU M LIKELIHOO D ESTIMATIO N J3F_TIME_FUNCTipN
_ <f-.00b000600000D+00>**9.3067441206 3

A2 9Oata fro m NT P (1983 )
. Specie s an d Sex : B6C3F Xmice , mal e , Endpoint : Alveolar/Bronchiola rcarcinom a •%-"-!«yr e acute : Gavag

e TH E 2 0 CBSERVATICN S A TLEVE LI WIT H ACCS E C F O.OOOOOOCO O fTIMEtTUHO R INDICATO R tNUMBERI I 

### 3, 0 1 ( 77. 0 I t •T. n 1 t 99. 0 2 ( "TH E 2 4 0 . 0 l l 44. 0 I f 83. 0 2 1 94. 0 I f 

### JliUj&JUL - —THE. - 2 9 

### "T97b"if " 71. 0 I f 85. 0 i t —?3f.0_.l t
. 97. 0 2 f .U3JJL11
_ TH E 3 4 3. 0 I t 74. 0 2 t 8 2. 0 I f 90. 0 2 1 96. 0 2 1 99. 0 2 1 102. 0 i t TH E MA X 1 7 l l » » I ) .36. 0 .I t
. 81. 0 I t 92. 0 t t IC2. 0 I t CeSERVATICN S A

T l l t ) l l l l _ 2 I fTIMEiTUMO R

, i I
. 0 t I 68. 0 I t 84. 0 2 ( 96. 0 I f 103. 0 I f QBSERVATICN S A

T 1 1 1 ) 1 1 t l l l 

# _u. tTIME,TUMO R

43. 9 I f 77. 0 2 1 87. 0 I t 54. 0 I f 99. 0 I t 1 0 3. 0 2 1 CB S ER VA TI CN S A T t 1I>EtTUM0 S l l 7. 0 l l 1 ) " I ) l l 1 1 I )
IML M 76. 0 1 1

87. 0 I f 93. 0 I t 57. 0 I t 100. 0 I t L02. 0 2 ( LIKELIHCC O ( 1 1 41. 0 l l 2 1

1 ) 82. 0 I t I ) 1 1 93. 0 2\

l l 3 1 IC3. 0 i f2 1 LEVE L2 WIT H AOCS E INOICATC R fNUMBERI I l l V 2B. O I t l l l l I'. O I t I ) I ) t«. 0 I fl l t ) 57. 0 I fH 2 ) IC4. 0 I t 18 )

y LEVE L3 WIT h ACCS E INDICATO R tKUMBER M l l 64. 0 2 t l l l l 76. 0 I t t ) l l 8 8. 0 I t l l 2 1 94. 0 2 1 1 ) l l ICC. O I f3 ) 1 ) 1C4. 0 I t 14 ) LEVE L4 WIT H AOOSE INC1CATC R INUMeEP) ) I ) 24. 0 I t I ) 1 ) 73. 0 I t I ) l l 6 E. O 1 1 2 ) 2 ) 95. 0 I t 2 ) 3 ) 5 7. 0 2 1 1 ) I ) 10C. 0 7 ( 1 1 43. 0 I t 85. 0 I t 97. 0 I t 104. 0 I f; O F 25.CCC C 38. 0 I t 75. 0 I t B«. 0 I f 109. 0 I f 104
. C 2 ( O F 50.000 0 66. 0 I t 83. 0 I t 89. 0 I f 95. 0 I f IC1. C I f 104. 0 2 1 O F ICC.CC O 54. C I t 8 1. 0 I t 85. C I t

. 95. 0 2 t 98. 0 l l " 10U C ! ' ' l l ' 1C4. 0 \

t 5 1 104T. 0 :- •STIMIT1C N O F CO

S E
_ C O € F FI C I E N TS 1 1

I ) I ) IS)

1 1 2 ) I ) 3 ) I ) » ) 2 ) .59. 0 86. 0 55. 0 104, 0

35. 0 81. 0 9C. 0 101. 0

. .
69. 0 84. 0 91. 0 9 7 X 1C2. 0

74. 0 81. 0 9C. 0 56. 0 ' " "99. 0 KU O

- — I f

I t I f 2 1

i f 2 ( 2 ( 2 t

I f 2 t 2 1 " l i i f

i f 2 ( I t 1 1 

## "i t Z3 1 ) 1 1 1 ) 3 1

. . . . 1 ) " l l 1 ) 2 )

— —

1 ) 1 ) 2 ) 1 1 2 )

. . .

1 ) 1 ! r1 i i l 1 1 !

Q t 0l«.346C443927500-0 3 Q t U«.6441939503e20-C 3 Q t 2 I-.0000000000000*0 0 _QL3i«.CCCCC000GOOOO»0O
_ TH E BATTPUP -ifKELfHCO O ES TIMI TIC KO F TIFF
. FUNCTIO N IT-.flQOOOaoOQ0OQP*O 0 !*>• ! .3189877156 5 A3 0P.7 8

Oat a fro m NT

P (1983 ) •>n«»de s an d Sex : B6C3F

Vmice , mal e tndpolnt : Lymphoma , NO S * Exposure Route : Gavage - TH C 2 0 CB5F.RVATICN S A TLEVE L I WIT H ACCS E C F O.O00000C*O O fTIME , TUMO

R INDICATO R t NUMBE R ) I _3_J3_1L
_ • » • » A•# • . +* 4 6 .87.0.I f 102. 0 I f ifH E 2~ 4 0, 0 .if. . 44. 0 I t .83. 0 I f 94. 0 I f AOj___,l_t
_ THE. . .2 6 • 29. 0 t t 71. 0 I f 85. 0 I f _93. 0 l l 100. 0 I t X 04».0_2 t . TH E 2 8



## ~ 3761 1 76. 0 I f 88. 0 I t 95. 0 I f 98. 0 I t 102. 0 2 ( 

## __n

_ 4 ' t l 3 1 _ . 36.0.1 1 81. 0 I t 92. 0 I f 103. 0 I f OBSERVATION S A

T t l l l l l 1 ) —2 1 .. fTIME , TUMO

R 1. 0 i t 68. 0 I f S4. 0 t t 96. 0 I t 103. 0 I t OBSERVATION S A

T I ) I ) 1 ) l l 3 ) . 5 1 CBS E l l t l 2 1 4 1 I ) 2 1 fTIME , TUMO

R 43. 0 I t 77. 0 I f 87. 0 I t 94. 0 t f toi. o I t R VAT I CN S A T "tfi>E , TUMO

R 7. 0 i t 78 . C l l 89. 0 l l 95. 0 2 t 99. 0 l l 104. 0 1 1 _l>_ . 41. 0 t t

l ) 82. 0 2 ( 1 ) 9 3. 0 I t I ) 103. 0 2 1 LEVE L 2 WIT H A 2 ) U I ) 1 1 OCS E INOICATC R tNUMBERI I l l 28. 0 I ft l I ) 74. 0 I t L ) 85. 0 I t l l 57. 0 2 t 2 ) IC4. 0 I t LEVE L 3 WIT H A l l I ) l l 19 ) OCS E INOICATO R tNUMBERI I 1 ) 64. 0 I t t ) l l 78. 0 I t I ) 88. 0 I t 1 ) 5 5. 0 2 1 l l 102. 0 I t l l 1 1 1 1 2 1 LEVE L 4 WIT H AOOS E INOICA'TC R tNUMBERI I l l 24. 0 I f I ) 81. 0 I I I ) 9C. 0 l l I ) 96. 0 2 ( 2 ) ICC . 0 I f :• » io<?c

O 2 t l l

3 ) l l I I 2 ) 2 1 43. 0 I f 85. 0 I f 97. 0 I f 1 1

1 ) 1 1 104. 0 I t 27 } O F 25.COC O 38. 0 I t 79. 0 I t 86. 0 I f 100. 0 I f 104. 0 2 1 C F 50.000 0 66. 0 I t 83. 0 t t 89. 0 I t 97. 0 I t 103. 0 I f O F 100.00 0 54. 0 2 t 8 2. 0 I t 9C. 0 2 ( 97. 0 I t 101. 0 1 1 •

1 ) 1 1 2 1 1 1 4 1

.. . . 1 1 1 1 1 1 2 1 2 1 59. 0 86. 0 95. 0 104. 0

39. 0 81. 0 9C. 0 101. 0

-

69. 0 84. 0 91. 0 99. 0 104. 0

74. 0 87. 0 93. 0 97. 0 '102. 0 I t I t i t 2 t

i t I t i f 1 1

i t 1 < I t I f I t

1 1 i f i t 2 ( 1 < 1 1 . 2 1 1

l l 1 . 2 ) 2
—.. . • 1 1 1 2 1 1 . 13 )

2 1 1 2 ) 2 ; 3
TH E MAXIMU M IIKELIHOQ O ESTIMATIO N O F COSE COEFFICIENT S CJLft!*L»42 9 T ' 64>5665 9 0- 0 7 Q t U- . 1010121803870-0 8 gt_ 2 l-jJOOOOOQOOOOOO D •0 0 Q t 3I«.3163454944710-1 3 TH E MAXIMU M LIKELIHOO O ES TIMA TIO N OF T t M

E FUNCTIO N (T-.OOOOOOCO0O00C*OOM*3.UO34 5 3C 8 3 7 A3 1P.7 9



### Dat a fro m NT P (1983 ) Spede s an

dSex : B6C3F ! mice , femal e Endpoint : Al l squamou s cel l carcinoma s Exposur e Route : Gavag e

TH E 1 6 OBSERVATION S A T LEVE L 1 WIT HA DOS E O F O.OOOOOOD+O O (TIME,TUMO RINDICATO R(NUMBER) ) 3. 0 1 ( ft . r » 1 t 

### 93. 0 1 ( 104. 0 1 ( THE 1 7

. . 1. 0 1 ( 81. 0 1 ( 93. 0 1 ( 103. 0 1 ( TH E 2 2 67. 0 1 ( 85. 0 1 ( 93. 0 1 ( 99. 0 1 ( 104. 0 1 ( TH E 2 6 3. 0 1 ( 72. 0 1 ( 84. 0 1 ( 93. 0 1 ( 97. 0 2 ( 104. 0 2 ( 1 )

! ) 1 ) 30 ) 29. 0 1 (

74. 0 1 ( 95. 0 1 (
OBSERVATION S A

T 5 ) 2 ) 1 ) 1 ) <TIME*TUMOF 32. 0 1 ( 83. 0 1 ( 94. 0 1 ( 104. 0 1 ( OBSERVATION S * T 1 ) 2 ) 1 ) 1 ) 1 )

1 ) 1 )
LEVE L 30. 0 1 ( 1 )

80. 0 1 ( 1 ) .99. 0 i( . _2)
_ 2 WIT HA

DOS E * INDICATO

R(NUMBER)) . 1 ) 1 ) 2 ) 24 ) LEVE L 70. 0 1 ( . 1 )

87. 0 1 ( 1 ) 97. 0 1 ( 1 ) %m 

### 3 WIT HA

DOS E (TIME»TUMO

RINDICATO

R(NUMBER) ) 68. 0 1 ( 87. 0 1 ( 94. 0 1 ( 100. 0 1 ( 1 )

1 ) 1 ) 1 ) 70. 0 K1 ) 90. 0 1 (

" 1 ) * 95. 0 1 ( 2 ) 101. 0 1 ( 1 ) 23 ) 104. 0 2 ( 1 ) .OBSERVATION S AT LEVE L _4_UITH_ A DOS E (TIME.TUMO

RINDICATO

R(NUMBE*R) ) 1 ) 1 ) 2 ) 2 ) 1 ) 4 ) 

### "TH E MAXIMU

M 48. 0 i < 76. 0 1 ( 87. 0 1 ( 94. 0 1 ( 99. 0 1 (

LIKELIHOOD 1 )

1 » 3 ) 1 ) 1 ) 64. n2 ( t )

77. 0 J

* < 1 • 8f l . 0 1 ( 1 ) 94, 0 2 ( 1 ) 100. 0 t ( 1 )

... . 

### 38. 0 K

87. 0 1 ( .100.0. K.. . O F 25.000 0 78. 0 1 ( 88* 0 1 ( 101. 0 l/_ . OF 50.000 0 71. 0 1 ( "91.0"l( " " * 96. 0 1 ( 102. 0 1 (
0F_

_10 0 ..00 0
*A. O 1 ( fl.7. 0 1 ( 90. 0 1 ( 95. 0 1 ( 103. 0 1 (

— - - 

### ESTIMATIO

N O F "til* E~CUE rF 1 CI E N

T S ' 1 ) 2 ) 1 )

1 ) 1 ) 1 )

1 ) "2" ) 

### 2 ) 3 )

- r • •

1 ) ' 

### 1 ) 1 ) 3 ) 1 )

_ 58. 0 1 ( 90. 0 1 ( .103. 0 1 (

80, 0 1 ( 89. 0 1 ( _102_

L 0__1_(
_

• • . ~



### . ._ _ .... . 8.0. 0 1 ( 92"."0 1 ( " 97, 0 1 ( 103. 0 1 (

71. 0 1 ( 83. 0 1 ( 91. 0 1 ( 97. 0 K 104. 0 1 (

• 

### 1 ) 1 ) 4 )

_ 

## X) . 1 ) J2>._ ;



### -

___ _ 1 ) 

## i ) l ) l )

~~2)~ 2 ) 1 ) 1 ) 14 )

- -

0 ( 0)-.000000000000D+0 0 0( " 1)«.OOO0OO000O00D+0 0 Q ( 2)«.O0O0O0OO000OD+O O Q ( 3>-.18A337667410D-l l

TH E MAXIMU M

LIKELIHOO DESTIMATIO N O F TIM E FUNCTIO N (t'-.000000000000n+00)**2,4916915140 5 

### A32Oat a fro m NT P (1982 ) Spede s an d Sex : B6C3F i mice , femal e Endpoint : Mammar

yalan d carcinoma , NO S exposure Route : Gavage

Tl- E 1 0 QUSERVAT10N S A TLEVE L 1 W

I T H AOCSE C F C.CC0000C*O 0 fTt»E,TUNC R INDICATO R tNUMBERI I

_3, 0 I f7 1 25. 0 I I l l . 3C. 0 I fI I 3e. O I f1 1 87. 0 I t 2 95. 0 I t l l 99. 0 I f2 ) ICC. O I t 1 1 103. C I t 4 1 1C4. 0 I t 28 1 TM E 1 2 OBSERVATION S A TLEVE L 2 W

t T H ACCS E C F 25.COC O tTIWE.TUMC R INCICITC R tNUMBERI I 1. 0 I f2 1 94. 0 I t 2 1 .103. 0 2i

I I 70. 0 t f

97. 0 I t IC4. 0 I t 1 )

1 ) 17 1 7!. 0 I f

99. 0 I f 1 1

1 1 81. 0 I t 101. 0 2 ( 1 1

1 ) 87. 0 I t 102. 0 I t 1 .

2 1

. TH E 1 7 CESERVATICN S A TLEVE L 3 WIT H ACOSE O F 5C.0CC 0 (TIME,TUMO R INOICATC R fMMBEPI I 68. 0 90. 0 96. 0 IC4. 0 i f i f i t i f 

# n i i 

# n i e i 70. 0

91. 0 100. 0 104. 0 2 1 I t I t 2 ( 1 ) 2 1 l l 2 ) 71. 0 54. 0 101. 0 I t I t I t 1 1 1 1 I ) 8C. 0 95. 0 IC2. 0 I f I f t t 1 ) 1 ) 2 1 £1. 0 95. 0 1C2. 0 l l Zi 2 f 2 1 I l i TH E 1 6 OBSERVATION S A TLEVE L 4 WIT H ACOSE O F ICC.CC O fTIME,TUfC R INCICATC P tNUMBEPI l 64. 0 i t 1 1 _87. 0 I t 2 ) 95. 0 2 1 1 1 104. 0 2 (3 ) 71. 0 I t 88. 0 2 1 57. 0 11 2 )

I ) I ) • 7«. 0 90. 0 55. 0 2 1 1 t l l 1 ) 1 1 1 ) 83. 0 9 3. 0 10C. 0 2 1 I t I t 1 ) 1 1 1 ) 84. 0 94. 0 104. 0 I t 2 ( i t 1 1 l i 1 5
TH E M4XIPU P LIKELIHCC C ESTIMATIO N O F COS E COEFFICIENT S C f0I«.0000000000000*0 0 Qt ll«.2S4C058399340-0 4 Qf_2l-.0CCC000C0OCOOtQ 0 Q l 3l«.OCQ0O0OOOOOO0«O O TH E MAXIMU M LIKELIICO C ESTIMATIO N O F TIM E FUNCTIO N tT-.OOOOC0C00CCaC+0OI»*l.0OC0OO0000 Q

A3 3P.8 1

I I Cat a fro m NT

P (1983 ) Spede s an d Sex : B6C3F i mice , femal e Endpoint : Alveolar/Bronchiola rcarcinom a "Exposur e Route : Gavage TH E 1 6 CASER'ATION S A TLEVE L 1 M TH ACCS E CF 0.O00O00CM3 0 »T1ME , TUMO

R INDICATO R tNUMBERI I J^Q-LL - T3, 0 I f 53. 0 I t 104. 0 I t TH E 1 8 

### 1. 0 

### I t 81. 0 I f

. 93. 0 I f 103. 0 I t

. TH E 2 3

..... . - 67. 0 I t 85. 0 I t 92. 0 I t 97. 0 I t JLP.3_.C_lt
_ TH E 2 5 3 . 0 I t 72. 0 I t £4. 0 i t 93. 0 I f 9 9 . 0 i t __1 1 29. 0 i t

1 1 74. 0 I f 1 1 95. 0 I t 30 1 CBSERVATICN S A

T t TIME , TUMOR, 5 ) 32. 0 I f 2 1 83. 0 I f 1 1 94. 0 1 t 1 1 1C4. 0 I f CeSERVATICN S A

T t TIME,TUMO R 1 ) 68. 0 I 1 2 1 67. 0 I f I ) 93. 0 I t 1 ) 99. 0 I t „ t l 104. 0 1 1 CBSERVATICN S A

T tTIME,TUMO R I ) 48. 0 I t 1 1 76. 0 I t 2 1 87. 0 l l 2 ) 54. 0 I C I ) •100, 0 c 1 1 1 ) 1 1 LEVE L 3C. 0 I t

S C O 1 1 99. 0 I t 2 WIT H A I t

1 ) 2 ) CCS E INOICATC R fNLMBERI ) I ) 7C. 0 I t I ) 1 1 2 1 21 ) LEVE L (7. 0 l l

9 7 c 0 I t 104. 0 2 1 3 WIT KA I )

I ) 3 1 CCS E INOICATC R tKLMBERI I 1 ) I ) l l 1 1 19 ) LEVE L 70. 0 1 1

90. 0 I t 54. 0 I t I OC O I t 1C<. 0 2 ( 4 k.tTr - A l l

I t 1 1 1 1 S I CCS E INOICATC R fNLMBERI ) 1 ) 64. 0 I I I 1 1 ) 3 ) 2 ) I) 71. 0 2 ( s a . o 1 1 9 S. 0 1 1 !C3c O 1 1 l l

1 ) 2 ) 1 ) 38. 0 I t

17. 0 I f 100. 0 i t O F 25.000 0 78. 0 i f ee. o i t 101. 0 i t O F fC.CCC O
.71. 0 i t 91. 0 I t 9«. C i t 101. 0 I t O F 100.00 0 66. 0 i t 82. 0 I t 9C. 0 1 1 95. 0 2 1 lC*o C 1 ? 1 1

2 1 1 1

1 1 1 1 l l

1 1 l l 2 ) 1 1

1 1 1 ) 1 1 l ) 14 ) 58. 0

9C. 0 103. 0

80. 0 89. 0 IC2. C

80. 0 91. 0 56. 0 102. 0

7 1. 0 83. 0 91. 0 97. 0 IC4. Q i t

i t I f

I t i t i t

I t 2 1 i t I t

it " i t i t L l ?i t l i ) 4 1

1 1 1 ) 2 )

* '
1 1 l . 2 ) i i

. .

2 2 . L i 2 4 i TH E MAXIMU M LIKELIHOO D ESTIMATIO N OF OOS E COEFFICIENT S Qt OI«.OC0C0C0C0OQO0*O 0 Q t l)«.56C 2 6 8 4 9 72 8 8 0^1 7 Q t 2)-.CCCCCCCCC0C0O*C 0 C t_ 3 )•.00000000000 0 C «0 0 TH E MAXIMU M LIKELIHOO D ESTIMATIO N O F TIP E FUNCTIC N J_T-,00O0CC00000CO»O0|4«7.295483€2e9 C A3 4

### TH E Dat a fro

m NT P (1983 ) So-de s an

dSex : B6C3F

Jmice , femal e Endpoint : Malignan t lymphom a Exposur e Route : Gavag e I B 0*Sf-RVAT I C>V

S A TLFVE L I WIT H AQOS r |T1MF,TIJMO« » INDICATO R INIJMBER) ) 

### r ro.ooooooc*o o 3. 0 1 1 73, 0 ! » 93. 0 i t 03. 0 2 ' I )

1 ) 1 1 2 ) 29. 0 74. 0 95. 0 104. 0 l l 1 1 ? t I t l l l l I ) 22 ) 30. 0

80. 0 99. 0 104. 0 I t I t K 2 1 1 ) I ) 2 ) 8 ) 38. 0

87. 0 100. 0 I t

i t i f I ) 2 ) 1 ) 58. 0 2 1 90. 0 2 1 103. 0 I t 1 )

1 ) 2 ) TH E 1 9 flSSFRVATION S A TLEVE L 2 WIT H AOOS F O F ITIMF,TUMO R INOICATO R tNUMBFR) ) 1. 0 41. 0 93. 0 02. 0 I f I t i t 2 t 5 1 ? ) 1 ) I ) ?2. 0 I t

R"U O t f 04. 0 1 1 103. 0 li 1 )

t ) 2 ) 1 ) 70. 0 87. 0 97. 0 104. 0 I f l l 2 ( I t 1 ) 1 ) l l 13 ) 25.000 0

78. 0 I t 88. 0 I t 101. 0 I t 104. 0 2 ( I )

I ) I ) 11 ) TH E 2 5 OPNrRVATION S A TLEVE L 3 WIT H AOOS F O F 50.000 0 tTIMF.TUMO P INOICATC R fNUMREF.I I 80. 0 I t 89. 0 2 1 102. 0 1 1 1 )

1 ) 1 )

67. 0 85. 0 92. 0 96. 0 102. 0 I )

2 ) 1 ) 2 1 1 ) 60.0 .

87. 0 9 3. 0 97. 3 102. 0 2 1 l l l l l l 2 1 70. 0

90. 0 94. 0 99. 0 103. 0 71. 0 91. 0 95. 0 10O. 0 104. 0 15 ) 80. 0 1 1 91. 0 2 1 95. 0 21 101. 0 i f 104. 0 2 ( 1 )

1 ) 1 ) 1 ) 9 ) TH E 2 7 CBSERVATTON S A TLEVE L 4 WIT H AOOS E O F fTIMF,TUMO R INOICATO R {NUMBER) ) 100.00 0
3 . 0 72. 0 84. 0 90. 0 95. 0 104. 0 44. 0 76. 0 A 4. 0 91. 0 97. 0 104. 0 1 1

I I 2 1 ? l l l 7 1 I ) I ) I ) I ) 2 ) 4 ) 64. 0

77. 0 H7. 0 l l 1 1 i t l ( 2 1 I ) I ) ?) 1 ) i ) *4. 0

«2. 0 •7. 0 m . o 100. 0 2 1 7 1 2 1 2 1 1 1 71. 0

83. 0 88. 0 94. 0 103. 0

_ 1 1 

### i t 1 1 1 1 1 1 2 ) 2 ) 1 ) 2 ) 1 )

TH E .MAXIMU M LIKELlHfiO D ESTIMATIO N Q F COS E C O Ei - : I C 16NT S Q t 0I«.2472739286150-0 3 Q t D-.OOOOOOOOOOOOO+O O Q t 2 )«.0000000000000*0 0 Q t 3)«.0000000000000*0 0 TH E .MAXIMU M L I KE L tHOOO . ESTIMATIO N O F TIME. . FUNCTION. . _ _ tT-i.OOOOUOOOOO O I•*!.59972385*6 6

A3 5