## Route -t o- RouteExtr apol ati on o f 1,1,2- Tri chl oroetha ne Stu di es

from theO ralRout e t o I nhal ati on Us i ng Phy si ol ogi callyBas ed

Ph armac okinetic Mod els: A cute N euro toxi city

P repare d f

or HAPTas k F or c e , Millwood,Vi r gin ia

P r epar e d by T he Sapphire Group , D ayto n, O hio

November 29, 20041, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

Page 2

EX EC UT I VE S UM M ARY

A n e e d h a s b e e n i d e n t i f i e d f o r a q u a n t i t a t i v e u n d e r s t a n d i n g o f th e h a z a r ds of 1, 1, 2- trich lo ro e th a n e (1 ,1 ,2 -T C E ) e x p o su re b yth e in h a latio n ro u te. U n d e r S e c tio n 4 o f th e T o x ic S u b sta n c e s C o n tro l A c t (T S C A ), th e U .S

. E P A iss u e dates tin g c o n se n t o rd e r (E n f o rc e ab le C ons ent A gr eement , E C A ) t o per form t oxi ci tyt es t i ng a n d m e c h a n istic a n dp h a rm a c o k in e tic
s tudi es t o s at i s fyE PA ’ s dat a nee ds for1, 1, 2- T C E ( U

. S. E PA , 2000, 2003a)

. A s part of Ti er I tes tin g , p h a rm a c o k in e tic stu d ies w e re c o n du c ted (P o e t e t a l. , 2 0 0 3 ) an d ap h y sio lo g ica lly bas ed pharm acoki net i c ( PB PK ) m odel w as devel oped thatdes cr i bes the di s pos i t i on of 1, 1, 2- T C E b yo ra l a n din h a la tio n ro u te s (T h e S ap p h ir e G ro u p , 2 0 0 3 ).

T h is re p o rt se rv e s to f

u lf illth e id e n tifie dd a ta n e e df o r ro u te- to -ro u te e x trap o latio n o f re su lts of ac ut e neur ot oxi ci tys tudi es conduct ed bythe or alr out e t o the i nhal at i on r out e. T he r out et o- r ou t e e xtr apo l a t i on of r e s ul t s of

the 1, 1, 2- TC E ac ut e ne ur ot ox i c i tyt e s tus i ng the PB PK
m o d e l w a s b a se do n se lec tio n o f a c ritica l e n dp o in t ( g a it im p a irm e n t), th e m o st a p p ro p ria te i nternal dose m easures, and an app ropri at e po i nt of dep arture. It i s o ur o pini on that the m ost appr opr i at e dos e metr i c forr oute to rout e extr apol at i on i s the peak conce ntr at i on of 1, 1, 2- T C E in the b rain. R o u te-t o -rou te e x tr ap o lat ion resu lt s fo r o ther E C A -spe cified en dp o ints are pr ovi ded as an appe ndi x. T he appr opr i at e poi ntof departu re w as det erm i ned t o be the N O A E L f

o r m a le a n d f

e m a le r a ts. B a se do n P B P K m o d e lin g re su lts, the ra t ac u te
n eu roto x ici ty N O A E L fro m g av ag e d o sing (95 m g /kg ) is eq u ivalen t to co n ti n u o u s (24 -ho u r) i nhal at i on expos ur e of r at s t o 163 ppm 1, 1, 2- T C E

. Sens i t i vi tyanal y s i s of the r atr out e- t oro u te e x trap o latio n re su lts in d ica ted th a t th e e q u iv a len t in h a latio n e x p o su re w a s se n sitiv e to several m od el param et er values, bu t m ost sensi t i ve t o the m axim al rat e o f m et abo l i sm ( V m axc) , vent i l at i o n r at e ( Q PC ) , abs orpt i on r at e ( K a) , and the dos e us ed as the bas i s for
e x tr ap o la tio n

.1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

Page 3
I NT RO DU CT I ON

S u m m aryo f H az ard o u s A irP o llu tants (H A P s) F ram ew o rk
1, 1, 2- T r i chl or oethane ( 1, 1, 2- T C E , C A S N o. 79- 00- 5) i s us ed as an i nt erm edi at e i n the pr oduct i on of vi ny l i dene c hl or i de, as a s ol vent , i n adhes i ves and l acque r s , and i n the pr o d u cti o n of Tefl on

. A need ha s been i dent i fi ed fora quant i t at i ve under s t andi ng of the ® h a z a rd s o f

1 ,1 ,2

- T C E e x p o su re b yth e in h a latio n ro u te. U n d e r S e c tio n 4 o f th e T o x ic S u b sta n c e s C o n tro l A c t ( T S C A ), th e U .S . E P A iss u e d a tes tin g c o n se n t o rd e r (E n f o rc e ab le C ons ent A gr eement , E C A ) t o per form t oxi ci tyt es t i ng a n d m e c h a n istic a n dp h a rm a c o k in e tic stu d ies to sa tisf

y E P A ’s d a ta n e e d s f

o r 1 ,1 ,2 -T C E (U .S . E P A , 2 0 0 0 ) th a t w a s s u b se q u e n tly
m o d if ied w ith re sp e c t to tim in g a n de x p a n d s c o n sid e ra tio n o f d o se m e trics f

o r ro u te d o sim etryex tr ap o lat ion s (U

. S

. E P A , 2 0 0 3 a).

Sum m aryof Phy s i ol ogi cal l ybas ed Pharm acoki net i c ( PB PK ) M odel

T h e o b jec tiv e o f ac o m b in a tio n o f e x p e rim e n tal s tu d ies (P o e t e t a l. , 2003) and model i ng ( T he S ap p h i r e Gr o up , 2 0 0 3 ) wa s t o d e v e l o p ap h y s i o l o g i c a l l yb a s e dp h a rma c o k i n e t i c ( PBP K)
m odel thatw oul d al l ow r out e- t o- r out e extr apol at i on fr om exi s t i ng and futur e dat a on haz ar ds
o f o ra l 1 ,1 ,2 -T C E e x p o su re to a ss e ss in h a latio n h a z a rd s. M o d e ls w e re d e v e lo p e df o r b o th
r at s and mi ce ( T he S apphi r e G r oup, 2003) , but s i nce onl y r at s ar e r el evantt o i nt erpr et at i on of the ac ut e neur ot oxi ci tys tudy , r es ul t s for m i ce ar e not di s cus s ed her e. For PB PK m odel d e v el op m ent and refi nem ent, fem al e rat s w ere expo sed t o 1 00 pp m 1, 1, 2-T C E for six hour s / day , fi ve day s /w eek f orfourw eeks , w i th bl ood s ampl i ng on day s one, thr ee, and fi ve of w eek four

. A ddi t i onal gr oups of fem al e ra t s r ece i ved dai l y dos es of 1, 1, 2- T C E bygavage ( w at erorcorn oi l vehi cl e) forfi ve day s , w i th bl ood s ampl i ng on day s one, thr ee, and fi ve. T a rg e t d o s e s w e re 1 .7 m g /k g in w a te r a n d9 2 m g /k g in c o rn o il f o r r a ts

.
Th e mo d e l i s a n e x p a n s i o n a n d r e f i n e me n t o f th e P BP K mo d e l f o r d i s p o s i t i o n o f

1 , 1 , 2

- TCE i n m al e F 34 4 r at s developed byG argas e t a l. ( 1989) bas ed on exha l ed br eath dat a fol l ow i ng inh alati o n ex p o su re. T h e e x p a n d ed m o d el i n clud es a sp leen (t o p erm itd o sim etry cal cul a t i o n s f

o rth i s t i s s u e f

o rth e i mmun o t o x i c i tye n dp o i n t s , U. S. EPA, 2 0 0 0 , 2 0 0 3 a ) a nd can be us ed t o cal cul at e s peci fi ed dose m etr i cs of i nt er es t( bl ood conce ntr at i ons , t i s s ue conce ntr at i ons , oramount s m et abol i zed) aft eri nhal at i on, gavage ( corn oi l or w ater) , and dr i n k i n g wat e rc o n s u mpt i o n

. M o d e l p a r a me t e r s d e t e rmi n e db yo p t i mi z a t i o n ( ma xi m um bi otr ans form at i on r at e, enzym e af fi ni ty , and abs orpt i on r at es ) pr ovi ded an a dequat e fi t t o the
r a td a t as e t s

. M o d e l c o d e i s p r o v i d e di n Ap p e n d i x A.1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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S UM M ARY OF KEY S TU DY

Study D es ign A s tudyt o evaluat e the ac ut e ne ur ot oxi c pot ent i al of 1, 1, 2- T C E w as conduct ed us i ng C r l : C D ( SD ) I G S B R r at s

. 1, 1, 2- T C E w as admin is t er ed i n corn oi l bygavage t o 12

®

an im als/ sex /do se, at a d o se o f 0 , 5 5 , 9 5 , o r 2 0 0 m g /kg o n stud yd ay0

. A n im als w ere obs erved tw i ce dai l y for m ort al i ty and m or i bundi ty ; cl i ni calexami nat i ons w er e per form ed dai l y , and bodyw ei ght s w er e r ecor ded w eekl y
. Funct i onal obs ervat i onal batt ery( FO B ) and l ocomot oract i vi tydat a w ere rec o r ded pr i ort o dos i ng, atthe es t i m at ed t i m e of pe ak ef fec t ( 45 m i nut es pos t

- dos i ng) on s tudy day0 and on s tudyday s 7 and 14. A teuthanas i a on s tudy d a y1 5 , b ra in w e ig h ts (e x c lu d in g o lf a c to ryb u lb ), a n d b ra in d im e n sio n s w e re re c o rd e df o r a ll ani m al s

. A neur opathol ogi calevaluat i on w as per form ed on s i x ani m al s / s ex fr om the contr ol
a n d2 0 0 m g /k g g ro up s (B e c k , 2 0 0 4 ). W h ile th e a c u te n e u ro to x icitystu d yw a s c o n du c ted in SD r at s and the P B PK m odel w as devel oped forF344 r at s , i ti s unl i kel ythatphy s i ol ogi cal
or m et abol i c di ffe r ence s w i l l have as i gni fi canti m pacton the model ’ s abi l i tyt o s i m ul at e the dis po si t i o n o f 1 ,1 ,2 -TC E i n the t eststrai n (Sim m on s e t a l. , 2 0 0 2 ; Sc h o ef fn er e t a l. , 1999; W ang e t a l. , 2 0 0 0 ).

S tu d y R e su lts A tthe t i m e of pe ak ef

fec t , few er m al e and f

emal e r at s i n the 200 mg/kg gr oups w er e found
w i th ey es w i de open. H ypoact i vi ty and di s rupt i on of habi tuat i on w er e observed i n the 95 and 2 0 0 m g /k g g ro up s o f

m a les a n df

e m a les in th e stu d yd a y0 lo c o m o to r a c tiv itya ss e ss m e n t. G ai ti m pai rm entand abnorm al gai ts cor es w er e i dent i fi ed i n the F O B t es t s of the 200 m g/kg gr oups on s tudyday0. T he change s i n neur obehavi or al endpoi nt s occurr ed i n the abs ence of neur o pathol ogy

. T he mot oract i vi tyeff ect s not ed i n the 95 mg/kg gr oups w er e not
c o n s i d e r e da d v e r s e b e c au s e o f th e l a c ko f

p e r s i s t e n c e a n dth e l a c ko f c o rr e l a t i n g F OB fi ndi ngs

. T he N O A E L w as thus defi ned as 95 m g/kg and L O A E L as 2 0 0 m g/kg ( B eck, 2 0 0 4 ).

S ELECTI ON OF CRI TI CAL ENDPO I NTS AND DO S E M EAS URES

Cr i t i cal E ndpoi ntand D os e Meas ur es

T h e c ri ti ca l end p o int, g aitim p airm en t, w as id en ti fied in F O B test ing o f ra ts ( B ec k , 2 0 0 4 ).

Par entcompound i n venous bl ood and br ai n (as Cm ax and a s A U C ) and met abol i t e, as amountm et abol i zed i n the l i ver or br ai n perdaynorm al i zed t o l i verw ei ght , w er e s peci fi ed as dose m etri cs i n the am end ed E C A (U

. S

. E P A , 20 03 a). C on si st ent w i th U S E P A ’s D ra ft Fi na lG uidel i nes f

or C arci no gen R isk A ssessm e n t (U

. S. E PA , 2003b) , the s el ect i on of an1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

Page 5

appr opr i at e dos e m eas ur e r equi r es a car eful cons i der at i on of the m ode of act i on by w hi ch a
c h e m ic a l e x e rt s a n e f

f e c t ( c a rc in o g e n ic o r o th e rw is e ).

T h e o b s e rv e de f

f e c t, g a it im p a irm e n t, w a s f o u n d to b e a c u te a n d tr a n s ito ry ( B e c k , 2 0 0 4 ). A
w i de var i etyof s ol vent s ar e know n t o pr oduce anes thet i c or s edat i ve ef fec t s i n ani m al s and hum ans byal t er i ng nerve ce l l m embra ne pr opert i es ( Sny derand A ndr ew s , 1 9 9 6 ). 1, 1, 2- T r i chl or oethane maydepr es s s pont aneous and evoke d act i v ity o f n eurons i n the br ai n, p o s s i b l y th r o u g h n o n - s p e c i f i c a c t i o n s w i th th e l i p i d m a tr i x o f th e n e rv e m e m b r a n e o rb y a

A m o re sp ec ifi c ac ti o n o n the G A B A rec ep tor ch lori d e ch an n el, a m ajor m ed iat o r of inh ibit o ry s ynapt i c tr ans m i s s i on ( T r evorand W hi t e, 2004)

. A m ode of a ct i on i nvol vi ng nerve ce l l i on curr entm odi fi cat i on bythe par entchemi cali s cons i s t entw i th obs ervat i ons m ade f ora w i de vari ety of organic vapo rs and sol ven t s ( R i chards et al

. , 1978; Pr i ngl e et

al

. , 1981; J anoff

and M i l l er , 1982, Fr anks and L ieb, 1987; C hi ou et al

. , 1 9 9 0 ; C u rry e t a l. , 1990; H onm a et al ., 19 85 ; Janes et

al ., 1 9 9 2 ; M e ss a o u d i et al

. , 1992; D i cki ns on et

al

. , 1 9 9 3 ; Slater et

al

. , 1 9 9 3 ). T hus , i ti s ouropi ni on thatthe mostappr opr i at e dos e metr i c for r out e t o r out e extr apol at i on is th e p e a kc o n c e n tr a tio n in th e b ra in

.
RO UTE TO RO UTE EX TRAPOLATI ON RES ULTS

R o u te-t o -rou te ex tr ap o lat ion s o f th e acu te n eu roto x ici tyN O A E L an dL O A E L fo r rats w ere perform ed u si ng the P B P K m od el (Th e S ap p h ir e G roup, 2003 ). R esul t s for the m ost ap p rop ri ate e n dp o int fo r th e e x tr ap o lat ion , p ea kco n ce n tr ati o n o f 1,1,2-T C E in the b rain, are
re p o rte db e lo w ; re su lts f o r o th e r d o se m e a su re s s p e c if ied b yth e E C A a re p ro v id e din A p p en d ix B

. G rap h ical pre sen tat ion o f ro u te-t o -rou te ex tr a p o lat ion cu rve s fo r rats are p re s e n te din A p p e n d ix C

.
Form al e r at s , bas ed on equal peak conce ntr at i ons of 1, 1, 2- T C E i n the br ai n, the ac ut e or al
neur ot oxi ci ty N O A E L o f 95 m g/kg i s equi val entt o i nhal at i on of 170 ppm 1, 1, 2- tr i chl or oethane, and the LO A E L of 200 m g/kg i s equi val entt o i nhal at i on of 255 ppm

. For fe m ale rats, o ral acu te ne u roto x ici ty N O A E L an dL O A E L o f 9 5 an d2 0 0 m g /kg are equi val entt o i nhal at i on of 163 ppm and 244 ppm 1, 1, 2- tr i chl or oethane, r es pect i vel y
. Si nce the N O A E L i nhal at i on equi val ent conce ntr at i on i n femal e r at s ( 163 ppm ) i s l ow erthan that det erm i ned form al e r at s ( 170 ppm ) , the fe m al e r atequi val enti s r ecomm ended f or extr apol at i on and any r i s k as s es s m ent purpos es

. T hes e r es ul t s ar e cons i s t entw i th fi ndi ngs of pr eviou s s tudi es of 1, 1, 2- T C E bythe i nhal at i on r out e. O ne s tudy( K i rkpatr i ck, 2001)
r eport ed evi dence of ac ut e neur ot oxi ci ty( at axi a) i n r at s expos ed t o conce ntr at i ons ator e x c e e d i n g 8 4 0 p p m 1 , 1 , 2

- TCE , b u tn o ti n a n i ma l s e x p o s e dt o 5 8 o r1 8 1 p p m.1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

Page 6
S E N S IT IV IT Y A N A L Y S IS

T he s ens i t i vi tyof the cr i t i caldos e metr i c, peak c oncentr at i on of 1, 1, 2- T C E i n the r atbr ai n, t o change s i n m odel par amet erval ues w as evaluat ed for s cenar i os i nvol vi ng corn oi l gavage o r c o n tin u o u s in h a latio n . In th e g a v a g e sc e n a rio , a d o se o f 9 5 m g /k g , th e N O A E L , to f e m a le
ra ts w a s u se da s th e b a sis o f th e a n a ly sis , a n d th e c o n tinu o u s in h a latio n e q u iv a len t f o r f e m a le
ra ts, 1 6 3 p p m , w a s u se d a s th e b a sis o f th e in h a latio n se n sitiv itya n a ly sis . S e n sitiv itya n a ly sis
w as conduct ed byi ncr eas i ng a par amet erv al ue by1% and not i ng the change i n the model pr edi c t i o n o f i n t e r e s t ( p e a k c o n c e n tr a t i o n i n th e b r a i n )

. Th e f r a c t i o n a l i n c r e a s e i n the pr edi ct i on di vi ded bythe fr act i onal i ncr eas e i n the par amet er w as defi ned as the norm al i zed
s ens i t i vi tycoef

fi ci ent

. T he r es ul t s ar e s um m ar i zed i n T abl e 1.

T abl e 1. Sensi t i vi t y of

P redi ct i ons of

P eak B rai n C oncent rat i on t o M odelP aram et er V al ues

Sens i t i vi tyC oeff

i ci ent Par amet er G avage I nhal at i on a b B l ood: ai rpart i t i on coef fi ci ent( PB A )

- 0. 42 - 0. 35 Fat : ai rpart i t i on coef

fi ci ent( PFA )

- 0. 14 - 0. 03 R i chl yper fus ed t i s s ues ( R PT ) : ai rpart i t i on coef fi ci ent( PR A )

- 0. 11 <0. 05 Sl ow l yper fus ed t i s s ues : ai rpart i t i on coef fi ci ent( PSA )

- 0. 11 <0. 05 B ra in :a irp a rt itio n c o e f

f ic ie n t ( P B R A ) 1 .0 1 .0 M axi m um m et abol i s m of 1, 1, 2- T C E ( V m axC )

- 0. 91 - 2. 42 M i chae l i s cons t antform et abol i s m of 1, 1, 2- T C E ( K M ) 0. 21 <0. 05 B odyw ei ght( B W ) 0. 44 <0. 05 N orm al i zed a l veol arvent i l at i on r at e ( Q PC )

- 0. 18 2. 67 N orm al i zed c ar di ac output( Q C C )

- 0. 39 - 0. 14 Fr act i onal bl ood fl ow t o l i ver( Q L C ) <0. 05 - 0. 15 Fr act i onal bl ood fl ow t o fat( Q FC )

- 0. 43 <0. 05 Fr act i onal vol um e of f

at( V FC )

- 0. 14 <0. 05 Fr act i onal vol um e of RP T ( V R C )

- 0. 11 <0. 05 Fr act i onal vol um e of SPT ( V SC )

- 0. 11 <0. 05 Or a l ab s o rp t i o n r a t e f

r o m c o rn o i l ( KA) 1

. 4 7 NA Do s e ( DOS E ) 1

. 8 6 NA C oncentr at i on ( C O N C ) N A 3. 30 Al l oth erpa r ame t er s : | s en s i t i v i ty c oef f i ci en t | <0. 05 G a v a g e d o se o f 9 5 m g /kg / 1 ,1 ,2 -T C E in c o rn o il to fem a le ra ts a Co n t i n u o u s i n h a l a t i o n e x p o s u r e o f f e m a l e r a t s t o 1 6 3 p p m 1 , 1 , 2

- TCE. b1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

Page 7
Forthe gava ge and i nhal at i on s cenar i os , the model pr edi ct i ons of peak br ai n conce ntr at i on
w e re se n sitiv e to sev era l p a ra m e ter s, b u t m o st s e n sitiv e to d o se /co n c e n tra tio n , m a x im u m ra te of m et abol i s m , abs orpt i on r at e, vent i l at i on r at e, and br ai n: ai rpart i t i on coe ff ici ent

. T he
sen sit i vi tyof the model pr edi ct i ons t o the br ai n: ai rpart i t i on coef fi ci ent , how ever , do not ent eri nt o det erm i n ing the val ue of the i nhal at i on- equi val entN O A E L becaus e the sensi t i vit i es ar e equ al for the inhal at i on and oral rout es.

CONCL US I ONS

T h e P B P K m o d e l-b a se dro u te- to -ro u te e x trap o latio n o f re su lts o f

th e 1 ,1 ,2 -T C E a c u te
n e u ro to x icitystu d yw a s b a se do n se lec tio n o f a c r it ic a l e n dp o in t, th e m o st a p p ro p ria te in tern a l d o se m e a su re , an da n ap p ro p ria te p o in t o f d e p a rtu re . T h e c ritica l en dp o in t w a s g a it di s turbance , as det erm i ned byB eck ( 2004)

. T he mostappr opr i at e i nt ernaldos e meas ur e, p e a k c o n c e n tra tio n o f 1 ,1 ,2 -T C E in th e b ra in , w a s s e lec ted f ro m d o se m e a su re s s p e c if ied in the EC A bas ed on l i kel ym ode of a ct i on. T h e fe m ale rat N O A E L of 95 m g/kg w as cons i der ed an appr opr i at e bas i s forr out e- t o- r out e extr apol at i on, r es ul t i ng i n an es t i m at ed equi val ent cont i nuous i nhal at i on expos ur e 163 ppm

. Sens i t i vi ty anal y s es of the se lect ed i nt ernal dos e m eas ur e t o change s i n m odel par amet ervalues w er e conduc t ed forgavage and i nhal ati o ns c e n ar i o s

. Atd o s e s / conce ntr at i ons r el evantt o the r out e- t o- r out e extr apol at i on, the
m od el predi ct i on s of peak concen trat i on s i n the brai n w ere s ensi t i ve to severalparam et ers

. W e r e c o mme n dth a tc o n t i n u o u s ( 2 4

- h o u r ) i n h a l a t i o n e x p o s u r e o f r a t s t o 1 6 3 p p m 1 , 1 , 2

- TCE be co nsi dered eq uival ent t o the r atN O A E L of 9 5 m g/kg-d for acute neurot ox i c effects

.1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

Page 8
REFERENCES

B eck, M

. J

. ( 2004)

. A n acut e neur ot oxi ci ty s tudy of 1, 1, 2- tr i chl or oethane i n r at s

. W I L

- 417- 004. Fi nal r eport

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. 1982. A cr i t i calas s es s m en t o f the l i pi d theor i es of gene r al
a n a e sth e tic a c ti o n . In : B io lo g ica l M e m b ra n e s. p p . 4 1 7 -4 7 6 . C h ap m a n , D . E d ., A c a d e m ic Pr es s , L ondon.

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. E qu i l i bria betw een mul t i pl e s pectr al form s of bac t er i orhodops i n eff ectof del i pi dat i on, anes thet i cs and
s ol vent s on thei rpH dependance. B i ochi m

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. 2003. Pharm acoki net i cs of 1, 1, 2- T r i chl or oethane i n R at s and M i ce. B att el l e P r oj ectN o. 4 1 6 0 8 . Ju n e 1 0 , 2 0 0 3 . A m e n d e dF in a l R e p o rt

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P rin g le, M . J., B ro w n , K . B . & M ill e r, K

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acc ountforthe cut off i n anae s thet i c pot encyi n hom ol o g o u s seri es of al cohol s

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Sny derR

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. I n: C as ar ettand D o u ll’s T o x ico lo g yT h e B a sic S c ien c e o f P o iso n s 5 e d iti o n . E dC D K las ss e n . M c G ra w -H ill

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. Jul y7, 2003, D ayt on, O hi o.

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. Feder al R egi s t er68, N o. 131, pp 40944- 40947, Jul y9, 2003.

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. S. E nvi r onm ent alPr ot ect i on A g en cy , R i s k A s s es s m ent Forum , W as hi ngt on, D C , 125 pp.1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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W ang X , Sant os t efano M J , D eV i t o M J , B i rnbaum L S. 2000. E xtr apol at i on of a PB PK m odel f o r d io x in s a c ro s s d o s a g e re g im e n , g e n d e r, s tr a in , a n ds p e c ie s . T o x ic o l S c i. 5 6 : 4 9 -6 0

.1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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APPE ND I X A P BP K M ODEL CODE G I S I R 3
. C MD

'File Name is GI.cmd, Rev 1/19/90 at 9:30 am' 'rev 5/1/01, 8/31/01 lms for 112tce only' 'rev 4/16-17/02 for sensitivity analysis, optimized values' 'rev 05/09/02 for reoptimized values' 'rev 071703 for rereoptimized values' SET TJNITG = 1.0 $'Threshold for Jacobian Error Messages' SET TSMITG = .T. $'Two sided matrix evaluation for increased accur.' SET NSTP = 1000 $'Allow the integrator to take very small steps' 'SET PRN=7 ' $'Save output in SIMUSOLV.LOG file'
PREPAR T,PPMOUT,CA,CV,CL,CVL,AUCL,DM,AM,AUCB,AML,DM1,csn,aucsn,aucv prepar cbr aucbr
PROCED MANY $ S NRWITG=.T.,FTSPLT=.T. $ END PROCED ONE $ S NRWITG=.F. $ END

PROCED CCL2CCL $'1,1,2-TRICHLOROETHANE, X MG/KG gavage dose' SET N=5 SET Flow=10700,vchc=2200, POINTS=240 SET KA=2.0,KAI=0.,KSI=0. SET DOSE=0.,TSTOP=2. END
proced bolus set drpct=1.0, 0, 0, 0, 0, 0 set drtime=0, 4, 8, 12, 16, 20 set tchng=120 end
proced perdwr set drpct=0.233, 0.1, 0.1, 0.1, 0.233, 0.234 set drtime=0, 4, 8, 12, 16, 20 set tchng=99999 end
proced begin ccl2ccl
mouse set n=1, points=30000, tstop=168 set ka=0.2 end

PROCED MOUSE $'PHYSIOL FROM BROWN ET AL 1997' SET TITLE = ' 1,1,2-TCE FEMALE MOUSE' SET MW=133.41,PB=71.1,PFA=1438,PLA=73,PRA=60.7,PSA=23,PBRA=56.1 SET PSNA=43 SET VMAXC=17.3,VMAXRC=0,KM=0.35,KFC=0.01, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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SET BW=0.025,QPC=14,QCC=14 SET QLC=0.161,QBRC=0.033,QFC=0.07,QSC=0.217, QSNC=0.011 SET VLC=0.0549,VBRC=0.0165,VFC=0.07,VRC=0.1958,VSC=0.5493 SET VSNC=0.0035 SET KDET=0.025, KDbi=0.0914 set fnight=0.79, per1=0.5715, dur1=0.014, per2=1, dur2=0.016 END $'of proced mouse'
PROCED MMOUSE $'PHYSIOL FROM BROWN ET AL 1997' SET TITLE = ' 1,1,2-TCE MALE MOUSE' SET MW=133.41,PB=71.1,PFA=1438,PLA=73,PRA=60.7,PSA=23,PBRA=56.1 SET PSNA=43 SET VMAXC=17.3,VMAXRC=0,KM=0.35,KFC=0.0 SET BW=0.025,QPC=14,QCC=14 SET QLC=0.161,QBRC=0.033,QFC=0.07,QSC=0.217, QSNC=0.011 SET VLC=0.0549,VBRC=0.0165,VFC=0.07,VRC=0.1958,VSC=0.5493 SET VSNC=0.0035 SET KDET=0.025, KDBI=0.0 set fnight=0.79, per1=0.57, dur1=0.014, per2=1, dur2=0.016 END $'of proced Mmouse'

PROCED rat SET TITLE = ' 1,1,2-TCE RAT' SET MW=133.41,PB=58.,PFA=1438,PLA=73,PRA=60.7,PSA=23,PBRA=56.1 SET PSNA=43 SET VMAXC=10.2,VMAXRC=0,KM=0.54,KFC=0.0 SET BW=0.25,QPC=13,QCC=13 SET QLC=0.183,QBRC=0.02,QFC=0.07,QSC=0.336,QSNC=0.011 SET VLC=0.0366,VBRC=0.0057,VFC=0.0896,VRC=0.2215,VSC=0.5946 SET VSNC=0.002 SET KDET=0.025, KDTE=0., kdbi=0 set fnight=0.8, per1=1.5, dur1=0.75, per2=3, dur2=0.5 END $'of proced rat'

PROCED FMSA1 SET N=1 MOUSE $START $ D AUCV, DM1 SET PB=71.811 $START $ D AUCV, DM1 $MOUSE SET PFA=1452.38 $START $ D AUCV, DM1 $MOUSE SET PLA=73.73 $START $ D AUCV, DM1 $MOUSE SET PRA=61.307 $START $ D AUCV, DM1 $MOUSE SET PSA=23.23 $START $ D AUCV, DM1 $MOUSE SET PBRA=56.661 $START $ D AUCV, DM1 $MOUSE SET PSNA=43.43 $START $ D AUCV, DM1 $MOUSE SET VMAXC=17.473 $START $ D AUCV, DM1 $MOUSE SET KM=0.3535 $START $ D AUCV, DM1 $MOUSE SET BW=0.02525 $START $ D AUCV, DM1 $MOUSE SET QPC=14.14 $START $ D AUCV, DM1 $MOUSE SET QCC=14.14 $START $ D AUCV, DM1 $MOUSE SET QLC=0.16261 $START $ D AUCV, DM1 $MOUSE SET QBRC=0.03333 $START $ D AUCV, DM1 $MOUSE SET QFC=0.0707 $START $ D AUCV, DM1 $MOUSE SET QSC=0.21917 $START $ D AUCV, DM1 $MOUSE SET QSNC=0.01111 $START $ D AUCV, DM1 $MOUSE SET VLC=0.055449 $START $ D AUCV, DM1 $MOUSE SET VBRC=0.016665 $START $ D AUCV, DM1 $MOUSE1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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SET VFC=0.0707 $START $ D AUCV, DM1 $MOUSE SET VRC=0.197758 $START $ D AUCV, DM1 $MOUSE SET VSC=0.554793 $START $ D AUCV, DM1 $MOUSE SET VSNC=0.003535 $START $ D AUCV, DM1 $MOUSE SET KDET=0.02525 $START $ D AUCV, DM1 $MOUSE SET KDBI=0.092314 $START $ D AUCV, DM1 $MOUSE END

PROCED FMSA2 SET N=1 MOUSE $START $ range cv SET PB=71.811 $START $ range cv $MOUSE SET PFA=1452.38 $START $ range cv $MOUSE SET PLA=73.73 $START $ range cv $MOUSE SET PRA=61.307 $START $ range cv $MOUSE SET PSA=23.23 $START $ range cv $MOUSE SET PBRA=56.661 $START $ range cv $MOUSE SET PSNA=43.43 $START $ range cv $MOUSE SET VMAXC=17.473 $START $ range cv $MOUSE SET KM=0.3535 $START $ range cv $MOUSE SET BW=0.02525 $START $ range cv $MOUSE SET QPC=14 $START $ range cv $MOUSE SET QCC=14 $START $ range cv $MOUSE SET QLC=0.16261 $START $ range cv $MOUSE SET QBRC=0.03333 $START $ range cv $MOUSE SET QFC=0.0707 $START $ range cv $MOUSE SET QSC=0.21917 $START $ range cv $MOUSE SET QSNC=0.01111 $START $ range cv $MOUSE SET VLC=0.055449 $START $ range cv $MOUSE SET VBRC=0.016665 $START $ range cv $MOUSE SET VFC=0.0707 $START $ range cv $MOUSE SET VRC=0.197758 $START $ range cv $MOUSE SET VSC=0.554793 $START $ range cv $MOUSE SET VSNC=0.003535 $START $ range cv $MOUSE SET KDET=0.02525 $START $ range cv $MOUSE SET KDBI=0.092314 $START $ range cv $MOUSE END

PROCED FMSA3 SET N=1 MOUSE $START $ D AUCsn, DM1 SET PB=71.811 $START $ D AUCsn, DM1 $MOUSE SET PFA=1452.38 $START $ D AUCsn, DM1 $MOUSE SET PLA=73.73 $START $ D aucsn, DM1 $MOUSE SET PRA=61.307 $START $ D aucsn, DM1 $MOUSE SET PSA=23.23 $START $ D aucsn, DM1 $MOUSE SET PBRA=56.661 $START $ D aucsn, DM1 $MOUSE SET PSNA=43.43 $START $ D aucsn, DM1 $MOUSE SET VMAXC=17.473 $START $ D aucsn, DM1 $MOUSE SET KM=0.3535 $START $ D aucsn, DM1 $MOUSE SET BW=0.02525 $START $ D aucsn, DM1 $MOUSE SET QPC=14.14 $START $ D aucsn, DM1 $MOUSE SET QCC=14.14 $START $ D aucsn, DM1 $MOUSE SET QLC=0.16261 $START $ D aucsn, DM1 $MOUSE SET QBRC=0.03333 $START $ D aucsn, DM1 $MOUSE SET QFC=0.0707 $START $ D aucsn, DM1 $MOUSE SET QSC=0.21917 $START $ D aucsn, DM1 $MOUSE1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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SET QSNC=0.01111 $START $ D aucsn, DM1 $MOUSE SET VLC=0.055449 $START $ D aucsn, DM1 $MOUSE SET VBRC=0.016665 $START $ D aucsn, DM1 $MOUSE SET VFC=0.0707 $START $ D aucsn, DM1 $MOUSE SET VRC=0.197758 $START $ D aucsn, DM1 $MOUSE SET VSC=0.554793 $START $ D aucsn, DM1 $MOUSE SET VSNC=0.003535 $START $ D aucsn, DM1 $MOUSE SET KDET=0.02525 $START $ D aucsn, DM1 $MOUSE SET KDBI=0.092314 $START $ D aucsn, DM1 $MOUSE END
proced FEMmusSA set hvdprn=.f., tstop=168, points=30000 bolus set dose= 390, ka=0.20 fmsa1 SET dose=393.9 $START $ D AUCV, DM1 $set dose=390 SET ka=0.202 $START $ D AUCV, DM1 $set ka=0.2 $START $ D AUCV, DM1 fmsa2 SET dose=393.9 $START $ range cv $set dose=390 SET ka=0.202 $START $ range cv $set ka=0.2 $START $ range cv set dose= 10, ka=2.5, tstop=23.5 fmsa1 SET dose=10.1 $START $ D AUCV, DM1 $set dose=10 SET ka=2.525 $START $ D AUCV, DM1 $set ka=2.5 $START $ D AUCV, DM1 fmsa2 SET dose=10.1 $START $ range cv $set dose=10 SET ka=2.525 $START $ range cv $set ka=2.5 $START $ range cv END

PROCED MMSA1 SET N=1 MMOUSE $START $ D AUCV, DM1 SET PB=71.811 $START $ D AUCV, DM1 $MMOUSE SET PFA=1452.38 $START $ D AUCV, DM1 $MMOUSE SET PLA=73.73 $START $ D AUCV, DM1 $MMOUSE SET PRA=61.307 $START $ D AUCV, DM1 $MMOUSE SET PSA=23.23 $START $ D AUCV, DM1 $MMOUSE SET PBRA=56.661 $START $ D AUCV, DM1 $MMOUSE SET PSNA=43.43 $START $ D AUCV, DM1 $MMOUSE SET VMAXC=17.473 $START $ D AUCV, DM1 $MMOUSE SET KM=0.3535 $START $ D AUCV, DM1 $MMOUSE SET BW=0.02525 $START $ D AUCV, DM1 $MMOUSE SET QPC=14.14 $START $ D AUCV, DM1 $MMOUSE SET QCC=14.14 $START $ D AUCV, DM1 $MMOUSE SET QLC=0.16261 $START $ D AUCV, DM1 $MMOUSE SET QBRC=0.03333 $START $ D AUCV, DM1 $MMOUSE SET QFC=0.0707 $START $ D AUCV, DM1 $MMOUSE SET QSC=0.21917 $START $ D AUCV, DM1 $MMOUSE SET QSNC=0.01111 $START $ D AUCV, DM1 $MMOUSE SET VLC=0.055449 $START $ D AUCV, DM1 $MMOUSE SET VBRC=0.016665 $START $ D AUCV, DM1 $MMOUSE1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

Page 15
SET VFC=0.0707 $START $ D AUCV, DM1 $MMOUSE SET VRC=0.197758 $START $ D AUCV, DM1 $MMOUSE SET VSC=0.554793 $START $ D AUCV, DM1 $MMOUSE SET VSNC=0.003535 $START $ D AUCV, DM1 $MMOUSE SET KDET=0.02525 $START $ D AUCV, DM1 $MMOUSE END

PROCED MMSA2 SET N=1 MMOUSE $START $ range cv SET PB=71.811 $START $ range cv $MMOUSE SET PFA=1452.38 $START $ range cv $MMOUSE SET PLA=73.73 $START $ range cv $MMOUSE SET PRA=61.307 $START $ range cv $MMOUSE SET PSA=23.23 $START $ range cv $MMOUSE SET PBRA=56.661 $START $ range cv $MMOUSE SET PSNA=43.43 $START $ range cv $MMOUSE SET VMAXC=17.473 $START $ range cv $MMOUSE SET KM=0.3535 $START $ range cv $MMOUSE SET BW=0.02525 $START $ range cv $MMOUSE SET QPC=14.14 $START $ range cv $MMOUSE SET QCC=14.14 $START $ range cv $MMOUSE SET QLC=0.16261 $START $ range cv $MMOUSE SET QBRC=0.03333 $START $ range cv $MMOUSE SET QFC=0.0707 $START $ range cv $MMOUSE SET QSC=0.21917 $START $ range cv $MMOUSE SET QSNC=0.01111 $START $ range cv $MMOUSE SET VLC=0.055449 $START $ range cv $MMOUSE SET VBRC=0.016665 $START $ range cv $MMOUSE SET VFC=0.0707 $START $ range cv $MMOUSE SET VRC=0.197758 $START $ range cv $MMOUSE SET VSC=0.554793 $START $ range cv $MMOUSE SET VSNC=0.003535 $START $ range cv $MMOUSE SET KDET=0.02525 $START $ range cv $MMOUSE END
proced MALEmusSA bolus set hvdprn=.f., tstop=168, points=30000 set dose= 390, ka=0.2 Mmsa1 SET dose=393.9 $START $ D AUCV, DM1 $set dose=390 SET ka=0.202 $START $ D AUCV, DM1 $set ka=0.2 $START $ D AUCV, DM1 Mmsa2 SET dose=393.9 $START $ range cv $set dose=390 SET ka=0.202 $START $ range cv $set ka=0.2 $START $ range cv set dose= 10, ka=2.5, tstop=23.5 Mmsa1 SET dose=10.1 $START $ D AUCV, DM1 $set dose=10 SET ka=2.525 $START $ D AUCV, DM1 $set ka=2.5 $START $ D AUCV, DM1 Mmsa2 SET dose=10.1 $START $ range cv $set dose=10 SET ka=2.525 $START $ range cv $set ka=2.5 $START $ range cv1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

Page 16

END
proced cancerSA bolus set hvdprn=.f., tstop=168, points=30000 set dose= 195, ka=0.2 fmsa1 SET dose=196.95 $START $ D AUCV, DM1 $set dose=195 SET ka=0.202 $START $ D AUCV, DM1 $set ka=0.2 $START $ D AUCV, DM1 END

PROCED RSA1 SET N=1 RAT $START $ D AUCV, DM1 SET PB=58.58 $START $ D AUCV, DM1 $RAT SET PFA=1452.38 $START $ D AUCV, DM1 $RAT SET PLA=73.73 $START $ D AUCV, DM1 $RAT SET PRA=61.307 $START $ D AUCV, DM1 $RAT SET PSA=23.23 $START $ D AUCV, DM1 $RAT SET PBRA=56.661 $START $ D AUCV, DM1 $RAT SET PSNA=43.43 $START $ D AUCV, DM1 $RAT SET VMAXC=10.302 $START $ D AUCV, DM1 $RAT SET KM=0.5454 $START $ D AUCV, DM1 $RAT SET BW=0.2525 $START $ D AUCV, DM1 $RAT SET QPC=13.13 $START $ D AUCV, DM1 $RAT SET QCC=13.13 $START $ D AUCV, DM1 $RAT SET QLC=0.18483 $START $ D AUCV, DM1 $RAT SET QBRC=0.0202 $START $ D AUCV, DM1 $RAT SET QFC=0.0707 $START $ D AUCV, DM1 $RAT SET QSC=0.33936 $START $ D AUCV, DM1 $RAT SET QSNC=0.01111 $START $ D AUCV, DM1 $RAT SET VLC=0.036966 $START $ D AUCV, DM1 $RAT SET VBRC=0.005757 $START $ D AUCV, DM1 $RAT SET VFC=0.090496 $START $ D AUCV, DM1 $RAT SET VRC=0.223715 $START $ D AUCV, DM1 $RAT SET VSC=0.600546 $START $ D AUCV, DM1 $RAT SET VSNC=0.00202 $START $ D AUCV, DM1 $RAT SET KDET=0.02525 $START $ D AUCV, DM1 $RAT END

PROCED RSA2 SET N=1 RAT $START $ range cv SET PB=58.58 $START $ range cv $RAT SET PFA=1452.38 $START $ range cv $RAT SET PLA=73.73 $START $ range cv $RAT SET PRA=61.307 $START $ range cv $RAT SET PSA=23.23 $START $ range cv $RAT SET PBRA=56.661 $START $ range cv $RAT SET PSNA=43.43 $START $ range cv $RAT SET VMAXC=10.302 $START $ range cv $RAT SET KM=0.5454 $START $ range cv $RAT SET BW=0.2525 $START $ range cv $RAT SET QPC=13.13 $START $ range cv $RAT SET QCC=13.13 $START $ range cv $RAT SET QLC=0.18483 $START $ range cv $RAT1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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SET QBRC=0.0202 $START $ range cv $RAT SET QFC=0.0707 $START $ range cv $RAT SET QSC=0.33936 $START $ range cv $RAT SET QSNC=0.01111 $START $ range cv $RAT SET VLC=0.036966 $START $ range cv $RAT SET VBRC=0.005757 $START $ range cv $RAT SET VFC=0.090496 $START $ range cv $RAT SET VRC=0.223715 $START $ range cv $RAT SET VSC=0.600546 $START $ range cv $RAT SET VSNC=0.00202 $START $ range cv $RAT SET KDET=0.02525 $START $ range cv $RAT END
proced RATSA set hvdprn=.f., tstop=168, points=30000 bolus set dose= 92, ka=0.45 Rsa1 SET dose=92.92 $START $ D AUCV, DM1 $set dose=92 SET ka=0.4545 $START $ D AUCV, DM1 $set ka=0.45 $START $ D AUCV, DM1 Rsa2 SET dose=92.92 $START $ range cv $set dose=92 SET ka=0.4545 $START $ range cv $set ka=0.45 $START $ range cv set dose= 1.7, ka=1.3, tstop=23.5 Rsa1 SET dose=1.717 $START $ D AUCV, DM1 $set dose=1.7 SET ka=1.313 $START $ D AUCV, DM1 $set ka=1.3 $START $ D AUCV, DM1 Rsa2 SET dose=1.717 $START $ range cv $set dose=1.7 SET ka=1.313 $START $ range cv $set ka=1.3 $START $ range cv END

PROCED ROIL CCL2CCL RAT bolus SET N=1, DOSE=94.2, BW=0.147, KA=0.45, TSTOP=8.02 END
DATA ROILDATA (T, CV) 0.52 12.13 1.01 8.45 2.01 4.04 8.02 0.16 END

PROCED RWAT CCL2CCL RAT bolus SET N=1, DOSE=1.66, BW=0.152, KA=1.3, TSTOP=11, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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END
DATA RWATDATA (T, CV) 0.11 0.047 0.25 0.026 0.51 0.024 1.00 0.024 END

PROCED MOIL CCL2CCL MOUSE bolus SET N=1, DOSE=365, BW=0.0194, KA=0.20, TSTOP=168.0 END
DATA MOIL1DAT (T, CV) 0.52 11.1 0.98 7.8 2.0 4.0 8.0 0.21 END

PROCED MWAT CCL2CCL MOUSE bolus SET N=1, DOSE=9.7, BW=0.0194, KA=2.5, TSTOP=1 END
DATA MWATDATA (T, CV) 0.11 0.19 0.25 0.045 0.51 0.049 1.0 0.026 END

PROCED MGAVEXH CCL2CCL MOUSE SET N=5, DOSE=26.6, BW=0.0228, KA=0.2, TSTOP=2 SET FLOW=10.7, VCHC=2.2 END

PROCED SHOWIT DISPLY QPC,QCC,QFC,QLC,QRC,QSC, ... VFC,VLC,VRC,VSC, ... PFA,PLA,PRA,PSA,PB, ... VMAXC,KM,BW,MW,ka,ksi,kai, ... VCHC,FLOW,DOSE,IALG,TSTOP,POINTS,contdose,N END $'of proced showit'
proced contmet set contdose= 2 $start $d contdose, aucv, dm1 set contdose= 4 $start $d contdose, aucv, dm1 set contdose= 10 $start $d contdose, aucv, dm1 set contdose= 30 $start $d contdose, aucv, dm11, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set contdose= 50 $start $d contdose, aucv, dm1 set contdose= 80 $start $d contdose, aucv, dm1 set contdose= 100 $start $d contdose, aucv, dm1 set contdose= 120 $start $d contdose, aucv, dm1 set contdose= 190 $start $d contdose, aucv, dm1 set contdose= 240 $start $d contdose, aucv, dm1 set contdose= 290 $start $d contdose, aucv, dm1 set contdose= 340 $start $d contdose, aucv, dm1 set contdose= 390 $start $d contdose, aucv, dm1

set contdose= 2 $start $range cv set contdose= 4 $start $range cv set contdose= 10 $start $range cv set contdose= 30 $start $range cv set contdose= 50 $start $range cv set contdose= 80 $start $range cv set contdose= 100 $start $range cv set contdose= 120 $start $range cv set contdose= 190 $start $range cv set contdose= 240 $start $range cv set contdose= 290 $start $range cv set contdose= 340 $start $range cv set contdose= 390 $start $range cv

end
proced contoral CCL2CCL SET tdur=12,TSTOP=168 set n=0, ka=2.5, dose=0
mouse contmet
mmouse contmet end
proced gavmet set dose= 2 $start $d dose, aucv, dm1 set dose= 4 $start $d dose, aucv, dm1 set dose= 10 $start $d dose, aucv, dm1 set dose= 30 $start $d dose, aucv, dm1 set dose= 50 $start $d dose, aucv, dm1 set dose= 80 $start $d dose, aucv, dm1 set dose= 100 $start $d dose, aucv, dm1 set dose= 120 $start $d dose, aucv, dm1 set dose= 190 $start $d dose, aucv, dm1 set dose= 240 $start $d dose, aucv, dm1 set dose= 290 $start $d dose, aucv, dm1 set dose= 340 $start $d dose, aucv, dm1 set dose= 390 $start $d dose, aucv, dm1

set dose= 2 $start $range cv set dose= 4 $start $range cv set dose= 10 $start $range cv set dose= 30 $start $range cv set dose= 50 $start $range cv set dose= 80 $start $range cv1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set dose= 100 $start $range cv set dose= 120 $start $range cv set dose= 190 $start $range cv set dose= 240 $start $range cv set dose= 290 $start $range cv set dose= 340 $start $range cv set dose= 390 $start $range cv

end

PROCED PERORAL CCL2CCL PERDWR set TSTOP=168 set n=0, ka=2.5, contdose=0
mouse gavmet
mmouse gavmet end
proced testdw set hvdprn=.f. CCL2CCL set TSTOP=168 set n=0, ka=2.5, contdose=0, dose=0
mouse set dwdose=390 $start $d aucv, dm1 end
proced OIL set hvdprn=.f. CCL2CCL bolus set TSTOP=168 set n=0, ka=0.2, contdose=0
mouse gavmet
mmouse gavmet end
proced cancer set hvdprn=.f. CCL2CCL bolus set TSTOP=168 set n=0, ka=0.2, contdose=0
mouse set dose= 150 $start $d dose $range cl, aucl, cv, aucv, dm1 set dose= 200 $start $d dose $range cl, aucl, cv, aucv, dm1 set dose= 300 $start $d dose $range cl, aucl, cv, aucv, dm1 set dose= 400 $start $d dose $range cl, aucl, cv, aucv, dm1
mmouse set dose= 150 $start $d dose $range cl, aucl, cv, aucv, dm1 set dose= 200 $start $d dose $range cl, aucl, cv, aucv, dm1 set dose= 300 $start $d dose $range cl, aucl, cv, aucv, dm11, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set dose= 400 $start $d dose $range cl, aucl, cv, aucv, dm1 rat set dose= 70 $start $d dose $range cl, aucl, cv, aucv, dm1 set dose= 100 $start $d dose $range cl, aucl, cv, aucv, dm1 end

proced gavmet2 set dose= 2 $start $d aucl set dose= 4 $start $d aucl set dose= 10 $start $d aucl set dose= 30 $start $d aucl set dose= 50 $start $d aucl set dose= 80 $start $d aucl set dose= 100 $start $d aucl set dose= 120 $start $d aucl set dose= 190 $start $d aucl set dose= 240 $start $d aucl set dose= 290 $start $d aucl set dose= 340 $start $d aucl set dose= 390 $start $d aucl

set dose= 2 $start $range cl set dose= 4 $start $range cl set dose= 10 $start $range cl set dose= 30 $start $range cl set dose= 50 $start $range cl set dose= 80 $start $range cl set dose= 100 $start $range cl set dose= 120 $start $range cl set dose= 190 $start $range cl set dose= 240 $start $range cl set dose= 290 $start $range cl set dose= 340 $start $range cl set dose= 390 $start $range cl end
proced OIL2 set hvdprn=.f. CCL2CCL bolus set TSTOP=168 set n=0, ka=0.2, contdose=0
mouse gavmet2
mmouse gavmet2 end
proced immuno set hvdprn=.f. CCL2CCL set TSTOP=144 set n=0, ka=2.5, contdose=0, points=24000
mouse set per1=0.5715 set dwdose= 3.9, bw=0.0303, vsnc=0.0060 $start1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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$d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 44, bw=0.0295, vsnc=0.0051 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 384,bw=0.0300, vsnc=0.0050 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set tstop=168 set per1=0.5715 set dwdose= 3.9, bw=0.0303, vsnc=0.0060 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 44, bw=0.0295, vsnc=0.0051 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 384,bw=0.0300, vsnc=0.0050 $start $d dwdose $range csn, aucsn, cv, aucv, dm1
mmouse set tstop=168 set per1=0.5715 set dwdose= 4.4, bw=0.0396, vsnc=0.0051 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 46, bw=0.0358, vsnc=0.0050 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 305,bw=0.0351, vsnc=0.0037 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 end

proced immuno2 set hvdprn=.f. CCL2CCL set TSTOP=144 set n=0, ka=2.5, contdose=0, points=24000
mouse set per1=0.5715 set dwdose= 50, bw=0.0295, vsnc=0.0051 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 100 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 150 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 200 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 250 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 300 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 350 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set tstop=168 set dwdose= 50, bw=0.0295, vsnc=0.0051 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 100 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 150 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 200 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 250 $start $d dwdose $range csn, aucsn, cv, aucv, dm11, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set dwdose= 300 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 350 $start $d dwdose $range csn, aucsn, cv, aucv, dm1
mmouse set tstop=168 set per1=0.5715 set dwdose= 50, bw=0.0358, vsnc=0.0050 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 100 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 150 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 200 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 250 $start $d dwdose $range csn, aucsn, cv, aucv, dm1 set dwdose= 300 $start $d dwdose $range csn, aucsn, cv, aucv, dm1

end
proced immunSA set hvdprn=.f., tstop=168, points=30000 set dwdose= 3.9, ka=2.5 fmsa3 SET dwdose=3.939 $START $ D AUCsn, DM1 $set dwdose=3.9 SET ka=2.525 $START $ D AUCsn, DM1 $set ka=2.5 $START $ D AUCsn, DM1 set tstop=144 fmsa3 SET dwdose=3.939 $START $ D AUCsn, DM1 $set dwdose=3.9 SET ka=2.525 $START $ D AUCsn, DM1 $set ka=2.5 $START $ D AUCsn, DM1 END
proced acuteneuro roil set bw=0.168 set dose=55 $start $ d dose $range cbr cv aucbr aucv dm1 set dose=95 $start $ d dose $range cbr cv aucbr aucv dm1 set dose=200 $start $ d dose $range cbr cv aucbr aucv dm1 set bw=0.226 set dose=55 $start $ d dose $range cbr cv aucbr aucv dm1 set dose=95 $start $ d dose $range cbr cv aucbr aucv dm1 set dose=200 $start $ d dose $range cbr cv aucbr aucv dm1 end

PROCED neurosa set hvdprn=.f. SET N=11, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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roil set bw=0.168, dose=95 $START $ range cbr SET PB=58.58 $START $ range cbr $RAT $set bw=0.168 SET PFA=1452.38 $START $ range cbr $RAT $set bw=0.168 SET PLA=73.73 $START $ range cbr $RAT $set bw=0.168 SET PRA=61.307 $START $ range cbr $RAT $set bw=0.168 SET PSA=23.23 $START $ range cbr $RAT $set bw=0.168 SET PBRA=56.661 $START $ range cbr $RAT $set bw=0.168 SET PSNA=43.43 $START $ range cbr $RAT $set bw=0.168 SET VMAXC=10.302 $START $ range cbr $RAT $set bw=0.168 SET KM=0.5454 $START $ range cbr $RAT $set bw=0.168 SET BW=0.16968 $START $ range cbr $RAT $set bw=0.168 SET QPC=13.13 $START $ range cbr $RAT $set bw=0.168 SET QCC=13.13 $START $ range cbr $RAT $set bw=0.168 SET QLC=0.18483 $START $ range cbr $RAT $set bw=0.168 SET QBRC=0.0202 $START $ range cbr $RAT $set bw=0.168 SET QFC=0.0707 $START $ range cbr $RAT $set bw=0.168 SET QSC=0.33936 $START $ range cbr $RAT $set bw=0.168 SET QSNC=0.01111 $START $ range cbr $RAT $set bw=0.168 SET VLC=0.036966 $START $ range cbr $RAT $set bw=0.168 SET VBRC=0.005757 $START $ range cbr $RAT $set bw=0.168 SET VFC=0.090496 $START $ range cbr $RAT $set bw=0.168 SET VRC=0.223715 $START $ range cbr $RAT $set bw=0.168 SET VSC=0.600546 $START $ range cbr $RAT $set bw=0.168 SET VSNC=0.00202 $START $ range cbr $RAT $set bw=0.168 SET KDET=0.02525 $START $ range cbr $RAT $set bw=0.168 SET dose=95.95 $START $ range cbr $set dose=95 SET ka=0.4545 $START $ range cbr $set ka=0.45 $START $ range cbr END

SET WESITG=.F., GRDCPL=.F., XINCPL=6.0, YINCPL=4.0 SET DEVPLT=1,CJVITG=.F.,HVDPRN=.T.1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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G I SI R 3. C SL

PROGRAM: GIsir.CSL 'Modified to describe off-gasing so we can refine gavage parms' 'Has provision for two/one compartment stomach comparisons. ' 'M.L. Gargas ' 'Revised 4/16/2001 and 8/31/01 by LM Sweeney' 'revised 12/17/2001, add suicide inhib rel. to tot enz' 'revised 6/25/2002 revise drinking water scenario' INITIAL 1.. FORMAT(/,' GI.CSL, Rev. 1/19/90 at 9:00 am ',/) WRITE(0,1) $ WRITE(7,1)
CONSTANT BW = 0.029 $'Body weight (kg) for MICE' CONSTANT QPC = 15. $'Alveolar ventilation rate (l/hr)' CONSTANT QCC = 15. $'Cardiac output (l/hr)'
'Flows to Tissue Compartments' CONSTANT QLC = 0.24 $'Fractional blood flow to liver' CONSTANT QFC = 0.02 $'Fractional blood flow to fat' CONSTANT QSC = 0.18 $'Fractional blood flow to slow' CONSTANT QSNC = 0.011 $'Fractional blood flow to spleen' CONSTANT QBRC = 0.02 $'Fractional blood flow to brain' QRC = 1.0 - (QFC + QSC + QLC + QBRC + QSNC) 'Volumes of Tissue Compartments' CONSTANT VLC = 0.04 $'Fraction liver tissue' CONSTANT VFC = 0.04 $'Fraction fat tissue' CONSTANT VRC = 0.05 $'Fraction Rapidly Perf tissue' CONSTANT VBRC = 0.0057 $'Fraction of brain' CONSTANT VSC = 0.5946 $'Fraction spt' CONSTANT VSNC = 0.0035 $'Fraction spleen'

'Partition Coefficients' CONSTANT PLA = 8.60 $'Liver/air partition coefficient' CONSTANT PFA = 263.0 $'Fat/air partition coefficient' CONSTANT PSA = 3.15 $'Muscle/air (Slow Perf) partition' CONSTANT PSNA = 53 $'spleen/air partition' CONSTANT PRA = 8.60 $'Richly perfused tissue/air partition' CONSTANT PBRA = 8.60 $'brain/air partition' CONSTANT PB = 10.8 $'Blood/air partition coefficient'
'Other Compound Specific Parameters' CONSTANT MW = 133.5 $'Molecular weight (g/mol)' CONSTANT VMAXC = 0.419 $'Maximum Velocity of Metabol.' CONSTANT VMAXRC = 0.419 $'Maximum Velocity of Metabol. in rpt' CONSTANT KM = 5.75 $'Michaelis Menten Constant' CONSTANT KFC = 0.0 $'First order rate constant' CONSTANT DOSE = 0.0 $'BOLUS GAVAGE dose (mg/kg/day)' CONSTANT ka = 0.6 $'Stomach Absorption Rate constant' CONSTANT kai = 0.0 $'Intestine Absorption Rate constant' CONSTANT ksi = 0.0 $'Stomach/Intestine Xfer Rate Constant' 'Timing commands' CONSTANT TSTOP = 6. $'Length of experiment (hrs)' CONSTANT POINTS = 72. $'Number of points in plot' CINT = TSTOP/POINTS1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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constant contdose=0 $'continuous oral dose (mg/kg/d)' Constant tdur =24 $'duration of continuous ingestion (hr)' CONSTANT TCHNG=120 $'allows exposure free weekends (hr)' array drtime(6) $'splits DW bolus into 6 boluses' array drpct(6) $'pct of dw ingestion at each bolus' constant drtime=6*0.0, drpct=6*0.0 constant dwdose=0 $'daily dose for drinking water mg/kg/d' constant per1 = 1.5 $'period during dark (hr)' constant dur1 = 0.75 $'duration of drinking during dark (hr)' constant per2=3 $'period during light (hr)' constant dur2=0.5 $'duration of drinking during light (hr)' constant Fnight=0.8 $'fraction of drinking during night'
'Constants associated with Off-Gasing Chamber' CONSTANT VCHC = 2.54 $'Volume of Chamber (liters)' CONSTANT FLOW = 7.2 $'Flow thru Chamber (liters/hr)' CONSTANT N = 1 $'Number of animals in chamber'
'Scaled parameters calculated in this section of Program' QC=QCC*BW**0.7 $ QP=QPC*BW**0.7 QL=QLC*QC $ QF=QFC*QC $ QS=QSC*QC $ QR=QRC*QC $QBR=QBRC*QC $QSN=QSNC*QC VL=VLC*BW $ VF=VFC*BW $ VS=VSC*BW $ VR=VRC*BW $ VBR=VBRC*BW $VSN=VSNC*BW PL=PLA/PB $ PR=PRA/PB $ PS=PSA/PB $ PF=PFA/PB $pbr=pbra/pb $PSN=PSNA/PB NEWDAY=0 INTEGER I I=1
VMAX = VMAXC*BW**0.7 $ DOSE2=0 $ KF=KFC/BW**0.3 VMAXR =VMAXRC*BW**0.7 VCH = VCHC-BW*N IF(VCH .LE. 0.0) WRITE(0,2) 2.. FORMAT(//,'Chamber Volume Less than ZERO!!!',//)
'parameters associated with suicide inact of enz and resynthesis' CONSTANT Kdes=0 $'rate of enzyme activity loss thru inhibition by ES mech' Constant kdte=0 $'rate of enzyme activity loss thru inhibition by TE mech' Constant kdfe=0 $'rate of enzyme activity loss thru inhibition by FE mech' Constant kdbi=0 $'rate of enzyme activity loss thru inhibition by BI mech' CONSTANT Kdet=0.025 $'normal turnover of enzyme'

END $'End of initial'

DYNAMIC ALGORITHM IALG = 2 $'Gear method for stiff systems' TERMT(T.GE.TSTOP) CR = AR/VR $ CS = AS/VS $ CF = AF/VF $ CL = AL/VL $ CBR = ABR/VBR CSN = ASN/VSN BODY = AL + AR + AS + AF + ABR + ASN + STOM + INT BURDEN = AM + BODY

DERIVATIVE
'ACH = Amount in Off Gasing Chamber (mg)' RACH = N*QP*(CX - CI) - CI*FLOW ACH = INTEG(RACH, 0)1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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CI = ACH/VCH RLOST = CI*FLOW LOST = INTEG(RLOST, 0.0) PPMOUT = CI*24450./MW

PROCEDURAL IF( T .LT. (drtime(I) + NEWDAY) ) GO TO SKIP2 DOSE2 = dose2 + dose*bw*drpct(I)*PULSE(0.0,168.0,tchng) I = I + 1 IF(I .LT. 7 ) GO TO SKIP2 I = I - 6 NEWDAY = NEWDAY + 24.0 SKIP2.. CONTINUE END $'of PROCEDURAL'

'Mass Balance for the Stomach' DWing = (dwdose/24)*bw*2*(PULSE(0.0,PER1,DUR1)*Fnight*per1/dur1* ... PULSE(0., 24., 12.)+ PULSE(0.0,PER2,DUR2)*(1-Fnight)*per2/dur2* ... (1-PULSE(0., 24., 12.))) RSTOM = -ka*STOM -ksi*STOM +contdose*bw/tdur*PULSE(0.0,24.0,TDUR) ... + DWing STOM = INTEG(RSTOM, 0)+dose2

'Mass Balance for the Intestine' RINT = +ksi*STOM -kai*INT INT = INTEG(RINT, 0.0) 'CA = Concentration in arterial blood (mg/l)' CA = (QC*CV+QP*CI)/(QC+(QP/PB)) AUCB = INTEG(CA,0.) CX = CA/PB
'AS = Amount in slowly perfused tissues (mg)' RAS = QS*(CA-CVS) AS = INTEG(RAS,0.) CVS = AS/(VS*PS)
'ASN = Amount in spleen (mg)' RASN = QSN*(CA-CVSN) ASN = INTEG(RASN,0.) CSN = ASN/VSN CVSN = CSN/PSN aucsn= integ(CSN,0.)
'AR = Amount in rapidly perfused tissues (mg)' RAR = QR*(CA-CVR) - RAMR AR = INTEG(RAR,0.) CVR = AR/(VR*PR)
'ABR = Amount in rapidly perfused tissues (mg)' RABR = QBR*(CA-CVBR) ABR = INTEG(RABR,0.) CBR = ABR/VBR CVBR = ABR/(VBR*PBR) aucbr = integ(cbr, 0.)1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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'AF = Amount in fat tissue (mg)' RAF = QF*(CA-CVF) AF = INTEG(RAF,0.) CVF = AF/(VF*PF)

'VMT = maximal rate of metabolism' RVMT = (VMAX-VMT)*KDET-KDES*RAML*RAML-KDTE*RAML*VMT ... -KDFE*RAML*VMT*KM/(KM+ CVL)-KDBI*RAML VMT = INTEG(RVMT, VMAX)
'AM = Amount metabolized (mg)' RAML = (VMT*CVL)/(KM+CVL) + KF*CVL*VL RAMR = (VMAXR*CVR)/(KM+CVR) RAM = RAML + RAMR AM = INTEG(RAM, 0.) AML = INTEG(RAML,0)
'AL = Amount in liver tissue (mg)' RAL = QL*(CA-CVL) - RAML + ka*STOM + kai*INT AL = INTEG(RAL,0.) CL = AL/VL AUCL = INTEG(CL,0.) CVL = AL/(VL*PL)
DM1 = AML/VL DM = DM1*1000/MW 'CV = Mixed venous blood concentration (mg/l)' CV = (QF*CVF + QL*CVL + QS*CVS + QR*CVR + QBR*CVBR +QSN*CVSN)/QC aucv= integ(cv, 0.)
END $'End of derivative' END $'End of dynamic' END $'End of program'1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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E X H S I R
. C MD

SET TITLE = 'EXHALED BREATH MODEL'
PREPAR T,CCH,CV,PPMOUT, AUCV, DM1, csn SET TJNITG = 1.0 $'Threshold for Jacobian Error Messages' SET TSMITG = .T. $'Two sided matrix evaluation for increased accur.' SET WESItG=.F. SET NSTP = 1000 $'Allow the integrator to take very small steps'
PROCED CCL2CCL $'1,1,2-TRICHLOROETHANE' SET TCHNG=6.,TSTOP=8.,N=5 SET MW=133.41 SET FCH=10.8,vmch=2.2,POINTS=2400,PLT=6 SET KFC=0.0,ABG0=0.0,KBG=0.0 END

proced minh1000
mouse ccl2ccl set conc=985.2, tchng=6, tstop=15, N=5 set bw=0.0194 end
proced minh500
mouse ccl2ccl set conc=492.6, TCHNG=4, N=5 set bw=0.0205 end
proced minh250
mouse ccl2ccl set conc=248.3, tchng=6, tstop=11, N=5 set bw=0.0196 end

PROCED M100 CCL2CCL MOUSE SET CONC=100, N=0, BW=0.0228, VMCH=2200, FCH=10800 SET TEXPOS=6, TCHNG=170, TSTOP=168 END
DATA M100 (T, CV) 4.07 0.608 6.1 0.951 6.3 0.960 8 0.022 52.07 1.84 54.07 1.73 54.3 0.43 56 0.007 100.07 1.981, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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102.07 2.16 102.3 0.592 104 0.055 END

PROCED rat $'revised by LMS 5/1/01, 041702, 071803' 'note addition of brain, spleen, and Vmaxrc' 'values from brown et al., 1997' SET TITLE = ' 1,1,2-TCE RAT' SET VMAXC=10.2,VMAXRC=0,KM=0.54,KFC=0.0, kdte=0, kdbi=0 SET BW=0.25,QPC=13,QCC=13 SET QLC=0.183,QFC=0.07, qbrc=0.02, qsc=0.336,QSNC=0.011 SET VLC=0.0366, VFC=0.0896, vbrc=0.0057, vsc=0.5946, VRC=.2215 SET VSNC=0.002 SET PB=58.,PFA=1438,PLA=73,PRA=60.7,PSA=23,PBRA=56.1 SET PSNA=43 END $'of proced rat'

PROCED R100 CCL2CCL RAT SET CONC=100, N=1, BW=0.160, VMCH=2200, FCH=10800 END
DATA R100DATA (T, CV) 4.08 1.73 6.06 1.88 6.3 0.78 8.0 0.15 END
PROCED MOUSE $'PHYSIOL FROM BROWN ET AL 1997 last rev 050902' SET TITLE = ' 1,1,2-TCE FEMALE MOUSE' SET MW=133.41,PB=71.1,PFA=1438,PLA=73,PRA=60.7,PSA=23,PBRA=56.1 SET PSNA=43 SET VMAXC=17.3,VMAXRC=0,KM=0.35,KFC=0.0 SET BW=0.025,QPC=14,QCC=14 SET QLC=0.161,QBRC=0.033,QFC=0.07,QSC=0.217, QSNC=0.011 SET VLC=0.0549,VBRC=0.0165,VFC=0.07,VRC=0.1958,VSC=0.5493 SET VSNC=0.0035 SET KDET=0.025, KDbi=0.0914 END $'of proced mouse'
PROCED MMOUSE $'PHYSIOL FROM BROWN ET AL 1997 last rev 050902' SET TITLE = ' 1,1,2-TCE MALE MOUSE' SET MW=133.41,PB=71.1,PFA=1438,PLA=73,PRA=60.7,PSA=23,PBRA=56.1 SET PSNA=43 SET VMAXC=17.3,VMAXRC=0,KM=0.35,KFC=0.0 SET BW=0.025,QPC=14,QCC=14 SET QLC=0.161,QBRC=0.033,QFC=0.07,QSC=0.217, QSNC=0.011 SET VLC=0.0549,VBRC=0.0165,VFC=0.07,VRC=0.1958,VSC=0.5493 SET VSNC=0.0035 SET KDET=0.025, KDBI=0.0 END $'of proced Mmouse'1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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PROCED rat SET TITLE = ' 1,1,2-TCE RAT' SET MW=133.41,PB=58.,PFA=1438,PLA=73,PRA=60.7,PSA=23,PBRA=56.1 SET PSNA=43 SET VMAXC=10.2,VMAXRC=0,KM=0.54,KFC=0.0 SET BW=0.25,QPC=13,QCC=13 SET QLC=0.183,QBRC=0.02,QFC=0.07,QSC=0.336,QSNC=0.011 SET VLC=0.0366,VBRC=0.0057,VFC=0.0896,VRC=0.2215,VSC=0.5946 SET VSNC=0.002 SET KDET=0.025, KDBI=0. END $'of proced rat'

PROCED FMSA1 SET N=0 MOUSE $START $ D AUCV, DM1 SET PB=71.811 $START $ D AUCV, DM1 $MOUSE SET PFA=1452.38 $START $ D AUCV, DM1 $MOUSE SET PLA=73.73 $START $ D AUCV, DM1 $MOUSE SET PRA=61.307 $START $ D AUCV, DM1 $MOUSE SET PSA=23.23 $START $ D AUCV, DM1 $MOUSE SET PBRA=56.661 $START $ D AUCV, DM1 $MOUSE SET PSNA=43.43 $START $ D AUCV, DM1 $MOUSE SET VMAXC=17.473 $START $ D AUCV, DM1 $MOUSE SET KM=0.3535 $START $ D AUCV, DM1 $MOUSE SET BW=0.02525 $START $ D AUCV, DM1 $MOUSE SET QPC=14.14 $START $ D AUCV, DM1 $MOUSE SET QCC=14.14 $START $ D AUCV, DM1 $MOUSE SET QLC=0.16261 $START $ D AUCV, DM1 $MOUSE SET QBRC=0.03333 $START $ D AUCV, DM1 $MOUSE SET QFC=0.0707 $START $ D AUCV, DM1 $MOUSE SET QSC=0.21917 $START $ D AUCV, DM1 $MOUSE SET QSNC=0.01111 $START $ D AUCV, DM1 $MOUSE SET VLC=0.055449 $START $ D AUCV, DM1 $MOUSE SET VBRC=0.016665 $START $ D AUCV, DM1 $MOUSE SET VFC=0.0707 $START $ D AUCV, DM1 $MOUSE SET VRC=0.197758 $START $ D AUCV, DM1 $MOUSE SET VSC=0.554793 $START $ D AUCV, DM1 $MOUSE SET VSNC=0.003535 $START $ D AUCV, DM1 $MOUSE SET KDET=0.02525 $START $ D AUCV, DM1 $MOUSE SET KDBI=0.092314 $START $ D AUCV, DM1 $MOUSE END

PROCED FMSA2 SET N=0 MOUSE $START $ range cv SET PB=71.811 $START $ range cv $MOUSE SET PFA=1452.38 $START $ range cv $MOUSE SET PLA=73.73 $START $ range cv $MOUSE SET PRA=61.307 $START $ range cv $MOUSE SET PSA=23.23 $START $ range cv $MOUSE SET PBRA=56.661 $START $ range cv $MOUSE SET PSNA=43.43 $START $ range cv $MOUSE SET VMAXC=17.473 $START $ range cv $MOUSE SET KM=0.3535 $START $ range cv $MOUSE SET BW=0.02525 $START $ range cv $MOUSE SET QPC=14.14 $START $ range cv $MOUSE SET QCC=14.14 $START $ range cv $MOUSE1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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SET QLC=0.16261 $START $ range cv $MOUSE SET QBRC=0.03333 $START $ range cv $MOUSE SET QFC=0.0707 $START $ range cv $MOUSE SET QSC=0.21917 $START $ range cv $MOUSE SET QSNC=0.01111 $START $ range cv $MOUSE SET VLC=0.055449 $START $ range cv $MOUSE SET VBRC=0.016665 $START $ range cv $MOUSE SET VFC=0.0707 $START $ range cv $MOUSE SET VRC=0.197758 $START $ range cv $MOUSE SET VSC=0.554793 $START $ range cv $MOUSE SET VSNC=0.003535 $START $ range cv $MOUSE SET KDET=0.02525 $START $ range cv $MOUSE SET KDBI=0.092314 $START $ range cv $MOUSE END

PROCED FMSA3 SET N=0 MOUSE $START $ D aucsn, DM1 SET PB=71.811 $START $ D aucsn, DM1 $MOUSE SET PFA=1452.38 $START $ D aucsn, DM1 $MOUSE SET PLA=73.73 $START $ D aucsn, DM1 $MOUSE SET PRA=61.307 $START $ D aucsn, DM1 $MOUSE SET PSA=23.23 $START $ D aucsn, DM1 $MOUSE SET PBRA=56.661 $START $ D aucsn, DM1 $MOUSE SET PSNA=43.43 $START $ D aucsn, DM1 $MOUSE SET VMAXC=17.473 $START $ D aucsn, DM1 $MOUSE SET KM=0.3535 $START $ D aucsn, DM1 $MOUSE SET BW=0.02525 $START $ D aucsn, DM1 $MOUSE SET QPC=14.14 $START $ D aucsn, DM1 $MOUSE SET QCC=14.14 $START $ D aucsn, DM1 $MOUSE SET QLC=0.16261 $START $ D aucsn, DM1 $MOUSE SET QBRC=0.03333 $START $ D aucsn, DM1 $MOUSE SET QFC=0.0707 $START $ D aucsn, DM1 $MOUSE SET QSC=0.21917 $START $ D aucsn, DM1 $MOUSE SET QSNC=0.01111 $START $ D aucsn, DM1 $MOUSE SET VLC=0.055449 $START $ D aucsn, DM1 $MOUSE SET VBRC=0.016665 $START $ D aucsn, DM1 $MOUSE SET VFC=0.0707 $START $ D aucsn, DM1 $MOUSE SET VRC=0.197758 $START $ D aucsn, DM1 $MOUSE SET VSC=0.554793 $START $ D aucsn, DM1 $MOUSE SET VSNC=0.003535 $START $ D aucsn, DM1 $MOUSE SET KDET=0.02525 $START $ D aucsn, DM1 $MOUSE SET KDBI=0.092314 $START $ D aucsn, DM1 $MOUSE END
proced FEMmusSA set hvdprn=.f. CCL2CCL SET VMCH=2200, FCH=10800 SET TEXPOS=6, TCHNG=170, TSTOP=168 set CONC= 100 fmsa1 SET CONC=101 $START $ D AUCV, DM1 $set CONC=100 $START $ D AUCV, DM1 fmsa2 SET conc=101 $START $ range cv $set CONC=100 $START $ range cv1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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END

PROCED MMSA1 SET N=0 MMOUSE $START $ D AUCV, DM1 SET PB=71.811 $START $ D AUCV, DM1 $MMOUSE SET PFA=1452.38 $START $ D AUCV, DM1 $MMOUSE SET PLA=73.73 $START $ D AUCV, DM1 $MMOUSE SET PRA=61.307 $START $ D AUCV, DM1 $MMOUSE SET PSA=23.23 $START $ D AUCV, DM1 $MMOUSE SET PBRA=56.661 $START $ D AUCV, DM1 $MMOUSE SET PSNA=43.43 $START $ D AUCV, DM1 $MMOUSE SET VMAXC=17.473 $START $ D AUCV, DM1 $MMOUSE SET KM=0.3535 $START $ D AUCV, DM1 $MMOUSE SET BW=0.02525 $START $ D AUCV, DM1 $MMOUSE SET QPC=14.14 $START $ D AUCV, DM1 $MMOUSE SET QCC=14.14 $START $ D AUCV, DM1 $MMOUSE SET QLC=0.16261 $START $ D AUCV, DM1 $MMOUSE SET QBRC=0.03333 $START $ D AUCV, DM1 $MMOUSE SET QFC=0.0707 $START $ D AUCV, DM1 $MMOUSE SET QSC=0.21917 $START $ D AUCV, DM1 $MMOUSE SET QSNC=0.01111 $START $ D AUCV, DM1 $MMOUSE SET VLC=0.055449 $START $ D AUCV, DM1 $MMOUSE SET VBRC=0.016665 $START $ D AUCV, DM1 $MMOUSE SET VFC=0.0707 $START $ D AUCV, DM1 $MMOUSE SET VRC=0.197758 $START $ D AUCV, DM1 $MMOUSE SET VSC=0.554793 $START $ D AUCV, DM1 $MMOUSE SET VSNC=0.003535 $START $ D AUCV, DM1 $MMOUSE SET KDET=0.02525 $START $ D AUCV, DM1 $MMOUSE END

PROCED MMSA2 SET N=0 MMOUSE $START $ range cv SET PB=71.811 $START $ range cv $MMOUSE SET PFA=1452.38 $START $ range cv $MMOUSE SET PLA=73.73 $START $ range cv $MMOUSE SET PRA=61.307 $START $ range cv $MMOUSE SET PSA=23.23 $START $ range cv $MMOUSE SET PBRA=56.661 $START $ range cv $MMOUSE SET PSNA=43.43 $START $ range cv $MMOUSE SET VMAXC=17.473 $START $ range cv $MMOUSE SET KM=0.3535 $START $ range cv $MMOUSE SET BW=0.02525 $START $ range cv $MMOUSE SET QPC=14.14 $START $ range cv $MMOUSE SET QCC=14.14 $START $ range cv $MMOUSE SET QLC=0.16261 $START $ range cv $MMOUSE SET QBRC=0.03333 $START $ range cv $MMOUSE SET QFC=0.0707 $START $ range cv $MMOUSE SET QSC=0.21917 $START $ range cv $MMOUSE SET QSNC=0.01111 $START $ range cv $MMOUSE SET VLC=0.055449 $START $ range cv $MMOUSE SET VBRC=0.016665 $START $ range cv $MMOUSE SET VFC=0.0707 $START $ range cv $MMOUSE SET VRC=0.197758 $START $ range cv $MMOUSE SET VSC=0.554793 $START $ range cv $MMOUSE1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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SET VSNC=0.003535 $START $ range cv $MMOUSE SET KDET=0.02525 $START $ range cv $MMOUSE END
proced MALEmusSA set hvdprn=.f. CCL2CCL SET VMCH=2200, FCH=10800 SET TEXPOS=6, TCHNG=170, TSTOP=168 set CONC= 100 Mmsa1 SET CONC=101 $START $ D AUCV, DM1 $set CONC=100 $START $ D AUCV, DM1 Mmsa2 SET CONC=101 $START $ range cv $set CONC=100 $START $ range cv END
proced cancerSA set hvdprn=.f. CCL2CCL SET VMCH=2200, FCH=10800 SET TEXPOS=24, TCHNG=170, TSTOP=168, week=168 set CONC= 27 fmsa1 SET CONC=27.27 $START $ D AUCV, DM1 $set CONC=27 $START $ D AUCV, DM1 END

PROCED RSA1 SET N=0 RAT $START $ D AUCV, DM1 SET PB=58.58 $START $ D AUCV, DM1 $RAT SET PFA=1452.38 $START $ D AUCV, DM1 $RAT SET PLA=73.73 $START $ D AUCV, DM1 $RAT SET PRA=61.307 $START $ D AUCV, DM1 $RAT SET PSA=23.23 $START $ D AUCV, DM1 $RAT SET PBRA=56.661 $START $ D AUCV, DM1 $RAT SET PSNA=43.43 $START $ D AUCV, DM1 $RAT SET VMAXC=10.302 $START $ D AUCV, DM1 $RAT SET KM=0.5454 $START $ D AUCV, DM1 $RAT SET BW=0.2525 $START $ D AUCV, DM1 $RAT SET QPC=13.13 $START $ D AUCV, DM1 $RAT SET QCC=13.13 $START $ D AUCV, DM1 $RAT SET QLC=0.18483 $START $ D AUCV, DM1 $RAT SET QBRC=0.0202 $START $ D AUCV, DM1 $RAT SET QFC=0.0707 $START $ D AUCV, DM1 $RAT SET QSC=0.33936 $START $ D AUCV, DM1 $RAT SET QSNC=0.01111 $START $ D AUCV, DM1 $RAT SET VLC=0.036966 $START $ D AUCV, DM1 $RAT SET VBRC=0.005757 $START $ D AUCV, DM1 $RAT SET VFC=0.090496 $START $ D AUCV, DM1 $RAT SET VRC=0.223715 $START $ D AUCV, DM1 $RAT SET VSC=0.600546 $START $ D AUCV, DM1 $RAT SET VSNC=0.00202 $START $ D AUCV, DM1 $RAT SET KDET=0.02525 $START $ D AUCV, DM1 $RAT END1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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PROCED RSA2 SET N=0 RAT $START $ range cv SET PB=58.58 $START $ range cv $RAT SET PFA=1452.38 $START $ range cv $RAT SET PLA=73.73 $START $ range cv $RAT SET PRA=61.307 $START $ range cv $RAT SET PSA=23.23 $START $ range cv $RAT SET PBRA=56.661 $START $ range cv $RAT SET PSNA=43.43 $START $ range cv $RAT SET VMAXC=10.302 $START $ range cv $RAT SET KM=0.5454 $START $ range cv $RAT SET BW=0.2525 $START $ range cv $RAT SET QPC=13.13 $START $ range cv $RAT SET QCC=13.13 $START $ range cv $RAT SET QLC=0.18483 $START $ range cv $RAT SET QBRC=0.0202 $START $ range cv $RAT SET QFC=0.0707 $START $ range cv $RAT SET QSC=0.33936 $START $ range cv $RAT SET QSNC=0.01111 $START $ range cv $RAT SET VLC=0.036966 $START $ range cv $RAT SET VBRC=0.005757 $START $ range cv $RAT SET VFC=0.090496 $START $ range cv $RAT SET VRC=0.223715 $START $ range cv $RAT SET VSC=0.600546 $START $ range cv $RAT SET VSNC=0.00202 $START $ range cv $RAT SET KDET=0.02525 $START $ range cv $RAT END
proced RATSA set hvdprn=.f. CCL2CCL SET VMCH=2200, FCH=10800 SET TEXPOS=6, TCHNG=170, TSTOP=168 set CONC= 100 Rsa1 SET CONC=101 $START $ D AUCV, DM1 $set CONC=100 $START $ D AUCV, DM1 Rsa2 SET CONC=101 $START $ range cv $set CONC=100 $START $ range cv END
proced inhmet set conc= 0.015 $start $d conc, aucv, dm1 set conc= 0.02 $start $d conc, aucv, dm1 set conc= 0.025 $start $d conc, aucv, dm1 set conc= 0.03 $start $d conc, aucv, dm1 set conc= 0.035 $start $d conc, aucv, dm1 set conc= 0.04 $start $d conc, aucv, dm1 set conc= 0.045 $start $d conc, aucv, dm1 set conc= 0.05 $start $d conc, aucv, dm1 set conc= 0.055 $start $d conc, aucv, dm1 set conc= 0.06 $start $d conc, aucv, dm1 set conc= 0.065 $start $d conc, aucv, dm1 set conc= 0.07 $start $d conc, aucv, dm1 set conc= 0.075 $start $d conc, aucv, dm11, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set conc= 0.08 $start $d conc, aucv, dm1 set conc= 0.085 $start $d conc, aucv, dm1 set conc= 0.09 $start $d conc, aucv, dm1 set conc= 0.095 $start $d conc, aucv, dm1 set conc= 0.1 $start $d conc, aucv, dm1 set conc= 0.15 $start $d conc, aucv, dm1 set conc= 0.2 $start $d conc, aucv, dm1 set conc= 0.25 $start $d conc, aucv, dm1 set conc= 0.3 $start $d conc, aucv, dm1 set conc= 0.35 $start $d conc, aucv, dm1 set conc= 0.4 $start $d conc, aucv, dm1 set conc= 0.45 $start $d conc, aucv, dm1 set conc= 0.5 $start $d conc, aucv, dm1 set conc= 0.55 $start $d conc, aucv, dm1 set conc= 0.6 $start $d conc, aucv, dm1 set conc= 0.65 $start $d conc, aucv, dm1 set conc= 0.7 $start $d conc, aucv, dm1 set conc= 0.75 $start $d conc, aucv, dm1 set conc= 0.8 $start $d conc, aucv, dm1 set conc= 0.85 $start $d conc, aucv, dm1 set conc= 0.9 $start $d conc, aucv, dm1 set conc= 0.95 $start $d conc, aucv, dm1 set conc= 1 $start $d conc, aucv, dm1 set conc= 1.5 $start $d conc, aucv, dm1 set conc= 2 $start $d conc, aucv, dm1 set conc= 2.5 $start $d conc, aucv, dm1 set conc= 3 $start $d conc, aucv, dm1 set conc= 3.5 $start $d conc, aucv, dm1 set conc= 4 $start $d conc, aucv, dm1 set conc= 4.5 $start $d conc, aucv, dm1 set conc= 5 $start $d conc, aucv, dm1 set conc= 5.5 $start $d conc, aucv, dm1 set conc= 6 $start $d conc, aucv, dm1 set conc= 6.5 $start $d conc, aucv, dm1 set conc= 7 $start $d conc, aucv, dm1 set conc= 7.5 $start $d conc, aucv, dm1 set conc= 8 $start $d conc, aucv, dm1 set conc= 8.5 $start $d conc, aucv, dm1 set conc= 9 $start $d conc, aucv, dm1 set conc= 9.5 $start $d conc, aucv, dm1 set conc= 10 $start $d conc, aucv, dm1 set conc= 15 $start $d conc, aucv, dm1 set conc= 20 $start $d conc, aucv, dm1 set conc= 25 $start $d conc, aucv, dm1 set conc= 30 $start $d conc, aucv, dm1 set conc= 35 $start $d conc, aucv, dm1 set conc= 40 $start $d conc, aucv, dm1 set conc= 45 $start $d conc, aucv, dm1 set conc= 50 $start $d conc, aucv, dm1 set conc= 55 $start $d conc, aucv, dm1 set conc= 60 $start $d conc, aucv, dm1 set conc= 65 $start $d conc, aucv, dm1 set conc= 70 $start $d conc, aucv, dm1 set conc= 75 $start $d conc, aucv, dm1 set conc= 80 $start $d conc, aucv, dm1 set conc= 85 $start $d conc, aucv, dm1 set conc= 90 $start $d conc, aucv, dm11, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set conc= 95 $start $d conc, aucv, dm1 set conc= 100 $start $d conc, aucv, dm1 set conc= 110 $start $d conc, aucv, dm1 set conc= 120 $start $d conc, aucv, dm1 set conc= 130 $start $d conc, aucv, dm1 set conc= 140 $start $d conc, aucv, dm1 set conc= 150 $start $d conc, aucv, dm1 set conc= 160 $start $d conc, aucv, dm1 set conc= 170 $start $d conc, aucv, dm1 set conc= 180 $start $d conc, aucv, dm1 set conc= 190 $start $d conc, aucv, dm1 set conc= 200 $start $d conc, aucv, dm1 set conc= 210 $start $d conc, aucv, dm1 set conc= 220 $start $d conc, aucv, dm1 set conc= 230 $start $d conc, aucv, dm1 set conc= 240 $start $d conc, aucv, dm1 set conc= 250 $start $d conc, aucv, dm1 set conc= 260 $start $d conc, aucv, dm1

set conc= 0.015 $start $range cv set conc= 0.02 $start $range cv set conc= 0.025 $start $range cv set conc= 0.03 $start $range cv set conc= 0.035 $start $range cv set conc= 0.04 $start $range cv set conc= 0.045 $start $range cv set conc= 0.05 $start $range cv set conc= 0.055 $start $range cv set conc= 0.06 $start $range cv set conc= 0.065 $start $range cv set conc= 0.07 $start $range cv set conc= 0.075 $start $range cv set conc= 0.08 $start $range cv set conc= 0.085 $start $range cv set conc= 0.09 $start $range cv set conc= 0.095 $start $range cv set conc= 0.1 $start $range cv set conc= 0.15 $start $range cv set conc= 0.2 $start $range cv set conc= 0.25 $start $range cv set conc= 0.3 $start $range cv set conc= 0.35 $start $range cv set conc= 0.4 $start $range cv set conc= 0.45 $start $range cv set conc= 0.5 $start $range cv set conc= 0.55 $start $range cv set conc= 0.6 $start $range cv set conc= 0.65 $start $range cv set conc= 0.7 $start $range cv set conc= 0.75 $start $range cv set conc= 0.8 $start $range cv set conc= 0.85 $start $range cv set conc= 0.9 $start $range cv set conc= 0.95 $start $range cv set conc= 1 $start $range cv set conc= 1.5 $start $range cv set conc= 2 $start $range cv1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set conc= 2.5 $start $range cv set conc= 3 $start $range cv set conc= 3.5 $start $range cv set conc= 4 $start $range cv set conc= 4.5 $start $range cv set conc= 5 $start $range cv set conc= 5.5 $start $range cv set conc= 6 $start $range cv set conc= 6.5 $start $range cv set conc= 7 $start $range cv set conc= 7.5 $start $range cv set conc= 8 $start $range cv set conc= 8.5 $start $range cv set conc= 9 $start $range cv set conc= 9.5 $start $range cv set conc= 10 $start $range cv set conc= 15 $start $range cv set conc= 20 $start $range cv set conc= 25 $start $range cv set conc= 30 $start $range cv set conc= 35 $start $range cv set conc= 40 $start $range cv set conc= 45 $start $range cv set conc= 50 $start $range cv set conc= 55 $start $range cv set conc= 60 $start $range cv set conc= 65 $start $range cv set conc= 70 $start $range cv set conc= 75 $start $range cv set conc= 80 $start $range cv set conc= 85 $start $range cv set conc= 90 $start $range cv set conc= 95 $start $range cv set conc= 100 $start $range cv set conc= 110 $start $range cv set conc= 120 $start $range cv set conc= 130 $start $range cv set conc= 140 $start $range cv set conc= 150 $start $range cv set conc= 160 $start $range cv set conc= 170 $start $range cv set conc= 180 $start $range cv set conc= 190 $start $range cv set conc= 200 $start $range cv set conc= 210 $start $range cv set conc= 220 $start $range cv set conc= 230 $start $range cv set conc= 240 $start $range cv set conc= 250 $start $range cv set conc= 260 $start $range cv end
proced inhal set hvdprn=.f. CCL2CCL SET VMCH=2200, FCH=10800 SET TEXPOS=24, TCHNG=170, TSTOP=168, week=1681, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

Page 39

set n=0
mouse inhmet
mmouse inhmet end
proced cancer prepar 'all set hvdprn=.f. CCL2CCL SET VMCH=2200, FCH=10800 SET TEXPOS=24, TCHNG=170, TSTOP=168, week=168 set n=0 end
proced inhmet2 set conc= 0.015 $start $d aucl set conc= 0.02 $start $d aucl set conc= 0.025 $start $d aucl set conc= 0.03 $start $d aucl set conc= 0.035 $start $d aucl set conc= 0.04 $start $d aucl set conc= 0.045 $start $d aucl set conc= 0.05 $start $d aucl set conc= 0.055 $start $d aucl set conc= 0.06 $start $d aucl set conc= 0.065 $start $d aucl set conc= 0.07 $start $d aucl set conc= 0.075 $start $d aucl set conc= 0.08 $start $d aucl set conc= 0.085 $start $d aucl set conc= 0.09 $start $d aucl set conc= 0.095 $start $d aucl set conc= 0.1 $start $d aucl set conc= 0.15 $start $d aucl set conc= 0.2 $start $d aucl set conc= 0.25 $start $d aucl set conc= 0.3 $start $d aucl set conc= 0.35 $start $d aucl set conc= 0.4 $start $d aucl set conc= 0.45 $start $d aucl set conc= 0.5 $start $d aucl set conc= 0.55 $start $d aucl set conc= 0.6 $start $d aucl set conc= 0.65 $start $d aucl set conc= 0.7 $start $d aucl set conc= 0.75 $start $d aucl set conc= 0.8 $start $d aucl set conc= 0.85 $start $d aucl set conc= 0.9 $start $d aucl set conc= 0.95 $start $d aucl set conc= 1 $start $d aucl set conc= 1.5 $start $d aucl set conc= 2 $start $d aucl set conc= 2.5 $start $d aucl set conc= 3 $start $d aucl1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set conc= 3.5 $start $d aucl set conc= 4 $start $d aucl set conc= 4.5 $start $d aucl set conc= 5 $start $d aucl set conc= 5.5 $start $d aucl set conc= 6 $start $d aucl set conc= 6.5 $start $d aucl set conc= 7 $start $d aucl set conc= 7.5 $start $d aucl set conc= 8 $start $d aucl set conc= 8.5 $start $d aucl set conc= 9 $start $d aucl set conc= 9.5 $start $d aucl set conc= 10 $start $d aucl set conc= 15 $start $d aucl set conc= 20 $start $d aucl set conc= 25 $start $d aucl set conc= 30 $start $d aucl set conc= 35 $start $d aucl set conc= 40 $start $d aucl set conc= 45 $start $d aucl set conc= 50 $start $d aucl set conc= 55 $start $d aucl set conc= 60 $start $d aucl set conc= 65 $start $d aucl set conc= 70 $start $d aucl set conc= 75 $start $d aucl set conc= 80 $start $d aucl set conc= 85 $start $d aucl set conc= 90 $start $d aucl set conc= 95 $start $d aucl set conc= 100 $start $d aucl set conc= 110 $start $d aucl set conc= 120 $start $d aucl set conc= 130 $start $d aucl set conc= 140 $start $d aucl set conc= 150 $start $d aucl set conc= 160 $start $d aucl set conc= 170 $start $d aucl set conc= 180 $start $d aucl set conc= 190 $start $d aucl set conc= 200 $start $d aucl

set conc= 0.015 $start $range cl set conc= 0.02 $start $range cl set conc= 0.025 $start $range cl set conc= 0.03 $start $range cl set conc= 0.035 $start $range cl set conc= 0.04 $start $range cl set conc= 0.045 $start $range cl set conc= 0.05 $start $range cl set conc= 0.055 $start $range cl set conc= 0.06 $start $range cl set conc= 0.065 $start $range cl set conc= 0.07 $start $range cl set conc= 0.075 $start $range cl set conc= 0.08 $start $range cl1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set conc= 0.085 $start $range cl set conc= 0.09 $start $range cl set conc= 0.095 $start $range cl set conc= 0.1 $start $range cl set conc= 0.15 $start $range cl set conc= 0.2 $start $range cl set conc= 0.25 $start $range cl set conc= 0.3 $start $range cl set conc= 0.35 $start $range cl set conc= 0.4 $start $range cl set conc= 0.45 $start $range cl set conc= 0.5 $start $range cl set conc= 0.55 $start $range cl set conc= 0.6 $start $range cl set conc= 0.65 $start $range cl set conc= 0.7 $start $range cl set conc= 0.75 $start $range cl set conc= 0.8 $start $range cl set conc= 0.85 $start $range cl set conc= 0.9 $start $range cl set conc= 0.95 $start $range cl set conc= 1 $start $range cl set conc= 1.5 $start $range cl set conc= 2 $start $range cl set conc= 2.5 $start $range cl set conc= 3 $start $range cl set conc= 3.5 $start $range cl set conc= 4 $start $range cl set conc= 4.5 $start $range cl set conc= 5 $start $range cl set conc= 5.5 $start $range cl set conc= 6 $start $range cl set conc= 6.5 $start $range cl set conc= 7 $start $range cl set conc= 7.5 $start $range cl set conc= 8 $start $range cl set conc= 8.5 $start $range cl set conc= 9 $start $range cl set conc= 9.5 $start $range cl set conc= 10 $start $range cl set conc= 15 $start $range cl set conc= 20 $start $range cl set conc= 25 $start $range cl set conc= 30 $start $range cl set conc= 35 $start $range cl set conc= 40 $start $range cl set conc= 45 $start $range cl set conc= 50 $start $range cl set conc= 55 $start $range cl set conc= 60 $start $range cl set conc= 65 $start $range cl set conc= 70 $start $range cl set conc= 75 $start $range cl set conc= 80 $start $range cl set conc= 85 $start $range cl set conc= 90 $start $range cl set conc= 95 $start $range cl1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set conc= 100 $start $range cl set conc= 110 $start $range cl set conc= 120 $start $range cl set conc= 130 $start $range cl set conc= 140 $start $range cl set conc= 150 $start $range cl set conc= 160 $start $range cl set conc= 170 $start $range cl set conc= 180 $start $range cl set conc= 190 $start $range cl set conc= 200 $start $range cl end
proced inhal2 set hvdprn=.f. CCL2CCL SET VMCH=2200, FCH=10800 SET TEXPOS=24, TCHNG=170, TSTOP=168, week=168 set n=0
mouse inhmet2
mmouse inhmet2 end
proced inhmet3 set conc= 0.015 $start $d aucsn set conc= 0.02 $start $d aucsn set conc= 0.025 $start $d aucsn set conc= 0.03 $start $d aucsn set conc= 0.035 $start $d aucsn set conc= 0.04 $start $d aucsn set conc= 0.045 $start $d aucsn set conc= 0.05 $start $d aucsn set conc= 0.055 $start $d aucsn set conc= 0.06 $start $d aucsn set conc= 0.065 $start $d aucsn set conc= 0.07 $start $d aucsn set conc= 0.075 $start $d aucsn set conc= 0.08 $start $d aucsn set conc= 0.085 $start $d aucsn set conc= 0.09 $start $d aucsn set conc= 0.095 $start $d aucsn set conc= 0.1 $start $d aucsn set conc= 0.15 $start $d aucsn set conc= 0.2 $start $d aucsn set conc= 0.25 $start $d aucsn set conc= 0.3 $start $d aucsn set conc= 0.35 $start $d aucsn set conc= 0.4 $start $d aucsn set conc= 0.45 $start $d aucsn set conc= 0.5 $start $d aucsn set conc= 0.55 $start $d aucsn set conc= 0.6 $start $d aucsn set conc= 0.65 $start $d aucsn set conc= 0.7 $start $d aucsn set conc= 0.75 $start $d aucsn1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set conc= 0.8 $start $d aucsn set conc= 0.85 $start $d aucsn set conc= 0.9 $start $d aucsn set conc= 0.95 $start $d aucsn set conc= 1 $start $d aucsn set conc= 1.5 $start $d aucsn set conc= 2 $start $d aucsn set conc= 2.5 $start $d aucsn set conc= 3 $start $d aucsn set conc= 3.5 $start $d aucsn set conc= 4 $start $d aucsn set conc= 4.5 $start $d aucsn set conc= 5 $start $d aucsn set conc= 5.5 $start $d aucsn set conc= 6 $start $d aucsn set conc= 6.5 $start $d aucsn set conc= 7 $start $d aucsn set conc= 7.5 $start $d aucsn set conc= 8 $start $d aucsn set conc= 8.5 $start $d aucsn set conc= 9 $start $d aucsn set conc= 9.5 $start $d aucsn set conc= 10 $start $d aucsn set conc= 15 $start $d aucsn set conc= 20 $start $d aucsn set conc= 25 $start $d aucsn set conc= 30 $start $d aucsn set conc= 35 $start $d aucsn set conc= 40 $start $d aucsn set conc= 45 $start $d aucsn set conc= 50 $start $d aucsn set conc= 55 $start $d aucsn set conc= 60 $start $d aucsn set conc= 65 $start $d aucsn set conc= 70 $start $d aucsn set conc= 75 $start $d aucsn set conc= 80 $start $d aucsn set conc= 85 $start $d aucsn set conc= 90 $start $d aucsn set conc= 95 $start $d aucsn set conc= 100 $start $d aucsn set conc= 110 $start $d aucsn set conc= 120 $start $d aucsn set conc= 130 $start $d aucsn set conc= 140 $start $d aucsn set conc= 150 $start $d aucsn set conc= 160 $start $d aucsn set conc= 170 $start $d aucsn set conc= 180 $start $d aucsn set conc= 190 $start $d aucsn set conc= 200 $start $d aucsn

set conc= 0.015 $start $range csn set conc= 0.02 $start $range csn set conc= 0.025 $start $range csn set conc= 0.03 $start $range csn set conc= 0.035 $start $range csn1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set conc= 0.04 $start $range csn set conc= 0.045 $start $range csn set conc= 0.05 $start $range csn set conc= 0.055 $start $range csn set conc= 0.06 $start $range csn set conc= 0.065 $start $range csn set conc= 0.07 $start $range csn set conc= 0.075 $start $range csn set conc= 0.08 $start $range csn set conc= 0.085 $start $range csn set conc= 0.09 $start $range csn set conc= 0.095 $start $range csn set conc= 0.1 $start $range csn set conc= 0.15 $start $range csn set conc= 0.2 $start $range csn set conc= 0.25 $start $range csn set conc= 0.3 $start $range csn set conc= 0.35 $start $range csn set conc= 0.4 $start $range csn set conc= 0.45 $start $range csn set conc= 0.5 $start $range csn set conc= 0.55 $start $range csn set conc= 0.6 $start $range csn set conc= 0.65 $start $range csn set conc= 0.7 $start $range csn set conc= 0.75 $start $range csn set conc= 0.8 $start $range csn set conc= 0.85 $start $range csn set conc= 0.9 $start $range csn set conc= 0.95 $start $range csn set conc= 1 $start $range csn set conc= 1.5 $start $range csn set conc= 2 $start $range csn set conc= 2.5 $start $range csn set conc= 3 $start $range csn set conc= 3.5 $start $range csn set conc= 4 $start $range csn set conc= 4.5 $start $range csn set conc= 5 $start $range csn set conc= 5.5 $start $range csn set conc= 6 $start $range csn set conc= 6.5 $start $range csn set conc= 7 $start $range csn set conc= 7.5 $start $range csn set conc= 8 $start $range csn set conc= 8.5 $start $range csn set conc= 9 $start $range csn set conc= 9.5 $start $range csn set conc= 10 $start $range csn set conc= 15 $start $range csn set conc= 20 $start $range csn set conc= 25 $start $range csn set conc= 30 $start $range csn set conc= 35 $start $range csn set conc= 40 $start $range csn set conc= 45 $start $range csn set conc= 50 $start $range csn1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set conc= 55 $start $range csn set conc= 60 $start $range csn set conc= 65 $start $range csn set conc= 70 $start $range csn set conc= 75 $start $range csn set conc= 80 $start $range csn set conc= 85 $start $range csn set conc= 90 $start $range csn set conc= 95 $start $range csn set conc= 100 $start $range csn set conc= 110 $start $range csn set conc= 120 $start $range csn set conc= 130 $start $range csn set conc= 140 $start $range csn set conc= 150 $start $range csn set conc= 160 $start $range csn set conc= 170 $start $range csn set conc= 180 $start $range csn set conc= 190 $start $range csn set conc= 200 $start $range csn end
proced inhmet4 set conc= 0.015 $start $d aucbr set conc= 0.02 $start $d aucbr set conc= 0.025 $start $d aucbr set conc= 0.03 $start $d aucbr set conc= 0.035 $start $d aucbr set conc= 0.04 $start $d aucbr set conc= 0.045 $start $d aucbr set conc= 0.05 $start $d aucbr set conc= 0.055 $start $d aucbr set conc= 0.06 $start $d aucbr set conc= 0.065 $start $d aucbr set conc= 0.07 $start $d aucbr set conc= 0.075 $start $d aucbr set conc= 0.08 $start $d aucbr set conc= 0.085 $start $d aucbr set conc= 0.09 $start $d aucbr set conc= 0.095 $start $d aucbr set conc= 0.1 $start $d aucbr set conc= 0.15 $start $d aucbr set conc= 0.2 $start $d aucbr set conc= 0.25 $start $d aucbr set conc= 0.3 $start $d aucbr set conc= 0.35 $start $d aucbr set conc= 0.4 $start $d aucbr set conc= 0.45 $start $d aucbr set conc= 0.5 $start $d aucbr set conc= 0.55 $start $d aucbr set conc= 0.6 $start $d aucbr set conc= 0.65 $start $d aucbr set conc= 0.7 $start $d aucbr set conc= 0.75 $start $d aucbr set conc= 0.8 $start $d aucbr set conc= 0.85 $start $d aucbr set conc= 0.9 $start $d aucbr1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set conc= 0.95 $start $d aucbr set conc= 1 $start $d aucbr set conc= 1.5 $start $d aucbr set conc= 2 $start $d aucbr set conc= 2.5 $start $d aucbr set conc= 3 $start $d aucbr set conc= 3.5 $start $d aucbr set conc= 4 $start $d aucbr set conc= 4.5 $start $d aucbr set conc= 5 $start $d aucbr set conc= 5.5 $start $d aucbr set conc= 6 $start $d aucbr set conc= 6.5 $start $d aucbr set conc= 7 $start $d aucbr set conc= 7.5 $start $d aucbr set conc= 8 $start $d aucbr set conc= 8.5 $start $d aucbr set conc= 9 $start $d aucbr set conc= 9.5 $start $d aucbr set conc= 10 $start $d aucbr set conc= 15 $start $d aucbr set conc= 20 $start $d aucbr set conc= 25 $start $d aucbr set conc= 30 $start $d aucbr set conc= 35 $start $d aucbr set conc= 40 $start $d aucbr set conc= 45 $start $d aucbr set conc= 50 $start $d aucbr set conc= 55 $start $d aucbr set conc= 60 $start $d aucbr set conc= 65 $start $d aucbr set conc= 70 $start $d aucbr set conc= 75 $start $d aucbr set conc= 80 $start $d aucbr set conc= 85 $start $d aucbr set conc= 90 $start $d aucbr set conc= 95 $start $d aucbr set conc= 100 $start $d aucbr set conc= 110 $start $d aucbr set conc= 120 $start $d aucbr set conc= 130 $start $d aucbr set conc= 140 $start $d aucbr set conc= 150 $start $d aucbr set conc= 160 $start $d aucbr set conc= 170 $start $d aucbr set conc= 180 $start $d aucbr set conc= 190 $start $d aucbr set conc= 200 $start $d aucbr set conc= 210 $start $d aucbr set conc= 220 $start $d aucbr set conc= 230 $start $d aucbr set conc= 240 $start $d aucbr set conc= 250 $start $d aucbr set conc= 260 $start $d aucbr

set conc= 0.015 $start $range cbr set conc= 0.02 $start $range cbr1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set conc= 0.025 $start $range cbr set conc= 0.03 $start $range cbr set conc= 0.035 $start $range cbr set conc= 0.04 $start $range cbr set conc= 0.045 $start $range cbr set conc= 0.05 $start $range cbr set conc= 0.055 $start $range cbr set conc= 0.06 $start $range cbr set conc= 0.065 $start $range cbr set conc= 0.07 $start $range cbr set conc= 0.075 $start $range cbr set conc= 0.08 $start $range cbr set conc= 0.085 $start $range cbr set conc= 0.09 $start $range cbr set conc= 0.095 $start $range cbr set conc= 0.1 $start $range cbr set conc= 0.15 $start $range cbr set conc= 0.2 $start $range cbr set conc= 0.25 $start $range cbr set conc= 0.3 $start $range cbr set conc= 0.35 $start $range cbr set conc= 0.4 $start $range cbr set conc= 0.45 $start $range cbr set conc= 0.5 $start $range cbr set conc= 0.55 $start $range cbr set conc= 0.6 $start $range cbr set conc= 0.65 $start $range cbr set conc= 0.7 $start $range cbr set conc= 0.75 $start $range cbr set conc= 0.8 $start $range cbr set conc= 0.85 $start $range cbr set conc= 0.9 $start $range cbr set conc= 0.95 $start $range cbr set conc= 1 $start $range cbr set conc= 1.5 $start $range cbr set conc= 2 $start $range cbr set conc= 2.5 $start $range cbr set conc= 3 $start $range cbr set conc= 3.5 $start $range cbr set conc= 4 $start $range cbr set conc= 4.5 $start $range cbr set conc= 5 $start $range cbr set conc= 5.5 $start $range cbr set conc= 6 $start $range cbr set conc= 6.5 $start $range cbr set conc= 7 $start $range cbr set conc= 7.5 $start $range cbr set conc= 8 $start $range cbr set conc= 8.5 $start $range cbr set conc= 9 $start $range cbr set conc= 9.5 $start $range cbr set conc= 10 $start $range cbr set conc= 15 $start $range cbr set conc= 20 $start $range cbr set conc= 25 $start $range cbr set conc= 30 $start $range cbr set conc= 35 $start $range cbr1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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set conc= 40 $start $range cbr set conc= 45 $start $range cbr set conc= 50 $start $range cbr set conc= 55 $start $range cbr set conc= 60 $start $range cbr set conc= 65 $start $range cbr set conc= 70 $start $range cbr set conc= 75 $start $range cbr set conc= 80 $start $range cbr set conc= 85 $start $range cbr set conc= 90 $start $range cbr set conc= 95 $start $range cbr set conc= 100 $start $range cbr set conc= 110 $start $range cbr set conc= 120 $start $range cbr set conc= 130 $start $range cbr set conc= 140 $start $range cbr set conc= 150 $start $range cbr set conc= 160 $start $range cbr set conc= 170 $start $range cbr set conc= 180 $start $range cbr set conc= 190 $start $range cbr set conc= 200 $start $range cbr set conc= 210 $start $range cbr set conc= 220 $start $range cbr set conc= 230 $start $range cbr set conc= 240 $start $range cbr set conc= 250 $start $range cbr set conc= 260 $start $range cbr end
proced inhal3 set hvdprn=.f. CCL2CCL SET VMCH=2200, FCH=10800 SET TEXPOS=24, TCHNG=170, TSTOP=168, week=168 set n=0
mouse inhmet3
mmouse inhmet3 set tstop=144 set n=0
mouse inhmet inhmet3 end

proced inhalneuro set hvdprn=.f. ccl2ccl SET VMCH=2200, FCH=10800 SET TEXPOS=24, TCHNG=170, TSTOP=24, week=168 set n=0 rat set bw=0.2261, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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inhmet inhmet4 set bw=0.168 inhmet inhmet4 end

proced immunSA set hvdprn=.f. CCL2CCL SET VMCH=2200, FCH=10800 SET TEXPOS=24, TCHNG=170, TSTOP=168, week=168 set CONC= 0.75 fmsa3 SET CONC=0.7575 $START $ D aucsn, DM1 $set CONC=0.75 $START $ D AUCsn, DM1 set tstop=144 fmsa3 SET CONC=0.7575 $START $ D AUCsn, DM1 $set CONC=0.75 $START $ D AUCsn, DM1 set conc=0.032 set tstop=168 fmsa3 SET CONC=0.03232 $START $ D AUCsn, DM1 $set CONC=0.032 $START $ D AUCsn, DM1 set tstop=144 fmsa3 SET CONC=0.03232 $START $ D AUCsn, DM1 $set CONC=0.032 $START $ D AUCsn, DM1 END1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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EX H SI R
. C SL

PROGRAM: PHYSIOLOGICAL PHARMACOKINETIC MODEL -- WITH DATA (EXH.CSL)

'Model to examine gas phase elimination rate data' 'M. L. Gargas 16 OCT 1987 .......................' 'Revised 4/16/01 by Lisa M. Sweeney, adding brain, qsc, vsc'

'qpc and qcc scaling changed to 0.7' 'suicide enzyme inhib and resynthesis added 12/14/01 LMS'

INITIAL

CONSTANT QPC = 14. $'Alveolar ventilation rate (l/hr)' CONSTANT QCC = 14. $'Cardiac output (l/hr)' CONSTANT QLC = 0.25 $'Fractional blood flow to liver' CONSTANT QFC = 0.09 $'Fractional blood flow to fat' CONSTANT QSC = 0.336 $'Fractional blood flow to slowly perf' CONSTANT QSNC = 0.011 $'Fractional blood flow to spleen' CONSTANT Qbrc = 0.02 $'Fractional blood flow to brain' CONSTANT BW = 0.22 $'Body weight (kg)' CONSTANT VLC = 0.04 $'Fraction liver tissue' CONSTANT VFC = 0.07 $'Fraction fat tissue' CONSTANT VSC = 0.5946 $'Fraction of slowly perfused tissue' CONSTANT VSNC = 0.0035 $'Fraction of spleen' CONSTANT VBRC = 0.0057 $'Fraction of brain tissue' CONSTANT VRC = 0.2235 $'Fraction of richly perfused tissue' CONSTANT PLA = 3.46 $'Liver/air partition coefficient' CONSTANT PFA = 86.5 $'Fat/air partition coefficient' CONSTANT PSA = 1.16 $'Slowly perfused tissue/air partition' CONSTANT PRA = 3.46 $'Richly perfused tissue/air partition' CONSTANT PSNA = 1 $'Spleen/air partition' CONSTANT PBRA = 3.46 $'brain/air partition' CONSTANT PB = 40.2 $'Blood/air partition coefficient' CONSTANT MW = 133.14 $'Molecular weight (g/mol)' CONSTANT VMAXC = 8.36 $'Maximum velocity of metabolism (mg/hr-1kg) in liver' CONSTANT VMAXRC = 0 $'Maximum velocity of metabolism (mg/hr-1kg) in rpt' CONSTANT KM = 0.36 $'Michaelis-Menten constant (mg/l)' CONSTANT KFC = 0. $'First order metabolism rate constant (/hr-1kg)' CONSTANT Kdet=0.025 $'rate of enzyme turnover (/hr)' CONSTANT Kdes=0 $'rate of enzyme activity loss thru inhibition by ES mech' Constant kdte=0 $'rate of enzyme activity loss thru inhibition by TE mech' Constant kdfe=0 $'rate of enzyme activity loss thru inhibition by FE mech' Constant kdbi=0 $'rate of enzyme activity loss thru inhibition by BI mech'

CONSTANT CONC = 1000. $'Inhaled concentration (ppm)' CONSTANT VMCH = 2.2 $'VOLUME OF METABOLISM CHAMBER (L)' CONSTANT FCH = 10.7 $'FLOW THROUGH METABOLISM CHAMBER (L/HR)' CONSTANT N = 1. $'NUMBER OF RATS IN METABOLISM CHAMBER' CONSTANT ABG0=10.0 $'TOTAL BACKGROUND AMT FROM FUR (MG)' CONSTANT KBG = 0.0 $'RATE OF FUR OFF-GASING (/HR)'
'Timing commands'1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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CONSTANT TSTOP = 24. $'Length of experiment (hrs)' CONSTANT TEXPOS = 6 $'Length of open chamber exposure' CONSTANT WEEK=120. $'exposure only on week days' CONSTANT TCHNG = 168. $'Length of inhalation exposure (hrs)' CONSTANT POINTS = 24. $'Number of points in plot' CINT = texpos/POINTS $'Communication interval' CHNG = TCHNG - 0.00001
VMC = VMCH - N*BW $'NET METABOLISM CHAMBER VOLUME (L)'
'Scaled parameters'
QC = QCC*BW**0.70 QP = QPC*BW**0.70 QL = QLC*QC QF = QFC*QC QS = qsc*QC qsn = qsnc*qc QBR = qbrc*QC QR = QC-(QL+QF+QS+QBR+QSN) VL = VLC*BW VF = VFC*BW VS = vsc*BW vsn = vsnc*bw VR = vrc*BW

VBR = VBRC*BW VMAX = VMAXC*BW**0.7 VMAXR= VMAXRC*BW**0.7 KF = KFC/BW**0.3 PF = PFA/PB $PL =PLA/PB $PR=PRA/PB $PS= PSA/PB $ PBR=PBRA/PB $ PSN=PSNA/PB

CII = 0.0
END $'End of initial'

DYNAMIC ALGORITHM IALG = 2 $'Gear method for stiff systems'

DERIVATIVE CI = PULSE(0., 24., TEXPOS)*PULSE(0.,168., WEEK)*CONC*MW/24450

'Amount inhaled' RAI = QP*CI

AI = INTEG(RAI,0.) 'CA = Concentration in arterial blood (mg/l)' CA = (QC*CV+QP*(CI+CII*CCH))/(QC+(QP/PB)) AUCB = INTEG(CA,0.)
'AX = Amount exhaled (mg)' CX = CA/PB CXPPM = (0.7*CX+0.3*CI)*24450./MW RAX = QP*CX AX = INTEG(RAX, 0.)1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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'ACH = AMOUNT IN METABOLISM CHAMBER (MG/L)' RACH = N * CII* QP * (CX-CCH) - CII*FCH*CCH - RABG ACH = INTEG(RACH,0.) CCH = ACH/VMC PPMOUT = CCH*24450./MW RATE1 = FCH*CCH TOTAL = INTEG(RATE1,0.0)

'ABG = AMT OF BACKGROUND CONC FROM FUR' RABG = -KBG*ABG*STEP(TCHNG) ABG = INTEG(RABG,ABG0)
'AS = Amount in slowly perfused tissues (mg)' RAS = QS*(CA-CVS) AS = INTEG(RAS,0.) CVS = AS/(VS*PS) CS = AS/VS
'ASN = Amount in spleen (mg)' RASN = QSN*(CA-CVSN) ASN = INTEG(RASN,0.) CVSN = ASN/(VSN*PSN) CSN = ASN/VSN AUCSN = INTEG(CSN,0.)
'AR = Amount in rapidly perfused tissues (mg)' RAR = QR*(CA-CVR) - RAMR AR = INTEG(RAR,0.) CVR = AR/(VR*PR) CR = AR/VR
'ABR = Amount in brain(mg)' RABR = QBR*(CA-CVBR) ABR = INTEG(RABR,0.) CVBR = ABR/(VBR*PBR) CBR = ABR/VBR aucbr= integ(cbr, 0.)
'AF = Amount in fat tissue (mg)' RAF = QF*(CA-CVF) AF = INTEG(RAF,0.) CVF = AF/(VF*PF) CF = AF/VF
'AL = Amount in liver tissue (mg)' RAL = QL*(CA-CVL) - RAML AL = INTEG(RAL,0.) CVL = AL/(VL*PL) CL = AL/VL AUCL = INTEG(CL,0.)

'VMT = maximal rate of metabolism' RVMT = (VMAX-VMT)*KDET-KDES*RAML*RAML-KDTE*RAML*VMT ... -KDFE*RAML*VMT*KM/(KM+ CVL)-KDBI*RAML VMT = INTEG(RVMT, VMAX)
'AM = Amount metabolized (mg)'1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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RAML = (VMT*CVL)/(KM+CVL) + KF*CVL*VL RAMR = (VMAXR*CVR)/(KM+CVR) RAM = RAML + RAMR AM = INTEG(RAM, 0.) AML = INTEG(RAML,0) DM1=AML/VL

'CV = Mixed venous blood concentration (mg/l)' CV = (QF*CVF + QL*CVL + QS*CVS + QR*CVR + QBR*CVBR +QSN*CVSN)/QC AUCV = INTEG(CV,0.)
'TMASS = mass balance (mg)' TMASS = AF+AL+AS+AR+AM+ABR+ASN+AX
'DOSEX = Net amount absorbed (mg)' DOSEX = AI+AX
TERMT(T.GE.TSTOP)

END $'End of derivative'
IF (T.GE.CHNG) CI=0. IF (T.GE.CHNG) CII=1.0 END $'End of dynamic'
END $'End of program'1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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APPE ND I X B

RO UT E

- T O- RO UT E E X T RA P OL AT I ON F OR 1 , 1 , 2

- T CE I N V E NO US B L OOD ( P EA K CONCE NT RAT I ON AND AU C) , BR AI N AUC, AND AMO UNT

M ET AB OLI Z ED I N T HE L I VE R

E q u iv a len t in h a led c o n c e n tr a tio n s, b a se do n b lo o dc o n c e n tra tio n s (p e a ko r A U C ), b ra in A U C , o r a m o u n t m e tab o lize d in liv e r p re d icte d b y th e P B P K m o d e ls, a re p ro v id e din T ab le B -1. M echan i st i c evidenc e in d ica tes that peak co ncen trat i on i n the brai n is the m ost appr opr i at e dos e metr i c forr out e- t o- r out e extr apol at i on (pro v ided i n the mai n r eport ) , but
r out e- t o- r out e extr apol at i on r es ul t s for other s peci fi ed endpoi nt s ar e pr ovi ded, as s peci fi ed in th e E C A

.
T abl e B

- 1. I nhal e d C onc e nt r at i ons Equi va l e ntt o t he R atA c ut e N e ur ot oxi c i t y N O A EL and

L O A E L base d on E C A

- Speci f i ed D os e M et ri cs

O ralD ose
m g/kg Sex Peak B l ood AUC

B l ood A U C B r ai n A m ount
m et abol i zed (l iver) 95 (N O A E L ) Fem al e 167 ppm 43 ppm 36 ppm 32 ppm 200 ( L O A E L ) Fem al e 248 ppm 147 ppm 139 ppm 50 ppm 95 (N O A E L ) M al e 174 ppm 52 ppm 43 ppm 34 ppm 200 ( L O A E L ) M al e 260 ppm 154 ppm 147 ppm 52 ppm

T he value of the “equi val ent ” i nhal ed conce ntr at i on w as depende nton the choi ce of i nt ernal dos e metr i c. For exampl e, the i nhal at i on “equi val ent ” of 95 m g/kg bycorn oi l gavage t o a
m al e r atr anged f

r om 34 ppm , bas ed on amountm et abol i zed, t o 174 p p m , b ase d o n peak b lo o dc o n c e n tra tio n . In g e n e ra l, th e p re d icte dc o n c e n tra tio n o f ac o m p o u n din aw e llp e rf u se d , n o n -m e tab o lizin g tissu e th a t is n o t a p o rta l o f e n tryw illtra c kth e c o n c e n tra tio n in the bl ood ( i

. e. , t i s s ue conc entr at i on 

### . bl ood co n centr at i on × t i s s ue: bl ood part i t i on coef fi ci ent )

. Such i s the ca s e forbr ai n, and th e rou te-t o -rout e extr apol at i on r es ul t s do not d if f e r s u b s ta n tia lly if

b a s e do n b lo o dra th e r th a n b ra in c o n c e n tr a tio n s

.1, 1, 2- T C E A cut e N eur ot oxi ci tyR out e- t o- R out e N ovember29, 2004

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APPE ND I X C

GR AP HI CA L P RE S E NT AT I ON OF RO UT E

- T O- RO UT E E X T RA P OL AT I ON FOR 1 , 1 , 2

- TCE I N RA TS

I n the figur es pr ovi ded bel ow , the dos e metr i cs w er e det erm i ned overa s i ngl e dayof exp osure. F i gu res C -1 and C -2 pres ent the route- t o-r ou t e extr apo l at i on curves for al l do se
m etr i cs forfemal e and m al e r at s , r es pect i vel y
. I n Fi gur es C

- 1 and C

- 2, one can cl ear l ys ee that the som e of the rout e-t o-r ou t e-extrapol at i on curves for the d i fferentdo se m etri cs cr oss. T hu s, i n the absence o f em pir i cal or m echan i st i c i nfo rm at i on supp ort i ve of a part i culardo se
m etr i c, the choi ce of

the most“conserva ti v e” dos e metr i c forr out e- t o- r out e extr apol at i on
m a yd e p e n do n th e d o s e f ro m w h ic h o n e s ta rt s

.1, 1, 2- T C E A cut e N eur ot oxi ci tyR out et oR out e N ovember29, 2004

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