Tobacco Documents Online

T.S;;/JUL/~:~-2 Groul~ ?,~setrch 8 DmlolmttuC Cent:re, ]5=itish-dmer£can Tobscco Co. Ltd., 31st &uSust, 1977 (~-poz"c !io. ]D).1317 ]lJsCticted) ~T 1"he uajm: ccme:lus£c.u to be d::mm £:mn tJd.s anslys~.s az~=- ~ level o£ :espomse ~ WLclr.h~ ILssem:cb Labo:a~o:£es is si, lp~,f£cancly bi4~:e:: Ch.., that ob~d st the ~sttelle I=stitut, rta:~tt, but the tumort4B~c ra:~s calc=~ste4 ~ the data fr~ these t~ 181x)=aJ:or~.es m not s~4pu~ica~tly d~..f£e~t:. 2, The tobscco cout=:ol is lienstL3.17 :note act£Te than the :E~ vaz~.a=t:s, and 4,, stone cases s~zd.f£can~ly so. 3. Base vei4r, M: bu • s~.sn~£c~m~ ef£ect on ~ ~:o~ot:~nS e=t£~.~7 of Pitt shoat, L~ased base ve~Sht lead~u~g to d~c=eued aet£v4tT. ~. Sheet tb~rJm~ss (a.s.~.) has no effect. 5. ZI: has not bean poss4ble to establish ~her.hm: o~: not tt~ tncl~siou of solublem has an eff~t c~ tummu~ptomot4eS a~t4v~t~. BAT Co LTD - MINNESOTA TOBACCO LITIGATION O ~O

I f/ k BAT Co LTD - MINNESOTA TOBACCO LITIGATION

--2-- ).. IHTR~CTZON T3IJLI encpenc:rBI4U~lct ¢8¢¢~.od out It: W¢c]~buun ~IIMrch L~borat:o¢4es LEd. • was des£8~sd to ezsm~e vha pr~not/~S e¢¢£v£¢y to mouse skin of condensares obtained from various fo~mlav~onJ of pu?; ¢he FI~ s~p~es were produced at d:LffsrenC b88~ weiKhcs, dJ~feremc 81rpsremt specifJ.c volumes, and vir~ d/~ferent levels of product soLubles. Convrol c~azetees were made fran =be orLl/~al ¢obamco (i.e. uncecosst£~ted), a~! ¢~o samplLes of ~te cisare=¢es used a¢ KavtelXe in JANUS ezpec~Lment ]59/3 and B9/5 we=e also /:zcluded for comparatLve purposes. 2. DESZGN OF EX]PF.R3~ENT Tbe exper/aumt coutataad 26 Sro:ps of animaZs, of whlch 18 were devoted to the inCe=-comparlsons of the FI~ vs~.uCs. Th=ee PEr variables were iwTesc~aced; base veLKh¢, sheet dens£~ (A.S.V.), and soluble materlel in the sheet. The or~K/~al design called for each of these variables I~ be held at ~dO levels, hlsh and low, giving a 2 x 2 • 2 expe=~tal pla~, u~th • nJ~h va=£ant, all var£ables at the uLLd-point of the range, provid/J~ a msdLan point:. Thus ~ ]PILT varlane8 were used, the condensers bates used a¢ 2 dose levels (40 ~ and 56.6 mS) g4ving 18 groups of an/male. XabLe I shows the design cou~isura¢iou of the g ~Er V~4smt::l. With the eYe.eKe values Of I~ ver~lbl_tl dtr leudy produced in I~e FltZ shee¢s sctus~ly manu~ct3med. The remat~a~ 8 Stoups used in ~he ezpe:£ment were made up of 6 :oudensaCe t=cemCed i~oups (roberts control. 39/3, ]9/$, each at ~vo dose levels) and 2 ~.o~t~ol poups, one painted wt~h acet:oue ou/7, an4 tle BAT Co LTD - MINNESOTA TOBACCO LITIGATION m OO r',o

INDEX HAS INDICATED GAP IN BATES RANGE HERE

or~tc v~ch scetout sud the tniCitl ~ preoCretcnenc counou to sll ckt couden~tCe e~eaced Kroups. Each condeasate SToup ~ece~ved • sizzle iJs~Cf~l dose of 120 ~ ~HBA O. 3 ml acetone m£ the beK~am:iJzS of ~ eJcpe=immzt. The g:coupm at low dose level trace then pad•Cad rich 40 mS of condeuseCe d£ssoZved Lu 0.3 ml eceCosz8 Ckcee times esch week. The hiSh dome level Woups nee p&l:Ced ~Lch 56.6 ms of coude:sace d£ssolved in 0.3 ml acecons chr£ce ~nekly. As ocizilmlly designed tlse ez~pe=/manc used L20 8n/smls in each of the cout:ol St•ups, 80 aai~tls 4~ each o£ the low dose level condensate Soups, and ~0 as/mAle in each of the b~sh dose level Soups. 14anu~actuz~uS d~£tculcles ho~nver led Co 8 sho=tage of mate:is1 for 8~oups 13, 14, 21, and 22, stud so =he number of animals used in St•ups 13 and 21 was reduced £z=m 80 Co 60, and the ember of anLma18 used 4~ So•ups 14 and 22 yes =educed from A• co 30. Thus m COC81 of 1620 mndm-ls ve:e used in t:ht.s e~periman~. Table 2 shows the complete des£Ku, and dm~s£1s of ~1 husbandr7 a=e ~ven Appendix Z. Wdth the ezcep~on o£ Kz~up 1 (acetone control) each ml :see/veal s single paint:inS of tntC£ator ou day 0 of the ezperiamuC. Lnic£aco:, 7,12-d/msChylbenzaeChracene (Eucman-Eod~k Co. ) yes l~epa=ed as m~ 0o04Z soluctou Ln ~lycic=l St•de acetone so r~sc esch 0.3 ml dose coaCs~d 120 ~8. 3. KESULTS OF Tables 3 mini ~ show the t~ctde~ce of tumor--bearing anfamls. Othe= paCholoK~c~tl daea collected from ch~s elpertmmtC ts reported elsevhere BAT Co LTD - MINNESOTA TOBACCO LITIGATION I t..r-I

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-4- (B£oloK£caZ Resmu~P..h =aport: B.39). ZI: srLZ1 be noted from T~I~]Le 4 r.b, sl: t.he.re uez-e ve~t fen+ mice vJ.t:h ms 3. £11n,sm l: ~tmours (11 out o£ 1620) mad 811 of these ~tre d£scovered at: 88crL~Lce. Since the numbe: of mal£Snancies was -o 8mall thLs data has not been analysed stat£st£cally. 4. The analys£s of the data from th4s e~pe~Lusut falls into thee se~t£ons:- (,i) & comps~ison of the data £~om 8staples B9t3 stud B9/$ with data obtaLne~ f:om these ssmples in ~n e~tl£e: expe~nsnt. A eomparLson o£ the PEr variants ~Lth tba ~obacco cant:ol. An Lavest~&:4on o£ thJ ~el~t£ve e~facts o£ the ~R~ v~rLables. A(£) A ~mpa:£son a£ 1913 and B9/5. Samples B9/3 and B9/5 tire coupazed Lu • prom0t£on ezpe:tnent st the )4tteLZe ZnJt£t~t, F~a~kfu~t-mn-Ha4~. This earl£et em~e~Lmen~ ~s zepo~ted in (1). These samples v~re ~clLuded ;zz ~h~0 cu~te~C e~per~Jaent to check that the 8v~tch £~om B~ttelle 1:o V~.c]r.h4~ has not ltd to -~ u=~n~ec~ed cha~e L= the es~---~e o~ the tumtLS~c z~t~. %~e data £~ram the Ksttella expe~:T~eat rare shown ~ Table 5, and J[=am the £oot=o~ to ¢l~s table ~t ~11 be ~ot~d that o~Ly one co.definite dose Level (40 mS) was =l~l, so tl~t no doee/Z~ml;m~se telat~onsh~p could 1~ obta~sed £~am the IL~ttelZe e~pet~t. ~so, the 4~4tL8~ ttestms~t of 180 UK o£ IN4]~ used &t B~=telle 4s h~Klutr than the 120 .S used &t Widd~m~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION LJ't oo -.,¢~ co

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-5- The analysis of a more complex Battelle p:ca0tion e~udy (2. 3) hie shown that pretTe•tm~xts of 120 ~g or 180 ~8 of DtQA j4ve subsequent ~u~ rates which are not sts~Lficant17 different| tmieed, thez~t Ls 8area evidence to suggest that the tumm~ rate subsequent to • preens•anent of 120 P8 may be h~gher alum r~st s~bsequent to a Fre~ea~ment of 180 ug. Z~ v~ev of th~s, it was decided to pool r~a da~a f~om the ~uo ptomotio~ exper~ts using condensate8 B9/3 and B9/5 so as to be able to use the do~~ ILne ar~8~ from rJka g£ekham dace eo KLTe tumor£8~4c ratios for both exper~,nants. Using the Weibu11 d£strlbutlon £unctlon, common values of k ~nd w, and sepeza~ values of b for esch 8p~oup, ~nre £1tted to ~ data of TabZ• S, and the R9/3 and B9/$ data £rom TsbLe 3. Th~ methods used are d~scrlbod in (4); the results aze shown in TabLe 6 end 7i8~ure ~. TabZe 7 shows the results of a soodness-of-£4t test foe these estJ~natee of the Weibull parameters from which it can be ~um that an adequate f£t to the h~a has be~n obtained. Table 8 81~w8 the assocLaced Wo£bu~L svat£stics 8 and V. Zn~pect/on of 7~Lq~re 1 show r~at an ~momaZous result has been obtained for coude~sa~e ]9/$ at WLckhsm; only 1 L~mourbea~luS mz/~al occuz~d in the high dose level 8~q~P. gLvt~g a nee••lye dose-~esponse ~e~nr~ou~h~p for th~s condensate. Because of its snams~c~s behsv~ou~ it was decLded to om~t the data from the B9[$. 56.6 m~ group of Shim•As from the subsequent ~nalys~s, Zts LucIusion ~ould tend to ~u~e the estfJ~ttt of the slope of the dose--response lt~e, thereby increasLn~ the umS~tude of any estfJates of ~mor£senLc ratio, v~rJ~ut improving the conf£d~e ~egim~ of such estimates. Also, s negative doSe-TeSpOns• relatim~hip BAT Co LTD - MINNESOTA TOBACCO LITIGATION O %0 r',o

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-6- is invuitively Implauslble and c~nt~adicCs a11 previous a~l~rlenee (except at smch hJLsbar dose levels). Table 9 sho~ tbm Cumori4eu/c =sties sad their 95Z =ouf£dmnce 1isles, mad from tlt~8 table Lt san be seen that the ij9[3 to n9/$ tumoriSenic =argo from the two ezpa=~msts CKstt~Ile a~d W~~ are uot s£ip~££csnt~7 d~fere~t. Also, if the Bg/S, 56.6 uS point is £Snored, Yi4~uz~ 1 sussescs that the ImSmral ~evel of response ob~ at giclcham 4s I~LKher thms that obr~ulxu~ at I~ttelle, and in £8ct the 4U£e:eace beCmmu the two laboratories 4s ~usC s~Lcamt at the 95Z 1Level of confidence. Zt is morCh nott~4~ that the hLKhm= :espouse at W~ckham ross obts~:ed vith the lows: level of ~ ptecre~cmsnt (120 ~ ac W£ckhmm; 180 ~ at Battelle). This tends to cou~Lrm the result repo~te~ ia (2) whecetn 4c was noted that in another p=~mot~ study at Bsttelle the 8zoup =ec~vtn4~ a 180 ~S pretreaCmant of IRfB~ gave • lomex response than chose receivLu4 120 ~g. h(£i) Comparison of l~It~ varLsncs. Using comm~ values of k a~d v and sepazate values of b for each group the ~e~bull d£str4but4ou ~unct4on m f£t~ed to the data of T~le 3 for groups 3 to 6 and 11 Co 26. The mthads used are described 4. (~)| the results axe shoun in Table 10 and plocte4 in Figure 2. Treble 11 shows the result of • Sootiness--of-fit test of these parameter est~unstes from which it can been seen that an adequate fit has been obtained (X2 - 7.60 with 6 deKrmm8 o£fza~dms~ 818n~£cance level 59.6Z). Table 12 shows the lge4b~11 scat4sttcs S and V derived from thsse est4-~tes of the pa=mttrs. BAT Co LTD - MINNESOTA TOBACCO LITIGATION O t.J-I

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-7- J~om FiKurt Z it uould appe~ that the tobacco control tends to be mote s£t£vo than the PEt vszl~ntSo Also uot£ce~ble £s t]~ aeSat£ve dooe-tmspmu~ tolations]~p fc~ the £s~tor combLzLst~ou OH, L, H). As noted eazlior, such neg&t£ve slopes are extremely $,~plausiblo, but tram tba £tj~uto £t £s not poss£ble to deto~ which of tba t~o points £s lilly to be ~ ez~or. Table 13 shows the results of an 8nalysis of vs~ianca of tha d~ta o£ T&bls 12 from wh£eh it can be seen that, sitar c~ndausate dose ~vol e££octs h~m been xllou~d £ot, tharo rema~s • hi4~h~y si83~icant betweon-r~n~lensate e.~feat, as miKht be expected from FiSu~e 2. Also, Table 13 shows that there are no s~Kni£1cent ~teract~ons! thus it m~y be ~J~ertod that the noB&tire dose-response I~nA £or (R, L, H) in P4Kute 2 is not stat£sticall7 si~£c4mt. Table l& shows the t~morisenlc tatlos betws~ the tobacco control and the atria ~]~ variants. As noted £tom F~4~u~o 2, the ratio £s loss than 1.0 £ot ~]L the ¢ompat~sous, but £s sis;n~ic~mt £ot o~ly two, those fo~ (K, L, L) sad (R, R, W). TILLs c~nfi~as the conclusion dtsva ft~n FiKure 2, that the ~R~ vs:~ants are Sea•rally 18so tmwr~Ke~ic than the control tobecco. 4(£££) R~lat£~s e~£eccs of F~t varLables. ~na re~&t£o~sl~Lps amonsst the £8~tors o£ the PR~ varis~ts ~nro ~u=vtstijtted bY two mtlbodo. (•) Fixed E£~.ects Model Using tills approach~ each o£ the Chloe vaz-£ables (bass v~iKlst, &.S.V., 8olubles), a~d abe condensate dose level, uere coded u baths at either BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-8- the high or the %or level. The median po~t was d~sre$&tded. (The ned~n point contt£b~tes uo Lu~ormst4on tosa~L~n| • test £or the um£n eJ~£ect of the variablt8. It only provides • test for non-lineaz£t7 of response, and in the context of • fJ.3ued-e~£ectJ model tk~s vest: yes ~p~oz~d.) The tmmlttjzK analys~s of variance i8 8hewn 4~ Table 15, £tom ~b~ch it c~m be seen that the X2 for the ma4~ effects (21.307 irlCh 4 desrea• of freedom) is hishly significant. PartitLoni~K this X2 8hove that the doe• e££eet m~d the base ve4Kht e~fect m biKhly siKntfL~t, and a.s.v, seems to have •1moat no effect at a11. TtLte latter coucZus£on 48 mod4££ed by the result that slthouKh the ove~aX1 X2 of 8.&34 with 6 de|tees of £:•edom for the 1st oz~le: £nteract£cms is not 81lp~£icsmt, pa~£tiou~ this X2 reveaLs that the dose • •.s.v. intetact~on £8 s£es~£1cant. Znsp~:tlon of FiKure 2 8ugKests thAC the results for the (R,~. L, H) combinat£on of the £actove, 8Lv~ns • nesat£ve dose/response line, may be respous£ble for th£s tnteract£on, and the hiKhly s£Kn/~£cant ef£ect of base weiSht £nd£cates the Oi, L. H) 40 ms Kroup as hay/n• pz~dueed an unszpectedly h£$h uumber o£ tumour-beatLuS animals, since the high base ~£8J~ Stoups have lenera~ly 8~Lven the lower response. • fuz~her pa:titJ.on£ng of the X2 o£ 5.019 Or£t~ 4 degrees of £reedom) £or the 2rid orde: £n~e:act£ou effect £8 due to base ~e£1iht • •.8.v. z solublas (X2 u &.876 with i degree o4v f::eedom. SI4p~Lt[L~t: at 97.28Z). The th£rd order ~Lute~aet4on 4s •18o sLezt~fLcant. Th~s althouKh a.n.v. ~ould seem to have a msgl£1;tble mL{n ef£ect, the £a~tor a.s.v, sppears In al1 the e~l~Lf~csnt £nteract£ons. A re-s~slys~s o£ tbm dsta omit~$ the ~esult for the rE, L, H) 40 q IWoup t8 shoun in Table 16. Note that the om£ss~on of tk4s data BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

~o point :sans that there is no test £or the third order intetsct£~, s~uce • destae 0£ treadle has l~sn lost. ¢~mpat~son 0£ Tables 15 and 16 s~nm Ct~c there is l£ctle chase ~ the results of r~a SilP~T~£cance r~sts as far u che msJ~ e~ects ate conce~d, but that in Table 16 ~e o£ t~ tnte:sctlcms ~s e~Lf£cant. Zt ~s a/so of ince=est to z~-calculete the tumorigenic ratios with (R, L, B) 40 s~ c~tta~I; t~ zlsu]Lts are shown in Table I7. Comparison of Tables I7 and 14 shows that in ram fetter the conf/dence I/m~ts are t/~hter, and • third ret£o, that £or ~obacca v. (a, L. B) is nov sil~L£1cant. (b) ms=:essiou Hodel UslnS this approach the average values £or base ~iEht, a.s.v., 8olubles, sad dose l~rel Rre used ~mJtaad o£ tlm 0/1 codtns used to denote the hish/lov levels of the var/~ables in the fixed e~£ects :o4el. The values of base wa£sht, a.s.~, a~d soLubles are shown in Table 1. The dose levels were 40 ~li and 56.6 ~1~ t:broufhout. ~ ~z~ss£on ~_els ~=e used:- 1. D in(b) - ~ + a~ (base =e£Sht) + a~ (base ~isb~Z) + a~ (a.s.~.) + as (solubLes) + =7 (does) + + + ] + 1-, these smdels, b £s the Ve/.b~11 parameter b £o~ m~ch o£ the 18 Irroups, sad I:he 8~L ~ the b~ 8re p~z'~ste=s to be detexmizmcl. ]rm: mc~lel I the scale4 4at;a shmm i,~ Table 1 were used. The sc~lia8 was a~opted to m~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION Oo r',o ~O

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-10- ¢ompu~ttioLtI probIemJ vi~h Iarge n~mbe:s. 7or model 2 ~he (n~zural) los~£cbms of cbe un~.sled da~t ~re used. Us~a~ methods described 4~ (4) Chose models ~tre ££Z:ed b~ maximum l~dkellh~od; e~ L'a~l~illE mmmlySe8 Of vaz"J.snce 41rm S~ ~J1 T&bles 18 aud 19. mlot:t that Cbe i.uclus£on of the me4£an po:[,nt in these reilreas:Lou. ammlysea doe8 not provLde • eeoc £or ~o~-ltJso~c£cy of dome response since onl.y Cue dose levels were used ClnrouShout. Theme two tables show Chat on~y the dose effect mnd the effect of base vm4KhC ere siKn~£cmnt, and chat the effect of bus ~8LSbt £s 8dequmcely represented by • s~npl• liJzezc model. The 4-~luence of the intermct4on~ becvoen She PIT £•ctors can be see~ in Tables 20 and 21 ~bere the coef£icieucs of the vexious ~eKceesiou models that mare E4tte~ to the dJca ~ce shmm. Znspoctiou of chose rye Cables 8ho~ that ~ter the dose and linear base ve£sht te~ms ~e t~cluded there is l£ttle chanSe in ~be l~tl£bood, but the tnclusLon of fuz~e~ terms in the model cm~es larks fluctuations in ~he estimates of the coaf££cienc8. ~J.tJ~oush the e£~ect of soluble• d~es not: reach siKn/~£canr.e, th, tre £s some ev£dence in. Tab~e 18 chat: £cs effect may not: be ne81~Lble; the 1~ses~ te~n ~s slK~L~mst at: 8.So&3•. T~ • model u8~ dose, broom ma~ht l~emr and 8o~uble 1~ £e f£tted to the data, the equ~t£on becomes ~n(b) - -9.9657 - 0.3562 (bsoe ~m£ShC) ÷ 0.2834 (soluble•) ÷ 1.26S0 (do~) [Tn:ILs equa, t£cm :ts for scaled data']. The l£k~l.Lhood o£ t:his u~lLeZ £8 L -- -107.136 aad ~ oo~ubles temm £s 8~sn~icant et 85.88~. BAT Co LTD - MINNESOTA TOBACCO LITIGATION m r',,o C~

INDEX HAS INDICATED GAP IN BATES RANGE HERE

, -11- The 8/~u of these coefflcients indicates that LncreaslnS the base ve~ht leads Co a teductlou in ~morigenic activity, and increasing" the paccmntqe selubles tends to increase rJ~t ~mor£aenic activity. The ma81itude of tbm base weight effect 4s such that a thanks of 100 in the average base wsighC (frum 50 to XqO, say) would rsMuce raw L~moriaemulc activi~7 bY t factor of about 2 i.e. the cunoci4je~Lc ~acLo of cuo ccmdeusates, m fcom a sheet of about base weiKht: 50 and the other from a sheet of about base ~lKhc 130 (all ocher factors beLn8 the same) smuld be azound 0.5. These reKression models ~tre re-e:cam/Jsmd wLth the dace for (H, L, H) AS mS om£tesd; tim results are lhmm In Tables 22 ~o 25. F~om chasm tables iC ca= be seem that the affect of bus ~milht remains h4|hly sLi~ficant, but there ks nov no evidence for an effect of solubles. Us~ a model /ncerporatin8 base weishc linear and solubles linear ~r~th the dose effect J:~ves Xn(b)- -9.8288 - 0.5633 ('Due wsishC) ÷ 0.1821 (soXuble8) ÷ 1.5001 Cdose) L~h£s equation £e £o: scaled dta~s~. ~ ~Lkelihood o~ r~i~Ls model is L - - 32,3(;5. 1"he test of 8i8z~£1csnce of the soLubles term show8 it to be s/4p~Lf£cant at o~ly 61.30Z level of conf/denzs. ~:e affect of base weisht is ~11usC:atml 4,, rt4;uz~ 3 ~re the loKsz~cha of the Welbull parammta: b (sham in Table XO) is sham plotted aKa/z~t the everest base we/4ht (shouu in Table 1) fo: the cvo condensate dose lm~s. The reswession Line is ales shouu plotted. s. c0s~sz0~s The conclusions co be dram ~rom this analysLs a:e as follmm: BAT Co LTD - MINNESOTA TOBACCO LITIGATION t.,,r'l CO r'O

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-L2- (a) & eompAt£som of the data from condens&tas Bg/3 and Bg/5 obc&£nad at ~?LcYJzam Reg4mrch Laboratorios, and at the BatteLle ZnJtLtut, Frankfurt, shays chat both 18borato=£es obt&~:ed compatible escLmmcu of Cl~ c~tLsm~c ratio B9/3 mxi B9/$. (b) Tba Sahara1 lave1 of response mc WLckha: vls hishec than &c ~csnkfurC, desp£ce Ohm lover level o£ DKBA pre-Creat~t use4 ac the fo=me= escabl£sbmeuC (120 ~g at Wlckbam compared ~ch 180 US at l~Ctelle). (c) This d4~£erence beCumAm Ohm two labotaCocies urns sL8x~££csnc 8C Cbe 95Z cou~Ldemce lave1. This tends to con~i~n rJbe =esult 8£ven in an ~trl£er report where £C vas concluded chat dose levels of 180 US for D~Sk p:e-tteatnauC vere too hish. (d) The tobacco cou~:ol m more active than the PEr vtrimntsp the cumorJ4Baa£c ~&cio beJ.n8 ]LtSl truth 1..0 for &1.1 ttt8 I:obac~o vs. PE eampa:isons, b ratio m siS~Lfic~mC, or appToacl~ng s£gn~ficsnct, (8C the 95: level of co:/idence) fo: chose cc~pa:~sons tJ~ ~h~ch r~e PR~ was smnu~aetu~ed ac the h~gher base ve48hc leve~s. (e) hoe wisl~ ~8s • bilil~7 siSZ~L~icsnC effect on ~ha pr~mo~4~| accLv~c~ of 1~T, t:~c:eased base vaLEh~ ~ead4~8 I:o • decreaJ~d sc~vL~7. (f) Sbd~t: r~Lc3meis (I.s.v.) has no i££ict: o~ tJ~8 promoct~q~ mct4v4i:~ of ~.l~t Pit1" sheet. The e££ect of c1~ £nclus4on 04; soluble msCe=J~LT J~ noc so cleat-cue. Z~ all the data ~s used ~n the amalysLs then Obese BAT Co LTD - MINNESOTA TOBACCO LITIGATION O Co

INDEX HAS INDICATED GAP IN BATES RANGE HERE

is same Lnd£ca~Lou thst solubles i~clus£on may have an effect on ehe ~mmJr-promott~8 8ctLvtty of the sheet, increased sol~bles leadfJ~ eo increased ant£v£t-y. On the orJmr hand, one of the Kroups seems to d~mpl&y an~malou~ beJmv:i.ou.t'. Lf this Sz'oup ,f.e cm,lt::tsd from the ~ysLJ than there La no evidence of a solubIes e~fect. REFEKENCZS "/~t promotion activity of tobacco smoke condensates to mouse skin; ciKmre~:es 59-2, B9-3, B9-~ and B9-5". E. F, ttbe. Kattalle Repoz~ No. 3.27, November 1972. 2. "l~t desi4n and snslysis of an emper4---~t to compare the t~ur- pr~motinI aetivLtit8 of t:he condns&rA from =£garette~ B9/1 and B9/6". K. B. W£1kss. BAT Kepoz~ Ho. RD.1L52-E, 0ctobe~ 1974. 3. "Same L%u~Jmr s~tlys4s of an empe:imane eo compmm rJm promoting activities of the cmuleasat~s f~ ciga:ettes B9/I end B9/6", L B. ~LLkJs. BAT Repore No. RD.1404 lestz£cted, August 1976. '~f~l/ll I~Jl plt3~.l~ ~r4mam(:l. ~ collectLon of the dats, and the sn~Lys4s of the t~ctdence of tmsouz-beati~8 ss~mls", E.IJ. g£1kes. BAT itapoz~ (not yet issued). BAT Co LTD - MINNESOTA TOBACCO LITIGATION r',o o'-,

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-16- Y3LELZ 1 71 s,~..,s Skmizza], bue R/4r~: lloa~ml a.8.v. BomLaal a;o),ublee Average bsse uei4ht J~Irer4qSe aoeov. Averaae 8elubgae Z Lov Lay 55 2.59 26.g ~Lsh 62 51 2.77 3.18 44.5 2g.0 us~ 66 3.73 i,A.6 Low 2ZO 2.63 3g.O ,,m m rash • i ~sh atSh ~, aiSh | 95 108 2.56 2.90 23.5 37.2 109 2.a~5 23.0 For co~m~l ~anca ~ha fol~ scale4 4ate wire uae~=- ~o~.~.. .t *'" I *"~'1 *'"°'i ~ "~.1*'° 11.,,57 1.0217 1.6176, scaling used was as followsx- Scaled base we/4ht Ave=age base we/~ht " 51 JLvtrllSe &.e.v. Scaled a. •. v. " .... 2.45 ScaLed eolubles Average sol~ble8 Z " 23.0 69 2.85 43.7 i l. 3529 1.1633 1. 9000 .° ". . . o BAT Co LTD - MINNESOTA TOBACCO LITIGATION O °. '~ r',o O",, CO

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-15- TABIJ[ 2 DZSZGN OF EXP~RIH~T (hr~ap 1 1 2 3 4 $ 6 7 8 9 tO I1 I2 13 24 15 16 17 18 19 2O 21 22 23 24 25 26 hlmummm,.~.,.~m 7acr.oz.8 s- t m )sedian Hedian o m L L L L L L L L H H H H R R H H 1 2 3 Fsct.or 2 3 m m ~Im4i-- L4~.dl-- ~Lmm Mmd~Jn L L L L L H L H R L R L R n R H L L L L H L H H L H L R R H H Htun, blr of ]~Lce 120 120 8O ~O 8O 40 8O 60 8O 40 80 4O 8O ~,0 80 40 60 30 80 40 8O ~.O 80 40 60 30 -- ke ~mi$ht a. 80'V. 30O 902 30O 3O2 303. 34O 301 356 302 302 356 303 340 303 356 3OS 34~) 305 356 311:34,O 31I 356 312 34O 312 356 313 340 313 356 314 340 314 356 315 ~O 315 356 316 360 316 356 317 340 317 356 318 360 318 356 Des,-t::Lpt:ion i Acetone control £ceraae + DtaA control Tobacco control 40 mK ?obtco0 nt.1 $6.6 ~dian point 4O ms ~edian point 56.6 mS 8ample B9/3 40 ml; Sample B9/3 56.6 mg Sample Bg/s 40 mS 8mnplLe Bg/s 56.6 mK "L $6.6 mg a, Oms ) 56.6 ,kOmg 56.6 pwr v~Lamzm 56.6 mS IjO~ .56.6 mK JK)~ .56.6 &O 56.6 mB &O m8 $6.6 mK BAT Co LTD - MINNESOTA TOBACCO LITIGATION o oo

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-16- mce3 ~LESOLTS 07 l~c1~ntmgT. M.L D1 Times to D1 D2 4 5 6 7 8 9 10 L1 12 13 14 L5 16 17 1 O 120 2 1 28 L19 3 17 15, iT, 20, 21, 22, 22, 24, 63 2.5, 25, 26, 26, 26, 27, 27, 28, 29, 30 13 l&, t4, 15, 16, 17. 19, 22, 27 23, 25, 26, 26, 27, 29 12 13, 18, 18, 19, 26, 26, 27, 68 27, 27, 27, 29, 29 10 l&, 16, 28, 19, 20, 22, 22, 30 26, 26, 30 16 13, 16, 16, 19, 21, 23, 24, 24, 63 2&, 24, 24, 24, 25, 29, 30, 30 12 17, t9, 21, 22, 22, 25, 27, 27, 28 27, 27, 30, 31 8 21, 23, 24, 24, 27, 28, 29, 31 72 1 29 39 ~7 14, 28, 19, 19, 20, 20, 23, 63 24, 23, 26, 26, 26, 27, 28, 28, 28, 29 IO 14, 16, 21, 22, 23, 27, 27, 30 28, 29, 29 17 12, 12, 17, 19, 20, 20, 20, 63 21, 22, 23, 24, 26, 29, 29, 29, 29, 30 13 15, 15, 38, 18, 19, 20, 23, 27 24, 26, 27, 28, 29, 29 8 20, 20, 2.5, 27, 28, 29, 29, 29 72 24 13, 20, 20, 20, 21, 22, 23, 26 24, 24, 26, 26, 28, 29, 29 13 11, 18, 20, 22, 22, 25, 27, &7 28, 28, 29, 29, 30, 31 ,ll TJ.mss r.o D2 ,tl, 8, -30 9, 9, l.q, 22, 27, -31 4, 26, -30 22, 23, 23, 26, -30 25, ~7, 23, 27, 28, -30 -30 23, ~I, 26, 28, -3I -31 26, -31 28, -31 16, 22, 23, -30 14, -30 22, -30 -30 13, 17, 20, 23, 23, 28, -31 BAT Co LTD - MINNESOTA TOBACCO LITIGATION 0 co

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-17- 3 (Couctu d) Group Number 18 19 2O 21 22 23 24 25 26 i|l D1 Tin: t= D1 D2 10 14, 16, 17, 18, 19, 21, 22, 20 24, 25, 30 8 21, 24, 23, 23, 26, 26, 30, 31 71 6 19, 20, 22, 26, 28, 29 34 18 15, 18, 18, 20, 21, 22, 25, 62 26, 26, 26, 27, 28, 29, 29, 30, 31, 31, 31 7 18, 19, 23, 29, 29, 29, 31 33 16 19, 2&, 25, 25, 26, 27, 28, 66 28, 29, 29, 29, 30, 30, 30 11 15, 16, 18, 22, 26, 26, 27, 29 28, 2g, 30, 30 4 12, 22, 2.5, 30 .56 7 17, 27, 28, 29, 29, 30, 31 23 Times co D2 23, 27, 28, -31 10, 22, -$1 15, 17, 22, -31 15, 22, 26, -31 17, 20, 23, 24, -31 23, -31 D1 - w:mbet of t~ouz'-bes:~:8 animals. T/ross to D I - expe:imaa~sl CLum Oh= msek8) mC wh£ch each of the D1 become t:umour-bea:J~:8. D2 - number of tumomrless demChs. Ti:ses to D2 - experLmmr~l time (in reeks) at which each of the D2 died. ~IE this Clme is ueSaCiTe, then sll the eurvivi~$ aniasls died (or were sa=rtJ~ce4) du:~:8 chac week. Yo: ezample, for Ircoup 26, ~:e animal died &c lmek 23 and the :ems~nS 22 amtamls died o: ~m:e ssc=:r~£ced du~ vme]k 31. BAT Co LTD - MINNESOTA TOBACCO LITIGATION o r',o

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-18- TABI~ 4 Group D1 TLms8 Co D1 D2 Timms Co D2 Humber t| 1 0 120 8, -30 2 0 120 9, g, 15, 22, 27,-31 3 2 30, 30 78 4, 26, -30 4 0 40 22, 23, 23, 26, -30 $ 1 30 79 15, 17, 25, 27, 28, -30 6 2 30, 30 38 26, -30 7 0 79 13, 21, 26, 28, 30, -31 8 0 40 -3I 9 1 31 79 26, -31 10 0 40 28, -31 tl 0 80 16, 22, 22, 23, -30 12 1 30 39 -30 13 0 80 S, 2~, 26, -30 14 O 40 14, -30 15 0 80 22, -30 16 0 40 -30 17 0 60 13, 17, 20. 23, 25, 28, -31 18 2 31, 31 28 20, -31 19 0 79 2.5, 27, 28, -31 20 0 40 1Op 22, -31 21 1 31 79 15, 17, 22, -31 22 0 40 29, -31 23 0 80 13, 20, 29, -31 24 0 40 LS, 22, 26, -31 25 I 31 59 17, 20, 23, 24, -31 26 0 ; 30 23, -31 D~L - mmber of 8nimals ~lth • malignant cumouc. Tines t:o D1 - ezpertmental cJ.uo (in reeks) at mbich the umourobe~rins ant~sl died. D2 -. number of demob8 of ~10 ~J.tbout 8 -.-lJ4~mC L'umm~,r. Tiams to D2 - ezpecimeutml time (in weeks) st which each of elm D2 died. TJ~ chin time 48 negative, Cben 811 of the 8ur3rl~rlnK ~41nsls d~ed (or were sacri£icexi) d~rtnK that: week. Yor emnzple, for frL~up 26, one mLtmLt died ~Ltbout • maIIKnaat tumm~ at ~ek 23 and tim remaining 29 muiuml8 died o: me=e sacrificed during mtek 31. NoCe Cha3C elm onset of amid.grimly 4s det~JJmd ms Ohm C4mm o~ dmsCh o£ an ~1 be~u8 • nmlt4p~nt tumDur. Zn this ezpsrLmm~t all the umlisnant Cummins were d:LjcoveLTed dCet~ h 8acrlflce of • ~mou~-bea~ ~4~sI at; the end o£ the experiment. Thus alt m~L4Knaucies 8re ~ecotded as be~nK detected in week 30 or week 3L. BAT Co LTD - MINNESOTA TOBACCO LITIGATION O r',,o

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-19- TkllI,E 5 DKT& lrRjoH ~ ~ PRm4OTZOH STUDY OT' SdU~I.J~S .~9~2""~ nglS D1 TL,me8 to DZ D2 Hi 14 10, 12, 16, 16, 18, 22, 24, 9I 26, 28, 29, 30, 32, 33, 34 S9/3 19 12, 14, 15, 17, 19, 19, 24, 86 24, 26, 27, 28, 30, 30, 31, 31, 33, 33, 34, 35 Times 1.o D2 3, 5, 13, 20, 20, 21, 23, 2.5, 27, 30, 31, 32, 33, 34, 35, -36 17, 17, 18, 23, 25, 27, 33, 35, 35, 35, -36 B9/4 8 8, 13, 26, 31, 34, 34, 35, 3S 97 8, 22, 28, 29, 31, -36 S9/5 7 l&, 14, 18, 21, 23, 26, 31 98 1, 13, 1..5, 16, 22, 24, 24, 2.5, 30, -36 Tfmms co D1 See £oocnoce Co Table 3. D2 Ttmm8 co D2 Za elL{8 mcperimmnC each animal receLved • sizzle dose o£ i80 ~qj ~ ac d~ O, follos~d by 40 q condemsace Cluree tines each week. -.,,.j BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-2O- T aa~ 6 k - 2.0265 "[ w - 6.6458f for all IWoup8 Sample n9/2 B9/3 S9/4 n9/5 B913 s913 n9/5 Dou 4O &O 4O 4O 40 56.6 4O 36.6 b • 10s | n 16.8638 22.4127 8.5901 7.9763 36.2058 $3.3863 16.1523 3.9112 lu(b) i i -8.687758 -8.403296 • -9.362312 -9.436 US -7. 923706 -7. $35371 -8.730863 -10.149078 t 1 BattelLe WL e.khx= BAT Co LTD - MINNESOTA TOBACCO LITIGATION O "1'~o O

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-21- T~e Period 1-16 17-20 21-24 25-26 27-29 30-32 33-36 Observed 14 8 21 6 13 13 10 ]hcpected 12.436 11.924 15.395 8.867 14.489 11.79G 9.91I Total Xz m X2 O. 197 1.291 2.041 0.916 0.153 0; 124 0.00i 4.723 This tsble shows the obse:vednumbe:s of ~u~-bea:i~lB animals, and the mmbe:s mcpeeted us J~i clu~ patmscers of TabLe 6. Tha t.or.al X" of 4.723 rJ.th 6 degrees of freedom ls s~Ip~Lf~casL: at the 42g level of confL4ence. BAT Co LTD - MINNESOTA TOBACCO LITIGATION Co OD

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-22- TABLE 8 VJd.UES OF S AND V DEIZ'VED FROM THE PARAIWT~ VAI,I.~S GZVEN IN TABLE 6 Condensate Dose $ V x 10"~ B9/2 60 l& 8.301823 19/3 a~O 19 8.&77319 B9/4 40 8 9.313019 B915 40 7 8.775950 :l:tlle n913 B913 B9/5 B9/5 S ~ D1 T14 .D 1:4---8 to D1 1"2. - times to D2 40 16 4.&19180 56.6 12 2.247768 IK) 8 4.952854 56.6 L 2.556753 V- ~[(Tl£-w)k + (T21"~)~ Values of DL, TI~ and T2~are 8£ven in Tables 3 and 5. The valul~s of k fbad w rare 8iven 4., T&bEe 6. BAT Co LTD - MINNESOTA TOBACCO LITIGATION k..r'l C~O r',o OO

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-23- TA3LE 9 TU.0"TG ZC Or coten, SX Zs mg/Z TO .915 CondmnsaCes B9/2 v B9/3 B9/2 v B9/4 KatteZXe qs. B9/2 v B9/5 B9/3 v B91& B9/3 v B9/5 19/4 v B9/5 W£clch~ ~9/3 v B9/5 Rat £o 1.290 0.547 O.512 O. 424 O. 397 0.936 95Z Limits Lover Uppe~ O. 586 2. 836 O. 135 2.21~ O. 112 2.350 0.069 2.592 O.057 2.767 0.375 2.338 O. 100 2.369 The 81opto! thtdooe-rtoponJt ll~t derived £~om rJ~ glcldumdats~ss used to estimate the tumoriSenic Ta~oe o~ the Bs~telledAr~. The tumorLK6~Lc ratio 18 the ratio of condensate dose ~eve18 required to pzoduce equal ¢usmur rates ~ r~e ~s o£ aulmals e.S. B9/2 v B9/3; t8tio - 1.290. Th~s smarts that a dose level of 129.0 ms o£ eoudeuJte B9/2 is equivalont to a dose lervel of 100.0 mg of condeamste ]59/3 (other dose levels pro rs~s). BAT Co LTD - MINNESOTA TOBACCO LITIGATION m %0 Qo .ClO O",

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-24- TJ,3LE 10 KST~'£S OF ~~ PARJd~'t'ZRS YOR THE DATA OF TABLZ 3. TOBACCO COtrl"~L ,Url)PRT V~S ONLY wk ~_ :~339908404888 ~ for 811 groups 3 4 $ 6 11 12 13 14 15 16 17 18 19 20 21 22 23 24 2.5 26 Factor ii 2 Tobal~co cont:~-ol Tobacco coutrol t4ed4--, Median Meal;-,, )htdt.lm L L L L L L L L L H L H L H L R K L R L E L H L W H H R H H H H iml | 3 ~d~Lm~ L L H H L L E H L L H R L L H K TB~:t:o~8: 2 m 8.8.V. 3 " 8oXubles b • LOS 20.4146 37.4535 14.1823 25.0710 20.8396 2&. 0~50 20.9163 34.8528 8.8278 36.5759 19.7553 34.4,r~1 8.1.216 12.9562 19.6032 14.3579 14.4070 23.6518 5.5217 19.3938 l,,(b) m -8.496676 -7.889824 • -8. 860932 -8.291213 -8.476072 -8.33299 7 -8.472396 -7. 961793 -9.335017 -7.91353S -8.529502 -7.973589 -9.418399 -8.95 I355 -8.537231 -8. 848624 -8.845214 -8.268311 -9. 804242 -8.547972 BAT Co LTD - MINNESOTA TOBACCO LITIGATION ¢..,n OO r',o oo oo

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-25- TAS~ 11 ~nc~S-OF-FIT TEST 07 TEE PARAMETERS OF TABI~ 10 i Time Period 1--18 19-.21 22--25 2& -25 26--27 28--29 304- Observed 4O 34 22 22 4). 49 21 Expect:ed 37.0 33.6 28.4 32.9 36.9 40.5 19.8 Tor.al X2 m X2 ,11 O. 24 0.01 1.~6 3.62 0.43 1.76 0.07 7.60 TILLs eable shows t:l~ observed nmabe:8 of tmaour-bea:~q; az.~zsals, sad the mmbe:s mcpected ust~41 elm pa=ameCe: vaXumo of Table 10. The total X2 of 7.60 vEth 6 def;rees of fz~mdom ]Ls silpuLficant at the 59.6Z level of c~.d~ce. BAT Co LTD - MINNESOTA TOBACCO LITIGATION co Q

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-26- TABLE 12 v~,uzs or s At~D V OZP.rV~ rnou 21z ii~ V~,uzs Grv~ n4 ~ lo S lrac:t:or Dome 8 V z ]LOs i ob c:o 40 17 8.3274 56.6 13 3.67LO ' M 4O ].2 8.4613 56.6 20 3.9887 L 40 1.7 8.1376 56.6 20 4.1389 H 40 17 8.2276 56.6 13 3.7300 L 40 8 9.O623 56.6 14 3.8277 E 40 1_3 6.58O5 56.6 10 2.9033 L 4O 6 9.8.503 56.6 6 4.63].O E 40 ].8 9.1822 56.6 7 4.8754 L L 4O 1.4 9.7175 56.6 11 &.2882 [ R &O & 7.2442 56.6 7 .. 3.6094 - ol v - ]~[(rlt---)k ÷ (~Zi-,,)VJ £ T2£ ," t:tmem I:o D1 1'2£ - I:£mt8 to D2 Val,.ut8 of D1, TI~ and 1:24, art 8£ven 4,., Tab1.e 3. The VSLtUe8 Of* tk and v are 8iven 4,, Table 10. BAT Co LTD - MINNESOTA TOBACCO LITIGATION (..7"1 Co r',o %0 r',o

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-27- ANALYSIS OF VAILTAHCZ. • II TABLE 13 TOBACCO COtrl~J~ AND PEZ VARLqNT5 Source of Vaz'taCiou hCq~aD dON levelm lknL~m~ condmsseCes/Dose levels T,,,,cm:~Cious , i Torsi X= d.£. It || J 15.16 • 20.68 9 lO. 65 9 46.49 19 Sisni£ic~mce (z) 99.99 98.58 69 • 95 lie TAN~ 14 TUHO~GaDqIC RATIOSF TOBACCO CON/3~L VERSUS PET VARIANTS CoDdS~JleCe8 Tobacco v M, N, M L, L, L L, L, H L, H, L L, R, E H,L,L u, L, H B, E, L R, H, E u-Cio 0.782 0.893 0.989 0.771 0.965 0.528 0.777 0.791 0.542 95Z Llsdcs Lomtr Upper 0.469 1.1.24 0.586 1.283 0'678 1441 0.457 1.106 0.638 1.434 0.233 0.807 0.474 1.103 0.483 1.122 0.237 0.854 For mxezplmmr.:Louof ~:iSm:£c =&c£os m the foocnor.~teo Table 9. Thome rmelo8 martkmd~lch an asterisk are 8ienificmsC me ~ 95Z congidence level. e BAT Co LTD - MINNESOTA TOBACCO LITIGATION d o r'.,o

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-28- TABLE 15 ANALYSTS 01;' VAKT.AlgCZ 01' PEr FACTOP..q.F.ZXED EFFECTS lqODl[I, 8ounce of Vauriat.Lo= Ha.Ln effect8 lee ode: inteztct~ous/M~Ln t£ftct8 2nd order £nCa:aet'4ons/Maj.n ÷ 1st 3:d orde: inCe:aet~ou/ltsLn ÷ 28t ÷ 2rid Total X2 m~mmammmmmemmmm 21.307 8.43& 5.019 4.284 39.043 /~e X2 fo= maJ.sz e~foccs my be paz~£t~Lonmd u'.- Dose Base ve:L 81u: Solubles &.8.V. 11.156 8.935 1.125 0.091 4 6 4 1 15 ~mmmmmummm The X2 £o: 1st order JLn~eracl=Lous may be DOSe X a. ll.V. Solubles x a.s.v. Dose • base vu:Lfiht: Base we:LlilU: • a.s.v. Base u~L81~ • solublu Dose • solubles pazl:JL t:J. omed 4.980 1 1.588 1 0.652 1 0.632 1 0.326 1 0.256 1 Jill*-- 2'he X2 for 2nd order iutersct::i.ons my be ps=t:/t::ioamd us- / t* I Base ve~shc • solubLes • 8.8.v. 1 4.876 ! [ R,,,-,~ ndez" O. 143 (:) 99.97 72.20 71. ~S 96.1.5 99.92 99.72 71.12 23.71 97.4,k 79.24 $8.02 $7.34 43.20 38.71 97.28 1.38 BAT Co LTD - MINNESOTA TOBACCO LITIGATION ¢,..r'l ",.,O Oo

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-29- TA]K,E 16 ~UJ, YSZ8 OF YAR/AHCE OF PID~ FACTORS. F3:X~D EFFECTS 14DDID. Sou:ce o£ VarLaclan t Ha Main effects lsc order Lnl:erRcc£ans/Y, sLu e~feccs 2rid order/KsLn + lsc , nl i J , t To~l X2 2.5. 713 7. 926 5.205 IIIJJ 38.845 d. f. & 6 4 a i 114, (z) >99.99 75.64 73.31 l'he X2 folr main effects may be pJrt:itJ.oued Dose ~se ue£shc Solubles &. 8oW. a8 12.646 12.853 0.121 0.092 ~m 1 1 1 1 99.96 99.97 27.20 23.84 Tht X: for 1st o:dtr inCericCiouJ ~,y Dole • &.l.V. Base ~8i8b~ : solubles Base me£sh~ : a.s.v. Solubles z a.s.v. Dose z 8olubles Dose z base ~i$~ be pe:r. J.r.J.cmed 2.975 1 2.35~1 2.460I O.07& ! I 0.O51I o.o13! 1 The .X2 for 2rid order inCer~Cions sty be part~Clousd Base misb~ z 8olubles • a.s.v. Dose x base ~Kht • 8otuble8 Dose • so2ubLes z a.s.T. Dose • base me£Kht = a.s.v. 1.657 • O. 798 1.O63 1.687 1 1 1 1 US" 91.$A 87.50 88.32 21.I,A 17.87 9.O8 a8:-- 80.20 62.83 69.75 80.60 BAT Co LTD - MINNESOTA TOBACCO LITIGATION CO r',o .,,,o Co

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-SO- TABLE 27 ,ml,mm~mumm~mmm ~IC ltATZOS~ ~. lt~CO CON'C~LVY, L~S ?R:r VAl~q'rS DamA (e. L. 'k) 40, ,,s oe 7..D,i CL~Q~leaLILtCQI L iiim Tobacco v N, If, N L, L, L L, L, H L, H, L L,. H, H H, L, L H, L, R H, H, L H, K, H ii ]bLt:£o O. 810 0.907 O. 99O O. 8O2 O. 970 O. 582 0.58(; 0.819 0.594 9.5Z LLmi.tn ii Lommr Uppez" O. 543 1.1,01 O. 645 2.226 O. 726 1.348 0.533 1.088 O. 691 1 o 3J,& 0.31.7 O.831 0.3].6 O.92A 0.557 1.101 0.319 O. 872 For an axp1.m---cLon of L'umoz'£s,..,;e ratios see r.he .rooCnoC~ Co Table 9. Those ratios markmd ~ch an asterisk are st~ficauc ac the 951 COUL~Ldence levi1. dr BAT Co LTD - MINNESOTA TOBACCO LITIGATION t..r'l QO

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-31- TABLE. 1.8 ~LYSIS OF V~CZ OF n~ TACTOnS. nS~ZSSZON .NODSLp Ln~Z 4 qU~n~ZC. Source o£ V~iat£on rim, Dose e£fect ~ae ~l#:ht Soluble8 a°SeV° e t Full model X2 12.858 7. Z04 3.01d5 1.534 t 26.523 Thoae e~fect8 m87 be psz~tt£oned d°J~. 1 2 2 2 7 am=-- , ,, , e SLsaLficance (z) 99.97 97.13 78.20 $3. $7 99.91 Base vaisht linear quad~at:Lc ~X~Xu &.OeV. Ruldual To~l quadraVic ii 7.052 0.052 2.117 o.g2g 0.073 1.461 16.22 40.763. 1 1 1 1 1 1 10 ~7 99.21 18.04 85.43 66./*9 21.36 77.32 90,64 m The order of the vmrtables in r~be above table IJzd~csces r3~ orde~ of ontL-y of the re:ms £nto the model. BAT Co LTD - MINNESOTA TOBACCO LITIGATION 0 t_n

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-32- TABLE 19 asaLYs~s 07 VAZL~C~ OF ~-rag-ross sv.G~sszos ~0DF.L~ LOG Lne.~ bad LOG ~AX~Sa~C Souz~a of VarLae4ou Dosa effect Base vdmLShe So lubles 8.80V. Full loSs~ithmLc model X2 12.8.58 7.737 1 • 926 1.723 24.245 These effects ssy be partitioned Base weish£ 1OK Iinea~ lo8 quadratic &. 8or. 88:-- 6.684 1.053 1.478 0.448 0.163 1.561 16.515 60.761 dofo 1 2 2 2 7 i ,i • n StJnifl~e (z) 99.97 97 • 91 61.83 57.76 99.90 1 99.03 1 69..52 1 77.59 1 49.67 1 31.34 1 78.84 10 91.42 17 The order of the vsrLables 4,, the above ~sb18 indicates the order of entz7 of tbt terms t~o tJ~ model. BAT Co LTD - MINNESOTA TOBACCO LITIGATION %.0 Qo

-33- TJ~LZ ~0 ¢l~rT[Cll]rrs 01' 1E~ItZ3$Z~ l: ~ • QGI~tAYZC st nm Hi. ii ~D lJ 4. li~ D W + ]l+ ll2 4 D w*li4..Jz 4 S4.D u 4,. B 4, 18 4. S 4. St 4. O U " " BZ * &4" IJ + SZ 4" D lj ,%1r% ll:t + A4. AZ . 8 4. ir~ • D -I. 63906 -IO.08888 ..@.4,9~JM -9. T;'60? .4.NTSl "S. 74,616 ,,.4j. nlH;9 -0. ~129 Lu r.be ~ove t*b]La, - t D o dON Leve& B - i~B* uelSl~ • u mo]amblmm A m l. ll.lr. -0. 01L~tl -0.11.M4 -O.46612 *0.03B7 -2. 20S60 *0. SSH6 -:.U&42 *0.$73U -0.8SS71 +0. Lt~ 8S ~ralmi m its Tab1.÷ 1. as *O.2JIltO7 -2.720U -3.•2ST? 46.28620 4.tL.t8173 I- e, L~lm]LiJmod + 1800 &. ~Lq3,3]L I..267(~5 1,.21452 1.21~72 4-1.351L59 1.26626 4-1.302].9 I. 26di66 -0.4S702 1.2Si3.5 L -11&. 173 -111. 764 -108.218 -1L08.192 -107.134 -106.669 -!.O6.633 -105.902 Tim uexLum ,mlue for L freu. modal uelu.IB all ~ d•lpSmm o£ freodimm ig Lm .,' -97.793. TAILS 21 m ¢D81rlrZCZ]~TS ~ ISGIIZSSZm lmmG.t LOG LZlq[M * L~ C~EMBATZ¢ Ib4el :~ I ki j, -.B.l~g0t * • -16. 3SI~I n 4. 9 4. D o11.86629 -0.Sgdi~ lm ,* *. Ir2 4. D -34.:13388 4~.1iJ:~5 U 4."*~4. I~t 4- 8 4. • -1.5.MNS *5.10318 U + • 4' I~ 4. S 4. jZ 4. D4.22.60306 -S.20aSO lJ $ • 4. ]lz 4. & 4. • 4. lJ~ 4. I~ *-~.~&N -4.1~5~ n* •4" ]Jt 4.•4. Az $ •* •z.l~ -Z~.]ZIOL~ 4.~.60J0 ~ b, bs -L. 1S5i63 "-O. 6/484 4,0.36071 ~0.S2~O@ -1a . •••tO 44).4?1151 "0.3U3~ -3L.1.55~06 -0./,8042 -2106972~! 44.2M67 $8.6~J105 ]Ln the ebe~e rJd~Le, ! t D la(emm 1.m,sd.) • In Ces~ ,mt.81u:) • In (eelub1-*) • l~(s.e.v.) ". Uueal~ *.5~.1S302 *.2.017N -I. I]667 by L -LIJJ. 173 1.49710 -111.7~ 1.51615 -tOS.aOZ 1. $17"J3 -IOr.87J /.SI~P8 -I01.13~ L.SIS12 -10~. 9]L2 Z.$Zs~'~L -1.06.831 1.50220 -&OS.OSl • 16 ", Lik~IU~ued 4. 1800 1'be --,.,a---- value Ltor L fram • uod~l etsist8 811 ÷be delF, J~ o:[ $ruedom I.• Lu~ - -..g~r.713. BAT Co LTD - MINNESOTA TOBACCO LITIGATION o oo (...r'l

v -3:)- C0~nC1~'tS Or lSGa~Sl~ lmOZi.; ~ * q0anla~c u u la*D u+3,+D u ÷Be•: +8 ÷B ~. Z. BZ +'8÷ SZ.D u +3.DZ*&* S,b liZ ÷D u.•..I;Z.A.•:. 8.~ JZ.D i -0.6~J06 -LO.~M8 .q).41t338 -@.sir/t1 -S.7~14 ,-S. 7ZMII -,0. ~ZZIP m above Cable. - t D = 40aa lsvel • - lk~m led4lb¢ • - oolakles • m 4LelD.V. LLz a~ "O. 38?5;0 -O.OL3Z1 -0.11556 '-,O.~U ÷0.O3257 --2.3O96O ÷0.54;2N o2.2~1&2 ,~O.57248 -O. ~$T1 ~O. 11414 emLle4 as la TabLe 1. as ~ as as . H 44.Z8620 *0.28607 -3.72013 03.5~t&77 -1.~175 L * LikaU.kood * 1JlO0 -1.35859 ÷1.30218 "0.49702 -118.173 L.15U1 o111.7~ 1.Z6765 -108.218 1.~AI52 -108.192 1. ~72 -107. L3& 1.26626 -106.449 I. Z6Ae6 -108.633 1.2.~35 -105.9O2 YIN mszlmss ,ralw ~ L £z~m a model uslm8 ,-~1 ~,t dqnu e~ fre84m t8 Lmz - -97.795. c0111rzc~wJ1 or ~~ li0gm.: Loa l.llzaI ,, la~; ~;aoaTJUC Medml ~4. D P*B*D m4. J+II.D It .6 n + BsP ÷ j 4. D ~÷ a*•Z ÷a.I..Sa÷D u + | . Sz . • ÷ &s ,|. 8 ,[, S.2 ÷ D -8.13906 -14.3.~1 -II.I1644! -3a.$)3M ÷22.10~ -26.31901 Za Use abo~e r, able. D o ls(4ose lew~L) • - ~-.¢k,,, =,4S~) • ,, l s(--~btee) • ". ls(s.s.v.) kl +9.86~2S o'S. 10318 -S. ~0~0 -~. 82512 *$.~OMO Unsaalod -1.1~IM$ -0.44~M ~.52709 4¢).A71L~L • '.O.dd)Ok2 i bs bS 44). )~071 -1L. SSSIO -13. $S206 4~.Z8067 ÷8.S9105 L o IJ.k411bood ÷ 1400 ~7 L -],18,173 1.411716 -111.74a~ L.516L~ -108.6~ 1.$17S3 --107.81• 1.$1298 -~L07.136 *2.15302 1.51512 -LO$.@Z2 ÷2.01789 1.51201 --10~.111 -1.1.~S67 1.~220 -105.0S1 ~ m~l~ ~ L ~'m s medal ~rLm8 811 .,I,- ~ o~ Ib:emlom ts b...= - ..@7.1'1t3. . . • • . ~ .. .. • . , 0 ,, ,.. : - BAT Co LTD - MINNESOTA TOBACCO LITIGATION (...rl

INDEX HAS INDICATED GAP IN BATES RANGE HERE

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-34- 22 n ss .. ,o F c • ~tu~x,,¢ ~t,~. a c' a 4o ckn-zzo .... Source of Vaz'J.aclon nl, Dose e£fec:c ILas4. ImlShc &o 8oVo Solublex ml | ,- X2 . ,. , ,., , 14.350 16.285 0.67S O. 455 31.766 These effects "~Y be pdurl::l.t::1.cmed d,. f. 1 2 2 2 7 411Z-- S:LsnlfLrJnce (z) 99.98 99.97 28.6& 20.35 >99.99 k~e ve~ Sbt 4E. M. V. l~s'J,duaZ e TotAl 12.900 1 3.385 1 0.000 1 0.675 1 0.453 1 O.O03 1 8.797 9 l~O. $63 16 99.97 93. &2 49.91 4.37 $4.38 The orda of verlttJlu in elm shove table lnd.Lc, aces the order" of entry of t:be tez'ms 4nto Cite model. BAT Co LTD - MINNESOTA TOBACCO LITIGATION m k..rl O "-.O

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-35- L ,,, TABI~ 23 ~Yszs o~ vaz~-~:z or ~T ~Acrons sv~'szss'zoN ~n~ LOG ,L3~.~ a:m r.oc ~an~c D&TA 17OR H L H 40 (N~t~L-~W~ Smm:e of Variar.£on X2 Dose eJEfecc 14.350 Base ~w£sht 16.659 a.s.v. O.$09 8olubles 0.058 tt tit Full model :31.577 These ef£ec~s may be p~citt.oned as:- Base we£Sh~ los li~ar los quadrar~L c a. 8. V. Solubles . | bstdual los linear ]Los quadraC£: u|ll O.O58 O.000 |t ts 8.986 40.563 Total d.J~. 1 2 2 2 7 ,n, | Sil~ificJac- (z) 99.98 99.98 22.47 2.86 99.99 1 1 1 1 1 3. 9 16 99.93 97.68 19.03 56.14 The oz~lenr of vaziablea in the above table £ndir..ates rJ34t or.de:: of ~tz7 of tern £nto tba model. BAT Co LTD - MINNESOTA TOBACCO LITIGATION O (_3"1 c.j-!

-M- II p ,e, II i. ,e. II,e* I) m ~-I* ~*A*D n ~]I.IF~.A.A2~II+D ~ ~li:.A. AZ. S. IZ*0 ljz r.he abo~ Ir.aiLa iJ ,, Ilaan I ,, 4oee 1Level I -- llium tml[I~ • - =olibl.e8 ,o~ ~-~on .m~ti ;_,~-~- + ?~-~_-_~-z¢. ii I~ al al 81 --11.14416 -lO. l~dlP7 • -9 o.53091 .-0.59226 -W. 17101 ~Z.17571 -LOM , -1L2.1.1039 4.t. II1r1~6 -I,.07444 ~O.O]L132 -?. SIIA2 4.2. S31137 -O.ttOl7 -7.001L~ -,S. 14.t47 +1.122a0 -0.77'JlS -10. 23282 -$. 17001 ,~!..IM271 -0.ll0ii -10.1111:57 ~t 1¢81iII ~ Lli T~ble I u~lel • b] I~ bs i | u .-I.t~14 lm 4. D -l&.lt2?411 u 4. •. I -11.101Lll] -0.llOS? p 4. • • Ill . D -lt4.NSi7 -34.1435"~ -l.lllT:l • " I1 * • * D -tTollllO *14.7GG10 -'1.15190 -0,07306 Is ~ II 4~ I1 . • ~ &Z ~ !) -41,.IAIIIIS 4,1a.ZOI;14 ,-1.1HI783 -7.191St) u 4. I ~" 1.1 . A * As • • * I -5S.T/O85 +~1.18N0 -I.133M -I~m~l~ Is 4, • • Ill • • • &t ~ I i III i I) -S?.001W3 il2.1M~J -2.142t -10.gs02S ZI r.be alo~ t.able lJ - I~a~ • - 111(4111 I1~11) • - h.Cbu* ~ILS~) • ,, ln(a.s.~.) • - Is(~elub~,,*) i~ is Is .I,2. 7SC~9 +.11.112ill *O. 21507 ,1.I,.07592 *O.$1.1~bib -0.I.0777 I.., I.£k~Lf, kml 4" !.710 17 L --16.6~1 1.37001 -$1;.129 3..$Z381 -32.7110 IL ..57211 -311L.0t7 1.57~11o -21..01"/ 1. SlOaO -IIO.7&S Z.I.llJOi -310.123 1. $$7~$ -:10. S22 usxLsmm ~lem let L ~ • uml~L mrLnll {11, It., l) d~O al i'0=111: +$ola317 44,.~1.$32 *0.11671 e.6.68301 4~. $7201L 11, = 1.Lk~lihe~d +1700 .-O.OlSlZ L .-~.~OS 1.42710 -lll) .I19 11.. 71101 -II.a77 11..IMi15 -IO.IIQO I.III19 -30.114 L, 171.TI -30.iI$ I..1~0~0 -]0.616 I. II~O|I~ -30.61~ Zi~ m~Lm m~l~e ~ t_ ~ • umiieL msl.nB -,z uu, 6,~-,,, ~ ~n,~, ~ ~ - -.~i.~. o c..,l-I (.jrl C~3 BAT Co LTD - MINNESOTA TOBACCO LITIGATION

t q~l[e ~'n 10 40 -,, Ifo~r~ 40.013.32 -7.00196 -LO. 131Jl:t -LO.61.OS? *4 +2.7Nit ÷3° NZi4 44.07SPS' *S i n as -o. 10777 . ~o5 1.37oo6 -39.229 L.$1386 --32.780 1 .S7tlG I 03L.087 L.ST'N0 -31.087 1.511060 -30.7451 LoS$0O~ -30. S?.3 1.o55743 -30.522 ~2,5 L o LL~l/boed + LTO0 Tb8 msz:Lmm 'vslue, £m: L ~ao • node1, u~LoS tim dasroe8 of £zledam 48 Lm ., -26.123. ~lrzll off ~,~,~11 ~i LOG v.~rim.~__ . LOG -'m'~m~'rTC.. _ ~. r.. ~ ~o q ~.ozz': ce.rz':z= I/m1~1 p p 4. D ~j 4. K÷D .~J+J24. D n 4,~ +BZ ~A4~IJ m 4. Ii 4. iz .. & 4. Az ,e. 8 ,e. ~Z 4. ~ ; -IA.~:~744 0L1..80163 • .4&. 985&7 .47.36360 • ..SL. ~JIZ.5 -43.770L5 --57°00873 bl -O.MOS? +~.543~2 4-2d1.. 7f~ IO 4.Z,k. 10~3~ +~L.II81~0 -2.92ST~ -2.953g0 -2.B8783 -,2.63311~ -2,662C~ Za r.ha sbem~ r.able "'- t D ,, 18(4ooo Zeal) • ,, la(bue ~dF.l~l:) mid ds~ • ,, 18(~.o.v.) 8 " ~,,(N1~Ze~) b$ -0,07306 -7.~Rig -lO.OJ.53Ld~ ,-10.ZZO~O t~ *.3..~b3~7 *,4. 41532 .4..68301 bs -4~.Q652L b7 L n -4~. 405 I.lt3700 --3S. 229 1.78803 -33.677 1.86605 -30. SlO0 ]..M499 -3O. In~ 7..87]72 --30.66S 1.860lid0 o30.618 ]L.SeOIA -)0.616 Tlm ~ v81,mt for L fl:mt • mo4eX I11 e.bt #Fete of fnmd~l, in Lu - -~i. 1.l~. • . . • : . • .. ,. . - BAT Co LTD - MINNESOTA TOBACCO LITIGATION O t.,r'l mmalab

INDEX HAS INDICATED GAP IN BATES RANGE HERE

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-37- ~BODS lSousLnZ ~LI an/reals uilZ be housed in ows room of the Laboratory Au/~I Hou8• at rAI~~ This luus a fIoor area of 12' • 13' and 4s mupp14~l by £iltered 81r entar/J~ it via two ducts. IL~cracced air ~s not reclrculaced. The rosa cempmracure mill be malncalned ac approxlmaceZy 22°C. The Laboratory Anlmml House 4s noC stricCIy an S,F.F. unlc buC is bar~e~- ~a4ncained and kids only L.A.C. catssory 3 or & animals. Personnel ontry is r•sCricto4 to W.K.L. •Ca~£ amSaKed 4n bioloKical z~szch ~:k. Entry procedur• includes • hand and arm wash wlCh ant£baccarLal •sap (Scec-r, ac, Bough, lisa••son & Co. Lr.d.), a complete oh•usa of cloch.ing bet not • shouer. £11 scaf£ must wear face masks 4n the m~mml rooms. AZI experimental mark, prior to autopsy, q~ll be ca~ed out in th IF•am reserved for this sL~dy and no ocher auimals ~Lll be housed in it. Also, p~or Co co~mncunmnt, the same :sam w111 act as a quarant4ne unlt. The u~e• vJLll be aeco~odAtmd, 5 to • ease. On arrival they wl.ll be d£scrlbuted in the cales at zm~lom dth respect to pup. Later, in~Lviduals Ln each ease vIII be ldm:t4££ed by ear punch. The eases az~ conscrucsr~d o~ polypropylezm Ir£th s~Linles• steel cops and urn•sure A8 eR • 15 en x 13 ~ (llor~h F~aC Plas~e CaSes Ltd.). They 411 be suspended £n ram of 8 on =ack• ~ch 7 shelves, i.e. 5S cases par rack. The 6 racks rRqu£red, £.0. 336 cakes. ~L~l be si~ted swound the wails of t~a room. Croups wLll be eouf/~ad co ram. 8o time 'the Iowa: eon4ensat~ dome ~zoup• (80 mice) vlll requ£ra ~tm and the b£~ae~ (40 =4ce) one. ~a~h ro~ of 8 cqe• ~11 be moved to s new shelf evaz~ we&, coumenc~n~ on BAT Co LTD - MINNESOTA TOBACCO LITIGATION ¢...r'e (..J'l oO

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-38- tha second ~Ql~r. of qua,c~.~c£~, so ~.izac evm',C~L811y .,-11 ax:.4.mls s~uld a.l:pelr'J.mm.ce a1"s ~ o£ mcl.clL-olm:v'1.r~t in ts.,.b zoom. 7o'Llmrin8 sponCa~tou8 dumb or sacrificts, icts proposed, uhtusvtr practical, ~o move mx/~als co d~L£fe~onc cases v~xin rata same dosa group in ord4r to mainealn a uniform sociaZ equtlibrLum. 2. Food and ]eddinE Wator and £ood - pelLleted diet PRD (C. IK~Z Oroup Ltd.) -vL~LX be suppL~ed ad lil~t~us. Bedding, of autoclaved rood sbavLngs, vLX1 be chan~ad once a vsek and cage8 ~11 be c)Lemsod m~l dlsi~l~ected (Tel;o, Hough, Hoseaoon & Co. Lcd.) sc regular ince~vaX8, HaLt wL~l be removed £~m the back of each mouse once • reek by ~um8 of an elecCrLc c~ippec (Oscmr SmaX~ Animal CT£pper Hodel A5 wLch size 40 blade). Yhe £ni~iaZ clipping ~11 probably extend over a period of severa/ days and ~hem r~e mice will be cllppod once m~re 2 d~ys pr~o~ Co appL~cacion of IxqliA. &. Skin Pa£nvLus Condensate (or aaetCone) ~iXl be applied ~o ~h~ e34ppod areas Ch~e~ ~m88 • w~k by means o£ an au~oma~Le d~spense~ (Sup4~spense~, Hook & Tualc~ %~st~umo~tS L~4.). BeCumms dose Stoups the lus~t rill be ~ashmd out vLth a st~mdszd labora~ory ~e48mst ace~onm. The dose orde~ o£ Stoups vL1). be FAxoA. )?a~nci~I may be. tmzporau=/.ly omitted when Clam akin is damqed, e-S- by clipp~aS Lujury, £nvmr/.~ c~ours, e~c. 5. ObservaCions gv~ry mouse ui11 be ~aiSbs~ and e.vam~ned for l.esLous once a vosk. Oenmral health uilZ be checked daily ~nd norLbund or severely £n~Ju~ed BAT Co LTD - MINNESOTA TOBACCO LITIGATION o ,,,,o

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-39- a~L:als ~11 be sacrificed by athe: £nhalar.ton. Les~ons, dlscove:ed duz~ug the weekly search, ~Lll be descrLbed and maasured wLr~ calLpe=s. room tempe=at~te ranks w£1I be recorded every 24 hours. 6. General Patholof~ All mica uh£ch die or are sacrL~Lced before :armLna~Lon of the exper~Jmmt will be subjected to • L~11 autop8T to detm=min8, i£ possible, the c~se of death, lttLce uay be sac~-~t£ced either £o: humm~ reasons or fc: 4~LslP:OSrJLc purposes. ~ nee~smury the autopsy ~Lll be supplmmmted b7 b~stolo~lLeal and/or mlc=ob~ologLcal examinations. At termi~t~Lon autopsies ~Lll be perfotmad oa all :mt~LtJLnK m4ee and, whe:e gross le~Lons are dtseove:e4, the appz~priate ~ssua8 ~L11 be processed for histolofff. Autopsies w~_11 not 4nelude exposure o£ I:he C.H,S. unless the:e a=e cl£u~cal indications £o~ th£s. 7. ~r Patl~log7 2L11 skin 1astoria (~:mludtq those outside the painted tea) present st te:mlnation, o: on m;ce utu~ch d~e bo£ore tetu~nat~on, ~lL be £~xed ~n LO:[ £otmal~n and processed £ot hLstology. Sections ~Lll be s~-4ned W. j Z. mvtA~ Wbdl~ &l~FJropg~8~t~ by ol:J38r 8]pt~4&~ 1lsl~hods. F01~ ~he purposes o~ tb~s experi~t (and £o: the JAHUS computer ptoSrm) sl~n ~esLons v£ZL be pLsr.e4, by m~c:oscoizLcal examLnatLon, L~co one o£ the £o22o~LnS broad cateSoz~es: Cs) Cb) (c) Cd) C*) !1o skin tu~ o= :eSressed L~m~. llo 4n~otmstLou, e.g. autolysLs, cann~bsltsm, etTOr. Bpltbel~al hypetplast8 or ueoplu£a. llo:-~ptbl~tl utoplas~a. Epidetso~d cyst or keratin gtanulm~. lhr£ua:~ inflammatory reaction. BAT Co LTD - MINNESOTA TOBACCO LITIGATION m O ',,O oo

INDEX HAS INDICATED GAP IN BATES RANGE HERE

LaJlone fou~ tlJt~tre rill W d~fined or ti~ssd.~re specifically ~mever thi• is possible. 8. itacord~ns (a) /n4iv~duA1 mouse reco:d cards ~ £n~ozus~Lo~ recor4ed on these will not be coded snd ui~1 include, on the top side: Identification and li~e history of r3~ house, tre~tmm~t type and dox level, tech~dsn dostns, bodywELsb~s. SeBe=al no~es - m.S. slsns of ILl health m~d seneral par.holofff - autopsy and hlgtoLosy. On the revarsa 81d8 the rmc~le~ Infotmatloa w£11 refer ~le-ly to skin t~s in tl~ painted ~ea. This will cmnpt~se: numbers, sites, sizes, durations {~ppemFInCil, z~KTessions, reappearances, etc.) and patholoL7 (macroscopic mxt nLcroscol~c). (b) Ezpez~unent d~7 book This ~I1 be used, almys in the mzLml ~, as • touKh diary of events, e.8. :ool tempe:at~:e, 4e&ths, cUn~=sl abnormalities, movene~t of -ace, unusual o~cuz~en~es etc. Ent~-les £~ the day book ~Lll, where sppz~pz~ate be tr~nsft=rtd ~o tin iodivldu~l souse record ¢ard~. (~) JmtopsF forms Fost moz~em ~Lnd~u~s, whenever these a=e a3~orm81, tu~11 be recorded on W.LL. standazst mmopsy ~ozu~ prior to e~tz7 on tha Indlvldb~al mouse re~otd ~8:ds. (d) aLstolo:y ben=h bo~ bush notes o~ mL~oe~Ol~Sl ~mSes u~11 be recorded in • separate book pz~o~ to entry on tha £udi~d~al ~mum :acord cards and subsequant coding. BAT Co LTD - MINNESOTA TOBACCO LITIGATION

FIG. I RD. 1517 RE.,~'t'RICTED .PLOT OF Cn (6) VER,SU..5 .On (,DOSE LEVEL). COHI~I.INE.D W'IGKHAM AND BATTELLE PROtVlOTION ,.3TUDIE5 i i |1 | i O ~I~TTELLE X W W~KI-~ (weeu-L ,;) -I'0 "~'0 -IO'D B=)/Z G tR/5 l~/4 IS~/5 3 • ,15.0d. BAT Co LTD - MINNESOTA TOBACCO LITIGATION co

PLOT OF iiii F~. Z ~n (b) VERSUS En (.DOSE LEVEO. GONTROL AND PRT VARIANT5 RD. ISI'T i:=.E~rR ICTED TOtSACC0 =') -8.O -1~.5 ,-9O -9-5 a:em BAT Co LTD - MINNESOTA TOBACCO LITIGATION a~oa "rococo LH L LLH LHH HH L IqEDU~ LLL HHH HLH H LL m <J-I (.,1"1 ',,,.0 (3O

PLOT OF @,a (.b~) FIG. ,.~ RD. 1=31'7 RE6"I'RICTE.D VER, SLJ5 BASEWEIGHT. PRT VARIANT3 i OO3E ,-,4Oa'~l DOSE"5~-6 mcj II ii i _ I~.SE W£ 1~4"r BAT Co LTD - MINNESOTA TOBACCO LITIGATION ea