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IEP01~r NO. ID. 1404 RE~C'IZD 24.8.1976 AUTHOR: R.B. W£1kas LSSI~.~ lJ~: B.E. W£11£s PROJECT JOB HO= 11.05.02 DZb'TRZ~L'ZON: Dr. S.J. Grean Copy Ho. 1 DE. D.G. ¥elCon " " 2, 3 Library I, " 4, 5 COI~N0: ii i i BAT Co LTD - MINN~TA TOBACCO LITIGATION C~

INDEX HAS INDICATED GAP IN BATES RANGE HERE

EBWlLX/46Z>'-2 Group Research & Development Centre, British-American Tobacco Co. Ltd., SO~HA~PTQ~. 2ACh August, 1976 SOb~ FURTI~R ANALYSIS OF AN EXPERIMENT TO com~J~J[ T~ zz~ou~-zqux~r~c Ac'rzvrrzzs oF c(x~zz~sx_~zs FZa~"CX~Z'nZ~ zzg/z ~.V' Z9/6 (Report No. RD. Z40A lestrlcted) SUHHAR¥ This report desc=ibes a stmtlsClc•l amalysls of the data arisln8 from the 3ANUS promoClon experiment cmzpmrlns condensaCes B9/1 end B9/6. The data were adjusted to simulate r~he situation as if the experLmmnt had been terminated •t week 32 or 36 or 40 or 44 o= 48 or 52 as well as the actual teWnLiZmlCiOU time of 57 weeks. Ic is concluded that doses of 120 US and 180 .1 o£ DH3A as Luitiltor mrs too h~sh, but ~he opC/=mm dose level cannot be determ£ned. The 60 U8 level of Dt4~A did however yield uae~uI date. lc is •leo concluded ~hac early tenatnation o£ the experiment may have been possible uelnS the 60 US DHBA groups, the C~oriSenlc raclo belng signlflcanc from week ~A onwards. It is recoemended Chat in future iniCieCor-promotor experimmmts of t.h:l.s kind at least 80 animals per group should be used, and as a rule of thumb the experiment should be terminated when the group ehowlng the lomwC response has • turnout--raCe o£ about 1OZ. BAT Co LTD - MINNESOTA TOBACCO LITIGATION o O4 o~ ".--4

2- L BAT Co LTD - MINNESOTA TOBACCO LITIGATION r~ OO

-2- INTR~DUCTION An earlier report (I) describes the desiKn of cheexper/ment and the analysis of the dace when the experiment was terminated. The objective of this further analysis is to estimate the effect on the s~alysis of terminating the experiment sooner. The exper~nent actually ended at week 56. all surviving animals being sacrificed du~iag week 57. Since the we@ks of occurremca of turnout-bearing animals and else wmek~ of death of animals dying tumourless are known the data can be adjusted to simulate the termination of the exper4~mut at any giv@n week, all surviv/ng mnjJnals be£nK resarded as having been sacrificed dur4~s that week. THE DATA The whole a~jpar~mJnc used 34 L~roups o£ mai~als, of .which 24 Kroups are used in this analysls. These Stoups were subjected to the 24 combinations arising from 2 condensates (Bg/L, B9/6), 4 levels of application (0, 60, 120, 180 ~S) and 3 condensate dose levels (20, 28.3, hO ag three t/~ms weekly). :In the oris/~al report Zhe data arm shown livi~s the incidence of turnout-bearing an/male and the incidence o£ tumourless deaths on a 6-weekly basis. SiJxce durlns the early weeks of the exper~nmnt the numbers of cumour-baarinK mnJJmls mad the numbers of cumourlass duths are small it was felt that the er=o=s introduced by grouping the data into &-week periods would be unacceptably hiKh and so, for this analysis, the data are used on a 1-~s@k bu£s. (Times of deaths and t/ross of turnouts are recorded on a week-b~-wmek bmsis.) Tables 1A r~ 2~A sho~ the data. METSOD OF ..ANALYSIS The data were analysed usinK the We£bull distribution function. Comnon values of the parameters k and w, and separate values 0£ b, were BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-3- fitted Co all 2~ groups by the method of maximum llke~thood. The values of b, k and w are 8hewn ~n Table 1; these values were obCalned ug£ng ~e dace as an week 57. Strictly spaaklng, 4f we ~ro to simulate Ehe analysis of the exper~nc terminated at var£ous times, then the maximum likelihood values of b, k and w should be re-asclmated for each elmg-polnt chosen for taz~inmclon. This procedure would however imvolve a large mmountlnK of co~putlng and iC was decided co fix the values of k and w arbitrarily and only re-compute the values of b. 7rou Table I it would seam Chat k - 3.0 azd w - O would probably fit the data quite well. Table 2 shows the values of b corresponding to chase values of k and w, ~ Table 3 showB the ~odnema of fie £emt for the parameters shown in Table 2. From Table 3 it can be seen that the parameters of Table 2 do indeed fit the data fairly wet1, the value of X2 - 12.088 wlCh 6 degrees of freedom be~ juaC noC significant (iC is siEnlflcanC aC the 94Z level of confidence). The mjor contributor Co chls X2 is Che zroup of animals receiv~ag 39/1, ~0 mE, 120 .8; as treatment. In this group there were more tw~mar-bearinE animals than expected in the ~eaks ~ to 47, trich fiver Chan expected 4n Che muccaedlng 10 weeks. In an expar~JnenC eont:a:tu~uK 24 frroups of an/reals, with relaCivaly few tumour-bemr~ an;,nals in each ~roup, it i8 onlT to be e~rpeeCed Chat one or Cuo groups may show unuemal patterns of inc£dem:e of fiamour-boar~ng animals. Thus the degree of lack of fit Lnd£cated by the above value of X2 is considered Co be acceptable mad the mmalTsis was carried cmC umtJaK k - 3.0 and w - 0 for all time points. The dace were analysed aC weeks 32, 36, 40, ~, 48, 52 and 57. At each of chase c~nm poises values of S mad V for each of the 24 groups BAT Co LTD - MINNESOTA TOBACCO LITIGATION

BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-4- were co,~.tad where S - I Dll ~d V - ~ CDIi + ~21> _Cai - V>k. ~ ~ese expressions DIi ks the number o£ turnout-bear!he animals occurring during week el, and D2i is the number of tumourleas deaths occurring during reek t.. Since we have chosen k = 3 and w = 0 we have V- ~ (DIi + D2i) ts. X Zt can be shown that the maximum likelihood estimate of the WelbuI1 paramtter b is the ratio S/V. Thus, at each o£ the time po/Jxts 32, 36, 60, ~, 48, 52 and 57 weeks ~e have available the max/~Jm likelihood values of b, and the values of S and V, for each of the 24 groups. RZSULTS OF ANALYSIS Using the methods dmscribed in (2) and (3), an analysis of variance was £ormed for each of the time po4ucs. The results are shown in Tables 1B to 21B. The four levels o£ DHBA pte-tre~taeat (0, 60, 120, 180 ,S) were treated separately, and at math of the time points, £or each of the DMBA levels, the Bg/1 to B9/6 tumorigenic ratio (sad its 95Z coufide~ce limits) were calculated. The data from the 0 D~MA Kroups was /~8ufgiclent to allow the calculation of the ~umor/~enic ratio (only 2 t~mour-bearing an/male occurred in these 4 8Taupe); the results o£ this analygi8 of the data £rou the ocher three l~vel8 of ~(BA pre-tteatmant is shown in Fisures 1 to 3. These Krephs show plots of the (natural) Iosarithm of the tumor£Kenic ratio of B9/1 to B9/6 with its 95Z eou£1dence I/wits, the slope o£ the dose/response curve, and the numbers of tUmOttT--bedLT~ anJJnals, versus time. In order to compute the tumoriSen£c rat£o, a parallel line regression of In Cb) versus In (condensate dose level) ks used, the two lines representing the two condensates. Than the In (tumorigenic ratio) i8 the distlmce between the lines divided by the slope of the lines; it i8 the slope of these parallel dose-response BAT Co LTD - MINNESOTA TOBACCO LITIGATION o c.,.rl %.0

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-5- curves that is shown in the graphs. It will be noticed that for the 180 DMBA, and for 6 of the 7 ti~e points for the 120 IMBA group, the confidence reKion of In (turnout rat£o) is not plotted. These confidence limits were not plotted because they could not be estimated, and this siCuatlon arose because the slope of the dose/response curve did noc reach siKnlficance. In Tables IB to 2IB the slope of. the condensate dose/response line is tested for sisnificance using a *'rule of thumb" t-test. The ratio of the slope to ice 8tmadard error is treated am s t-statistic with (N- 3) deKrees of freedom, where N is the number of tumour-bearins animals used in tstlmatinS the slope. Tables 1B to 21B show that only for the 60 DMBA Kroup at week 36 onuards, at reek 48 for the 120 DMBA Stoup, is this t-statistic siKnific~nt at the 95Z level; for the 180 DMNA Kroup it never attains siKn~ficance. The results are shown plotted in FiKures 4 to 10. Where po£ncs are noc shown (for example, 60 DMBA, 20 mK in Figures 4, 5, 6) the number of cumour-bearln8 =~-ls in these groups at the alms-point of the plot is zero. Thus it can be seen that it is not until the analysis at week &8 chat there are turnout-bearing animals present in all the 24 Kroups. Tables 1B Co 21B also show Chat, for the 60 DMBA Stoups zha difference between the condensates B9/I and B916 is siKnif£cJnt from week ~A onwards (actual sisnlficamce level at week 44 - 94.60., 95:[), for t:bm 120 Kroups the betveen-condene~tte effect is always s~nlflcant, and for cht 180 ~ Kroups the coudemsace effect 4s s:LIp~ficamt fz'om week AO ouvards. Thus alr3,oujh ~ slope of the condemsate close-:espouse curve £s, except for the 60 DMBA S:otrpz, lll-de~tamd a difference between the condensaCes is readily detectable. FiEures 4 co 10 quite clearly BAT Co LTD - MINNESOTA TOBACCO LITIGATION k..rl ................................................................................ --'-'r-

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-6- illustrate the situation. Rice often in these fi|ures the dose-response line £or the 120 and 180 D]4KA Kroups is near horizontal or hag a ve~-y shallow slope. On the other hand the seneral ~evel o£ response of the animals to the two ¢ondensates £s always clearly di£Serent, Bg/1 pz~ducL~K am obviously hiKher response than B9/6. DZSCUSSIC~ Two questions are o£ interest:- (a) Is there an optimum level of Dm~ pre-t-reatmant? (b) CouZd the experlmsnt have been teru~ated belore reek $7? (a) FiSures I. 2 and 3 and the analyses of variance, shov quite clearly that, 8enerally sp~tklns, only the 60 Dt4~A 8~oups provide a satlsfactoz7 ulysis. Only at week &8 do the ~20 ~ ~roups provide an estimate of the tumor£Se~ic ratio, and the 180 INiKA 8~oups never do. As noted previously, this ar£ees because the condensate dose-response curves of the 120 DNBA and 180 DKBA cannot be estabZ~shed. This seems to me to ~nd£cete that these latter two lemtls o5 ~ preotreetmsnt are too hlgh. The e~£ect o5 the ~ in4t:Letor has overud3alJned the e~£ect o5 the condensate promotor to such an extent that all condensate dose levels look al~e. All that remains to be seen 4e the ve~-y larks d£55erence betveen the condensatas. The B9 lank term sir'in paiztt~g experiment is now complete, and an initial ana1?sls of unvalidated data gives a tumorisenic ratio 5or )9/1 to B9/6 o5 5.31, i.e. the dose level o5 B9/6 must be about 3.31 times the dose ~evel of B9/]. to produce equal response Ln the animals. The results o£ this interim mmlys£s o£ the B9 long-term experiment are also shown plottnd on lt4ruz~ns I to 3, and inspection o5 these ££Kures shows that £or all the ~ 8Temps the esti~tte of the t~smoz~gen4c ratio is fairly comparable with the lon4;-tetm BAT Co LTD - MINNESOTA TOBACCO LITIGATION ........................................................................ ---.v

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-7- result, but only for the 60 DI~A groups does the slgpe of the condensate dose/response curve become comparable ~th that of the lon4~cerm test, and then only from about week ~ ouvards. Thus the conclusion to be drawn from this analysis seems to be that the 120 ~g and 180 ~g levels of D~ pre-tremCmeut ee certaLuly too h~sh. but whether or noc the 60 uZ level is optima.l is difficult Co establish. Tf it is intended to repeat an experiment of Chlm nature, then • wuld suggest thmc DHBA l~cer-treatmmnt levels of 30 VS, 60 ~K, and 90 US be tried. (b) Obviously. as far as the 120 DMBA and 180 DMBA ~roups are concerned very little would have been lost by carac~c~nK the ozper~nmnc earlier. In general for these groups the condensate dose/response curve is never established and the confidence region for the Cumocigenic ratio cannot be estimated. For the 60 ~ IFcoups however the situation is far from clear. Although a confidence rqion for the tumor/~m~c ratio could usually be calculated, the width of the region varied mnormously, this variacien being governed by the pattern of incidence of the Cumour-bearinl animals. At weak 44 a good analysis was obtained, but st the two succmedin8 t~mm poLucs (weeks 48 and 52) the upper l~mit of In (c~tour ratio) bec~e very high (30.05 and 18.74 respectively). This sharp ~acraaae tea the e upper limit m occasioned by the fact that the numbers of t~mour-baaring 8n~mals occurring with the a9/l condensate continued to increase wlth ttme, whereas the number of tumour-bear/n~ animals occurr/ng with the B9/6 condensate bec~me static from weeks 44 to 52. &c week 57 the incidence of turnout-bearing animals increased in the B9/6 E~oups and the upper l~It of the In (Cutout ratio) was correspondingly reduced. BAT Co LTD - MINNESOTA TOBACCO LITIGATION J ¢...r'l %.0 ............................................................................... -T-

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-8- T~ practice 0£ course it £s the lover 14m~C of_ln (CUnour rttlo) vh£ch is of £nceresc, whe~ In CCtmour reclo) is sruCer Ckan zero i.e. vhen the cumorisen£c ratio is K=eacer chart 1.0. Zf the ~over I~n~c of In (Surtout ratio) is SreaCer Chart sere Chert the t~mor£ge~ic rac£o £s 8izn~££cantly Kremcer Chsn 1.0. ThLs s£cuac£on occurs for the 60 DHBA groups after week 44. Thus aC any time on. or afcer week 44 the experia~nc could have been term/hated and the 60 DMBA SToups would have shown the tumorigenic =atio between the coudensmtes to have been significant • Much of the fluctuations in the Krsphs shown in FLsures I co 3, e.g. the exceptionally high upper limit for In (Cumour retie) at weeks 48 and 5 in ¥£Sure 1, is due to the fact Chat there ~tre only 21 m~dmAls per group £. e. at etch level of condensate dose and ~ pre-t~eatnnmsC only 21 animals vere used and thus the 4ncldence o£ only ]L or 2 hey tumour-besr£uK enLmals has • marked effect on the m~ly8£8. ~ larger poups of m~m-ls had bee used then the inc4dmnce of ctunour--bear~aq~ ~le is usually smoother and the situation as ac weeks ~8 and 52 in Fisure 1 would have been less l£kely Co ar£se, so thac the effect of ~s:ly termLnatiou on the 60 DHJA ~oupe (or the other ~HBA levels) would have been clearer. The overall conclusion seems to be therefore t~st there -.=,y be some advanCase in terms of t~ne saved (and consequently ~ Co:ms of cost of experiment) Lf the 60 DHBA Stoups had been cermtz~ted on or after the 44Oh week. But 4f £t is intended Co adopc th~s procedure £n future exper/mencscion the nmnbers of animals used oushc co be considerably increased so as Co scab£14se the incidence o£ cumour-bear£uZ BAT Co LTD - MINNESOTA TOBACCO LITIGATION O

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-9- anLmals. As a rule of thumb Z would sussesC us£n4 e~ least 80 anLmals per Stoup, and scopp£ng the exper~aenc when about IOZ o£ the animals have become cumour-bearins An the Eroup showing r.he lowest response. assumes thac morcallty effects rill be relatively 8mmll, CONCLUSIONS 1. ~e o ~e Thls Dose levels of 120 ~S and 180 ~g of DMBA as prrtrut~:ts in an in~tia~or-promotor experiment are too h~Eh. A dose level of 60 ~S of DH~k produces useful data, but 4t yes not possibie ¢o esr~tblieh that this m the optimum dose level. Xarly tetz~Lnation of the experiment (i.e. before week 57) may be advantaseous if the 60 ~S DHBA level of /nltiator is used. The determ~uatlon of the stopping time would be made easier by the use of larKer ~:oups of animals. ..KEFFJLEHCES 1. "The dtsip and analysis of an experiment to compare rJ~e ~mour- proaott~K activitles o£ the condensate from ciKarettes B9/1 and B9/6". E.B. Wilkes. G.l. S D.C. Keport No. RD.11$2-u, October 1974. 2. "Pseudo analysis of variance o£ mouse skin ptintinS emperimmnts uslnS • ge£bull dlstrlbutlon with known k and v". P.N. Lee. Z.R.C. Docmaent E828, RlO03, 1970. 3. ''We£bull dlstr~but:ions £or continuous catc/JBolenesls ezperCmonts". R. PeSo and P.H. Lee. Biometrics 29, 3, pp. 457-470. BAT Co LTD - MINNESOTA TOBACCO LITIGATION .-,.,j

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-10- TABLE 1 VALT~S OF T~EZBULL PARAHETJ~ Det:a as at: week 57 k - 3.036928 w - 1.257767 C"; gareCte Type 159/1 B9/6 Values of b x 107 mm 0 B 2.448O 2.6652 D Condensate Dose 2O 28.3 20 28.3 4O Dtl3Al,evels 6O 13. 7647 23. 1557 40. 6180 8. 6951 9.O304 18. 7469 120 34.4362 62.6274 61.6589 11.A721 6.5674 11.6800 180 32.0980 22. 8662 39.5213 13.23~3 6. 6154 16.7/,04 TA3LE 2 VALUES OF ~IEZBULL P~TERS Dat:a as at: week 57 k-3.O v-O Ct|a:et:ee Ty'pe B9/1 39/6 CoDdensMte Dome 20 28.3 40 20 28.3 JK) Values of b x 107 | ~& ~e18 i ll= O ,i | i ! 2.6535 era. 2.8855 6O 1/,. 8728 27.1010 &3. &077 9. 3973 9.7~9 20.2857 220 37. 7067 A5.3070 65. 7015 12,3981 7.O738 12,6156 180 34.5525 24.6570 42.5377 14. 2497 7.1285 18.0446 BAT Co LTD - MINNESOTA TOBACCO LITIGATION m %.0 C C...r'l

INDEX HAS INDICATED GAP IN BATES RANGE HERE

C -11- ( N O ~3 I Z Z 3~ @ © w--q @1 Z Z Ol, lC>l;,c O 1 Tuu~.._._.! GOODNS$ Of ~T Or ~ fMtNl'rlNJ ~ TJdil.Z 2 0 " obeerved mire e| tumom~-bea[[u8 mitotic. | - ezpeeted mmbere of L~amur-bemrin8 Aimle. aroup m/I N.0 89/I 21.3.0 I~ll W.0 M/6 110.0 Bg16 28.3.0 19/6 4O.O Igll 2O.t0 HII 21.3.60 Hit W.60 m16 2O.60 W16 n.3.eo MI6 w.60 J911 10.120 mll ~1.3.12o M11 ia,12o rot6 10.12O B16 |1.3.12o 1916 W.12O Hll 110.1110 Nil 21.1.180 n911 40.180 1916 2e. 1110 8916 2|.3.11O 11916 ~,100 TLue ferlod8 ToteLe o - 26 40- tt ~5 - 49 50 - 53 54 - 57 0 l 0 B 0 l 0 I O l 0 • I0! 0 .III 0 .573 0 1.03;~ i 1.627 0 .34~ 0 .3;3 I .7Y8 1 1.399 1 1.634 1 2.333 0 .459 O .26t l .487 ! 1.271 2 .~2 3 1.599 ! .550 I .277 ! .666 I-- 0 .115 1 .112 1 .TM 4 1,167 0 !.116 1 .117 2 .162 1 ,970! 2 1.481 1 1.313 5 1.091 O .Srdl 0 .3OI 0 .605 0 I, 32¢ 0 1.140 2 !. 722 o .601 0 .283 O .790 27- 3* t 35- 39 o I o S m w m 0 .118 0 .113 . ~ m m 0 .128 0 .116 0 .6;00 .595 1 1,178 1 1,012 2 1,73t 3 1,414 0 .401 O .)(DO 0 .425 1 ,301 0 ,NO 0 ,79o 1 1.505 i !.254 2 1.603 1 1.21| 1 |.330 1 1.770 o ,535 o .tSt .295 o .2,7 0 .$74 1 .507 1 1.400 1 !.103 1 hOOt 1 ,938 0 1.767 3 1.678 o .613 1 .5~) 0 .304 0 .237 1 ,725 1 .(A0 11 18.307 16 15.285 .0331 m 0 .179 0 .17~ m m 2 .82O 0 1.547 ! 1.253 0 .4J7 0 .513 0 1,124 3 1.660 3 1.31S 4 1.94| 3 .67t 0 ,365 2 ,693 3 1.490 3 1.130 1 1,900 1 .609 1 .343 1 • 097 m o i .163 m 0 .168 1 .729 1 1.110 1 1.oa$~ o .4~6 0 .4t8 I0 .9711 1 1.413 o 1.049 1 1.509 0 .5Q3 o .216 0 .635 1 1.284 o 1.o34 1 1.$88 o .534 0 .302 o .iM o I m 0 ,163 m 0 .162 m m 1 ,/00 1 i,0|12 0 .917 2 .411 O .439 5 ,SiS ! 1.~0 1 .|IS 0 1.2:~ 1 .513 1 .~15 0 ,592 1 1,068. o .~)41 1 1.40~ 1 ,517 0 .277 1 .61~ 1 .993 m 1 1.003 5 t.O0~ 8 1.86~ | 9,600 3 1.88t 3 3.041 1 6.151 10 9.912 9 1l.O4~ 13 13.03) t 3.|26 1. !)13 4 t .093 9 9.020 7 7.309 II II,4~0 4 3.9S4 2 Z.023 $ ~.o23 Tot+el Xz - I|,M8| vith 6 dqiree8 of freedom. SilnffJceuce level 93.S971. Terrain 17 16.814 10 l;.ttt 28 lg.021 8 16.005 17 14.115 i17 117.163 Xl .001| .3739 4.2386 4.0030 0.5202

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-12- TkBLE N=21 D~SA - 0 ~umber turnout-beaten8 animals = 0 Weeks of detect£on = - Nu~er eumourleas de~hs .. 3 Weeks o£ detection = &&. 50, 52 Number sacri£icod at week 57 - 18 Dose = 20 mg. Bg/1. TABLE 2A N- 21 DHBA- 60 Humber cumour-bearins an4s~ls - 5 Weeks of det:ect~on - &3, &7, &8, $0, 56 Number cumourless deaths m 2 Weeks of detectLon - 40, 48 Number eacr~Lf£ced et week 57 = 14 Dose - 20 mS. Bg/1. N = 21 DMBA = 120 Number Cumour-beacr/~i animals - 10 Weeks of detect~on~ 11, 27, 36, AO, 41, A7, &9, Ag, 50, 56 Number tumou=lss8 deaths m 2 Weeks Of deCect£on- 29, 55 Nuaber ~acrL££ced at mk 57 - 9 Dose = 20 m8. B911. BAT Co LTD - MINNESOTA TOBACCO LITIGATION %.0

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-13- TABLE 4A H - 21 ~- 180 Humber ~u~our-bear~ an4~=18 - 9 Weeks of detect£on- 20, 20, 29, 36, A6, 47, 48, 52, 56 Humber ~Lmourless deaths = 4 ~eks of detection - 19. 39, 55, 56 Humber sacr/~£ced at rock 57 - 8 Dose - 20 mg. B911. T~SA N - 21 DMBA - O Humber cumour-bearlnS auimaZs - 0 Weeks of 4e:ec~ion - - Number ~umourZess deaths = 3 Weeks of detectlo~ = 23, 34, 49 Humber sacrificed at week 57 . 18 Dose - 28.3 mS. 3911. TABLE 6& B = 21 DHB& = 60 Humber tunouz~-bear4-8 an~Jnals - 8 Weeks of detection - 29. 37, 42, &A, ~, ~, 52. 57 Number ¢umou~less deaths - 2 Weeks of detection - 39, 50 Humber sacrif£ced at woel~ 57 - 11 Dose = 28.3 ms. B9/1. BAT Co LTD - MINNESOTA TOBACCO LITIGATION c..r'l %..0 u

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-14- TA3LE 7A N - 21 DHBA = 120 Nmaber tumour-besr~ anJ~mZs = g ~eeks of detecC£on = 22, 27, 33, 36, AO, AS, AS, A6, 56 Number L~Jmourless dear.hs - 6 Weeks o£ de~ectio= - 22, 23, 29, 34, 39, 46 Number sacr{fLced 8¢ week 57 - 6 Dose - 28.3 ~. B9/1. TJJLE 8A - 21 DH3A - 180 Mumber ~Jmourobesring anneals - 7 Weeks of deCecclon m 9, 22, 27, 38, &7, &9, 49 Number tumourIsss deaths - 3 Weeks of detecClon m £6, 47, 56 Number sacrificed me ~tak 57 m 11 Dose - 28.3 ~g. n9/1. YJ~LE 9A 8 - 21 . ~ - 0 Number Cumour-bear£~ an~ls = 1 Weeks of detection = 50 Humber tumourles8 deaths - 1 Week8 of detection m 50 Number sacrificed at mk 57 - 19 Dose - &O m g. n911. BAT Co LTD - MINNESOTA TOBACCO LITIGATION m C~

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-15- IOA N - 21 m~KA - 60 Nunber tuuour-bearin$ tn~uaZs - 9 Weeks of 4etec:ian - 18, 23, 28, 30, 35, 37, 37, 48, 50 Number tumourless deaths - 5 ;/eeks of de~ec:ion - 30, 40, &l, &4, Humber 8acri£iced at week 57 = 7 w° Dose - 40 :K. B9/1. v TABLE 11A N - 21 D)fl~ - 120 Dose ~ 40 mE. B9/1. Number tumou~-bear~g animals - 13 Weeks of detection - 18, 27, 38, 40, 40, 41, 44, ~, 46, 48, 46, 47, 50 Number cumourles8 death8 m 3 Weeks of detection m 17, 29, 38 Number "sacrificed at: week 57 - 5 12A N - 21 ~ - 180 Dose - 40 inK. ttumber L~mour-beaT£nS 8nJ~sls - 11 Weeks of detection - 17, 21, 22, 36, 37, 37., 40, &2, 46, 52, 57 Humber tumourless deaths - 0 Weeks of detection - - Humber sacrificed at reek 57 - 10 S9/1. BAT Co LTD - MINNESOTA TOBACCO LITIGATION o ,,,..o

V ./7 BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-16- 13A N'21 ~-0 Humber turnout-bearing animals -0 Weeks of detection - - Hwnber L'dmourltse deaths - 2 Weeks of detection - 25, 49 H~mber ss~r~£ced at reek 57 - 19 Dose - 20 ~. B9/6. ~ .. 21 DMK~- 60 Number tumou~-bear~ enamels - :3 Wee~s of detection o 40, 55, 56 Number twnourless deaths - 6 Weeks of 4etect::Lon ~ 11, 38, 39, 46, 56, 56 Numbe~ sae~££iced at week 57 - 12 Dose - 20 mK. B9/6. N - 21 ~ - 120 l~unbe: t~ou~-beart~8 ~ls - 4 Weelus of detection - 46, 49, 49, 57 Humber t~mou~less deaths - 4 Weeks of detection ~ 13, 34, 48, 53 lqumber sac:/~£ced at week 57 - 13 Dose - 20 ms. B9/6. BAT Co LTD - MINNESOTA TOBACCO LITIGATION "'.-,d

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-17- TA3LE 16A J N - 21 nMK& - 180 Number tumour-be~rinK animals - 4 Weeks of detection - 25, 38, 45, 57 Humber tumou=les8 deaths - 6 Weeks of decoction m 27, 3P, 40, 44, 45, 47 Number sacrificed st week 57 - 11 Done - 20 inK. 3916. 17A N - 21 ~t4~A - 0 Humber t~mour-bearinK animals - 1 Weeks of detection- 43 H,--ber t-umourlese deaths - 3 Weeks of denection = 23, 39, 55 Number sacrificed at week 57 - 17 Dose m 28.3 inK. rag16. TJJu~ 18A N = 21 m~R& m EO Number t~mou~-beariu~ Jmimals - 3 Weeks of detection- 36, 41, 43 Hmaber t~/mottEles8 deJtth8 - 4 Weeks of detection = 24, 42, 44, 4g Number sacrificed at week 57 = 14 Dose 28.3 ug. ]J916. BAT Co LTD - MINNESOTA TOBACCO LITIGATION C...~ ................................................................................ • ---r

BAT Co LTD - MINN~TA TOBACCO LITIGATION ".,.O r,,o

-18- TKKLE 19A N - 2I ~ - 120 N,--bet C~ou~-bear~g an~nals - 2 Weeks of detection = 34, 54 Humber tumourZess deaths . 10 Weeks of detection - 18, 26, 41, 41, 42, 51, 52, 53, 53, 5A Humber sacrificed aC week 57 - 9 B' Dose - 28.3 mS. B9/6. T~LE 20& N - 21 ~ - 180 Humber turnout-bearing animals - 2 Weeks of deCecClon - 25, 46 Humbe: turnout'less duChs - 7 We~s of dete~c£ou - 3~, 32, 32, 33, 40, 49, 54 N~e: sac=if iced at week 57 m 12 Dose - 28.3 mK. Bg/6. TABLE 21A N=21 DHB& m 0 Humber Cunouz'-be~a4 m~aals - 0 We~i~ of detect:£on - - Humber tumourless de.st:hs - & Weeks of dececC~- 22, 32, 69, 51 Humbe= smc::J.flced at week 57 - 17 Dose m AO mS. 3916. BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-19- 22A ...... = N " 21 ~ - 60 Humber tumou~-bearLn$ anLma$s - 7 Weeks of detection - 26, 40, 54, 55, 55, 56p 57 Humber t~mourXeml death8 - 1 Weeks of detect:~on " A8 Number lecri££ced at week 57 - ~3 Dole = 40 mK. B9/6. TABLE 23A N " 21 ]~t4B& m 120 Number Cumour-beari~S aniuULll - 4 .m Weeks o£ detection = 22, 35, &7, &7 Number CumourIel8 deaths - 3 Weeks of detection m 39, 45, 55 Humber lacrif£ced at reek 57 - l& Dole - AO ms. B9/6. ~4 TABLE 2~A N " 21 ]DH]tA " 180 Humber Cumour-bearins au/:~ll = $ Weeks of detection m 20, 30, 39, ~7, $7 Number t3Jmourlemsd88the m 6 Weeks of detect£ou = 21, 24, 48, &8, 50, SS Number ~ncr~£ced at week 57 - 10 Dose - &O ms. )916. BAT Co LTD - MINNESOTA TOBACCO LITIGATION r,,o

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-20- level:- 60 uS TAN~ 1B AI~LYSZS 0Y V&KIJ~CZ Time'- 32 weeks So~irce Between ciKs~ceCte8 Condensate doses/cigarettes CiKs~ecces ~ doses Dose linear Dose non--1 ~aear Total X2 d.£. 2.9366 1 8.2838 2 0.3704 2 8.0041 1 0.2797 1 ii 11.5908 5 In (b) = tt + a l 4. a2 In (dose) Cisarect:e ed~fec:t - aI - 1.679211 Dose/response Fadleut - 82 - 5.661305 T~rJ4~enic ~st:io m up (ml/a2) - 1,345 95X limLcs:- 0.91 to 1.15 x lOs Ratio:- az/S.Z. (a2) - 2.01 (93.1X) Total .C.b.a. - 6 s~m. z 91.34 98.41 16.91 BAT Co LTD - MINNESOTA TOBACCO LITIGATION %O "-.d r',o

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-21- level:- 60 ug 2B JL~U~I.TST.S OF VAP.~CE Time:- 36 vee~s Source X2 Be~een cilitreCCts Conde.t]dsat;e d~s es/cigareCCes C~K~L~eCtes e doses Dose l£neax Dose nou-l£neo.r i i Total 2.1768 9.3460 O. 9623 8.5374 O. 8086 • i , • ,el 12.4851 d.f. 1 2 2 i 1 5 Hode1"- in (b) - . 4- a: + s2 1-, (dose) CiKa~eCte effect .- a1 - 1.19631& Dose/response ~adJ.ent m s - &o601098 2 Tu~nriemstc ratio " 8Xp (el/82) -- 1.297 gsz t~nics:- 0.905 to 7.057 Bal:;o:- 82/S.E. (a2) - 2.30 (96.5Z) Toes1 o.b.e. - 8 SiS. Z 85.99 99.07 38.19 99 • 65 63.15 BAT Co LTD - MINNESOTA TOBACCO LITIGATION O (..J'l %0 .-..,q

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-22- level -- 60 ug TABLE 3B ANALYSIS OF VARIANCE Time:- 40 weeks Source Between ciglureCCes Condensate doses/cigarette8 C£sarecces *dolts X2 2. 1652 9. ~363 3. 1002 d.f. Sis. g 1 85.88 2 99.09 2 78.78 Dose l£nesr 9.4024 Dose non-l£neer 0.0039 Total 14.6716 1 99.78 1 4.98 5 Model:- in (b) u ~ + aa + 82 In (dose) C£1;axel:ce effect - aI - 0.939528 Doge/response jTadient . m2 . 3.444056 Tumorigenic raC£o - exp (alia2) - 1.314 95g limltss- 0.926 to 3.382 EaC£o:- a2/S.E. (a2) -2.66 (98.8Z) Tonal t.b.a. - 13 BAT Co LTD - MINNESOTA TOBACCO LITIGATION c.am r',o

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-23- 2eve1- .m 60 ~g TABLE &B LNALYSIS OF VARIANCE T4m*=- ~4 reeks • eL~eem ciKmreCtes Condeussce doses/c£sm:eCtes C£lmrectes * doses X2 3.7118 7.228O 1.1888 d.fo 1 2 2 8iS. Z 94.60 97.31 44.81 Dose linear Dose non-llnear ToCal 5.3318 1.8962 12.1286 1 1 5 97.91 83.15 Hodel:- lu (b) -. ÷ aI ÷ a2 In (dose) C£$a:eCCe e~£ecC - s1 - 0.972316 Dose/~espoDse ~iemc m, s2 m 1.908144 Tumor£sen£c ratio - amp (ml/&2) m 1.665 95Z l~m4Cs=- 1.008 ¢o 81.822 ~Clo=- e2/S.E. (s2) - 2.22 (98.0Z) Total t:.b.&. - 20 BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-24- level:- 60 ~g TABLE 5B ANALYSZSOFVARXANCE T~:- Source BeCvssn CLKaZettes Coudens&te doses/c£gazettes CiKarettes * doses Dose linear Dose non- 1£near Tor~tl X2 i 6.37/,9 4.6925 1.0056 A.2297 0.&628 12.0730 ~del:- In (b) - V ÷ aI ÷ a2 In (dose) CiKarette ef£ect = a1 = 1.198353 Dose/response gradient - a2 t 1.557830 Tumorigenic ratio - exp (al/a2) m 2.158 9SZ 1is~.=s:- 1.176 to - Kat/o:- 82/S.E. (a2) - 2.01 (97.1Z) Tor~l t.b.a. - Z3 d.f, I 2 2 1 1 S 48reeks SiS. Z 98.84 90.43 39.52 96.03 50.37 BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-25- o~ 6O ~g TABLE 6B or yxnJJ cz o' Time:- 52 Source i i BeL~Veel~ cilax'et tea Coudensate doses/cigarettes C£Sm.rel:tes * doJeJ X2 9.6L81 4.7251 1.0970 !d.f. sis. z 1 99.81 2 90.58 2 42.22 Dose 1Lnear 4. ~)28 Doses uon-l£near O. 3223 Tot81 15. ~02 1 96.~1 42.98 $ L~del:- In (b) - ~ + a1 + a2 In (dose) Cigarette e~fect - aI - 1.&O39&6 Dose/response gradient - • = 1.&92938 2 T~mor£gen£c rat£o - e~ (a:l/a2) = 2.561 95X 1£m£ts:- 1.337 to m ]Lst£o:- a2/S.K. (a2) -2.06 (97.5Z) Total t.b.•. - 26 atom-- C> BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-26- DHBA level:- TABLE 7B ANALYSIS OF VARIANCZ 60 US Becveen ciKmrec~ex CondeneaCe domes/cismzetCoe ClsaceCtes * doses Dose linear Dos8 non-lLn~ar X2 3.86OO $. 4132 O. 3209 Total 9.5942 Tim4= - d.f° I 2 2 1 1 5 57 v~ks Sis. Z 95.06 93.32 14.82 g7.96 14.26 Modsl:- In (b) - . ÷ aI + a2 In (dose) CismrecCe effect - a1 - O.765875 Dose/response sradlent m a2 m 1.420382 TumoriKenic ratio - oxp (al/a2) " 1.715 95Z ltmLCs:- 1.058 eo 42.027 hCioz- a2/S.E. (82) . 2.28 (98.$Z) Total c.b.a. ~ 35 BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-27- DHBA level : - 120 ug 8B &t~J..YSIS OF VJU~[J~ ~o' TjX~:- Source X2 Jl Ni, 3eL~ee= ciKa~Te~tes &,. 2855 Condensate doses/cigazettes 0.28~ Cigazet~es w doses 1.8863 d.f. 1 2 2 Dose l~:ea: 0.2~Jd) 1 Dose not~ linear 0. O&IA 1 Total 6.A571 5 Hodel'.- In Cb) - U + aI ÷ a2 1= Cdose) Cigs~ette e~fect - a1 = 1.8587&4 Dose/respoDee gYsdient - a2 m 0.659777 Tu~ori6e:L~C ratio - e~p (al/a2) - 16.730 95Z Z~J~ts:- cannot be calculated Eatlo:- e2/S.E. (a2) -0.49 (67.5Z) Tote1 t.b.a. - 7 32 vee~s SiS. X 96.16 13.30 61.06 37.87 16.12 BAT Co LTD - MINNESOTA TOBACCO LITIGATION ",,o ",O

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-28- DHBA leveI--- 120 ~B J~kLYSIS OY VAR3ANCZ Source Betveen ciKarettes Condeumate domes/¢~Karette8 C£Karettes * doses Dose linear Dose non-linear X2 3.6854 0.6724 2.8698 O. 1~0 O. $183 Tot81 7.2276 p° Time=- 36 weeks d.£. S£g. Z 1 94.51 2 28.55 2 76.19 1 30.$3 1 52.8~ 5 Hodel:- In (b) - ~ + aI + m2 lxa (dome) ¢Lgaretce e££ecc - a1 - 1.188336 Dose/response K=adient - a2 m 0.397060 T~r£menic ratio - exp (81/82) - 19.942 9SZ limits:- cannot be calculated Ratio=- a2/S.Z. (a2) - 0.39 (64.7Z) Total t.b.a. - 12 BAT Co LTD - MINNESOTA TOBACCO LITIGATION k..rl %.0

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-29- DMBA level:- SOUECe 120 ~8 TABLE 10B ANALYSZS OF VARIANCE Between ciKa~sttes Condensate doses/ciKarettes Cisa:ettes * doses Dose l£ne~sr Dose non-linear X2 9.0432 1.O847 1.99.50 0.89h9 0.1898 Total 12.1229 Time:- d°f. e 1 2 2 1 1 5 40 weeks SiS. Z 99.74 41 • 86 63.12 Model:- In (b) - ~ + a1 + a2 In (dose) Cisarence effect - aI - 1.659857 Dose/response Er&dlent . a2 m 0.804559 TumoriEenlc =atlo - exp (al/a2) " 7.870 95Z Limits=- cannot be calculated Katio:- a2/S.Z. (a2) - 0.96 (81.8Z) Total t.b.a. = 17 BAT Co LTD - MINNESOTA TOBACCO LITIGATION %0

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-30- lave1:- 120 ug TABLE lib Ab~LYSIS 0Y VAR3ANCE B, Time:- 44 week8 Source X2 d.f. Sis. Z k~wten cigarettes 14.3973 1 99.98 Co~de~sitt dolts/c4j&rettts 2.1209 2 65.37 Cigarettem t doses 1.6982 2 57.22 Dose linear Dolt non--linear 2.1142 0.0067 Total 18.2164 1 85.tl 1 6.52 5 ~>dtl:- In (b) - U ÷ aI + a2 In (dose) C~8arette e~£ect - 81 - 1.958985 Dole/~espouse ~adLent - a2 - 1.116325 Ttsmori.geslic =triO m 48~p (81/82) m 5.783 95Z 14mit8=- cannot be calculated lac:i.o:- a2/S.E. (a2) - 1.43 (91.$Z) Total t.b.a. - 21 BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-31- level:- 120 ~g TABLE 12B ANALYSIS OF VAKIAHCE Time=- Source BeL~een ciKarettes Condensate doses/c~Karettes Cigszettes * doses X2 18.1682 5.0542 0.8114 d.f. 1 2 2 Dose linear $.0323 Dose uon-l£uear O.OO19 Total 2A. 0338 1 1 5 Hodel:- In (b) = u + a1 + a2 ]L~ (dose) C£$arette e££ect - 81 - 1.703231 Dose/response Krsd£ent - 82 - 1.401A32 Tumor~Sen£c rat£o - ezp (ez/a2) - 3.371 95X li:~ts:- 1.391 to- ILac£o:- a2/S.E. (a2) - 2.L9 (98.2.Z) Toes1 t.b.8. - 32 68 veeks SiS. >99.99 92.01 33.35 BAT Co LTD - MINNESOTA TOBACCO LITIGATION %.0

INDEX HAS INDICATED GAP IN BATES RANGE HERE .......................................................................... --""T

-32- DH2~ ZeveX: - 120 Ug A)gALYSZS OF VA]tZANCE Time=- 52 weeks Source X2 BeL~esn CiilLCaCCeS 20.3990 Co,,AensaCe doses/c£Sareeces 2.9172 Cigm:oCees * doses 1.0170 1 2 2 SiS. Z >99.99 76.74 39.86 Dose linear 2. 1929 Dose =o~-linesr O. 7243 To tel 24.3332 1 1 5 Hodel:- lu (b) - . ÷ a! ÷ s2 1- (dose) Cigarecce effect - a1 - 1.619968 Dose/response gwed£enc - a - 0.833235 2 Tumorisenic ratio - exp (al/s2) -- 6.988 95Z 14m;CS:- cannot be c41culsced Ratio:- s2/S.E. (a2) - 1.47 (92.5Z) Toes1 C.b.a. - 38 BAT Co LTD - MINNESOTA TOBACCO LITIGATION m C~ ',..O

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-33- level-- 120 tJg T.~LE 14B ANALYS~S OF VA~CE Time :- 57 weeks Source X2 Between c~lla~ettes 20.3813 Condensate doses/eiK~ettee 1.7613 CiKaretts8 . doses 0.7346 Dose liuea~ 1.453~ Dose non-linear 0.3079 Total 22.8773 d. £ • Sis. Z I >99.99 2 58.54 2 30.7h 1 77.20 1 42.10 5 Hods1:- 1= (b) - ~ + & + s 1= (dose) 1 2 C£Karette effect - • -- 1.511051 1 Doee/=eeponse sradilmt m S " 0.643794 2 TumoriKen~¢ ra~Lo - e~p (Sl/a2) " 10.455 95X limits:- cannot be calculated Ratio:- s2/S.E. (a2) - 1.20 (88.1Z) Total t.b.a. - &2 BAT Co LTD - MINNESOTA TOBACCO LITIGATION m

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-34- DMB& Zevel:- 180 pg Tk~.£ 15]S ,. sis oF v,utu.. Time" om 32 weeks ~Otl~Ce Between ¢tSaLTettes Co~ensate doses/cigarettes C~sarettes i doses X2 d.f. Sig. Z 2. 2506 1 86.6/, O. 1800 2 8.61 O. 3971 2 18.01 Dose l;,,eaz O. 1.25~ 1 Dose non--linear O. 05~6 1 Total 2.8277 $ Model:- In (b) - u + a1 + a2 In (dose) Ciiarettt effect = aI = 0.861093 Dose/respoDJJe Sradi.eDt" - a2 " 0.349306 Tumorigenic ratio - exp (al/a2) - 11.765 9SZ ltmJ.ts:- cam~t be calculated Lst£o:- a2/S.E. (a2) - 0.35 (63.3Z) Tor.al t.b.a. - 13 BAT Co LTD - MINNESOTA TOBACCO LITIGATION -1::,. k.m

-35- 180 u6 16B ~qALYSZS OF VARIANCE Source X2 Betveen Cil;aXettes Condensate doses/c£1~a~ette8 Cigarettes e dolt! Dose linear Dose non-llnear Total T~=- do~. 3.6431 1 0.4396 2 0.3604 2 O. 1OO9 1 O. 3388 1 6. &231 5 36 weeks SLS. Z 94.37 19.73 13.65 Model:- In (b) - ~ + aI + a2 In (dose) CiKaretts effete - a - 1.042530 1 Dose/response ~radlent - a - 0.291057 2 TumoriKen£c ratio - exp (al/a2) m 35.9&I 95Z llmlts:- canton be calculated Ratio:- a2/S.E. (a2) - 0.32 (62.3Z) Total t.b.a. - 15 BAT Co LTD - MINNESOTA TOBACCO LITIGATION -....~

INDEX HAS INDICATED GAP IN BATES RANGE HERE

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-36- TJ~3L~ 17B J~q&LTSIS OF VJ~I&HCE D" DMBA 2eve1:- 180 WaS Time:- ~K) weeks Source X2 d.f. Becveen ciSa~atces 4.3275 1 Condensate doses/cigarettes 2.0764 2 Cigarettes * doses 0.2121 2 Dose l£neer 1.2045 1 Dose non-linear 0.8719 1 ! Tote1 6.6161 5 SiS. Z 96.25 64.59 10.06 72.76 64.96 ill Model:- In (b) - . ÷ a1 + a2 In (dose) Ci$.zette effect - aI - 0.94A481 Dose/~esponse I;rmdieur. " a2 m 0.859230 Tumordsen~Lc :sC£o - ~cp (sl/a2) - 3.002 95Z l/rains:- cmanot be calculated Ratio:- az/S.E. (a2) - 1.O9 (85.5Z) Total r.b.a. - 21 BAT Co LTD - MINNESOTA TOBACCO LITIGATION k.,r'l

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-37- DM~,A level:- 180 P8 7JLEI~Z 18B ANALYSIS OF VARIANCE Time" o~ ~ource Be~een ciKarettes Co~tnsate doJts/¢i|trtttts Cigarettes * doses X2 $.0870 3.0348 0.1652 d,~o 1 2 2 Dose linear 1.8686 Dose non-linear 1.1662 Total 8.2871 1 1 5 Hodel:- In (b) - . + aI ÷ a2 In (dose) -Cigmrette ef£ect - al " 1.012049 Dose/response Ir=adlm~t - a2 - 1.053571 Ttmor~$eeaic ratio " eXp (al/a2) " 2.613 95Z 1;m;ts:- caauot be calcul&ted !~£o=- a2/S.5. (a2) - 1.35 (90.4Z) To1~1 :.b.a. - 22 reeks S£S. Z 97.59 78.07 7.93 82.84 71.98 BAT Co LTD - MINNESOTA TOBACCO LITIGATION ",.O

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-38- DI~A l~el :- 180 ;~g ~LE 198 ANALYSIS OF YAKIA~CE T:iJs8 =- Sc~cce X2 ,. ii i htveen c£Karettes 5.3378 Condensate doses/c£SSXettes 2.3036 C£Karsttes * doses 0.0014 d.f° 1 2 2 Dose l£near 0.5~k Dose non-llnear 1.7592 Total 7.6&28 1 1 5 )lode1:- In Cb) - p + aI + a2 In (dose) C£gaxecte effect - a1 - 0.881178 Dose/response 8radient - 82 " 0.4823].5 TumoriK~nlc ratio - exp (81/82) - 6.215 95Z limits:- ~t be calculated Ratio:- a2/S.E. (a2) - 0.7A (76.7X) Total c.b.a, m 30 h8 weeks S£g. X 97.91 68.39 0.07 BAT Co LTD - MINNESOTA TOBACCO LITIGATION m O',, ...................................................................

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-39- DKBA level-- ~80 ug TABLE 20B J~U~LYSIS OF V.~R3..~CE D'" Time:- Source Between cigarettes Condensate doees/cigarettem C£guettts * doses X2 d.f. 8.370A 1 1.4971 2 0.0599 2 Dome lineutr O.4721 1 Dome non-linear 1.0250 1 Total 9.9274 $ - + a2 In (dooe) Hodel:- In (b) u + a1 Cigarette effect mal - 1.055620 Dose/response 8radient " • - 0.421762 2 T~motiKen£c rat~o - up (el/e2) - 12.218 95X l~itms- cannot be ¢81culated Ratio:- •2/S.E. (a2) - 0.69 (75.2~) Total t.b.a.. 3A 52 reeks S£g. Z 99.62 52.70 2.95 50.80 68.87 BAT Co LTD - MINNESOTA TOBACCO LITIGATION O',, ................................................................... ---r-

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-40- TABLE 21B ANALYSIS OF VARIANCZ wo" DMBA level:- 180 US Time:- 57 weeks Source X2 do£. Sis. X i I BeL-veen ciEareCte8 7.6595 1 99.44 Condensate doses/c£1r~LTetCeS 2.5460 2 72.00 C£SareCCes * doses 0.1791 2 8.57 Dose l£uear 0.3894 1 Dose non-llnear 2.L567 1 Toes1 10.3846 5 Hods1:- In (b) - ~ + a ÷ • In (dose) 1 2 Cisa:e=te ef£ecc = aI . 0.940983 Dose/response $=adienc . a2 . 0.362373 Tumorisenlc reels - exp (el/e2) - 13.&20 95Z limits:- cannot be calculated Lscio:- a2/S.Z. (a2) - 0.62 (73.0Z) Tonal t.b.a, m 38 BAT Co LTD - MINNESOTA TOBACCO LITIGATION

~,G -£. '-4" 30 3-0 ,T.8' "1" £~ -s' -Z~ 7.0 'Z~ II ' "S' I£ ' -6" 14 • -~ It. -Z I0 'I-O I "-I G "'& 4"-4' 2-- .Z. o. 0 FI& I RD. I404 RESTRICTED PL.OT OF LN ('TIJHOFLIGENIC iI~TKI) NUMBERS OF TUMOUI~- I~EAFWNIG AHIHAL5 v.. WEEK OF Ex .Em" 40 "0" "tmUUE~S "LA" ......... I ~. -' I)OSE/I~SeONSE SCOeE X-.-- -- - ~X. . "- 38 "17." '10 " 2" o 4~ "Z' Ot II . ~ ! ! I ,, I ,~ ~ 40 44- 41 2 57 TIME IN WEEKS C~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION

FIG.2 R[3. | 404 RESTRtCTED PLOT OF LN ~'TUHORISENIC P, ATIO~ 95% CONFIBENC, E LIMITS OF LN ('TUM. IU~TIO") SLOPE OF. OOSE I RESPOf~SE LINE NUHI~ER$ OF "TUM01~,IIL- I~IEARING ,4~IIMAIS, Vs WEEK OF EXPERII~EN'I" El LPI ~IIIPIL ItATI0 ~ .¢ONDENSAlrlE3 B~ll ~B~/Ib 95% UNITS + ~----~ II0~Mj OMIA ~ ~ DOSE/IIfIPOINSE IL01~ X .... X -- | NUNBEitS T. I)-/~ .......... 3O ZI" Z4~ ~C II 14 II I G 4. O. Omoe •o el sS° oa,~ L,w° ,,° ~- .E LD X 4- G) 4- I I I I I I I 3~ 40 44- 48 5Z 57 TIME IN IIN~EKS BAT Co LTD - MINNESOTA TOBACCO LITIGATION

Ft6.3 RO. 140 4 RESTRICTED PLOT OF LN (TIJHORIGENtC P.A"rl0"~ 95% CONFIDENCE LIMITS OF LN ('TUM. RATI~ SLOPE ,.OF DOSE I RJ'r.SPONSE LINE- .NUI~SF.R,S OF "t'UMOUR-BEP, RING ANIMALS ~ wEE~ OF EXPEmH~NT i" "~ 9s % UMITS +--.---~ ISO/,~ DMIJJ~ ~ DOSE/RESI~NSE SLOPE ~- - ---~ ~.. ~ ttUMIbf.l~ T.I~.A. - ......... " olI ~" 14.0"~ 2.6"" "6~" 2A-'" -4.'I l'L- 0"i" 2Z-" -L'~- Zo- Z~-tto0# 16, - . II-O-I- 14- "~1" 60"1" ,-o~- " -I ,4.,o-I- ''& 4 -4 -Z~" Z --t. @ ,0 O_ B O~ J pPP•• ,° ~ 0S4'/•4' -° &qll X X ~ ..o • t% /' .-'"~' \,'..-'- .......... \ + ® + 1 # I ' I .... I ! I .liP., 36 40 44 41 52. 57 TIME IN ~NEFJKS BAT Co LTD - MINNESOTA TOBACCO LITIGATION ¢.r"t C7'.,, (DO ........................................................................................ --'r

FIB. 4 P,I). 1404 REST~LCTF..D PLOT OF LN ~ Vs WEEK 3Z LN 6 911 ¢~ ..... bWl; X-- -- -- '-X (WElaUU. I!-0" I~'0 14 -O i I ' 3<) 3-34 3-&9 DOSE LEVEL-) f.n (~ONDE NSATE BAT Co LTD - MINNESOTA TOBACCO LITIGATION 60 I?..0 180 t LEVELS m (.71 '.,,C -...j C"-

.PLOT OF LN FIG.5 RD. 1404 RESTRICTED (~#EIBULL ~ Vs WEEK 36 LN ~DOSE LEVEI~ bg! I. @ 3, BgI& ~ ..... K ~('WE,BJLL @ IZ-O . /6O III0 8o Iso 13-0 I1~0 / ":'" // / ,,:," / ,'," ........ X ...... "X f,O I t I 3- 0 3-34- 3-69 t.n ~ONDE NSA'I'E DOSE LEYE~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION m

FIG. 6 PLOT OF LN ~WEIBULL b") V5 LN RD. 14-04 RESTRC.TED CDOSE LEVEI..~ BAT Co I~,°0. ~°0' m/& x .... x 60 IlO XllUD / / I / I I / I / XIZO ~'CONDEN°~a~TE .OOSE LEVEI..~ | I 3-O 3-34 Cn LTD - MINNESOTA TOBACCO LITIGATION I

PLOT OF LN FIG.'/ CWEmULL 0 V~ WEEK 44- LN RD. 1404 RESTRJC'TED (OosE t.~VE L9 ~1 I Q ® Bgl k X ,X t.~ ('W'EIBULL b) I:'-0- 120 IIW3 13-0- / 1 / / / / / / ! LEVEL) C~T~ DOSE BAT Co LTD - MINNESOTA TOBACCO LITIGATION r,,,o

FIG. B PLOT OF L.N (WEilSUL.L b~ V$ WEEK 4.8 ~. (I~EmULL 0 RD. |4.04. RES'TRIC'TED LN (DOSE LEVEL.'~ v IZ-O / / / I I I / / / / / / i / / / / ! / / ! I ~. (CONDENSATE / / / / / • D,C~E LEVEO / / q~ Xt, O O ii 5~9 0 -¢..~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION

FIG. 9 PLOT OF L N (~WEIE~JLL ~ V5 LN (DOSE LEVEL) WEEK 5Z e,~ CWEmUUL. 6") - 0 e,9ll B'~I¢, IZ.O- &O " IZO 13-0 ~ / /,X IBO /// /X lEO 14-0- mo x,. ILO X \ \ \ 7,-.. \ /" ,,X/ \ / x / \ I \// ,\ / \ / \ / \ / \ I I I I 60X I ..~-0 / / / I / / / / /,, / i~- / ", / / / I I I I I I \ / \ / X t.a. CCONDEMSATE" DOSE LEVEL~) ,X f,,O ! KD. 14.04 RES'I'RICTED BAT Co LTD - MINNESOTA TOBACCO LITIGATION k.,"l ".4=> -.,,,.,j

BAT Co FIG. I0 RD.1404. RES"I"~ICTED PLOT OF LN ~WEIBULL b~ V$ LN(OOSE LEVEL_,~ w£,,,,, EK 57 b~I/I (; BIP/¢ X .... x ~,~ O~IEIE~IJLL b.) " -- llZ.O ~-0" 13 • 2 ~4"'0' mo y s / % / I t2.0 X,,. ~' s % s / % ,, / % % • / GOX-- .... x-c- -- -- • / • / / / "~'s " / / I ,I S-O S-:34- ~.ONDF..NSATE DOSE LEVEt~ I LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

BAT Co LTD - MINNESOTA TOBACCO LITIGATION