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