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BAT Co LTD - MINNESOTA TOBACCO LITIGATION

DEADLlq~- ]lATE.: I Ii II I t :DT~ZON: i|. Ol.b~ FILE 9~O.: ~L~b . Check List ~hoto~-aF~l ~o. : Reductions= T~ Pa~8: S3G ~) : Z;~t (1) : RAS (2) : RMG (I) : RSW (3) : :4nKr., P-- & V.P. Ausc. [2) : ItS (I) FS (I) : ~K--~Z': CJP de S (I) : DGF (~) : L~br=ry (2) : FiL© TAPE ~= (21i • Typin~ Check:Lr.~E o.. '0~ Sent Rood Ret~-,-ned ~e co=mock,ann (i) ~ ~ ~" ~" 77 ~-- (2) ~,~,~'~ ~ 'L, ~.,I~ ; ~ ... , • h~l ~o ~ol ~I ~tll~l~ to £~tlit&te ~n~ ~e~&ll ~he ]~'08~111 o~ GoR. & D.C. Repo~tI t]=~ ~esc:gL19~. ir~a4p9 lx1111;il thl x~=~)o=~; 'lid ~"izIi],,~r ~p]pg~o~rt~ ~ ~II~l~. The ~o EQZIa =aster after pz~paz~t£on) &t &ll mabeequen~ Ita4~m. It It be Ien~ to cent=~ ££1~=~ trllda the =amte~ when ~he ~ ie £eam.ent. 1. ~r~o~ev= posa4hlo, ~8~"~0 ~o~ ~j~ E~Ot~d be t~itten in ink. 2. ~T ~rp~n~. ~he ~es=lpt Ihould n~llly be rot'Ill.mid to the J~ho=, who vilI iubIOqUent~ ob~tn the G~up Lea~e='I and leIUe~'= &pp~81. ~. CI=~zlatlon should be ~etezm/ne~ by the Issuer. the pro $o~ aCa~urt "Prepi~e M~s~er". 5. AK%o~ 31~gLnt~, one ltx~nd oow IUmt be z~tu~ned to ~e ZemAe~ £~T ~',tn~l &~ and the Ismaer will ecAsu~e t~t one ¢o]p~ Am neon ~:r ~he M~uager. BAT Co LTD - MINNESOTA TOBACCO LITIGATIO_N_ ............. I r,.....,~ ~

ATTENTION This work was produced on the Hagnetic Card typewriter. It is imperative that all corrections, alterations, etc., ! are made clearly. E.G. penc~Iled commas, full-seops could be easily missed. A cross in the marBin, in line with the correction would draw our attention to the insertion. Would you please be kind enouBh to write 1%tEe insortions on a separate sheet of paper, and no...~c cut out portions of typed work. ~his is because the ~Snet£c Cards d~ffer from Paper Tapes. / BAT Co LTD - MINNESOTA TOBACCO LITIGATION O'-,

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3-Mo~. im~TIo. Toxzc!~ s~-oY oN xxTs CI~TE ..~Poe.z so. ~. 14;,;, ~s~zc~D " 23.3.1977 AUTHORS : Lynda V. Wilton G. Smith It. Binns ISSUED BY: S,R. EveLyn PROG. REF. : 11.01.02 DTSTR'rBUT$0N: Dr. S.J. Green Dr. I.W. Bughes Dr. R.A. Sanford R.H. Gibb, Eeq. R.S. Wade, EIq. R.G. Nicholla, Esq. Herr H.E. SotCorf Dr. F. Seehofer Dr. C.J.P. de Siquelca Dr. D.G..Felcon Library Copy No. 1 II II 2 " " 3, 4 lell tt ..~ " " 6," 7, 8 " " 9, 10 " " 11 " " 12 " " 13 " " 14 " " 15, 16 BAT Co LTD - MINNESOTA TOBACCO LITIGATION COFY NO: __ i C C:x

INDEX HAS INDICATED GAP IN BATES RANGE HERE

V' CONTENTS ,| el SUMMARY AND CONCLUSZONS INTRODUCTION MATERIALS AND METHODS C£gara~te Type Animals Exposure System Experimental Design Oh servati.ons Te~m£nal St:udies RESULTS Monitoring of Exposure System Blood C&rboxyhae~oglobin Levels Growth Races Food Co~sump¢ion MorCali¢ies Microbiological MonLnorinK Terminal Studies Bodyvelght s OrEs= weighcs Hi• topal:ho lol;y DZSCUSSION REFERENCES PAGE NO. 1 4 4 5 5 5 6 7 8 8 9 11 12 13 17 17 18 19 20 40 51 BAT Co LTD - MINNESOTA TOBACCO LITIGATION ¢..rl k.,"l CO

• ,..',rwl~l(;S 14 6o Group Research & DeveIopme=t Centre, BrLtish-American Tobacco Co. Ltd., SOU~TON. 23rd March 1977 3-)lOFfE .INitIATION TOXICITY STUDY ON RATS EXPOSED TO ,|.~ s.o r oM a C (Report No. llD.1477 ltestricted) ~:. ~.~, V" z co.,. ..szo.s An inhalation Cox£city study has been carried out to determine how chanses An lung petbolo|Ly Lnduced in rats exposed Co smoke £or six weeks were affected by continufng exposures for up to 12 weeks and by termfnating smoke treatment. Animals were exposed to three dilut£on leve:Ls o£ smoke gram a standard £1ue-cured cigarette. Honltorfng of the smoke concencratfons to which an£mals were subjected end blood carboxybaemoglob~n levels o£ animals imned£acely agcer exposure, confirmed that animals Ln the varlous treament &coups recelve~ sf&ni£icantly di££erent smoke dosage levels. Average daiZy good consumption and growth rate were reduced in sham-smoked end particularly in smoke-exposed rats. Animals fncreased the£r food consump=£on and shoved a marked increase in growth rate when both these treatments were stopped. Hortal£ty rates were d£rectly related to the concentration o£ smoke to wh£ch animals were exposed. The pattern o£ £nd£vidual BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-2- v mor~alic£ea showed tha~ throughout the study deaths occurred more often at: the beginning of the week and became less frequent as the week progressed. Exposure to smoke did not produce any significant change in heart or lung we~ht of animals over the 12-week exposure period. Thymus weights of sham-smoked and smoke-exposed rats were reduced relative to those of cage controls. All lesions of the respiratory systa~ previously showu in rats exposed to smoke were again recorded in this experiment but their rate o£ development was shown to be di£ferent. Coblet cell hyperplasia o£ tracheal and bronchial epithelia, increased numbers of alveolar macro- phages, squamous metaplasia and hyperplasla of the larynx were seen after two weeks o£ exposure to smoke. With the exception o£ tracheal goblet cell hy~erplasla, after 6 weeks og exposure all these changes showed a maximal zesponse. These responses were either maintained (macrophages, bronchial goblet cells) or possibly reduced (laryngul hyperplasla) as exposures ~ontinued up .to 12 weeks. The frequency o£ tracheal goblet cell hyperplasia and alveolar metaplas~a ~acreussed projrssslvely throughout the study. ~hen exposure to smoke was discont£nued, all smoke induced lesions, excep~ alveolar :etaplasia, rasressed and tissues approached normality during a holding period of 6 weeks. In contrast., the frequency of the alveolar me~spLasia induced during the smoke-exposure pwr£od, comt~nued to increase even when an/~als were not being exposed to smoke. The pathology findings presented here from those animals exposed to smoke diluted T:12 with air will be compared with observations made on BAT Co LTD - MINNESOTA TOBACCO LITIGATION v'O