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-11- Because characteristics of atmospheres ~ exposure systems tend to be characte~ist£c o£ the machines used to generate the smoke, chamber atmospheres should, if possible, be defined more precisely than by the initial smoke d£1u~ion, since this may thanks. Xt is expected that some chmnber smnpl£ng for determination o£. for example, smoke particulate phase concentration or carbon monoxide lev~l will be" ca~ed out du~£nS Iong-te~m experLmantSo For the purposes o£ chLs report, re£e~snce to smoke dilut£on ratios will be adequate. For the work summar£sed here, smoke d£1ucion £8 expressed as the ratio o£ volume o£ smoke to volume og dilutinB a£r. Preliminary studies were carried out to determine the extremes o£ the ran~e o£ tolerance o£ rats to smoke £rom G295 cigarettes. Under the conditions no~ed above, usinK the B-A.T. exposure system, e smoke dilution o£ 1:3 was not tolerated, whereas a d£1utlon o~ 1:19 was eas£1y tolerated by the animals. Work van c~ried out to wssess H~ZL using concentratlon8 from the less dilute end o£ the smoke tolerance ranks. Three dilutions of smoke were used: 1:5, 1:8 and 1:12. Groups of ~ an~nals were acclimatised over 5 days to exposure at these dilutions, and subsequently exposed t~rice da41y for approximately t~o weeks. DecaLls o£ body vaight changes and survival o£ ~nimals under these cond4tion8 are Ki~en in ¥£Ku~e 2 and 3 raspacti~tLy. Tube control anLmals ax~ includLexi £o3 conwarLson. Compared w~ch case control rats, tube control rats showed scene reducclon £n growth race. However~ th£s was slight and much less marked than the reduced srowch rate seen in 811 smoked animals compared trLch Cr% BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-12- controls. This effect of smoke exposure on K~owth =•Ca has been veil documenc~ for several species. 7~ this study the reducc£on ~n grov~h race was noC ~ela~ed to the smoke dilut£on (FiEure 2). The effect o£ smoke d£1utlon on survlval of animals was clearly related to dilution, and this information is most useful in the esti~uation o£ HT.KL £or a study o£ up Co 6 weeks. On the basis of the survival data sho~n ~ Figure 3, a smoke dilution in the r~gion 1:12 vc~id probably be used for such a study w£th G295 cigarettes over • period o£ •ix reeks. &t the end of this ranSe-£indini study blood samples vere oaken ~lnediately £ollov£nK the final exposure at the various dilutions and COI~ levels detained (Table 4). For the Do ~coups v£ch several surv£v£nK animls, blood COHb levels were quite s~lac at • p•rt£cula,c smoke dilution, £nd~c•tlng consistent exposure o£ anlmals within • frcoup. Blood COHb level was extremely high after exposure to 1"5 smoke dilution, Xt is interesting to compare blood COMb levels in those animals accl~nacised to various dilutions of smoke, with COMb levels £ound in rats a£ter one un•cclimac;aed exposu:e under identical conditions (Figure 4). For all rats, over m vide range o£ dilutions, CO~ levels increased as smoke dilution decreased. At co.non dilutions, blood COlib levels in non-accl£umtised and •ccllmatised rats vere very siaL~laz. Th£s Indic•ass, i£ one •ccepts COHb levels as at least • rough index, Chat smoke dos•Ks £or particular conditions may not change markedly as annals become acclimatised. However, there is no question that the tolerance o£ an;male to the exposure, there£ore ~he smoke 'dose'. is much improved i£ • short period o£ ac¢l~tisation precedes the proposed max~um exposure zeg£me. m 0 C~ c~ c~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION Co

-~3- SUMMARY A brief description has been ~ven of the B-A.T. an~l exposure system developed for iuhe~&tion to~ci~y studies ~r~th smoke. Su~ies are gLven of phys£ologlcal m~nitorin$ methods and the dosimecry cechr~que, using a~ ~labelled p&rticulaCe phase marker, which wilI be used for inhalation work. These special methods will be uses in addition to sCand&rd pathological techniques for assessins tissue response to smoke ~osu~e. Some details are 8£ven of experiments Co assess tolerable smoke exposure condicionJ £or ciKaretce G295, one standard cigarette to be u~ed £or comp&rst£ve s cud£es on smoke. Th£s ~eport should be taken principally as an introduction to some /xLhalation ~thods to be used in investisa~ions of the potential biological activity o£ foamed BATFLAK~. BAT Co LTD - MINNESOTA TOBACCO LITIGATION l_,r-i Lrl

-14- TABLE 1 DEPOSZTION OF DCBP IN RAT RESFZRATORY SYSTEH AND ~- -- BLOOD -COHb' -I.EVELSt- FOLLOWI~i(;- ~.X-POSt[RE~ O'F- - - - 3 4 o 7 8 J TOTAL MEAN Total DCBP Recovered (ps) L2,096 7,911 4.463 9.676 6.853 6..501 Z Distribution of DCB3P DCBP ~n Lover .............. Kmsp~raCo%~/ SysCe~ Head Lo~r Jaw mL L 10.69 3.07 10.52 4.39 13.44 10.51 • 6.63 1.70 9,15 4o28 0.84 2.33 21.43 8.44 15.33 6.98 ~.34 14.55 I_ - _" I m - l ..... I' _ l 9.368 8.95Z 6.62Z Trachaa L.40 3.60 4,20 Z,44 6.61 10.94 IL _ 4.87Z Blood Lung (Lat-y~x, Trachea, Lunl) COHb (~S/S T£ssue) (Z) ,L ........... J~ .......... m _ L u 83.14 8.965 48.2 68.28 71.79 76.31 75.81 46.45 4. 838 2.409 7.013 4.071 2.312 28.6 24.0 24.4 23.0 17.6 70.30Z & .935 11A8/8 27.63Z 18.3ZZ 81.79Z BAT Co LTD - MINNESOTA TOBACCO LITIGATION ,,..3-1 -O", "O"-

-15- TABLE 2 DZFOSI'rloN OF DCEP ~ tL~HSTER RESPXKATORY SYSTEH AND J BLOOD CO!Lb LEVELSF ¥OLLOWZNG EXPOSURE OF- - ,~z~s To S~,ozZ, FR~~, DCpp-~^aC~D +~+FxGu~rzs IL, 17 18 ToTal DCBP Recovered CPs) Larynx 4. 440 Z DLscrlbuCion of I)CI~ Trachea 0.97 8.504 1.339 0.798 6. 790 4. 388 "A'0~AL HE/d~ _~=- 0.63 6.31 7.64 1.56 7.17 4.33 4.26 3.63 5.01 2.12 6.72 1.21 J | IN, 5.56Z 2.25Z 7.81X | it _ 15.99 .~. g6 8.zs 6.63 3.19 i i i 7.37Z 3.35 1.64 1.25 0.46 8.55 1 2.56Z L II 92.05Z * Animals subjected ¢o 1.4m4Ced exposure only. Lung Ill 89.53 71.44 82. gO 82.71 85.79 8O .33 82.12Z DCBP in Lover Respirmcoz7 System (~I~rynx, Trachea, Lung) (IPK/I Tilmue) II J |1 6.77g 9.882 2.211 1.. 182 IO.O57 5.343 5.9O9 US/S Blood COBb (=) 1.5.9 25.4 8.4 10.0 27.4 13.8 16.82g TA~E 3 Co.r~so. OF .c~ D ZmS=m. O. ~GZONS- oF z.z LO~R RESPLRATORY TItAC~ OF AJ, i,I.HJ~S EY~L*OSI~D TO TAGGED SMOKE o..,,zxo,S .... ....... UNDER SIHILAR C 8pee£es 4.243 2.977 Hamster 11.421 5.340 ptiX:llP/8 iislue |,. Larynx Trlrhil Linsi 5.175 Jt 15.648 i ,::ND J, BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-16- TAmE msmummmmmm~ BLOOD C~BO~GLOBr.S LEVELS IN RATS EXI"OSZD TO A -RA-NGE OF-DZLUTIONS OF' SNOKE FROH czGARETTES Saz~les taken £~mediet:ely eft:er she second 10 minute exposure on day 17 (121:h full smoking day) of the exposure period (Cigareel:e G295). Smoke Dilu~iou Anlmal Blood (SmokezA£r) No. COHb (Z) 1:5 14 59.6 92 35.8 1:8 9~ 29.0 96 26.7 21 24 97 101 102 _ Jm ...... * Blood sample clo~ted. 22.7 18.4 15.5 18.1 Mean COHb 59.6Z 18.7Z emmmmmumm m 0"-, BAT Co LTD - MINNESOTA TOBACCO LITIGATION

• _T0 S)~KE EXPOSURE_" SYSTEM, SHOWING SMOKE GENERATION UNIT AND E~pOSURE CHAMBER ~¢I~H A'FTACHED~ AN '~[AL HOLDING TUBES BAT Co LTD - MINNESOTA TOBACCO LITIGATION CO

J:'JG. e THE P, ELATIONSHIP .P,~TWEEN FO~ RATS SUBJECT'ED TO A GROUP MEAN BODY WEt~HT ~ND T!~,~r, RANGE OF DILUTIONS OF SMOKE Ir~.OM CIGARETTES rIVE DAY ACt'.,L, rMAT|ZATI~N PCRIOD, I,'DL.LOWED. BY ~ X IO mJn IEXI~OSUR£S/DA" I~OR UP TO I~- DAYS. CAGE (:ON'rROL. L 1:8 1:18 I: S ! [I~,~I.IMATIZ, A?'ION ! P.X I0 iii MINUI"C r.:~DOSUIRI=S I=l -I~R DAY T,M= C=AYs) BAT Co LTD - MINNESOTA TOBACCO LITIGATION I cr,,, c~

THE REL ATION~.HIP BETY~/EEN rio. 3 ~;URVIVAL OF ANIMALS AND TIME, FOR RATS $UDJECTED TO A RANGr OF DILUTIONS OF SMQKE FROM 62 95 DAY ACrwI.IMATIZATION ~OERIOOt UP TO I1"~ DAYS. CIGARE TTES ~0660WED BY E X I0 mm EXPOSuRES/DAY, ANIMAl.S/OROUP v w w v . SMOKE: AIR = = ,,:~-- i - : : - = : ~1 "12 ' J ' I:| | X '0 MINUTr I[|XPO,,.','II,,II=:IES m~R DAY I • r,,,,,= CoA','=) L..rl L-P,, CO (_rl f.jrl BAT Co LTD - MINNESOTA TOBACCO LITIGATION

BLOOD RANGE VALUES ACCI.Ih4 A'I'IZED RATS. ~'01~ P..,RACK c'r's INDICAT¢ NUMBI~R FIG. 4 CARBOXYHA~MOGLOBIN LEVE:i.,S IN RATS EXPOSED TO A O1=' DILU.TION,S OIr 5MOKC FROM G295 CIGARETT.E5 ARE ,SHOWN FOR ACCLIMATIZED ('I'ABLE 4.) AND NON- THE LATTER, Ir'IGURES IN OF" ANIMAl. l SAMPI.E~. SO (4) ACCLIMAT/Z,~D NON.ACCI.JMA'riz~ ID O I :aO 1 : 15 I : .SMO|tC DILUTION I0 c~ c~ -:::x:) 0-, BAT Co LTD - MINNESOTA TOBACCO LITIGATION