Tobacco Documents Online

CO~J3JZZVE TOXZCZTY STUDT OM ~ PROM c~s ~z~G s~msTrru~ ~s l SC " ~ ~ ~ ~ ~ ~l'l~ .u.s.N.m~m~ TOBACCOS (~~ ~0~) R.EI:'OR~ NO. RD. 1.506 ,EESTR~CTED zz..,8.1977 AUTHOI: R. BLnns ISS~..D BY: 5.E. Evelyn rROG...RZF. 11.01.05 o I.S'L"S,.T.r~ZO~, z Dz. S.J. Green Dr. Z.I/. Hughes Dr. R.A. Smxford IL.K. G£bb, Esq. I.S. Wadt, Esq. l.G. H£cholls. Esq. E. Ricte=shaus I)1:. F. Seebofen: Dr. C.J.P: de Siqueira Dr. D.G. FeIton Library Copy NO. i, 2 I| " " 4, 5 IIII tl 6 " " 7, 8, 9 " " 10, Ii " " 12 " " 13 " " 14 " " 15 " " 16, 17 COFY NO. BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

D/Z~,/:~6D Group Research & Development: Cent:re, Bc£c£sls.-.Amer£can Tobacco Co. Led., llchAu4L'u4t 1977 COer~'_~lNG ~b"l'J.~:U~:~ ~S SC, T,,'C, (geporc No. ]LD. 1506 it.escc£cced) SUJ@fAR,Y Zssential detaLls are Kiven of ohm :esults of a larse-scA1e inhalaC£on 8tnuiy carried out to compa=e 8C~ WC and ~ Mark B. Conclusion. drmm as • result of the e.,zpmrinmaC hzv. been 8mma~£se4. Complete details of the cox.:LcLcy study are Zivem in a sepax'sce 0 C~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

An experiment has been caz=£e~ out to assess the comparative toxicity o£ smoke from c£ga:ettes coutsJ~L~ ~he sheet mate:~sls SC, WC and ~ Hark 3 (BK). The control c£sarettes used contained 100Z tobaccos oF a standard U.S. blend. Fo= each of the sheet mSCL~iSls be~8 tested, cisL:ettes were made to tazSet f~clusion Zevels of 17Z sad 30Z of the substitutes. Du:~ the ezpe:~t anLmals ~ere exposed £o: & reeks to smoke at eve &ilut£on levels from each of the clSacettes. The ¢ompZete examLn~ciou iuvolved p:ellmlnaz7 assessment oF mate:eels, TI~ dosJJ~tz7 and exce~slve mm~cor~ of exposure coa4£t~oa~. At the end of the main ~o~LcoZogy study the response of lunK tissue Co ¢n~osu~e to maoke fram the VL=iOUS cigarettes was e.zamla~4. On the bas£s of these observations, the relat£ve ~ox~ci~ of smolte from cigarettes cou~f~ins SC, I~C and lie has been assessed. Complete ezperf~eur~l details of tb~e study are presented i~ mn accompan~ng :sport. To alloy a more rapid appra£s:l of the expe:iaumt, this su~aaz~ report co=~s the essences1 points ~r£e~g from the complete to~clL~7 s~ud~. THE CIGd3~F~ES ~L1 three sheet m~l~el:~ls affected ~he basic cha~acte:istics of c~Kazettes. Puff tombs: was alcezed by each of che sheet :mcec£als, wi.ch both WC and pa~CicuZa:17 SC tending to increase puff m~be:, whereas add~;tiou o£ BE to c£Smrettes ten4ed Co reduce puff number. BAT Co LTD - MINNESOTA TOBACCO LITIGATION .(..~

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-3- De£ivery | There yes no affect on ~ del£very of adding up to 30X SC to cleat•tee. WC sheet c~uetd 8 reduction in ~ delivery which, at both /~clusioa levels, was rouKhZy 1A2[ oE ~at from the control elK•retie. B[ caused • prosress£ve reduction 4n TIM dellv~ (7£eure l(a)). TTH delivs-~y from c£satette8 to the an/x~Z exposure chamber was slilhtly 10wex than that from the butt of the a4sarettee, due to daposit£on of putt:uZttt8 in Zhe smoke 8emeration untt (F4Kure Z(b)). 7or each ¢£earette couta/~£nS • 8ubet£tute, the e~mbLuod e~£ects of thanked T~M del£very and pu££, numbe~ o~ ciKarettes caused • reduction in ~4 deZ4vory pex puff. The reduction was the 8mna £rom SC and MC c~KRxettes and Kreacex than the e££ect on this per•meter o£ addLnK BK to tobacco (Yis~re ICc)). Carbon. 14onoxide. ~C0~ Del£ver7 ~atar£•18 SC and UC both had the ef£ect of £ncreu4x~ total CO delivery from c~earettes. The inczease was 84m41a~ [or both sheets at the 172[ inclusion level, but at the h~Khar ~ne~usion level the dfect of SC was more marked. CO del~v@ry from e4Karettes vizh ~K was 84m~Zar to that from ~he con~xol ¢isarette (Y£~e 2(8)). • aeh sheet ~atex~•l caused an increase in CO delive~ pew pu~£, but ~he increase was not cle~xly related to the level o£ ~nelua£on of the substitute mat~£ale. Over•~l, the /x~rease in CO deZ£very pew pu~£ for 8~ the expew~mau~8~ cLKa~ettes was foully ~1~ of ~ o£ the aontrol (FLIp~e 2(b)). T~/ m~d GO del£vewias of cij~e~tes were a~fe~ted to 8 d~f£exent extent by each o£ the sket materials. However, despite these Oh•hieS, and ~he effects of the ~ubg~tutee on pu££ number, the relative del£veri~g of CO and TFH remained constant in ell experimental c~Ea~ettu (TabLe 1). BAT Co LTD - MINNESOTA TOBACCO LITIGATION u

INDEX HAS INDICATED GAP IN BATES RANGE HERE

100:{ TOB 17Z SC 17Z WC 17Z 31~ 30Z SC 30X WC 30:{ BR CO (:s/cis) (.) i .m 1 13.2 15.7 15.6 13.6 18.1 15.9 12.7 CO/'t"l~ ~t£o sxeos .= ss TPM Relative Co (mg/cia;) atb 1OOX Tobacco (b) | 15,34 0.86 1.O 15.31 1.O3 1.20 12.91 1.21 ~,.41 12.29 1.11 1.29 15 • 46 1.18 1.37 13.51 1.18 1.37 11.36 1.12 1.30 The effect of 8ddinl esch of the |heat uater£ats Co ci|a~eCtts vas Co reduce the avetase smoke concentraC£on to which an~ss18 were exposed. SC and gC sheets produced a s~nilar reduction in chamber TPN concentration vhich~t8 directly proportional Co the leveX of ~nclusiou. ]X cue~l a less pronotn~ed buc proporclou.al reclxu:Ciou 4,. averaKe ¢oucentz'aCiou of d£1u~od smoke. The deKree o£ exposure CExpoaure LevaZ) expelr£enced by an~m.,lo Ls related to averaie smoke coucentraClou (~I/£) x ~xposure t/al (= p~tt[£ number Lu~nuCa8). ~dLt£ou of aS1 8heat ~ater£als aC tJ~e 17S £nclus£on level caused a reduction In T1~IExposura Level. This was tar|ely due to the reduced average maoke concentration VtLtch~LshC a18o be accompanled by a chanae in exposure time (SC+, BE~). ][ncreasiLnE the level o£ shear BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-5- nutter£al8 to 30Z did not cause 8 £u=ther co~sietmst reduction in E:poeu~e Level fOE shy of the substitutes (FLKure 3). S~D~ DOS ~I~Y e Desp£te chaises in average smoke con~en:ration sad puff mmbe~ p:oduce~ by the i~troductlou of the substitutes, the level of TPN deposition ~ sequels was :el&ted to ~h8 product of the two factors. Heasu=ements of the deposition of pazt£culetes in an~nals exposed to smoke from both control and experimenttl cle~:et~es showed that TFH dose to the lover respirator7 system (LRS) tms closely co=related to E~osu~e Level (7£Kuze 4), ~thin the range of smDka concentrat£ons and exposure times used in this emper4,nent. The demonstzat£on of this simple =elat£onsh~p indicates ~t sdd£t£~ o£ the sheets 4£d not not4cetbly thanks T~M 4epos£tion cl~racte=£st£cs not, p=emmably, the ~:med~Ats response of aa~n~ls to smoke £:om 8n~ of the c~Se=ettes. ~ the u~n toz£c£ty study, me&sure.star of blood ca=boz~hemnoK%ob~n (COHb) levels in An~,SSlS |Jmnedlately following exposu:e to m~ke should a s~u~laz relAt~m~sh~p be~veen COHb level and ca:bon mono~Lds E:posu=e Level. Even more s~nply, blood COHb levels in animals ~trs s~8~Lficantly related to totsl CO deliver7 from c~Za~ettes, ms mssessed by 8 conv-nt~onal cbaL~cal Assay method (~able 2). BAT Co LTD - MINNF~SOTA TOBACCO LITIGATION SO

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-6- T~2 •OraL CO DXLrV~Z ~ cIca~r~s aND C0ab L~LS ~aLS ~OSZD" T0" r~o n~-~rzo.s' o~' ~o~ ~u~ ~asn CiKarette IOOZ TOB 17Z SC 17Z WC 17Z BK 30Z SC 30Z WC 30Z i • CO De Iivez7 (~,/e:LS) 13.2 15.7 15.6 13.6 18.1 15.9 12.7 i e i Correlation co~£ i~ient o£ CO deligezy/COBb Siluif icance Level TOXICOLOGY The raapo~Iss of l"mi~lla Tozicolo~ 1:7 1:11 30.1 26.6 33.1 29.1 33.0 26.2 26.8 23.6 41.6 33.8 38.& 29.6 30. & 22.9 0.88 O. 91 99Z 99Z Blood COHb (Z) el nosi~etr7 ii 1=7 28.0 31.5 30.8 25.7 31.3 27.9 23.5 0.80 95Z lzll 22.7 26.1 26.0 20.7 28.8 2A.1 18.1 0.92 99Z to mke £rom rJ~ vat-£ous c£Ka:ettaa vere :~ilaz i:o those seed in other to:L~colo~ atud£es. Growth rate og animals e~posed to smoke was less than that of sha~-smoke4 ~ case aou~rol ra~s. Rid ~11 numbers and ~k~ baamos).ob:Ln content o£ the blood o£ smoke-exposed rata vote hJLI;h~ than £u the ccmtrola. Presumably tb~a latter e~fect m a compensatory response to t~e pote=t~I reduction in oxysen cax-tT£n8 csp~c£cy o£ the blood due to ~he regular increase in the COBb levels in smoke-exposed rats. A small number of ~--~ls died during ~he at~ady. BAT Co LTD - MINNESOTA TOBACCO LITIGATION m ~o "--O

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-7- mout of the toxicologlcal obsarvacLons were crmmcment-~elated, 4~ the sense that they were more prev&1~t amongst m~Lmals subjected co smoke £roa cigareCr.es con~m~";'tZ one particular subsc~.cut:e. IiZSTOF£TBOLOG'Y The resp£racor7 sysc"~ of ~4,m, ls e=eposed 1~o smoke from 811 c£earect:es ac a common d£1uc£ou (1:7) leveZ was zr~m£ned in der.ail. • su~mx7 o£ the h~scopacholo$1cal fludLnae 4s liven 4~ Table 3, which Lucludls dup1~cmce 100Z tobacco ~oups. F~c each l~ZaneCe:, the response of tissue £r~ e~ch of the expe¢~c&l iproups £s shorn as a pewcem~aee of the snaz~nml IrrOUp mean =-.spouse ehou~ far Chat- pmrl:lcular parmCe:. An overall assessment of the dezz'ee of ehanee 4,, luns structure due Co mnoke exposure can be made for each of the creaCssmsc &,coups. TAm, Z 3 s~Y oy -tS"~p+~r'~LO~ Y~ND~GS. ZELATZV~ USPC~SZ FOR Pacmaec~c Desc~LpcLou ~tle Sham IOOZ lOOZ l?Z I?Z I?Z 30:[ 30Z Conc~ol Smoked ~ob4Lcco Tobacco SC WC BIt SC ~TC 1. ~crophaee acCiv£cy 23 27 88 81 100 77 73 77 77 73 2. Goblec cell dieCrib.cio. 26 35 95 g5 I00 86 86 100 81 71 3. Bronch£al 8oblat cell hyperpl~s£a 6 11 77 9& 100 81 58 77 77 66 Trachea 4. Ep£~heli~l ~h£¢knee8 (%e~ 78 78 87 91 96 78 91 96 83 83 traehea£ ring, vauCral)• • 5. Goblet eelZ bTperplasia 16 0 33 83 83 100 17 SO 67 16 (LS) (Upper Craahma) 6. Goblet ceil hyperplas£a (TS) (Mid L'tachea) 23 23 77 10o 8.5 69 77 38 8.5 56 7. Squamous metaplasL8 39 39 72 78 100 9A 83 100 89 78 (v~nC:a~ em:f ace) 8. Squsmous hyparplu/.a S& 54 83 88, 92 88 8.5 100 73 80 (vocal cord) g. ICerac/.u.£eac:Lou (vocal O 0 14 71 100 ~3 29 ~7 71 29 cord) • IOOZ Zxposu=e co 100~ ~L~]~ 1:5. BAT Co LTD - MINNESOTA TOBACCO LITIGATION k.,,,a

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-8- To assist the assessment o£ r.he various raise:ire respOU~es to smoke exposure from the d£fferent c£KarecCes, ~hose paCholo~ paruttrs ~t~ch are cons£dared co be most :eL4able /~ this study have been combined t~o a "sevexi~ :[j~ex" as sho~ ~ Table A. TA~LZ 4 A~ F&~ RESPOHSE (ZXC:LUD:~G OOmLET ~ Iff~RPL~ AWl) ~3:NZSATX0t4~) Group in AscendiJ~ Order of Sevezi~ CaKe control Sham-smoked 30Z BK 30Z k~ 17Z 3K 17Z Severity :L~dex 44 47 77 81 84 83 85 87 ms Less ,p Severe The respon~e of the eve fproups of an~JmLm exposed to IOOZ tobacco smoke was s~m~Ler. CigaxsCtes couts~ E and g[ produced t response which tsn~ed to be Less ~ that: for the LOOg tobacco cLS~sCta8. The severity of the :espouse reduced as the Level of substitute m&ter£a~ /ncreAsed. Me r~bLe also shows that st each LncZusion leveZ h~ Kwre a slightly greater response thau BE;. ]Seth groups of animals exposed to 8mohe from ¢£jarettes with SC shoved J distiuc=ly more severe pachoLo8~ response. However, for ~h£s pair of cigarettes the degree of clumse was pract£cAlly the salt for both £ncZueLon levels. BAT Co LTD - MINNESOTA TOBACCO LITIGATION m

-'t- o BAT Co LTD - MINNESOTA TOBACCO LITIGATION w

-9- Smoke F~poeu~e Level (£~om F£~e 3a) £8 used to try to account £~r absolute differ,nee, in PUff u.mber ,~i ~b averaKe smoke concent~atlon produced by equal dilution of smoke £rom dt£fe~ent cisarettee. Tak~ this expreeeion Lnto a~count the changes 4n smoka-~uced ltu~ pa~holo~ caused by exposure to mooke from tJ~ control and eheet-con~ai~0~ cigarettes az~e shown :i~ ¥iKtt~e 5. Overall, smoke from ciKareCte8 ~outa~n/~s SC, even at slightly redu=ed Exposure Levels, produc4Kl a Fearer response in the Itm8 than that £ro~ c£Sarette8 ¢o=~£~u~s ~ and ~ or 100Z tobacco. A re£/~ed averaKe patholoay index, based on par~ter8 1. 2. A. 7 and 8 and excludimg those psrmters ~soblec cell h~perpl~a) which ~re not well uudersCood or coa~idexed Co be of doubt£~Z v&lue Lu th/~ study (low Z £nc£dence of aXLI~sls wlCh ke~atln£satlon). ~re clearly isolates SC u the worst of the rJ~ee substitutes. CO~CLUSZO~S The study was complicated because o£ ma~ked cha~es in ciKaretce chmracter4st~cs iucroducod by the use o£ di£ferenc sheet m~terials and the relat£vel7 low i~clus£on lovelm o£ sheet ~ate~cials used. Neve~t:helee8, ~t 18 cons£dered chat the complete experiment (based on a balamced appraisal o£ dos~cry, tox£colo~y and pathololry) has been mucceme£ul in achlev£n~ the objective o~ eho~£n~ the relative tox~L~ o£ s~oke from c~$arettes couCa4~is~ St, WC and !~. Cisarectes conca/~n8 wc up .to the 30% inclus£ou l~ve~, deep£te hav/~ an /~cteased pu~£ nuabe=, caused ¢hanses in rat lu~S patholor~ vh~ch were 8~m~]La~ i.n deerae or sl~jht:ly 1tess then those produced by the 100% tobacco c£$arette. BAT Co LTD - MINNESOTA TOBACCO LITIGATION

BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-10- The response to smoke from eisa~attes couca£ulng a= was Zess chart chat to smoke from I00! tobacco clSsret~es, possibly becsuse of the reduction /~ pu~£ numbe: produced by ~h~s substitute. Smoke f:om c£Ka:ecces couc~K SC produced tun8 lesioua mmee severe chart Chose produced by smoke £-:om 1001 cobscco c~Sawectes. This incressed response is not cons~lered to be due solely to the change in puff uuabe: caused by SC. F:cm • Cox~colozl:=1 po~zt of v£mw. evs- when d~£e:mzces Lu ezposu:e level ate consldered, SC is the least attractive of the tl~ee substitute mcerials examined. ~e£cher WC nor 1~, in comb/~ac£on irLth blended tobaccos, produce any untoward indications o~ Lucreased aBoke Coz~ciCy compared ~ch smoke £rom IOOZ tobacco c£gareCtes. BAT Co LTD - MINNESOTA TOBACCO LITIGATION

DO > o [-, -4 | Z: Z Z > "4 © DO > © t" > -,] Z 15 14. 13 IZ II 860ff17 ;01 ( ( ,',6., RD./~O6 flE,TrRIGTEO THE EFFECT OF ADDIN6 ~G, WC, AND 5ATFLAKE SHEET5 ON TPM DELIVEFFY CHAR,~TERISTIC5 OF CIGARETTE3 "1'1~ AT EXPOSURE ~BER ! 0 B ii 17 % INGLUSlON LEVEL (~) • (b) 15 14 13 IZ I! I ,¢ , I 30 0 17 °/eINCLUSION LEVEL ~) Tm A'r EXPOSURE GHAI,4BER Z'O ! 51)

03 > --I N o r- --] # Z Z > ,.-] O 03 > A O t" --] > --] © Z THE ( ( RO. ~0~ RE'~I"RICTED EFFECTS OF ADDING ,..%, WE, AND B, ATFLAKE 3HEET3 ON C,O DELIVERY i=, GHARAGTERISTIG5 OF CIGARETTE5 i i ii • ii im (,,) (b) TOTAL CO 17 Co DELIVER~ (n~/PUFF Z.O 16 We I.q i . 1.1~ 1.7 13 ~K :- I • i I&= : : : 0 17 30 0 1"7 30 e~ INCLUSION LEVEL % INCLUSION LEVEL 660~'[1z~01

~6.s (a~b) ~ 15o6 ~F..~¢T~ E.XPOSURE .L_EVEL5 DUE TO EQUAL DILUTIOM$ OF SMOKE FROM CIC~ARETTES CONTAINING DIFFERENT INCLUSION LEVELS OF 8UI~TITUTE8 __ i EXPOSURE LEVEL (n~.~n.l=') 6O SO 4O ZC • -I 8R 0 17 ij~ INGLUSION LEVEL BAT Co LTD - MINNESOTA TOBACCO LITIGATION • c~ I-'7 DILUTION _1- I I DILUTION 0 ¢-,,,a

( ~o > -.] o THE RELATION FIG. 4 RO. 1.50& RE~)TRICTED BETWEEN TPH DEPO31TION IN LOWER RESPIRATORY 3YSTEH AND TPM r'-' ! Z Z > .-} O > r-" -.] C] > ,..] m O Z EXPOSURE, LEVE,L, FOR CI8,ARFTTE5 WITH 100% TOBACCO AND ADbED SHEET MA_T_ERIAL~ TeM =N L~(r~) 0'9 08 0-7 O'~l. 0 "ll, 0"3, 0.2 i) • J + =O'~;' • • aoo% roe, Acco / " .I..~ wc - ./ .- • x rt% e~ / m x Ji 30°/. SC ./, v~%~ ,,4 -- : ......... ; - ; • I .... I ..... I ZO 30 40 50 sO 7O TPM EXPO,TgJRE LEVEL ('lno.m(n./t')

FtG.5 RD. 150E~ RESTRICTED THE RELAT I ON BETWEEN AVERAGE PATHOLOGY,,,, INDEX AND TPM E.XPq, SURE LEVEL AS/ER/~E PATHOI_D6Y INDEX IO0 9O 5K 4O I I ,, I : 42 44 4b 41~ EXPOSURE LEVEL (mg, n~.n.~) © 4, I 5O 52. I00% BAT Co LTD - MINNESOTA TOBACCO LITIGATION C~

BAT Co LTD - MINNESOTA TOBACCO LITIGATION