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group of dogs as ascertained at autopsy. Some of the dogs apparently died f a combination of causes; and all had at least slight indications of On this table, each dog is clas;ified according to what appRared ' to.be the most severe morphologic r:anirestation of cisease. We cannot rule out the possibility that the acute toxic effects of cigarette smoke may have precipitated the death of some of the dog's including some of those with morphologic manifestations of disease-ufiich appeared to be sufficient to account for -de..th., Furtheimore, we cannot ruLe out the possibility that the effects of car'',on monoxide in cigarette smc'cc may have contributed to the death of some of the dogs. Two deaths (H517 and 11563) were due principally to pulmonary fibro- sis and e,.physema, and eight were due to cor pulmonale. - All ten of these -f 14 ..i 1, i'F,n firot nrriirrnfj ?ft-or smoking. In those that died of cor pulmonale, great enlargement of the right -heart was a more pro;~inent feature than was fibrosis and enp5ysema. the degree of pulmonary Nine of the 28 .:eaths were due to pulmonary ;_:-ifarction. A thrombus was found in tha right auricular appendage of most of these dogs and sc:ve_al also had a thrcmbus in the left auricular appendage. One had a thrombus in -the vena cava and several had thrombi in other veins. absceas probat ly contributed to death. AL 1 four had moderately advanc :d Four deaths (11198, 11203, 11259 and 1~I287) were due principally to .bronchopneumonia. In one of these pulr:lonn;.y i.nfa.r.ction and in one pul.r;ionary

11. ->Ar=autopsy, food particles were found in the larynx of one dog ;;_V:3-471 and in both the larynx and trachea of another dog (IF380). The. lutigs ° of dog 7380! were collapsed. One of tliese dogs died sud: en:y while smol:ing a cigarette and the other died shortly after smoking. Asphyxiation resulting from aspiration of food appeared to be the major cause of death; but reduction : =Vf:_~Ugrsi 4upply or acute toxic effects may have been a contributing cause. The principal cause of death of three of the dogs is.uncertai~.n . . . . . .-:. . . : . . . . . ; . . : . : . - (H135, h289 and 11858). Dog H135 had a sligf,t to modezate r:i£fuse fibrc3sis emphysema in all lobes of the lungs. Dog h289 died shortly after the morning smoking session. lie had pulmor_ary fibrosis and emphysema in all lobes of the lungs and organized bronchopneumonia in the left diaphragmatic but these morphologic cha::ges did not appear to be sufficient to cause death. Dog 118:i8 died~ suddenly after smokiag his fifth cigarette in the _°:----mvz n in g s e s s i on . He had pulmonary fibrosis and emphysema in all lobes of the lung of a degree probably insufficient to account for death; and alarge number -..- of granulomata with brown pig:nent and fat with reaction around these areas in Jobes of the lungs. Since morphologic -findings at autopsy did not. appear to be sufficient to cause death of these three dogs, it may be that death was ;.aiiu*,-:principally to acute toxic- effects. ~40SQ9~:"~`71 : As shown in table 2, non-iiivasive. bronchiolo-alveolar tumors were' found in the lungs of 12 of the 28 dogs which died and invasive bronchi:olo- ` alveolar tumor. were found in the lungs of four of them (dogs h626, hG49, 9

Food Intake and F!eizht In F;eneral, the appetite of the smoking dogs as well as the ;-on- scrmewhat in ,eight from one weighing to'thz next. A few lost weight and ' The dogs were weighed periodically. Most of the dogs -flucttiated =•regained_it and a few ga'-ned and later Lo.-t weight. ?':owever, the different xhat is to say, they usually ate all of the 400 grams of food provided each day, although occasionally some of the dogs .failed to do so. .&roups of dogs did not vary significantly in_this respect. Two dogs of group F and two group L dogs died before day #876. Their -weigfits shortly before. death were approxiyaately the same as at start. a. r. ~. 11 a' -~r L..a .7....4..T.tr FT..,.n.. avi ic bzvuy ii-uub~ lllGll. U'iCa~ VcAVLa:- ..ca~ .~.1,., . .~ .- . o~- -- --c~ -, --- 10050991772 Findi.n ,s' in T6unR Pai1cncl«^na and Pleura Autopsy was performed and the lungs removed as soon as possible had lost weight and seven were at close to starting weight. Of 12 group h.- - dogs %fnich died, 8 weighed less just before death _ than at start; one had '.gained weight and three had'the same weight as at start. Of 40 dogs WhUc;I were sacrificed after day "875, 21 weighed more than at start, 17 weighed about the same as at start and two (one a group L:and. one a group 11 dog) t•.*ei~:&hed less than at start. into the tr.ac_,ea after which time was allowed for'adequ<<te fixation of the after death. Tte lungs were inflated by instillation of gxavity-fed fornialin tissue. The lungs of beagle dogs have seven lobes, four on the right side

13. ..apical, cardiac, intermediate and diap:hragmatic) and three on the left side (i.e. apical, cardiac and diaphragnatic). Olie specimen of tissue was cut froas-each of the seven lobes extending from the pleurQ irn4ard about two i r re arcd from each of these seven p p centimeters. ~ microscopic sect on as Altogether, there were 490 microscopic sections, seven from each of the-70~dogs th~:t died or were sacrificed (including the two dogs that died before ddy #57). The 490 sli.des were put in random oraer by computer- geherated random numbers, and, while in this order. labeled with consecutive the reader nuuibers, O:h.). had no clue as to.tl-he identity of the dog from which a section was On ex,^iination, the degree of each of the following factors '•as estimated• 1) fibrosis, 2) emp,rysema (rupturing or destruction of alveolar ta) 3) pad-like attachments to a].veolar sept.~a, 4) thickness of kalls of sep , - ,rt.n Has used to c arterioles, and 5) thickness of the pleura. k grading s)s record .the de:;ree of each type of histolog ic ch-1rnge. in each instance ,~tGrade 0 " means "no rhange" or "nor.r:~al" . For example, Grade 0 f ibros i_s cr,eans no

- .-z_ . .. . . . indication • of fibrosis. The walls of arterioles are normally thin and the .."normal" thickr.ess of these structures. G;:ade 0 for pad-like attachment:s Co pleura is normally fairly thin. 'Grades above "0" indicate greater than alveolar septa means that no such attach:nents were'found. 1'anphysenia was classified in four grades, 0 through IiI; but ;;rade III was only found in tbree sections (group H dogs). Pad-like attach-nents. Were classified in three grades; thic}oless of walls of arterioles in t:zree The various grades of each type of histologic change mentioned ' four gra3es. It may be that when more mon ths , greater changes will be than any so far observed. If so, higher grades will. be utilized in classifying the changes. ; In.uany instances,• all seven sections from the same dog were. graded the sz,_,ne in respect to a particular type of finding; and~there were no in- :: stances in which the seven sections fro-..c a dog varied •greatly in this respect. For example, there was nc. Instarice in which grade 0 c.:,physema was found i some of the aeven sections and~ grade II e-nphysema in other sections f-:om the same dog. Because of this 10QS09177-4 Sections fro:a~ the two dog: tThi:ch had c;,ioked only filter-tip cigarette and died befcre day V-1'57 showed a elight cegree of fibrosis, a very slight degree of emphysema, no pad-lil:e attacli*.r:enta to alvcolar &epta, normal many con;iEtency, in table8 4 and 5 the findings are shown in terms of all the sections-fro:n specified groups of dogs rather than being sho:an for each individual do?,.

thickness of the walls of ^,r.terioles and no greater thickness of pleura than yas found in uaany sections from the non-smoking dogs. . Sections from dogs F380 and F854 were not much different than those from the two.dogs ment:ioned above. Sections from dogs L347 and L812 were again about the same except that pad-like attachments (grade I and a few grade II) were found in all of shows findings in sections from the 5 group 11 and 6 group It dogs which eied between days f 57 and f-499; the 6 gr,,up H and 6 group h'dobs which~ died between days u500 and P875 and the 12 group H dogs which were between days i7576 and 16899. In both group. H and group h dogs, -there was a progression in the degree of-each of the five types of histologic change recorded. That is, in both H and h dogs, greater changes were found n sections from dogs dying between days ~:5O0 and x875 than in iihose dying between days V'57 and 0499, and the greatest changes were found in sections from~ group H dogs which were sacrificed betveen days #876 and f899. the 12 group H(non-filter) dogs which were sacrificed after day #875. As pre- Table 5 shows che findings in the 8 group C(non-smoking control . dogs),' the 10 group F (f iltcr-tip) dogs, the 10 group L (non-f ilter) dogs and .. . . ~ (non-fi_1t:er) as the group F(fi.lter-tip) dogs. However, the group F dogs had viously described, the group L doi,s stnoke<:t only about half as many cigarettes about 6% more exposure to tar and about 29% more exposure to nicotine than

/0( . .-'~_ . , . . number of cigarettes ac the group F dof;s. Far greater histologic changes were found in sections of lung parenchyma fror the group 11 (non-filter) than in sections fro-•n the group L_ (non-filter) at~d group F(fil.ter-tip) dogs. Except in respect to tile wall.s' of=arterioles, greater changea were found in sections f::olm group L than in sections from group F. Except as noted below, sections from group C (controls) and_89,3% shoued only a slight degree of fibrosis (grade Z). All of the sections from group F, L and if showed at least grade I fibrosis; and most were of higher-grudc. Grade IV or V fibrosis was found in 0% of the sectiona frow , 6LVUt+ v, .. • Of the 56 sections from group C, 10.7% showed no fibrosis (grade 0) S "7 °14~r r.rrs o•-~~~» F. 12.9% from group L and 91.7%" from group H, - (See A comparison may be made by consi-d!ering individual dogs rather than akl :the sections from each group of dogs.' Of the J.& dogs of group I', 8 had no -sections of grade 'IV ^r higher while two dogs each had just two sections of =grade IV (the other Bect"ions being gxttles Ix or XIZ) . Of the 12 dogs of these dogs all seven ce"ctionc were of grade IV or V. In otiier words, every gr_oup•f[; all had a majority of the sections grade IV or V and for six of one of the 12 group It dogs had a greater degree Of f.ibl:osis than any one of the ten dogs of group F. This di.fferencc-. is s,tatistically significant

'diffcrences notcd above, is statistically significant by both tests (p .( 0.05). significant by- both the t test (p ..-~ 0.0001) and the Wilcoxon rank sum test. =Tie• difference between group F and group L, though smaller than the other None of the 56 sections from group C showed any evidence of emphysema. Grad:e:xl:or III emphysema was found in 070 of the sections froa group C; 12.97. from. Proup F. 24.37. from firoup L and 98.87o from Aroup H.. Considering individual dogs,.the :iifferences between group F and group-1I, and between group L and group H are statistically significant (p<0,0001). 7ti'e=difference between group F and group L is not statistically significant the.sections from group C, but nonc of these were above grade I. Grade II ,padtJ:ike attachments were Found in 0% of sections from group C, 22.97o froin group F, 4E.67; from group i: and 97.6°l from group H. Pad-like attachments to alveolUr septa were found in over half of 17. (See table 5 and figure Considering individual dogs, the 2iifferences between group F and 11 and between group L and 11 arc statistically significant. (p < 0.0001). The difference betvecn group 1:' and 1, is statisti,ca,l1y sign ific,~1t (p G 0.05) . . Thiclcness of the Walls of Arteriol.es walls of arterioles were of rormal thickness in all the sections Thickneas of grade I or 11 was found in 0`l, of sections from 2,97; from group L and 41.77. from group H. :

18. table 5 and figure 8). The differences bctwecn group F and li and between Group L and H are statisticai ly significant (p lz, 0.0001). There was no difference between group F and L.. Thickness of rleura . The thicl-,ncss~of the pleura was evaluated as grade 0 in 30.4% and -grade I in 64.57, of the sections from group C. 2'liickness of grade II or III was found in J% of sectio-B from group C, 7 0% from group F, 21.4% froagroup L and 90.57o from-gi oup H. (See table 5- and .Ci gure 9). The differences betueen group F and It and between Group L'and It are statisticall-y sign.ificant (p ( 0.0001). The difference bet4een group F and L is not statistically ~.ignificant (p > 0.05). The mortality of the dogs in relation to ci.barette smoking pnra.llels : the finding in- epi_demiological atudies that death rates are far higher in cigarette nWokers than in non-smol:ers anu increa:se with amount of cigarette 1-4) u~coking. 10Q+.~?Q9177s J?uUnonaxy c~rl~r~yse~a and fibrosis uad cor puln,onale are rare ca:ises of death in dog.:y but of 62 he'avy smol:crs of non-filter cigarettes (groups It and h), 10 (16%) died of these di.ser:scs within 875 days. This paralie2s the finding in epidenaiologica1 studies that ci.garette cmoking is accomp;1nicd by a great inc7:Gasn in dcath ri:tes fro-.n theae disezsea. .I1i..tolcgic fi.ndings in the 1Llnf; pazencl7yna of the smol:ing do,s were , of the srune, typcc as h ia tologic f i:ndings in the lung parench}nna of h"„n z. ,. .._...r,. . . .... ..

19. -1 5) beings with a history of ci e smoking. Both in hu:nan beings and in "dogs, emphysema (rupturing :atzuction of alveolar septa), fibrosis, the occurrence. of pad-like attachments to aLvcol.ar septa,., and thickening of the' wal].s of arterioles seldom occur, or occur to only a slight degree, in the lungs of non-smokers (except non,.-smokcrc with occupational eYposure to certain 'dusts and vapors). Cigaret~ t:~~oking is acco-npanied by these histopathologic' -:: changes; the changes •beccr.n:°;°pi1ogressively more advanced so long as smoking is . smokers. this er.perintent, one group of dogs smoked- filter-tip cigarettes -and other groups of dogs smol:ed the same brand of cigarettes but with the fil:ter removed. The smoke from~ the filter-tip cigarettes contained 49% less lctX iut 'R% l:as PLrOLi1iG FY^-'~ rifiarettes Without the filters. G~- . Considering dogs i'nich smoked the same number of cigarettes per day, _ the death rate wds lower among those" that smoked fiZtex-tip cigarettes than among those 'which smoked non-filter cigarettes. Sruoking filter-tip cigarettes produced less extensive da-mage to the lung parenchyma (i.e. emphysem,a, fi:b1•oGis, etc.) than smoking thc same ntmrber of non-filter cigarettes for the s,we length of time. Ho;rever, smoking filter-tip cigarettes for a period of £:75 to 899 days prod«ced si&nificant damage to the lung parenclx}..~~a. Since the degree of such dUnage progresEes caith duration of smoking, the evidence indicates that lunE; parench}^x,-cl d'ainage -ndvances Ie.is rapidly tAth the smot.ing, of filter-tip cigarettes thzr. with the