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.: >•- # E.C. / ~.._.. (Diseases of the Chest) For P.M. (CDT). Release ?une 24, 1970 IN r~ t'~,r F'r

t 3;ffectB of Cigmrette S:aol:ing Upon. Doga `~~:::r .ri nent; Moxtali.ty; 1'indinrgn in Lung Parenchyma. by. E. Cuyler Sircr;nond, Sc.D., Dr. Med. (=scar Auerbach, M. D. David Kirwan, B. S., and Lmixcnce Garfinl;el, M. A. In ntimerous epidemiologic and histologic studies, it has been found . , . , that the ill of cigarette smoking increrse Vith the nursber of ciga-- . 1-6) rettes smoked per" day. 1lia points to a do, e-roopons.e relation5h3p. The dose of tar 2nd nicotine dewive;.ed in the ccncLp fr= a cig3rette can be reduced in any of several ways, one way being the use of a filter. Thus it _pight be suppoae.d that if tar and nicotine are =inly responsible for the i12 effects, then scro~~;ing cigarettes equippcd with an efficient filter may be less harmful than sWoRing the aame nt=ber of identical cigprettes not so equippcd. i~]`v j.Ts:sC:..''. .^.Xj':.Timer,t V'm-. conducted to test- tt1'-F !1'yPuLiico~: _...F .,., .i c i- t• i`t;1 i ii ~. vnether cigarette smoking i=ould evcutually lead: to lung cancer in dogs. ,In a-prelivin,~ experirment, ten beagle dogs smoked ci:garettes .: ..:.=-t_~ ...: . - 7,8) daily by means of a tube in: crted i_n a tracY,eostcmn. Five of the dogs died within the fir:rt 415 daya of vnol:ing, one deQth being duie to br.onchopncu.r:onfa and the other four to pulmonary ~nfa.rction duc to eraboli. In three of thc.^,e cases the enbol3: apparently ca.^e from a thrc :bus in the right auri_cular appen- dage. xhe remaining ff_%,e dogs were sacrifi.ced on dayn 421 to 423 -sftei- having . : . . ' swokeeet 3,700 to 4,100 non-filt:er cigarettes of a br,-.jid x-ehich Was reported to be high in tar and nicotine. At autopsy, all of the cacrifiGed dr,g, were ,. ' 100509i'761

2. focuid to have cmphyser~a togetY~er r~ith heurt cnlFZ~ge3ent; ~^.nd' it in doubtful whether they would have survived for p:ny more moiiths. They also had raoder- ately sdvanced histologic changes in the bronchial epithcli=; and three of them had lesions (dyskeratosis) resenbling cwrcinc-ma-in-situ. In addition, all five dogs showed hy~.~.^..rpla'sia ualls of the bronchial tubes.. beings. However, at relatively higr, d.aily duFage (up to 12 non-filter cigarettes with distended goblet ce;.ls a glands in the The preliminary experiment indicated that beagle dogs are suitable experimental animals for teating various t,-pcs of cigarettes in respect to ~ < •. . -. ~.: - - • • . severaT of the effects Vnich cigarette smol:ing is knout; to produce in htm;an a day), most of the animals are likely to die too soon for the investigation of Iong-tern effects. Therefore, in the pre; ent experi;mcnt, . we started with a 1ov daily dosage and very gradually increased it up'to 9-cigarettes a day. In. the Ili~'heSL exposure group in l:Tli~~' f:oiiiu wou ...•+ reached until the 858th day of cc,o kinp. atream smoke vhcn.a cigarette is uicchznicull.y ;,Taoked under stundard test Cig:1rctt-eg i ested Our desire was to deterr-aine the biologicul effectivenesa of a filter which re:soves exactly half of the tar e-nd: half of the nicotine from the main conditions. Several brands of filr.cr-typt: cige.rettc:.> were tc:•ted For us by Dr. Jacob Fitelson (a cl3emist with ].ong eYpcrience in this ficeld); but none .of the-,n precisely met the desired spe-cifi~~~a'ti.o:ls. The nearest was a popular brand of American cigarettes cold in cruch-rroof pac1:F9'e3. Each cigarette was 80 =: long with a 17 =. t:hit•e filtcr:.. - In testi'tig and later t:hcn givcn to dogs, each cigarette was sVLokc.'d until the first. 49 i; n. of the cigarette

filter attached, the t:,mol:e contained an aver4t,;e of 17.8 mg. of total tar (dry was consumed, (i.e. until the glowing tip reached the 49 n~. mark) . With the '3. wei:&ht) and 1.17 mg. of nicotine. With the filter removed, the smoke contained an_average of 34.8 mg. of tar and 1.85 mg. of nicotine. ';r-us ehe. filter - xeduced the tar by 497. but reduced the nicotine by only 37°io. We purchased 480,000 of these cigaretteswhich ca.me pc.cked in Heil-sealed boxes, each box containing 60 cartons with 10 pacl:ageg of cigarettes per carton. The boxes = were stored_ir a temperature-controlled, humidified room until used. P.xperi*^ental l~nitn~ ?. s -2linety-3even pedigreed male beagles Kere purchased from breeders who stated that the dogs were in good health. They were kept under.observa- tion in our Iaboratory, for several wceks to make sure that they were in good _ health. - TYacheostony was then performed on each dog. The tracheostoma was . - - . ~ . • . .,kept open by a hollo~.~ tube made of Teflon. In smoking, the tube was c`iangc:a Teflon tube equipped with a. socket -for coupling to tubing leading to a to a z. - . . _ . . cigarett.e holder. - . At the start of the experiment, 'the dogs ranged in age from 1.7 ?_0 cages. They were fed each day following thF: afternoon smoking set;rion, experiment -they were housed in five air ctnditio:led va.rds, each ward 1taving .from 20 pounds to 39 pounds, the mean being 28.3 pourtid3. Tnroughout the years to 3.3 -;eara, their mean age being 2.7 years. . They ranged in veight the ~e~l consisting of 400 grLms of cc.rr:7crci<:l dog food. The ni.nety-aeven dogs were a.ss)Vried to crzF;cs by compater.-bencratcd'

4. kept as controls. There was one or more of these dogs in each of the five randcxn numbers_. Eight of the doga were then sel.ected by rartdom ntic:bera and .I : wards. The ci€,ht control dogs, hereafter r?ferrcd to as. group C, never sr~oi:ed cigarettes; but their tracheostomas were I:ept open or the duration of i.he - experiment. During seven c,onaecutive days the other.89 dogs (i.e. all except -the eight group C control dogs), were given unlit cigarettes in order to let them become £artiLinr with the 'situation, We smoking of lit cigarettes began on May 2, 1967 %4hich we will hereaf ter cal:, "day -4.1". The first 56 conse- .period. On days 1-1411 each~ dog smoked one filter-tip cigarette in the morninfi; cutive days were used to train the doL-,s to smoke and to habituate them to tobacco smoke. Only filter-tip cigarettes were administered during this 5'wvr.ov days 22-35 each smoked lll- in the afternoon; on one in the morning and two in the afternoon; and on days 36-56 each smoked two in the morning and two in the afternoon. 'Plius each dog (except three that were ].ost) smoked a total of 154 cigarettes during the first 56 days. Each dog Wmoked cigarettes in the morning and in the afternoon of each day, seven days av'c.ek, from then on. At the beginning, sraol:e from the cigarettes was delivercd in puffs under forced draft. Gradually, the dogs became used; to smoking cnd "inhaled . the smol:e voluntarily by drrving on the cigarette. In between each five puffs (or more often when necessary to prevent anolia) the smoking tube was clampeci off allo:ring the dog to breathe fresh «ir through its motsth or nostr.i~:s. . ~ ". .

Whenever a ciog -showed signs of" d~tr~.` .. ,~z longer. period of air inhalal ion was:permitted. After a while the dc4-.:=appeared to enjoy, the experience as indicate& by tail-wagging and jumping into thi. sinoking box voluntarily. Forccd inhalation was discontinued and the dogs smoked voluntarily from t~en Three of the dogs were lo'~: -"z3'uring the 56 day training period: .Stzortly after smoking was`, 'started, the' eyes of the dogs were ex- . amined by Ur. Ha :old Spalter (Opthalmologist) and he discovered that one of them had a brain tumor. This dog ua5`°'withdrzwn frozr, the study and will not . . . sr..; : be mentioned hereafter. One dog died on the 32nd day of smoking after having smoked 61 filter-tip cigarettes. Autopsy revealed the cause of death to -he pulmonary infarction with multiple emboi i in Lite iukLr;ZY hrcint-}r,n- pneumonia on the 52nd d'ay after havinig smoked 13'4 filter-tiP cigarettes. On day f57, the rcmaining 86 smoking dogs were divided into four groups (F, L, li and h) . As described below, 12 dogs were put in group F, [2 cigarettes for the duration of the experiment. Group L, H and h dogs were group L, 24 in group It and 38 in group h. Group F dogs smoke& f i l t er-• t i p gradually transferred to non-fiLter cigarettes (i.e. the sz,:ne brand of citi;a- . .A Since tl,ere was reason to suspect that effective dosage (ir, contrast * to ahso2ute, do:.ai;c) 'in influenced by the site of animals, we attempted to obtain dogs all of close to the same si'-.: Unfortunatel.y, due to shortage of suphly, - . . _ ,. . _ . . _ _>.;

c~ 6. ti -the dogs delivcrcd to us va.ried in weiEht from 20 to 39 pounds. For this reason, we net. ut;ide the 38 heaviest dogs vhich will hercafter be referred to as group h. These dogs, which ranged in weight from slightly over 29 pounds to 39 po.unds,- were used in a sapRrr.te experiment, the prcliminary findings of which are reported . . . .. the averar;e being 25.0 pounds. By stratifiecl randoni selection they were . into gt'oups F, L and H(F for filter•-tip, L for ='lighter smol:er." , .. non-filter cigarettes and H for "heavier smo~cer" of each group in remaining 48 dog& ranged in weight from 20 pounds to 29 pounds, each of the five frurds. On any given non-filter cigarettes). t<ou 1 d be some dogs of day., the same technicians hzndled the sr:~oking of all the dogs in a-particular ward. 057 throus,h L140 may be referred to as a transitiom period. Group F dogs were kept on filter-tip cigarettes Vrile group L, 11 and-h dogs were gradually chanSed fro.~, filter-tip to non-filter cigarettes. On days #141- throu8h #210, group F dogs snloi;ed' 6 filter-tip ci8arettes, group L dogs smvl:ed 3 non-filter cigarettes, and group IT and Ii dogs smol.ed 6 non-filter The daily nwnber of cigarettes 'Has gradually increased there- We ai.r~ied to expose the group L dogs to half as much tar and nicotine after up to 9 cigarettes per day for group p,.H and Ii dogs. As the group 11 and h~ dogs during the courpc of the experiment. The'ref-ore, in order to co:spen:sate for the fact t:lrrt all the dogs stnoS:cd the sanie ntm,bet- af cigarettes during the first 56 days, ths group 1. dogs clcre 8iven fe~r,:r ::.than half as many cigarettes as the'H and li dogs during, the remainder of the .

7. e>:peri.ment: The surviving g,roup L dot;s smoked five cigarettes per day :_dura.nS 49 day:5,but smoked less than this nunber on all other days. During ,the last year before being sacrificed, they smoke.d' just four cigarettes a It should be noted that during the course of the experiment three . of the dogs became acutely ill (fever and other symptorrs) . One was of group- H and 'two were of group h. They were taken off of smoking for a, few days, treated with .:ntibiotics and when they recc-vered, put back on smoking. of these three dogs surv'_ved for many mon'_hs after the eFisodes of illness. Table 1 provides some information on each of the four groups of :smoking dogs and the control group. For ease of comparing groups, data are given on the total exposure during 875 days for those dogs that survived for. t'•tliti> lon6 v- iZ~ .. LC 1 ~..r-..7 f~ar anrl rnYal nico:.lne consmried are based upon the assumption that the dogs received the sanie quantity from each cigarette as was found when the cigarettes were smokcd by a smoking machine. -. As previously described, dogs of group.: L, 11 and h smoked filter-tip cigarettes at the start of the exp:.riment but smoked non-filter tip cigarettes during most of the experiment. This was taken into account in computing total tar and nicotine consumed in 875 dayn. . convenient measure of size. For this reason, table 1 shows: the grams of tar The size of the animal should be•consi:dered in estimating effective dosage; and body •eight of the animalt; at the start of the experiment is a and nicotinis consumed in 875 days divided by the mean starting weight of each group of anicials. By this index., group h had lower effective exposure to tar t _-.. , a;._ . .. . . . . .

I .and nicotine than group H. labeled Group F had 1.06 ti-mes as much exposure to :nicotine as group 1~. - Sacrifice of Dogs - - I- - _ ~ . - _ ---- for-a 150 lb. man" is base& ~upon the constant,'relative dosage nd H than man} Lhi"s experiment smoked no more cigarettes per day on the average t The lan was to sacrifice all of the remaining group F, L, a plan figures are_intended.only ' v .dl7pJ 4./ actical reasons sacxificin~; ~*as deferred for 16 days during which' but for pL ~ term ef fects) lialf of the group H dogs c'ere dead by the end of day V85v , s had di i,~1 f of the do~;s ini any onc of these four groupe l 7 •. t.~:~'"O}{C)~f'(~ VPYV lCnZ (Dogs of group h were to continue smo~:iub ,.~c orU4~ -. ~• - ' 1005091768 Thee a;icrificing of all remaining group F, L and I~ dogs was started on on day PS7Cand completed on day ~jS4'~• 7.1ie set of figures The exposure of sroup, L was half that of group H.. "equivalc ,t ntm=ber of ci,;arettes per asstr.n'ptio:~ that, holdins absolute dosage is inversely proportional to body waight. These to show that, in relation to size, the dogs in Sacrifi.cinp, was conducted in This length of *time Was requi.:'ed to zr out thoroughr post-rnortc,n cr.~ir.ations. stratifi:ed random or.der, of the . time. the 4tratif j-caLi.oit being such that the doSs of e<~c i three group; would be kept a'li\Ie for al=pro>timw.tely the same lcn,n,ttl^. of Until s.:crificed, each, F dof'l smolccd, 9 fil:tcr-tip ci.garc.ttes a d,ay, each L dog smoked 4 non-filter cigt;rettes, a day and eacl~r H' dog, smoked S Group C doga were sacrificed between days to tar and 1.29 times as much exposure 4

One cf the F dobs c' ~d on day.V879 which was prior to the day on -uhich he otherwise would have been sacrifi.ce6. The principal cause of death : in this case was pulmonary- infarction; and thrombi were found in veins of For simplic.`-t~I -n presentation, we will hereafter include - - ,. - . . . _ :. .,. ~_ ..- . : . . . : this dog with those• that werc-sz;crificcd. , Hons of ~the remaining group h dogs .of the-n died b:_ween days #876 a..d 2,,=906. All of them continued to smoke r -non-filter cigarettes. Later findings in this group will be reported after Hpne of the 8 control dogs died; two (16.77) of the 12 group F dogs died; two (1b.7%) =of the 12 group L dogs died; 12 (50i) of the 24 group 11 dogs died; and 12 (31.67o) of the 38 group It -dogs died. Thus the death rates of the five groups of dogs were in aligrwient with the dosage o; tar and nicotine relative to their rnean body weight at start of the experir_-lent.. (See table 1) . Table 2 shows the principal cause of death . of each dog that died, they have all died. F,-...,, riay f57 (the CIay vP(-n rb` smoking doos were divided into four groups) th-rough day i875. dog of group It which died on day P237. : TAble 3 shovs a stmtnary of the principal causes of death in identify each dog by group and day of deatl7. ' For example, dog 11287 weans the the day of death, and the nimiber of cigarettes smoked. We will hcreaf:ter.