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Y_ F„0*"ih~ 41 V.-lall .

74-1215. aviado, D. tl.; Watanabe, T. Functional aad' Biochemical Effects on the Lung Follotiring Inhalation of Cigarette Smoke an~d Constituents. I. High- and Lov-Hicotinz Cigarettes in H.ice. Toxicology 3nd! gpplied Pharmacolo3y 30 (',2) : 185-2'00, xovembez 1974, Eng,lish!. If cigarette saoke causes pulmonary e-mphysema and chtonic bronchitis in man, then pulmonary impairment should be noticeable on lu.ng~ function t,sts. Sviss and I'CE 9ouse strains were used, to test this relationship. Daily inhalation of cigarette smoke for five or taa veaks~ elicited an n increa se . in pulmonary compliance, a decrease in fuacticnal residual capacity, a decrease in pulmionary compliance, m.decreasa in tidal volume, no changa in phospholipid content of the lung, and an increase in vet weight of the lung relative to, body weight, which was reduced. The iscrease in pulmonary resistaince and' the decrease in functional residual capacity were elicited by nonfiltered smoke as vell as by the vapor phase, and their appearance was related to the nicotine content of' the -'igairettes and the d'uration of exposure. Thiese results ind!icate:that these two effects are elicited by a combination of the nicotine contained : in particulate material and constituents of the vapor Fhase. The d!ecrease in pulmonary compliance aras elicited by inhalation of nonfilt_red smoke but not by the vapor phase,, indicating, that the causative Sactor is in the particulate matter, probably nicotine, because the appearance of decreased compliance depen&ed' on the: nicotine content.. The~ decrease in tidal volume as Yell as the increase in: pulmonary' resistance, or, bronchospasm, occurred more readily in ICB strain mice than in the Swiss strain. Both strainis developed, tolerance to broachospasm after ten weeks of exposure. There tiras' no incraase in fuactional residual capacity and, hence, no functional sign of pulmonary emphyszma in mice that had been erpos2& to cigarette smoke for five or . ten veeks- ( A'uth. Abs. Codl. )

79-13148' B'ernf'eld,, P'.:' 8omburcer, F, : Soto, E'.: P3i, R, J. Ci'g,arette Saoke. Inhalation Studies in Inbredl Syrian Golden Mazsters, Journal of the National Cancer Institute 63 (;3) : 675-689, September 1979, English. Invasive carcinoma of' the llaryr.x was induced in 36~,8' percent of i'nbred Syrian golden haasters from strain E10 15,1'6, susceptible to this type of , cancer when exposed toismoke from reference filter cigarettes for 59 to 80 weeks, xear'ly: half the animals (u7,u percent) shored laryngeal cancer, inc3udling noninvasive carcinoma and carcinoma, in situ, which occurred with daily smoke exposures (twice a day for 1'12 min each time, for 27' sec out of' each a,in) 7'days a week at smoke concentrations of 22 percent. Yhen the smoke concentration was reduced to 111 percent, the number of induced lesions was reduced'Froportionately, when a portion of tobacco was replaced in the cigarettes by a tobacco supplemens (Cytrel) a reduction of -carcin.ogenesis proportionate to the Cytrel content of the ciqarette took place. Smoke from, cigarettes cor.taining only Cytrel and no tobacco induced no carcinomas under the conCitiocs used. Other dose-related changes observed were laryngeal paFilloe+as, laryngeal epithelial hyFerplasia, . tracheal epitheliall hyperplasia, and metaplasia and accumulation of a1!veol'ar macrophages. Tar deFosit,ion in lungs and larynges was determined ina a separate study by means of a marker (d'ecachlorobiFhe.nyl) added to the cigarettes, Admixture of Cytrel to cigarettes reduced ta€'deposition in the respiratory tract, vhich: paralleled the decrease in the incidence of laryngeal earcinoma, However, the amounts of tar d'eposiied' in the larynx when 100 percent Cytrel was ssoked: were still signlif'icant, eventhouich no earcinoaas wer-e observed. Thus, smoke from Cytrel tobacco~suppleuent may be less carcinogenic than equal amounts of tobacco smoke, (Auth. Abs,)

79-11I2& Bozall, 8. B.; Field, E. 0. Substitute-Tobacco Tar Toxicity. (Letter') . Lancet 1(a!Oo7):: 773, 1pri1 8,, 197'8. Eng,lish. I'nvestigatioa of' the mutagenicity of cigarette condensate from ""Silk Cut" both with and without tobacco substitute material revealed' that both types exhibit mutagenlicity (Ames test). However, only 7 percent of the~ total tar is derived' from the substitute material. d'ouse skin painting tests have shown, a significant reduction (1p<0.05) in tumorigenic activity in cigarettes containing 50 percent ""1Cytre2" (contributing, 19 percent off the total tar) compared with all-tobacco cigarettes. The use~ of substitute materials facilitates reduction of' total tar content in less hazardous cigarettes, with resulting' health benefits for those who continue to smoke. 76-0974' Brun,aemana, if. , D. ; Hoff maaa, D. ;, Wynd'er, E. L. ; Gor'i. G. . 8. Chemical Studies on T'oba~cco Smoke. . XXXVII. Determination of Tar. Jiicotine, and CarWon Conoxide in Cigarette Smolce. , A Comparison of Iater'natioaal Smoking Conditions. pp.. 44 1-449. 1976, In: Vynder, E~. L. ; fioffmaan, D.;. Gori, G. B. (Editors)',. 8odlifyinq the &isk for the S'moker, Volume 1. Proceedinqs of the 3rd World Conference on S'mokin4 and Health, Dtew York, June 2-5, 1975. DdE:iP'ublication No. . (NIH) 76-1221, English. A U. S. non "ril ter cigarette and a U. S. f ilter cigarette were smoked under the various sm1okinq conditions that are declared standards of' sevea countries and one l~n:ternational organization. The values, as reported for the methods of different countries, varied for the noafilter cigarette betveeni 29.4 and 42.6 md for tar, and 1.73 and 2.09 mg for nicotine, and for the filter cigarette between 18.1 and 21.9 mq for tar and 1.31 and 1.42 mq for nicotine. These siqnificant differences must be considered when tar and nicotine data for cigarettes of various cou~ntries are evaluated. This study also emphasizes the need for standard smokinq, procedures to be used internationally. A correlation was found toa tar and, CO of 3'2 exper'imental nonfiltar ciqarettes made with the same cigarette paper and of 68, UT'.S'.. comne.rcial filter and nonfilter cigarettes. The correlationi coefficient for the commerciall cigarettes was less significant (r=0.o1) thaa the correlation c'oefiicieut of the experimental cigarettes (r=0~.81) indicating, that cigarettes can be marketed with some selective reduction of CO in the smoke. This finding, of differences in the smoke CO of commercial U. S. . cigarettes and the possible selectiva CO reduction support the concept that in addition to tar and aicotine. CO values should' be reported. (Auth. Abs. ) 1005052828

70-0533. Burton, H. R. The Pertinence of Tobacco Product Modil:cation to Chemical Composition and' Biolo¢_ical Activity. In: G~ciffith, R..B'. (Director) Proeeeding; of the Tobacco and' Hezltfi Conference, Conference R~eport • 2: February 24, 25, 1970, Lrxington, Kentucky. University of'Kentucky,, Tobacco and Health Research Institute, 1970; pp. 21-28. On the basis of research at the University and results reported in the literature, data are presented which show significant alterations in smoke composition as a result of add'ung, compounds such as sodium nitrate, sodium molybdate, sodtum stannate, ammonium vanadate, and potassium chlorate to tobacco before cigarette manufacture. Smoke yields and composition are aiso affected by product changes involving the type of cigarette paper used„fi7ters, and inclusion of reconstituted tobacco. Moisture content of the cigarette afFects smoke yields and composition. Biological activity of'smoke condensate as measured by tumor production oni mouse backs is affected by chemicai' additives ~ to tobacco, the inciusion of reconstituted tobacco, moisture content of cioarettes, and extraction of tobacco with organic solvents. Acute toxicity of smoke as measured by inhalation techniques is also affected by some or all of these product modifscat2otu. In some iastances mouse skin activity may be reduced but acute toxicity increased, indicating the need to conduct more than one kind of bioassay before eoncluding tsut a given modification resttlu in a , "safer vroduct" (Auth. Abs.) 78!-0763 Pyckiing, E. Ontersuchung der FiitErYirksazkeit des IaDncstraz.gies bei Cigaretten verschiedener fiarte iz lbaanyi3ftit votl der a'n,csuchlazga. [Filter Effectiveness of the Tobacco hod of Cigarettes of DirraraLt Bensities ir fielation to the Smoked :.enyta. ] aeitraege zur Tanioxforschung 8(6') : 3'82'-3'57,, June 1976, German, with cigarettes of diff.ering density tae smoke condensats aua nicotiWe yields in re2'ation to the smokedi length ot' tne cigarette Verii aaterminad. The aacunts cf these substances QuriLy tz2 saoxistg of the first third are generally saal.ler in cigarettes Lith Liyh dlrnsa.ty, about the sama in tae second third aina only in tae last thsrd' are taey greater than .:L cigarattes with low, density. The iilter efficiency ot the tobacco rod' ria~ mctermzzed by smoking equal lengths of rcd cf tne normal and the shortenas cigartttes. The coef'ficiEnt of filtratioa was caiculatEfl. TLe coefficiezt or t3.itration . (mu), is, for condensatE, independent of the iangth of the fil.tar+ng tobacco rod. For the nicotine retention, on the other hand, a clear cLduye ir, the coe f'ficient cf filtration is shoca. The ss"tration power of tLa tobmcco, rod declines vita, decreasing lengthi. The causes oi' this haYe nct Y,at be<n investigated in detail. These results aprly vottt to,filter ana pias.n cigarettes. The coefficient of' filtr3t+oL ('$u) increases in tr.,;. area investigated almost linearly with the aeLssty. The median ccezr;.cieLt of filtraticn for nicotine is nearly 60 percent of' the coezficiez,t ofl filtration fcr, connensate. I further iZvestigaticn was condactii isto, the influence cf the puff freguency on tae couaensate ana nicotint a,aounts. With a ccnstant p.uf.,60 numoer, cigarettiis Vare smoked with changca puff frequencies and the smoking values for s&oka coa&ensate and nicotine content were ccmFared' riith each cther (j.,&r c:.garette and pier rus=) .(duth. Dbs.). 100 5052 8 ~9

7~5-0159'4 Dontenrrill, W.; Chevalier, S.-J.; Harxa, Ii.-P.; 1Climisch, H.-~I.; ~, •irig,k, C.; Reckzeh, G.; Schneider, Bi. untersuchungea uber don cffEkt der. d kb `1~_ronischen Z:igarettenra chl.ahalatioa beiz syrsschen Goldhaaster un, m er die Bedetung des Vitamin A auf die bei b'eraucauag gefunden Orgaaveranderung2n. .[Studies on the Sffi:ct of' Chronic CsgarEtte Smoke Inhalation in Syrian Golden Hamsters ana the Imr.ortaaca of vitamin A on C.orpholog'ical Alterations after S'moke B,xFosure. ]', ZEitschrift icrensforschua und Klinische 0'nkologie 89' (2') : 1'53-1 cs0, 157'7, Gteraan.. Chronic inhalation of cigarette smoke fromi reference cigarettes and modified cigarz~tes induced different stages ©f leuxoplaxias and carcinomas in the larynx oi' Syrian Golden Hamsters. Incydence and intensity of alterations were distinctly dose- and tise-depiEndent; moreover, they were '' dependent on cigarette type or its tar ccateat. Laryngeal changes were less in the group exposed to smoke flrom c.Lgarettes vith, a low tar content. C1odified cigarettes were made from 50 percent ot the tobacco, mixture froa reference cigarettes and 50 percent of' pufiEd tobacco, tobacco sheets or ~' new smoking material. Smoke exposure reductd' oody weight and' increased iaflammations of the nasall•and' oral cav;.ty as well as the nuimfer of pt7alcliths and the incidence of "'"saoxe-cslls" in the lung. The nnmber of spoataneous tumors and iindings in the iuver, spleen, kidney and adrenal glands as well as vascular diseases yare not dependent on treatment. kd'3itior.al chronic treatment of 9itam.:n A inauccd a considerable increase of laryngleal papillary leukoplakias ana a d'istizct decrease of verrucous leukopZakias. An increased incidence of cares.aomas could not be observed. inimalls treated with Vitamin A and smoke more oiten, showed tumors in the thyzoid' gland. The survival time was reduced. llniaals treated only with ~ ttamin A showed an increased' rate oi dysplasias and carcinomas in-the `--~ .igestive tract- (gluth. Abs. )

74-©6T5. Gordon, B'. l.; Wiseman, $..F.; Pesti, L.; Bruckner, G.. ,Germfree lnimals. Proceedings of the University of Kentucky Tobacco and Health Research Institute, Tobacco and Health Aorkshop Conference , Lexingtoa,, Kentucky, pp.:360-38'6, !Sarch 26-28, 1973, English. Investigations on the Effects of Tobacco Smoke on Conventional and The purpose of this work was to studly the effects of' tobacco smoke and .of the airway flora on respiratory and related;, fnnctions in rats; . developaent of'a bioalssay on acute tobacco smoke exposure was also ~: :• type isolators nader conditions ranging from conventional to near- successfully tested, and routinely used outside.and inside of geraifree- 'consider-ad.. An apparatus for smoke exposure studies in rats was built, .steriLity. !leasurements of arterial blood pressure and regional blood distribution, total numbers, and composition of the flora s!uggested that subacute smoke exposure intensified' the penetration of the flora into deeper, normally sterile portions of the airYays; (2) on snoking, the d ele9ated in the hich nicotine g,roup.. A study on the regional depressed in low or intermediate cigarette nicotine groups, an& was episodes (particularly in abd~oainal organs) was normal or, slightly . via the release of catecholaaines; and (3) blood flow, .following these reversible on discontinuation of smoking, upito a threshold of approsimatel:y 3 mg nicotine/cigarette, and above this level either marked' depression or excitation phenomena.occurred; (;2) on using, specific blocking d'rugs it appeared'that these effects were indirect, mediated paralleling ''smoke puff/air breathing" cycles were fairly unifocm and flow in various organs of rats thait were exposed to acute, graded' nicotine-content sm3ke inhalation indicated that hyperteasiYe spikes, pred'ominantlT D.- paeumoniae type flora of normal rats shifted to a fora ,°in which fiemophilns Sp. , was sost f=eqnent; and (3) -exposure to low- or " hihiii g-ncotne content cgarettes did not particularly vodify these ., resnlts. , (Auth. . Abs. )

79!-0187 Go ri,, G. B. (Editor)!. Report No. 3. Toward Less~ Haza rdo cs Cigarettes. The Third Set of Zxperi2ental Cigarettes. 152 pp. 1 S77, U.S. Department of Health, Education, and Welfare, Public H~ea3th Service, National institutes of' HeaLth, National Cancer Institute, Smoking and Health Program, DHEW Publication No. ('SIH) 77'-1128'©. English. Experiments conducted since the earlT 11950!•s have indicatEd that certain modificaticnis of ciqa.rettes can influence tte chemieal comiposition, and tumorig,enic actiYity of the resultinq! saoke a3d! condensate. During 1!9b8' and : 19619, the Tobacco vorking Group andi the National Cancer Institmte reviewed -experiments, consulted vith doaestic and' fo rei'gn. ezperts, ainid f craulated a: set of experimental cigarette aodels for sntseqnent stndy in the search for the characteristics of' a less hazardous cigarette. The third' cigarette ezperisent• was begun in .1974, based, on- results from: first two series, on agronomic factors, and on-additionaZ industrial consideratiozs~. Erperimental variables in the third ezp.eris Ent consisted of: (1), tobacco additives that affect the flavor and chemistry cf the smoke; (2) tobacco addit; ve variations (sugar, cocoad and hnmectant) that affect the burn rate of, the cigarette, the flavor of' the! saoke, and the tumorigenicity cf the coadensate; (3), variations in paper porosity to evaluate the relationship, betveen this factor, and the tnaoriqenic.ity of the condensate; (4) filter var;ations to test the effects of'filtratior on the tumoaigenicity of•the, smoke ; and ('S) variations in artificial tob acco substitutes (AT S) andl physical characteristics to compare their relative tuaoriqeaicity. This .report details the ezperimental conditions, 2aterials and'Imethods e.ployed, including procedures of tobacco anialysis, ccndensate! preparatioln and bioassays, and presents the results obtained, in order to qualify andi support the cverall conc3usion. The resnlts can-be sumaarized as follovs: Comparisons aaonq the additive variabZes indicate that .agnesinf nitrate rednces the tnmorigenicity of cigarette condensate. itihen the adcitives. sugar, humectant and cocoa are compaxedl, ne3ther sugar nor humectant see~-s to affect the tnmorigenicity of the tobacco smoke at lover (12. 5 aq) dose levels bmt may contribnte to tumorigenidtq at- higher d'ose! levels. Powdered coc.caappea,rs to increase the- tumorigenicity of' the saoke at both dose levels. There were no significant differences, amonq the paper pcrosit7 variables or between these variables and Standard Ezperimental Elend III >' of the two artificial tobacco- substitutes (denoted by kTS-b1 and 1TS-B), 0 included, in this experiment, the 1TS'-3 cigarette fared ve1S Yith respect to redncingi cigarette tumorigenicity, whereas- the ITS-B cigarette fared poorly. EzperiAental difficulties arose- rith 1TS-B regarding th e solvent used in the second and' third ezperisents. Tt.is cigarette is beiIIg retested': dinrin4, the foarth ezperiment with. & dilfere=t soivent. (lnth. llts. Hod. )

79-018'8 Griest, W. 8'.; Quincy, H. B. ; Guerin, H. 8. Selected Constituents in the Smoke of' Domestic Low Tar Cigarettes. 20 pp. December 1977, Oak 8.id!ge National Laboratory, Analytical Chemistry Divisi=, Tobacco Smoke Research Program, Oak Ridge, Tennessee, 0&IN I/T:!-b 14w/P 1, Englis& C The Director of the National Cancer Institute Smoking and' Health Program has recently reported the practicality cf p roducing low risk ci garettes and' suggested that a ""critical number"• of' cigarettes might exist tihich, d'efines safe smoking, practices for each disease state. The ""critical number" of' cigarettes may be related to the quantity of saoke ;roduced by the cigarette. Tar, nicotine, carbon monoxide, oxides of 4troqen, hydrogen, cyanide and' acrolein were chosen as biologa.cally significant constituents of smoke vhich may serve:as markers of smoke production related to various disease states. Thirt7-txo brands of domestic, commercial cigarettes have been analyzedi for their production of the mzrker constituents and carbon dioxide. Cigarettes were smoked under standard smoking canditions by a smoking machine. 3esults were ezpressedl: as the average delivery per cigarette including, standard deviations. Tar de 'ivery ranged frcm 14.5 ' mc to 1.2 mg per cigarette, -Yith the nicotine delivery ranging! fro Q 1.03 tg to 011,14 mq per cigarette. Cigarettes of high tar and nicotine deliveries also produced relatively larqer amounts of'the other, constituents. High delivery iroducts considered, in the report are lcwer in delivery than most popular ,zoducts and therefore are still considered lov deliver7r: Results of the study are compared with Federal Trade Ccmmission data on tar and nicotine and vith the F.D. Snell Laboratory data for carbon monoxide, hydrogen cyanide and ozides of nitrogeni. levels in ci garettes. The data,  ay serve as an input to the computation of' ""critical aumbers## for currently availablee name' brands. -

72-04,64'. Hoffmann, D., Wynder, E. L Selective Reduction of Tumorigenicity of Tobacco Smoke. U. Experimental Approaches. Journal of the Mational Cancer lnstitute 4'8(6).1I855'-I86i8, June 1972. Tobacco smoke contains tumor in7tiators, tumor accelerators, tumor promoters, volatile carcinogens, and bladder car• cinogens. Most tumor initiators were identified as poi,vnuclear aromatic hydrocarbons (P?.H) and nitroa_encontairting heteroaromaticsi Tumor accelerators have comparabie polarity witlt, the PAH' and are uiactive as tumor initiators andi ttrmor promoters. They increase: however, the activity of carcinogens and tumor initiators. So far, tumor acr.eierators have been identitied, as N-alkyl indoles, u-aii,yl carbazoles, and 4,4'-dichlorostilbene. Volatile phenols and'some saturated and, unsaturated fatty acids. contribute to the tumor•promoting, activity of the the particulate matter of tobacco smoke. However, most tumor-promoting,agenu in tobacco smoke remain to be identified. It is suspected that the volatile pirase of tobacco smoke contains trace amounts of several types of eareuto, ns. Until' now, only some volatile V-nitrosamines have been identifed. The only bladder carcinogens so far found in tobacco smoke are traces of ;3-rtaphthylamine and uf an, aminofluorene. At, present, however, enzymatic ehan;es induced by inhaled cigarette smoke are more likely correlbted' with. the higlter risk of the cigarette smoke to induce bfadder cancer than the presence of traces of bladdzr, car~r.rtogetis ut, tobacc o smoke. Since the First World' Conference on Smoking and Healtih, a considerable number of studies reported on, the reduction of the tumorieenicity of tobacco srnoke.l'hese include reduction by changes in the agricultural practices of. growing and harvesting tobacco, changes in the selection of tobacco types and tobacco leaves according to stalk positions utd' nitrate content, the modification of the curin¢ and fermentation processes. andi the preparation of' reconstituted tobacco sheets. Model studies with additives contnbuted' to an understanding of the mechanisms of the pyrofotmation ot the tumorigenic agents in the smoke. Chemicali analytical data and bioassay results are presented for the smoke tiom ci¢arettes made from tobacco stems and from different types of reconstituted tobacco sheets. I1he particulate matter t'rom, tobacco sterrts was signii'icarttlv less tumorige;tic and had'a si¢nimcsnt'ly lower tumor-oromoting activitv than that from the. Istnuna portinn. From the various types of reconstituted tobacco tested, the foamed sheets gave the most encoura~ng results with respect to selective reduczibn of total tumorigeniciry and~ with it, selective reduction of tumor-initin:inY activity. The possible imnortance in tobaccp, carcinogenesis of the various types of components in the wax laver oi tobacco leaves is also d'ucusved. (Auth. Abs. 41od.) 7'9-C7,7tt Hudson, &, D. Central Nervous System Responses to Cigarette Smoke I'nhalation in the Cat. Archives internationales de P'harmacodlYnaaie et de Therapie 2I37(2) . 19'1-212, F'el:rttar7 1979, English, ~ Intaet, pentobarbital aniesthetized cats (with and without brainsteri stimullating electrode implants) and unanesthetized Sherington (gamma- d'riven) decerebratE cats ""smoked'' cigarettes of varyinig nicotine content (0.2-2.5 ma) via a tracheaL catheter. Nicotine-free lettuce leaf eigarettes vere used as eontrols, ""smokina doses", of' nicotine base (10-25 mug/kg) were ad!ainistesed intravenously for comparison. Smoke inhalation produced mator, rreflex depression vhich parailleled' the nicotine content of the cigarettes ""'smoked'',, Patelliar reflex facilitation due to mesencepbalie reticular stimulation trac reduced by doses of' nicotine and cigarette snoke, Cigarettes (2.5 mg nicotine) and doses of nicotine ('25-5,0 muig/kg, i,v,) significantll7 reduced rigidity and patellar reflex amplitude in the ganma- decerebrate cat. Ditsydiro-beta-errthroidine reduced the nicotine andl cigarette smoke iaduced patellar reflex depression but not the diminution in the rigidit7, Smoking doses of nicotine suppressed' pentobarbital-induced EE'G spindles in acutely prepared cats, ?tlicotine (10-25 mug,/kg) produced EEG and behavioral arousal in cats with chronic deep electrodes. It was concluded that cigarette smoike produces its pharmacological eflfec'ts via its nicotine content, (Auth. Abs,), 1005052834