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11. ti 3ELEC3TVE' REDUCTIO\ LN TOBACCO CA1tCSNOICE\'ESLS significantly and selectively reducedl These data are supported by the significant selective'reduetion of tumorigenicity of the tars from foamed re* constituted tobacco' sheets. As in the past, we have compared in the bioassay the tumorigenicity of' the tars on a gram-to-gram basis. Therefore, by using these reconstituted sheets, we have selectively reduced the potential of tobacco to form carcinogens in the smoke. However, again comparedl on a gram-to-gram basis, the tars from these foamed' tobacco sheets showed only a minor reduction of tumor-promoting activity. Tobccco Substitutes . Several years ~ ago, we showed that the tars of cigarettes made exclusively of hay had minimal carcinogenic activity an& little tumor-promoting activity (50). Tar from cigarettes made of spinach had~ a significantly lower tumor-promoting activity than the particulate matrcer, of the tar of the stand- ard' tobacco cigarettes. Since hay contains practi- cally no ..•aaees and spinach has a relatively low concentration of' waxes, compared to tobacco leaves, these studies suggested that the precursors for the tumor-promoting activity of tobacco sffioke'e reside mainly im the wax layer of the leafl a~ resuitt in accord with our tobacco-stem studies. We tested the particulate matter of cigarettes made e.ecllusivel~~ from oxid'ize& cellulose for their. ; tumorigenicity and tumor-promoting actz,~-ity. As -' sla9wn in text-6gure 11, the particulate matter of these cigarettes produced tumors im only 2 of 100 mice after 14 months of testing and, therefore, showed no significant tumorigenic activity. The same tar, however, showed significant tumor- promoting actirity, although much lower: thann that of the tobacco tar. Presently we are analyzing the smoke obtained from other tobacco subsutues and are repeating the miologFcal tests. Although. the studies are not completed, they appear encouraging. SUMMARY Tobacco smoke contains tumor initiators, tumor acceleratwrs, tumor promoters, volatile carcinogens, and bladder carcinogens. Most tumor initiators were identified' as PAH and nitrogen:-containing, VOL. 48, NO. 6, JUNE 1972 /. 1865 •rr. "Tar- IhxniCesviase Der+v ..r. 'tar'from Bi.na.a U S: cpOr.n. CanCfHf.CoronoqMicusq~ ~. _ 24 3E 40 _ 481 6 We.hs Ttxr-slovu,1i1.-Tumorigeniciiy of a"tzr" derivedi from cigarettes made froia a eellulose derivadve (50"7. . uoncentratioa): heteroaromatics. Tumor aecelerators have compar- able polarity with the P.4H' and are inactive as tumor initiators and tumor promoters. They ia- crease, however, the activity of carcinogens and tumor initiators. So far, tumor accelerators have been identified' as X-alkyl indoles, X-alkyl car- bazoles, and~ 4',4"-dichlorostilbene. Volatile phenols and some saturated and unsaturated fatty acids con- tribute to the tumor-promoting activity of the pareiculate matter of tobacco smoke. However, most tumor-promoting agents in tobaeco smoke remain to be identified. It is suspected that the volatile phase of tobaccoo smoke contains trace amounts of several types of carci'nogens. Untili now, only some voliatile M' nitrosamines have been identified. The only bladder carcinogens so, far found in tobacco smoke are traces of 0-naphthylamime and of an amino- fluorene. At present,, however, enzymatic changes induced by iahaled' cigarette smoke are more likely correlarted' with the higher risk of the' ciga- rette smoke to induce bladder cancer than the presence of traces of bladder carcinogens in tobacco smoke. Since the First World Conference on Smoking and Health, a considerable number of studies reported on the reduction of the ttunorigesucity

t866 HOFF\tA\Ji' AND WYNDER of tobacco smoke. These : include reduction by changes in the agrir:ubtural' practices of growing and harvesting tobacco, changes in the selection of' tobacco types and tobacco leax•es according to stalk posiRions- and' nitrate content, the modifica- tion of the curing and fermentation prouessses; an& the preparation of reconstituted tobacco sheizts: Vlodkl stud!ies' with additives' contributed to our tmdentanding' of the mechanisms of' the pyro- formation of the tumorigenic agents in the smoke. Chemical analytical data and bioassay re- sults were presented' for the smoke from ciga- rettes made from tobacco stcrns' and from different types of reconsdrtuted tobacco sheets. The par- ticulate matter from tobacco stems was significantly less tumorigenic and had a significantly lower. turnor-promoting activity than that from; the latttina portion. From the various types of', re- constituted tobacco tested, the foamed sheetss gave the most encouraging results with respect to, selective reduction of' total tumorigenicity and,. with it, selective reduction of tumor-initiating activity. Discussed aLso was the possible importance: in tobacco carcinogenesis of the various types of components in the wax layer of' tobacco leaves. REFERENCES (1) Horrsu.etx D{ WvNor.tt EL: Selective reducdonof the tumorigenicity of tobacco smoke. Eicperimentai approaches. Nat Cancer Inst %4onogr 28r1'5,1-172, 1968 ' ((2) The Health Consequences of Smoking, A report of the . Surgeon General, 197 1. U.S, Deparaaentof'Healtli, Education, and Welfare. (3) h'UiuLEx R, AiouaENx..vzs: W, Scxtsswerst P:~ ()ber die Cerminderung gesundheitsschadigendtr In- halt¢stoffe des Tabakrauehes. Ber Iast Tatiakforsch (DresdLKt ) 15:,1 w6 ~~-190, 1968 (4')' WrhrnaR EL, HorrxANN D: Experimental tobacco earcinogenesis. Science I62:862-871, 1968 (5) Sexizuatrat P: Uber die Vermindcrung gesundheits- scb3digender Inhaitsstoffe des Tabalrauches. Birr Inst Tabakforsclt (Dresden) 1i6i11i6-i25, 1969; 17:66-93, 11970 (6): WYNOCn EL, WietaxtT G': A study of tobaeeo careino- genesis. 16 The primary' fractions. Cancer, 10,:255- 271, 1957 (7). SL6LKOPr C, RicxzN W, DHou G: Untersuchungen 8ber die krebserzeugenden Eigenschaften des Zigarettenteeres: Z Krebsforsch 63:241-749, 1963 (8) HorrstrtcN D, Wn.•Dett EL: The tumor initiators in tohacco,smoioe. Proc Amer Assoc Cancer Res 7:32, 1966' (9) BoxtNSrvtc YP: Blastomogenic activity of' smoking products. Vop Eksp Onkol 3:47-33{ 1968 (10) Ror, FJ, KEwxxs F, BtsHor D: Examinatioa of! the: neutral, (raction of tobacco smoke condensate for tumor promoting activity. Iot Alkylierend wirkende Verbindungen. 2. Konferenz Ober aktuelle Problerne der Tabalcforschung (Weber KFhI; ed.). Hamburg, Wissenschafii.icbe Forsehuagxstelle im Verband' der Cigarettenindustrie, 1968, pp 112-1 l3 (11) Donru+wtu. W, EtaaxxoasT H; Hwxrc HP, et al: Expctimentdle Untersuchungen tlber die tumorer- •. zeugende Wirhung von Zigarettettraueh-Konden• sa'ten an der Mausehaut: I: Gesamtversuch. II.. Einzelvergleiche zwischen den Kondesaten tnudi- fiaierter Zigaretten. III. Untersuehungen zur Identi5¢ierung' und Aareicherung, tumorausl8'. sender F'rahdonen, Z Krebsforsch 73:263'-2'84; . - 285-304; 305-314;1970 (12) WxtrxxzAo JI:, RomtwuL K: The mouse s1'in carcinogenicity of cigarette smoke condensate: Fractionated' by solvent partition methods. Brit J Cancer 231: 840-857, 1969 (73), HorrM.vN D, Wtrecnca EL: A itudy of'tobacco car- cinogenesis. XI. Tumor iaitiators,, tumor aecelcra- tors, and tutttor promoting activity of condensate fiactions. Cancer 27:848-864, 1971 (1;4')' Ros FJ, Pato R, K=wstrts F, et' al: The mechanism (LS) of careinogenesis by the neutral'fraction of cigarette smoke condeawte. BritJ Caater 24: 788-806;,1970 WtrNnete EL, HoFrwANN D: Tobacco and Tobacco Smoke. Studies im Experimentai Carciaogeaesis. New York, Acadernic, Press Inc., 1967,130 pp (Ib) HorritwNN'D,,RArFtsWwrG, NzsNowS, et a1:Chetnical studies on tobacco smoke. XVI.,A1kydAuoranthenes: -Quantitative determination in cigarette smoke formation by pyrolysis and tumor initiating actnvioy: In preparation (J7) BAocf:x G.M, DonxELLSt JK, S'roTSCVooo T\'i: The formation of aromatic hydrocarbons at high tem. peratures: Aust'J, Chem, 18:1249-1266; 1965 '. (18) HorrNANN D, Wmout EL: Chemical anadysis and carcinogenic bioassays of organic particulate pol- liuants. In Air Polludon ('Siern AC, ed.), vol, II, chapt 20. New York, Acadoatic, Press Inc., 1968,, , pp 187-247 (19) GtLLNOw+t A: Cocancino4enie aetia-ity of cigarette tobacco tarw Caneer Res 18: 51o-5;U7,, 1958 (20) Hor~r>u.arN D, RATHCASCr G: Chesaical studies on tobacco smoke. XIV. Quantitative deterrainationn of fluorenes in cigarette smoke and their formation by pyrosynthesis. Anal Chem 44:899-905{ 1972', (I?T) Boax FG, SwwtN AP,,SrEnuarr R11,: Bioassay of'major fraction of cigarette smoke condensate by an accel- erated technic. Cancer Res 29!:384-387„ 1969 (2?)' WvNoa3t EL, HorrstANY D: A study of tobacco car- cinogenesis. Jfi. Tumor promoting activity. Cancer 24I:289-301, 1969 JOt1R.1.ai: O'F' THE NATIONAL CAXCER IASTITUT&

studies on tobacco. XIL. Changes in,smoke composi- tion and,Sltration by artificial alteration'of'smofce I 1868 HOFFMAYY AYD WYNDBR (S7)' Baxntcst D, Bc.vrmit JF, BtrnToK HR: Thermal' de- composidon of'tobacco. IV. Apparent correlations between thetsnograviameeic daca and certain con- stitttents in,smoke from chemieally, teeated tobaccos. Tobacco Sci 13:138-141, 1!969'. (3d)', Trataa'ts: JH, Siexstxt:rz I: Alteration of eigaaettee smoke composition. I'. Influence of certain additives. Tobacco Sei 14':18-81, 1970' (S9) Cxrwtasoary BB; Ktt:xon.V KD, Tttart.tiToK R: Re- duction duccon in the eoncentration of aromatic polycyclic hydrocarbons in cigarette smoke. Chem, Ind (Lon- don) 1,971, 672 pp (60)' Lwzarrz L, Szaamwv RL, SrxAxcE ED:,Composition 7 f h . r .- Fiomtt 1'.-Smo:ing'machine with collection device for analysis of.Y-niirarosanninea in eiguette smoke. pH: Fotnie acid and' acetic acids and volatile pbenolb. Beitr Tabakforsch S:d44-li08, 1968 ('6d) Bz:xzacar RC, L,uattsz L, STxA.vcs ED, et al; Redox characteristics of cigarette smoke. Chem Ind' (London) 1'9D0, pp 800-802 ('¢2) Central Research Institute, Japan Nionopoly Corpo- ration: Evaluation of tobacco quality from pyrolytic aipects. Scientific Papers 110, 111, 112, 1'968, 1969, 1970 (63) Niostnr RJ, Hss.rasa HW: Reconstiiuted-tobaeco.kaf- tachnology: A tool' for tobacco-smoke modification. Nat Cancer Itsst Monogr 28:133-1'48, 1968 (64) Hwssza HM, I7o 'TI: Reconstituted tobacco--stnok- ing and health possnbilities. J Nat Cancer Inst 48t 1869-1883, 1972' :_.., srSt~.-~~'' '~y~ y- ~y ~S}fIF Ti~~~. . _ ~ t .7 :~.