Wyndcr and Cllr"llCld, 1053. U.S.A. (314). M G3 physicinn reported in AMA 133 vhysicinns of same group dying of can- Mail qucationnnire to eutntca of dccnlcnta. Journal *a dYlnR or CDnCcr of ECT uf certain other sites. the lung. Lickint, 1163. Grrmany (170). hl-F W ul hlnlcs Fcmnlcs Author. CO\C3 Controls CilYC3 Cunlrols ycnr. Rclntive Rcliitivc Cumrncnta rrrcrc"rc I'r,rcrnt rrrccnt rcrccnt Percent ritlk rcrccnr Pcrccnt risk I,,`". hrnvy non- hcitw ratio Pr1crnt 1y;t "Cl". / ll"n- hcaw wtiu Number snrukvrs rmx,kcrs' Number smokers smokers1 Sht:NS Number smokrrs smokers' Number emokcn, smokers' SM:NS' miiih, RG 3.5 G5.1 86 1c.3 36.0 `5.4 (`) (1) (1) (`I (`I (`I . 1939 (196). Schnircr nnd OR S.? 31.2 270 16.0 9.3 lG.7 (`) (1) (`1 (`) (`) (`) I6 fcrn,~lc Schunlccr. CDII(LY nr4t 1943 I?IP). Rllnl) LL.II Potter and 43 7.0 30.2 2.RO4 26.0 23.0 14.1 (1) (`) I') (1) (`1 (`I . Tully. 1945 (?I."). Milla end 444 7.2 430 30.L .I. 6.7 I') i') I'1 I') I') I') r'urlrr. 1950 (186). Wrndcr nnd 605 1.3 51.2 7HO 14.G 19.1 13.0 40 57.5 25.0 552 71.6 1.2 2.!, Crnhnm. 1350 (JJ6). hl, I*J5R ("3:). rr!,wh,~il. ---- _-_.--._ WYntlcr and GR I.1 C7.G 133 20.G 23.3 `C.l (1) (`1 (`1 (`1 (`) (`I ,.. Curlblirld. 1:15:1 ,314). ~- Kuulumtcs HI2 0.0 GR.`) 300 18.0 25.0 3c.o , (`) (`I (`) ,~,------- 1053 (121,. LickinL - _-. 2'2 4 1.8 36.X 1,000 lC.0 4.n `10.1 22 G 1.0 66 1,002 00.4 0.1 5.3 IV53 (170). Ilnndic. 415 1.2 34.2 381 6.8 17.9 35.1 33 51 G 3.0 131 70.3 0 2.2 l'J54 (.'IS). Cellond cl ul.. 32 G.3 32 c3.0 `26.3 (`I (1) (0 (1) (1) (1) 1065 19x1. - \Vyncicr ct al., 210 1.4 67.5 420 21.0 40.`) 220.8 30 lG.7 14.0 13? 57.6 23.3 6.78 li~ni~ TABLE A?`-Grouping of pulmonary carcinomas Group I: A. Epidermoid carcinoma. B. Small cell nnaplastic carcinomn ("oat-cell" carcinoma). Group II: A. Adenacarcinoms. B. Bronchi&-alveolar cell carcinoma. C. Carcinoid tumor. D. hlucous gland tumor. Extra (not included in I and II): A. Large cell undifferentiated carcinoma. B. Combined epidermoid and sdenocsrcinama. Un.uitab!e for diagnosis. 360 Little et al., Po"' 1rrcLt in vorioue liaaucr (PC/g tissue) Vcrlcbral budicY. rcnul 1961. Pcribronchia! Bronrhinl eorlcx. spleen and U.S.A. (173). lymph mdcr Lung (nvcrogc) rpilhclzutn ur,n,iry Lloilllcr stliiwcd NS ,. . . . 6 0.011 0.001-Z nrglisiblc SM no dificrencrs. . . . . . . . . . . . ..12 0.011 0.00s 0.028-I .2G TABLE AlZ.-Autopsy studies concerning the presence of radioactivity in the lunga of smoker8 (cant,) NS = Nonsmokers. SM = Smokers. Ferrl end Nran Pa"@ htlr in various ttbs~ca (PC/~ wet hue) Bnratta, LUW Liver Kidney 1866, NS , ,. ,,,,.... . ..lO 0.031 0.103 0.080 U.S.A. (98). SM . . . . . . . * . . * . * .14 0.066 0.126 0.070 Rajewasky and StAhlhOfWl. 1966, Canmy (927). hfoan PdlO levela in various ltiruo (PC/g) tData not given. Smokcrn Lung narrnchyma Uronchid trrrr Bronchial bijurcution were connldcrcd those NS . . . . . . . . . . . . . . . t 0.0026 0.0020 0.0012 using more than 1 pack SM .*. . . . . ,, ., . ..I2 0.0078 0.0017 0.0047 P dnu. The authora noted tbht thclr tln~rcs were con- nldcrablu nm.sller tbhn thoak! of LItlIe et al. (27~. 171) and alao dianereed with tbel? data on bilurcatlon. Rsdford, 1967, U.S.A. (17)). SM ............. .zs Plpe ............. 2 Ex-ekarttte .. , ... 1 Never ............ 8 Bronchial wall snd aubmucoaa .: ..;. .................. .......... 0.004 Bronchial epithelium: Trachea .................................................... 0.120 Lobar bronchi ............................................... 0.190 Segmental bifurcalion ....................................... 4.soo Wynder CAFt mice A. Painting shaved skin. ct .I, II. Jiwcck fur 2 years. 1963. C. Whole cigarette smoke U.S.A. condensate in acetone. (317). Croton oil oncc/wcek. PBlSCY 5 different A. Painting unshaven CL al.. rnO"IC akin. 1955. Strains IJ. Z/week for 9 England (101). months. (109). C. Whole "tar" or neutral fraction. w Q\ w TABLE A13.-Expetimenta concerning the ejects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cmt.) Author. year. country. rcfcrcme Anlmrl and strain Commcn*a Wynder et A, 1966. U.S.A. (316). Author. Anlmrl A. Method. A. Method. year. and B. Frequency and/ B. Frequency and/ country. strain or dur~tio". or dur~tio". Resultd Resultd Commcn*a rcfcrcme C. Material C. Material Wynder Mice of 4 Mice of 4 A. Painting shaved skin. A. Painting shaved skin. Sfrain Sfrain PopiUoma4 PopiUoma4 Corc~a Corc~a No tumor8 noted with No turrrora noted with et A, acparste acparste ll. Z./week for 80 days. ll. Z./week for 80 days. C57BL . . . , . . . . . . C57BL . . . , . . . . . . lo/89 10/89 2/89 2/89 aectune alone. aectune alone. 1966. straina. straina. C. Whole condensate C. Whole condensate Swiss Swiss . . . . . . . . . . . . 22/86 22/86 12/86 12/86 strwsea strwsea U.S.A. I" ~EClO"C. I" ~EClO"C. diRcrcncc8 in diRcrcncc8 in (316). susceptibility of susceptibility of strain. strain. Hamar and Outbrrd A. Plintlng unshaved WOOdhOUW, albino skin. 1966. 8trfiin B. Varied for 18 months. U.S.A. mice. C. Whole "tar"/scetone. (IJU). IJenrLJyrene [D(a)Pl, crotun oil. Trcalmmt: P4piUomor "Tar" P/week . . l/60 "Tar" and etoton oil l/week. . . . 2130 B(a) P 3 times then "tar" `2/wwk 4130 ll(n)l' 3 time . . . . . . . . . . . . . . . . . o/30 Author, A22"' A. Method, yrnr. Il. Frn,,wncy and/ country, atrrin or durntion, Rcnulb Commcntd rcfcrc"ca C. hlntrrinl Wyndcr Swh mice A. Pnintina skin. Percrnt PCKClll ct ul,, B. Vsricd for 12 TRblmCnt: Nnmbcr pap~llomar carrinmnor 1957, months. S/week ..,.....,...,,,, ,,,,. so 12.0 8.0 U.S.A. C. Whole condensate Jiweek 50 38.0 16.0 (3?J). in acetone. Z/week 40 10.0 30 l/week ..I 40 ti.0 Wynder and CAF, or A. Painting shaved skin. Percent PL-rCClll Swiss mlcc nolcd Wright, Swiss Ll. J/week far lifespan. Trcalmcnt CAF,: Xirmbcr poplllomad carcinomor ,o br l\lOi-e I",. 1957. mice. c. whole "tar" 07 nicotine Whole "tar" I.,, 30 53.0 27 .o rrptiblr. U.S.A. free "tar" derived Nicotine free "tar" , ,, ., 40 73.0 26.0 hlnlorlty of carcino- (J?Bl. from pipe and CiKarelte "tar" ., 30 30.0 30.0 grns noted to br cigarette tobacco. ripe -tRT'* 30 60.0 20.0 in nciitral fraction Trcalmc~~t Swiar: of condenrntc. Whole "tar" ,, ,, ,, 30 63.0 10.0 Nicotine fret "tar" I, ,. 40 43.0 20 0 Cignrette "tar" ,, 30 63.0 33.0 Pipe "tar" .,... ,, ,.. .,, 30 63.0 60.0 Celihorn, Pnris R III A. Pointing shaved skin. Trcnlmcnt: Fapilfomas Carcinoma0 1358, mice B. Vnricd for l-2 years. Benrpyrcnc (twice only) _, ,, 20/529 5/%5:9 U.S.A. C. "Tnr" in acetone. Cru:on oil (516 wcrk) .., ._, ,, 4126 O/26 (991. bcnzpyrene, "Tnr" 1516 rveck) 3/551 2/5G9 croton oil. Acetone (5,`G \vcck) ,, ._ ., o/30 O/30 Bock and Swiss A. Painting skin. "Tar" and croton oil (5iG week) 101175 o/175 PCWCtll bloore. female B. S/week rol. lifespan. Group: Number liuirly ot G montha Skin tumor8 at C4 wcrl;s 1959. mice C. Whole condensate Painted 4'3 U.S.A. 13.0 irradiation. Painted and irradiated c5 44.0 (29). Irrndiated I. 36 w 2 Bock et al.. ICR Swiaa A. I'alntlna ahtved akin. 19t2. mice B. IO/week for 1 year. Trcritmcnt: U.S.A. C. Cigarette "tnr". Stnndnrd cigarette (JI). Standard cigolvtte Stnndnrd ciRarcLtc Standnrd ciKnrctte . . Pcrrcnt Skin neopla0ia 64.0 51.0 44.0 62.0 27.0 23.0 I.. IDGZ. U.S.A. (225). Druckrey and Rnte Schildbsch. 1063, Germany (82). B. J/week for 84 wcrka. C. Whole smoke "tar" withaddadB(n)P in acetone. A. Subcutaneous injection. B. l/week for 700 dsya. C. B~IIZDYEYI~ in tries rylin. Homhurscr CAFi mice A. Pointing shaved skin. (`O,"l,lClC Pcrccnt I'CICC7Il EL al.. 11. Z-3/week for 2 years. Condcnaalc: Uiit"pSiCS Pa,"ii"mol Corcirioirtna 1963. C. Various tobacco Pipe tobnccu ,. 77 U.S.A. 35.0 15.0 condenantea I" CiEnr tobacco Ml 21.5 (IS!,. 16.0 tlCeto"e. Cianrette tohncco H2 27.0 lG.O Uc"zpyrc"c 54 10.0 20.0 Acetone only . . ..I...... G2 Bock ct &I., Swiw ICR A. Painting clipped akin. - I'( TCC,IL I'crrcnt 1965. mice II IO/week for 11 wwks. Percent conccntrntion of tRr U.S.A. aurb,ii,irlg Pcrrsnt C"IICCI und C. Various smoke (WPC ciporcttc) : I I werka (IO). c0llrt-I ~~~:pillomo conaensatee in 9.2 (.3tnndlhrd) !iLO 30.0 Gi.0 neetone. 8.3 (stnndntd) ,,..,,,... ..,.. 33.0 ?7.0 61.0 7.9 (English stsndnrd) .I,..,.. 90.0 24.0 KS.0 8.7 (king) ,, 100.0 2M.O CU.0 4.0 (Rltcr) `IX.0 0.0 36 0 4.4 1 liiter) , 100.0 10.0 41.0 2.5 (filler) 07.0 4.0 16.0 Acetone control . . 94.0 Untrcstcd cmltrvl . ..I 100.0 Van Duurcn Swiss ICR/ A. Painting shaved akin. Cumulntil'c number 01 mire with t l.ll-dimclhyl- et al., Ho mice B. Initinting agent once-- Itrilinlor P'romolcr 1966, I'a],iilolriaa Corcirio,nM livlir(ll,u"ll~r,lcr"c. Promoter J/week for DXIUA ,.Ether t(ihaccn lent cxtlnct ,, ,, ., ,, U.S.A. 4/20 o/20 12-14 months. (006). 0 . . 5. .Ethcr tobacco IrnI exttnct o/20 O/20 C. DhlBAt. tobacco DhlBA . ,Chulorufurm tobacco lcof extract . l/20 O/?O extrncts cige,. 0 . , . Chuiurolorm tvbncco Ical cxtrnct . , , , O/20 o/20 rette "tar" DhlBA ,.Cimrcllc "t,ir" .~~,,.,...~....,... ..,, 11/:0 4120 0 . . . . .CiEnrette "tnr" .., .., ,, ,. ., ,,, ., o/20 o/20 TABLE A13.-Ezpcri~r1rnls conccnring the eflccts of tltc skin painting or subcutuncous injcctiott o/ ciga7.cttc smoke condensate or ifs cans~it~tenls upon animals (cont.) Author, A. Method yrnr, Animal u. Frcqucncy and/ CO""LlY, snd relersncc or duration. Results Commrnla slrnin C. Material Munaz tt al.. Swiss ICW A. Painting shaved akin. Dark tobacco "for" At risk TUmOrI Carcinoma, The aulhura noled 1868, 40. mice IS. Vnrid. 4.0 percent ,, ,. 81 50 17 & JtiurlrntYl Intent U.S.A. C. "Tar" from dark 8.0 percent I.. . . . 71 46 1G gcnud for dark and (Colombian) and Liohl tobacco for: tutJncev. Colombia light (U.S.A.) 4.0 percent . . , , . . , , ,. . . . , 95 26 6 (197). Lobaccoa. 8.0 percent . . . . 18 64 20 Acetone , . . . . . a . . , 8.. . 91 0 0 ._ Davlea and Albino A. Pslntlngahaved akin. Percent of cnrcinama-bearing attimala a( 116 wcckr Tbe suthurs concluded DlY, mice Il. Varied rcRimrn. T*CatTtlcl,l: th.t thr lnrk of 1868. (acfual number of animala in porcnthracn) C. Cinnrette and SOL) mu, 150 mo. 78 mp. 87.3 mu. diflrrrncc In rc- Crcrt cimr condensate. Uritrln Stnndrrd ci~arctte . t , a . . 20.1(20l 13.2(10) 0.7 (1) . . tiulta Ircbm the Ant Ciwr 27.1(31) (86). lI.l(lG) 2.1(3) and thlrll YFIIODI Cigar lubacco ciunrcttc 13.9(10) . . u,,dcr trrutmrnt rdvvrata that Ibc lncrrallcd turnuri- weniclly ol cluLr tobrco is duel0 physical ~race~lne Iretars. TILE Al&-Erperimenta concerning the effect of cigarette smoke or itu constituents On tiSSUe and T?an mltU?`Cs Author. yea*. countly, rclercncc Boucbard and Mw, 1960, Frmcs (95). Tiaaus or 0rg.n culrurr Mouse lung. Materlal/deUvev Tobacco amokc condensate perfusion for 24 hours and aubseauent praftinx under renal capsule of mice. Re_"ltd Increased number of mitotic abnormalitin In the treated CUhUres; vntiicula*b in the nrat 6-10 dsra after prafting. AWS et 81.. 1961. J&pan (la). Direct exposure to smoke from: a. Whole cIgareLLen. b. Tobacco alone. e. Paper alone. Paper smoke Induced the moat scvcre chanpet. conslstin'iz of CYtODlnlmiC VnrJ- olization and nuclear pyknoais. Alao noted were & decrease in the mitollc index and an incrcaac in abnormal divirionn, more L)O with paper amoke tbnn With the other two. Tharcr and Kcnaler, 196d. U.S.A. (276). KB mammslian tumor cells. Cisarctlc smoke condensate applica- tion: filtered mnd untiltercd cigarettes. SipniRcanr prowth inhibition was shown In unfiltered smoke. C~tot~xlc COmDD- nentr were noted in both the pls e.nd particulate phases. Berwald and Sscha. 19CB. Israel (PO). Cracker ct al.. 1965. U.S.A. (6-J). SWR mice and golden hamrter embryos. Suckling mt traches in oretin culture. Direct application of bcnro(n)pyrene [B(a)Pl. Application of U(a)P in acetone. ~rnro(a)pyrcnc caused lncrcastd cell trnnsformatlon M manlfrr!nl by: a. Ilcrcditary random growth pattern. h. Prusrnaivc p.rovth 81 tumor8 after rulruLrnevur injection Into adulld. C, Ability to Bruw continuously in culture. --- Treeled culture, revrolcd cellular mcteplnsia. baanl cell hypcrplaaia, izicwaoryl mitotic rate, and incrstiard HI-thumidinc incorporntiun pro@ortiun*l to t.bc con* centration of material and durstinn of spplicatiun. Dirmond. Vnriuus con- Avolication of - 196G. tinuoue cell II(n) P in either U.S.A. (68). Itrain* dimcthylsulfoxide (mammalian). (DMSOI or pnrnffin. K \o TADLE Al4.--Ezpcrimente concerning the cfect of cigarette smoke or ile consliluct~te on lireue and organ cttIL~rc8 (co?I~.) Aulhor, yr*r. CD"",tY. rcfvrcnce Burcnfrc""d et LI., Hamster luhr Application of e... lncreawd ~ppc~~rnnce of new rmrll chromoaomts and tclocrntrle ehromosomca. 1966, t1BIue. B(a)Pineither b. Incre~rcd ability tu grow in hnmsler cheek pouch and there become Bpindle- U.S.A. (33). DMSO or dimetbyl- cell s~rColn*~. Iormamldc. Cuimard. Chlcken embryo Application 01 lncrc~ecd mitotic activity and incrrlaed incidence 01 snomalou# mltoacs. 1966, muscular robaccu extract. France (110). eXphtl. Lasnitrkl. Mice nmnatal Appllcatlun of II hy. u. Incrcnscd buanl cell hypcrplarla and pleomorphlam of newly lormrd cclla. IPGR. trachea. droclrbon-enriched b. Increa~rd cyllhclial mi:oair. England (160). fraction of whole smoka condensate. Larnitzkl, Human fetal lung Application of a hy- a.. Cellular enlargement and promotion of growth of new bronchi. 1868, In orpsn culture. drocarbon-enriched b. Increased mitoae,, bronchial epithelial hyperplssia. and a~u~rnou~ mctaplnsln. England (161). fraction of whole c. Inhibition of stromal growth. smoke condensnte. Ghan et al.. hlouae lung 1969. bud embryonic U.S.A. (S4). cuIturcs, Application of D(a)P in DMSO. a. Cellular disorganization. b. Ccllul~r pyknosis: nuclear ahape and size Irrepularlties. c. lncrcaac-d cllithclinl milotic rntc and decrcrsed mcacnchymol mltotic rnlc in thorc cul~urw exposed to D(a)P ver~ua those cxpnrd to pyrcnc or DMSO. Lcuchtcnbcrger MouYe lung Exposure to fresh smoke: and and kidney a. Unfiltered. a. Decreared RNA production, pyknoslr. and death of cella. Leuehtenberger. tissue and b. Activated b. Similar rcsulh. but chanpts were of minlmal severity. 1969. orlcsn culture3. charcoal Rker. Switzerland (16s). c. Cigarette or c. Similar elects as group a., but Ins severe. cigar tobacco. Author. Y<~llT. Tirnuc or rountry. oryon culture hlntrriolldrlivcry llrrults tef,,tCr,CB Cruckcr. Various organ Apvlicntion uf Squnmoug mrtaylusls: frcqucnt plcomor~~bic CPIIO: dnliflrrcntlutlon ol cpllbrllum _-.- 1970. cult"rca: Il(u)l'in8er"m. (inhl!~ited by L'itlimin A). U.S.A. 162). n. Whole suck- ling hamster trncheer. b. Whole bron- chin1 tubes from late fetal dogn and monkws. TADLE A15.-Erperiments concerning the cflecl of the insti[[ation 01 implantation of cigarette smoke or its constituents into the tracheobronchial tree of animals Author, YCI r. COUntPI, Animal and A. Method B. Fre~uencu and/ or duration Rnults reference atrain c. nlntcrial nlacklock. CD white A. Injection into 3.4-brnrpyrcne: Number wilh lumorr/numbcr erporcd 1967. ,a,,. Lund parrnchyma .5. 3 mg. in olive oil K/6 Barcornll. crrht by tharacotomy. b :I mu. in ulive oil with dead Tb bacilli Z/4 sarcoma, 4/B sguamou~ cell carcinomr. Uritain B. Once. c. 5.15 rn~. in cholrstcml pellet l/8 ~qui1rnou8 ccl1 tarcinoms. IPO. C. 3.4-benrpyrrne Cignrctlr "tnr": in olive oil, II. In olive oil o/10. with ~lcad Tb b. In ulivc oil with dad Tb bncllll I/8 aureoma, l/8 ~pue.mou~ cell crrcinomm. bncilli or in ClllltVUlY: cholesterol, 8. U 15 cc. olive oil O/4. cigarette "tar". b. 0.15 EC. ulive oil with dead Tb bacilli O/I. c. Cholntcrol pcllcts O/4. Della Port& Syrisn golden A. Direct tracheal et al.. hamstera. instilllstlon. 1968, B. Weekly'up to U.S.A. 46 weeks. (67). C. 1 percent 7,12-dime- thylbenz(a)nnlhra- cent (DMUA). cigarette "La," concentrate. hlnterial: lYetk4 n. DMBA 50 ,,c./wek , . . ., , 46 b. "Tar" 200 /,,g./wrk 32 c. DMBA hO,,c./wcek . 12 then "tar" 200. ,,a./ NWk I.,..,...... 30 d. DhlDA 100 ug./week . . 17 e. DMDA 100 irK./wffk 1 and "tar" 500 20 ,&week ...I..*II.**I Suruivorr at t0 vwke/orioinal number erportd 10/20 11/21 9/20 - T/20 9/20 - - Ripdon. White Pekin A. Intratracheal No nronlastic chanacl noted in either the exocrimentrl or control PTOUDB. _ ducks. injecti,,rr. Control3: 99 B. Dsily for 721 days. Experimental C. Tobacco cundensate group: 62 1 In liauid petrolntum. thorncutumy. B. Once and auriflced at I week-2 YEBTB. C. Cigarette tubscco smoke condensnte In eucerin. Rockry et nl., Dupy. A. llrunchial inoeulntion SQllonlo", 19GZ. or 3:imulntion. PTC- ~~lUpl,l,lU U.S.A. B. 3-5 times/week NU"LbCr IItuosruc Carcinoma- Canccro"` W\lli al",`i