T,ong-term continuous oxygen therapy in hypoxemic patients with chronic airwy ol&ruct.ion has been noted to have a beneficial effect of reducing pulmonary arteriolsar resistawe (30) . It, is lwrtinent to note at this point that there is a developing body of experimental evidence discussed in previous Reports and in this c1mpte.r t.hnt cigarette smoking may have acute delet-erious effe&s on airway re.sistnnce and pulnlonnr~ vasoconstrictiSon which can be espe- Aally hnrmful t.o the patient whose pulmonary funct,ion is already compromised. The disordered pulmonary ventilation-perfusion rela- tionships and pulmonary hypertension found in some patients with severe chronic bronchitis can only be lvorsened by further broncho- nonst,riction and possibly by pulmonary vasoconstriction caused by continued cigarette smoking. These. can enhance cardiopulmonary dccompcnsation and lead to heart failure from car pulmonale. Further research is necessary to clarify more precisely t.he inter- re.lationships between the disturbances of veiltilatioll-~rfusion clawed by chronic obstriicti\-e ~~ro~ic~l~ropi~li~io~i~~~~y disexses ant1 cwtlio\-ascular abnorn~nlities as they relate to cigaret,te smoking. SIXMARY A\NT) RESJLIRCH SGGGESTTONS AIc~dit.ion:~l evidence compiled since 1967 c,onfirms previous positive fintlinm and estends our knowledge about, some of the. effec,ts of cipnre,tte smoking on pulmon:lr;v function. There has been furthe.r clnrific~;ltion of some of tlw illt.err~lntionships between chronic obstruc- tire broncllitis n11d ;ltl\-t:rae carcliopulmon;~ry cffe.ct.s indioaling that pulmon:~r;v hJ.pertrtlsion ant1 (*or pulrnon:~le map result from the more se,vere fornls of vltronic ol)strllvtive l)rollc,llopnmonnry disease. 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Pittsbnrgh. Penns~lrania. Graduate School of Public Health. JIn$ 1, 1967. [T'nl~ul~lished] 104 pp. S.?C,. FTnr.r..\sn. W. \Y., REID. D. D. The urban fnc+or in chronic& Ilrowhitis. 1,nncet 1 : 44.544X. Febrnar~ 27. 19%. S3i. HYBTT. R. E.. WILCOX. R. E. Extrathoracic airwa;r resistance in man. Journal of Aipplied l'hyiiology 18 : 32C~3.10, l!Kl. s.?8. .~OII.\XXSES. z.. I'REIRISZ, a. Bezpnsredni wl)l~w lmlrnia 1)al)ierosow nn slrirogram u ztlrcw~c.11 i c.hor,v(.h z rozedmn 111uc i l~rzrwlekl~m niezytem oskrazeli. I'olskie Airchiwum JIrdycyny W'rwnetrznej 36 (0) : 7PSi8K 1966. S.W. .Tnxm. S. L.. TII-RROWS. B.. FIXTCHER. C. 11. Serial studies of 100 patients with chronic airway obstruction in T,ondon and Chicago. Thorax Z(4) : 327-335, July l%?`. S-W. KISS, G. T. Pulmonary surwy in the aged. Diseases of the Chest 40(3) : 30.X308, March 1966. 82 S41. KUEPPERS, F., BEARN, A. G. A possible experimental approach to the associa- tion of hereditary alpha-1-Aatitrrl,sill dt~lic+erw~ snd pulmonav tmphy- sema. Proceedings of the Society for Experimental Biology and Medicine 121: 1207-1209, 19%. S-l?. Laws, J. TV., HEARD, B. IO. Enlphyserna and the chest film. A retroswtire radiological and pathologic*al study. British .Journ:ll of Radiology 35(419) : 73&X1, November 1962. S4R. LECLAIR, R. A. Recovery of culturable tobnc*co mosaic virus from sputum 321~1 thnracentwiis fluids obtained frow vigarettr 9mnliew \\`ilh a history of pu1monar.y diwaw. .\nlrrican Rr\-iew of Rexl~irntory I)isease~ %(3) : 516511, March 1967. S-M. LIXDALL, A., MEDIXA, A., GRISMER. .J. T. A rr-evaluation of norrnnl lnilrno- nary funcation n~easurwnrnts in the adult fvni:rle. i S~~trs) Aruerican Re- view of Respiratory Diwnsrn Xc<;) : lcl(il-106-l. .Junr 1967. S-6 T,YPI-. X. G., PELICAN. C. Histocheruistry of c.onrw+iw-t isill,' n~uqwlysac~- charides and proteins after eslwrinlental inhalation of tollnccw w~oke. Federation 1'rcwwtlings [Trauslaticvtl S1~l,lvlvll~t*t~t j "1! I :(. lbt. 2 I : 4!17XOl. May-June 1963. 848. LTJPI'. S. G.. YEIXAN. C., YELICAS. I). Sal~l~~~tlcni~-n 1~ ~mrodu vnutrilr- gochnFkh nakoplcniy kislykh ntnkol~)lis:~kh;~ridov. ArkiT Patologii ( Jloskva) 21(G) : ;,l-59, 19X SSi. MILLS, 11.. BA~SCT~, B. F. Slwntaneow lnirun~c~tlioras : A wrirs of -MM vases. The Annals of Thoracic Surgery 1 (::) : W%Z)i, May 1%;. S.i4. MITCIIELI.. R. S., RYAS, S. F., I'ETTY, T. I,.. E'IMXY. G. E'. The significance of niorl~hologic~ chronic` hyperplastic bronc,hi tis. Anlcric,nn Rwic~n trf Res- piratory I)iwasw 3% (5) : i?O-iL.??~ Nag 1%X. S.X. ~AUEI.. J. A., (`OIIKOE. J. H.. .Jr. Acute effrc~ts of illhalation of c*igarettr sn~oke on airway (~orftl~l(~t;irl(.f~. .Jour~~al of .\ltl,lic~tl I'hyiioloyy 16 (4) : 71%ilfi. X361. S.ifi. SADEL. .J. A.. SAI.EM, II.. TAMPLIS, I<., TOKIW~. T. Jlrchanisni of broncho- vonstricotion during inhalation of sulfur dioxide. Journal of Alqjlied I'hyxiology 20: I(i&lW, 1(X5. S.3. S1co~.4ss. R. Iiliniuc.h-c~xltrrilllrlltf~lle Sl,n~l~rlllltltt~r~;nchungen lwi chroniwhrr Bronchitis. JIw.lic*ina ThoracGalis 21 : 2"`$-"XT. l!Ki-l. 83 S.51). PAIS. 11. C. F.. GLAZIER. J. B., Pnros. H., WEST, J. B. Regional and overall ineqna1it.v of ventilation and blood flow in patients with chronic airflow obstruction. Thorax 22 : 4X!461, 1967. S6O. I'aPAnoPor~os, S. Jletabolism of nicotine in animal tissues in Vitro and in riz'o. In: Tobacco Alkaloids and Related Compounds. Proceedings of the 4th International Symlwsium, held at the Wenner-Gren Center, Stockholm. F~brnary I!K4. I'[). 101-la. 861. PARSELI,. J. I,., ASDERSOS-. D. 0. KISSIS. C. Cigarette smoking and respira. torg infections in a class of student nurses. Kew Englmand Journal of l\iedicine 274( 18) : !)7%9S4. JIay 3, 1966. SW. I'IXZER. .\. 11.. Tno~sou. 11. I,. Effecrt of age. sex, stature, and smoking habits on human airway conductance. Journal of Applied Physiology 21(3) : 469476, AIarch 1966. %X3. PEMBERTOS. .J. Ownpntional factors in chronic bronchitis. Joint Meeting So. 1. Section of 0cwl)ational Medicine with Section of Epidemiolo,gg and I'rerrntire JIedicine. Chronic Bronchitis and Occupation. Proceed- ings of the Rosa1 8ocirt.v of Mrdicinr 61(l) : 95-98, *January 1968. S64. RAKKIX, *J., GEE. J. R. I,., CIIOSY, L. W. The influence of age and smoking on pulmonary diffusing rapacity in healthy subjects. Jledicina Thorn- calis 22 : R6KX4, 1965. S6.5. REID, 1,. Mucous secretion and chronic bronchitis. Medicina Thoracalis 24: 4013,1967. SCXI. Rmn. I,.. MILLARD. F. .J. C. Correlation hetxveen radiologi~~al diagnosis and structural lung changes in emphysema. Clinical Radiology 15 : 307-311, October 1964. SW. ROSE, R.. PIIILLS. .J. A. The immurw reaction in pnlmonary disease. Ar- chives of Environmental Health l-ICI ) : 97-110, January 1967. SW. Ross, (`. A. (`.. ~I~~.\~Ic.II.wI.. S.. EAIIIE. 11. Ii.. 1~~s. -1. TV.. 111.RRAY. E. A, I'ISKERTOS. I. Inftbc,tive newts and c.hronicd bronchitis. Thorax 21 : 4iil- 4CA. 1966. SW. Ross. .J. C.. JXY. C. D., KKTMIIOLZ. R. A.. RAKBARI. H. A technique for evaluation of gas mixing in the lung: Studies in cigarette smokers and non-smnkcrs;. A\mrrican Rrvie\v of Rrsl)irntory Diwasrs !L5 i 3 ) : 447-1.;3. JIarch 1967. Si3. SIMON. G. R:ltliolopy and vmphywmx (`linic.al Radiolog 1.7 : XC%-306, October 1964. ST-L S~~osssos. R. G. Clinic:\1 xnd physiological studies on chronic bronchitis. I. (`linicxl tlt*5c,rilltion of thcb pntirnt mntrri:~l. .\ct;l ~~llt~rgologirn 20 (4) : 257-300, 19G. 84 577. STANESCU, D. C., PILOT, L., GAVRILESCU, N., TECULESCU, D. B., CRITESCU, I. Aspects of pulmonary mechanics in arc welders siderosis. British Jour- nal of Industrial Medicine 24(2) : 143-147, April 1967. S78. STERLISG, G. M. Mechanism of bronchoconstriction rawed b.r cigarette smoking. British Medical Journal 3 : XT-277. July 29, l!MX. RTR. STRIEDER, D. d., RAZE&II, H. Effect of body position on the alveolar-arterial PO* difference in smokers. Clinical Research 16(2) : 474, April 1968. SSO. STRIEDER, D. J., MURPIIY, R., KAZEMI. H. Hyposemia in as;vmgtomatic smokers. Clinical Research 16(2) : 376, April 1968. SRI. SCKT~~IALCIIASTRA, T.. \VII,LIAMS, 31. H., Jr. Serial studire of pulmtmarr function in patients with chronic obstructive pulmonary disease. Ameri- can Journal of Medicine 39 (12) : 941-945, December 1965. 8x". R~TIsEs, 8.. (`IIRISTDFOKII~IR. A. a.. Kr.x-nor. (:. A., ~`R~TT. 1'. (`. Rlwnt,wno- logic criteria for the recognition of nonqmptomatica pulmonary emphy- sema : Correlation between roentaenologic findings and l~ulnionary path- ology, American Review of Respiratorg Diseases 91 : 69-76, 196.5. SM. TALAMO, R. C., BLESSERIIASSETT. J. R., AVSTES, K. F. Current concepts: Familial emI)hysrma and hlI)l~:ll-.~lltir~I)sill tlefic~irnc~~. Sew England Journal of JIrdicine 27.51 Z3 1 : 1301-130~. I)wember X. 19% SR4. THCRLRECR. 1%`. >I., ASGUS. G. E. The variation of Reid index measure- ments within the major bronc*hial tree. .%mcrican Review of Rrspirator~ Diseases 95 (4) : 551-555, April 1967. SK.Ti. Trsr. G., WOLFE. IV.. FAILAT. I<., S.UXL .I. II.. I,aso.\r-. 11. The Sashrille Air I'o1111- tion Studs. V. Mortality from diseases of the respiratory system in re- lation to air pollution. Archives of Environmental Health 15(Z) : 214 224, August 1967. S90. ZWI, S., SLUIS-CREMER, G. K., Du PREEZ, I,. -4 survey of pulmonary func- tion in male office workers. Medical Proceedings 13( 23) : 369-554, So- vember 11, 1967. 85 CHAPTER 3 Smoking and Cancer Contents Introduction_-__--______-________________-___-___-_-__- Conclusions of the 1964 Report- - _ _ - _ _ _ _ - _ _ _ - - _ _ _ _ - _ - Highlights of the 1967 Report_--_--__---___---------- General Aspects of Carcinogenesis-____~-___--___--__------ N-Nitrosamines_--_~-------____---_~---_---__---__-~ Polonium-210_-------____________________--~--~~-~~ Selenium---___---_-----~--.____~-__~--___~-__~----- Tobacco Pesticides and Growth Inhibitors- - - _ _ _ - - - - - Possible Fungal Contamination of Tobacco - _ _ - - _ _ - - - - - Experimental Aspects of Carcinogenesis- - - - - - - - - _ - - - _ _ Passive Inhalation of Tobacco Smoke- - - - - _ - - - - _ - - - _ Active Inhalation of Tobacco Smoke- _ _ _ _ _ - - - - _ - - - _ _ - - I~ungCancer--__-__--__----__--___---_---_----__--___-~ Illortality-__-__~-_----_--_-__--------_---~__- ______ Retrospect'ive Studies ______ -_----_--~__- _____ ~__~___ Prospective Studies- _______ -__--------~----__--_____ Lung Cancer Relat#ionships in Women- _ - - _ _ - - - - - _ - - - - Additional Considerations and Conclusions_ _ - - - - - - - - _ Cancer of the Oral Cavity____--__-_~--_--_-_---~_----_-- Cancer of the Larynx-_---~__-_---~---~---------~~-~~~~~~ Cancer of the Esophagus---~_-_~~-_~~--________________ Cancer of the Pancreas ______ -~---~-~--~----_--~__-~ _____ Genito-urinary Cancer__----_-_~--~~---_______________ Cancerof theBladder------__~ __.____ ~-_~--__---~_-- Cancer of the Kidney ________ -------------___- ______ Cited References-__-------____________________~.~~~~~ Supplemental Cancer References-_-~--~__--~_________ Page 89 89 90 90 91 92 92 92 92 93 93 93 94 94 94 96 97 97 99 101 102 103 104 104 105 106 112 87 INTRODUCTIOS The pri.mary purpose of the 1968 Supl~lemental Report is t.o re\-ien the pertinent literature that has become a\-ailable subsequent to the 1967 Report. Brief mention of the, conclusions of the lS6-f Report and the hiph1ight.s of the 1967 Report is made to facilitate an understand- ing of the significance of the most recent information. The current, research findings should beg considered in the perspec- t,ive of the B?Sf2i\ITll cGtlencr previoiisly reported in tlw lS64 ($1) and lSG7 (92) Reports. 1. Cigarette smoking is causally related to lung cancer in men: t,he magnitude of the effect, of cigarette smoking far outweighs all other factors. The data for n-omen, though less estensive, point in t,he same direction. 2. The risk of developing lung cancer increases wit,h duration of smoking and the number of cigarettes smoked per day, and is dimin- ished by discontinuing smoking. .3. Tie risk of developing cancer of the lung for the combine41 group of pipe smokers, cigar smokers, and pipe and cigar smokers is pwater than for nonsmokers. but much less than for cigarette smokers. The data are insufficient. to warrant a conclusion for each group individually. Ornl Cancfv 1. The causal relationship of the smoking of pipes to the develop- ment of cancer of the lip appears to be est.nblished. 2. Although there are suggestions of relationships between cancer of other specific sites of the oral cavity and the several forms of tobaxo use, their causal implications cannot at prese.nt be stated. Laryngeal Cancer E~aluntion of the evitlrncc Icads to ilp ,jutlpnwilt thilt, c*iprrtte smoking is a significant factor in. the causation of laryngeal cancer in the male. Esoplbag~al Guncc7~ The evidence on the tobacco-esol)ha~eal cancer relatlonshlp supports the belief tilat an association exists. However, the dat,a are not ade- quate to decide nliet.her the relationship is c.nnsa,l. i'unciv of Urin.ary B?ad&r Xvailable data suggest an association bet.ween cigarette smoking and urinary bladder cancer in the male but, are not sufficient to support, judgment on the causal significance of `this a.ssoc,int.ion. 89 So relationship ha.s been established bet,ween tobacco use and stomach cancer. HIGHLIGHTS OF TITE 19S7 REPORT (92) 1. -\ditional epidemiological, pathological, and experime.ntal data uot, onlv confirm the conclusions of the Surgeon Gneral's 1964 Repovt regartlicq lung cancer iii men l)llt stwngthen the causal relationship of smoking to lung cancer in women. 2. Cessation of cigarette smoking sharply reduces the risk of dying from lung cancer rrlatiw to the risk of those who c.ontinue,. R. ,1lthough additional experimental studies substantiate previous experimental data, ntltlitiou:~l resenrc9~ is needed to specify the tumor- initiating and tnmor-l)ro"`otiil,v agents in tobacco smoke and to eluci- date the basic mechanisms of t.he pathogenesis of lung cancer. La~ryngca7 Can.rc, The. conclusion of the Surgeon General's 1964 Repent that cigarette wiokinp is a. siqlificallt factor in the causation of laryllgeal cancer iu the male is supported 1)~ additional e.piclemiological evidence. Other Cancer8 Additional evidence supports the conclusions of t,he Surgeon Gen- eral's 1964 Report and indicates a strong association between various forms of smoking and cancers of the bucal cavity, pharynx, and esoph- agus. In tlic absriic~~ of f1irthe.r information concerning the interaction of smoking Stli other facto15 known or snspectacl as causative agents, further cowlasiolls canntrt be made at this time, although a causative relntionsliip seems likely. Aidditionnl [,I'itlt~nliolopical? clinical, and experimental data strengthen the asswint ion between cigarette smoking and cancer of the urinary bl:~dtlcr~ but the presently :~vailnble data are insufficient, to infer that the relationship is causal. Since the IN7 report. recent nclrances iii the tobacco chemistry field were revieIved in Tao articles (65,8.%`). The chnracteriza,tion of tobacco smoke by gas chronlntc~~ral,hv and digital comp\~ter opened a new areniie for the csploratiol 1 of tobacco smoke. Thr first. preliminary data indicate the l)resence of several thousands of compounds in to- I);~tw sn10ke. `I`lli 1i111i11wi~ f:ti. rswcds thil 700-x00 compounds pres- ently identified ($3). The 1067 Reljort discuswd the major concepts of experimental to- bacco carcinogensis. Al recent nlo~lo~rapl~ 1,~ n'ynder and Hoffmann (10-j) tlioroiiglilv describes and :~nnl~zes experimental carcinogencsis as it relates to tobacco and tobarco smoking. The reduction of tumori- genicity is of particular concwn. This can be accomplished by : (1) iwluc't ioii of total "tar" wnteut, and (2) reduction of specific tuniori- 90 genie agents. It has been well established that experimental tumor production is close-related to the amount of "tar'* in cigarette smoke condensate (7). The a.mount of "tar!' yield varies with parameters xwh as: (1) type of tobacco, (2') curiiqg and l~iwccssing. and (3) fil- tration. It, has been demonstrated that by selecting. curing and blending as we.11 as by using specific filter mx~terials and cigarette pal)erl one can significantly reduce the "tar" yield of mainstream cigarette smoke (39: 83,88). Over the, past. 15 years there, has been a general decrease in the amount of `%ar" and nicot.inc content of cigarettes (97. 1O.j). One. rea- son probably is the decreased nicotine ant1 ?ar" content in the "lighter" tobaccos now being grown . ,Inotlier is the increased public de.mand for "filtered" cigarettes. Increased nitrate content of tol)ncco and the addition of nitrate to cigarettes has been reported t.o reduce the tumor yield in cslwriniental animals ( 10-i). kSniokc from air-curccl tol~~cco is less tumorigrnic than flue or sun-cured tobacco (,W. I0.j ) and cigarettes using more sheets and st.ems rather than whole leaf have been shonn to be less tumori- genie (64,104). Also, more porous cigarette palmer (TO), and the atldition of nitrate, citrate, or phosphate to cigarette pper increases tlw burning rate of the cigarette, t.hereby lowering the number of p11tl.5 taken l)er itnit of cigarette (104). Filtration \Till decrease the total "tar" yield ((il. 67. 96. 104). but except for the phenolic component, conunerical filters do not, selec- tively filter specific carcinogenic components from the "tar". It has been shown that. "tars" of tobacco extracts have increasing carcinogenic proper&s in direct, relationship to the. teml)erature of pyrolysis (lU.$) . It is important to note that tobacco extract itself contains relatively high amounts of tumor promot,ers. The tumor promoting activity of tobacco extracts is of the same magnitude as thnt of tobacco smoke condensate (104) but so far no clear tumoripcnic relationship is evi- dent between them (6). Despit,e recent publications on the presence. of N-nitrosamines in tobacco (76) a.nd cigarette smoke (55)) the l)resent el.idcnce must be regarded as insufficient. because of the high lnobnbility that this is arti- fact,ual (66). The studies described so far hare failed to identify these a.gent.s in fresh tobacco smoke ($5. C6). However, since sercral of the N-nitrosamines are strong carcinogens (58) and tobacco smoke con tains several dozen secondary amines and oxides of nitrogen which may be precursors for nit,rosnmines (6~. 76. 80, I&T), tobacco smoke should be regarded as a potential source of S-nitrosamines. 91 POLONIUM-210 Kew data. on polonium-210 in t,obacco leaf and cigarette smoke have originated from various countries (8: 13,26,.%`7, ~38~ 51: 52,68,89). The polonium-210 values vary between l-50 picocuries per 1.0 g. tobacco; 3-50 percent of it is recovera.ble, in the mainstream smoke of ciga- ret.tcs without filter tips, Using speci~al filter material, up to 90 percent of the polonium-210 can be filtered out of the mainstream smoke (8). One major source for polonium-210 in tobacco was reported to be phosphate fertilizer (89). Analyses of human tissues demonstrated that. lung, blood, and liver of smokers contain higher concentrat.ions of polonium-210 than t.he corresponding organs of nonsmokers (B7,@, 41. 57. 68). Rajewsky et. al. (68)estimate a daily polonium-210 inhala- tion rate of 2 picocuries for a. smoker of 20 cigarettes per clay. Their autopsy studies indicate an alpha dose exposure for the basal cells of the subsegmental and twminal bronchi of 41 mrem and 79 mrem per year, respectively, in smokers of 20 cigarettes per day. In view of the fact, that, Jacobi (44) calculated a dose rate in these same basal cells of l-2 rem per year from the deca.y of naturally occuring radon and thoron in the air, Rajewsky, et al. (68) consider it. unlikely that cancer is caused by the inhalation of polonium-210, in tobacco smoke. In a review of the role of radioactive substances on the effect of smoking, Casarett, was of a similar opinion (Id). SELENIUM At, present, there is still no substantial evidence implicating selenium as a respiratory carcinogen, although this is still somewhat disputed (29,lUO. 101). Tor~\c:co PESTICIDES AM GROWTH INHIBITORS The most widely used sucker growth inhibitor is maleic hydrazide. This agent was recently reported-to be carcinogenic (25). Tobacco leaf and ciyare.ttc smoke are known to contain organic pesticides (32, 104). The first identified carcinogenic pesticide in tobacco and cigarette smoke is l,l-dichloro-2- (o-chlorophenyl) -2- (p-cholorophenyl) ethane (o,p'-DDD) ($3. X), whicli is it technical by-1)roduct of the commer- cial insecticide p,p'-DDD. At present there is no known evidence of chlorinated insecticides contributing to tobacco carcinogenesis. POSSIBLE FUNGAL CONTAMINATION OF TOBACCO The mold Aspergi77aus fEnz*us is knownto synthesize the carcinogens of the afla.toxin group (17). However, a recent. investigation reported 92 the absence of these agents in tobacco and cigarette smoke (9U). h'ever- tIleless, further studies are indicated to evaluate the possibility that, some tobaccos may be contaminated with carcinogens produced by fungi. EXPERIMENTAT, ASPECTS OF CARCIKOGENESIS PASSIYE INIT.UATIOK OF TOBACCO SNOHE In attempting to reproduce lung cancer in experimental animals, the limitations of presently arailnblc bioassnys? mninl~ passive inhala- tion studies, I~:I.IY I)ew cliwlssctl in tllv pre\.ious Rel)orts (91. 92). T,argc scale studies in whirl1 :I variety of animals have been exposed to the passi\-e inhnlntion of tobnccw smoke have essentially failed in producing squan~oas ccl1 cancer of the lung (204). The dificultics wit11 I)assive illh;llation studies ill animals relate in part to the tosivity of (`ill'l)Oll nlonositlc and nicwtine. The defensive "filtri~tiOl1" cnpal)ilities of the nasal l)nssngc5 alId the epithelium of the 1lpJm respirator? tract, necessitate rclntively higIl exposure kdSy which in the case of tobacco smoke cannot adequately be accomplished by passive inhalation methodologies. Some laboratory studies failed to produce squamous cell cancer in (`5'7 black mice even though some of the animals were previously inoc.ulated wit.h Swine influenza virus (10(i). Harris and Srgroni (&), in experiments with C57 black mice, some of which were inoculated with viruses, achic\-ed sonic enlJ:~JJcenleJl~ of ildCllO~RI'CiJ10JJl~l~ hit did not. produce :ms pr0wn sqnanwus wll caners. T,ong-term cigarette smoke exposures in hamsters led only occa- sionally to tracheal papillomas and not to squamous cancer (20). However, one could sensitize these animals with diethylnitrosamine and enhance the tumor production initiated by this carcinogen by a variety of volatile irritants including tobacco smoke. Active tobacco smoke inhalation studies as reported in the 1W Report. (92) have shown that hyperplastic and metaplastic changes can be produced in the lungs of dogs. These studies are expensire and ic is difficult to keep the dogs alire long enough to permit the expected development of ncoplastic transformation. Auerbach, et al. (4) in continuing experiments with "smoking* clogs, have shown all the bronchial epithelial changes including tlysplasial n+i& is the most advanced stage of prc-mali~~nnt change. More research is needed to elucidate the biomechanisms involved in the pathogenesis of lung cancer caused by tobacco smoking. 93 LUNG CANCER MORTALITY The annual number of deaths in the United States from cancer of the lung (ICD Code 162, 163) increased from 18,313 deaths in 1950 to 48,483 in 1965 (95). During the same period of time the crude death rate rose from 12.2 deaths per 100,000 population to 25.0 deaths per 100,000 population. The lung cancer age-adjusted mortality rate for males increased from 18.5 per 100,000 population in 1950 to 39.2 per 100,t)OO 1)opulation in 1965: while in the females, the age-adjusted rates increased from 3.9 to 6.4 per 100,000 population over the same period. The age-specific death rates for males show an increase with age up to the 65 to 74 year age group, and then a decline. On the other hand, the female lung cancer death rates show a relatively steady increase with age, averaging approximately 7 additional deaths per 100,000 population between each ten year age group. As a result, the male to female mortality ratio varies from a low of 2.0 for the 25 to 34 year age age group, to a high of 8.5 for the 65 to 74 year age group. TABLE l.-Death rates per 100,000 population for lung cancer, by age -i- and sex, 1965 3% 2634 35-44 lb54 5H.4 6674 years Yem YKUS YCWS years __~ -i- ~ Males--------~~.~... 1. 2 13. 2 ~ 58. 2 159.2 269. 3 Females-.----------. 0. 6 4. 4 / 13. 7 22. 1 31. 6 Ratio M/F--_----... 2. 0 3. 0 4. 2 1 7.2 ~ 8. 5 I I / - 7.wu 85 years years and over ~- 226. 4 152. 7 36. 5 45. 6 6. 2 3. 3 SOURCE: Satioml Center for Health Statistics (95). RETROSPEXTICE STUDIES Studies in Iceland uniquely support the evidence that t.he increase in lung cancer is related to the increase in cigarette consumption. Iceland is a small country with a total popukion of about 200,000. There is relatively lit,tle air pollution, due mainly to the use of hot water springs instead of the combustion of fuel 118 men and Jvomen in Japan show that the death rate from lung cancer is significantly higher in cigarette smokers as compared to non- smokers for both males and females. There is also a posit'ive correlation between lung cancer death rates and both the amount smoked and the I- l- l- l- )- I- ,- ,- BY sex and smoking habit : : :. + ~ .:: `: ,:: Non- Smoker NOW 1-24 25. smoker -- smoker cigarettes per day Number 3 studied -346 9 J 23350 119136 97047 17473 23350 m Male m Female -20 21 22-- 21 36912 7 9 16644 34769 FIGTXE l-Death rates for lung cancer, among persons age over 40 years, classi- fied by sex and extent of cigarette smoking, and by age smoking began : Study of 29 Health Center Districts in Japan, danuary 1966 to March 1967. SOUBCE: Hirayama, T. (37) 96 age smoking began, but the number of deaths is too small for adequate analysis at. this time. LUNG CANCER RELATIONSHIPS IN WOMEN Critics have tried to throlr- doubt on the smoking-lung cancer rela- tionship by saying that the lung cancer death rates for u-omen have increased only slightly as compared to the greater relative increase in the number of women smokers. It is true that the lung cancer death rates for women are presently much lower than the corresponding rates for men. Women presently account for onl,y about one-sixth of the total deaths from lung cancer. But since 1930 the lung cancer death rate in women has increased over 400 percent. Over the past 14 years alone this increase has been over 50 percent (94). ,Z most likely reason for the difference in male/female lung cancer death rates is that women still have not had the same degree of total exposure to cigarettes as haw men. For instance, as late as 1955. only 24.5 percent of the adult female population (age 18 and over) were regular smokers compared to 52.6 percent of the adult. male populat.ion (33). In 1966 the figures show only 33.6 percent of the adult females smoking (age 21 and over) as compared to 51.8 perwnt of the adult males. Also, the female smoker's per capita consumption was about 26 percent less than that of the male smoker in 1955, and about 20 percent less in 1966 (93). In adclition, it has been show-n that women smoke differemly than men do (c9t9). They do not, smoke cigarettes as far to the end, where proportionally more nicotine and "t,ars" are inhaled than from the first part of t.he cigarett.e.. Won1e.n smoke more filter-Cl> cigarettes than men, and smoke more "low tar and nicotine" cigarettes than do men. They also inhale less frequently and deeply than men. Furthermore, cigarette smoking still tends t.o be heavily concentrated in those women under the age of 50 years, prior to the age at, which lung cancer is mostly likely to occur. An anlysis of the Iun g cancer death rates (94) shows that,, "Vntil 1960 the rat,io of the death rate in the male population for this cause to the corresponding death rate in the female population continued upward. But after 1960 this ratio leveled off, reflecting the greater relative rise in mortality from lung cancer in the female population." ADDITIONAL (`IoNSIDEIL~T~O~`S `IND CONCLVSIONS Filter cigarettes, in general, have lower "tar" and nicotine ra1ue.s than comparable non-filter cigarettes. In this respect, a study by Brass (9), shows preliminary evidence that smokers who switched to filter cigarettes have a decreased risk of developing lung cancer. (;raham (3'0) studied the smoking habits of male lung cancer patients and controls. Previously he showed, on smoking machines, that dif- 97 fcrent, patterns of cigarette smoking gave different "tar" yields. His lung cancer patients had significantly greater high "tar?' yield cigarette smoking patterns than the controls. The risk of lung cancer increased with increase in : (I) the mean number of puffs per cigtwette, (2) t.he average length of time taken to smoke a cigarette (except in the highest, number of puffs category) and (3) taking more puffs towards the end of the cigarette. These findings add further support to t,he dose-re- sponse relationship between lung cancer and cigarette "tar" exposure. As pointed out in the 1964 and 1967 Reports, there appear to be several other factors which may also contribute to the etiology of lung cancer, especially in the presence of cigarette smoking. However, there has been no evidence to refute the statement in the 1964 Report. that, "Cigarette smoking is causally related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors. The data for n-omen, though less extensive, point in the same direction." Of particular interest are the studies of Ruell, et al. (II, 12). They reviewed various prospective and retrospective studies which shelved that the urban-rural differences in lung cancer death rates in non- smokers n-ere of the range of 2 : 1 to 4.4 : 1. However, the much greater effect. of smoking on increasing the lung cancer death rates was evident by their statement "that smoking can act independent.ly of the urban factor, the gradients among rural dwellers rising to as much as 10 to 15 fold for heavy smokers." TJ?th regard to the high levels of photo- chemical air pollutants in Los ,Ingeles, they concluded: `With controls for cigarette smoking and length of residence, the risk of pulmonary canc.er in Los ,Inpeles, where photochemical air pollution levels are highest, was not greater than in other major met.ropolitan areas of California." hlthough photochemical air pollution might not be a contributing factor to lung cancer mortality in man, as is the "sulfur dioxide" air pollution found in most industrial areas, it may be too early to ascer- tain any effects. since air pollution in TAX Angeles only became a prob- lem between 1945 and 1960. Storks (@. 85) shows that per capita solid fuel consumption has a positive correlation with lung cancer death rates but to a much lesser degree than per capita cigarette consumption. He sug,mts, therefore, that air pollution from solid fuel combustion is related to lung cancer death rates and that this might possibly be independent of cigarette smoki~lg. However, Stocks did not de.termine the specific smoking histories of indiriduals ~-ho died from lung ca.ncer. Concurrent st,udies of cigarette smoking and air pollution, in the same populations with precise smoking histories on individuals who have died from lung cancer, might serve to clarify the probable inter- action between cigarette smoking and air pollution or possible inde- 98 pendence of cigarette smoking from air pollution as they relate to the etiology of lung cancer. The preponderance of evidence [ 1964 Report (91). 1967 Report (5%`)) and this report] continues to indicate that most lung cancers occur in cigarette smokers and that cigarette smoking is the major cause of lung cancer. A majority of lung cancer cases are of the squamous cell rnriety and most investigators are in agreement that squamous cell carcinoma is rare in the male nonsmoker (3. 15, 103). The elimination of cigarette smoking would in time eliminate most lung cancer. That this is a real goal is supported by the study of British physicians (18, 2,9) reriewed in the 1967 report.. It is not, disputed that some cases of lung cancer can occur in those people who have never smoked ciparette,s or inhaled any form of tobacco smoke. In these cases air pollution possibly pln~s a larger role in the cawation, but in most cases, it appears that it is the ciga.ret,te smoker nho is especially susceptible to whatever additional risk for lung cancer may be presented by certain types of air pollution or other fnctors such as asbestos or uranium dust inhalatSion. `l'he 1967 report showed that the overall death rates for oral cancer remained about the same during the period 1950-1964. This was in- fluenced somewhat by recent changes in the ICD Code. It is intere&ing to note that the incidence rates of oral cancer have also remained relatively constant over the period 19X-19&2,* in spite of increased cigarette smoking (24). This may be explained, in part, by the fact that the numerators of such rates often include neoplasms coded to the International Classification of Disease, rubrics 140 through 148. These rubrics identify many oral and pharyngeal diag- nostic sites which do not contribute equally to either the. morbidity or mortality experience resulting from the use of tobacco, For example, preliminary findings in an unpublished study by Keller (47) suggest that. salivary cancers (ICD rubric 142), unlike tongue and floor of mouth cancers, are not associated with the tobacco habit,. The fact that pipe and cigar smoking in this country began to be replaced by cipar- ette smoking among men born subsequent to 1900 may also be signifi- cant, although this trend has leveled off and may even have been re- versed since the health consequences of smoking cigarettes first came to public attention in the mid-1950's. In the population which accounts `There is no ntitional ctata collection on inddenw rates of ddseam. Sewral &ates have mncer wgi&-ier whirh have information cm the incidence of caner in that particu1a.r state. Thr data from Connecticut are generally thought to reflect the ch~ngiing patterns of cmcer incidence throughout the I:nited States. It is realized that there might he indi- vidual state differences. Krfcrencw to incidence rates in this chapter section are taken from the Connecticut Dunn unless otherwise specified. 99 EUCCALCAVlTYANDPHARYNX ? ? ? ? ? ? 1935 1940 1945 1950 1955 1960 YCXS - Maler ---Females FIG~RF. Z-Age-adjusted rates of the iucidence of caucer of the buccal cavity aud pharynx, for males and females : Connecticut, 19351962. SOURCE : Eisenberg, et al. (24). for the bulk of oral cancer cases-men over 45-there has been a greater change in the form in which tobacco is used than in the proportion of men using tobacco. Since pipe and cigar smoking is associated with oral cancer, with mortality ratios not very different from those for cigarette smokers, the constant incidence rates may reflect the fact that the proportion of t,obacco users among men over 45 has been fairly stable. A review of the recent retrospective studies shows a relationship of oral caucer to all forms of the tobacco habit (22. 2%. .53,5$. 77, 78. 79, 98). This includes the use, in the nlucobuccal fold, of either snuff, among n-omen (lo, 22, 71, 7.2, 81), or the betel nut quid with tobacco, among the residents of India and Southeast Asia (~6, j$,77: 78,79,,%?). Reddy has 1noduce.d tumors in mice by daily instillation of a "pan" mixture with tobacco (the same mixture used for chewing) into the vaginas of virgin mice (69) . There is evidence that in the presence of tobacco consumption, alcohol may also be a factor in the etiology of oral cancer (48, 4.9> 50, 97). In a recent study on male veterans, Keller concluded, "* * * heavy smoking, heavy drinkin g and liver cirrhosis (either alone, or as a measure of heavy drinking) are associated with cancer of the 100