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1969 s~mP~ To The i~o? Public Eealth Service Review July i~ 1969

THE h~ALTH CONSEQUenCES OF BMOEI[NG 1969 SI~ i. Ac ~uowlCdgmea bs Sum~1~ry o~' th~-~eport Smoking and Cardiovascular Diseases Smoki~l~ ~d Chronic ODstruct]v~ Bro~chopL~l~omary Dise~s~ 5- Sm~klng and Cancer Effo~t~ o~ S~king on prega~ncy 7- Smoking and Noncancerous Oral Disease

b $UP~RY OF TItE REPORT This report is a review o£ the pertinent ~edlcal literature on the health consequences of smoking which has appeared since the publlcation of rbe 1968 Supplement to the i967 ~ubllc Health Service Review. The 1964 Report of the Advisory Comlttee on Smoking and Health, the 1967 Pchllc Health Service Review and rbe i968 Supplement bare presen=ed the broad base of converging epldemielogical, physlologlcal, pathological and clinlcal evidence on which knowledge of¸ the health hazards of smokln8 is ba6ed, included in this evidence are da~a whlch sho~ che magnitude of che excess ~ortallty ~d morbldlty ~ong smokerso The followlng co~clusloas ~ega~dlng the heal~ Consequences of smokln8 were s~arlzed in ~he 1968 Supplement. Genecal Mortality Informatlon Pr~vlous findings reported in 1967 Indicate that cigarette smoking is associated with an increase in overall mortality and morbidity and leads to a substantial excess o£ dsaths i~ those peopl~ who smok~, In ~dditle~ ~vide~ herein prese~d sh~s ~ha~ llfe ~xpe~amcy ~ong you~8 ~en is reduced by an average of 8 years in '~eavy" cigare~te smokers~ those who ~m~ke over ~wo pa~k~ a day~ ~nd an ~ver~ge of 4 yea~ in '111ght~ ~igarette smokers, ~hose who ~moke less than one-h~if pack per day° Emokin8 and Cardlovascular Disease~ Curren~ physiological e~idence, i~ combinatlo~ wich addltio~al epide~iological evidence, conflrme p~vious findings ~nd ~ugge~ts addlt±on~l biomechanlsms whereby clgaret~e ~moking c~i e~atribute ~o coron~t~ he~t dive.See Cigarette 8moklng adve~saly affect~ rbe inte~actlon be~w~ea~ the demand of the hea~ for oxygen a~ other nutrlents and their supply. Some of the harmful cardlo~ v~scula~ effect~ a~pea~ to be reversible af~e~ ces~tlon of clgare~e ~mo~. ~=~

Because of ~be increasing convergence of epidem/ological and physiological findings relating cigarette smoking to coronary heart disease~ it is concluded ~hat cigarette smoking can con- tribute to the development of cardiovascular disease and partic- ularly to death from coronary he~r~ disease. Smoking and Chronic Obstructive Brenchopulmonary Diseases Additional physiological and epidemlologlcal evidence confirms the previous findings that cigarette smoking is the most important cause of chronic non-neoplastic hronchopulmonary disease in the United grates. Cigarette smoking can adversely affec= pulmonary function and disturb cardiop~imonary physiology. It is suggested =ha~ this nan lead =o cardiopulmonary disease, notably pulmonary hyper- tension and cot pulmonale in those individuals who have severe chronic obstructive bronchi=is. Smoking and Cancer Additional evidence substantiates the previous findings that cigarette smoking is the main cause of lung cancer in men. Ciga- rette smoking is causally related to l'~g cancer in women but accounts for a smaller proportion of cases than in wen. Smoking is a significant factor in the causation of c~cer of the larynx and in the development of cancer of the oral cavity. Further epidemiological data strengthen the association of cigarette smoking with cancer of the bladder and cancer of the pancreas, The rues6 r=cent Public Realth Service review of the effects of smoking on pregnancy was presented in the 1967 Report. The conclusions of ~hat review were as follows: Clearly, more research is needed to elucidate the siEaificance of the relationship of smoking in pregnancy and low birth weight. Addi=ional long-range morbidlty studies are needed, as well as s~udies on the effect of smoking on uterine activity and placental blood flow. Smoking does have an effect on the outcom~ of pregnancy. Eow- ever, it is no= k~0wn whether this effect is deleterious or no=.

C Until such evidence is presented so as to clearly define the role of smoking in pregnancy, it is more prudent at this time to advise pregnant women to stop or decrease thelr edgarette- smoking practices. No substantial negative evidence has appeared which refutes these Judgments. On the contrary, studies made available since ~he publication of the 1968 Supplement and reviewed by panels of experts in the relevant medical areas confirm previous findings and add new evidence that smoking is a health hazard. Highlights of the 1969 Supplement are as follows: I. ~ and Cardiovascular Diseases: Further data from prospective studies eonflrm the Judgment that ciga- rette smoking is a significant risk factor that contributes to the develop- ~an~ of coronary heart dlsease~ apparently by promoting myocardial infarct and cardiac arrhythm±as. Analyses by several investi~tors of othe~ 8~soclated factors (high ser~ cholesterol, high blood pressure and body weight) show clearly that the effect of cigarette smoking persists and is appreciables even when these other factors are carefully evaluated. Autopsy studies suggest that cigarette smoking is associated with a significant increase in atherosclerosis of the aorta and the coronary ar~erles. Experimental studies dn animals have provided new information on the pathological effects of cigarette s~king on the arteries. This further supports the view that cigarette smoking promotes aKherosclerosIs. GO

il, s~kinjl and Chronic Obstructive Broncho ulmona Diseases; Recent studies have demonstrated that cigarette smokers m~y have significant disease of the small airways in the absence of bronchopulmonary symptoms. This disease is demonstrated by the finding of abnormalities in the ventilatlon/perfuslon relationships in the lungs of cigarette smokers. Animal experiments have demonstrated the pathological effects caused in the lung by exposure to clgare=te smoke or to specified concen- trations of products found in cigarette s~ke. Conditlons similar to pulmonary e=.physema in man have been produced in some of these experiments. Other studies have inves=igated the pa=ho~ogical effects of smoking on pulmonary clearance mechanisms and demonstrated that pulmonary clearance may be signlfican=ly impaired by =he effec=s of cigarette smoking. Kpidemfological a~d laboratory evidence supports the view ~ha~ cigarette smoking can contribute to the development of pul~onary emphysem~ in =~n. l£I. S~kln~ and Cancer: A major pathological study of histological changes i= the larynx has de~nstrated a dose-relationship between smoking ~id pre~llgnant changes in the larynx. New animal models for ~he experimental study of respiratory cancer, which may be helpful in e~ucidating the mschanlsms of respiratory ~r~cc carelnogenesis, have been developed and refined. More studies have been done =o £den=ify those subs=antes in tobacco smoke which ~O

cake part in carcinogenesis. ~lese studi~s may help t.o define the exact biomechanisms involved in the cause and effect relationship between ciga- rette smoking a~d lung cancer. IV. Effects of S~k~/~ on P~: New data are presented which ~onfirm the finding that maternal smoking during pregnancy is associated wiKh low birth weight in infants ~nd also indinate that mnterz%al smoking is associated with an increased incldeRce of prematuri=y defined by welghK alone, l~ addition, it appears that m~ter~ai slnohing during pregnancy may b~ associated with ~u~ increased incidence of spontaneous ahor=ion, sKillblrth and neonatal death and that this relationship may be most marked in =he presence of other risk factors. V. $mokin~ and Noncancerous Oral Dlsease~ The chapter on noncancerous oral disease is the first Publla Health Service review of this sub~eet. The data available lead ~o the conclusion that ulceromembranous gingivitis, alveolar bone loss a~d sto~a~dtds ~ico~ina are ~re eo~mnly found among s~kers ~han a~ng no~smokers° ~%e i~fluenee of smoklng on periodon=al disease and gingivitis probably operates in con- j~uc=ion wlth poor oral hygiene. In addi=ion, there is evidence =hat smoking may be associated wlth ede~tulism and delayed soeke~ healing. Tobecco smoke contains a large number and ~ wide variety of compounds which may ~esul~ in co~i~x and multiple pa~ho-physlologlcai effects o~ the varioms tissues and orga~ sys=ems. While further research is needed ~o -J

Investlgate the e~ac~ biomeehanlsms involved in the paKhological ~ffec~s of s~klng, the ev£~en~e clearly shows that clgaret~e smoking constituteo a major health hazard in ~he Oni~ed States. 6

ACK NOWLEDGMEh~S The National Clearinghouse for Smoking and Health, Daniel Horn, Ph.D.~ Director~ was responslble for the preparation of thls report; Albert C. Kolbye, Jr.~ M.D.. M*P.H.~ LL.B., was consulting editor. Staff director for ~hls report was Daniel P. Ashes, M.D. The professional staff has had the assistance and advice of a number of experts in ~he scientific and technical fields, both in and outside of ~he Government. ~elr con~rlbutlons are gratefully acknowledged. Special thanks are due ~he following: ANDERSON, WILLIAM }I., M.D.--Associate professor of medicine, University of LouSsville, School of Medicine, Lo,~i~ville, Ky° AL~F~BACH, 0SC~, M.D.--Senior medleal investigator, Veterans Administration Hcspi~al~ East Orange~ N.J. AVIADO, DOMINGO M., M.Dq--Professor of pharmacology, Departmen~ of Pharma- cology, School of Medicine, University of Pennsylvanla~ Philadelphla, Pa. AYI~E~, SEEPHEN M., M.D.--Director, Cardiopulmcnary Laboratory, Saint Vineen~ts Hospital and b~dical Center of New York~ ~New York~ N.Y. BATES, DAVID V., M.D.--Cha£rman, Department of Physiology, MeGill Univer- sity, Montreal, Quebec, Canada. BELLET, S~EL, M°D.--Direetor, Division of Cardiology, Philadelphia General Hospital, Philadelphia, ~a. BINC~ RI~AP~ J.. M.D.--Professor and chairman, Department of M~dicine~ Wayne S~a~e University, Detroit, M~ch. BLOMQUIST, EDWARD T., M.D.--Chief, Chro~ic Respiratory Disease Control Frog~am, Health Services and ~ntal }{eal~n Adm~nistratlon, U.S.P.H.S~, Arling ~on. Va.

BOOK, FRED O., Ph. D.--Director, Orchard Park Laboratories, Noswell Park Memorial Ius~itute, Orchard Park, N.¥. BOREN, BOLLIS, M.D.--Chlef of pulmonary disease, Professor of medicine, Marquette~ School of Medicine, Wood VA Center, Milwaukee, Wise. BOUTWELL, ROSWELL K., M.D.--Professor of oncology, McArdle Laboratory for Cancer Research, University of WisconslnI Madisonj Wise. COOPER, THEODORE, M.D.--Director, National Heart instltu=e, National institutes of Health, Bethesda, Md. CORNFIELD, JgROME--Biostatlstfcs Project, Bethesda, Mdo DE LA PUENTE, JOSEPH--Chlef, Program Studies Section, Kidney Disease Con- trol Program, Health Services and Mental Health Administration, U.S.P.M.S., Arlington, Va. EASTMA~I, NICNOLSON J., M.D.--Professor emeritus of obstetrlcs, Johns Hopkins Hospital, Baltimore, Md. ELIOT, ROBERT S., M.D.--Assoclate professor of medicine. Divlsi0~ of Cardlolosy, College of Medleine~ University of Elorlda~, Galnesvllle, Fla. E~DICODT, KENNETH M., M.D.--Director, Natioual Cancer Institute, National Tnstltutes of Health, Bethesda, Md. EPSTEIN, FREDERICK H.. M.D.--Professor of epldemiology, Department of Epldemlology, Unlversi~y of Michigan, School of Public Health, Ann Arbor, Mich. FALK. HANS L,i Ph. D.--Assoclate director for laboratory researehp National Institute of Environmental Health Sciences, Research Trian8le ParkI S.C. FERRIS, BENJAMIN G., JR., M.D°--Prefessor. Department of Physlolosy~ Harvard School of Public Health, Harvard University, Boston, Mess. FOX, SAMUEL M.i lli, M.D.--Chiefi Heart Disease and Stroke Control Pro- gram. Health Services and Mental Health Admlnis~raKion, U.S.P.H.S., Arlington, Va. G~

C FRAZIER, TODD M.--Asslstant director, Harvard Center for Community Health and Medical Care, Earvard School of Public Health, Boston, Mass. }LASS, GEORGE M., M.D.--Chairman, Division of Pathology, Presbyterlan-St. Luke's Hospital, Chicago, Ill. HIGGINS~ IAN T. T., M.D., M.R.C.P.~Professor, Department of Epidemiology, University of Michigan, School of Public Health, Ann Arbor, Mich. HOFFMANN, DIETEIOI, Ph. D.--Associate memher, Environmental Carcinogenesis, Nloan-Kettering Institute for Danc~r Research, New York, N.Y. KELLER, ANDREW Z., D.M.D., M.P.H.--Chlef, Research in Geographic Epi- demiology ~eseerch Service, Veterans kdmlnist~a~ion Central Office, Depar~enL of Medicine and Surgery, Waghington, D.C. *KERSI[BAUqM, ~LpRED, M.D.--Asslsta~t Chief, Division of Cardiology, Philadelphla General Hospital, Philadelphia, Pa. (Dr. Kershbaum, who contributed to this and prevlo1~ report~ died suddenly in March 1969 .) KOTIN. PAUL, M.D.--Director, National Institute of Environmental llealth Sciences, Research Triangle Park, N.C. KRL~OLZ, RICILARD A., M.D.--Director, Institute of Respiratory Diseases, Kettering Medical Center, Kettering~ CaiN. LEUCHTENBERGER, CECZLE, Ph* D.--Head, Department of Cytochemistry Swiss Institute for Experimental Cancer Research, Laus~ne, Switzerland. LEUC}[TENBERGER, RUDOLF, M.D.--Professor, Swiss Institute for Experimental Can~er R~search~ Lausanrve, Swltzerland~ LIREOW, AVhHILL A., M.D.--Professor and chairman, Department of Pathology, Eniversizy of California, San Diego, La Jolle, Calif. LILLIE~:FELD, A~KAHAM, M.D.--Professor and chairman, Department of Chronic Diseases, Johns Hopkins School of Hygiene and Public Health, Baltlmore, Md. LYON, HARV~X W., D.D.S., Ph. D.--Secretary, Co,ell on Dental Research, American Dental Association, Chicago, Ill. *Deceased t¢

~Lac}~HON, BRIAND, M.D.--Professor of epide~aiology, Harvard University SehoDl of Public Health, Boston, Mass. McLEA~N, ROSS, M.D.--Professor of medicine (pulmonary disease), Emory Uni- versity, School of Medicine, Atlanta, Oa. MITCI{ELL. ROGER S,, M.Do--Ddrector. Webb-Waring Institute for Medical Research, U~iversity of Colorado ~ledical Center, Denver, Colo. MURPHY~ EDMOND A., M.D., Sc. D.--Associate professor of medicine, The Johns Hopkins Hospital, Baltimore, Md. PAFFENBARGER, RALPH S., JR., M.D.--~*lef, Bureau of Adult Health and Chronic Diseases, Department of Public Realth, Berkeley, Calif.¸ PRTERSON, WILLIAM F., M+D.--Chief, Obstetrics and Gynecology Service, USAF Hospital Andrews, ~}[CB, Andrews Air Force Base, Washington, D,C. PETIt. T~O~K~S L., M.D.--Assistant professor of medicine. University of Colorado ~ddc~l Center, Denver, Colo. ROO|kMIB. PAUL C.~ M,D.--Heart Disease and Stroke COntrol Program. Health Services and Mental Health Administration, R.S.P.H.S., Arlington, Va. ROSS, WILLIAM L., M.D.--Calef, Cancer Control Program, HealS5 Services and Mental Health Administration, D.S.P.H.B., Arlington, Vao SAFFIOTTI, UMBERI'O, M.D.--Associate scientific director for carcino- genesis, etiology, National Cancer Institute, National Institutes of Health, gethesda, Md. SCKA~{TER, JOSEPH--Statistician, Adult Heart Activities, Heart Disease ~d Stroke Control Programj ~ealth Service~ and M~ntal Health Administration, U.S.P.H.S., Arlington, Va. SCHL.~L&N, LEONARD H., M.D.--Professor of epidemlology. University of Minnesota. School of Public Health. Minneapolis. Minn. SRI~IN, }dCHAEL B., }i.D.--Director, Regional Medical Programs, University of California at San Diego, La Jolla, Calif. SIL%~Z~v~LN, SOL~ JR., D.D.S .--Professor of oral biology. School of Dentistry, L~iversity of California, Sa~ Francisco, Calif. ~O

SP/'fl{, LOWELL C., D.D.S.-~hief. Preventlve Servicms Section, Go~z~unity Programs Branch, Division of Dental llealth, U.S.P.~.S. ~ 8ethesda, Md. ST~ER, JEREMIAH, M.D.--Executlve director, Chlcago Health Research Foundation, Chicago, IIi. STEDMAN, RUSSELL L., D. So.--Head, Smoke Investigations, Tobacco Labora- tory, U.S. Department of Agriculture, Philadelphia~ Pa. TIECKR, RICILARD W., D.D.S.--Director, Research Institute, American Dental Association, Chicago, Ill. TOBIN, C~LiELRS E., Ph. D.--Professor of human hlology, U~iver~ity of Colorado School of Dentlstry~ Denver, Colo. TYLER, WALTER S.~ D.VoM., Ph. D.-~Professor and chairman, Department of Anatomy, School of Veterinary Medicine, Universlty of California, Davis, Callf. UNDERWOOD~ PAUL, M.D.--Assistant professor of obstetric.g and gynecology, Department of Obstetrics a~d Gynecology, U~ivers±~y of South Carolina Medical School, Charleston, S.C. V~ DUUREN, BENJA~N L., M.D.--D~ssoclate professor, N~ York University Medical Center, Instltute of Enviror~ental ~ealth, New York, N.Y. WEIR, JOhq~ M°--Director~ Bureau of Den~al Realth Education, Amerlcan Dental Assoclatlon, Chicago, Ill. WYNDER~ EP/~E~Y Lo, M.D.--Associate member, Sloan-Kett~rlng Instltut~ fo~ Cancer Research, New Yo~ N.Y. The following professional staf~ of the Rational Clearinghouse for Smoking and Health contributed to the preparation of this report: Lolls Nemser, M.D., David V° Sharpe, M.D,, Dorothy E. Green~ Ph.D., Richard Elsi~ger~ RoSert S. Hutchin~s, Emil Corwln and Richard W. White. S~ec1~i ~ilanks are due Jen~i~ M. Jer~in~s, ~M~idred ~. P~Itehle a~d Donald ~. Shopland° #¢

SMOKING AND CARDIOVASCULAR DIS~%SE3 SU~RY Cozonaz~] heart disease (C~D) among men in the Western world is an epidemic whi~ Guts short the lives of many in their prime productive years. The evidence linking smoking and CHD has been re?orted not ouly from s£udies in the U~ited gtates~ but also from ~uch diverse a~as as west Germa=y, the U.S.S.g., Fr~ace, Israel, Italy and the British ~sles. The 1968 Supplement (27) stated: Because of the increaslng convergence of epldemlologlcal and physiolo~laal findings relating cigarette smoking to coronary heart disease, i£ is concluded that eigarett~ smokln~ ca~ con- tribute to ~he development of cardlovascul~r disease ~d particularly to death f~'o-a eor~nu~I heart disease. The convergence of autopsy da~a and experimental data presented in ~hls and previous reports suggests tha~ cdgaret~e smoklng promotes atheroselerosls~ including thac of the coronary arteries. The results of phys~ologlcal research and the finding of diminished rlsk of CHD in those who have s~opped smoking indicate ~ha~ there is also a T~re imedla~e ~chanism operative° The mechanisms which mi~h~ be responsible for the promotion of myocardial infarction and fatal cardiac arrhy~hmias by cigarette smokin~ were ex- tensively reviewed in the 1968 Supplement (27)° gzlefly stated, nutrient supply ~o the myocardi~ in ~e~eral and, perhaps more impor~m~ly, to focal ischemic areas of ~he myocardim~ may be seriously compromised by a comblna- ~ion of effects caused by smoking, and the deprived myocardlum may become infarcted or develop an arrhy~hmia. These effects include diminution of ~j G~

blood flow through atheroscleroti= coronary vessels and dimiBution of available oxygen for tissue use resul£1ng from the binding of carbon monoxide to hemoglobin in the place of oxygen and possibly, although presently speculative, the poisoning of respiratory enzymes by hydrogen cyanide. Cigarette smoking has been shown to be an important risk factor in the development of ClID. It is important bo~h by itself amd in the pres- ence of other significant risk fa~tors. In combination with certain other risk factors~ the Joint effects appear to be even greater ~ha= those accounted for by these risk factors independently. EPIDEMIOLOGIC~L STUDIES Hammond, et al. (ll) have presented new data on mortality from C~D, stroke ~d nonsyphilltie aortle aneurysm among more ~han 800,000 ~n and women who were between the ages of 40 aad 79 in 19S9. The authors were attempting to evaluate the significance of mul~iple factors (s~x, age. diabetes, higil blood pressure, body weight, change in weight, exercise1 cigarette smokisg, sleep a~d nervous tension) in the variations in death rates from Khese three diseases. It should he noted ~hat this informa- tion consls~ed of self-reports obtalned by ques~ior~naire and were not obKained from medical exami~atlon. Causes of death were based on death e~rKificate reports. As illustraKed in table i, coronary hear= disease death rates ~d ~or=ali~y ratios increased wiKh increased cigarette smoking for men in all

Table 1.-- ,e ~h rates and mortality ratios for coronary heart disease and stroke, by a~ount of cigarette smokins~ sex~ and a{~e Sex an~l age Males 40-49 years 50-59 60-69 70-79 Females 40-49 years 50-59 60-69 70-79 Males 40-49 years 50-59 60-69 70-79 Females k0-49 years 50-59 60-69 " 70-79 ~ever ~ Dk~d Corona~y hcart disease _ Re~"glarg]~ smoked cigarettes_ c J g~rettes 67 263 711 1,720 13 59 268 979 Number s~oked d ~il : Deat~ Z09 176 256 375 409 548 616 718 961 1,184 1,241 1,166 1,970 2,43l 2,573 2,5~8 17 27 47 43 68 140 158 220 279i 479 558 542 740 963 .,243 Mortalii 1.63 2.63 3.82 5.60 1.561 2.o8 2.34 2.73 1.351 1.67 1.75 1.64 1.15 I.~i 1.50 1.48 1.31 2,08 3.62 3.31 1.15 2.37 2.68 3.73 1.04 1.79 2.08 2.02 0.76 0.98 1.27 ~eYer smoked Sex and age cigarettes FemaLes 40-49 years 50-59 60-69 70-79 Ratios I/ 1.00 1.O0 1.00 1,OO lO 27 llO 487 1.O0 1.00 1.00 1,00 Stroke ~e~ularly smoked eisarettes Number smoked or /aor~ 1.00 1.00 1.00 1.00 Females 40-49 years 50-59 60-69 70-79 i/ The mort&lity ratio is the observed rate divided by the expected rate. SOURCE: Ha~aond, E. C., et al. (ii). 57 95 5.70 3.52 IIII

age groups and for womeu under the age of 70. Although the mortality ~atlos were hlgILer in the yo~g~ age group61 the differences in death rates b~tween nonsmokers and heavy smokers became progressively higher with Inc~easing ag~° Although C~D rates we~ higher for thos~ who were I0 pea- cent or more above the average weight for their height-age-sex g~oup~ and for those who reported gavlng hlgh blood pressure, the trend is clear that the effect of smoklng persists and Is appreciable, even when these other ~actors are held constant (table 2). ~a~ondj et al. also s~udled CHD mortality ~mong men who were ex- Bmokers of c±garett~. The de~th rates f~om CHD wer~ lower a~ong the e~- smokers than among those still smoking at ~he beglnu£ng of the study, the size of the dlfferenc~ being larger the longer they had been off smoking (table 3). Some people s~op smoking because of illness or symptoms and ~hese people would be expected ~o have high¢~ ~-ath ~a~es t~an those who stop for o~r reasons. E~rly deaths among ~hos~ with pre-existing disease may account, at leas~ ~n par~, for the high death r~tes from C~ a~ong ex~s~okers ~ th~ ~ly years of abstention° Mortality ratios fo~ stroke w~re higher among ~igar~t~ smo~r~ w±~h the exception of those over 70 years of age. Male ex-c£garette smokers had m~rtality ra~ios ~or stroke approximately equal to those of non- G~

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T~ble 3.--Observed and expected number of deaths and mortality ratios for ex-eigarette smokers with history of s~oking only cigarettes, by number of years sluee last cigarette smoking and for current cl~are~ s~okers~ coron~ heart dlse~se and stroke; compared to persons who never smoked regularly, in men ~ged h0-79 ___TY~ of smoker Ex-sigaz~t 5e smokers (Fonu<r smokers of 1-19 cigalettes a day): Stoppe~l: Less than 1 year 1-4 years 5-9 i0-19 " 20 or more years Total Curre~ cigsmette smokers Never smoked regularly Ex-cigarette smokers (Former smokers of 20 or more c~garettes a day): Stopped: Less than 1 year i-~ years 5-9 i0-19 " RO or more years Total Current cigarette smokers Never ~moked regularly Coron~z heart disease Observed 29 57 55 52 70 263 1,o63 1,841 Expected Ratio 17.9 1.62 46.6 1.22 h].7 1.26 5~.i 0.96 64.7 1.08 226.9 ±.16 559.5 1.90 1,8~i.0 l.OO 38.6 1.61 i01,9 1.51 116.5 1.16 106.1 1.25 76.~ 1.05 ~39.7 1.28 1,104.7 2.55 1,841.0 1.00 StrOke ~ected 57 56.9 2O7 134.5 501 501.0 9h lOl.l 440 234.7 501 5Ol.O SOURCE: Hammond, E. C., et al. (ii). 62 154 135 133 80 564 2,822 1,841 Observed Ratio / 1.00 1.5h l .O0 0.93 1.87 1.00 I !

( A clear increase in mortality from nonsyphilltlc aortic aneurysms with increasing cigarette smoking among men aged 50-69 is seen in table 4. The mortality ratio for heavy smokers was 8.00. Table 4.--Aortic aueurysm death rates and mortality ratios for m~n aged 50-69, clasaified by cigarette smoking habits [Rates per 1,000 population] Never smoked Measure regularly Death rate 13 Mortality ratio 1.00 2.62 Current smokers, by daily cigarette consumption 1-9 i0-19 20-39 40 or ~re 34 50 59 104 3.85 4.54 g.O0 SOURCE: Hammond~ E. C., et al. (ii). Han~mond, et al. 8tare: "Death ra~es from the three diseases varied consideraSly with rela- Give weight, amount of exercise, amount of cigarette smoking and hours of sleep per night, guhjects who were obese~ took little or ~o exercise, smoked many cigarettes a day or slept nine or more hours per night had high death rates. Those wi~h a combination of th~se factors have espe- cially high death rates from the three disease6." "Death rates from C~D and stroke were l~er in ex-cigere~ smokers than in men wi~o were currently smoking cigarettes at the ~ime ~hey ~n- rolled in the study. ~ne death rates of male ex-cigerette smokers who had not smoked for ten to ~wen~y years were no higher or only slightly higher the% the deaLh rates of men who had never smoked reKularly." ~J

"~eath ra~es fro~ the three diseases were ~ni~l ~ng 8uhJmcts without a history of diabetes or high blood pressure who were not obese, took at least moderate exercise, never smoked regularly and slept 6 to 8 hours per night. Nevertheless, these sub~cUS had substantial death rates from CHD, stroke and non-syphilitic aortic aneurysm." Stamler (24) has ~nalyzed lO-year mortality data on a total cohort of men~ aged 40-59 in 195g, who were employees of the Chicago Peoples Gas Light end Coke Company. Of 1,465 men examlned, 1,325 were found initially to be free of definite ~[D and have been followed without systematic intervention, lii~ler overall death rates were found among the smokers in the study. Table 5 shows the death rates from CHD and from all causes for men with various risk factors. Recent papers by Theme, et el. (25) and by Paffenbarger, et el. (19) report further results of studies of CHD amour former college students. College health records and o~her college records were reviewed to as- cerCaln the presence or absence of factors ~der consideration, gases were identified from death certlffcates in the study of fa=el CdD (19) and from ques~ionnalres and physical examinations in ~he s~udy of non- fatal C~D (25). Matched controls were obtalned for each case. lal both ~onfatal a~d fatal C~{D, slg~Ifican=ly more smokers were found among the Cases ~k~ among the £on~rols. Combinations of risk factors restti~ed IR greater CHD morbidity and mortality ratios thK~ did single factors. 3~

Tab], 5.--Ten-year morbality rates for sudden death, earona.~y hesmt disesse, stroke, cardiovascular-renal, and all c~use~ co~bJ~i~d a~ng men aL~d ~5--59, classified aec~rdlng to cigarette s~oking~ cholesterol and blood p2essure [Peoples Gas Light Company Study, 1958-1968. Men originally f~'cc of coronary heart disease ~d followed witkout systematic intervention.] 1958 risk factor status - cigarette si~[:ing (10 or more a day), hypercholest~role~nia, ~per~ension i/ No risk factor Rypercholesterolemia or hyper- tension only - one factor Cigarette smoking only (i0 or more a day) - one factor N~ercholestc~olemia and hyper- tension only- two factors Cigarette s~] iDg (iQ or more a day) and hy~ercholeaterolemla or cigaz~tte smoking and hyper- tension - t~o factors Cigarette smoking (10 or more a day), hypercholesterolemia, hypert~nalon - all three • Total N~her of ~e~ in cohort 28h • 216 4O5 6o 293 67 31,325 Suddet, death All CHL _ St roae ] All CVR~:i causes ............................. ] I ~umber Number of Death of deaths rate 2/ deaths 0 0.0 i h 19.6 13 4 i0.0 15 1 9.9 3 Number Nmr~ber Ntmtber Death' of D~ath I of Death I of rate deaths rate I deaths i"ate ~ des,t~h~ -- 3.0 2 5.9 I ~ 11,9 I 13 53.1 6 19.51 19 72.6 I 27 37.i 5 11.81 20 48.9 I hh 29.6 1 40.7 I t~ i 70.3 I 8 ll 2 22 17 25.1 6 16.2 ! 55 57.1 6 19.9 I 26 76.0 2 25,~1 8 39.2 22 lh,9 I 81 86.4 I 53 ioi.5 1 17 I ---- 56.6 I 162 ~/ Risk factors include: Ser~n cholesterol 250 or more mg,/dl. ; diastolic blood pressu~,e 90 or more ram. Hg~ l0 or more cigarettes/d~y. 2/ All rates are nge-adjusted by 5-year age groups to the U.S. m~le population, 1960. All rates per thoUSand, 3/ Smoking data were not obtained for ~ of the 1,329 men. SOURCE: Stamler, J. (2~). b~ath rate 101.5 107.7 121.9 169.9 225.~ if3.1

Table 6.--Estimated corollary heart disease death ratios in a 17-51 year follow-up among former college students, classified according to combiued presence {+) or absence (-) of e~ch of three specified risk factors, aud by age Zigarettes i0 or + + + Risk factor Systolic BP 130 or more ~m. Hg ÷ ÷ ÷ ÷ Ponderal Index less than 12.9 + + + ÷ Age (years) at death from coronary heart disease Total 30-69 years 4.3 1.8 1.9 1.7 1°3 1.1 1.0 3o-',4 years 1(1.9) 2.3 2.9 e.9 2.2 1.2 1.4 1.0 45-5~ ye~rs 5.7 1.6 1.6 1.9 1.2 1.O 55-69 ~rears l(h.8) 1(2.0) 5.6 1.8 1.3 0.8 1.0 l_/ N~mbers in parentheses indicate el@coted number coronary hesrt disesse decedents less th82/ 5. SOURCE: Paffenbarger, R. S., et sl. (19). II

.J Sys. BP 1304~mn. NE.-A Height < 68 in.-B A- A+ A- A+ A- A+ A- A+ B- B- g+ B+ B- B- g+ B+ PRESENCE (+) OR ABSENCE (-) OF FACTORS (A or B) Nun~bers in bars are age- and interval-adjusted attack fanes af nonfatal CHD from college case-taking to 1962. Figure i. --Morbidity ratios of coronary heart disease for paired combinations of factors in college. SOUKCE: Thorne, M.C., et al. (25). ll 3 2 1 0 4 3 2 i O 3

Figure i shows the morbidity ratios for combinations of pairs of risk factors in nonfatal CI[D and table 6 shows mortality ratios for combina- tions of risk factors in fatal ChDo in a study of participants in the Health Insurance Plan of New York~ Weinblatt, et al. (29) reported that cigarette smoking males who developed angina pectaris ware ~re llkely to develop Infarction than were D~n- s~oklng anginal patients, but there wez~ no~ enough ¢as~s ~o draw deflnite co~cluslo~s. Welnhla~t~ et el. ~(30) also reported that the prognosis after the de- velopment of a ~jocardial infarctlon appears to he independent of smoking 6ta~us prior to the infarct. In the absence of data indicating which patlents stop smoking and how ~topplmg smoking is related to the s~verity of myocardial dam~ge~ ome c~u%no~ evaluate the effect of smoking o~ progno- sis. If th~ p~rsons who stop smoking tend to Includ~ ~he ~st debilitated~ the ~ffe~t of ~ontlnued smoking on prognosis would be %mderesti~ted. In a prospective study of over 3,000 men, Jenkins, et el. (14) re- ported tha~ ~he incidence of CIID in m~n aged 39-49 was 3 ~im~s hlgher emong the cigarette smokers than among the nonsmokers (table 7}. The incidence o£ CI~ increased with increased daily clgarette consumption. For men aged ~0-59, the relationship between clgaretth smoking and CHD was ~ound bo be si~ifican~ only for th~ heavy smokers (~able 8). Former clgare~e stokers also had signlflca~y hlgh~r CIED incld~nc~ ~he~, hu~

Table 7.-.Am~u~ incidence razes of coron~_~ heart disease for men 39-h9 yearz Of age, classif~ed by s~$king histo~J and by ~rent p~ctiee~ a~ to cigarette s~oking [Age as of the beg~£n~ of the ~ i/2 year period of ob~e~ation] Morbidity status : T°~l subjects lio. ~a~,elJ ~ota/ nmuber at risk 2.258 ~o~al number C/D eases 63 6.2 Lll myocardial in,arc=ion 52 5.1 S~p~matic 3B 3-7 Unreeo~£~d lh 1.4 Fatal 9 o.9 aglna pectorls only ii i.i I_[ A%uu~l rate per 1,00O men at risk. Smokln~ Pipe & ~ever cigar smoked only NO • Rate NO. R~ze 5~0 ~0~ 7 22.9 3 1,6 1.7 3 1.6 i 0,~ 2 l.l 3 1.2 i 0.~ 0 D.O 0 0.0 3 1.2 0 0.0 C~rrent Former Current Nona ~ cl~arett~ ~. Rate I~o, lt~=e NO, R~;~ 2~9 - 1,07~ - 1,191 i0 ~.3 43 B8.9 20 23.7 i0 9-3 35 7.2 17 3.1 8 7.h 2y 5.6 ii 2.0 2 1.9 O L7 6 i*i 1 0.9 8 1.7 1 0.2 O 0.0 8 1.7 3 0.6 Th~se 6istrib~tions of cases for vsrious smokin~ categories are si~nifi~sntly different from chance at P=0.001. i~arctte smOkin~ by nu=be~ >ur d%y 1-15 16-25 ~6 or more N~. R~t¢ NO• Rate ~o• ~a~ 211 ~3~ ~2~ 5 5.3 18 ~.2 20 ~i0.~ a.2 z3 6.7 18 9.~ L.2 Zl 5.6 I~ 6.2 0 0.0 ~ 1.0 6 3.1 0 0.0 5 2.6 3 i.~ z z.o 5 2.6 ~ 17% ~/ Difference in CHD ~requency between :hls grou~ 8rod ~hese who never smoked clgaret~es (cold.us i & 2 combined) is si~iflcant at p=0,01 b~ ~ s%u~re test corrected for co.inulin. D~f£erene~ im CK~ tre~ncy be~wee~ ~hls ~oup an~ ¢ur:e~ noneig, aret~e smokers ~s sIE~ifiean~ ~ P=-0.01. SOL~CE: J~kin~. C. D.. et ~I. (i~).

~800178BG ~'~ [aT L'~ 16T ~,~ ~ :~-~1~ [:-~,~ 9 ~ 6T: E*:~ 19T ~*~C 19 !;9: - !L?: I - I~o: o% OT ~*gT :: 9": IT :'9 I~ O'IT 19 L'E I: E'~I }:?T h~uo s~o~o~cl ~;u::SuV v i 0"0 9 6"~ g'L 0 "T':-~ 5 - .'~T .rglA~g I'*l ILT ~*~T 101 o~s~ ~ ~ Tr~o~

no data are given on ien&~h of time since stopping smoklng, or r~esons for stopping. Pipe and cigar smokers did not have higher CHD incidence rates. After controlling for ether risk factors such as lipid levels, diastolic blood pressure and body build, the authors found that the association be- tween cigarette smoking and CHD remained (tables 9~iO). The relationship between smoking and CHD was stronger among those men who e~hiblted behavior type A ~han ~hose exhibiting b~lavior type B (Cables II,12). Behavior type A is characterized by e~hanced competitiveness, drive~ aggresslve~ess~ hos- tility aa%d all exeesslve sense of tim= urgency. Behavior type B indicates absence of these charaeterlstles. Analysis of the data On behavlor ~d c£garetce smoking showed that both factors have effects on the £~D ra~e. Again, these assoela~ions were s~ronger in ~he younger age group. Epidemlological studies linking smoking and CHD have been carried o~t in various countries. In a Eetrospective study in D~blln, of 400 patients u~der the age of 65 who experienced myocardial infarction, Mulcahy, et el. (ig) ¢*bserved a defi~te assoclaKion between smohinB ~d the development of the disease. A prospective epidem±ologlcal study of risk factors of (~D, i~ a~ Israeli population, indicates tha~ smoking is associated wl~h a higher risk of CIID (17). i5 &n ~j

% Table 9.--Annual incidence r&tes of new eorouary heart disease by smoking habits adjusted for age and seriatim for specified other risk f~etors [Rates are annual incidence per 1,000 m~n, aged 39 to h9 years at entry into study] S~elfled c~hez. risk factors Cholesterol Beta/alpha ratio Lipalbumin • Systolic BP Diastoli~ ~P Fondersl index Pl~sical activity ~oun~ of exercise ~ncome lev~l All of the above Trislyeerides smoked 33 31 31 ~9 29 29 ~9 29 ~6 ror~er clgaret~e smokers 93 91 95 91 91 93 91 91 93 88 Pipe & cigar only 22 18 18 18 ~6 16 18 18 18 2O 20 D~ilv 1-3.5 49 51 h9 a9 bp ~7 h9 h9 51 ~o igarette eons~m t~on - 89 zo0 91 io~ 89 io2 95 io0 99 io4 95 107 93 104 93 lOg 93 1o4 89 98 80 104 p lJ o.oo5 o.ooi 0.002 o.o01 o.ooi o.ool 0.001 0.001 0.001 0.007 0.002 ,.--,% ~/ Level of significance of F-ratio for analysis of coy&fiance. SOURCE: Jenkins, C. D., et el. (lh).

Table lO.--Annu-~l Incidence: r&tes of new coronary heart disease by smoki~g habits adjusted for age and serlati= for ~pecified other risk factors [Bates are annual incidence per i~000 men, age~ 50 to 59 years at entry into study] Specified other risk factors Cholesterol Beta/elpha rstio Lipalbumin Systolic BP Diastolic ~P Ponderab in&ex Physical activity Amount of exercise Income level All of the above Triglycerides smoked 115 lO7 109 i18 lO9 107 ]a3 ll3 ll3 113 ll3 rorme~ cigarette smokers lh2 lh2 lh0 12[ 127 131 ih2 144 138 ll8 i~7 Pipe & ei~aron]~v 153 lhh 151 lhh 135 140 149 151 lh7 138 lh4 l_/ Level of significance of F-ratio for aualysis of covarianee. SOURCE: Jenkins, C. D., et ah (lh). !-15 ~!&r - ~--~5 --L &ret be consum_~tio~ ll5 211 264 120 213 262 122 218 262 129 211 266 127 220 273 122 222 269 ii~ 213 2h9 i18 211 255 i20 220 258 140 213 258 80 195 260 o.z54 o,127 0.135 0,136 0.066 O,08h 0.2!6 0.203 0.156 o.158 0.121

Table ll.--Incidence of new coronary heart disease by smoking category and behmviol type for men, ~ged 39-49 [Rates are age-adjusted ann~al incidence per l~00O men] Behavior Never type smoked Rates I Cases A 5.31 5 B 1.31 2 Total 2.9 I 7 SOURCE : ~urrent Former and former cigarette pipe ~ud smokers cisar only Rates ICPASe~ I R~tes ICases 13.8 I 7 1 1.3 I 1 5.1 L B e.a I e 9.1 I i0 1.8 i 3 Jenkins, ~. D., et sl. (14). Daily cigarette consumption 1-1 -[5 26 o; m__ora__ Rates Cascs ~ Cases_. Rates cases I 1.6 1 I 15.8 15 14.9 16 7.3 4 3.1 3 h.9 h.9 5 9.3 18 10.4 No Total 9.3 I ~5 3.3 18 6.2 63

Table 12.--Incidence of new coronary heart disease by smoking category and behavior type for men, aged 50-~9 [R~es are age-ad3usted armual ineidenee per 1,000 men] Behavior Never type smok_~d A 12.4 I 5 N 1o.o I 4 Tots2. ii.i ] 9 SO[mCE : Current Former aud former cigarette pipe and smokers ci~ only R~tes C ases~ Dates C,~ses 18.6 8 21.8 8 5.1 l 8.4 3 14.2 9 i~.9 ii Jenkins, C. D., et al. (14). Daily cigarette consumption 1-15 16-25 i 26 or more 16.4 5 21.5 9 30.0 14 4.7 1 21.1 7 19.1 5 11.5 6 21.3 16 26.0 19 Total 20.4 I 49 12.0 ] 21 16.8 { 70 ,% e.•

In a retrosi~ctive study of 503 male p~tient~ with myocardlal ia1~arct ~n~ Ti4 ~i~iE~b~hed controJ~ in I~ulli¢~ ~chi~tmi~r~ et ~]~. (22) repor~ that cigarette ~molii~ play~ ~n ~igni~i~ant role ~s ~ ~rIsk factor. A rec~nt ~ap~r by Cederlof~ et al. (5) employs the t~in-study method o~ a l~o[~±~±on of ~nn~rica~ tw~1 ~si~g a similar ap~r£oach to t~at ~- v~oilsly employed in a ~wcdlsh twin population, The purpose is to compare the c~ntr~bution of genetic and enviro~tal inf~ue~ce~ to ~h~ d~velop- m~1~t of ~i~g~n~ pec~o~is~ The authors imp±y tha5 their study i~dica~ a ~Io~ iin~o~a~ role ~©r g~etic ~c~ors th~ for smoki~. Ho~ver~ this ~tudy can be criticized on se~al grounds. T~e authcrs based ~h~ir d~te<~ion of a~i~a ~ctoris on th~ r~sults of a self-am~i~iat~r~d cardiac origin~ ~viou~ studi~ i~ $-~±sh t~ns hav~ ~how~l a ~o~ rate by q~estionnai~. No data are available on the health and smoking habits of 58 p~rcent of tn~ original group o~ the 4± percent of ~he %±iglble t~il ~ir~'r l~no ~r~ ~on~nd~t~. Th~ ~thor~r d~fi~i~io~ Of a present ~io~er i~ic~d~s l~rsons who have stopped s~okin~ clg~rett~ for ul~ to ~ y~ars and thus includea person~ who i~ other studies have been cl~L~Ifi~d a~ ex-~[~1~ers. Th±~ d~fi~itJ.o~ o~ ~ ~igar~t~e s~ok~r ~i~t cont~iS~t~ to a~ ~restlmation of th~ i~d±ate ~ct of c~r~t i~c~uded in the saln~ card,gory a~ cu~r~n~ cigarette smokars. Th~ r~latio~hip b~t~e~ ciga~(~ttc ~iokin~ a~id ~h~ dev~lopm~iit of ai~g~n~ pe~tor~s ha!! not been clarified. IIowev~r~ Arono~,', et ah (i) have 2O

~hown tha~ smoking one cigareK=e before exercising reduces Khe energy expenditure req,~ired for patlen~s with classical angina pecteris to de- velop ehes~ pain while exercising on a bicycle ergemeter. ATHEROSCLEROSIS A revlaw of autopsy studies by Strong and Auerbach, suggesting thac cigarette smoking has a chronic effect leading to advanced degrees of atherogenesis~ was presented in ~he Health Consequences of $~oklng~ 1967 (26). Further studies have recently been published in this area. Sackett~ e£ el. (21) have demonstrated a clear dose-relationship he~waen cigarette smoking and ~he severity of aortic atherosclerosds at autopsy. Their study of I~019 consecutive au~opslesj on patients who had been interviewed about ~leir smoking habits prior to their de&th, sh~ed a signlfic~gnt incresse in ~he severity of aortic atheresclerosis with In- creasing use of ~Igaret~es, measured both by intensity and by duration of smoking. An autopsy s~udy f~om Russia by AvEandilov, at el. (3) demonstrated a significantly greater degree of a~herosclerosls in uhe coronary artaries of smohers ~%an in Those of nonsmokers. Vlel~ et el. (28) have reported on the severity of coronary atherosclerosls at autopsy of 1,150 men and 290 women who died violent deaths in Chile. Infozma~ion on smoking habits was available on 566 man. ~he a~hozs repor~ no ~elati0nship between athezos~lerotic lesions and the 21

C usa of tobacco. Th~ deBr~e of ath~ro$clerosls was axpressed as the psr- centage of the surface of the intlma of ~he left anterior descending~ coronary ar~e~ covQred by fa~y 8~reaks and ~ibrous plaq~s. An examina- tion of the data presented in gra~h£c form ind±catas tha~ the modera~ and heavy smokers appear ~o show consistently higher percentages of diBea~ed are~ th~n the nonsmokers. But, Eh~ statement of the authors Implles that these dlfferences were not statlstlcally slgnlf~can~ when Rubjected to an analysis of variance. A study by Astrup was r~vlew~d in ~he 1968 Repor~ (27). Th~s s~udy showed that in rabb~.~s on a h£gh ¢h~las~erol ~i~ chronic carbo~ m~noxide ~xpasure has a marked a~h~rog~nic effect° K~eldsen, et al. (15) compared the vascular pathology in rabbits fed high chol~s~rol die~ and maln~alned in an hypoxic a~m~sph~re (I0 per- cent ~x~gen) wi~h tha~ ~n rabblts expused only ~o ~he high cholesterol d~et. Th~ authors demonstrated ~ha~ hypoxla leads ~o an increase in =h~ degree o£ plaqu~ formation in ~he ~oronary ar~erles and in the amount of visible ~ortic a~eroma~o~i.~, as well as to a~ increa~ in ~h~ aor~i~ Cont~n~ of cholester~l and trlglycar£de~. I~ addition, th~ hearts of ~ha hypo~/c ,~n~mal~ 8how~d ma~k~d per~vascular xanthomatosi~ often in~il~rati~ ~e surrounding ~o~a~di~. In s~marlzin~ ~hls exper£men~ and their prev£ous fi1~i~g~ of increased atheromatos~s in hyper~holesterolemic rabbi~s 22 G~

subjected to high carbo~h~mo&lobin (CO~) levels, the authors (2) state ~ac ~iss'~ hypo~i~ seems to be an important factor in initlating ~es~ lesions, regardless of the m~ner in which the hypoxia is produced. Al- though ~e CO~b !evels in the r~bi~s and the d~r~e of hypo~a were much hi~er ~ thet e~p~rienced hy h~an s~kersj these res~s s~gest a mechanism by which s~oking migh~ con~ribu~e ~o a~herosc~osis. H~ss, e~ al° (12), e~t~ndin~ studi~ reviewed i~ ~ 196~ ~po~t (27), have demonstrated ~hat the administr~tlon of in~ec~io~ of nicotine ~o hyperchol~s~eroi~c rabbi~s who are also ~iven vi~a~ D~ e~a~c~s th~ peripheral atheromatous nalcific arterial disease which is produced by the co~bina~ion of hypercholester~iemla and vitamin D adminls~racion. The addi£ion of nico~i~ ~o ~he regi~ also resul~ed in ~he frequen~ occurrence of ~hromboarter~t~s in the dls~al calcified arteries of cardiac and skeletal ~uscle~ and of the smooth muscle of the gas£rointestlnal tre~t. ~ ni~otlne ef~c~ was reproduced by substituting appropriate dosages o~ adr~nali~ for nicotine and abolished by adrenalectomy. Leil~u~h, e~ ~i. (16) have reported Chat the adminls~ration of a mono-~mine o~±d~se (~O) i~ibi~or to rabbits on a regimen of daily nicotlne injections significa~ly redu=ed the number of animals who devei- oped fibrotlc lesions of the aorta in resp~e to nicotine° Further work i~ in pro~ess to ~clda~e the ~ch~s~ of ~h~ ~o affect. 23 G~

< Evidence p=esented in this ~md prevlotm reports suggests that clga- rett~ s~king promotes a~he~osclerosls. THRO~US FORMATI~N baND BLOOD FLOW Hess, et al, (13) discovered aBgregations of platelets, erythrocytes, fibrin, detached epithelial cells and so~e as yet unidentified cells on the aortic and carotid walls of rabbits subjected to cigarette smoke, The discovery of a plasma factor wbich increases the in vitro synthe- sis of flbrinogen by ht~na~ liver biopsies has been reported by Pilgeram, et el. (20) in older patients who have recovered from myocardial infarc- tion. This factor has been tentatively identified as free fatty acid (FFA). The authors sta=~ that the association between FFA and flbrinogen synthesis may provide the link between hyperlipemla ~d clotting. Ciga- =ett~ smokimg causes an increase in FFA through its stlmulatlon of eat echolamine release. Several recent studie~ have begun to elucidate the role which changes in blood viscosity and certain features of the mlerocirculation might play in the development of atherosclerosls and coronary hear~ disease. Dint~nfass (7) has suggested tha~ myocardial infarction and coronary thron'bosis may be the result of a number of factors, separate or inter- related, all leading to a high viscosity of the blood. These factors may affect the migration and adheslon of pla~elets, the volume of plasma, and 24

~he rigidity of the red blood cell. Phenomena leading to high hlood viscosity may Occur in foca~ arabs leading to occlusion of small vessels~ resul~aat Isehemla, a~d an iufarctlon of either subcliuical or catastrophlc proportimn~, depending on the ioca~iou and n~ber of vessels involved. Din~eafass also believes that an increase in blood v~o~i~y p~eced~ the cllnlc~l manifestations of the high blood viscosity syndroma and that the increasad blood viscosity seen in post myocardial infarc~ patients is a reflection of tha etiology rather ~han the affect of the disease. Local hypo~la leading to an increase in the rigidity of the blood cell might he produced by cigarette smoking through ~i~ iucrease in COHb. Fla~elet adhesiveness is inczeased by smoking, probably secondary ~o ~he releas~ of ¢atecholamiaes (27). In a etudy of 50 white males wi~h myocardial infarcts and 40 controls, gtahl~s, e~ al. (23) found that the patlen~s with myoeardlsl Infarc~ had a ~e~n hematocri~ level sigr.iflcantly higher than tha~ of ~h~ con~rois. S~udie~ of blood volume indicated ~ha~ a reductlon in plasma volume ra~her than an increase in red c~ll mass among the myocardial infarct patients accow~ed fo~ the elevated hema~ocrlt. Seve~ai~evlews of the pathophyslology of ~xl~osu~ to carho~ms~o%- ide <CO) have appeared rec~n~ly. These are p~r~i~e~ ~o ~he dis~slon of 25 uD ~0

the rel~tionshlp of s~>king to health, since clg~retto smoke contains amounts of CO sufficient to cause a COdb level of 5-10 percent in the smoker, d~pending on the amount smoked and degree of inhalation (9, I0}. Bartlett (4) has pointed out that because the absorption of CO from ~he ambient environment is dependent upo~ the concentration of CO in the e~vi~onm~n~ as Contrasted Co tha~ in the ~lood, smokers wlth a COBb level of 5 percent will n~t absorb CO from inspired ~ir unless the ¢o~ce~ratlon of CO in the air exceeds 30 p~rts per million. ~0wever, he als~ sta~es that because the excretion of CO bet~eeu clgarettes will be lower In CO polluted alr, the smoker will have a higher long-term average COBb level in a polluted envlronm~nt. Patients with heart disease may be particularly susc~ptlhle ~o ~ hypoxlc burden ~aused by the p~sen~e of COHb. Coldsmith~ et al. (i0) have s~ata~ tha~ for ~he U.$. urbaa population, eiK~rette smoking ~s probably the most important cause of in~reased COBb above the en4osenous level prodaced by heine catabolism, followe4 by auto- ~ohlle exhaust, occupatlonal so~rces, an~ home heating and cookln~ devices in that order. Although Dinman [6) minimizes the importance of ~he effec~ of CO levels of 5-10 percent on the myocardlu~, h~ states that a shortcoming in his approa~1 is that focal areas of myocardial ischemla are not reflected in th~ determin~tlon of oxygen saturation ~ade from samples of blood taken 26 G~

from the coronary sinus. Such areas of isehemla might be importer In Ini- tiating fatal arrhythmlas. Levels of C0~hwhichdecrease further the oxy- gen supply to the Ischem~e myocardlum might he readily provided hy clga- re~e 6mohlng. Ello~, et el. (8) have reported effects of cigar~ s;~oking on =he o~-gen affinity of he~globln independent of ~h~ presence of CO. ~nelr results sugges~ that cigarette smoking inay have both acuEe and chronic effects on Oxygen affinity which differ i~ dlrec=len, Th~ authors cautlon, however, that th~ in vlvo oxyge~ a~fi~i~y of he~globln ~y he different =hen the sKa=ic equilibrium data imply, Further research is in progress. CITED REFERhq~CES (i) ARON~, W. S., KAPLAN~ M. A.j JACOB, D. Tobacco: A precipitating fae~or in angina pectoris, Annals of Internal Medicine 69(3): 529-536, Septer~er 1968, (2) AST[~5~, P.~ K~ELDS~, K., W~NS%~AI~, J. Enhancing infl~enee of car- bon reonoxlde on ~he develop~n~ of athero~o~is ~n Cholesterol- fed r~bbi~s. Journal of Atheroselerosis ~asearch 7:343-354, 1967. (3) AVTANDILOV, G. G., KOLENOVA, V. i., PONOI~m~RE~KO, O~ V. Kureniye t~baka I stepen' aterosklero=leheakogo pora~eniya koronarnykh arterly serdtsa i aor=y. (Tobacco smoking and ~he degree of atherosclerotic lesions of coronary arteries of =he heart and aorta.) Kardlologiya 5(i):30-3&, January-February 1965. (4) B~ETT, D., J~. Pa=hophysdo!~i2~ of e~sure =o low co~car~z~- ti~s of carbon mo~oxlde. Archives of ~viron~ntal ~ealKh 16(5):~19-727, l~my 196g* 27 ~0

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$58. ZUSSMAN~ B. M. Atopic symptoms caused by tobacco hyperse~sltlvi=y. Southern Medical Journal 61(11):1175-1179, November 1968. 37

SMOKING AND CHRONIC OHSTRUCTIVE BRON6~OPU~MONARY DISEASE SU~42~%Y Addltional evldence which supports the previous judgment of a cause and effect relationship between cigarette smoking and chronic obstructive bronchopul~mnary~ diseases, especlally chronic obstructive bronchltlsp ¢ontluues to accumulate from bo~h the UnILed States and abroad. ~ew work has bee*~ published in che pas~ year which provldes additional information on the possible mechanis~ by which clgarette smoking can lead to the pro- ductlon of pulmonary ~mphysema. These ~echanlsms include coilaps~ of small alz-~ays~ changes in pulmonary s~rfacteal~ impairment of pulmonary.clearance, dlscuption of the norm~l archltecture of the bronchial epithelium and obstruction of capillaries of che bronchi and alveoll. A~ present, there is no ~-~ified hypothesis for the pathogenesls of pulmonary e~physema~ how- ever~ the patho~enetic mechanisms may involve more ~han one component of lung ~issue. Epidemloleglcal and laboratory evldence supports the view tha~ C~are.tLe smokin~ c~ contribute to the development of pulmonary emphysema in man. CNP.ONIC BROnChITIS Cigarette smo~i~ is ~he most importan~ cause Of chronic bronchitis. In the past year, studies from various coun~rles have appeared ~n the li~ratur~ reconfirming this assocla~ion° In studies of populations of workii~g ~en in Italy (15), che Netherlands (6), England (16,35) and the United S~ates (9), s~kers were found to have a s±gni£1can~ increase i~ either i~cidence or prevalence of chronic ~ro~ch~is as compared ~o ~h~ -4

a nonsmokers, gtudies of populations from rural and urban Sweden (31) and rural Australia (25) produced similar findings. A south Afrlcan study (45) demonstrated decreased forced explratory volumes (FEVI) and peak expiratory flow rates (PEFR) with increased tobacco oons~ptlon, even in those who did not have chronic bronchitis. PREVALENCE OF CHRONIC 0haT.ClIVE BRO~CHOPULMONAbY DISEASE The prevalence of chronic obstructive bronchopulmonary disease is p~ohahly underestlma~ed. I~ a study of death certificates, Moriyama, et a]. (39) have reported ~hat chronic obstructive bronchopulmo~ary dis ease is often o~llt=ed as a contributing cause of death. Mitchell, etal. (38) also found that the disease often goes unreported. Barsch. etal. (5) maintain that much of ~he reported increase in the prevalence of chronic obstructive bronchopulmonary disease can be accounted for by he%ter diagnosis. ~owever~ Bar.oh, etal. base their statement On the supposltlo~ that the rising death rates from ¢~,ronlc obstructive hron- dlopulmonary disease are incompatible with the fact that ma~y people are giving up smoking. However, it should be pointed out that ehronge obs~ruc=ive bronchop~imonary disease associated with cigarette smok- in, may be ~ result of many years of exposure ~o elgarette smoke and the mortality rates from hronchitls and emphysema would not reflect large-scale smoking cessation for som~ time ~o come. Burrows (lO) has pointed ou~ tha~ ~he effects Of cessation of smokisg on the course of -j GO

already existi~p chronic obstructive bronchopulmsnary disease may be difficul~ ~o assess, since it may be that those who are dfsab!ed by sever~ disease £end to s~op s~king mor~ often than those who have milder forms of ~ disease. The beneficial ef£ects of cessation of smaking could ~hus be r~sked. Many agents appear to contribute to ~he development of emphyse~, but epidemiolopical and experimental evidenc~ indicat~s that cigarette smoking is ~he mos~ important agent in the developmen~ of pulmonary emphyse~ in man. Mention of the theories of pa~ogenesis of pul~nary emphysema, long the s~bJec~ of debate among medical scie~tists (1,34~ ~6,47~8), may help to serve as background for ~he presentation of recent research on the role of cigarette smok~g in the development of emphysema. ~o major theories of the pathogenes~s of ~hronic obstructive pu1- ~ e~phy~e~a have been proposed. One theory sta~ that the primary lesion of e~physe~a is vascular ~nd involves obs~ruction either by thrombosis or by endarteritis of the pulmonary or bronchial arterial branches. The resultant loss of nutrient s~pply is thought to result in isehemic necrosis of ~he alveolar wall and septa. The other major ~h~ory s~a~s ~ha~ chronic ohst~etive pul~nary emphysema resu~s ~rom the direct effect of toxic inhalan~s on the pui~nary tissue, in ~he

areas of the termlnal bronchloles and alveoll, According to this theory. changes S~en in ~h~ pulmonary and bronchial vessels are secondary ~o the destruction of nonvascular tlssue. It ~ay well be ~hat the pathogenesls of pul~on~ry emphysema can involve several mechanls~s and that both cf ~ese the~rie~ ~ay be applicable but not ~utually exclusive (44). EEPE~I~NTAL STUDIES IN MAN Anderson. et al. (2) have reported ~rellminary results which indl- ca~e ~hat clgare~e ~moki~g causes acu~ changes in ~he v~n~ila~ion/ perfus~on r~l~tlonshlps of th~ l~g and that patients wi~ chronic ob- structive bronchopulmonary disease appear to be particularly llabl~ to these d~anges. In some pa~i~n~s the changes are predominantly in per- fusion, a finding which lends s~pport ~o the v~cular ~heory o~ pul- monary emphysema. I~ o~h~r pa~i~s~ ~he ch~ge~ are pre~orli~n~ly i~ ventilatlon~ a finding whlch lends support to ~e t~heory of ~he dlr~c~ ~£~ec~ of iwh~lan~s in the p~thogenesis of pulmonary emphysema. Anthoni~en, et al. (3) investigated pulmonary function in iO male smoke~s wi~h clinically ~id chronic bro~chitls, all of whom had smoked cigarettes for ~ l~a~ 20 yea~s. Besides ~he usual pulmonary fu~eti~ te~ts, th~s~ investigators employed ~ technique ~or the a~sessme~ of regional pulmonary function using r~o~ctive xenon. Despite ~he f~¢~ O0

that overall pulmonary function was nearly normal in several patients. all had decreased ven~ilatlon and depressed ventilation/perfuslon ratios in some itu~g reglo~s~ with the basal areas being those most commonly affected. IFn~ author suggested that significant dlse~se in ~he peripheral airways may exist in patients whose chronlc bron-~hltis is clinically mild and who show no present impalrment of ventllatory capacity. The radioactive x~non tes~ may reveal severe compromise of ~le overall gas exchange when usual studles of ventilatory capacity do not reveal impair- ~ant. These ~langes in the dlstal airways may become more significant d clini~ally as the patient ages, since aging has been shown to b~ asso- elated with a dlmun£~ion in the compliance of the lung (29). Peters, et al. (40) have reported that the lower flow rates found among college s~udents who ~moke, especially at lOWer lung volumes, may reflect disease in the small airways° The diminution in flow in these subjects was ap- proximately proportionate to ~he to~al llf~-~ime nu~e~ of ~igare~es s~oked. Fullmer, et al. (22,23,2~) have found a high prevalence of C~rschms~'s ~yp~ spirals in the sputum Of cigarette smokers. Th~ easily recognized spirals consls~ of insp~ssated mucus and are casts of the lumens of small bronchloles. These spirals were found in the sputum of 23 of 24 clgare~e-smoklng women and in 97 of lOg clgarette-smoklng men. The total n~er of splr~is on four slides prepared for microse~plc ex- -4 00

am~nation varied from 0-500. Six o£ ten =x-smokers had spirals in their sputt~n, but the nL~ber of spirals was reduced to a total of ten or less on four slldes. A nonsmokil%g control group exposed to cigarette smoke at work showed a low prevalence of spirals, While a Control group of ~on- smokers .~ot ~xpcsed to cigarette sm, oke at work showed no spirals in ~heir sputum. Ful!mer has suggested that Cnrschmann's spfrals may play a role im the development of emphysema by producing obstruction at the bro~- chiolar level. The spirals may also allow prolonged contact between admixed l~%alants including cigarette smoke and the bronchlolar walls. A stu4y of £h~ presence of spirals in =he sput~ Of a group of nsnsmoking as~|L~a~le bzo~chi~ics would 5e useful in an attemp~ to determine whether She prasence of splrsls is a dlre¢= result of exposure to cigare=te smoke, or is a charaetergstlc of the sputum of bronchi~ics~ whatever the cause of ~heir bronchitis. STUDIES IN ANIMALS Frasca, etal. (17.18) have reported on electron microscople oh- s~rva~lons of the bronchial epithelium of dogs exposed to cigarette smoke by active ir~halation =hrough a =racheostoma. The epithelium of a dog exposed to 44 days of smoking by methods previously described by Cahan, et el. (11) showed a prollferaKion of goblet =ells and a partial loss of cilia in the surface lining cells. After 420 days of exposure to eiga- r±=~e smoke, =he number of cell layers in the epi$hel~um was found to

, C C be twice that of the nonsmoking dogs. Goblet aells and ciliated columnar cells w~re no longer present; instead, the surface was lined by aoluuu~ar and cuboldal cells ~rith stubby projection~ in place of cilia° D~totic figures were frequently observed in the basal cells. These findings ~y he rel~v~nt to aar~inogene~is as well ~s to th~ development o~ =hroni¢ obstructive Dronchopulmonary d£sease. Tyler (49} ~nd MeLaughlln, et el. (37) have studied the physiology and morphology of pul~on~ry emphysema in the horse. The lung of the horse has been repo~ted to he similar in subgross anatomy ~o that of man (36). They have studied hoth the spont~eous disease, one of the several causes of the sTndrome known as ~eaves" and a1~o a similar but not iden- t±cal pul~onary disease ~nduced by the injection ef chlorpromazine or of s~yrene bead~ into ~he bronchial arterial clrculatlon. Their £i~dings of obstru~tlve 1~slons in the bron~h£al ci~cul~tio~ and of accompa~ylng omphy~ma~us changes in ~e pulmonary pa~e~hym~ provide indlrect ~upport of a vasc~l~r theory of emphysema. Rieketts~ et al° (gl) were t~able to prod~e emphysematous lesions in sheep by occlus$o~ of t~e bronchial a~tery; ho~ever, species differences in the distribution of this vessel may be an important factor in both ~perlmental ~d spontaneous disease. ~e bron- c1~lal arte~ in the horse is reported to s~pply the alveolar sepia; wh~re- as, i~ the sheep it is r~por~ to reach only as far as t~e terminal ~ ronchiol~ (3~).

A pulmonary disease similar histologically to pulmonary emphysema in m~n appears spentaneously in certain populations of rabbits (12). goatmm%, et al. (8) have studied this disease by means of the electron microscope. Three of their findings which tend to support the theory that the disease is primarily vascular in origin are as follows: Less of capillary endotheliu~, partial or complete filling of the capillary lumens with collagen and frequent recanaldzation of the damaged capillaries. Freem~n, et al. 41g,20,21) have investigated the effect ef chronic expesuce of rats to varying concentrations of nitrogen dioxide 4N02), a gas which is found in cigarette smoke and in industrially polluted air. These investigators showed that the exposure of rats ever their life-time of 2-3 years to eoncemtratlons of 2 4± I) parts per million of NO2 resulted i~ reduction in cilia of ~he hronchi&l epithelium, a reductd~ in normal exfoliatlon and ~he appearance of ~identlfied crystallold inclusions, gxpesure for only 16 weeks to a higher concentration of~ 4 (± i) parts per million led te hypertrophy of the epithelium of the ret- inal 5ronchioles. Rats exposed to cencentrations varying from l0 4-+ i) =o 25 (-+ 2) parts per million of DI02, developed large, heavy, nonedematous lungs accompanied by dorsal kyphosis. The increase in weight of the lung ~;as shown to he caused by widespread hyper=rophy of the

respiratory epithelium, especially in the bronchloles closely associa=ed with alveolar ducts and in the terminal bron~hioles. Hypertrophy of the bronchial epitheliun~ and accumulatlon of amorphous proteinaceus ~te- ~lal, flbrin strands and ~acrophages resulted in narrowing of the l~ens of the terminal bronchioles at their junctions with the alveolar ducts. Focal hypertrophy of alveolar eplthellum appeared to be ~8ociat~d with ~ompr~sion of alveol~r capilla~les. The alrspace6 of ~he lung were increased in volume. Other investigators hav~ also reporte~ an increase in alveolar s~ze in rodents exposed to NO2. Blair, et al. (?) e~pose~ mi~e to 0.5 pert~ per million of NO2 ~or 6, 18 or 24 hours each ~ay. The ~ni~is were ~xpo~ed to NO2 for periods v~rying from 3-1/ months~ the dsgree of change i~ the p~l~onary histology appeared to ~ncre~e with incre~ed ~ot~i l~ngth o£ exposure. Besides producing enl~rged alveoli~ exposure to ~02 ~Iso produced e~rly bronchiolar infl~atlon with a concomltant ~e~uctlon in the si~e of the dlst~l air.aye. OTHER STUDIES In ~ r~cent ~tensiv~ revle~ of ~ nature and role of pulmonary sur~actan~. $carpelll (43) states that the lowering of ~urface tension producad hy ~e action o~ cigarette s~oke on S~rfac~nt may predispose to the development of emphysema.

Cigarette smoke contains powerful eiliostatie agents (50,51,52) which Can interfere with pulmonary ~learance. Components of ~o~h ~he particulate and the gaseous phases adversely affect ciliary activity. Dalhamn~ et al. (14) have pointed out that in assessing the effect of one or another of the components of cigarette smoke on ciliary activlty in various an~r~l systems particular attention must be paid to the level of exposure~ since at i1ifferent dosages~ ~he particulate and gaseous phases have different relative effects on ciliary actlvlty. Other recent work by D~lh~mn, et al. (13) has further clarified the extent to which certain ¢ompo~en~s of cigarette smok~ are retained in the human lung and includes the ~bservatlon ~hat r~ten~ion of gaseous co~one~ts depends in part on adsorptlo~ of the gases on particulate matter. ~ali~nger, et al. (4) have indicated that the in vitro cll$ostatle effects of oxidized nicotine are enhanced by prior infection of the tissue explants with Influenza B Virus. Holma (30) h~ re~orted that cigarette smoke has acute depressant e~fects on pulmonary clearance in llvlng rabbits. Reeently~ ~hservations have been published on the metabolism and function of the pulmonary alveolar maerophag~ which~ together ~ith mucus tra~spor~ performs the f~nction of ridding the lung of 5o~h inanimate particles and bacteria. Green (27) points out the importance of the alveolar macrophage i~ gulm~nary clearance of infectious agents. ~e has I0 -J

also observed ~ deleterious dose-response effect of cigarette smoke on the phagocytic activity of the macrophage and suggests that this effect may be related to the development of chronic bronehopulm0nary disease. In another paper, Green (26) found that the cytotoxic activity of cigareKKe snake on pul=~nary Vmcrophages may be inhibited by glutathlone and cysteine. Izard (32) observed that the gaseous phase of cigarette smoke or one of its co=~p0nents, acrolein, inhibited the multiplication of cultures of D~lallella bioculata and also observed that the addition of cysteine to the medium protected against these effects of acrolein. Heise, e= al. (28) have reported that rabbit pulmonary alveolar macrophages secrete lysozyme into a culture medium. Lysozyme may be active in the clearance of bacteria from the lung. Roque, et al. (42) found a decrease in the activity of oxiodoreductases and hydrolases in the alveolar macrophages of smokers. They also found that the redu~tlon in these eRzymes was directly propor- tional to the amount of stored fluorescent material present i~% the maerophages. This material is thought to originate in tobacco smoke. Roque, et al. suggested that the tobacco s~oke ~ay have induced abnor- malities in the mitochondria of the macrophage. Kilhura (~3) theorizes that the pathogenesls of chronic obstructive bronchepul~onary disease is related to the failure of macrophages =o be cleared from the alveoll and bronehloles because of impactlon of mucus. ll a0

He suggests that dissolution of the cells exposes ~he alveoll and bron- chioles to damaging enzymes and £o the phagoeytosed particles conta±med in the maerophage. CITED REFERENCES (i) ADEL>h%N, J. U. A review and reappraisal of emphysema. Diseases of the Chest 51(2):156-161, February 1967. (2) ARDERSON, W. H., WILLIAMS, Jo B. Effects of cigarette smoke on dis~rlbution of pulmonary perfusion. IN: Cur~enL Rc~ear~h i~ Chronic Re~plratory Diseases. P~oceedlngs of the llth Aspen EmpEysema Conference, Aspen, Coiorado. U.S. Department of ~ealth, Education and Welfare, Public gealth Service Publica- clon NO. 1879, 1969. Pp. 75-79. (3) ~NTHONISEE, N. R., BASS, N., ORIEL, A., PLACE, R. E. G., BATES, D.F. Regional lung function in patients with chronic bron- chitis. Cli~ical Science 35:495-511, December 1968. (4) BALLEECEK, 3. d., I~¢FARLAND, C. R., HA/iDING, E. B., KOLL, M., EALSTEAD, D. ~e effect of air pollutants on pulmonary clearance. Laryngoscope 78(8):1387-1397, August 1968. (5) BARACH, A. L., SEGAL, M. S. The increased recognition and incidence of chronic bronchitis and pulmonary emphysema. Annals of Allergy 26(7):353-357, duly 1968. (6) BIERSTEKER, K. Bronchltisklachten bij Rotterdams gemeente- personeel. Nederlands TiJdschrift veer Geneeskunde 112(26): ~O8-1211, June 29, 1968. (7) BLAIR, W. H., HENRY, M. C., EHP~LICH, R. Chronic toxicity of nitrogen dioxide, lB. Effect on histopathology of lung ~issue. Archives of Environmental Realth 18(2):186-192, February 1969. (s) EOAI24AN, E. S., MARTIN, R. B. Elaetren microscopy in pulmonary emphysema of rabbi~s. American Review Of Respiratory Diseases 91(2):197-205, February 1965. 12 ~j 00

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ggl. WEISS, W. Cigarette smoke gas phase and paramecium survival. A method for intermittent exposure. Archives of F~vironmental Health 17(1):62-64, July 1968. $82. WEISSBECKER, L~, CARPE~rfER~ R. D., LUEHSINGER, P. C., OgDENE, T, S. In vitro alveolar macrephage v~ability. Effect of gases. Archives of Environmental Health 18(5):756-789, May 1969. $83. WE~RL, H. Zur gedeutung des Kauchens fur die chronlsche gronchitls. Zeltschrift f~r die Ges~te Innere M~dizin 23(5):147-151, March i, 1968. S84. WEST, J. B., GLAZIER, J. B., HUGHES, J.M.g., MKLENEY, J. E. Effect of gravity on the morphology of pulmonary capillaries and alveoli. IN: Current Research in Chronic Respiratory Diseases. Proceedings of the llth Aspen Emphysema Conference, Aspen, Colorado. U.S. Department of E~alth~ Education and Welfare, Public Heal~h service Publication 1879. 1969. Pp. 138-137. S85. WINKELSTEIN. W., JR., KANTOR, S. Respiratory symptoms and air pollu=ion in an urban population of Northeastern United States. Archives of RnvironmeBtal Health 18(5):760-76;. Hay 1969. 87 ~J O~

$~KING ~D CANCER SD~NY Previous ~ports (59~60~61) have presented the evidence that clga- retie sm.~ing is a ~jo~ Ca.use of lung Cance~ ~d ~a~ c~ssa~io~ of ~Ig~re~te smoking sharply reduces the rIBk of dying from iung cancer a8 compared to the rlsk o£ those who continue to smoke° Cigarette smoking was also shoWn ~o be a s~gni~lcan~ factor in the causation of cancer of ~he larynx. A strung a&s~i~tian hetwe~ various forms of smoklng and c~c~rs of ~e buccal cavlty~ ?ha~yn~ and esophagus was also shown. Dat~ w~re pre~ented which indlc~ed tha~ elgaret~e ~moklng w~ ~5ocla~ed wi~h can- cer of ~he urinary bladder, Data ~ere ~iso presented which suggested ~ha~ ~er of t~e kidney and pancreas may be ~ed to ci&a~et~ sm~klng, During ~he past year, both population s~d~es and laboratory stud1~s f~o~ various countries have added to the welgh~ of ~he evlde~ce llnkln8 smoking and canter. A major study of hls~ologlcal changes in ~he larynx has d~mon~trat~d th~ higher r~sk of prem~llgna~ ~a~ges among smok~r~° Mo~e s~udi~ hav~ been done ~o identify those substances in ~obac¢o ~moke which take p~rt in carclnog~nesis* New animal ~del~ for the experimental study ~f respiratory can~e~ which may he helpful in elucidating ~he m~hanlsms of r~spira~o~y trac~ carcinoge~e6is, have been developed ~d r~flned.

EPIDEM£OLOGZCAL STUDIES It is interesting to note that epidemlological information on ciga- retce smoking and lung eancer~ s~milar to that which hag been collect~d i~ the United States and Western European count~les~ ~s now being ~eported ~om Easte~ Europe a~id Africa as wet1, LUNG CANCER In Rorway, a study o~ hlstologlc~Zly proven cases o£ Zung cancer by Kreyberg demons~&ted tile low frequency of itumg ga~Icer amoRg ~on~molo~r~° The c~ses were collected between i950 and i964 from two hospitals and a diagnostic laboratozy which ~erv£ce a11 parts of Rorway~ ~ The author states thaC the popul~tlon represented in ~hls study Is: most probably geog~phlcally r~presen~atlve o~ the who~e country, £~ comparing his ~e- suit~ i~ Norway with Chose of o~her European countries, Kreyberg st~ed that a nonsmoking Nozw~gian population today shou~ p~g Zung cance~ ~ases in the s~e ~u~ber~ w~th ~he same sex ra~oI ~LRd~Wlth ~h~ 8~ ~ep~- sentation o~ histological types as prevailed in Norway ~0 yea~s ago, and £n Europe in general a~ the b~glrming o~ ~his century {2~25)° The ~isks of developing v~lous hls~ologicai ~ypes of lung cancers among s~okers~ as con- t~as~ed to nonsmokers~ are presented in ~able i. Two ~ac~s a~e st~iklngly mpp~rent from the table. First, the p~eponde~ance of the higher risk o~ lung eance~ £~ s~oke~s £1es £n the c~t~gories of epi~rmoiR ca~cino~ amd ~mapl~sti~ 8mall cell c~ci~oma. Seco~d~ w~lle ~em~l~ smokers have 0~ 0q

Q Table l.--Tumor prevalence among males and females 35-69 years of age, by type of tumor and smoking Cstegory [Smokers constituted 85 percent of populations studied] Sex and type of tumor ~ales: Eptdermold carcinoma Small cell a~aplastlc Ca~ci~o~ Adenocarcino~ Eronchlolo-alveolar caTclno~a Carcinoid Bronchial gland tumor Total Fe~les: Epldermoid carcinoma Small cell anaplas=ic carcinoma Adenocareino~1 Bronchiolo-alveolar carcinoma Carednold Bronchial gland tumor Total Total 434 117 88 46 685 12 8 56 32 i08 Smokin5 category Expected ~umber Smoking Non- among all methods smokers! smokers Z-2 431 3 17.0 116 1 5.7 83 5 28.3 39 7 39.7 669 16 90.7 9 3 O.75 5 5 0.75 14 42 10.5 7 25 6.3 35 73 18.5 Risk ratio a~o~E s~kers 25.4 20.4 2.9 1.0 7.4 12.0 6.6 1.3 1.1 1.9 SOURCE: Kreyherg. L. (24). Number that would be expected if incidence rate among smokers was equal go chat of nonsmokers. CE O~

hiEhor risk of developin$ £un$ c~ac~r than £ex~le nons~kers, t~-~ relative ~isk~ are smaller than thoae f~r ~ales. At least ~art of ~,~ ~±~£erencQ r~ay be accounted for by dif~r~nces in amoking habits between ~n and woman° Worn tend ~o smoke £~er ~igaret~s, to smoke brands l~ar in tar and nicotine, inhale les~ and smoke less of each ci@arette ~ do men; ~ett, e~ al. (8) found ~ha~ the mor~ali~ r~t~ for i~g ~x~r in shakers in England w~ espeeiollF high for the amokers who "d~oop~d~' the cig~re~s off ~he lip while they smoked, a habit which ~y r~sul~ in ~he delivery of a ~z~ate~ dose o£ s~ke fzom each cigarette. celfand, e~ al. (19) ~ a stL-dy of ~ng ~c~r in ~e~i~n A~ricans, ~epo~ted a p~epo~der~e of ~mo~r~ a~on~ ~e 1~ ~er pati~n~ as co~- pared to a control ~oup. The authors express th~ opi~o~ t~a~ air pollution does not pLaF a role In respirato~ ~ce~ in Khodesia. the 1967 ~eaith Coneequences Report (59), it was po~n~ed ou~ ~hat ~he iun~ cancer risk of ex-s~kar~ daclined~ ~l~v~ ~o ~hos~ ~o Co~t~d ~o or~oke. I~ equalled ~ha~ of nonsmokers abou~ ten yea~ ~f~r s~ppin~ s~oking, and th~ ra~e of d~cline dep~ded ~n the number o£ cigaret~s ~r~viousiy smoke~ and ~h~ duration o£ ~king. Bross, et el. (10) r~poz~ed ~ha~ the r£sk of developiu@ lung cancer ~s lower among fil~e~ ci~are~e g~,~er~ly l~r ~n ~ar conten~ ~a~ non-££1~er cisarettes~ ~=s s~uay

supports the inference that the tar content of cigarettes is a meaningful measure of exposure EO risk. £n vle~ of the fact that practlcally all l%u~g.cancer patients start6d to smoke unfiltered cigarettes and have smoked filter clgaret~e8 only in recent years and for a variable length of time, a more exact comparison of the risks of filter and unfiltered cigaret~ smokers must await further studies (67}. The relationship of smoking Eo lung cancer in women is a~ area of Con=inulng eo~cern~ since We may expect a co~tlnued increase of lung cancer in wom~n wiKh ~he increase in ¢igaret~ smoking amQng them since World War II, Lombard, et el. (.°2) sh,~ a relatlo~hip of cigarette s~oking to epidermold lung c~cer in women but ~ot to adenoearei~o~. Z= is generally agreed that the ~n~rlbutlon of cigarette smoking to the development of epiderm~id a~d oat-cell l%u~g cancer (~.Teyberg Group I) i~ males is significantly grea~er than to the development of adenocareiDoma (Kreyberg Group II). An assocla~ion of other dlsease~ to cancer of the lung is fo~ad in a report by Salzer, et el. (48). Salzer ~d his colleagues have reported in ~ autopsy s~udy that lung cancer and scars from stomach ulcers are ~atis~.Ically associated and suggeszed ~ha~,clgare~e smoking' m~y have cor~rlb~d to ho~h conditions. A study by gta~ler, e~ ~l. {5~) i~di- ca~e~ ~haK ma~e clgaze~te smokers wlzh elevated cholesterol iev~is had

L C C higher rates of lung cai~cer than those with lower cholesterol levels. Addltlon~l studies are needed to confirm and elucldate ~hese ob~e=va~lons. Programs have been recently establlshed to perform cytological exaltations on the sputum of smo~rs, Bince they represent 8 popu~tion at a high ~£sk for the development of Carclnoma of the lung. Thes~ pro- grams have detected individuals wi~h atyplcal or frankly malignant ¢~£Is in thelr ~putum befor~ ~ 6hadow has appea~ed in the 1~ng fields o~ x-ray (18,62). Valai~is, et at° (62) reported tha~ some degre~ oE ¢ytolag£~al ~bnormality w~s f~und i~ th~ sputum of 4.8 percent o~ ~he smokers ~nd 0.9 per¢~n~ of ~h~ non~mo~r~. ORaL CANCER In the Soviet Union~ Orlovshly has ~hown an association between ~i~- ~et~ 8~o~n~ ~ lung ~an¢~ ~s w~ll a~ ~ ~6~o~latlom b~ the u~e Of 1'~as~' (a ~x~ure of tobacco and ~he~ a~ ~h~ dev~lopme~ of ca~ of ~he oral cavity (37). O~he~ studies of interes~ f~m a~ound the wo~Id in- clude on~ by Pindbo~g~ et al. (39) o~ ~he epid~miolo~y and h£s~ology ~£ oral leukoplakia and leukoedema among Papuans and ~ew Gulnea~s. They re- por~ tha~ smoklng may b~ mo~ Closely associated w~th th~se conditions than is th~ chewing of betel nu~ whleh previously was =o~si~red the obviously asso~$a~ed hab~to A ~tudy by Wahl (64~ reports on the r~la- t~onshlp of ~o~a=~o ~hewlng ~o o~al ~nd oroph~y~g~al Cancer in dlstr~ct in India. Pindhor~ also preBents evlden=e from Indi~ Snd$ca~Ing

that oral submucous fibrosis (38) may be associated with tobacco usa and may result In an oral epithellum more susceptible be the earelnogenic sub- stances in tobacco. In a study of oral malignancies indexed in a large tumor registry in Callfornia~ Chierlci, et al. (13) found that 88 percent of the cancer patients were smokers. The proportion of smokers ranged from 81-83 percent for cancers of the gingival ~xd alveolar mucosa, huccal mucosa, hard palate and llp, to 94 percent or more for cancers of the floor of the mouth~ soft palatej tonsil or oropharynx. U~fortunately, comparable per- Centages of smokers in a control population are not presented. No new studies have appeared which clarify the relative contributions of other environmental risk factors for oral cancer; such as alcohol consumption, nutritional problemsj and poor oral hygiene. LARYNGEAL CANCER Auerbach, et al. (i) studied the histology of the larynx of 942 men, aged 21-95, who were au~opsled at a slngle hospital between 1964 and 1967. Cases of primary cancer of the larynx were excluded from the study. Smoking histories for all cases were obtalned from family members of the deceased by tralned interviewers. The n~erous randomized histologlcal sections were graded by one observer. Table 2 shows the percentage of cells with atypical nuclei foumd in the true vocal cord. Of the men who never smoked, 75 percent had nO cells with atypical nuelei~ only &.5 percent had sections with areas containing 60-69 percent of cells wi~h atypical nuclei, and no~e had a higher percentage.

.-? Table 2.--N~ber and percent distribution by relative frequency of atypical nuclei among true vocel cord cells, of men classified by smoking catego~"J [100 percent atypical cells defined as carcinoma] .-% Percent Never Ex- Cigar/ atypical s~ked cigarette pipe nuclei regalarl~ smokers smokers Number Percen~ Number Percent ~ber Percent Total 88 i00.0 ll6 lO0.0 94 i00.0 ~one 66 75.0 86 74,1 1 i.i Gess th~a 50 8 9.1 14 12.1 k h.3 50-59 i0 ll.h 13 i1.2 50 53.0 50-69 4 4.5 1 0.9 28 2~.5 T0-79 o 2 l.T 9 9.6 B0-89 0 - 0 2 2.1 )0-99 0 - 0 l 1.1 LO0: ~cinomain situ 0 0 8 3.2 [nvasive eareino~ 0 O 1 i,I SOURCE: Auerbach, 0., et al. (i). Current cigarette smokers Less than 1-2 packs 2 or more 1 pack a da.~ a da~ packs a ds~v Number Percent N~ber Percent Number Peroen~ 125 i00.0 329 lO0.O 190 i00.0 1 0.8 o - 0 25 2O .0 4 1,2 0 54 43.2 8T 26.4 29 15.3 21 16.8 116 35.3 75 39.4 9 T.2 44 13.4 38 20.0 2 1,6 19 5.8 ii 5.8 o - 5 1.5 o /" 13 10.4 52 15.8 35 18.~ 0 - 2 0.6 2 i.I

7 The 116 ex-smokers had laryngeal histology similar to that of the nonsmokerss as far as atypical nuclei were concerned. However~ disintegrating nuclei were found in 40.5 percent of the ex-cigarette smokers and in only 0.4 percent of the remaining cases. Only one of the 94 cigar and/or pipe smokers had no atypical cells. Three had carcinoma in situ and one case had a section showing early invasive primary car- clnoma. The highest percentaSe of atypical cells was found among the cigarette smokers. The proportion of cases with a high degree of cellular change increased with increase4 daily smoking. None of the pack or more a day smokers was free of atypical nuclei. Of those who smoked two oT more packs per day~ 85 percent had lesions with 60 percent or more atypical cells as compared to 4 percent of the nonsmokers. " Between i0 and 18 per- cent of the cigarette smokers had areas of carclnoma in situ~ and four of the 644 cases showed early microscopic invasion. The'thlckness of the basal level of the true vocal cord was also directly related to the amount smoked (table 3). CANCER OF THE URINANY BLADDER AND KIDNEY Several studies have dealt wlth the relatlonship of smoking to caucer of th~ bladder and kidney. James. et al. (23) demonstrated that an association existed for cancer of the hlad4er. The study by Fraumenl (i?) also showed epide~iological evidence for such a relationship fo~ bladder and kidney cancers. Be~.ington, et al. (8,4) indicated a~ .j

< Table 3.--Number and percent distribution by highest number of cell rows in the basal layer of the true vocal cord, Of men classifie~ by smoking category Number Never of cell smoked rows re~larly Number Percent Total 88 100.0 ]e~s than 5 cell rows 30 34.1 cell rows 29 33.0 cell rows 8 9,1 cell rows 6 6.8 cell rows 8 9.1 ~ll rows l I.i ~0 or more cell rows 6 6.8 SOURCE: Auerbach, O., et al. (i). Nx- cigarette smokers Number Percent 116 I00,0 7 6.0 27 23.3 15 12.9 12 10~3 i~ 12.1 7 6.0 29.4 Cigar/ pipe smokers NUmber Percent 1oo.0 4 ~.3 20 21.3 15 6,o 18 19.1 9 9.6 2 T.~ 21 22.3 Current Less than i paak a ®ay Number ~ Percent 125 i00.0 3 2.~ 27 21.6 25 20.0 12 9.6 ~3 10.4 6 ~.S 39 31.2 cisarette smokers I-2 packs 2 or more a day packs a day Number Percent Ntmber Percent 329 iO0.O 190 i00.0 I 0.3 0 - 38 11.6 20 10.5 51 15.h 2h 12.6 38 11.6 19 lO.0 30 9.1 23 &2.1 26 7.9 I~ 7.~ 1h5 ~h.1 90 ~7.~ 9GS&i.OOS9

C association betwee= all kinds of tobacco usage and adenocarclnoma of bke kidney as well as adenoma of the kidney. However, on the basis of this study alone, the relationship between "all kinds of tobacco" and cancer of the kidney cannot be considere~ as established in view of the small number of cases involved. In a preliminary report of a study on the epldemiology of cancer of the kidney, Wynder, etal. (68) have shown a strong associa- tion between excessive cigarette smoking and adenoearcino~ of the kidney~ and although the disease is not ~eo~on in nonsmokers, they considered excessive cigarette smoking to be a contributory factor. This study found no relationship to pipe smoking~ and only a very weak relationship to cigar smoking. A signdflcaut association was found between cigarette smoking and epldermold cancer of the kidney, a relatively Uncommon type of cancer. Further research on the strength and mechanisms of the as- sociation between smoking and cancers of the urinary tract is needed, CANCER OF THE PANCREAS The previously suggested association hetween cigarette smoking and cancer of the pancreas was again noted in a Japanese study by Ishii, etal. (22), in which the authors reported a higher relative risk for pancreatic cancer 8~nong smokers than among nonsmokers, GENEK~L ASPECTS OF CARCINOGENICITY The majority of the t~orlgenic agents in tobacco smoke are found in the particulate matter "tar." The well established carcinogenieity iI

of tobacco "tar" in a variety of animal speeles an4 tissues (66) was reeouflr~d r~cently (II,35,40,52,56). A small portion of the smoke particulates (0.03 percent) is made up of polynuelear aromatle hydrocarbons (PAH) with two or ~re rluys. A ~ouceutrate ~ontai~ug polynuelear aromatic hydrocarbons and amountlug to 0.6 perceuY of the whole 'liar" was found to be the ~ost earci~oger~ fractlon of tobacco smoke (66). Another preparation of a PAB concentrate induced slgnlflcant cytologic ch~yes In ~use trachea and h~an fetal lung when gzown in organ culture (28,29}° Other applications of concentratlons of selected polynuclear aromatic hydrocarbous have produced similar results (27)° Of the Ideutlfled PA}[, at least 12 are kno~ tu~or iultlators. These partlcular compounds have been 5how~ to be carci~o~ic, eve~ whe~ applied lu doses of a few micrograms (63,66). Tumor i~itiators induce changes in the target cells, especially in DNA (9,1~)° Tu~r promoters are agents which pro~te the neoplastic transformation of imitiated cells. Al~houyh ~he structures of ~s~ of these ~or pro~ters ar~ ~ii unknown, there appear to be several dlffereut types in tobacco smoke (5,41j~9,66). Recently, Back, et al (6) published data which conflr~ad earlier flndlngs ~hat whole cigarette tar, the ueutral fracz~on, ~wo neutral su~frae~ions and ~he weak acidic (phenolic) fractlon contaln tumor promoters. O~e recen~ study i~dleated that "tar" o~aln~d fro~ tobacco stems only had essentially no tu~r pro~tlng activity (65). 12 C~

/ During the last year, several studies have reconfirmed the find- ing that selection of tobacco and the use of tobacco sheets and filter can lead to a significant reduction of "tar" a~d PAH i~ cigarette smoke, as well as to a reduction of the tumorigenicity of tobacco "tars." Similar results have also been reported for con~erclal cigarettes (21,34). Experimental studies demonstrated that with tobacco additives one can reduce "tar," nicotine, PAN and ttm~rlgeniclty of cigarette smoke (12,21). In terms of selective reduction of tobacco smoke components, these investl- sations map be of practical value, as well as of academic interest (57). TOBACCO ALKALOIDS Present evidence does not indicate tha= tobacco alkaloids are car- cinogenic. A possible exceptlos map be coKini~e, which was reported to induce malignant tumors in rats [principally leukemlas (58)] and adenomas of the bladder in mlce (7). goyland recently suggested that one or more of the three possible nlcotlne-N-oxides may be present in tobacco smoke a~d may be carcinogenic (7). Tobacco alkaloids could theoretically contribute to the overall ear- clnogenlclty of tobacco smoke, based on the possibillry that in tobacco smoke nornIcotlne and other secondary amines ~y react with nitrogen oxides to form the N-nitrosamlues, of which several are knowncarclnogens, espe- cially N-nltrosonornlcotlne and N-nitrosoanabasine (56). So far, however, C~

r , ( f N-nitrosamlnes of nornicotine and other alkaloid N-nitrosam/nes have not been detected in tobacco smoke (36). NICKEL The relationship of nickel compounds to the development of cancer has been discussed in a recent review by Sunderman (55)~ who suggests that there is a posslbility that nickel oarbonyl may be present in cigarette smoke and may act as a co-carcinogen by inhibiting the induction of pulmonary benzopyrene hydroxylase, an enzyme which converts 3,4 benzpyrene to non- carcinogenic hydroxylated derivatives. EXPERIMENTAL ASPECTS OF CARCINOGENESIS RETENTION OF SMOKE CONSTITUENTS Studies on human smokers by Dalhamn, et el, (15) demonstrated that about 60 percent of the volatile, water soluble compounds of cigarette smoke, 20 percent of the volatile, non-water soluble compounds and 16 percent of the particulate matter of cigarette smoke can be retained in the mouth when the smoke is held in the mouth for up to two seconds. Under conditions in which the smoke is immediately deeply inhaled, between 91 and 99 percent of the components of cigarette smoke in- vestigated (particulate matter, toluene, acetonitrile, acetonei isoprene, acetaldehyde) were retained, with the exceptlo= of carbon mo~oxlde of which 30-60 percent was retained (16). 14

CLL~NGE$ IN CELL Cb~TURES INDUCED BY CIGARETTE S>IOKE Leuchtenberger, et al. (30) have reported that passing cigarette smoke through a charcoal filter prevented the damage caused by either whole smoke, or the isolated gas phase of cigarette smoke, to cultures of mouse kidney cells. In the s~e papec~ they reported th~ the slng1~ exposure of t£ssue cultures to puffs of charc~al-fiLtere~ smok~ produced a signlflcant increase in the mlt0tic index of the kidney ceils. In ano~le~ ~t~dy~ Leuch~enberger~ et al. (31~ r~ported ~h~ sin~le exposure ~o 9 puff~ of the ga~ phase from charcoal-£ilte~ed cigarette smoke quickly stimul~ed ~h~ synthes~s of DNA and RNA by cultures o~ mouse fibroblasts. Repea~ed exposure of ~he cul~res to the filtered gas phase ~es~te~ im morphological and eytochemical changes indicative of ~bnormal proli£e~- ~io~. ~i~ce the s~e a1~e~at~o~ ~re fo~d ~o be p~esent~ to a much le~ e~en~ im some Control cultures, ~ ~u~ho~s ¢o~si~e~ed ~h~ ~he filtered gas phase ~nhanc~d characteristics already possessed by the =ells. They concluded ~ha~ the gas phase of unfiltered cigarette ~mok~ contains no~ only substances whi=l~ inhibit cellula~ me~abol£sm~ but also f~c~ors which stimulete cellular met~bol~sm. These latter fa~ors may be unmasked by pass~n8 ~he gas phase through a =~ar¢o~l filter. The id~nti~les of ~he sp~clfl= gase~ ~emov~d by ~he 15 -d

charcoal filter and the extent to which each was removed were not reported by the authors. Investigation of the relationship b~tween the changes observed in the tissue cultures and in vlvo metabolism is necessary for the interpretatlon of the results o2 these experiments. EXPERIMENTAL STUDIES OF BRONCHOGENIC CAKCINOMA IN ANIMALS Because of the technical problems involved in inhalation experiments in small anlmals (59,61), various animal model8 have been developed which do not employ the inhalation of smoke. These models have been used to ~tudy the role played by ¢arcinogenin substances found in tobacco smoke in the induetinn of bronchogenlc carcinoma. gafflottl (43) in a recent review of experlmental respiratory tract carcinogenesis ~escrlbed the development of experimental models for the induction of pulmonary tumors and discussed a method of Indnclng broncho- genie carcinomas in Syrian golden hamsters by intratracheal instillation of a finely particulate4 crystalllne carcinogen (e.g., benzo(a)pyrene) attached to a suspension of fine particles of a carrier dust (e.g., ferrl¢ oxide). This method reproduces some of the condltions of human exposure to inhaled carcinogens and has resulted in incldences of up to Ig0 percen~ of respiratory tumors, mostly sguamous cell and anaplastie ¢arclnomas of the larger bronchl. These ~ors have been found to be Invasive, metastaslzing and transplantable. Safflottl reported that the

carrier dust particles play an essential role in transportlng the car- einogens through the bronchiolar and alveolar wall into the lung tissues where they are phagocytized. The carcinogens are then eluted by the plasma and diffused i~to the lung tlssuep reaching up to the ~ucosa of the larger bronchi (42,44,45,46). Varlations in particle size and distribution in the suspended partleulate matter affect the retention rates of be~zpyrene In the lungs (47). The development of this ezperimenta/ model has led to the undertaking of new research in many laboratories attempting to define the factors responsible for carcinogenesis in the zes~izatozTtza¢~. I~o other techniques used to produce sq~mou$ ¢e~Ii carcinoma In small laboratory animals are the passage of threads impzegnated with car- cinogenic hydrocarbons into the lung and the Implantation o~wi~e ~sh pellets i~ the hronchus. The latter technique gives a dose-response relationship between earelnogenle hydrocarbons and squamous cell carcinoma of the lung in rats (27). In order to overcome the t~auma£1e effects Of the surgery involved In these procedures, two addltlonal techniques have been utilized. In one method~ the eazeinogen is suspended in Preundls adjuvant and upon =raoheal instillation ca= lead to bronchial cancer (69). In this experiment~ even more cancers were found when the rats were pre- treated with tubercle bacilli. Pretreatment of the animals with tubercle bacilli produced infarcts, as well as scarring of the lung. This flndlng 17 &:

is of inte=est because earlier studies showed that scarring of rat lung by the halog~nated hydrocarbon hexachlorotetrafluorobutane increases their susceptlbillty to the development of squamous carc~o~ when exposed to carcinogenic hydrocarbons (54). That scarrinE of the lung may Increase the susceptibility of the lung to carcinogens is in line with some recent ob- servatlons on humans by Bennett, eb el. (2) who showed the frequent occurrence of pulmonary scars in males with ~denocarclnoma of the lung. EXPERIMENTAL A~PECTS OF CANCER OF THE BLAD~ERAND KIDNEY Tobacco smoke ~ppears to Co~ta~ traces of s~veral aro~tlc~ines which are established bladder cacclnogens. Of these, however, only ~eta- naphthylamlne has thus far been identified in tobacco smoke with 2.2 x 10-8 g. per cigarette (20). At concentrations such as this, it appears unlikely that such aromatlc amines can account for the increased risk among clgarett~ smokers of developing kidney and bladder cancer. A more likely correlatlon may exist between these types of cancers In Smokers and their elevated urinary excretion rate of carcinogenic metabolites of tryptophan, and their oxidation products (49,50). Recently, the tobacco alkaloid cot~nine was reported to induce adenomas in the bladder of mice [16 percent (7)]. This observatlon needs further testlng. Cotinlne is one metabollc product of nicotlne and is found in tobacco, cigarette smoke (26) and the urine o~ ~mokers (35). 18 L0

A study by Schlegel, et al. (51) iDdleates an elevated concentration of certain o-amlnophenols plus their phenoxazen-oxidation producLs in the urine of certain types Of bladder cancer pa=lents and cigarette smokers, when compared to the urine of nonsmokers* Further studies are needed on this problem. CITED P~EFERENCES (I) AUERBACE, O., HA~OND, E. C., GARFINKEL, L. Personal Communication. April 1969. (2) BENNETT, D. E., gASSER, W. P., FERGUSOE, T. B. Adenocarcluoma of the lung in man. A cllnicopathologlc study of lO0 cases. Cancer 23(2):431-~39, February 1969. (3) B~NINGTON, J. L., FERGUSON, B. R., CAMPBELL, P. B. Epidemlologlc studies of carcinoma of the kidney. II. Association of renal adenoma with smoking. Cancer 22(4):821-823, October 1968. (4) BEh~INGTON, J. Lo, LAUBSQIEE, F.A. Epldemlolo@ic studies on carcinoma of the kidney. I. Association of regal adenocar- cinema with smoking. Cancer 21(6):1069-i071, June 1968. (5) BOCK, F. G. The nature of tumor-promotlng agents in tobacco products. Cancer Research 28(Ii):2362-2368, November 2968. (6) BECK, F. G., SWAIN, A. P., STEDMAN, R. L. Bioassay of major fractions of cigarette smoke condensate by an accelerated technic. Cancer Research 29(3):584-587, March 1969. (7) BOYLAND, E. The possible carcinogenic action of alkaloids of tobacco and betel nut. Planta Mediea Supplement II(14):13-23, June 1968. (a) BRETT, G. Z., BENJAMIN, B. industry, and mortality, 82-85, July 13, 1968. Smoking habits of men employed in British Medical Jouraal 3(5610) : 19

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a $41. GSELL, O., REICH, T. Bro~chlalkarzinom: Bemerkungen zu elner Sektionsstatlstik. Medizlnlsche Kllnlk 60(47):1886-1889, 1965. S42° HACKETT, R. L+, SUNDERMAN. F. W., JR. Pulmonary alveolar reaction to nickel carhonyl. Ultrastructural and hlstochemleal 8Ludies. Archives of Environmental Health 16(3):349-362, March 1968. $43° ~AENSZEL, W., KURIIL~, M. Studies of Japanese migrants. I. Mortality from cancer and other diseases among Japanese in the Unlte4 States. Journal of the National Cancer Institute 40(1): 43-68, January 1968. $44. |biHA~Ip Y. Tabako ha fL~mmatsu kyunyu ni yo~te hansel suru shosh~ no shlnselmotsu nl. Tsulte 2. (DevelopmenE of various kinds of ~eoplas~s through the inhalatio~ of tobacco leaf dust 2.) Transactiones Socletatls Pathologlcae Japonlcae 56:127-128, 1967. g45. IDIRBERS, E., LEDUREK, g°, SANDRITTER, W., SPAAR, U. Untersuchunuen an Nucleohlstonen. IV. "Heterochromatisler~g" in der Mattenleber w~hrend der Carclnogenese. Virchows Archly Arbelten B Zellpathologle I(2):88-108, June i0, 1968. 346. HEMS, G. Factors associated wi~h lunU cancer, grltlsh Journal of Cancer 22(3):466-473, September 1968. $47. HENNINGS, H., gOUTWELL, K. K. The inhibition of DNA synthesis by Inltlators of ~use ski~ tumorige=esls. Cancer Research 29(3): 510-514, March 1969. $48. |IIRAO, F.. FUJISAWA, T., TSUBURA, H., AKAMATSU, Y., YA~, ¥. Experimental cancerous changes in the lung induced by chemical carcinogens in rabbits. Gann 88(8):427-434, October 1967. $49. HYDE, L., YEE, J., WILSON, R., PATNO, M. 8. Cell type a~d the natural history of lung cancer. Journal of the American Medical Association 193(1):82-54, July 5, 1965. $50. KE~, W. B., JONES, J. C., C/LiPMA~, N. D. Pathology of bronehogenlc carcinoma in long-term survlvors, cancer 21(4):772-780, April 1968. 81 00 %0

S51. $52. S53. $54. $55. $56. S57. S58. S59. $60. KIRIKAE, I. Koto gan no eklgaku ni okeru. Mendaiten. (Some as- pects of the epldemiology of cancer of the larynx.) Nippon Rinsho 26(8):lS08-1811, August 1968. KOZ}[EVNIKOVA, E. F. 0 Senslbilizatsil organlzma k kanserobennomu veshches~bu. (Concerning senslbillzatlon of the organism ~o a carcinogenic substance.) VoprosyOnkologll 14(4):57-60, 1968. LEMOINE, J. M., FAUVET, J., VASSELIH, M. 194 turnouts bronchlques J mallgnes des fe~es demontrees par blopsle bronchlque. JourDal Francais de Medecine et Chlrurgle Thoraciques 20:329-345, 1966. LINDNER, J., GRIES, G., FREYTAG, G., BRACK, W. J., HOLZ. 3. Morphologlsehe und biochemlsehe Untersuch~gen zur Geschwulstbil- dung. Cegenbanrs morphologlschas Jahrbuch 109(i):37-42, 1966. LITTLE, J. B., McGANDY, R. B. Systemic absorption of polonium-210 inbale4 in cigarette smoke. Archives of Envlronmental Health 17(5):693-696, November 1968. MADEY. J. Clinical evaluation of 745 cases of primary lung car- cinoma. Polish Hedleal Journal 7(4):917-927, 1966. ~N}[OLD, J. R., RUSTOGI, K. N., DOYLE, J. L°, M~/~ROLD, B. S. M~croscoplc and mlcroresplrometer (QO2) study of the effect of • cigarette smoking on human oral soft ~iss~es. Prellm~nary report of an in v~vo study. Oral Surgery, Oral Medicine, Oral Pathology 26(4):567-572, October 1968. MARTINOTTI, G°, FERRERO, L. ll cancro prlmitivo del polmone nolle rilevazlone dispensarlale. (Risultanze clinleo-statlstiche de1 1947 al 1966). Lotta Contro La Tubercol0sl 37(4):308-316. October-December 1967. IL~SIN, F., >i~SIN, M. Alveolar ceils of sputum in pulmonary car- clnoma. Cancer 21(6):1042-1051, June 1968. MEINSMA~ L. Longkankerstmrfte in Nederland. Nederlands Ti~dschrift voor Geneeskunde I07(32):1432-i~36, August i0, 1963. 32

S61. ~INSMA, L., VE~SLUYS, J.J. De lon kankersterfLe blj volwassenen stljgt ~let m~er. Nederland~ Tijd~chrift Voor G~neeskunde I12(19):891-$95, Hay ii, 1968. $62. I~I~JER, J. A., MILLER, E. C. Metabollsm of drugs in relation to carcinogenlcity. Annals of the New York Academy of Sciences 123: 125-140, 1965. $63. MONTCO~Ry~ p. O'B° Nucleolar studies. Bulletln of PatholoSy 7C3):66-67, M~c=h 1966. $64° ~ORRF~, C. E., DAO, T. L., ESKINS, K., KING, C. L.~ DIENSTAG, J. Peroxide induced binding of hydrocarbons to DNA. Biochi~ca e~ Biophysi~a A~a 169(1):224~229. November 20, 1968. $65° MU~EP~, C. Studles on ~he nature of the hindlng products of beta~proplola¢~one and mouse skin pro~eln° M.S. Thesis, University of Wiscun~in~ 1968. 86 pp. $66. MUIR, C. S. ~e incldence of ~arynseal cancer in Singapore. Journal of L~ryngolog~ and OtoloSy 79(3):203-213, 1965. $67. NEI~N, J. M. The se~si~izlng carcinogenic ~ffe~t of small doses of carcinogen. European Journal o£ cancer 4(5):53?-545, October 1965. $68. Occupatlon, che~Icals~ and cancer. British Medical Journal 2(5553): 6~9-650, Jun~ I0, 1967. $69. OTT~ G., DAUM, R. Lungenkrebs bal Frauen. Langenbecks Ar=hlv £~r Kl£nis~e Ch~ru~gle verelni~t ~ l~utsche Z~its~rlft f~r Chirurgle 310(2) :93-i0&, 1965. S?O° OTTO~ If., ELMI~IOR~T, H. Experimen~elle Un~ersuchungen zur T,mor£nduk~ion ~ der Gasphase des Zigare~enrau~s° Zei~s~rlft f~r Krebsfor~chun~ 70(i):45-47, 1967. $71. pARK, ~Y., KIPROWSKA, I. A ¢ompara~ive in v~o and in vlvo s~udy of induced c~rvical lesions of ~c~. Cancer Research 28(8): 1478-1489, Augu~ 1968. 33

$72. PILHEU, J, A., Yh~GA, M., CKOXATTO, O. C. C~ncer broncopulmonar prlmi~ivo. Con6ideraclonQ~ sobre 522 c~os. R~vlsta ~.soclaclon Medlca Argentina 82(5):159-162, May 1968. $73. PINDBOP~ J. J., K~ESSI~ H. K.~ K~E~ S° A., SING~ B., TALYERK~h~N, B.N. Frequency of oral leukoplaklas and related conditions m~ong i0,000 Bombayites. Journal of the All India Dental Association 37:1-2, July 1965. $74. PINDBORG, J. J°, KIAER, J., GLTTA, P. C., ~AWIA, T. N. Studies in oral leukoplakias. Prevalence of leukoplakla among i0.000 persor~ in Luckn~, Indla~ with Speci~l reference to use o~ to- bacco and be~el nut. Bulletiu of the World Heal~h Organization 37:109-I16, 1967. $75. POPOFF, N., S~ON, C. H.~ ZI~RMAN, ~° ~° Vir~s-like particles in reactive cells associated w~th crystals of ~mplanted =ar- cluogen. Acta Neuropathologlca i0(4):308-323, June 7, 1968. $76. PUISEUX-D~D, S.~ IZAR~, C. Les e~fe~s de l'acrol~ne e~ de la phas~ ~azeuse de la fu~e de clgarett~, sur l'ultra~ructure cellulaire du Dunalieila bloculata. Comptes Rendus Hebdomadaires des S~ancee de l'Acade~e des Sciences; Series D-Sclences Na~urelles 267(I); 74-75, July i, 1968. $77. RIMINGTON, J. S~okin~, sputum, and lung cancer. British Hedlcal Journal i(5594)~73~-734, March 23~ 1968. $78° ROWE, N. H. Eplde~ological concepts relative to cancer of the oral cavity. Missouri Medicine 65(8):660-664~ 668; 579, August 1968. $79. SACIIS~ L. In vlcro cell transformatlon by carcinogenic hydro- c~rbons: A system for ~he s~u~y of tumor sp~=l~ic antigens in ~he absence of i~munological selac~ion. IN: Ha~rls, R° J. C.. editor. Specific T~mor Antigens. A Symposium° UICC Monograph Series 2:361-355, 1967. $80° $EDA, II. J., ~NOW, J. B., JR. Carcinoma of ~he ~onsil. Archives of Otolaryngolosy 89(5).'756~761, May 1969. S8L SHA~AD, L. H. On ~he dls~ributlon and the rata of ~he carcinogenic hydrocarbon benz(a)pyrene (3,4 benzpyrene) in ~he soil. Zeitschri~t f~r Krebsforschung 70:204-210~ 1968. 34

8 S82. S}IEETS, T. J., SMITH, J. W., JACKSON, M. D. Insect:ic£de residues in cigarettes. Tobacco 166(Z5)*'26-29, April 12, 1968. $83. SIMECKOVA~ B. Pilcni" rakovlna u zen. (Lung cancer in women.) Rozhledy V Yuberkulose A V Nemochech Plicn£ch 28(8):565-568, September 1958. $84. TAKANO, K., OSOGOSHI, K., KAMII~JRA, N., KANDA, ll., KANE, K*, gAMIYAMA, R., SAKAFDTO, K°, SATe), ll., $IIIRAZ, Y., SEI, M., TANABE, T.~ HORINO, M., MINAS, ¥., MDTOJI, l/., MORITA, R°, ORIHATA, H., IIZRAYAMA, T. Shokudogan no ekigaku~ toku ni a~:sul inshokubu~su, £nshu, kitsuen na~-ab£ nl eiyo ~tsubo Ri csulte° (Epidemlolog). of cancer of ~he esophagus, with particular refer- ence to the ~ffect of hot food and drink, d~'inking, amokSng~ and nutrltlonal deficiencies.) Nippon Rinsho 26(8):1823-1828t Au~;us~ 1968. S85. TAKAYAMA, S., St~GANO, H. Induction of mallgnan~ lymphomas £n ICR mice treated with cigarette ~ar. Gann 59(4):363-365. Augus~ 1968. S86. TAPPAN, 14. B.~ VAN MIDDELEM, C. If°, F~Dy]~, I/o A. DDT, endosulfan, and parat.hlon residues on ~i~r-wr~per toba~e.o. JouKl%al ~f Economlc E~tomology 60(3):765-768, June 1967. S87. TREFNY, J. Rozsirenl zhoubnych nadoru dychaclho ustroJl v Ceskoslovensku a v Jlny~h zemlch. (occurrence of mallgnan~ tumor~ of ~he t'espiratory system in Czechoslova~cla and in o~he%" coun- tries.) Casopis Lekaru Ceskych i07(26);790-796, 196~. $88. VON ESSFh~, Co F., SI{EDD~ Do Po, CONNELL¥, it.¸ R., EISENBERG, If. Cancer of the larynx In Connecticut, 1935-19S9. Cancer 22(6)~ 1315-1322, December Z968. $89. WAI{I, P. N., IAHIItl, B., g2~RAR, tl. E]pidemlology of oral m~d oropharyngeal cancer. A ~dy of re~;~on~l factors in U~r~r Pra~esh. Journal of ~he Znd~n Medica:t A~socla~ion 46(4): 175-I~II, February 16~ 1966. $90. WALLER, R. E.. COM~NS, B. T° Studies o~ the smoke and polycyclic aromatic hydrocarbon con~ent of ~h~ ai~" in large urban al:e~. Environmenta£ Research i(4):29~-306, December 1967. 35

$91. $92. $93. S94. WARD, N. 0., CORE. W. A., ACQUAILELLI, M. J. Carcinoma of =he tonsil American Journal of Surgery I16(4)~487-490, October 1968. WATTENBERG, L. W., LEONG, J. L., G~LBRAII~E, A. R. Induc=lon of increased benzpyrene hydroxylase aetlvity in pulmonary tissue in vitro. Proeeedlngs of the Society for Experimental Biology and ~dicine 127(2):467-469, February 196B. WEISSMANN, G., TROLL, W., VAN DWJREN, B. L., SESSA, G. Studies on lysosomes-X. Effects of tumor-promoting agents upon blologieal and ar~iflcial membrane sys~ams. Bioehemlcal Pharmacology 17(12):2621-2434, December 1968o ZE~INEK, G. Zum Begriff des Raueherkehlkopfes. Eine klinische und pathologlsch-anatomlsche Un~rsuehung. Monatsschrift f~r Ohrenheilkunde und Laryngo-Rhinologie i02(4):250-259, 1968. 36

a EFFECTS OF SMOKING ON PREGNANCY SL%R~RY Maternal smoking during pregnancy ~s associated with decreased infant birth weight and increased incidence of prematurity, as defined by weight alone, and may be associated with an increased incidence of spon- taneous abortion, stillbirth and neonatal death. Changes in the metabolism of the placenta and in various hem~ologlcal factors in the newborn infant have been found to be associated with maternal smoking~ but the mechanism of the effect of smoklng on the outcome of pregnancy remains to be de~erm~ned. New studies on the effect of maternal smoking on the outcom~ of pregnancy have been published since the review of this topic in the 1967 Report (ii). In the 1967 review, the literature cited supported a re- lationship between maternal smoking and low b£rthwelght and prematurlty in infants. However, the evidence relating the maternal s~oklng to fetal or neonatal death was not definitive. The additioR of new studles have reconfirmed the relationship between maternal smoking and low birth weight and prematurlty. The relationship between maternal smok£ng and spontaneous abortion, stillblrth~ and neonatal death has been investigated in several studies. As detailed below, some of the studies re- ported a statistically significant increase in ~successful pregnancies in mothers who smoked when compared with mothers who did not smoke. ~0

In a prospective study of more than 2,000 pregnant women. Russell. et al. (8) examined the effect of the mother's smoking habits and blood pressure on the outcome of the pregnancy and on the birth weight of the infant. A smoker was defined as one who regularly smoked five or more cigarettes a day. In each blood pressure categoryI the per- centage of unsuccessful pregnancies (abortion, stillbirth, neonatal death) was higher for smokers. Although fewer smokers were found in the hlgher blood pressure ca~egorles~ women who smoked and had blood pressure levels equal ~o, or greater chan 150/i00~ had a rate of unsuccessful pregnancy • of 31.4 percent as compared to a rate of 14.5 percent among nonsmokers with the same blood pressure levels. For those with blood pressure leveis of less than i40/90, the percentage of unsuccessful birth was 6.5 among smokers and 2.7 among nonsmokers~ for those w~th blood pressure levels in ~he range of 140/90, the percentage was 6.8 among smokers and 4.1 among nonsmokers. Although the number of women in the two groups was small (35 and 138~ respectively), the difference observed was statistically significant. Extrapolating from his series, Russell (7) estimated cha~ one out of every five unsuccessful pregnancies in women who smoked regularly would have been successful if the mother had not smoked regularly during the pregnancy. This statement implies a cause-and-effect relatlonshlp be- tween maternal clgarette smoking during pregnancy and abortion and

perlnatal death. In the absence of proof of a cause-and-effect relation- shlp~ the least that tan be said is that on the basis of the findings of hu~sell, et al.~ one out of every five ~succe6sful pregnancies among women who smoke regularly during pregnancy would not have been unsuccess- ful~ if these women had ~he same ri~k o~ ~succes6ful outcome of pregnancy Wom~n who do ~o~ Smoke, In keeping wlth previous findings, Russell, et al. found that the mean birth weight of the infant was lower for the smoking mothers in each blood pressure cateSo%7. Various factors were ~xa~in~d as ¢onfo~dlng varifies for thelr possible effect on birth welght and the productlon of spurious ~soclatlons. Th~se included: Soclal class of con~ort~ maternal age~ parity, maternal height, so=lal class of womanls father, educational level, age of consort, ~rnal attitude toward the pregnancy, work during preg- nal~cy and sex of offsprlng. For e~ch variable~ the smokln~ effect was clearly distinguished as a separate effect even when the individual factor was itself associated with smokin~ (consort's soclal class, father's social cI~, and maternal educatioual lev~l). A study of increases in the infants' wei~t and in their head cir- cumference during the early weeks of lSfe revealed that the bables of smoking mothers grew faster ~han those of nonsmokers through the sixth month after b~r~h. However, the ~an welgh~ ~afn per week of conception age (duration of pregnancy, plus age after birth) was greater in bahles

of nonsmokers through the six=h week, the effect not being visible at the sixth month examination. These gast two findings support the theory that smoking during pregnancy aces as a retard~g $nfguenee on fetal growth and that a catchlng-up phenomenon begins among the babies of smoklng mothers at blrth when the toxic Influence is ~emoved. In a controlled study of 197 premature births among Negroes, Terris, et al. (9) found a significantly higher prevalence of smoking among the mothers of premature infants. Prematurity was defined as a birth weight of 2,500 grams or less. Mulcaby~ etal. (6) studied the relationship between smoking habits and the outcome of pregnancy in 3~681 women admitted t~ the Coombe Lying-in Hospital in Dublin, Ireland. Besid~s finding a significantly lower birth weight for infants born to mothers who smoked, they discovered a signffleant increase in the incidence of neonatal death, stillbirth and spontaneous abortlon° These effects were independent of age or parity. No significant difference in the rate of congenital abnormalities w~ found between the offspring of the smokers a~d those of the nonsmokers. Kizer (g) studied the effect of maternal smoklng on the outcome of pregnancy in 2,095 patients in Venezuela. He fo~ a slgnifi~ant diminu- tion in the birth weight of infants of smoking mothers and ~ higher

*% incidence of premature rupture of the membranes, but did not find a difference In the incidence of abortlon or perinatal mortality. Duffus, et al. (2) studled the refatlonshlp between smoking during pregnancy and the incidence of albumlnurlc preeclamptlc toxemla in 2,543 marrled~ urban primigravlda~ attending antenatal cllnlcs in Aberdeen in 1960. Alb~inurlc preeclampsla is defined as albumlnur£a i~ pregnancy in which the urine contains at least .25 grams of albumin per liter accompanled by a rlse in diastolic blood pressure to 90 m ~g. or more, on two or more days after the 26~h week of gestation or progressively during labor. The incidence of albuminurle preeclampsla was lower in smokers than i~ nonsmokers. Among the preeclamptlcs, however~ smokers lost more babies in the perinaLal period than the nonsmokers. The babies of smokersp both normal and preeclamptl¢, had a lower mean weight than the babies of nonsmokers. In ~he preeclamptlc group~ a greater percentage of the babies Of smokers weighed less than five ponds. These differences are in keeping with those found in other studies but do not reach statlst£cal significance. The £mplleatlon is that smoking mothers are less likely to be preeclamptln~ possibly by way of blood pressure effect~ hut are more likely to have their pregnancy result In a perlnatal death in the even~ they are preeclamptlc. In a study of 5,843 deliveries in H~gary, FUI@p (3) found a statistically siEalf~cant increase in premature births among women who ~J

smoked during their pregnancies, whether the women were married or un- married, held a job, or were unemployed. Lacuska, et al. (5) found a hlgher frequency of premature births and abortions among women who smoked durlng pregnancy th~n a~o~g nonsmokers, although the differences fell short of statistical significance. Tokuhata (I0) a~alyzed the fertility history in relation to smoking in groups of married women ~ho died of breast cancer, genital cancer, and various noncancerous diseases. Statistically significant increases in both the rate of infertility (as ~udged by absence of pregnancy) a~d in fetal loss (defined as abortions and stillblr~hs) were found in smokers who died of ~onca~cerous diseases. These differences withstood analysis for a number of possibly eonfo~ding factors. However, since the sample was made up of women who died i~ a certain geographfeal area in a given amount of ~Ime, biases may have been introduced. Retro- spectlve findings is a group of dead people are not necessarily the same as findings derived in a prospective study of a living population. Al~hough by this Cime the evidence for reduction in birth weight of babies born to smoking too=hers is overwhelming, a problem ~hat remains =o be solved is why some studles do and others do not appear to show fetal wastage as measured by abortion, stillbirth, and neonatal death. I~ may be that the method of selection of the population under study, especially the degree to which entire obstetrical histories are included, accounts for this variation. &O ~2

EXPERI~I~AL Younoszai, et al. (13) compared various hematological factors in the blood of 16 smoking mothers and newborn infants with those of 16 non- smoking mothers and their offspring. Both groups of infants were de- livered at term and appeared clinically well. The smoking mothers had a mean earhoxyhemoglohln saturation of venous blood of 8.3 percent as compared to 1.2 percent in the nossmoking mothers. Corresponding figures for the umbillcal vein cord blood were 7.3 percent and 0.7 percent. A mild metabolic acidosis was seen in the infants of smokers. These infants also had a higher ~an capillary hematocrlt th~ those of the nonsmoking mothers. The authors point out that the differences although real probably are not of clinical slgnlfleance in the newborn. H~ever, the effect of chroDic exposure of the embryo and fetus to earhoxyhemoglobln levels and other hematological abnormalities has not been elucidated. Welch, et el. (12) reported that the placentas from women who smoked during pregnancy show a much greater ~ility to hydroxylate henzo(a)pyrene than the placentas from women who ~d not smoke 4urlng their pregnancy. The placentas from women reporting similar cigarette consumption varied greatly in the degree of BP hydroxylas~ activity. ~owever, no information is available on the brand of cigarettes smoked or the degree of inhalation, 4/fferences in which may result in different

dosages of BP. Ic is possible, but not likely, that carcinogens in to- bacco smoke reach the fetus in significant amounts. The ultimate effect of the exposure of the human fet~s to carcinogenic substances is unknown. gecker, et aL (1) studied the effect of subcutaneous injections of increasing doses of nicotine on groups of pregnant rats and their off- spring. They found that the rats receiving nicotine injections consumed less food and gained less weight than control anlmals and that the magnitude of this effect increased when the dose of nicotine was greater. ~here~ no other differences were fo~md in the rats receiving lower dosages, those receiving g.O mg/kg or 5.0 mg/kg daily had offspring which differed from those of the controls in being llghter~ having a longer gestation, a higher mortality rate during the first 48 hours of llfe and a fetal appearance. CITED REFEPdEKCES (I) NECKER, R. F., LITTLE, C. E. D., KING, J. g. Experimental studies on nicotine absorption in rats during pregnancy. III. Effect of subcutaneous injection of small abroni~ doses upon ~ther, fetus, and neonate. American Journal of Obstetrics and Gynecology I00(7)~957-96g, April 1~ 1968. (2) DI~FUSp G. M.~ MacGILLIVRAY, I. The incidence of preeclamptic toxaemla in smokers and non-smokers. Lancet 1(7550):994-995, Hay 11, 1968. (3) FUL~P, T. "~er Fruhgeburten allelnstehender berufst~tiger Frauen. Sant~ Pablique 8(4):381-394, 1967.

(4) KIZER~ S. Influencia del habito de fumaz sobre el el,barazo, parto y reclen nacldo. Revlsta de Obstetrlela y G±necologla de Venezuela 27(4):595-643, 1957. (5) LACUSKA, A., BOHUNICKY, F., FILO, S. Fajcenle a gestacla. (Smoking and pregnancy.) Ceskoslovenska Gynekologle 33(3):197-200, 1968. (6) MULCAHY, R., KNAGGS, 3. F° Effect of age, parity, and cigarette smoking On out¢o~ of pregnancy. D~merlcan Journal of Obstetrics and Gynecology I01(6):844-8~, July IS, 1968. (7) RUSSELL, C. S. Another ha=~rd of smoking. Ne~ Scientist 41(631): 64-65, 3anuary 9, 1969. (8) RUSSELL, C. S., TAYLOR, R.t LAW. C. E. Smoking in pregnancy, maternal blood pressure, pregnancy outcome, baby weight and growth, and other relate~ factors. A prospective study. Brltish Journal of Preventive and Social Medicine 22(3):119-126, July 1968. (9) TERRIS, M., GOLD. E. M. As epidemlologic study of prematurlty. L Relatlon to smoking, heart vo1~me, employment, and physique* American Journal of Obstetrlcs and Gynecology 103(3)=358-370, February i, 1969. (I0) TOKUHATA, G. K. Smoking in relation to infertility and fetal loss. Archives of Environmental Health 17 (3) : 355-35g, Septe~ez 1968. (11) U. S. PUBLIC ~EALTH SERVICE. The Health Consequences of Smoking. A public Health Service Review: I~67° Washington, U. S~ Depart- merit of Healthp Educatlon and Welfare~ Publlc Health Service Publication NO. 1696, 1967. 199 pp. (12) WELCE, R. M.~ HA~RISON~ Y. E.~ CO~41, B. W.~ POPPERS~ P. J.~ FINSTER, M., CONNEY, A. H. Stlmulatory effect of cigarette smoking on the hydroxylation of 3,4-benzpyrene and the N-demethylatlon of 3-methyl- 4--mono~thyl~u~uoazobenz~ne by enzymes i~ h~m~ plae-ent~. Cllni~1 Pharmacology and The~apeutlcs i0 (I) :100-109, J~nuary-~e~zuary 1969. (13) YOUNOSZAI, Mo K., KACIC, A., ~LAWORTH, 3. C. Cigarette smoking during pregnancy: The effect upon the h~atocrlt and ac£d-~ase balance of the newborn infant. Canadian Medical Association Journ~l 99(5): 197-200, August 3, 1968. 9 ' -J

SMOKING AND NONCANCEROUS ORAL DISEASE The previous Reports have not presented findings on noncancerous oral disease. Several recent studies have made a review appropriate at this ti~. This review of the available lltera=ure leads to the concluslon that ulceromembranous gingivitis, alveolar bone loss, and stomatftls nicotina are more co--only found among smokers than among nonsmokers. The influence Of smoking on periodontal disease and gingivitis probably operates in con- ~unctien with poor oral hyiene. In addition, there is evidence that smok- ing may he associated with edentullsm and delayed socket healing. While further experimental and clinical studies are indicated, it would appear that nonsmokers have an advantage over smokers in terms of their oral health • Periodontal disease is a chronic destructive process affecting ~he supportdn8 structures of the teeth (glnglva, perlodon~al fibers and alveolar hone). It is generally considered inflammatory in nature. Solomon,¸ et al. (21) studied data on 3,552 nonsmokers and 3,639 smokers, all white and between the ages of 20 and 79. He found that perlodontal disease occurred without slgniff=ant statistical difference in male and female nonsmokers of the same age, but that ~mokers of both sexes had a higher prevalence of the disease. The prevalence in female smokers paralleled that in male smokers in the younger age groups but resembled

a that of the nonsmokers in the older age groups. The authors believe that this difference is related to increased smoking in younger women. Brendtzaeg, et al. (3) examined 206 Norwegian Army recruits between the ages of 19 and 25 and found a trend toward increased perlodontal dis- ease with increased smoking. Hogever~ when an a/%alysis of covariance was perfollmed, most of the changes in periodontal disease severity were accoutred for by changes in oral hyglene. This finding suggests that to- bacco consumption may influence the periodontal tisnues but only with accompanying changes in oral hygiene. A seemingly contradictory paper reporting o~ periodontal diseases in 8,206 Ceylonese was published by Waerhaug (25). He feared tohaccu smokers to have less periodontal disease th~ nonsmokers. He pointed out, however, that for many individuals the alternative to smoking tobacco is chewing betel nuts, which is associated with even more periodontitis than cigarettes. Thus, tobacco users are relatively better off. The relationship of s~klng to gingivitis, the initial stage of peri- odontal disease, has also been studied. Arno, et el. (2) examined 1,346 employees of a manufacturing company in Oslo and found that tobacco smoking was associated with ~ increase in the prevalence of gingivitis. H~ever~ its importance as compared with that of oral hygiene was not a dominating one. Ludwiek, et el. (15) studied 2~577 naval enlistees at the Great Lakes Naval Training Center and found no relationship between smoking and simple

marginal gingivitis, but a slgni£ic~t one between smoking and ulcero- membranous gingivitis (necrotlzlng ulceratlve gingivitis, Vincent's glnglvitls~ trench ~ou~). Thls is an acute form of periodontal dls- ease of apparent sudden onset~ ~aracterized by ulceration of the tips of the interdental papillae, glngival bleed£ng, pain, and foul odor. In the United States and Europe, it occurs primarily in adolescents and young adults, gac~erla, local factors, systemlc factors, and psychogenic factors have bee~ suggested as ~ontrlbuclng to Its etiology (i0). Pindborg's s~udy (17) of 1,433 D~£sh ~oyal Marines beCwee~ the ages of ~ and 28 revealed that the prevalence of chronic marglnal gdngdvltls was not affec~e~ by smoking, but that the prevalence of ul~eromembranous gingivitis was much greater in smokers chart nonsmokers. A second stay by Pdndb~rg (16) of 3,505 Danish ~llltary personnel confirmed these fi~dlngs: Nonsmokers had a prevalence of ulceromembranous gX=givltls of 2.2 per- cent; whil~ for those who smoked iN g. or less of tobacco daily, the prevalence was 7.0 percent, and for more than lO 8. a day it was 9.5 per- Ce~t. gmltt (2D) found a prevalence of ul~eromembranous gingivitis of 2.5 percen~ in D~t~h Navy recruits. In ~hose who smoked 50 g. of tobacco for a week o~ more~ the prevalence ~as i0.5 peree~t. Frandsen, et aL (9) investigated the ~orrelat~on between the form of tobacco used and o~curren=e of glnglvltls in Danish Marines. ~e fo~d

that 1,848 cigarette smokers and 273 pipe smokers had essentially the s~me rates of simple marginal and ulcerome~branous gingivitis. Arno, et el. (I) and Herulf (ii) have investigated alveolar bone changes in smokers, Arno studied 728 men between the ages of 21 and 45 and found that alveolar bone loss, measured as the percentage of maximum hei2ht adjacent to the meslal and distal surfaces of each tooth present, was higher ~ong those with high tobacco eonsump~on. The author suggested that tobacco cons~mptlo~ is a complicating factor in periodontal disease and when aco~mpanled hy poor oral hygiene and unfavorable systemic back- ground may help speed up the destruction of the supporting tissues of the teeth. Herulf measured interdental boney sepia in 389 men and 215 women at the Institute of Dentlstry in Stockholm. He, too, found a si2niflcan~ relatlonshlp between smokln8 and bone loss. (., Th~ r~latianshlp be~een clgareKte smoking and edentullsm has been studied et (n) in a - Id ntS of Michi2an. Information on 324 dentulous and 84 edentulous people revealed that among males in both groups those with the greatest evidence of peri- odontal disease smoked slgnlflcantly more cigarettes than those with md~ium or little evidence of the dise~e. Solomon, et el. (21) found si~nlficantl~ more edentullsm and advanced periodontal disease in both men and women who'smoked ci2arettes than in nonsmokers of the same a~e. .j

Jackson (12) has cited heavy smoking as a factor in delayed healing of tQoth sockets after extraetion. Stomatlt~s nlcotlna ds a form of palatal leukoplakia (4). it is characterized by raised umbilieated papules with small central red de- pressions located primarily on the soft palate and the posterior region of the hard palate. The papules represent blocked palatal mucus Elands and the red depressions are their inflamed duct orifices. Saunders (18) note8 that ~he lesions begin as tiny red dote and may progress very rsrely to ulceration. Although it sometimes o~c~s in cigar and cigarette smokers, stomatltis nicotgna Is found most frequently in pipe smokers (4, 5,19). According to Chapman, et al. (4), pipe ~moki~g points a stream of smoke 41rectly onto the palate, thereby allowing iQ~ge~ contact between it and ~he smoke ~hau £n other forms of tobacco use~ The condltion disappears with the eessatlon of smoking (6,7,8,14,18,19,24), though Kerr (13) warns that healing may be slow, sometimes requiring mo~ths before no leslo~s are present. Thoma (23) observed a patlent who wore dentures for over forty years an4 showed lesions of stomstitis nicotina only on the part of the palate that was not covered by the prosthesls. He concluded that the changes were due ~o local surface rather than to systemic influences.

L~wls (14), Saunders (18), and Thoma, et al. (24) advise biopsy =o rule out malignancy in advanced cases. Forsey, et al. (8) feel that no assocla£ion between s£omatitis nicotina and Cancer has been de~n- strated. CITED REFERENCES (i) A/%NO, A., SCHEI, O., LOVD~L, A., WAERHA~, J. Alveolar bone loss as a function of tobacco consumption. Acts Odontologlea Scandinavlea 17:3-10, 1959. (2) A~O, A., WAERBAUG, J., LOVDAL~ A., SCHEI, O. Incidence of gingi- vitis as related to sex, occupatlon, tobacco co~st~ptlonj tooth- brushing, and age. Oral Surgerp, Oral Medlclna and Oral Pathology 11(6):587-595, J~e 1958. (3) BR~NDTZAEG, P.p J~2{ISON, H. C. A study of periodontal health and oral hygiene in Norwegian army recruits. Journal of Perlodou- tology 35:302-307, July-August 1964. (4) CHAP~L~21, I., }L~LKIN~ M. Palatal leukoplaklaln a female cigaret smoker. Contrlbutlon to study of tobacco-induced epithelial hyperplasla in h~mau beings. New York Sta~e Journal of Medicine 61(12):2044-2045, June 15, 1961. (5) CHAgMAN, I., REDISH, C.H. Tobacco-lndueed epithelial prolifera- tion in h~an subject. Long-term affects of pfpe smoking on epltheli~ of hard palate. Archives of Pathology 70(2): 133-140, August 1860. (6) DEC~UME, M., GP~LET, M., PAYEN~ J. Leueoplasfe papuleuse e/%ez les fumeurs ou stomatlte nleotlnlque, preaae Madlcale 69(56): 2583-2585, December 25, 1961. (7) E1 tabaco y la mucosa oral. Odontoia~ria 12(10):619-621, October 1955. (g) FORSEY, R. R., SULLIVAN, T.J. Stomatitis nleotlna. Archives of Dermatology 83(6):945-950, Juae 1961o -J

C (9) (1o) (ll) (12) (la) (14) (15) (16) (17) (18) (19) pRANDSEN, A., PIN.BORG, J. J. Tobacco and g~nglvltis. III. Difference in the action of cigarette and pipe smoking. Journal of Dental Research 2g(5):464-465, 1949. GRANT, D. A., STERN, I. B., EVERETT, F. G. Necrotizing ulcerative gingivitis. Chapter 18. IN: Orban's Perlodontlcs. A Concept-- Theory and Practice. 3rd edition. St. Louis, C. V. Mothy Co., 1968. Pp. 285-298. HERULF, G. On the marginal alveolar ridge in students: A roent- genographic study. Acta Genetlca et Statfstfca Medlca 2(3): 256-288, 1951. JACKSON, J. A. Heavy smokgng--a factor in delayed socket healing. National Dental Association Quarterly: 15-18, october 1960. KERR, D. A. Nicotine stomatitis. Journal of the Michigan State Den~al Society 30:90-91, May 194B. LEWIS, A. B. Effects of smoking on oral mucosa. Oral Surgery, Oral Medicine, and Oral Pathology 8(10):1026-1033, October 1955. LDDNICN, W., MASSLER, M. Relation of dental caries experience and gingivitis to cigarette smoking in males 17 to 21 years old (at the Great Lakes Naval Trainfng Center). Journal of Dental Research 31(3):319-322, June 1952. PINDBOEG, J. J. Gingivitis in military personnel with special reference to ulceromembranous gingivitis. Odontologlsk Tidskrift 59(6):403-499, 1951. PINDBORG, J. J. Tobacco and gingivitis. I. Statistical exa~na- tion of the significance of tobacco in the development of ulceromembranous glngivitfs and in the formation of calculus. Journal of Dental Research 26:261-264, 1947. SAUNDERS, W, H. Nicotine stumatitls of the palate. Annals of Otology, Rhlnolosy and Larynsology67:618-627, 1958. SCHWARTS, D. L. S~omatltls nlcotina of the palate. Report of two cages. Oral Sursery, Oral Medicine, and Oral Pathology 20(3): 306-315, September 1965. ~J9 C¢ G~

(20) SMITT, P.A.E.S. Some cllr/cal and epldemiological aspects of Vinc~nt's gingivitis. Dental Practitioner and Dental Record 15(8):281-286, April 1965. (21) SOLOMON, ~. A., PB/ORE, E. L.~ BROSS, I. D. J. Cigarette ~moking and periodontal disease. Journal of the American Dental Association 77(5):1081-1084, November 1968. (22) $U~ES, C. J., OBERMAN, A. Association of oral disease with 12 selected varlables~ If. Edentullsm. Journal of Dental Research 47(4):594-598, August 1968. (23) THOMA, K. H. Stomatltls nicotlna and its effect on the palate. American Journal of Orthodontics and Oral Surgery 27(1):38-47~ January 1941. (24) THOMA, K. H., GOLDMAN, H. M. Oral Pathology+ 5th ed.~ 1960. St. Louis, C. V. Mosby Co. Pp. 955-958. (25) WAERHAUG, J. Prevalence of periodontal 4~sease in Ceylon. Association with uge~ sex~ oral hygle~e, soelo-economlc factors~ vi~amln deficiencies, malnutritlon~ betel and tobacco consumption m%d ethnic group. Final report. Acta Odontclo~ca Scandinavica 25(2) :205-231, 1966. if ~j