TABI E AX.-Outline of ttretllods used in ?etrospcctivc studies of sl)loki)/g in ?-elation to lung cancc)` (cont.) Author, Year, country, reference Sex of enscs Number of persons and method of selcctinn C*SeS Controls Collection of detn Randig. 1054, Germany (2f8). M-F 44X lung cancer patients in a 512 pntients with other diagnoses, matched Controls were interviewed at about the ssme "ulnber of West Berlin haspi- for XK:p. time as the crtses, each case-control pair ta1s. by the same physician. Wynder et al., 1956. U.S.A. (311). Segi et al.. 1957. Japan (f.50). Mills and Porter, 1057. U.S.A. (187). F 105 patients with lung cancer in several New York City hospi- tals. M-F 207 patients with lung wncer in 33 hospitals in nil parts of the country. M--F 578 residents of defined areas dying of respiratom cancer. 1,304 patients at Memorial Center with tu- Cases: Personal interview or questionnaire mors of sites other tha" respiratory or mailed to close relatives or friends. upper alimentary. Controls: Personal interview. ~.(i:~li patients free of cancer in 420 local Case- and controls by personal interview health centers, selected to approximate using long questionnnirc on occupational the sex and age distributions of cases. and medical history nnd living habits. 3.310 rwpuletion sample approximately pro- portionnl to cases as regards areas of resi- dence. and 10 years or more in the area. Cases: From death certificates. hospital rec- ords, and close relatives or friends. Controls: Personal home visits or telephone CZlll.9, usually interviewing housewife. Stocks. M-F 1957, England (263). Schwartz and M Denoix, 1957. Fra"Ce (247). .- 2,356 patients suffering from or 0.362 unselected patients of the same area Cases: Histories taken at the hospital from dying with lung cancer within admitted for conditions other than cancer. relatives by health visitors. certain areas. Controls: Personal interview in hospital. - 602 patients with bronchopul- 1,204 patients (3 groups) in same hospitals Personal interviews in t,he hospital; eases monary cancer in hospitals. with other c~"cer, with nonmalignant ill- and controls at about the some time by ness. and accident cases, matched by 888 the same interviewer. gr"Up. TABLE AX-Outline of methods wed in retrospective studies of smoking in relation to lung cnnccr (cont.) Author, yCir. rountry, referenre Sex of c*ses - Number of persons and method of selection CS.SlS. Controls Collection "f data Haenszel and Shimkin, lY58. U.S.A. (113). F 153 lung cancer patients avail- 33Y patients in same hospital and service at Personal interviews by resident, medical so- able ior interview in 29 hos- same time, next older and next younger cial worker, or clinic secretary. pit&. than each case. Lombard and M Snegireff, 1959, U.S.A. (176). 500 men dying of lung cancer. 4,23X controls in 7 groups including volun- Personal interviews by trained workers. microscopically confirmed. teers, hospital and clinic patients, random population sample, and house-to-house sur- vey samples. Pernu, 1960, Finland (211). -~ Haenszel et al., 1962, U.S.A. (112). MF 1,606 respiratory cancer patients 1,773 cancer-free persons recruited by Parish Cases: From ease histories or mailed ques- in 4 hospitals and from cancer Sisters of 2 institutes in all parts of the tionnaires. registry. rountry. Controls: Questionnaires distributed by Par- ish Sisters. - ___- - M 2,191 sample of 10 percent of 31,516 random sample from Current I'OPU- Cases: Uy mail from certifying physicians white male lung cancer deaths lation Survey. and family informants. in the U.S.A. in 195X. Clmtrols: Personal interview by census enu- mer:,t,,rs. __ Lancaster. 1962, Australia (158). M 238 hospital patients with lung 476 in 2 groups, 1 with other cancer, 1 with Personal interviews of both cnws and con- cancer. some other disease, matched by sex and trrlle in hospitals. age. Haenszel and F Taeuber, 1964. U.S.A. (115,. .-___-~ .___ 749 sample of 10 percent of RIJXY random sample from Current Popula- Casts: RY mail from certifying physicians white female lung cmxer deaths tion Survey used to estimate population and family informants. in the U.S.A. in 1968 and hnse. Controls: Personal interview by CC~SUS enu- 1959. merntors. Author, w?*r, reference TABLE A4.-Group characteristics in retrospective studies on lung cancer and tobacco use SM = Smokers. NS = Nonsmokers. Males Females Cases Controls Cases Controls __ Percent Percent Percent Percent Re%Y- .__ Relative Comments Percent Percent Percent Percent risk no"- heavy non- ratio IlO"- non- ratio Number heavy heavy smokers smokers' Number heavy smokers smokers' SM:NS? Number smokers smokers' Number smokers smokers' SM:NS' ____ Miiller, X6 3.6 66.1 86 16.3 36.0 "5.4 (4) (1) (4) (`) (`1 1') . . 1939 (196). Schairer and Scbiiniger, 1943 (242). 93 3.2 31.2 270 15.9 9.3 "5.7 (4) (4) (4) (4) (4) (4) . . . 16female case* not analyzed. Potter and 43 7.0 30.2 2.804 26.0 23.0 34.1 (4) (`) (`) (4) (4) (4) Tully, 1945 (218). -__ _______ Wassink. 134 4.3 54.x 100 19.2 19.2 4.7 (0 (`) (4) (4) (4) (`1 . . . Percentages 1948 (304). estimated from chart. Schrek et al., x2 14.6 18.3 522 23.9 9.2 1.8 (4) (4) (4) (4) (4) (`) . . . 1950 (24G). _____ Mills and 444 7.2 _.. 430 30.6 . . . 6.7 (4) (4) (4) (4) (4) (4) . . . Porter, 1950 (186). Levin et al., 236 15.8 481 21.7 1.5 (4) (4) (4) (4) (4) (4) . Quantity 1950 (171). smoked not considered. Wynder and 605 1.3 51.2 780 14.6 19.1 13.0 40 57.5 25.0 552 79.6 1.2 2.9 Graham. 1950 (316). ii Q TABLE AL-Group ckamctev?stics in retrospective stzc,dics on lung cancel and tobacco use (cont.) 0 SM = Smokers. NS - Nonsmokers. ~- __~ MZllCS FC"lRleS Author. C*.x% Controls Cases Controls Year. - Relative Relative Comments refrrencr 1'cHYnt rrl?cnt rcrcent Percent risk Percent PrlTent Percent Percent risk ,,c>n- heavy non- heavy ratio IlO"- heavy Iloll- heavy ratio N umlwr srnllhcl,b smokers' Number, smokers smokers' SM:NS" Number smokers smokrrs' Number smokers smokers' SM:NS? ~_____ ~... - - - nirchnell 93 5.4 3X.5 IRF 6.5 23.2 1.2 7 57.1 14 7X.6 . . . 2.8 et al., 1!,6'2 (180), 25.1 1,357 4.5 13.4 9.4 10X 37.0 11.1 10X 54.6 0.9 2.1 Percentage "heavy" smokers understated. __--~~ ~__ ___-. __. Sndowsky 477 :3.X 615 13.2 .,. 3.9 (1) (1) (1) (1) (1) (`1 Gradient et ill., with amount 1953 (IOS,). smoked. _____ ~~~ Wyndrr and (i :3 4.1 67.6 133 20.6 29.3 36.1 (`) (9 -(a) (`) v ) (4) COlVlfit?kl, ,053 (314). Watson and 265 1.9 71.7 287 9.7 61.6 35.6 36 58.3 2.x 181 32.0 1.1 3.3 Conte, 1954 (305). -~ (;stdl, 135 0.7 6X.1 135 16.9 14.0 326.8 t') (1). (`) (`1 (1) (0 1954 (107). TABLE A4.-Group characteristics in retrospective stzcrlies on lung cancer and tobacco use (cont.) SM z Smokers. NS = Nonsmokers. Md.3 Females Author. CCiSC?S Controls Cases Controls Year. R%ve - Relative Comments reference Percent Percent Percent pc;t Percent Percent Percent Percent risk 2 non- heavy non- ratio Num- non- heavy non- ratio smokers smokers' Number smokers smokers' SM:NF heavy ber smokers smokers' Number smokers smokers' SM:NS? Randig, 415 1.2 34.2 381 6.8 17.9 35.1 33 51.5 3.0 131 70.3 0 2.2 1954 (218). Wynder et al., (`) (4) (`) (4) (4) (`) . . . 105 56.2 16.2 1,304 66.0 3.4 1.4 1956 (911). Segi et al., 166 .~I . . . 2,124 . . . . ,. . Quantities 1957 (?50). smoked stated as averages only. Differences are statistically significant. Mills and PlTter, 1957 (187). 434 x.4 26.0 1,588 27.6 5.3 4.2 94 83.0 4.3 1,722 73.3 0.5 0.6 Percent "heavy" smokers under- stated. Only 50:; S"1`YLIJ response among female cLlscs. Stocks, 2.101 1.9 28.2 6.960 8.7 22.3 4.9 255 57.6 17.2 3,402 68.6 10.7 1.6 1957 (268). Schwartz and 602 1.0 53.2 1,204 9.6 36.2 10.4 (`1 (4) (4) (`) (1) (4) Denoix, 1957 (147). Haenszel and (*) (`) (6) (`) (4) (4) 15x 51.9 14.6 339 694 8.2 2.6 Shimkin, E 1968 (113). d TARLE A4.--Group characteristics in mtyospective sfrc.tlics OPL lung camcr and tobacco MC (cont.) SM = Smokers. NS = Nonsmokers. M&S FelI%-&S Author, CFXSCS Controls CCiSf3 Controls war, R&W reference Percent Percent Percent Percent Relative Commrnts Percent Num- non- heavy Percent heavy Percent Percent risk non- ber ratio heavy smokers smokers' "all- Number non- heavy ratio smokers smokers' SM:NS? Number smokers smokers' Number smokers smokers' SM:NS' Lombard and 500 1.6 4,238 11.0 7.9 (4) (4) (1) (J) (1) Snegireff, (`1 Authors' 1959 (176). calculations for heavy smoking based on lifetime number of packs of cigarettes. PLWlU, 1,477 6.6 34.5 713 37.2 20.8 8.4 129 85.3 26.4- 1,060 91.6 ; 0.7 1960 (211). 1.9 Quantities given only in grams per day. Hal?llSZel 2,191 3.4 41.9 (4) 16.2 12.0 6.2 (4) (1) (1) - (1) (4) (`) . . Population et al., 1962 (212). sample of R1.516 used as base. Not a case- control study. Lancaster, 23x 2.5 86.1 476 20.1 11.2 9.8 (`)T (`1 (4) (4) (4) 1962 (158). (4) . Haenszel and (`) (4) (4) (4) (4) (4) . . . 749 60.9 11.5 (&I 67.3 Taeuber. 2.5 1.3 Population 1964 (11.5). sample of 34.33S used 88 base. Not a case-control study. TAHLE Al.-Grout cltaructeristics in retrospective studies on lung cancw nnd tobacco usr (cwt.) SM = Smokers. NS = Nonsmokers. M&S Females Author. Cases controls Cases Co"trols Ye==, *fitiF Relative Comments reference Percent Percent Percent ?erc;t Percent Percent Percent percent risk %?- "On- heavy non- ratio non- heavy non- smokers smokers' Number smokers smokenl SM:NS Number smokers smokers' Number heavy ratio smokers smokers' SM:NS? Wicken, 803 4.0 40.0 803 14.0 22.0 8.9 151 58.0 29.0 151 80.0 17.0 2.9 Heavy smokers- 1966 (308). greater than 23 a day. Gelfand et al., 32 6.3 . . 32 63.0 . . . `26.3 (4) (`) (`) (4) (4) (1) . 1968 (98). -- Hitosugi. 124 6.6 67.8 1,839 13.2 66.0 2.6 61 54.1 6.6 2,352 80.5 2.9 2.3 Air pollution 1968 (225). fou"d to have no effect on lU"Y Cancel rates of non- smokers. Heavy amokers-great- er than 15 a day. Bradshaw and 45 0.0 341 31.7 . . (4) (`1 (`1 (`1 (4) (4) . . Schonland. 1969 (41). Or"los et al., 94 7.5 58.5 1,811 42.9 58.9 9.3 24 95.R 0.0 1,278 Xl.7 9.7 0.2 Heavy smokers- 1969 (204). greater than 15 R day. Wynder et al.. 210 1.4 67.5 420 21.0 40.9 320.8 30 16.7 44.0 132 57.6 23.3 6.18 Heavy 1970 (334). sm<,kers- grenter than 20 II day. ' For this table, heavy smokers are defined BS those smoking 20 or more 3 Based upon fewer than 5 case nonsmokers ii cigarettes per day, unless otherwise stated. 4 Does not apply. w `Computed according to method of Cornfield. J. (61). TABLE A?`.-Grouping of pulmonary carcinomas Group I: A. Epidermoid carcinoma. B. Small cell anaplastic carcinoma ("oat-cell" carcinoma). Group II: A. Adenocarcinoma. B. Bronchiole-alveolar cell carcinoma. C. Carcinoid tumor. D. Mucous gland tumor. Extra (not included in I and II): A. Large cell undifferentiated exrcinoma. B. Combined epidermoid and adenocarcinoma. Unsuitable for diagnosis. SOURCE: Kreyberg, L. (15.3). 334 TABLE AlB.-Autopsy studies concerning the presence of radioactivity in the lungs of smokers NS = Nonsmokers. SM = Smokers. AlIthOt+, Year. Number country. of Results Comments reference cases Little et al.. 1964, U.S.A. (175). NS . . . . . . 5 SM _. . . . . . . .1!2 Port0 level.3 in vavioue tisauelr (pclg tissue) Vertebral bodies, renal Peribronchia! Bronchial cortex. spleen, and lymph nodes Lung (average) epithelium urinary bladder showed 0.011 0.001-2 negligible no differences. 0.011 0.008 0.028-1.25 Hill, 1965, U.S.A. (1%`). Mcaw Pd'o levels in variown tiswrss (pc/kg tissue) The authors found no Brmchial tree AlVLdZC Total lung Liver Kidneu excessive concentrations NS . . . . . . 6 3.1 3.4 3.2 14.8 15.0 at bronchial bifurca- SM . . . . . . . . . . . . 4 7.3 9.9 8.6 20.0 20.5 tions. Little et al.. 1966, U.S.A. (274). NS . . . . . . . . 8 SM . . . . . . .26 P&O levela in variou.4 epithelial tiusw regions of lung (pc/g)t Site: Mainstem bronchus . l year. tc. 112 51 O/61 O/61 f Experimental group. strain.) C. Whole condensate. SE. 672 . . . 220 10/220 6/220 TABLE AIS.-Experiments concerning the efects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cont.) Author, A%Y' A. Method, year. B. Frequency and/ country, strain or duration. Results Comments reference C. Material Wynder Swiss mice A. Painting skin. Percent Percent et al.. B. Varied for 12 Treatment: Number papillomw carcinomas 1967, months. S/week ..,................ 60 12.0 8.0 U.S.A. C. Whole condensate B/week . . . . . . 50 38.0 16.0 (828). in acetone. Z/week . . . . . . . . 40 10.0 3.0 l/week . . 40 6.0 . Wynder and CAFl or A. Painting shaved skin. Percent Percent Swiss mice noted Wright, Swiss B. S/week for lifespan. Treatment CAFI: Number papillomaa carcino7naa to be more smt- 1951, mice. C. Whole "tar" or nicotine Whole "tar" . . . . . . . 30 53.0 27.0 ceptible. U.S.A. free "tar" derived Nicotine free "tar" . 40 13.0 26.0 Majority of carcino- (S28). from pipe and Cigarette "tar" . 30 30.0 30.0 gem noted to be cigarette tobacco. Pipe "tar" .__.._......... 30 60.0 20.0 in neutral fraction Treatment Swiss: of condensate. Whole "tar" 30 53.0 10.0 Nicotine free "tar" . 40 43.0 20.0 Cigarette "tar" . 30 63.0 33.0 Pipe "tar" . . 30 63.0 60.0 Gellhorn, Paris R III A. Painting shaved skin. Treatment: Popillumalr Carcinomas 1958, mice B. Varied for l-2 years. Benzpyrene (twice only) 20/529 6/629 U.S.A. C. "Tar" in acetone. Croton oil (5/6 week) 4/26 O/26 (99). benzpyrene. "Tar" (5/6 week) . 3/659 Z/559 eroton oil. Acetone (E/6 week) o/30 o/30 "Tar" and croton oil (5/6 week) 10/175 O/176 Bock and Swiss A. Painting skin. Percent Moore, female B. S/week for lifespan. Group: Number living at 6 mo?tths Skin tumors at 64 weeks 1959. mice C. Whole condensate Painted . . . 49 13.0 U.S.A. irradiation. Painted and irradiated 65 44.0 (28). Irradiated . . . . . . . 36 . . . 3 TABLE A13.-Erpwimnts concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or its comtituents u~)ot~ nni),lrrls (uIw~.) Author, Animal A. Method. Year. and a. Frequency and/ country. strain or duration, Results reference C. Material Comments Druekrey, Rats A. Subcutaneous G70up: 1961, Sarcowm.3 t Control group. inlectiu". tc . . . . . . . . . l/75 GW"l?2"Y 13. l/week for 60 weeks. i Expeumental group. $E ..._........_..._............,,, 15/75 (7.9). C. Smoke condensate in trirauwli" nnd alcohol. Bock et al., ICR Swiss A. PRintins shaved skin. - Sllr?~iz~illg Pcrcc n t Z'urcnt Sl;iu 1962, mice R. IO/week for 1 year. Trcutment: nt 1x WCT/,~S Skin Cnnccr U.S.A. neoplasia (`. Ciwrette "tar". Standard ciaarette 24/30 (Sl). 25.0 54.0 Standard cigsrette 21i30 5.0 57.0 Stnndard cigercttc 18130 33.0 44.0 Standnrd cigarette 13'30 23.0 62.0 Filter cigarette 30/30 7.0 27.0 Filter cigarette 30130 3.0 23.0 Acetcme only fin/fit? Control . . . 65/65 Roe, Albino mice A. Painting shaved skin. Trer.tment: 1962. Sur~iwws Pcrccnt skin twnors H. S/week for 84 weeks. Author concluded "Tar"a"d0.025mg.B~o~P .._. 26 1J.S.A. 12.0 C. Whole smoke "tar" that cigarette "Tar"and0.06mg.B(a)P 15 (225). 27.0 smoke contains with added B(a)P "Tar" and 0.25 mg. B(a)P 15 13.0 cocarcinogens. in acetone. "Tar" and 1.25 mg. B(a) P 14 64.0 B(a)P 1.25 mg. ,. _. 14 Druekrey and Rats A. Subcutaneous Treatment (BP mg.:wecli): Schildbach. Snrconln.9 injection. 30 1963. s/30 Il. l/week for 700 days. 10 Ger"L_"Y 14140 C. Benzpyrene in (82). 3 X/60 trirapwlin. - (solvent) ,. ,, ,. ,, Z/75 Author, yeal-9 country, reference TABLE Al3.-Ezperinwnts concerning th effects of the skin painting OT subcutaneous injectiorr of cigarette smoke condensate or its constitzen,ts upon, animals (co~f.) ~___ ..__~~ Animal A. Method, ana 13. Frenuency and/ strain or duration, C. Material Results Comments __- Hornburger CAFl mice A. Painting shaved skin. CO"l,h2Ll~ Percent et al., B. Z-3/week for 2 years. Condensate: autopaiea Papillomaa 1963. C. Various tobacco Pipe tobacco 77 35.0 U.S.A. (131). cOndensates in acetone. Cigar tobacco x4 Cigarette tobncco x2 Benzpyrene 54 Acetone only _. 62 27.5 27.0 10.0 Bock et al., 1965, U.S.A. (29). Swiss ICR A. Painting clipped skin. mice B. lo/week for 11 weeks. C. Various smoke condensates in acetone. Percent concentration of ta, (type cigsrette) : 8.2 (standard) 8.3 (standard) 7.9 (English standnrd) 8.7 (king) 4.0 (filter) ,.. 4.4 (filter) 2.5 (filter) Acetone control untreated cOntlol Z'wrcnt szcr7,ivitz.u 1 I zrr~cka !)(i.O !)3.0 90.0 100.0 9X.0 100.0 97.0 94.0 100.0 . . Pcrwnt CLl?LC-<`? 30.0 27.0 24.0 28.0 9.0 10.0 4.0 ____ Pwccnt Carcinomas 15.0 16.0 15.0 20.0 Prrcent cancer ana papillama 67.0 67.0 58.0 69.0 36.0 41.0 16.0 .___ ____.___ Van Duuren Swiss ICR/ ___. A. Painting shaved ski". et al.. Cumulative ?~wnbcr of mice: roith t 7.12-dimethyl- Ha mice B. Initiating agent once- Initiator Promotor Par~illoma.9 Carcinomas 1966. benz ( B ) anthraccne. Promoter 3/week for DMBA .Ether tobacc,) leaf ,`strnet 4120 U.S.A. o/20 12-14 months. 0 . .Ether tobncco leaf wtrxt _. o/20 (296). O/20 C. DMBAt. tobacco DMBA .Choloroform tubacro leaf extract l/20 O/20 extracts riga- 0 . .Choloroform tobnrw lenf extract _ o/20 o/20 rette "bd'. DMBA Cigarette "tar" 11120 4/20 0 . .Ciunrctte "tnr" O/20 o/20 0 . . .Awtone E o/20 o/20 ~ ~~~~___ .I__.__~~ ~-~. __- ~~ ~___~~ _-__ TABLE AlS.-Experiments concerning the effects of the skin painting or subcutaucous injection of cigarette smoke condensate or its constituents upon animals (cont.) Author, yeal'. country. reference Animal and strain A. Method l3. Frequency and/ or duration. C. Material Results C0ltlllleTlts Munoz et al . . Swiss ICR/ A. Painting shaved skin. Dark tobacco "tat" 1968. 48 mire B. Varied. 4.0 percent ................. U.S.A. C. "Tar" from dark 8.0 percent ................. and (Colombian ) and Light tobacco tar: Colombia light (U.S.A.) 4.0 percent ................. (197). tobaccos. 8.0 percent ................. Acetone ..................... I At risk TUWUJKi 81 SO 71 46 95 26 98 64 91 0 Carcinomas The authors noted 17 a shortened latent 16 period for dark tobacc". 6 20 0 Davies and Day. 1969. Great Britain (65). Albino mice A. Painting shaved skin. IS. Varied regimen. C. Cigarette and cigar condensate. Percent of carcinoma-bearing animals at 116 weeks The authors concluded Tmatmcnt: (actual number of animnln in parentheses) that the lack of 300 mg. 1.50 n&g. 75 mg. 37.5 mg. difference in re- Standard cigarette . . . 20.1(29) 13.2(19) 0.7 (1) sulta from the first Cigar 27.1(39) 11.1(16) 2.1(3) and third groups Cigar tobacco cigarette 13.9(10) . under treatment suggests that the increased tumori- g&city of cigar tobacco is due to physical processing tsctors. TABLE A14.-Experiments concerning the effect of cigarette smoke or its constituents on tissue and organ cultures Author, Ye*=, country, reference Tissue or org*n culture Material/delivery Results Bouchard and May. 1960, France (35). Mouse lung. Tobacco smoke condensate perfusion for 24 hours and subsequent grafting under renal capsule of mice. Increased number of mitotic abnormalities in the treated cultures: particularly in the first 5-10 days after grafting. Awa et al.. 1961, Japan (16). Human fetal lung. Direct exposure to smoke from: a. Whole cigarettes. b. Tobacco alone. c. Paper alone. Paper smoke induced the most severe changes, consisting of cytoplasmic vacu- olization and nuclear pyknosis. Also noted were a decrease in the mitotic index and an increase in abnormal divisions, more so with paper smoke than with the other two. Thayer and Ke"Sler, 1964, U.S.A. (275). KR mammalian tumor cells. Cigarette smoke condensate applica- tion; filtered and unfiltered cigareftes. Significant growth inhibition was shown in unfiltered smoke. Cytotoxic compo- nents were noted in hoth the gas and particulate phases. Berwald and Sachs, 1965. Israel ( 1" ) SWR mice and golden hamster embryos. Direct application of benzo(a)pyrene IB(a)PI. Benzo(a) pyrene caused increased cell transformation as manifested by: a. Hereditary random growth pattern. b. Progressive growth as tumors after subcutaneous injection into adults. c. Ability to grow continuously in culture. Cracker et al., 1965, U.S.A. (63). Diamond. 1965. U.S.A. (68). Suckling rat trachea in orgnn culture. Variuus con- tinuous cell strains (mammalian). Application of B(a) P in acetone. Application of II (a) P in either dimethylsulfoxide (DMSOI or paraffin. Treated cultures revealed cellular metaplasia. basal cell hyperplasia. increased mitotic rate, and increased H"-thymidine incorporation proportional to the con- centration of material and duration of application. Inhibition of cell growth. TABLE A14.--Ercprri)tlents concerning the effect of cigarette smoke OT its constituents on tissue and organ cultures (cont.) Author, year. CXJ""tl-Y, refercnw Material/delivery Results Il,,renfreund et al., Hamster lung Application of a. increased appearance of new small chromosomes and telocentric chromosomes. 1%x, tissue. B(a) I' in either b. Increased ability to grow in hamster cheek pouch and there become spindle- U.S.A. (89). DMSO or dimethyl- cell sarcomas. fc~rmamide. Chickerl embryo ~. Application of .-.~__ Increased mitotic activity and increased incidence of anomalous mitoses. 1:1(x. muxular tobar?,, extract. F'wlnre (110). explants. Lxhnitzki. Mice nronatnl Application of a hy- a. Increased basal cell hyperplasia and pleomorphism of newly formed cells. l!KX. t, achra. drocarbun-enriched b. Increased epithelial mitosis. EnKland (160). fraction of whole smoke cundensate. I,us"itzki, Human fetal lung Application of a hy- a. Cellular enlargement and promotion of growth of new bronchi. 196x, in organ culture. dmcarbon-enriched b. Increased mitoses, bronchial epithelial hyperplasia. and 8c1uamous metaplasia. E"gla"d (161) fraction of whole c. Inhibition of stromal growth. smoke condensate. - - Char, et al., Muuse lung Application of a. Cellular disorganization. I!l6!l. burl embryonic B(nlP in DMSO. b. Cellular pyknosis: nuclear shape and size irregularities. U.S.A. (54). cultures. c. Increased epithelial mitotic rate and decreased mesenchymal mitotic rate in those cultures exposed to B(a) P versus those exposed to pyrene or DMSO. Leurhter,bergel Mouse lung Exposure to fresh smoke: and and kidney a. Unfiltered. a. Decreased RNA production, pyknosis, and death of cells. Leuchtenberger, tissue and b. Activated b. Similar results, hut changes were of minimal severity. l!f68. t3I'&?an cultures. charcoal filter. Switzerland (165). c. Cigarette or c. Similar effects as group a., but less swerc. cigar tobacco. __- TABLE Al4.--Ezf,c,rit,crt/ts cowcerning the effect of cigarette ,ytttol<(' 01' its constit/(ents 0~1 tissue and organ cf(ltures (cont.) __~ ~~..____ ~_____~__-~~~ Author, ______- YCBI`, Tissue OP country. urgan culture Mntcrial/delivery reference Hr5ults ~-__~ Cracker, Various organ ~__~ __~ -- Ayplirntion of ___~ -__ Squamous metnplasia: frwuent pleumuuphic cells: dedifferentiation of epithelium 1910. cultures: I%(n)P in scrutn. (inhibited by Vitamin A). U.S.A. C/X?), a. Wholr suck- lina hamster tracheas. 1). Whole brvn- rhinl tubes from late fetal doas and monkeys. ~__~ ~--__~ ~ ---~ ~._~~~ ~ ..--~ ~. -~__ L v. Author. war, countlY. reference -__ Blacklock. 1051. GlY*t Britain 124). - Della Porta et al.. 195X, U.S.A. (67). TABLE A15.--Ezpm-iments concerning the effect of the instillation or implantation of cigarcttc> smoke or its constituents into the tracheobronchial tree of animals Animal and strain CR white rats. A. Method B. Frequency and/ or duration Results C. Material .- A. Injection into 4.46bcnzpyrene: Number with tumors/number czposed lung parenchyms a. 3 mg. in olive oil 5/6 **rconl*. by thol.ncotomy. b. :: mg. in olive oil with dead Tb bacilli Z/4 sarcoma. 4/8 squamous cell carcinoma. I{. once. c. 5.75 mg. in cholesterol pellet l/R squamous cell carcinoma. (`. 3.4~ber,zp.vrene Cigarette "tar": in olive oil, a. In olive oil O/10. with dead Tb b. In olive oil with dead Tb bacilli l/X sarroma. l/R squamous cell carcinoma. bacilli or in Controls: cholesterol. a. 0.15 cc. olive oil o/4. cipnrette "tar". b 0.15 cc. olive oil with dead Tb bacilli n/4 c. Cholesterol pellets o/4. - Syrian golden hamsters. A. Direct tracheal instilllation. B. Weekly up to 45 weeks. C. 1 percent 7,12-dime- thylbenz(a)anthra- cene (DMBA). cigarette "tar" roncmtrate. Mate&l: a. DMBA 50 pg./week b. "Tar" 200 pg./week c. DMBA 50 ,*g./week then "tar" 200. WFEka 45 32 12 ,& week d. DMBA 100 fig./week e. DMBA 100 pg.lweek 1 and "t.al." 500 \ pg./week ) 30 17 20 Survivors at 20 twskslosiginal number exposed 10/20 11/21 9/20 l/20 9/20 Number of hamsters with tracheobrmwhial carcinomas at death 2 4 3 Rigdon. 1060. U.S.A. (221). White Pekin A. Intrntrarheal No neoplastic changes noted in either the experimental or control groups. ducks. injection. Controls: 99 B. Daily for 721 days. Experimental C. Tobncro condensate group: 52 in liquid p&r&turn. TABLE A15.-Experiments concerning the effect of the instillation or implantation of cigarette smoke or its constituents into the tracheobronchial tree of animals (cont.) Author, A. Method Year. B. Frequency and/ country, A:iIT' or duration Results reference strain C. Material ___. Blacklock. CB white rats. A. Inoculation at Number Percent with 1961, thoracotomy. of rats malignant tumo+e Great B. Once and sacrificed C""tr"ls . . . . ~. . . . . . ~. 276 1.5 (1 carcinoma, 3 sarcomas) Britain at 1 week-2 years. Cigarette condensate _. _. . 72 11.1 (6 carcinomas. 2 sarcomas). (15). C. Cigarette tobacco Eucerin alone _. _, 44 2.3 (1 sarcoma). smoke condensate rn eucerin. Herrold and Syrian golden A. Intratracheal Number of Number with Number of tracheo- Dunham, hamsters. inoculation. Material: hameters tumors bronchial tumors 1962, B. 0.5 ct./week for B(a) in TweenGO 6 3 5 (3 pspillomas, 2 carcinomas). U.S.A. 5/6 months. B(a)P in TweenFO' 6 3 9 (4 pspillomas, 5 carcinomas). (121,. c. Benz0 (a) pyrene Tween60 6 0 I" Tween60 B(a) P in olive oil 6 0 or olive oil. Olive oil _. 6 0 Rockw et al.. Doas. 1962, U.S.A. (azr). A. Bronchial inoculation 0~' stimulation. B. 3-5 times/week for rr* to 5 years. c. Cigarette smoke condensate. Sqlcamous P7C- metapluaia Number Invasive Carcinoma- enneeroua with atypical lnflam- Procedure: of dog.9 carcinoma ii1 sit76 changes changea mation Controls 27 6 24 Manipulation of bronchus 25 - - 7 26 Smoke condensate 130 1 3 25 98 128 ____. ______ __- Tipton and Mongrel dogs. A. Bronchial Crockw, Control proup and inoculation. 1964, experimental B. Daily for 8 days. U.S.A. Kl`OllP--19. C. Cigarette smoke (177). condensate. iz _____ ._I_ .-____- Y Rapid induction of swamous metaplasia in condensate-exposed animals. No tabular data is presented. TABLE A15.-Experiments concerning the eflect of the instillation or implantation of cigarette smoke or its constituents into the tracl~eobronchial tree of animals (cont.) Author, year, country, reference Animal and strain A. Method B. Frequency and/ or duration C. Material Results Saffiotti et al., Syrian golden 1966, hamsters. 1J.S.A. (237). A. Intratracheal inoculation. B. Weekly for 15 weeks. C. B(a)P (3mg.j attarhed to fine hematite dust. Number autopsied: Male 23 Female _. _. 17 Percent tumor- Nwmber of bearing of tmnor-bearing auruivors at animal8 15 zoecks 15 100.0 11 100.0 Total Total number nscmbcr of rcspiratorv of turnore tract ca?wPT* 24 18 17 16 Kuschner, 1968. U.S.A. (1.57). Hamsters A. Wire mesh pellet implantation into bronchus. B. Lifetime. c. B(a)P. methylrholan- thwnr (MCA). Number of surrivors/original Implant: number in group Wire mesh only _. __ __ _. _. _. _. 34135 MCA RR/91 D(a)P x9/91 Number of animals with lung canecr -- 43 57 Saffiotti et al., Syrian golden 196X. hamsters. U.S.A. (235). Borisyuk, Wistnr rats. 1969, Russia (J4). A. Intratracheal inoculation. B. Weekly for 15 weeks. C. B(a) I' attached to a fine hrmatite dust. A. Intratrarheal intubation. B. Monthly up to IO months. C. Cigarette "tar". Number of hamster8 with Number alctopaied respiratory Inoculate: tract tumor.3 Control 176 B(a)P in hematite 55 36 Hematite only _. _. _. 41 Number final/ Dumtiou of initial inocz&tion Inoculate: (months) Controls 11/20 12 Unfractionated "tar" 24/200 10 Denicotinized "tar" 9/45 R (l/9 metaplasia) Neutral "tar" fraction 14/100 8 (Z/14 carcinomas, l/14 papillary adenoma). TABLE Al&-ll'xperiments concerning the eflect of the inhalntion of cigarette smoke or its constituents upon the respiratory tract of animals (Figures in parentheses represent total number survivors in specific group) - -~-~__~~ Author, war. At%=' A. Type of exposure c0untl-Y. B. Duration Hesults reference strain C. Material Comments Lorenz et al.. Strain A mice: A. Chamber. -~ 1943, E. No increase in tumor formation over that noted in controls.This strain of mice does tc. 97. R. Up to 693 hours. U.S.A. (177). have a hereditnw IE. 97. C. Cigarette smoke. tendency t<, tumol formntion. tc'. Crs were Netherlands c. 32. up to 684 days. E. 79.0 found. (295). E. 29. C. Cigarette smoke. - Leuchtenberaer CF, albino mice: A. Chamber. 23 of tkc espr~imcntnl mice showrd: et rd., C. snd E. 275. B. To 8 cinarettes 15 basal cell hyperplasin. 1958. per day from 14 atypical bnsnl cell byperplasiu. U.S.A. (166). 11-201 days. 7 dynplnsia. C. Cigarette smoke. 2 squamous cell metnplasia. .~ Cuerin, .__ IC and Wistar A. Chamber. Pmwutrrgc of rats with t~trlmo~rr~rti tamom 1969. strain rats. B. 45 minlltes C. 2.4 percent of :(!I survivors. Frence (loa). c. 40. per day from E. 5.1 yercent of 68 survivors. Ix. 100. Z-6 months. C. Cigarette smoke. ~. -___.__ -~~ -~ TABLE AlG.-Experiments concerning the eflect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals (cont.) (Figures in parentheses represent total number survivors in specific group) Author, Year. country, reference Animal A. Type of exposure and B. Duration strain C. Material Results Comments Leuchtenberger Female CFI mice: A. Chamber. et. al.. c. 243. B. 54-G cigarettes 1960. E. 360. per day for 1 U.S.A. (167). month to 2 years. Namber C. Cigarette smoke. of mice 151 150 36 __.... 36 . . . 34 ,..... 51 . . . 63 __.... Number of cigaseltes 25-1.626 0 loo- 200 25& 500 600-1.600 loo- 400 IO& 400 Ezposwc length (months ) 1-23 0 l- 3 4- 8 9-23 3- 6 3- 6 Number with wvcfe bronchitis; pcribronchilis; atypical &the- lial prolifcrntion 30 2 7 7 8 4 17 Leuehtenberger Female CFI mice: A. Chamber. Number Pcrcsnt of mice Presence of tumors et al.. c. 166. B. l/+3 cigarettes of mice Ezpomre with pulmom+y showed an age. 1960, E. 231. per day for examined ( daua I adenomatous tumom relationship U.S.A. (168). 17-600 days. 81 0 66 independent of C. Cigarette smoke. 39 17- 99 41 smoking exposure. 35 , 100-199 37 61 _. _. . . , 20&600 66 Otto. 1963, Ger"la"Y (206). Albino mice. C. 60. E. 169. A. Chamber. B. Approximately 12 cigarettes per day for varying intervals. C. Ciaarette smoke. Number of mice examined C. 60 E. 189 Ew~osrre Number with NO"& lung tulnorr Varying 3 pulmonary adenomas. upto 21 pulmonary adenomas. months. 2 epithelisl carcinomas.