S68. 869. $70. 871. $72. 873. S74. S75. S76. ST7, S78. $79. $80. ceedings of the 11th Aspen Emphysema Conference, Aspen, Colo. U.S. Department of Health, Education, and Welfare, Public Health Service Publication 1879, 1969. Pp. 159-181. QuInLaN, M. F., Sataan, S. D., Swit, D. L., Waener, H. N., Jr., Proctor, D. F. Measurement of mucociliary function in man. American Review of Respiratory Diseases 99(1) : 18-23, January 1969. Rao, B. S., Conn, F. E., Evpripce, F. E., Hancock, E. W. Left ventricular failure secondary to chronic pulmonary disease. In: Current Research in Chronic Respiratory Diseases. Proceedings of the 11th Aspen Emphy- sema Conference, Aspen Colo., U.S. Department of Health, Education, and Welfare, Public Health Service Publication 1879, 1969. Pp. 129-134. Ryoer, R. C., THUBLBECK, W. M., Govan, J. A study of interobserver varia- tion in the assessment of the amount of pulmonary emphysema in paper- mounted whole lung sections. American Review of Respiratory Diseases 99(3) : 354-364, March 1969. RyYLanver, R. Alterations of lung defense mechanisms against airborne bac- teria. Archives of Environmental Health 18(4) : 551-555, April 1969. Ryrwanver, R. Environmental air pollutants and lung defense to airborne bacteria. In: Current Research in Chronic Respiratory Diseases, Pro- ceedings of the 11th Aspen Emphysema Conference, Aspen, Colo. U.S. Department of Health, Education, and Welfare, Public Health Service Publication 1879, 1969. Pp. 297-304. SAINDELLE, A., Rurr, F., GumtterM, R., Parrot, J.-L. Libération d’ histamine par la fumée de cigarette et certains de ses constituants. Revue Francaise D’Allergie 8(3) : 137-144, July-September 1968. Scuasort, J. C. Lactic dehydrogenase from human lung inhibition by cer- tain water-soluble ciliastatic components of tobacco smoke. Journal of the South African Chemical Institute 20: 103-112, October 1967. Spain, D. M. The distribution of tracheobronchial metaplasia (regenerative hyperplasia) (age, sex, cigarette smoking, and relation to Reid Index)— Preliminary report. In: Current Research in Chronic Respiratory Dis- eases. Proceedings of the 11th Aspen Emphysema Conference, Aspen, Colo. U.S. Department of Health, Education, and Welfare, Public Health Service Publication 1879, 1969. Pp. 183-186. Sranescu, D. C., Gavritescu, N., TecuLescu, D. B. Effect of smoking on pulmonary mechanics and ventilation in young healthy males. Respiration 25(5) : 484-440, 1968. Sranescu, D. C., Tecutescu, D. B., Pacuragu, R., GavgiLescu, N. Chronic effects of smoking upon pulmonary distribution of ventilation in heaithy males. Respiration 25(6) : 497-504, 1968. Stone, R. M., Ginssera, R. J., CoLAPENTO, R. F., Pearson, F. G. Bronchial artery regeneration after radical hilar stripping. Surgical Forum 17: 109- 110, 1966. TAKENOUCHI, S. Boji gyosho gyosha ni okeru mansei kokyuki shogai ni kansuru ekigakuteki kenk yu. (Epidemological studies on chronic respira- tory disturbances among employees in a certain organization’s work- shop.) Nara Igaku Zasshi 19(5-6) : 749-763, December 1968. ULMER, W. T., REICHEL, G., WERNER, U. Die chronisch obstruktive Bronchitis des Bergmannes. Untersuchungen zur Hiufigkeit bei der Normalbe- viélkerung und bei Bergleuten. Die Bedeutung der Staubbelastung und der Einfluss des Rauchens. Internationales Archiv fiir Gewerbepathologie und Gewerbehygiene 25(1) : 75-98, December 20, 1968. 51 $81. Weiss, W. Cigarette smoke gas phase and paramecium survival. A method for intermittent exposure. Archives of Environmental Health 17(1) : 62- 64, July 1968. $82, WeissBecKeEr, L., CARPENTER, R. D., LucHsINGER, P. C., OSDENE, T. 8S. In vitro alveolar macrophage viability. Effect of gases. Archives of En- vironmental Health 18(5) : 756-759, May 1969. S83. WenbDEL, H. Zur Bedeutung des Rauschens fiir die chronische Bronchitis Zeitchrift fiir die Gesamte Innere Medizin 23(5) : 147-151, March 1, 1968. $84. West, J. B., Guazier, J. B., Hucues, J. M. B., Matoney, J. E. Effect of gravity on the morphology of pulmonary capillaries and alveoli. In: Current Research in Chronic Respiratory Diseases. Proceedings of the 11th Aspen Emphysema Conference, Aspen, Colo. U.S. Department of Health, Education, and Welfare, Public Health Service Publication 1879, 1969. Pp. 135-187. S85. WINKELSTEIN, W., Jr., Kantor, S. Respiratory symptoms and air pollution in an urban population of Northeastern United States. Archives of Environmental Health 18(5) : 760-767, May 1969. 52 CHAPTER 3 Smoking and Cancer Contents Epidemiological Studies_______.-.-..___--.----- 2-2 eee Lung Cancer_________---.---------- eee Oral Cancer____---.-----.-------------2- 2 e eee Laryngeal Cancer..__.-.-.-------------------------- Cancer of the Urinary Bladder and Kidney_____.._____- Cancer of the Pancreas________..____-.-------------- General Aspects of Carcinogenicity__....___....__.-.-_-__- Tobacco Alkaloids._____.-..-_----.--_---- eee Experimental Aspects of Carcinogenesis. ___._______...____- Retention of Smoke Constituents. .____.....__._..22-- Changes in Cell Cultures Induced by Cigarette Smoke. __ Experimental Studies of Bronchogenic Carcinoma in Page 55 55 55 58 58 60 60 61 61 62 62 62 62 63 64 65 69 53 SMOKING AND CANCER SuMMARY Previous reports (59, 60, 61) have presented the evidence that ciga- rette smoking is a major cause of lung cancer and that cessation of cigarette smoking sharply reduces the risk of dying from lung cancer as compared to the risk taken by those who continue to smoke. Ciga- rette smoking was also shown to be a significant factor in the causa- tion of cancer of the Jarynx. A strong association between various forms of smoking and cancers of the buccal cavity, pharynx, and esophagus was also shown. Data were presented which indicated that cigarette smoking was associated with cancer of the urinary bladder. Data were aiso presented which suggested that cancer of the kidney and pancreas may be related to cigarette smoking. During the past year, both population studies and laboratory studies from various countries have added to the weight of the evidence linking smoking and cancer. A major study of histological changes in the larynx has demonstrated the higher risk of premalignant changes among smokers. More studies have been done to identify those substances in tobacco smoke which take part in carcinogenesis. New animal models for the experimental study of respiratory cancer, which may be helpful in elucidating the mechanisms of respiratory tract carcinogenesis, have been developed and refined. EPIDEMIOLOGICAL STUDIES It is interesting to note that epidemiological information on ciga- rette smoking and lung cancer, similar to that which has been collected in the United States and Western European countries, is now being re- ported from Eastern Europe and Africa as well. Lung Cancer In Norway, a study of histologically proven cases of lung cancer by Kreyberg demonstrated the low frequency of lung cancer among nonsmokers. The cases were collected between 1950 and 1964 from two hospitals and a diagnostic laboratory which service all parts of Nor- way. The author states that the population represented in this study is most probably geographically representative of the whole country. In comparing his results in Norway with those in other European 55 360-928 O—69-——5 countries, Kreyberg stated that a nonsmoking Norwegian population today should present lung cancer cases in the same number, with the same sex ratio, and with the same representation of histological types as prevailed in Norway 40 years ago, and in Europe in general at the beginning of this century (24, 25). The risks of developing various histological types of lung cancers among smokers, as contrasted to nonsmokers, are presented in table 1. Two facts are strikingly apparent from the table. First, the preponderance of the higher risk of lung cancer in smokers lies in the categories of epidermoid carcinoma and anaplastic small cell carcinoma. Second, while female smokers have a higher risk of developing lung cancer than female nonsmokers, the relative risks are smaller than those for males. At least part of this difference may be accounted for by differences in smoking habits be- tween men and women. Women tend to smoke fewer cigarettes, to smoke brands lower in tar and nicotine, inhale less and smoke less of each cigarette than do men; therefore, women have lower exposure to cigarette smoke. TaBLE 1.—Tumor prevalence among males and females 36-69 years of age, by type of tumor and smoking category [Smokers constituted 85 percent of populations studied] Smoking category Expected Risk Sex and type of tumor —_—_- Os onumber ratio Total Smoking Non- among among all methods smokers smokers! smokers Males: . Epidermoid carcinoma. --_------ 434 431 3 17.0 25. 4 Small cell anaplastic carcinoma__ 117 116 1 5.7 20. 4 Adenocarcinoma.__...-.--.-..- 88 83 5 6.28.3 2.9 Bronchiolo-alveolar carcinoma... - __ ---- weoe weeeee ---- Carcinoid__.....-----..-.----. 46 39 7 39.7 1.0 Bronchial gland tumor-_.._____. ---- ---- ween Hone ee a Total__...-2.2--- 22 lee 685 669 16 «©90.7 74 Females: Epidermoid carcinoma. ---..... 12 9 3 75 12.0 Small cell anaplastic carcinoma... 8 5 3 75 6.6 Adenocarcinoma.._--------.... 56 14 42 10.5 1.3 Bronchiolo-alveolar carcinoma... __-_ —— wane eee eee —— Carcinoid_.._---.-------.--..- 32 7 25 6.3 lil Bronchial gland tumor-__._._.__ a--- wee eae ow eeee ~--- Total. ....---2 2-2 ee 108 35 43 18.3 1.9 ' Number that would be expected if incidence rate among smokers was equal to that of nonsmokers. SovuxncE: Kreyberg, L. (#4). 56 Brett, et al. (8) found that the mortality rate for lung cancer in smokers in England was especially high for the smokers who “drooped” the cigarettes off the lip while they smoked, a habit which may result in the delivery of a greater dose of smoke from each cigarette. Gelfand, et al. (79) ina study of lung cancer in Rhodesian Africans, reported a preponderance of smokers among the lung cancer patients as compared to a control group. The authors express the opinion that air pollution does not play a role in respiratory cancer in Rhodesia. In the 1967 Health Consequences Report (59), it was pointed out that the lung cancer risk of ex-smokers declined, relative to those who continued to smoke. It equalled that of nonsmokers about 10 years after stopping smoking, and the rate of decline depended on the num- ber of cigarettes previously smoked and the duration of smoking. Bross, et al. (10) reported that the risk of developing lung cancer is lower among filter cigarette smokers than nonfilter cigarette smokers. Since filter cigarettes are generally lower in tar content than nonfilter cigarettes, this study supports the inference that the tar content of cigarettes is a meaningful measure of exposure to risk. In view of the fact that practically all lung cancer patients started to smoke nonfilter cigarettes and have smoked filter cigarettes only in recent years and for a variable length of time, a more exact comparison of the risks run by smokers of filter and nonfilter cigarettes must await further studies (67). The relationship of smoking to lung cancer in women is an area of continuing concern, since we may expect a continued increase of lung cancer in women with the increase in cigarette smoking among them since World War II. Lombard, et al. (32) show a relationship of cigarette smoking to epidermoid lung cancer in women but not to adenocarcinoma. It is generally agreed that the contribution of ciga- rette smoking to the development of epidermoid and oat-cell lung cancer (Kreyberg Group I) in males is significantly greater than to the development of adenocarcinoma (Kreyberg Group It). An association of other diseases to cancer of the lung is found in a report by Salzer, et al. (48). Salzer and his colleagues have reported in an autopsy study that lung cancer and scars from stomach ulcers are statistically associated and suggested that cigarette smoking may have contributed to both conditions. A study by Stamler, et al. (53) indicated that male cigarette smokers with elevated cholesterol levels had higher rates of lung cancer than those with lower cholesterol levels, Additional studies are needed to confirm and elucidate these observations. Programs have been recently established to perform cytological examinations on the sputum of smokers, since they represent a population at a high risk for the development of carcinoma of 57 the lung. These programs have detected individuals with atypical or frankly malignant cells in their sputum before a shadow has appeared in the lung fields of x-ray (78, 62). Valaitis, et al. (62) reported that some degree of cytological abnormality was found in the sputum of 4.8 percent of the smokers and 0.9 percent of the nonsmokers. Oral Cancer In the Soviet Union, Orlovskiy has shown an association between cigarette smoking and lung cancer, as well as an association between the use of “nas” (a mixture of tobacco and ashes) and the development of cancer of the oral cavity (37). Other studies of interest from around the world include one by Pindborg, et al. (39) on the epidemiology and histology of oral leukoplakia and leukoedema among Papuans and New Guineans. They report that smoking may be more closely associated with these conditions than is the chewing of betel nut which previously was considered the obviously associated habit. A study by Wahi (64) reports on the relationship of tobacco chewing to oral and oropharyngeal cancer in a district in India. Pindborg also presents evidence from India indicating that oral submucous fibrosis (38) may be associated with tobacco use and may result in an oral epithelium more susceptible to the carcinogenic substances in tobacco. In a study of oral malignancies indexed in a large tumor registry in California, Chierici, et al. (73) found that 88 percent of the cancer patients were smokers. The proportion of smokers ranged from 81 to 83 percent for cancers of the gingival and alveolar mucosa, buccal mucosa, hard palate, and lip, to 94 percent or more for cancers of the floor of the mouth, soft palate, tonsil, or oropharynx. Unfortunately, comparable percentages 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 problems, and poor oral hygiene. Laryngeal Cancer Auerbach, et al. (7) studied the histology of the larynx of 942 men, aged 21 to 95, who were autopsied at a single hospital between 1964 and 1967. Cases of primary cancer of the larynx were excluded from the study. Smoking histories for all cases were obtained from family members of the deceased by trained interviewers. The numerous ran- domized histological sections were graded by one observer. Table 2 shows the percentage of cells with atypical nuclei found in the true vocal cord. Of the men who never smoked, 75 percent had no cells with atypical nuclei, only 4.5 percent had sections with areas containing 60 to 69 percent of cells with atypical nuclei, and none had a higher percentage. 58 TaBLE 2.—Number and percent distribution by relative frequency of atypical nuclei among true vocal cord cells, of men classified by smoking category [100 per cent atypical cells defined as carcinoma] Never Erx-cigarette Cigar/pipe Ke ker: smoked smokers smokers Current cigarette smokers regularly Percent atypical nuclei Lessthanl 1-2 packsa 2 or more Num- Per- Num- Per- Num- Per- packaday day packs a day ber cent ber cent ber cent Num- Per- Num- Per- Num- Per- ber cent ber cent ber cent Total..... 88 100.0 116 «100.0 $4 100.0 125 100.0 329 100.0 190 6100.0 None_-.-...---.. 66 75.0 86 74.1 1 Li 1 8 0 ...-- 0 ..-.. Less than 50...- 8 91 14 «121 4 4.3 2 20.0 4 1.2 0 Lu... 50-59... ----.-.. 10 «ine 13° (11.2 50 «53.0 54 43.2 87 4 29 15.3 60-69. -.-.----.. 4 465 1 9 23 (24.5 21 «168 116 35.3 75 = (30.4 70-79. 2. 2---2- 0 ..... 2 UL? 9 926 9 7.2 44 °«13.4 3820.0 80-89. 2.22228. 0-2... 0 -LLL. 2 2.1 2 16 19 5.8 11 5.8 90-09. 22.22... 0 .LL- 0 ..L. 1 Lt 0 Le 5 15 0 ...-- 100: Carcinoma in situ_._...... 0 Le. Q@ we. 3 3.2 13° 10.4 52 15.8 35 18.4 Invasive car- cinoma. _-__- 0 2... O@ 2.2L. 1 Ld OQ we... 2 6 2 Li Source: Auerbach, O., et al. (/). The 116 ex-smokers had laryngeal histology similar to that of the nonsmokers, as far as atypical nuclei were concerned. However, dis- integrating 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 car- cinoma zn situ and one case had a section showing early invasive pri- mary carcinoma. The highest percentage of atypical cells was found among the cigarette smokers. The proportion of cases with a high de- gree of cellular change increased with increased daily smoking. None of the pack-or-more-a-day smokers was free of atypical nuclei. Of those who smoked two or more packs per day, 85 percent had lesions with 60 percent or more atypical cells as compared to 4 percent of the nonsmokers. Between 10 and 18 percent of the cigarette smokers had areas of carcinoma in situ, and four of the 644 cases showed early microscopic invasion. The thickness of the basal level of the true vocal cord was also directly related to the amount smoked (table 3). 59 TaBLe 3.—Number and percent distribution, by highest number of cell rows in the basal layer of the true vocal cord, of men classified by smoking category Current cigarette smokers Never oan Excigarette Cigar/pipe than x 2 regularly smokers smokers Less than 1-2 packs a or more Number of cell pack a day day packs a day Num- Per- Num- Per- Num- Per- Num- Per- Num- Per- Num- Per- ber cent ber cent ber cent ber cent ber cent ber cent Total_..-_ 88 100.0 116 100.0 94 100.0 125 100.0 329 «100.0 190 = 100.0 Less than 5 cell rows.......--- 30 34.1 7 60 4 43 3 24 1 03 0 -..-. 5 cell rows. ...-. 2 693.0 27 23.3 2 «(21.3 27 «216 38 «11.6 2 810.5 6 cell rows. -_... 8 9.1 15 129 15 6.0 25 «420.0 5115.4 24 12.6 7 cell rows. ..-. 6 68 12 10.3 18 19.1 12 9.6 38 «11.6 1910.0 8 cell rows_.-.-. & 91 4 «(121 9 9.6 13 10.4 30 9.1 23 12.1 9 celi rows.....- 1 Ll 7 60 7 #7.4 6 48 6 7.9 “4 74 10 or more cell TOWS..-.----- 6 68 34 (29.4 21 22.3 3931.2 145 44.1 90 «47.4 Source: Auerbach, O., et al. (1). Cancer of the Urinary Bladder and Kidney Several studies have dealt with the relationship of smoking to can- cer of the bladder and kidney. James, et al. (23) demonstrated that an association existed for cancer of the bladder. The study by Fraumeni (17) also showed epidemiological evidence for such a relationship for bladder and kidney cancers. Bennington, et al. (3,4) indicated an as- sociation between all kinds of tobacco usage and adenocarcinoma of the 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 considered as established in view of the small number of cases involved. In a preliminary report of a study on the epi- demiology of cancer of the kidney, Wynder, et al. (68) have shown a strong association between excessive cigarette smoking and adenocar- cinoma of the kidney, and although the disease is not uncommon in non- smokers, they considered excessive cigarette smoking to be a contribu- tory factor. This study found no relationship to pipe smoking, and only a very weak relationship to cigar smoking. A significant association was found between cigarette smoking and epidermoid cancer of the kidney, a relatively uncommon type of cancer. Further research on the strength and mechanisms of the association between smoking and can- cers of the urinary tract is needed. Cancer of the Pancreas The previously suggested association between cigarette smoking and cancer of the pancreas was again noted in a Japanese study by Ishii, et 60 al. (22), in which the authors reported a higher relative risk for pan- creatic cancer among smokers than among nonsmokers. GENERAL ASPECTS OF CARCINOGENICITY The majority of the tumorigenic agents in tobacco smoke are found in the particulate matter “tar.” The well established carcinogenicity of tobacco “tar” in a variety of animal species and tissues (66) was reconfirmed recently (11, 35, 40, 52, 56). A small portion of the smoke particulates (0.03 percent) is made up of polynuclear aromatic hydro- carbons (PAH) with two or more rings. A concentrate containing polynuclear aromatic hydrocarbons and amounting to 0.6 percent of the whole “tar” was found to be the most carcinogenic fraction of to- bacco smoke (66). Another preparation of a PAH concentrate induced significant cytologic changes in mouse trachea and human fetal lung when grown in organ culture (28, 29). Other applications of concen- trations of selected polynuclear aromatic hydrocarbons have produced similar results (27). Of the identified PAH, at least 12 are known tumor initiators. These particular compounds have been shown to be carcinogenic, even when applied in doses of a few micrograms (63,66). Tumor initiators induce changes in the target cells, especially in DNA (9, 14). Tumor pro- moters are agents which promote the neoplastic transformation of ini- tiated cells. Although the structures of most of these tumor promoters are still unknown, there appear to be several different types in tobacco smoke (5, 41, 59, 66). Recently, Bock, et al. (6) published data which confirmed earlier findings that whole cigarette tar, the neutral frac- tion, two neutral subfractions and the weak acidic (phenolic) fraction contain tumor promoters. One recent study indicated that “tar” ob- tained from tobacco stems only had essentially no tumor promoting activity (65). During the last year, several studies have reconfirmed the finding that selection of tobacco and the use of tobacco sheets and filters can lead to a significant reduction of “tar” and PAH in cigarette smoke, as well as to a reduction of the tumorigenicity of tobacco “tars.” Simi- lar results have also been reported for commercial cigarettes (27, 34). Experimental studies demonstrated that with tobacco additives one can reduce “tar,” nicotine, PAH and tumorigenicity of cigarette smoke (72, 21). In terms of selective reduction of tobacco smoke components, these investigations may be of practical value, as well as of academic interest (57). Tobacco Alkaloids Present evidence does not indicate that tobacco alkaloids are car- cinogenic. A possible exception may be cotinine, which was reported to induce malignant tumors in rats [principally leukemias (58) ] and 61 adenomas of the bladder in mice (7). Boyland recently suggested that one or more of the three possible nicotine-N-oxides may be present in tobacco smoke and may be carcinogenic (7). Tobacco alkaloids could theoretically contribute to the overall car- cinogenicity of tobacco smoke, based on the possibility that in tobacco smoke nornicotine and other secondary amines may react with nitro- gen oxides to form the N-nitrosamines, of which several are known carcinogens, especially N-nitrosonornicotine and N-nitrosoanabasine (36). So far, however, N-nitrosamines of nornicotine and other alka- loid N-nitrosamines 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 sug- gests that there is a possibility that nickel carbonyl may be present in cigarette smoke and may act as a cocarcinogen by inhibiting the induction of pulmonary benzopyrene hydroxylase, an enzyme which converts 3,4-benzpyrene to noncarcinogenic hydroxylated derivatives. EXPERIMENTAL ASPECTS OF CARCINOGENSIS Retention of Smoke Constituents Studies on human smokers by Dalhamn, et al. (15) demonstrated that about 60 percent of the volatile, water soluble compounds of cigarette smoke, 20 percent of the volatile, nonwater soluble com- pounds, 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 2 seconds. Under conditions in which the smoke is immediately deeply inhaled, between 91 and 99 percent of the components of ciga- rette smoke investigated (particulate matter, toluene, acetonitrile, ace- tone, isoprene, acetaldehyde) were retained, with the exception of carbon monoxide, of which 50 to 60 percent was retained (16). Changes in Cell Cultures Induced by Cigarette Smoke 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 same paper, they reported that the single exposure of tissue cultures to puffs of charcoal-filtered smoke produced a significant increase in the mitotic index of the kidney cells. In an- other study, Leuchtenberger, et al. (97) reported that single exposure to nine puffs of the gas phase from charcoal-filtered cigarette smoke quickly stimulated the synthesis of DNA and RNA by cultures of mouse fibroblasts. Repeated exposure of the cultures to the filtered gas phase resulted in morphological and cytochemical changes indicative 62 of abnormal proliferation. Since the same alterations were found to be present, to a much lesser extent, in some control cultures, the authors considered that the filtered gas phase enhanced characteristics already possessed by the cells. They concluded that the gas phase of unfiltered cigarette smoke contains not only substances which inhibit cellular metabolism, but also factors which stimulate cellular metabolism. These latter factors may be unmasked by passing the gas phase through a charcoal filter. The identities of the specific gases removed by the char- coal filter and the extent to which each was removed were not reported by the authors. Investigation of the relationship between the changes observed in the tissue cultures and in vivo metabolism is necessary for the interpretation of the results of these experiments. Euperimental Studies of Bronchogenic Carcinoma in Animals Because of the technical problems involved in inhalation experi- ments in small animals (49, 67), various animal models have been de- veloped which do not employ the inhalation of smoke. These models have been used to study the role played by carcinogenic substances found in tobacco smoke in the induction of bronchogenic carcinoma. Saffiotti (43) in a recent review of experimental respiratory tract carcinogenesis described the development of experimental models for the induction of. pulmonary tumors and discussed a method of in- ducing bronchogenic carcinomas in Syrian golden hamsters by intra- tracheal instillation of a finely particulated crystalline carcinogen (e.g., benzo(a)pyrene) attached to a suspension of fine particles of a carrier dust (e.g., ferric oxide). This method reproduces some of the conditions of human exposure to inhaled carcinogens and has resulted in incidences of up to 100 percent of respiratory tumors, mostly squa- mous cel] and anaplastic carcinomas of the larger bronchi. These tumors have been found to be invasive, metastasizing, and transplant- able. Saffiotti reported that the carrier dust particles play an essential role in transporting the carcinogens through the bronchiolar and alveo- lar wall into the lung tissues where they are phagocytized. The carcino- gens are then eluted by the plasma and diffused into the lung tissue, reaching up to the mucosa of the larger bronchi (42, 44, 45, 46). Varia- tions in particle size and distribution in the suspended particulate matter affect the retention rates of benzpyrene in the lungs (47). The development of this experimental model has led to the undertaking of new research in many laboratories attempting to define the factors responsible for carcinogenesis in the respiratory tract. Two other techniques used to produce squamous cell carcinoma in small laboratory animals are the passage of threads impregnated with carcinogenic hydrocarbons into the lung and the implantation of wire 63 mesh pellets in the bronchus. The latter technique gives a dose-response relationship between carcinogenic hydrocarbons and squamous cell carcinoma of the lung in rats (27). In order to overcome the traumatic effects of the surgery involved in these procedures, two additional tech- niques have been utilized. In one method, the carcinogen is suspended in Freund’s adjuvant and upon trachea] instillation can lead to bron- chial cancer (69). In this experiment, even more cancers were found when the rats were pretreated with tubercle bacilli. Pretreatment of the animals with tubercle bacilli produced infarcts, as well as scarring of the lung. This finding is of interest because earlier studies showed that scarring of rat lung by the halogenated hydrocarbon hexachloro- tetrafluorobutane increases their susceptibility to the development of squamous carcinoma when exposed to carcinogenic hydrocarbons (54). That scarring of the lung may increase the susceptibility of the lung to carcinogens is in line with some recent observations on humans by Bennett, et al. (2) who showed the frequent occurrence of pulmonary scars in males with adenocarcinoma of the lung. Experimental Aspects of Cancer of the Bladder and Kidney Tobacco smoke appears to contain traces of several aromatic amines which are established bladder carcinogens. Of these, however, only Betanaphthylamine has thus far been identified in tobacco smoke with 2.2 x 10° g. per cigarette (20). At concentrations such as this, it ap- pears unlikely that such aromatic amines can account for the increased risk among cigarette smokers of developing kidney and bladder cancer. A more likely correlation 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 cotinine was reported to induce ade- nomas in the bladder of mice [16 percent (7) ]. This observation needs further testing. Cotinine is one metabolic product of nicotine and is found in tobacco, cigarette smoke (26) and the urine of smokers (33). A study by Schlegel, et al. (57) indicates an elevated concentration of certain o-aminophenols plus their phenoxazon-oxidation products in the urine of certain types of bladder cancer patients and cigarette smokers, when compared to the urine of nonsmokers. Further studies are needed on this problem, CITED REFERENCES (1) AUERBACH, O., HamMMonp, E. C., GARFINKEL, L. Personal Communication. April 1969. (2) Bennert, D. E., Sasser, W. F., Fercuson, T. B. Adenocarcinoma of the lung in man. A clinicopathologic study of 100 cases, Cancer 23(2): 431-439, February 1969. (3) BEennineton, J. L., Fercuson, B. R., CAMPBELL, P. B. Epidemiologic studies of carcinoma of the kidney. II. Association of renal adenoma with smoking. Cancer 22(4) : 821-823, October 1968. (4) BENNINGTON, J. L., LavescHesr, F. A. Epidemiologic studies on carcinoma of the kidney. I. Association of renal adenocarcinoma with smoking. Cancer 21(6) : 1069-1071, June 1968. (5) Boox, F. G. The nature of tumor-promoting agents in tobacco products. Cancer Research 28(11) : 2362-2368, November 1968. (6) Bock, F. G., Swain, A. P., StepMan, R. L. Bioassay of major fractions of cigarette smoke condensate by an accelerated technic. Cancer Research 29(3) : 584-587, March 1969. (7) Boyvianp, E. The possible carcinogenic action of alkaloids of tobacco and betel nut. Planta Medica Supplement 11(14) : 13-28, June 1968. (8) Brett, G. Z., Bensamin, B. Smoking habits of men employed in industry, and mortality. British Medical Journal 3(5610) : 82-85, July 13, 1968. (9) Brookes, P. Quantitative aspects of the reaction of some carcinogens with nucleic acids and the possible significance of such reactions in the process of carcinogenesis. Cancer Research 26 (9, Part 1): 1994-2003, September 1966. : (10) Bross, I. D. J., Gusson, R. Risks of lung cancer in smokers who switch to filter cigarettes. American Journal of Public Health and the Nation's Health 58(8) : 1896-1408, August 1968. (11) Brune, H. Experiments with cigarette smoke condensates and nitrosamines on mice. In; Weber, K. H., editor. Alkylierend wirkende Verbindungen. Zweite Konferenz tiber aktuelle Probleme der Tabakforschung. Wissen- schaftliche Forschungsstelle im Verband der Cigaretten industrie. Ham- burg, 1968. Pp. 53-64. (12) Burprcx, D., Benner, J. F., Burton, H. R. Apparent correlations between thermogravimetric data and certain constituents in smoke from treated tobaccos. 22d Tobacco Chemists Research Conference, Richmond, Va., October 19, 1968. (13) CHIERIcI, G., SitverMAN, S., Jr., ForsyTHE, B. A tumor registry study of oral squamous carcinoma. Journal of Oral Medicine 23(3) : 91-98, July 1968. (14) CoLsugn, N. H., Bourwer., R. K. The binding of beta-propiolactone and some related alkylating agents to DNA, RNA, and protein of mouse skin; relation between tumor-initiating power of alkylating agents and their binding to DNA. Cancer Research 28: 653-660, 1968. (15) DaLuamn, T., Eprors, M-L., RYLANDER, R. Mouth absorption of various compounds in cigarette smoke. Archives of Environmental Health 16(6) : 831-835, June 1968. (16) DaLHamn, T., Eprors, M-L., Rytanper, R. Retention of cigarette smoke components in human lungs. Archives of Environmental Health 17 (5): 746-748, November 1968. (17) Fraument, J. F., Jr. Cigarette smoking and cancers of the urinary tract: Geographic variation in the United States. Journal of the National Cancer Institute 41 (5) : 1205-1211, November 1968. 65 (148) Forimer, C. D. Microscopic observations of sputum of chronic cigarette smokers. A preliminary report. Rocky Mountain Medical Journal 65(8) : 18, August 1968. (19) Getranp, M., Gragam, A. J. P., LigoTMAN, S. Carcinoma of bronchus and the smoking habit in Rhodesian Africans. British Medical Journal 3 (5616) : 468-469, August 24, 1968. (20) Horrman, D., Masupa, Y., Wrnprk, E. L. Alpha-naphthylamine and beta- naphthylamine in cigarette smoke, Nature 221(5177) : 254-256, Janu- ary 18, 1969. (21) Horrman, D., Wynper, E. L. Selective reduction of the tumorigenicity of tobacco smoke. Experimental approaches. In: Wynder, BE. L., Hoffman, D., editors. Toward a Less Harmful Cigarette. Bethesda, U.S. Public Health Service, National Cancer Institute Monograph No. 28, June 1968. Pp. 151-172. (22) Isuu, K., Nakamura, K., Ozaki, H., Yamapa, N., TAKEUCHI, T. Suizogan no ekigaku ni okeru mondaiten. (Some aspects of the epidemiology of can- cer of the pancreas.) Nippon Rinsho 26(8) : 1839-1842, August 1968. (283) James, A. F., Brrro, R., Jacopson, M. E. Bladder carcinoma—Natural his- tory and behavior in males in Kansas. Journal of the Kansas Medical So- ciety 68(8) : 336-339, August 1967. (24) Keryperc, L. Aetiology of lung cancer. A morphological epidemiological and experimental analysis. Oslo, Universitetsforlaget, 1969. 90 pp. (25) Kreygere, L. Nonsmokers and the geographic pathology of lung cancer. Chapter 18. In: Liebow, A. A. Smith, D. E., editors. The Lung. Interna- tional Academy of Pathology Monograph, 1968. Pp. 273-283. (26) Kuuwn, H. Tobacco alkaloids and their pyrolysis products in the smoke. Jn: Von Euler, U. S., editor. Tobacco Alkaloids and Related Compounds. New York, MacMillan, 1965. Pp. 37-51. (27) Kuscuner, M. The J. Burns Amberson Lecture. The causes of lung can- cer, American Review of Respiratory Diseases 98(4) : 573-590, October 1968. (28) Laswrrzxt, I. The effect of a hydrocarbon-enriched fraction from cigarette smoke on mouse tracheas grown in vitro. British Journal of Cancer 22 (1): 105-109, March 1968. (29) Lasnrrzx1, I. The effect of hydrocarbon-enriched fraction of cigarette smoke condensate on human fetal lung grown in vitro. Cancer Research 28(3): 510-513, March 1968. (80) LEUCHTENBERGER, C., LEUCHTENBERGER, R. Cytologic and cyto-chemical effects on primary mouse kidney tissue and lung organ cultures after ex- posure to whole, fresh smoke and its gas phase from unfiltered, charcoal- filtered, and cigar tobacco cigarettes. Cancer Research 29 (4) : 862-872, April 1969. (81) LevcHTENBERGER, C., LEUCHTENBERGER, R., BLANCHARD, J., DECKERT, M. Ab- normal proliferative effects of the gas phase of charcoal filtered fresh cig- arette smoke on 3T3 cells. Presented 53d Annual Meeting, Federation of American Societies for Experimental Biology, Atlantic City, April 17, 1969. 3 pp. ($2) Lomsarp, H. L., Huyox, E. P. An epidemiological study of lung cancer among females. Growth 32(1) : 41-56, March 1968. (883) McNiven, N. L., RaisineHani, K. H., PaTASHNIK, S., DorFMAN, R. I. De- termination of nicotine in smokers’ urine by gas chomatography. Nature 208 (5012) : 788-789, November 20, 1965. ($4) (35) (86) (37) (38) (39) (40) (41) (42) (43) (44) (45) (46) (47) (48) (49) Moors, G. E., Boox, F. G. “Tar” and nicotine levels of American cigarettes. In: Wynder, E. L. Hoffman, D., editors. Toward a Less Harmful Ciga- rette. Bethesda, U.S. Public Health Service, National Cancer Institute Monograph No. 28, June 1968. Pp. 89-94. Munoz, N., Correa, P., Bock, F. G. Comparative carcinogenic effect of two types of tobacco. Cancer 21(3) : 376-389, March 1968. Nrurata, G. On the occurrence of N-nitroso-compounds in tobacco smoke. In: Weber, K. H., editor. Alkylierend wirkende Verbindungen. Zweite Konferenz tiber aktuelle Probleme der Tabakforschung. Wissenschaft- liche Forschungsstelle im Verband der Cigarettenindustrie, Hamburg, 1968. Pp. 95-102. OrgLovskry, L. V. Znachenie sotsial’no-gigienicheskikh issledovaniy pri izychenii paka. (Significance of the social hygienic investigations in a study of cancer.) Gigiena I Sanitariia 33(6): 71-73, 1968. PrnpsoreG, J. J. Oral submucous fibrosis as a precancerous condition. Jour- nal of Dental Research 45 (Supplement toe No. 3) : 546-553, 1966. PrinpzorG, J. J., BARNES, O. D., RoED-PETERSEN, B. Epidemiology and his- tology of oral leukoplakia and leukoedema among Papuans and New Guineans. Cancer 22(2) : 379-884, August 1968. Ror, F. J. C. Comparison of carcinogenicity of tobacco smoke condensate and particulate air pollutants and a demonstration that their effect may be additive. In: Weber, K. H., editor. Alkylierend wirkende Verbindungen. Zweite Konferenz iiber aktuelle Probleme der Tabakforsuchung. Wissen- schaftliche Forschungsstelle im Verband der Cigaretteindustrie, Ham- burg, 1968, Pp. 110-111. Rot, F. J. C. Examination of the neutral fraction of tobacco smoke con- densates for tumor promoting activity. In: Weber, K. H., editor. Alkylie- rend wirkende Verbindungen. Zweite Konferenz iber aktuelle Probleme der Tabakforsuchung. Wissenschaftliche Forschungsstelle im Verband der Cigarettenindustrie, Hamburg, 1968. Pp. 112-113. Sarriorry, U. Lung cancer: An experimental approach. Cancer Bulletin 19(4) : 72-73, July-August 1967. Sa¥FFIortr, U. Experimental respiratory tract carcinogenesis. Progress in Experimental Tumor Research 11 : 302-333, 1969. SaFFIOTTI, U., Ceris, F., Kos, L. H. A method for the experimental in- duction of bronchogenic carcinoma. Cancer Research 28(1): 104-124, January 1968 Sa¥Fiorti, U., CEFIs, F., SHUBIK, P. Histopathology and histogenesis of lung cancer induced in hamsters by carcinogens carried by dust particles. In: Severi, L., editor. Lung Tumors in Animals, Perugia, Division of Cancer Research, University of Perugia, June 1966. Pp. 537-346. Sarriorri, U., MonTesano, R., SELLAKUMAR, A. R., Bora, §. A. Experimental cancer of the lung. Inhibition by vitamin A of the induction of tracheo- bronchial squamous metaplasia and squamous cell tumors. Cancer 20(5) : 857-864, May 1967. Sa¥FrFiorti, U., MonTESANO, R., ToMPKINS, N. Benzo(a)pyrene retention in hamster lungs: Studies on particle size and on total dust load. Proceed- ings of the American Association for Cancer Research 8:57, March 1967. Sauzer, G. M., KurscHera, H., Decristororo, A. Zur Frage einer Syntropie von Ulcus pepticum und Bronchuskarzinom. Bruns’ Beitrage zur Klini- schen Chirurgie 216 (4) : 316-321, June 1968. SCHIEVELBEIN, H., ZieeKrar, T. Tumoren der Harnblase. In: Schievelbein, H., editor. Nikotin. Pharmakologie und Toxikologie des Tabakrauches. Stuttgart, Georg Thieme Verlag, 1968, Pp. 242-249. 67 (50) (52) (82) (53) (54) (55) (56) (57) (58) (59) (60) (61) (62) (63) (64) (65) (66) 68 SCHIEVELBEIN, H., GruMBacH, H. The influence of tobacco smoke compo- nents on the activity of kynureninase, Chapter 15, In: Deichmann, W. B., Lampe, K. L., editors. Bladder Cancer. Proceedings of the 5th Inter- American Conference on Toxicology and Occupational Medicine. Coral Gables, University of Miami, School-of Medicine, 1967. Pp. 180-186, ScHLEGEL, J. U., Pekin, G. E., NisHimura, R., DuKE, G. A. Studies in the etiology and prevention of bladder carcinoma. Journal of Urology 101(3) : 317-324, March 1969, ScHMAHL, D. Vergleichende Untersuchungen an Ratten tiber die carcino- gene Wirksamkeit verschiedener Tabakextrakte und Tabakrauchkonden- sate. Arzneimittel-Forschung 18(7) : 814-817, July 1968. STAMLER, J., BERKson, D. M., LINDBERG, H. A., Minter, W. A. SoruGENc, R., Toxicu, T., WHrppte, T. Does hypercholesterolemia increase risk of lung cancer in cigarette smokers? Circulation 38 (4, Supplement 6) : 188, October 1968, Stanton, M. F., BLacKweELt, R. Induction of epidermoid carcinoma in lungs of rats: A “new” method based upon deposition of methylcholan- threne in areas of pulmonary infarction. Journal of the National Cancer Institute 27 (2) : 375-407, August 1961. SUNDEEMAN, F. W., Jr. Nickel carcinogenesis. Diseases of the Chest 54(6): 527-534, December 1968 TaxayaMa, §., Suseano, H. Induction of malignant lymphomas in ICR mice treated with cigarette tar. Gann 59(4) : 363-265, August 1968. TERRELL, J. H., SCHMELTz, I. Cigarettes: Chemical effects of sodium nitrate content. Science 160(3885) : 1456, June 28, 1968. TRUHAUT, R. DECLEREQ, M., LoIstcLier, F, Sur les toxicites aigue et chro- nique de la cotinine, et sur son effet cancerigene chez le rat. Pathologie et Biologie 12(1) : 39-42, January 1964. U.S. Pusiic HEATH SERvice. The Health Consequences of Smoking. A pub- lic Health Service Review : 1967. Washington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1696, 1967. 199 pp. : U.S. Pustic Hearrx Service. Smoking and health. Report of the Advisory Committee to the Surgeon General of the Public Health Service. Wash- ington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1108, 1964. 387 pp. U.S. Pusiic HEattH SmErvice. The Health Consequences of Smoking. 1968 Supplement to the 1967 Public Health Service Review. Washington, U.S. Department of Health, Education, and Welfare, Public Health Service: Publication No. 1696, 1968. 117 pp. VALaItis, J.. McGrew, E. A., CHoMET, B., Corre, N., Heap, J. Broncho- genic carcinoma in situ in asymptomatic high-risk population of smokers. Journal of Thoracic and Cardiovascular Surgery 57(3) : 8325-332, March 1969. Van Duvren, B. L. Tobacco carcinogenesis. Cancer Research 28 (11) : 2357— 2362, November 1968. Waui, P. N. The epidemiology of oral and oropharyngeal cancer. A report of the study in Mainpuri District, Uttar Pradesh, India. Bulletin of the World Health Organization 38(4) : 495-521, 1968. Wrworr, E. L., HOFFMANN, D. A study of tobacco carcinogenesis. X. Tumor promoting activity. (In press.) Cancer : 1969. Wrnoer, E. L., HorrmMann, D. Experimental tobacco carcinogenesis. Sci- ence 162 (3856) : 862-871, November 22, 1968. (67) Wrwnorr, E. L., Masvcut, K., Beattie, E. J., Jr. The epidemiology of lung cancer, Some recent trends in hospital data. (Unpublished. ] (68) Wrnprr, BE. L., Masucui, K., WHITMoRE, W. F., Jr. The epidemiology of cancer of the kidney. [Unpublished. ] (69) Yasunira, K. Experimental induction of lung cancer in rat and mouse 81, 82. 83. 84. S5. S6. 87. S8. 89. $10. $11. $12. $13. 814. S15. with 20-methylcholanthrene in Freund’s adjuvant. Acta Pathologica Japonica 17 (4) : 475-493, 1967. CANCER SUPPLEMENTAL BIBLIOGRAPHY AHLsrrRom, C. G., Heaton, J. Combined action of Rous sarcoma virus and chemical carcinogen in rats. Experientia 24(4): 411-413, 1968. ALFRED, L. J., Drpaoto, J. A. Reversible inhibition of DNA synthesis in hamster embryo cells in culture: Action of 1,2-benzanthracene and 7,12- dimethylbenz (a) anthracene. Cancer Research 28(1) : 60-65, January 1968. ATHERTON, J. G. Formation of tobacco mosaic virus in an animal cell cul- ture. Archiv fiir die Gesamte Virusforschung 24: 406-418, 1968. Baron, F., Jornviiiz, R., Kerneis, J. P., pe LaJarme, LEnNe, Bruneau, Y. Tumeurs blanches du larynx et cancer. Journal Francais d’Oto-Rhino- Laryngologie et Chirurgie Maxillo-Faciale 16(3) : 181-188, March 1967. Baron, C., Berrori, G., Faris, N. Risposta immunitaria primaria in topi di ceppo albino iniettati alla nascita con un’unica dose di 7,12-dimetil- benz[a]antracene. Tumori 54(2): 117-126, March-April 1968. BENAGIANO, A. Influenza del fumo sulla cavita orale. Annali di Stomatolo- gia 12: 575-578, 1963. Benepicr, R. C., STepMAN, R. L. Complexity of enzymatic inhibition by cigarette smoke. Hxperientia 24(12): 1205-1206, 1968. Buack, 8. C. Polonium in tobacco and tobacco smoke. Radiation Bio-Effects Summary Report : 46, January—December 1967. BrenKINsopp, W. K. Particle accumulation in the lung as a possible factor in the aetiology of lung cancer. Journal of Pathology and Bacteriology 96 (2) : 297-304, October 1968. Brookes, P., HEIDELBERGER, C. Isolation and degradation of DNA from cells treated with tritium-labeled 7,12-dimethylbenz(a)-anthracene: Studies on the nature of the binding of this carcinogen to DNA. Cancer Research 29(1) : 157-165, January 1969. BueEt., P. E., Menez, W. M., Dunn, J. E., Jr. Cancer of the lung among Mexican immigrant women in California. Cancer 22(1): 186-192, July 1968. Capy, B., CatTtin, D. Epidermoid carcinoma of the gum. A 20-year survey. Cancer 23(3) : 551-569, March 1969, CavaLLazzI, G., Bercomr, A. I carcinomi primitivi della ghiandola sotto- mascellare. Archivio Italiano di Otologia, Laringologia e Patologia cervico-facciale 78(6): 8385-846, November-December 1967. CzaRnik, Z. Zmiany poziomu 5-HT w surowicy kobiet zwiazane z paleniem papieros6w. (Changes in the serum 5-hydroxy-tryptamine level con- nected with cigarette smoking and women.) Przeglad Lekarski 24(6): 561-563, 1968. . Date, E., Scurcurretp, F. D. Adrenal lipid and plasma corticosterone depletion after 7,12-dimethylbenz(a)anthracene administration to the albino rat. Experientia 24(7) : 723-724, 1968. 69 S16. S17. $18. 819. S20. $21. $22. $23. 824. $25. $26. $27. 828. $29. $30. 831. $32. 70 De Groor, M. J. W. Recente trends in de Kankersterfte bij manuen en vrouwen. Tijdschrift voor Sociale Geneeskunde 46(23): 824-827, November 15, 1968. DEICHMANN, W. B. Introduction. In: Lampe, K. F., Penalver, R.A. Soto, A., editors. Bladder Cancer. A Symposium. Fifth Inter-American Conference on Toxicology and Occupational Medicine. Coral Gables, University of Miami, School of Medicine, 1967. Pp. 3-33. De Magis, A., BeRTIni, P., DE Betua, E. Studio clinico su 1000 casi di eancro del polmone. Archivio di OChirurgia del Torace 21(3) : 341-399, July-September 1964. Driamonp, L., SARDET, C., RorHsiatT, G. H. The metabolism of 7,12-dimethyl- benz(a)anthracene in cell cultures. International Journal of Cancer 3(6) : 888-849, November 15, 1968. Dickens, F. Alkylating lactones and lactams. In: Alkylierend wirkende Verbindungen. Erste Konferenz tiber N-Nitroso-Verbindungen und Lac- tone. Hamburg, Wissenschaftliche Forschungsstelle in Verband der Cigarettenindustrie, 1964, Pp. 9-22. Dripple, A., Lawry, P. D., Brooxs, P. Theory of tumour initiation by chemical carcinogens: Dependence of activity on structure of ultimate carcinogen. European Journal of Cancer 4(5): 493-506, October 1968. Do.t., R. Carcinogens in the environment: Human evidence. Tidsskrift for den Norske Laegeforening 88(12b) : 1187-1194, June 25, 1968. DoNnTENWILL, W., ELMENHorRST, H., Reckzen, G., HagkKe, H.-P., Stapier, L. Experimentelle Untersuchungen tiber Aufnahme, abtransport und Abbau cancerogener Kohlenwasserstoffe in Bereich des Respirationstraktes. Zeitschrift fiir Krebsforschung 71(3) : 225-243, August 27, 1968. DorxKen, H. Binige Daten bei 280 Patienten mit Pankreaskrebs. Hiufigkeit, vor-und Begleitkrankheiten, exogene Faktoren. Gastroenterologia 102: 47-64, 1964. DunHaM, L. J., Ranson, A. 8., Stewart, H. L., Frang, A. 8., Youna, J. L. Rates, interview and pathology study of cancer of the urinary bladder in New Orleans, Louisiana Journal of the National Cancer Institute 41(3) : 683-709, September 1968. , DugAaN-REYNALS, M. L, Combined effects of chemical carcinogenic agents and viruses. Progress in Experimental Tumor Research 3: 148-185, 1968. Duran-Reynats, M. L. Enhancing effect of chemical carcinogens on ex- perimental viral infection: Its significance and probable mechanism. In: Rich, M. A., Moloney, J. B. editors. Conference on Murine Leukemia. National Cancer Institute Monograph No. 22, September 1966. Pp. 389-396. Exrezo, K. Growth kinetics of the mouse epidermis after a single applica- tion of cigarette smoke condensates. Acta Pathologica et Microbiologica Scandinavica 73 (3) : 316-322, 1968. Ericsson, J., Rincertz, N., Ssostrom, A., Swenson, D. Svenska cancer- registret 10 ar. Lakartidningen 65(16) : 1648-1653, April 17, 1968. Faraco, L. Bericht iiber oto-rhino-laryngologische Krebsreihenunter- suchungen. Monatsschrift fiir Ohrenheilkunde und Laryngo-Rhinologie 102 (10) : 588-601, 1968. Fiorentino, M. Lung cancer in the U.S.: Observations on the age at death. Medical Record and Annals 61(7) : 228-230, July 1968. , Fuaks, A. The effect of 9,10-dimethyl-1,2,benzanthracene on young mice of low and high cancer strain. British Journal of Cancer 19: 547-550, 1965. S33. 834. $35. S36. 837. $39. S40. 841. $42. $43. S44. 845. S46. S47. S48. S49. $50. 851. Francis, OC. W., CHESTERS, G., Ermarpt, W. H. 210-Polonium entry into plants. Environmental Science and Technology 2(9) : 690-695, September 1968. Franke, R. Die hydrophobe Wecheselwirkung von polycyclischen aromati- scben Kohlenwasserstoffen mit Humanserumalbumin. Biochimica et Biophysica Acta 160(3): 378-895, August 13, 1968. Frost, J., Sackett, W. M. Polonium radioisotopes in tobacco and the atmosphere. Nuclear Science Abstracts 22(6) : 1093, March 31, 1968. Gorrin, R., Musin, L. Fréquence et localisation du cancer parmi un groupe @assurés sociaux. Archives Belges de Médecine Sociale, Hygiene, Méde- cine du Travail et Médecine Legale 26(4) : 279-295, 1968. Gotustsov, F. 8. Khronicheskiy bronkhit i rak legkogo. (Chronic bronchitis and lung cancer.) Sovetskaya Meditsina (3) : 129-130, 1968. . Gear, W. Uber natiirliches Vorkommen und Bedeutung der kanzerogenen polyzyklischen, aromatischen Kohlenwasserstoffe. Medizinische Klinik 60(15) : 561-565, April 9, 1965. Grarvt, A., Horn, K.-H., PasteenaK, G. Antigenic properties of tumors induced by different chemical and physical carcinogens. In: Harris, R. J. G., editor. Specific Tumor Antigens. A Symposium. UICC Monograph Series 2 : 204-209, 1967. Grottet, L. Progression du cancer du poumon chez ’homme et les animaux. Revue de Pathologie Comparée et d’Hygiene T 2-7(770) : 405-410, 1965. GsELL, O., Retcu, T. Bronchialkarzinom: Bemerkungen zu einer Sektions- statistik. Medizinsche Klinik 60 (47) : 1886-1889, 1965. Hacxert, R. L., SunperRMAN, F. W., Jr. Pulmonary alveolar reaction to nickel carbonyl. Ultrastructural and histochemical studies. Archives of Environmental Health 16(3) : 849-3862, March 1968. HarnszeL, W., Kurruana, M. Studies of Japanese migrants. I, Mortality from cancer and other diseases among Japanese in the United States. Journal of the National Cancer Institute 40(1): 48-68, January 1968. Hamazaki, Y. Tabako ha fummatsu kyunyu ni yotte hassei suru shoshu no shinseimotsu ni. Tsuite 2. (Development of various kinds of neoplasms through the inhalation of tobacco leaf dust 2.) Transactiones Societatis Pathologicae Japonicae 56: 127-128, 1967. HaAgseERs, E., LEDERER, B., 'SANDRITTER, W., Spaar, U. Untersuchungen an Nucleohistonen. IV. “Heterochromatisierung” in der Rattenleber wihrend der Carcinogenese. Virchows Archiv Arbeiten B. Zellpathologies 1(2): 98-106, June 10, 1968. Hems, G. Factors associated with lung cancer. British Journal of Cancer 22(3) : 466-473, September 1968. HENNiNGs, H., BourwEL1, R. K. The inhibition of DNA synthesis by initia- tors of mouse skin tumorigenesis. Cancer Research 29(3) : 510-514, March 1969. Hirao, F., Fustsawa, T., Tsusura, E., AKAMATSU, Y., Yamamura, Y. Ex- perimental cancerous changes in the lung induced by chemical carcino- gens in rabbits. Gann 58(5) : 427-484, October 1967. Hype, L., Yer, J., Witson, R., Patno, M. E. Cell type and the natural his- tory of lung cancer. Journal of the American Medical Association 193 (1) : 52-54, July 5, 1965. Kern, W. H., Jones, J. C., CHapman, N. D. Pathology of bronchogenic carcinoma in long-term survivors. Cancer 21(4): 772-780, April 1968. Kiercakg, I. Koto gan no ekigaku ni okeru. Mondaiten. (Some aspects of the epidemiology of cancer of the larynx.) Nippon Rinsho 26(8) : 1808- 1811, August 1968. 71 360-928 O—69 6 852. S53. $54, S55. S56. 857. 858. S59. S60. 561. $62. S63. S64. S65. S66. S67. S68. 869. 870. 72 KozHEvNikova, E. P. O. Sensibilizatsii organizma k kanserobennomu ve- schestbu. (Concerning sensibilization of the organism to a carcinogenic substance.) Voprosy Onkologii 14(4) : 57-60, 1968. LEMOINE, J. M., Favvet, J., VASSELIN, M. 194 tumeurs bronchiques malignes des femmes démontrées par biopsie bronchique. Journal Francais de Medecine et Chirurgie Thoraciques 20: 329-345, 1966. LINDNER, J., Gries, G., Freyrac, G., Brack, W. J., Horrz, J. Morphologische und biochemische Untersuchungen zur Gesehwulstbildung. Gegenbaurs morphologisches Jahrbuch 109(1) : 37-42, 1966. Little, J. B., McGanpy, R. B. Systemic absorption of polonium-210 inhaled in cigarette smoke. Archives of Environmental Health 17(5) : 693-696, November 1968. Mapey, J. Clinical evaluations of 745 cases of primary lung carcinoma. Polish Medical Journal 7(4) : 917-927, 1968. ManuHotp, J. H., Rustoer, K. N., Doyzez, J. L., ManHoLp, B. S. Micro- scopic and microrespirometer (QO2) study of the effect of cigarette smoking on human oral soft tissues. Preliminary report of an in vivo study. Oral Surgery, Oral Medicine, Oral Pathology 26(4): 567-572, October 1968. MarTINoTTI, G., Ferrero, L, 11 cancro primitivo del polmone nella rileva- zione dispensariale. (Risultanze clinco-statistiche dal 1947 al 1966). Lotta Contro La Tubercolosi 87(4) : 308-316, October-December 1967. Mastin, F., Masin, M. Alveolar cells of sputum in pulmonary carcinoma, 21(6) : 1042-1051, June 1968. Meinsma, L. Longkankersterfte in Nederland. Nederlands Tijdschrift voor Geneeskunde 107 (32) : 1482-1436, August 10, 1968. Meimsma, L., VersLuys, J. J. De lon kankersterfte bij volwassenen stijgt niet meer. Nederlands Tijdschrift Voor Geneeskunde 112(19) : 891-895, May 11, 1968. Mutter, J. A.. Miter, E. C. Metabolism of drugs in relation to carcino- genicity. Annals of the New York Academy of Sciences 123: 125-140, 1965. . MonrTeomery, P. O’B. Nucleolar studies. Bulletin of Pathology 7(3) : 66— 67, March 1966. Morreat, C. E., Dao, T. L., Eskins, K., Kine, C. L., Drenstac, J. Per- oxide induced binding of hydrocarbons to DNA. Biochimica et Biophysica Acta 169(1) : 224-229, November 20, 1968. MuckerMan, C. Studies on the nature of the binding products of beta- propiolactone and mouse skin protein. M.S. Thesis, University of Wis- consin, 1968. 86 pp. Muir, C. 8. The incidence of laryngeal cancer in Singapore. Journal. of Laryngology and Otology 79(3) : 203-213, 1965. NEIMAN, J. M. The sensitizing carcinogenic effect of small doses of car- cinogen. European Journal of Cancer 4(5) : 587-545, October 1968. Occupation, chemicals, and cancer. British Medical Journal 2 (5553) : 649- 650, June 10, 1967. Ott, G., Daum, R. Lungenkrebs bei Frauen. Langenbecks Archiv ftir Klinische Chirurgie vereinigt mit Deutsche Zeitschrift fiir Chirurgie 310 (2) : 93~106, 1965. Orro, H., ELMENHoRST, H. Experimentelle Untersuchungen zur Tumorin- duktion mit der Gasphase des Zigarettenrauchs. Zeitschrift fir Krebs- forschung 70(1) : 45-47, 1967. 871. S72. 873. S74. 875. S76. S77. S78. S79. S80. 881. $82. S83. S84, S85. S86. Park, H-Y., KiprowsxKa, I. A comparative in vitro and in vivo study of induced cervical lesions of mice. Cancer Research 28(8): 1478-1489, August 1968. Prrzev, J. A., YERGA, M., Croxatto, O. C. Cancer broncopulmonar primi- tivo. Consideraciones sobre 522 casos. Revista Asociacion Medica Argen- tina 82(5) : 159-162, May 1968. Pinpsor¢, J. J., Kavapessi, H. K., Kare, S. A., SineH, B., TALYERKHAN, B. N. Frequency of oral leukoplakias and related conditions among 10,000 Bombayites. Journal of the All India Dental Association 37: 1-2, July 1965. PrinpsonaG, J. J., Kraer, J., Gupta, P. C., Coawra, T. N. Studies in oral leukoplakias. Prevalence of leukoplakia among 10,000 persons in Luck- now, India, with special reference to use of tobacco and betel nut. Bulle- tin of the World Health Organization 37: 109-116, 1967. Poporr, N., Surron, C. H., ZOMMERMAN, H. M. Viruslike particles in re- active cells associated with crystals of implanted carcinogen. Acta Neu- ropathologica 10(4) : 308-323, June 7, 1968. Purseux-Dao, S., Izarp, C. Les effets de l’acroléine et de la phase gazeuse de la fumée de cigarette, sur l’'ultrastructure cellulaire du Dunaliella bioculata. Comptes Rendus Hebdomadaires des Séances de 1’Academie des Sciences; Series D-Sciences Naturelles 267(1) : 74-75, July 1, 1968. Riuineron, J. Smoking. sputum, and lung cancer. British Medical Journal 1(5594) : 732-734, March 23, 1968. Rowe, N. H. Epidemiological concepts relative to cancer of the oral cavity. Missouri Medicine 65(8) : 660-664; 668; 679, August 1968. Sacus, L. In vitro cell transformation by carcinogenic hydrocarbons: A system for the study of tumor specific antigens in the absence of im- munological selection. In: Harris, R. J. C., editor. Specific Tumor Anti- gens. A Symposium. UICC Monograph Series 2: 361-366, 1967. Sepa, H. J., Snow, J. B., Jr. Carcinoma of the tonsil. Archives of Otolaryn- gology 89(5) : 756-761, May 1969. Suapzap, L. M. On the distribution and the fate of the carcinogenic hydro- carbon benz(a)pyrene (3,4-benzpyrene) in the soil. Zeitschrift ftir Krebsforschung 70 : 204-210, 1968. Sueets, T. J., Smiru, J .W., Jackson, M.D. Insecticide residues in ciga- rettes. Tobacco 166(15) : 26-29, April 12, 1968. Simeckova, B. Plicni rakovina u zen. (Lung cancer in women.) Rozhledy V Tuberkulose A V Nemochech Plicnich 28(8: 565-568, September 1968. TAKANO, K., Osocosuy, K., Kamrmura, N., Kanna, K., KAne, K., KAMIYAMA, R., Saxamoro, K., Sato, H., Sutrar, Y., Ser, M., TANABE, T., Horio, M., MrinaMI, Y., Morosr, H., Morrra, R., Onmmara, H., Hrrayama, T. Shoku- dogan no ekigaku, toku ni atsui inshokubutsu, inshu, kitsuen narabi ni eiyo ketsubo ni tsuite. (Epidemiology of cancer of the esophagus, with particular reference to the effect of hot food and drink, drinking, smoking, and nutritional deficiencies.) Nippon Rinsho 26(8) : 1823-1828, August 1968. Taxayama, 8. Sucano, H. Induction of malignant lymphomas in ICR mice treated with cigarette tar. Gann 59(4) : 363-365, August 1968. Tappan, W. B., VAN MIppELEM, ©. H., Moye, H. A., DDT, endosulfan, and parathion residues on cigar-wrapper tobacco. Journal of Economic Ento- mology 60(3) : 765-768, June 1967. 73 S87. S88. S89. S90. $91. S92. $93. $94. 74 Trerny, J. Rozsireni zhoubnych nadoru dychaciho ustroji v Ceskoslovensku a v jinych zemich. (Occurrence of malignant tumors of the respiratory system in Czechoslovakia and in other countries.) Casopis Lekaru Ceskych 107 (26) : 790-796, 1968. Von Essen, C. F., Suepp, D. P., Connetty, R. R., E1senperc, H. Cancer of the larynx in Connecticut, 1935-1959. Cancer 22(6) : 1315-1322, Decem- ber 1968. Wahl, P. N., Lanini, B., Kenan, U. Epidemiology of oral and oropharyngeal eancer. A study of regional factors in Uttar Pradesh. Journal of the In- dian Medical Association 46(4) : 175-181, February 16, 1966. Wa ter, R. E., Commins, B. T. Studies of the smoke and polycyclic aro- matic hydrocarbon content of the air in large urban areas. Environ- mental Research 1(4): 295-306, December 1967. Warp, N. O., Gore, W. A., ACQUARELLI, M. J. Carcinoma of the tonsil. American Journal of Surgery 116(4) : 487-490, October 1968. WatTTensERG, L. W., Leone, J. L., GALBRAITH, A. R. Induction of increased benzpyrene hydroxylase activity in pulmonary tissue in vitro. Proceed- ings of the Society for Experimental Biology and Medicine 127 (2) : 467- 469, February 1968. WEISSMANN, G., TROLL, W., VAN Duvuren, B. L., Sessa, G. Studies on lyso- somes-X. Effects of tumor-promoting agents upon biological and arti- ficial membrane systems. Biochemical Pharmacology 17(12) : 2421-2434, December 1968. : ZECHNER, G. Zum Begriff des Raucherkehlkopfes. Eine klinische und pathologisch-anatomische Untersuchung. Monatsschrift ftir Ohrenheil- kunde und Laryngo-Rhinologie 102(4) : 250-259, 1968. CHAPTER 4 Effects of Smoking on Pregnancy Contents Page Summary....------------------------------------------ 77 Epidemiological Studies___.._..........-.-.-------------- 77 Experimental Studies__---------------------------------- 80 Cited References___.._..__.______-_--_--_-__-_---------- 81 75