The relationship between pulmonary infection and AHH activ-
ity was investigated by Nettesheim, et al. (CA 16) who found
that at 10 days postiinocuIation of infiuenza virus, AHH activity
mas reduced in mouse lung tissue to 20 percent of control
levels.

Flesher and Sydnor (CA 6) reported the synthesis of 6-
hydroxymethylbenzo (a) pyrene by incubation of benzo (a) pyrene
with rat liver homogenates as a result of enhanced AHH
activity. This metabolite was carcinogenic; it produced sarcomas
in rats when injected subcutaneously, as did injection of benzo-
(a) pyrene and 6-methylbenzo (a) pyrene. No control rats were
utilized. The authors postulated that methylation and/or hy-
droxymethylation may be a key step in the metabolism of
benzo(a)pyrene, and that the products thus formed may be po-
tent carcinogenic agents in vivo. The fact that 100 percent of
the injected rats developed sarcomas, and that no sham treated
or solvent injected rats (controls) were utilized, limit the con-
clusions which may be drawn from this study.

Flaks, et al. (CA 5) demonstrated that the 7-hydroxymethyl-
K&methyl and 12-hydroxymethyl-`7-methyl derivatives of `i',E-
dimethylbenz (a)anthracene showed similar carcinogenic poten-
cies to the parent compound. In testing for the carcinogenicity

1500






1000






500

0      1      2      3      4

   Cigarette Smoke Exposure (hr)

FIGURE b-Effect of cigarette smoke on benzo (a)pyrene-hydroxylase activity
in rat lung. Four rats were placed in a chamber and exposed continuoufdy to
smoke from 5 cigarettes per hour for various time periods. After expo6ure,
the rats were killed and the lungs were examined for benm(a)PYNm?-hY-
droxylase activity. The data are representative of 4-5 experiments (mean
* SE).

SOURCE : Welch, B. If., et aL (CA 36).

61


of these compounds, these investigators utilized the mouse lung
explant experimental model.

Nitrogen dioxide is a known component of cigarette smoke.
Palmer, et al. (CA 18) found no change in AHH activity
of tracheobronchial mucosa of rabbits after exposure to 5, 20, and
50 p.p.m. of NO,.

ORAL CANCER

Introduction

In the United States, oral cancers comprise approximately
2.5 percent of all cancers reported. These include cancer of the
oropharynx, lip, tongue, hard and soft palate, floor of the mouth,
gingiva, alveolar mucosa, and buccal mucosa. The relationships
of cigarette and pipe/cigar smoking to the development of oral
cancer are summarized below:

1. Prospective and retrospective studies have shown an as-
sociation between mortality for oral cancer and tobacco usage in

men and women.

2.000






1.000

Puromycin

FIQURE 9.-Effect of actinomycin and puromycin pretreatment on the induction
of benzo(a)pyre.ne-hydroxylase by cigarette smoke in the rat. Rats were
treated with actinomycin or puromycin and exposed to cigarette smoke for 4
hours. Benzo(a)pyrene-hydroxylase was measured in lung immediately after
exposure. Results represent the mean + SE from 4 rats.

SOURCE : Welch, R. Y., et al. (CA $6).


2. This association has been demonstrated for all different
modes of tobacco usage-cigarette and pipe/cigar smoking, tobacco
nnd snuff chewing, reverse smoking, and "pan" chewing.
3. Several studies have shown that the development of recur-
rent oral cancers has a highly significant correlation with con-
tinued smoking.

4. Tobacco usage may act in concert with alcohol consumption
to increase the risk of development of oral cancer.
5. The association between tobacco use and oral cancer in
both men and women has been demonstrated for Caucasian,
Indian, and Asian populations.

6. Epidemiologic data suggest that premalignant lesions in
the oral cavity (e.g., leukoplakia) are associated with tobacco
usage.

7. Results from experimental studies indicate that cigarette
smoke may contain tumor promoters active in oral carcino-
genesis and is a promoting agent in the hamster cheek pouch.

Epidevniologic Studies

In a st.udy of 483 patients with cancer of the mouth and pharynx
selected from three New York City VA hospitals, Rothman and
Keller (CA 21) found that the relative risks of development of

Days After Exposure

FIQURE l&-Time course for maximum induction of benzo(a)pyrene-hydroxylase
in lung after exposure of rats to cigarette smoke. Rats were exposed to cigarette
smoke from 20 cigarettes (4 hours) and killed at various times after exposure.
The activity of benzo( a)pyrene-hydroxylase was determined at various in-
tervals after exposure. Each point represents the mean -C SE from 3 rata.

SOURCE: Welch, R. M.. et al. (CA JS).

63


Smoke Exposure (minutes)

FIGURE Il.-The relationship between lung benzo (a)pyrene-hydroxylase activity
and the dnration of exposure to cigarette smoke in the rat. Rats were exposed
to cigarette smoke from 30 seconds to 180 minutes and killed 24 hours after
exposure ; the lung benzo( a) pyrene-hydroxylase was measured. Each result
represents the mean z SE from 3 rats.

SOURCE: Welch, R. N., et al. (CA 36).

these cancers were higher for men who consumed either tobacco
or alcohol than for nonsmokers and nondrinkers. When both
tobacco and alcohol consumption were present, dose-response
relationships for combinations of the two were demonstrated
(table 2). The data presented strongly suggest that both inde-
pendent and additive effects of tobacco and alcohol consump-
tion were operative in the development of these oral cancers.
The authors concluded that the increases in the relative risks of
development of these oral cancers produced by smoking and
alcohol consumption were additive and, therefore, independent.

Ramanathan, et al. (CA 20) examined 40'7 medical attendants
and health workers in Malaysia for evidence of oral precancer-
ous lesions. The authors found significant relations between

TABLE 2.-Relative risk* of oral cancer according to level of ex-
        posure to smoking and a&oh.ol

Alcohol         0      1.00      1.62      1.43      2.43
(oz./day)      co.4    1.40      1.6'7      3.18      3.25
            0.4-1.5    1.60      4.36      4.46      8.21
           1.6+     2.33      4.13      9.69      15.6

o Riab are expressed relative to o tick of 1.00 for pemnl who neither amoked nor drank.
SOURCE: Rothm~n. K.. Keller. A. (CA 92).

64


tobacco smoking (P <.05) and mixed habit (smoking, chewing,
and/or drinking) (P <.OOl), and the prevalence of oral pre-
cancerous lesions in MaIay men. Significant differences in the
prevalence of oral precancerous lesions were also observed between
Indian men with smoking, chewing, and mixed habit and those
without these habits. Many oral precancerous lesions were found
among women who used tobacco, but the control group of women
was too small to make statistically significant comparisons.

Lee, et al. (CA 18) retrospectively studied 356 men with
squamous cell carcinoma of the oral cavity, matching 316 of these
patients with controls of similar age and smoking habits. They
concluded that alcohol consumption was significantly correlated
with development of oral cancer. They then took 96 of the
matched pairs who had similar drinking habits and found no
differences in smoking habits.

CANCER OF THE ESOPHAGUS

1. Prospective and retrospective studies have shown a re-
lationship between cigarette smoking and mortality from esoph-
ageal carcinoma in men and women.
2. Dose-response relationships have been demonstrated for this
association.

3. These relationships have been observed in Caucasian, Asian,
and American Indian populations.
4. The effect of cigarette smoking on esophageal cancer mortal-
ity rates has been shown to be independent of and synergistic
with the effect of alcohol consumption.
5. Experimental data show that benzo(a) pyrene can induce
esophageal cancer in mice.

PANCREATIC AND GASTRIC CANCER

1. Data from prospective and retrospective studies of men
and women have demonstrated an association between smoking
and mortality from pancreatic cancer.
2. Dose-response relationships have been shown for this asso-
ciation.

3. No firm relationship between stomach cancer and cigarette
smoking has been established.

Wynder, et al. (CA 40, .41), in a retrospective study of 100
men and 42 women with adenocarcinoma of the pancreas, found
a significantly higher percentage of male cigarette smokers (P

65


<.026), female cigarette smokers (P C.06)) male cigarette and
pipe/cigar smokers (P <.026), and male cigar smokers (P <.025)
in the pancreatic cancer group than in the age, sex, and race-
matched controls. For male cigarette smokers, a dose-response
relationship was demonstrated for numbers of cigarettes consumed
in the pancreatic cancer group (figure 12). The number of cases of
women smokers with pancreatic cancer was too small to draw
statistically significant conclusions with regard to dose-response
relationships. Patients who smoked cigars only had a relative
risk of 3.1 compared to nonsmokers, and this was also statistically
significant (P <.025). (Although the association between
cigarette smoking and pancreatic cancer was significant, it was
not as strong as the association between cigarette smoking and
lung cancer.) Patients who smoked pipes predominantly did not
demonstrate a significantly higher risk of development of pan-
creatic cancer than nonsmokers.

Never
Smoked

11-20        2140

Cigarettes per Day

FIWJRE 12.-Relative risk of pancreatic cancer by number of cigarettes smoked
                       in males.

SOURCE : Wynder, E. L., et al. (CA 41).

66


lvith gastric cancer in Kanagawa prefecture from 1960 to 1961,
be noted no association between smoking habits and gastric can-
cer. However, 67 percent of the cases were diagnosed either by
X-ray or "clinical methods". In 1963, he studied six prefectures;
in 1,524 patients with gastric cancer, there was "no striking
nssociation" between smoking habit and gastric cancer. In 1965,
Hirayama began his prospective study of 265,118 adults. Anal-
ysis of the S-year follow-up data revealed a higher death rate
from gastric carcinoma for males who smoked cigarettes and
drank hot green tea. In addition, the age-standardized death
rate from gastric carcinoma for male smokers was 128 per 100,000
compared to 85 for nonsmokers ; mortality ratios for male
smokers:nonsmokers were 1.51. Differences between female
smokers and nonsmokers were minimal. The author suggested
that, in future studies, a detailed examination of the possible
relationships between cigarette smoking and gastric cancer be
performed.

CANCER OF THE LARYNX

1. The epidemiologic, autopsy, and experimental data which
suggest a strong association between cancer of the larynx and
smoking habits have been reviewed in past editions of this re-
port. No new data have been presented within the past year
which significantly add to our knowledge of the association
between smoking and laryngeal cancer.

CANCER OF THE GENITOURINARY SYSTEM

Introductim

1. The association between cancer of the urinary bladder and
kidney and cigarette smoking has been reviewed in previous
editions of this report. No new epidemiologic data has been
published within the last 12 months which amplifies our knowl-
edge of this association.

2. Data from experimental studies dealing with tryptophan
metabolism have demonstrated that metabolites of tryptophan
can be carcinogenic in the bladders of mice. These metabolites
are found in increased amounts in the urine of patients with
non-occupational bladder carcinomas. Some data show an effect
of cigarette smoking on tryptophan metabolism, while other
data have not shown such an effect.

67


Thomas (CA SO), in a retrospective study on cytologic and
histologic abnormalities of the uterine cervix, reported a signif-
icant association between current smoking habits and the in-
cidence of carcinoma in situ (P <.05), with a relative risk for
smokers being 1.71 (P ~~05). The "adjusted" risk for smokers
was 1.47 times that of the nonsmokers. Intensity and duration
of smoking were not analyzed ; ex-smokers were also not accounted
for. The controls consisted of a hospitalized group of patients
with normal cervical smears and may have contained a higher
percentage of smokers than the population as a whole. Further
epidemiologic studies are needed for full investigation of the
relationship between cigarette smoking and development of car-
cinoma in situ of the uterine cervix, as suggested by this study.

Experimental $tudiea

Humans

Schievelbein, et al. (CA 28) reported no significant differences
in the excretion of various urinary metabolites of tryptophan
between smokers and nonsmokers, nor between patients with
bladder carcinoma (also smokers) and those without this car-
cinoma. Problems in the design of this study limit the conclusions
which may be drawn from the data.

Animals

Wagle and Lee (CA 35) found a 2 percent incidence of
transitional cell bladder tumors in rats whose bladders were im-
planted with- pellets of cigarette smoke condensate. A total of
22 percent of the rats developed squamous metaplasia.

SUMMARY OF RECENT FINDINGS ON THE RELATIONSHIP
         OF SMOKING ANDCANCER

1. Recent epidemiologic evidence confirms the finding that
  cigarette smoking is the major cause of lung cancer for
  both men and women.

2. Current evidence suggests that, even in the presence of a
  possible genetic susceptibility to the development of lung
  cancer, cigarette smoking remains the major cause of lung
   cancer.


3.

4.





5.

6.

7.





8.






9.

10.




11.

1. A

Results from several studies demonstrated a dose-response
relationship between smoking and oat cell carcinoma ; a
major prospective study demonstrated such a relationship
for well-differentiated squamous cell carcinoma, oat cell
carcinoma, and adenocarcinoma.
The current epidemiologic data suggest that the incidence of
lung cancer in women continues to rise. The rising in-
cidence of lung cancer in women correlates well with the
increasing trends in smoking among women.
present data are conflicting with regard to dose-response
relationships for cigar and pipe smokers and the develop
ment of lung cancer; the data are consistent for the fact
that light cigar smokers are at a low risk of developing lung
cancer.

Recent data confirm the synergistic effect of asbestos and
smoking exposure on the risk of developing lung cancer in
both men and women.

Results from experimental studies in hamsters continue
to demonstrate that exposure to benzo(a)pyrene results in
the production of respiratory tract malignancies, especially
squamous cell carcinomas.

Data from experimental studies in animals suggest that
chronic respiratory infections may enhance the carcino-
genicity of components of cigarette smoke, as may altera-
tions in the immune system.

Current evidence suggests that components of cigarette
smoke induce AHH activity in pulmonary macrophages
in humans and in pulmonary parenchymal tissue and em-
bryo cells in animals. The role of AHH in tumorigenesis
and/or as a host defense mechanism against potential car-
cinogens is presently unclear.

Recent epidemiologic data strongly indicate that cigarette
smoking plays an independent role in the development of
oral cancer.

Recent epidemiologic data confirm the association between
smoking and pancreatic cancer.

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73-6163. DE COBBAL S-A, F. J. Clinica de 10s tumores vesicales. (Clinical
     signs of bladder tumors.) Arehivos Espanoles de Urol~gia
     25(2) : 209-224, 1972.
72-0490. DOLGINTSEV,  V. I. Matematicheskiye metody v epidemiologii
     xlokachestvennykh opykholey. (Mathematical methods in the
     epidemiology of malignant tumors.) Voprosy Onkologii 17(8) :
      95-101,197l.

73-9403. DGNTENWILL, W., ELMENHORST, H., HARK& H.-F., IWKZEH, G.,
     WEBEU, K. H., MIS-, J., TIMM, J. Experimentelle Untersuch-
     ungen iiber die tumorerseugende Wirkung von Zigarettenrauch.
     Kondensaten an der Mlusehaut. III. Miteilung: Untersuchungen
     sur Identitisiemng und Anreicherung tumorausliisender Frak-
     tionen. (Experimental studies on tumorigenic activity of cigar-
      ette smoke condensate on mouse-skin. Third communication.
     Investigations with regard to identifying and enriching the
     tumor-inducing fraction.) Zeitschrift fiir Krebsforschung 73 (3) :
     306-314, January 29,197O.

`72-0733. DROCENDIJK, A. C. De vrouw en het roken-longkankervraagstuk.
     (Women and the smoking-lung cancer problem.) Nederlands
     Tijdschrift voor Geneeskunde 116(23) : 967-960, June 3, 1972.
73-0446. ESTEVEZ VALDEZ, R. Analieis e information estadistica de 435
     historias clinicas de 10s pacientes egresados de1 Servicio de
     Neumologia desde el lo de Mano hasta el 31 de Agosto de 1970.
     (Analysis and statistical information on 435 clinical histories
     of discharged patients from the Pneumological Service from
     March 1 to .August 31, 1970.) Revista Cubana de Medicina
      ll(2) : X3-162, March-April 1972.

72-0736. FARR, H. W., ARTHUR, K. Epidermoid carcinoma of the mouth and
     pharynx 1969-1964. Journal of Laryngology and Otology 86(3) :
      243-263, March 1972.

72-0941. FERON, V. J., EMME~, P., VOSSENAAR, T. Lower respiratory
     tract tumours in Syrian golden hamsters after intratracheal
      instillations of diethylnitrosamine alone and with ferric oxide.
     European Journal of Cancer 8(4) : 446-449, August 1972.
73-0497. GIACOBBE, E., CARUSO, P. L. Cytologic changes in the oral cavity
     of reverse smokers. Acta Cytologica 17 (1) : 49-50, January-
     February 1973.

`72-9492. GSELL, 0. R., ABELIN, T. Cigar and pipe smoking in relation to
      lung cancer and excess mortality. Journal of the National Cancer
      Institute 48 (6) : 1795-1803, June 1972.
72-0907. HAMNER, J. E., III. Betel quid inducement of epithelial atypia in
      the buccal mucosa of baboons. Cancer 30(4) : 1001-1005, October
       1972.

72-0714. HAPLPPERT, J. L., ENGEL, J. C. Le role nocif du tabac vu par
     l'exp&imentateur. (The noxious effects of smoking in experi-
     mental pathology.) Revue de Tuberculose et de Pneumologie'
      36(2) : 209-224, March 1972.

72-0638. HEALY, T. M. Carcinoma of the lung: 326 eases. Irish Journal of
      Medical Sciences 140 : 564-571,1971.

72-0493. JAYANT, K., BALAKRISHNAN, V., SANGIIVI, L. D. A note on the
     distribution of cancer in some endogamous groups in Western
     India. British Journal of Cancer 25(6) : 611-619, December 1971.

64


;2-6494. KANNEB~TEIN, M., Crrunc, J. Pathology of carcinoma of the lung
    associated with asbestos exposure. Cancer 30(l) : 14-21, July
       1972.

i2-64g5. KENNEDY, A. Lung cancer in young adults. British Journal of
     Diseases of the Chest 66(2) : 147-154, April 1972.
;3-0448. KM, M. A., J-9 N. A. Oral exfoliative cytology for diagno-
    sis or oral lesions. Journal of the Pakistan Medical Association
     22(l) : 3-6, January 1972.

734449. KISSIN, B., I(ALEy, M. hf., Su, W. H., LEBNER, R. Head and
    neck cancer in alcoholics. The relationship to drinking, smoking,
    and dietary patterns. Journal of the American Medical As-
     sociation 224 (8) : 1174-1175 May 21, 1973.
724496. KOSZARPWSIU, T. Rak pluca. (Lung cancer.) Polski Przeglad
     Chirurgiczny 44 (1) : 9-13, 1972.

72-1078. LEMOINE, J. M. Tabac et cancers bronchiques des femmes. (Tobacco
     and bronchial cancers in women.) Rehabilitation, Priiventivme-
     dizin, Physikalisehe Medizin, Sozialmedizin 26 (l/2) : 3940, 1972.
72-0738. LEMoINE, J. M., FAUVET, J. Cancers bronchiques des femmes et
    tabac. (Bronchial carcinoma and smoking in women.) Revue de
     Tuberculose et de Pneumologie 36(2) : 297300, March 1972.
72-1079. MEFITA, F. S., GUFTA, P. C., DAFTARY, D. K., PINDBORC, J. J.,
    CEoKsI, S. K. An epidemiologic study of oral cancer and
    precancerous conditions among 101,761 villagers in Maharashtra,
     India. International Journal of Cancer 10(l) : 134-141, July 16,
       1972.

72-0739. MEHTA, F. S., SAHWR, B. E., DREARY, D. K., GUPTA, P. C., PIND
    BORG, J. J. A correlative histocytological study of carcinoma and
    epithelial atypia of the palate among Indian reverse smokers.
     British Journal of Cancer 26(3) : 230-233, September 1972.
73-0985. MEBTA, F. S., SHROFF, B. C., GUPTA, P. C., DAFTARY, D. K. Oral
     leukoplakia in relation to tobacco habits. A ten-year follow-up
    study of Bombay policemen. Oral Surgery, Oral Medicine, and
     Oral Pathology 34(3) : 426-433, September 1972.
72-0642. MERRICK, D. K., CUR, D. T., PIIYNE, W. S., WOOLNER, L. B.
    Multiple primary cancer of the lung. Geriatrics 27(6) : 71-79,
      June 1972.

72-0740. Mm, A., R~CEEMAURE, J., NADJAR-FOSSE, G., BIENTZ, M. Cancers
     primitifs BpidermoIdes des branches et tabac. (Primary epider-
     moid carcinoma of the bronchi and smoking.) Revue de Tuber-
     culose et de Pneumologie 36(2) : 312-316, March 1972.
73-0059. MICIETA, I., VAGAC, M., BADAL~K, L., CECEVALOVA, A. O`vaha o
     niektorych prfznakoeh pri diagnostike bronchog&tneho karcinbmu.
     (Certain symptoms to be taken into consideration in the
     diagnosis of bronchogenic carcinoma.) Bratislavskd Lekarske
     Lists 68(3) : 353-359, September 1972.
72-9771. OILAMOTO, T., CHAN, P. C., So, B. T. Effect of tobacco, marihuana
     and benzo(a)pyrene on aryl hydrocarbon hydroxylase in hamster
     lung. Life Sciences 11(15, Part II) : 733-741, 1972.
72-0742. PINDBOBG, J. J., MEHTA, F. S., DAFFAR~, D. K., GIJ~TA, P. C.,
     BBoNsLE, R. B. Prevalence of oral lichen planus among 7,639
     Indian villagers in Kerala, South India. A& Dermato-Venereo-
     logica 62(3) : 2X-220, 1972.

65


73-0044. PUTNEY, F. J., CHAPMAN, C. E. Carcinoma of the larynx: Analyst
    of 311 cases treated surgically. Annals of Otoiogy, Rbinologp
     and Laryngology 81(4) : 465-464, August 1972.
72-1273. RAMANATHAN, K. Oral carcinoma in the first three decadea of
     life. Medical Journal of Malaysia 27(l) : 26-26, September 1972.
73-0630. RAMULU, C., RAJU, M. V. S., VENKATAIUTANAM, G., REDny, C. &
     R. M. Nicotine stomatitis and its relation to carcinoma of the
     hard palate in reverse smokers of cbuttas. Journal of Dental
     Research 62(4) : 711-718, July-August 1973.
72-0743. RAMULU, C., REXIDY, C. R. R. M. Carcinoma of the hard palate
     and its relation to reverse smoking. International Surgery
      57(8) : 636-641, August 1972.

72-1265. REDDY, C. R. R. M., RAMULU, C., RAJU, M. V. S., Rxnnr, P. 0.
     Relation of reverse smoking and other habits to the development
     of stomatitis nicotina. .Indian Journal of Cancer 9(3) : 223-230,
      Sentember 1972.

72-1306. ROEDPETERSEN, B., GUPTA, P. C., PINDBORC, J. J., SINGE, B. As-
     sociation between oral leukoplakia and sex, age, and tobacco
     habits. Bulletin of the World Health Organization 47(l) : 13-19,
       1972.

72-0745. SILVERMAN, S., JR., GRIFFITH, M. Smoking characteristics of pa-
     tients with oral carcinoma and the risk for second oral primary
      carcinoma. Journal of the American Dental Association 86(3) :
      637-640, September l972.

72-9193. SPELL, P. 211. Smoking and laryngeal cancer. Lancet l(7751) : 617-
     618, March l&1972.

72-0746. WAGNER, J. C. Current opiniona on the asbestos cancer problem.
     Annals of Occupation Hygiene 15 (1) : 61-64, April 1972.
73-0464. WAPNICK, S., CASTLE, W., NICHOLLE, D., ZANAMWE, L. N. D.,
     GELFAND, M. Cigarette smoking aIcobo1 and cancer of the
     oesophagus. South African Medical Journal 46 (51) : 2023-2026,
      December 23,1972.

73-0634. WEISS, W. Cigarette smoke as a carcinogen. American Review of
     Respiratory Disease 108(2) : 364-366, August 1973.
73-0616. WEISS, W., LANCSTON, H. T. Lung cancer-future projection.
      (Letters). Journal of Tboracic and Cardiovascular Surgery
      65 (2) : 332-334, February 1973.

72-0953. WYNDER, E. L., MABUCFII, K. Etiological and preventive aspects of
     human cancer. Preventive Medicine l(3) : 300-334, August 1972.

Part rz

(Additional articles which were reviewed but not discussed in the text.)
73-0281. ABBEY SMITE, R., NICAM, B. K., THOMPSON, J. M. Influence of
      parental age on survival after resection for lung carcinoma.
     Lancet l(7808) : 843-845, April 21, 1973.
`724727. ABBE, D. W., WILKINS, M. M., KIRSCHNER, G., WESTON, D. L.,
     BROWN, R S., BUXTON, W. D. Self-frustration5 nighttime smoking
     and lung cancer. Psychosomatic Medicine 34 (5) : 395-404, Sep-
       tember-October 1972.

66


72~900. Ano, A., VAINIO, H., HILNNINEN, 0. Enhancement of drug oxlda-
    tion and conjugation by carcinogens in different rat tissues.
     FEBS Letters 24(3) : 237-240, August 15, 1972.
73-oo11. AWM, B. S., JARAMILU), F. E., SCHLEGEL, J. U., DE~UHEN, T. A.
    The effect of ascorbic acid upon bladder uptake of p-napbtbyla-
    mine metabolites. Proceedings of the Society for Experimental
    Biology and Medicine 141(3) : 1008-1013, December 1972.
72-0901. ALEXANDROV, K., FRAYSSINET, C. The effect of cigarette-smoke
     condensate on the in vitro fixation of benzo(a)pyrene on DNA.
     Experientia 28(8) : 932-933, August 15, 1972.
73-0240. AYES, B. N., SIMS, P., GROVES, P. L. Epoxides of carcinogenic
    polycyclic hydrocarbons are frameshift mutagens. Science 176
     (4030) : 47-49, April 7, 1972.

73-0442. ARCHER, V. E., WAGONE& J. K., LUNDIN, F. E., JR Uranium
    mining and cigarette smoking effects on man. Journal of 00
     cupational Medicine 15(3) : 204-211, March 1973.
   BAUER, F. W., ROBBINS, S. L. An autopsy study of cancer patienta.
    I. Accuracy of the clinical diagnosis (1955 to 1965)) Boston City
    Hospital. Journal of the American Medical Association 221(13) :
     1471-1474, September 25,1972.

72-0707. BENEDICT, W. F. Early changes in cbromosomal number and strut-
      ture after treatment of fetal hamster cultures with trans-
    forming doses of polycyclic hydrocarbons. Journal of the
     National Cancer Institute 49(2) : 585-589, August 1972.
72-0698. BOCK, F. G., SWAIN, A. P., STEDMAN, R. L. Carcinogenesis assay
     of subfractions of cigarette smoke condensate prepared by sol-
    vent-solvent separation of the neutral fraction. Journal of the
     National Cancer Institute 49(2) : 477-483, August 1972.
73-6618. BOUCOT, K. R., WEISS, W. Is curable lung cancer detected by
     semiannual screening? Journal of the American Medical Associa-
      tion 224 (10) : 1361-1365, June 4,1973.
73-9243. BRIGGS, M. H., BRIGCS, M. Induction by topical corticosteroids of
     skin enzymes metabolizing carcinogenic hydrocarbons. British
     Journal of Dermatology 88(l) : 75-81, January 1973.
72-1069. BBOWN, R. R., FRIED&L, G. H. LEKLEM, J. E. Tryptopban metabo-
    lism in patients with bladder cancer of occupational etiology.
     American Industrial Hygiene Association Journal 33 (4) : 217-
     222, April 1972.

72-1063. BURBANK, F. U.S. Lung cancer death rates begin to rise propor-
     tionately more rapidly for females than for males: A doze
     response effect? Journal of Chronic Diseases 25 (8) : 473-479,
      August 1972.

72-1303. BURTNER, D., GOODMAN, M., MONTCOMERY, W. Elastic cartilaginous
     metaplasia of vocal cord nodules. Annals of Otology, Rhinology
     and Laryngology 81(6) : 844-847, December 1972.
73-0040. CASE% A. E., GRA~LEE, J. F., DOWNEY, E., COPELAND, H. A
     template of serum chemistries in cancer of the lung. Alabama
     Journal of Medical Sciences 9 (4) : 376-382, October 1972.
73-9621. CLEMMESEN, J., Bxx~ggsxov, V. Parallel morbidity age-curves for
     neoplasms of lung and bladder. Biomedicine 19 (5) : 198-199,
      May 20, 1973.

67


73-0401. CROCKER, T. T., O'DONNELL, T. V., NUNES, L. L. Toxicity of
     benzo(a)pyrene and air pollution composite for adult human
     bronchial mucosa in organ culture. Cancer Research 33(l) :
      88-93, January 1973.

73-0758. DALE, M. M., EASTY, G. C., TCHAO, R., DESAI, H., ANDJARGnoLI, 116,
     The induction of tumours in the guinea-pig with metbyIcbolan.
     threne and dietbylnitrosamine and their propagation in viva and
     in vitro. British Journal of Cancer 27(6) : 445-450, June 1973.
72-1268. DIPAOW, J. A., TAKANO, K., POPESCU, N. C. Quantitation of
     chemically induced neoplastic transformation of BALB/3T3
     cloned cell lines. Cancer Research 32(12) : 2686-2695, December
       1972.

73-0583. ESBER, H. J., MENNINGER, F. F., JR., BOCDEN, A. E., MASON, M. M.
     Immunological deficiency associated with cigarette smoke inhala-
     tion by mice. Archives of Environmental Health 27(2) : 99-104,
      August 1973.

73-0447. FIGUEROA, W. G., RASZKOWSKI, R., WEISS, W. Lung cancer in
     cblorometbyl methyl ether workers. New England Journal of
     Medicine 288 (21) : 1096-1097, May 24, 1973.
72-0491. GANGADHARAN, P., PAYMASTER, J. C. Leukoplakia-An epidemiolog-
     ical study of 1504 cases observed at the Tata Memorial Hospital,
     Bombay, India. British Journal of Cancer 25 (4) : 657-668, De-
       cember 1971.
73-0252.  GAUDIN, D., GREGG, R. S., YIELDING, K. L. Inhibition of DNA repair
     by cocarcinogens. Biochemical and Biophysical Research Com-
      munications 48 (4) : 945-949, 1972.
73-0022. GULLINO, P. M., GRANTHAM, F. H., L~SON~Y, I., BERCHOFFER, B.
     Mammary tumor regression. III. Uptake and loss of substrates
     by regressing tumors. Journal of the National Cancer Institute
      49 (6) : 1675-1684, December 1972.

73-0288. HENSCKE, U. K., LEFFALL, L. D., Ja., MASON, C. H., REINHOLD,
     A. W., SCHNEIDER, R. L., WHITE, J. E. Alarming increase of the
     cancer mortality in the U.S. black population (1950-1967). Can-
      cer 31(4) : 763-768, April 1973.

    HICKS, R. M., WAKEFIELD, J. ST. J., CHOWANIIX, J. Co-carcinogenic
      action of saccarin in the chemical induction of bladder cancer.
      Nature 243(5406) : 347-349, June 8, 1973.
73-0154. KOVI, J., HESHMAT, M. Y. Incidence of cancer in Negroes in
      Washington, D.C., and selected African cities. American Journal
     of Epidemiology 96(6) : 401-413, December 1972.
72-1272. KRAIN, L. S. Cancer incidence. The crossing of the curves for
     stomach and pancreatic cancer. Digestion 6(6) : 356-366, 1972.
73-0534. KRAIN, L. S. Wby is pancreatic cancer incidence up; stomach
     cancer down? Geriatrics 28 (4) : 140-145, April 1973.
73-0986. LANCSTON, H. T. Lung cancer-future projection. Journal of
     Tboracic and Cardiovascular Surgery 63 (3) : 412-415, March
       1972.

73-0418. LASNITZKI, I. Effects of carcinogenic agents on organ cultures.
      Oncology 25(l) : 263-268, 1971.

72-0641. LINDEN, G., DUNN, J. E., JR., HOM, P. H., MANN, M. Effect of
     smoking on the survival of patients with lung cancer. Cancer
      30(2) : 325-328 August 1972.

68


i3-0769. LOUIS, C. J,, BLUNCX, J. M., RICHMOND, L. M. Agarose-gel elec-
    trophoresis of soluble proteins from bronchial mucosa and
     bronchogenic carcinoma. Oncology 27 (4) : 324-335. 1973.
;2-0497. MACDONALD, W. C. Clinical and pathologic features of adeno-
    carcinoma of the gastric cardia. Cancer 29(3) : 724-732, March
      1972.

72-0948, MADEY, J., LACHOWICZ, E., OSSOWSXA, K., SZYMANSXA, D., ZAJACZ-
     XOWSIUL, J. Rak oskrzela wspolistnejacy z gruzlica pluc. (Bron-
     chial carcinoma associated with pulmonary tuberculosis.)
     Gruzlica i Choroby Pluc 40 (4) : 285-296 1972.
73-0625. MANDEL, M. A., DVOVORAK, R., DECO.%%, J. J. Salivary immunoglobu-
     lins in patients with oropharyngeal and bronchopulmonary
     carcinoma. Cancer 31(6) : 1408-1413, June 1973.
    MITELMAN, F., MARK, J., LEVAN, G. Chromosomes of six primary
     sarcomas induced in the Chinese hamster by 7,12-dimethylbenz-
     (a) anthracene. Hereditas `72 (2) : 311-318, 1972.
73-0451. O'DONNELL, T. V., CROCICER, T. T., NUNES, L. L. Maintenance of
    normal, metaplastic and dysplastic states of adult human bron-
    chial mucosa in organ culture. Cancer Research 33 (1) : 78-87,
     January 1973.

73-0775. POUND, A. W., LAWSON, T. A., HORN, L. Increased carcinogenic
     action of dimethylnitroeamine after prior administration of car-
     bon tctrachloride. British Journal of Cancer 27(6) : 451-459,
      June 1973.

72-0920. RANDERIA, J. D. Tobacco induced changes in the bladder buccal
     and vaginal mucosae. Indian Journal of Medical Research 66(S) :
     694-698, May 5,1972.

73-0263. RHIM, J. S., CEO, H. Y., JOCLE~& M. H., HUEBNER, R. J. Com-
     parison of the transforming effect of benzo(a)pyrene in mam-
     malian cell lines in vitro. Journal of the National Cancer Insti-
     tute 48(4) : 949-957, April 1972.

73-0424. RHIM, J. S., HUEBNER, R. J. In vitro transformation assay of
     major fractions of cigarette smoke condensate (CSC) in mam-
     malian cell lines. Proceedings of the Society for Experimental
     Biology and Medicine 142 (3) : 1003-1007, March 1973.
73-0425. RHIM, J. S., HUEBNER, R. J, Transformation of rat embryo cells
     invitro by chemical carcinogens. Cancer Research 33(4) : 695-
     700, April 1973.

72-1274. ROTH, D., HAYE% R. L., Ross, N. M., GITMAN, L., KISSIN, B.
     Effectiveness of acridine-binding method in screening for oral,
     pharyngeal, and laryngeal cancer. Cancer 29 (6) : 15'79-1583,
      June 1972.

    SMITH, R. A., NIGAM, B. K., THOMPSON, J. M. Influence of parental
     age on survival after resection for lung carcinoma. Lancet
     l(7808) : 843-845, April 21, 1973.
72-1254. SPENCER, T. A comparison of aryl hydrocarbon and estrogen micro-
     somal hydroxylases of rat liver. Enzymologia 43(5) : 301-310,
      November 30, 1972.

73-0610. THOMAS, W., HOLT, P. G., KEAST, D. Effect of cigarette smoking
     on primary and secondary humoral responses of mice. Nature
     243 (5404) : 240-241, May 25,1973.

69


78-6277. WIEEEL, F. J., LEUTZ, J. C., GJZLBOIN, H. V. Awl bdmarboa
     (benso [a] pyrene) hydroxylase : Inducible in extrahepatic tissues
    of mouse strains not inducible in liver. Archives of Biochemistry
     and Biophysics 154(l) : 292-294, January 1973.
73-0010. WILK, Y., GIRKE, W. Reactions between benso(a)pyrene aad
     nucleobaees by one-electron oxidation. Journal of the National
     Cancer Institute 49 (6) : 1585-159'7, December 1972.
73-0436. WUNSCEMANN-HENDEMIN, B., ASIIIUP, T. Relation of fibrinolytic
     activity in human oral epithelial cells to cellular maturation:
     The influence of smoking. Journal of Pathology 108(4) : 293-301,
      December 1972.

78-6293. ZACEO, A., CEDERQVIST, C., NIELSEN, J., LARSEN, V. Duration of
    smoking and quantity of tobacco used by patients with gastric
     cancer. Acta Medica Scandinavica 193 (l/2) : 45-48, January-
      February 1973.

72-0748. ZAKRZEW~~I, A., DUIWKA-Z~xcazxw SXA, A., SKONIECZNY, J., KON-
     CZEWSKA, Z., LISSOWSKA, B. The content of some trace elements
     in blood serum of patients with larynx cancer. Acta Oto-Laryn-
     gologica 73 (2/3) : 227-229, February-March 1972.

70


CHAPTER3

iv~N-NEOPLASTIC BRONCHOPULMONARY DISEASES

INTRODUCTION ___-__--_-_-_--_-___--~~~~~~~-~~~
EPIDEMIOLOGIC STUDIES

SmokingandCOPD ____ --_-___--_--__-- __________
The Eflects of Smoking on Pulmonary Function in
Patients with COPD _- ____ ---_-___-___--__-__-
The Effects of Smoking on Pulmonary Function in
Healthy Populations _--- ______ --__---_-- ______
The Roles of Smoking and Pollution in the Development
of COPD -____-__-__--__-____----------------
The Relationship Between Cigarette Smoking and
Small Airways Disease ___--____-- _____________
The Interactions Between Cigarette Smoking and the
Genetic Susceptibility to the Development of COPD _
The Effect of Smoking on the Development of Bullous
Disease of the Lungs __--_- _____________-___-__
Smoking and Post-Operative Complications _ _ _ _ - _ _ _
The Influence of Cigarette Smoking on the Develop-
ment of Pulm0n.a~ Disease Associated with Rheu-
matoid Arthritis ___-___-__- ____ -___-- _______--

Occupational Diseases and Smoking
  Byssinosis _ - _ _ _ - _ _ _ _ _ - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
  Asbestosis  ____ - _______________________ -___-
Chronic Bronchitis and Pulmonary Symptoms in
  Cement and Rubber Industry Workers _ _ _ _

AUTOPSY, STUDIES

The Effect of Smoking on the Prematurity of De-
velopm.entandSeverit~of COPD __- ____ -_- __.__.

Page
75

78

80

80

82

84

87

90

92




92


93
95


95





97

71


Smoking and Mucous Gkmd Abnormalities __ _ _ __ _ _   97
Abnomdities of the Small Airways _ _ 7 _ _ _ _ _ _ _ _ _ _ _ _ _   97

EXPERIMENTAL STUDIES

Studitw in Rummz8 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - _ _ _ _ _ _ _   99
Studies in Animals _________________ - ____ --_- ____  102

CYTOLOGIC AND HISTOLOGIC STUDIES _ _ _ _ _ _ _ _   104

SUMMARY OF RECENT NON-NEOPLASTIC BRON-
CHOPULMONARY FINDINGS  _ - _ _ _ _ - _ _ - _ _ _ _ _ _ _ _   106

BRONCHOPULMONARY DISEASE REFERENCES _ _   107

BRONCHOPULMONARY DISEASE SUPPLEMENTAL
REFERENCES _________-_______________________   112

List of Fignres

Figure 1.Prevalence of chronic nonspecific respiratory
disease by cigarette smoking habits and traffic exposure _ _
Figure 2.-Relationship between "closing volume" and
agein39smokers ___----________-__________________
Figure S.-Prevalence of abnormal closing volume/vital
capacity ratios in nonsmokers, cigarette smokers, and
ex-smokersbyagedecades ____ - _______ -__-- _________
Figure 4.-Comparison of the prevalence of respiratory
symptoms and pulmonary function abnormalities in male
smokers according to their daily cigarette consumption _
Figure L-Comparison of the prevalence of respiratory
symptoms and pulmonary function abnormalities in fe-
male smokers according to their daily cigarette con-
sumption _-______________________________________-
Figure 6.-The distribution of smoking histories in men
with bronchitis and/or emphysema - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Figure `(.-Chronic bronchitis in female wool and cotton
textile workers __-- _______________________ -___- ____
Figure &-Chronic bronchitis in male wool and cotton
textile workers _______ - _______________ -__-___- ____
Figure 9.-Effect of smoking on pulmonary ventilation
at different levels of time-weighted dust exposure __ _ _
Figure lO.-Effect of smoking on prevalence of byssinosis
at different time-weighted dust exposure levels _ - _ _ _ _ _ _

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Page

Figure Il.-A frequency distribution curve of the inter-
nal diameters of the small airways in an autopsy
population of nonemphysematous patients with and
without histories of chronic bronchitis  _ _ _ _ _ _ _ _ _ _ _ _ _ _
Figure 12.-Mean clearance curves for normal subjects,
subjects with airway obstruction, and restrictive im-
pairment of the lungs - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Figure 13.-Mean clearance curves for smokers, ex-
smokers, and nonsmokers in the healthy group and the
group with respiratory impairment _ _ _ - - - _ - _ _ _ _ _ _ _ _ _ _
Figure 14.Effects of aqueous cigarette smoke extract
on initial oxygen uptake, final oxygen uptake, and cell
viability of pulmonary macrophages  _ _ _ _ _ _ _ _ _ - _ _ _ _ _ _

List of Tables

Table l.-Number, percentage, and age-standardized per-
centage of chronic bronchitics among 5,438 cigarette
smoking male volunteers for mass radiography, aged 40
and older, by amount and method of smoking _ _ _ _ _ _ _ _ _ -
Table 2.-Prevalence of chronic nonspecific respiratory
disease grouped by current cigarette categories and traffic
exposure ____________-___________________________
Table 3.-Prevalence (percent) of cough day or night
in both sexes in winter by air pollution index, social
class, cigarette smoking, and history of chest illness
under 2 years of age _____________ -___- ____ _-__ __ __
Table $.-Estimated rates of bullous disease of the lung
per 1,000 men by age, race, and cigarette smoking habits -
Table IX-Estimated rates of bullous disease of the lung
per 1,000 men with no demonstrable odcupational hazard
(class 1) __-________________ -_- ____ __ _________ ____

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CHAPTER3

NON-NEOPLASTICBRONCHOPULMONARYDISEASES

INTRODUCTION

Chronic obstructive pulmonary disease (COPD) (defined here
as chronic bronchitis and emphysema) accounted for approxi-
mately 25,000 deaths in the United States in 1969. In 1970, in
the U.S., the combined prevalence of chronic bronchitis for mem-
bers of both sexes over age 17 was 29.5 per 1,000 population,
and for emphysema was 9.8 per 1,000 population. In 1970, per-
sons with chronic bronchitis lost, on the average, 1.4 workdays
per year, and those with emphysema lost greater than 5 work-
days per year due to disability from these diseases.

Epidemiologic, autopsy, and experimental data presented in
previous editions of this report (1964, 1967, 1968, 1969, 1971,
1.972, 1973) indicate that cigarette smoking is the primary cause
of chronic bronchitis and emphysema. A summary of that evi-
dence is presented below:

1. Results from numerous prospective studies show a markedly
increased mortality from COPD for male smokers compared to
nonsmokers. There is a limited amount of data dealing with the
relationship between cigarette smoking and COPD mortality in
women.

2. Dose-response relationships between cigarette smoking and
mortality from chronic bronchitis and emphysema were demon-
strated in all studies in which dose-specific mortality rates were
evaluated. Heavy cigarette smokers ran relative risks of mortal-
ity from chronic bronchitis ranging from 3.6 to 21.2 times those
of nonsmokers, and relative risks of mortality from emphysema
ranging from 6.9 to 25.3 times those of nonsmokers.

3. Data from many studies demonstrate that male and female
smokers suffer from symptoms of COPD (including cough, spu-
tum production, and dyspnea) more frequently than do nonsmok-
ers.

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