LUNG CANCER RELATIONSHIPS IN WOMEN

Lung cancer death rates for women are presently much lower
than the corresponding rates for men. In addition, it has been ob-
served that among certain strains of mice exposed to carcinogenic
agents, the male animals show a greater tendency to develop lung
tumors than do the females (200, XV) although there are strains
for which this is apparently not so. The extent of the influence of
endocrine factors in the sex variation in the incidence of lung
tumors is unknown.

As of 1967 in the United States, women accounted for only about
one-sixth of the total deaths from lung cancer (289). However, the
lung cancer death rate in women has risen by over 400 percent in
the past 40 years. From 1950 to 1967 alone, the rate per 100,000
population doubled, increasing from 4.5 to 8.9 (289,290).

A number of retrospective studies concerning lung cancer and
cigarette smoking among women have found that the difference in
the prevalence of lung cancer between males and females is ac-
counted for principally by those tumors classified as Kreyberg's
Group I (154,311) . These, as was noted above, are the tumors, par-
ticularly in males, which show the closest relationship with smok-
ing. Haenszel, et al. (123), in a study of 158 women with lung
cancer, observed that the sex differential for lung cancer death
rates diminishes, but does not fully disappear when only non-
smokers are considered,

Hammond (118) found that the death rate for lung cancer in
nonsmoking males was somewhat higher than for nonsmoking fe-
males. However, the difference in male-female rates was much
greater when smokers were compared. It appears that a substantial
part of the difference in death rates between male smokers and fe-
male smokers can be explained mainly by differences in their smok-
ing habits.

These differences in smoking habits between males and females
are of two types. First, overall consumption among females is still
significantly lower than that among males. In 1966 (,%?I), 30 per-
cent of males reported that they had never smoked while for fe-
males the corresponding figure was 59 percent. This study also
noted that nearly three times as many males as females reported
consuming more than 20 cigarettes per day. Second, it has been
shown that women smoke differently than men (303) : They begin
smoking later than men (114) and do not smoke cigarettes as close
to the end, where proportionally more nicotine and "tar" are in-
haled. Women smoke more filter-tip and "low tar and nicotine"
cigarettes than men. Furthermore, cigarette smoking still tends to
be heavily concentrated among women under the age at which lung
cancer is most likely to occur.

251


Finally, analysis of the ratio of male and female lung cancer
death rates (283, 284, 285, 286, 287, 288, 289, 2.90) reveals that
since 1960 this ratio has shown a steady decline, reflecting the
greater relative rise in mortality from lung cancer in the female
population.

LUNG CANCER, THE URBAN FACTOR, AND AIR POLLUTION

A number of studies have been concerned with the relative influ-
ences of smoking, urban residence, and air pollution in the etiology
of lung cancer. Table 9 lists studies performed in the United States,
Great Britain, and Japan which have dealt with this question. Kotin
and Falk (149, 250) and more recently the Royal College of Physi-
cians (228) have reviewed the literature concerning the influence
of atmospheric and environmental factors in the pathogenesis of
lung cancer.

The studies listed in table 9 show a number of important trends.
Lung cancer death rates are found to be higher among urban popu-
lations than among rural populations. It is not known to what ex-
tent this urban factor in the etiology of lung cancer is due to
differences in the levels of air pollution. Other factors associated
with urban residence which may influence the etiology of lung
cancer are : differences in smoking habits between the two popula-
tions, occupational differences, and possible differences in the re-
porting of lung cancer deaths (228).

The studies also uniformly show that within each urban/rural
grouping, lung cancer death rates increase with increased smoking.
Whether air pollution acts with cigarette smoking to influence lung
cancer death rates in a combined manner is presently unclear (112,
126, 261, 265), and the evidence concerning a separate role of air
pollution in the etiology of lung cancer is still inconclusive (228).

The recent report of the Royal College of Physicians on air pollu-
tion and health (228) concluded that "the study of time trends in
the death rates of lung cancer in urban areas demonstrates the
overwhelming effect of cigarette smoking on the distribution of the
disease. Indeed, only the detailed surveys that have taken individual
smoking histories into account have succeeded in separating the
relatively very small influence of the `urban factor' on the over-
riding effect of cigarette smoking in the development of cancer of
the lung."

252


          TABLE 9.-Epidemiologic investigations conwxing the wlationsl,ip of hng cancer to
                   smoking, air polhtion, and urban or rural residence
                               (Actual "umber of deaths shown in parentheses)

  Author,      Population
  Ye*=.       studied and
country.      method of                               Results
reference     data collection                                                                  Comme"ts


Doll,       Estimated death rates                Lung canecr mortality (1950) per 1,000                  Authors noted that
1953,       from lung cllncer                    M&.9                 FC?Tl&S        Nonsmokers   estimates are based on
England     in English                London Other urban Rural    Londo?~ Other urban Rum4   All area8   very few deaths.
(70).       population and    Age:
          among nonsmokers   25-44  0.126    0.095    0.070      0.028    0.028    0.012    0.020
          obtained from      45-64  1.672     1.264    0.861      0.194    0.162    0.120    0 090
          general register.     65-74 3.124    2.00G    1.164      0.440    0.32F    0.288     `219

Stocks and   Death rates in                         Male lung cancer death rates 195161 (prr 100.000) ngctl 51-74  The authors noted the
Campbell,    England and                                                                upward gradient among
1955,       Northern Wales.                                  Rural (68)   Mixed (118)   Urban (5.79)   nonsmokers. pipe
England     Review of patient  Nonsmokers __.............._.......,......_      14                 131
(8.55).                                                                            smokers and light
          chart or interview  Pipe    .._.........__...      41        25        143      c.igerette smokers and the
          with kin or      Cigarettes: Light      87        153        297      lack of a similar
          physicians.       Moderate ,,.,,........._....._,.......,...     183        132        287      gradient among
                       Heavy ._....................,..........     363        303        394      moderate and heavy
                                                                           cigarette smokers.

Hammond    187,783 white males                Age etandardized death rates dve to bronchogcnic carcinoma (males) -
                                                                           Data excluded
and Horn,    in 9 states.                                                                  adcnocarcinoma. when
1958.       Questionnaire                                  Suburb       City of      City of       standardized for age and
U.S.A.      and interview.                       Rural        or town     10,300-50,000
(120).                                                                   >SO.OOO      smoking, rural rate was
                      Nonsmokers  .            4.7 (2)      9.3 (3)      14.7 (4)      still noted to be 26
                      Cigarette smokers  66.2 (62)      71.7 (67)      70.9(69)      85.2(83)      percent less than urban.
                                                            .~


        TABLE g.-Epidemiologic investigations concerning the relationship of lung Cancer to
             smoking, air pollution, and wban or rural residence (cont.)
                           (Actual number of deaths shown in parentheses)

  Author,      Population
   Ye-.       studied snd
  country.       method of                               Results                                comments
reference     data collection

HW"SZ.4     10 percent of all           Age- md emoking-standardized lung cancer mOrt&tU rsaQtii%           Standardized Mortality

et al..      white male lung              (epidermoid and undifferentiated carcinontas mh)             Ratio = IOO for U.S.
1962,       canwr deaths in
U.S.A.                                                          white males age 35 and
           U.S.A. for 1958           Metropolitan counties            Nonmetropolitan counties
(11.3).                                                        over in 1958. The authors
          for whom next of         >50,000  ,119             2.600-50.000  . .QO
         kin or physicians                                              *ISO noted ". . joint
                          lO,OOO-50.000  .I61             Rural nonfarm .74         eff'Xt.s Of residence and
         supplied smoking        2.600-10.000  . .99             Farm  . . . . . . . . . ...57         smoking histories in the
          data. 2.191 cases                                               @chedule of hng-cancer
         with adequate                                                 =ateS far greater than
          information.                                                      those expected on the
                                                               a.%umption of additivity
                                                                           of the separate
                                                                           effects. . :'

DOU       41,000 male British                     Standardized death rates for lung cancer          The authors noted that
and Hill,     physicians.
1964.       Questionnaire and                                                       rural mortality data

England                         Conurbation(49) Large Towns (34) Small Towns (ad)
         follow-up of death                                                 Rural (IS)
                       Nonsmokers       0.03                                      were affected by a

(74).                                                 0.00         0.11          0.12
          certificate.      Cigarette smokers:                                            significant number of

                        1-14  . . . . . . . . . . . . . .._     0.48                                    city residents
                                                    0.32          0.87          0.52
                        16-24 .._..........     1.31                                  retiring to the country.
                                                    1.66          1.06          1.16
                        >25  . . . . .._.........     1.90          4.43         2.20          1.17

Wicken,     1,908 male and
1966.                          Lung tamer death rate pe+ lOO,OOO--age- and smoking-standardized
         femalelu"gcs"eer                                                           Total number of deaths

Northern     deathsover 35                 Inner      outer     Belfast   urtmn                    noted under method of
                                                                    STlUdl
Ireland                                                                        data collection include
          Years of *ge from              Belfaet     Belfast    Environs   AT.X8      TOWM
(308).                                                                        RUTal
          register. Personal                                                             964 contTob3.
                      Males     X7(241)    139(167)    136(46)    118(185)    137(26)    47(149)
          interviews with    Females     22 (38)     17 (24)    12 (6)     23 (35)
          kin or physicians.                                               22 (6)    12 (43)


TABLE 9.-Epidemiologic in.vestigations concerning the relationship of lung cancer to
     smoking, air pollution, and urban or rural residence (con&)
              (Actual number of deaths shown in parentheses)

Author.      Population

Yea=,       studied and
COUIltrV.       method of

Results

referenee

Buell
et al..
1967.
U.S.A.
(49).








Hitosugi,
1968,
Japan
(126).

  data collection

304 lung cancer           Age-adjusted lung cancer death rates per 100.000 man years and mottalitg ratios  The authors noted the lack
deaths among                                                                of death-rate difference
American                                         San Francisco/      AU other     between Los Angeles and
Legionnaires                           Los Angeles      San Diego     California countiee   San Francisco regions
aged 25 and over.                         Rate    Ratio    Rate    Ratio    Rate   Ratio   and concluded that
Questionnaires to   Nonsmokers  _,.,..._.__.....    28.1     2.6     43.9     3.9     11.2     1.0   photochemical smog ia
next of kin.      Smokers :                                                      not related to
             <I pack/day  .,,...........    63.6     6.7     11.1     6.9     61.02     6.4   lung cancer.
              k-1  . . . .   126.0    11.3    134.6    12.0    124.9     11.2
             >l  . .   241.3    21.6    226.0    20.2    137.6     12.3

185 male and                                     Lung caacer death rate per 100,000    The authors postulated a
female lung cancer                                                       slight synergistic
deaths and 4,191                                          PoUution region         effect between smoking
matched controls   Males                                LOW      Intermediate     High  and air pollution.
aged 36-14. Data   Nonsmokers  .._.......,.,...,........... . . . . .     11.6         3.8         4.9
from          Smokers :
questionnaires      1-14 cigarettes/day  _. . .     10.6        14.2        23.6
and interviews.     >16 ,,,,,....................................    21.3        18.6        31.4
             Fern&a
             Nonsmokers  ,,.,...__.._._._..._...............     4.6         6.9         3.8
             Smokers:
              1-14 cigarettes/day .     19.7        16.6        16.3
              >16  . . . . . .     12.4        20.6        17.1
                                     Age- and smoking-adjusted lung cancer
                                               death rate per 100,000

E

Males . . ..___._.................................
Females  . . . . . . . . . . . . . . . . . _.._.._...............

LOW      Intermediate     High
16.1        22.4        28.4
7.6        11.6         8.1


LUNG CANCER AND OCCUPATIONAL HAZARDS

Uranium Mining

The excess risk for the development of lung cancer among uran-
ium and fluorspar miners has been known for more than 30 years.
In a recent review, Bair (17) noted that radon and radon-decay
products are the only inhaled radionuclides to be epidemiologically
related to lung cancer. Lundin, et al. (178), in a continuation of
the work initiated by Wagoner, et al. (299, 300, 301)) have re-
cently reported on a l7-year follow-up of 3,414 white underground
uranium miners. The authors estimated that smoking uranium
miners experienced an excess of lung cancer ten times greater than
did nonsmoking miners.

Saccomanno (231)) in recent testimony, analyzed the data of the
United States Public Health Service (USPHS) Study Group as
presented by Lundin, et al. (178) above. He reported that cigar-
ette smoking uranium miners incurred lung cancer rates four times
greater than those of other cigarette smokers.

Of the 62 lung cancer deaths in this population, 60 occurred in
smokers. He also observed that among 100,000 uranium miners
700 lung cancer deaths per year would be expected to occur among
cigarette smokers compared with only 4 among nonsmokers.

Other Occupations

Nelson (199) has recently reviewed certain environmental and
occupational hazards as they relate to inhalation carcinogenesis.
He observed that cancer of the respiratory tract has been linked
epidemiologically and, in some cases, experimentally with occupa-
tional exposure to the following materials: chromium, nickel,
arsenic, and asbestos. Doll (72) and Goldblatt (100)) in earlier
reviews, also noted an association with coal, natural gas, and
graphite exposures.

Nickel

Morgan (194) noted that much of the nasal and lung cancer at-
tributed to nickel exposure may have been due to arsenical impuri-
ties found in processed nickel prior to 1925. Doll (69) found that
the number of excess deaths among nickel workers under 50 years
of age had declined following the change in nickel manufacturing
processes. The experiments of Hueper (1.~1) and Sunderman, et al.
( 267,268,26.9) have shown that both guinea pigs and rats develop
lung cancer following chronic exposure to nickel carbonyl or nickel
dust. Sunderman and Sunderman (270) also reported that ciga-
rette smoke contains nickel and that this concentration of nickel

256


may be capable of inhibiting the induction of lung aryl hydroxylase,
an enzyme which is able to detoxify aromatic hydrocarbons includ-
ing known carcinogens such as benzo[a]pyrene.

Asbestos

In 1955, Doll (71) found that lung cancer was a definite hazard
among asbestos workers, In a more recent study, Selikoff, et al.
(Zl,ZnZ) examined the relationship of smoking and asbestos ex-
posure to lung cancer. These authors followed 370 people who had
been asbestos workers during the years 1942-1962. Over a 5-year
follow-up period, 94 deaths occurred in this group, of which 24 were
due to bronchogenic carcinoma. The authors noted that according
to data obtained from Hammond (118), only 3.16 deaths from lung
cancer would have been expected among smokers, and calculated a
7.6 to 1.00 mortality ratio due to asbestos exposure. None of the 87
nonsmokers or pipe and cigar smokers died of lung cancer. When
the expected number of nonsmoker deaths (0.26) is compared with
the actual number (~4) which occurred among the smoking asbes-
tos workers, an extremely high mortality ratio of 92 to 1 is obtained,
thus reflecting the possible interaction of asbestos exposure and
cigarette smoking.

Exposure of mice (179) and rats (106) to asbestos dust or the
intratracheal injection of chrysotile asbestos dust has resulted in
the production of significant numbers of primary pulmonary car-
cinomas. Miller, et al, (181) exposed hamsters to intractracheal
injections of benzo[a]pyrene. These authors observed that the addi-
tion of the chrysotile variety of asbestos to the injections appeared
to promote benzo[a]pyrene carcinogenesis in the respiratory tract,
as determined by the time of appearance and yields of papillomas
and carcinomas.

Auenic

A recent epidemiologic study by Lee and Fraumeni (16.3) has
indicated an excess of lung cancer deaths among smelter workers
exposed to arsenic for more than one year. Cigarette smoking was
not taken into account in their computations. Experimental work
on the induction of cancer in animals using arsenic has yielded
either negative or inconclusive results (133,135).

Chromium

Exposure to industrial bichromate compounds has been associ-
ated with an excess of lung cancer deaths (22,25cJ). Laskin, et al.
(159) have recently reported that intrabronchial pellet implanta-

257


tion of various chromium compounds in rats is associated with the
development of squamous cell carcinomas and adenocarcinomas.
However, Nettesheim, et al. (ZOO) exposed mice to chromium oxide
dust and observed that it had no discernible effect on lung tumor
incidence.

PATHOLOGICALSTUDIES

Investigators who have conducted detailed autopsy studies on
patients who died of lung cancer have reported the increased pres-
ence, when compared to noncancer patients, of bronchial epithelial
changes which they considered to be precursors of bronchogenic
carcinoma (7, 8, 23, 51,. 101, 208, 220, 279, 309). Such changes
include squamous metaplasia, atypical squamous metaplasia (with
acanthosis, dyskeratosis, and numerous mitotic figures), and car-
cinoma in situ. Carnes (51) noted that carcinoma in situ was pres-
ent in 119 cases of lung cancer but not in any of the 119 controls
who were matched for age, sex, and race.

Autopsy studies comparing the frequency of these cancer-
related changes in the lungs of smokers and nonsmokers are pre-
sented in table 10. Virtually all the studies noted an increased
prevalence of these epithelial alterations among smokers as com-
pared with nonsmokers. Definite dosage-dependent relationships
were evident in the results of many of the reports. Also, Auerbach,
et al. (14) observed that the number of cells with atypical nuclei
decreases progressively in the bronchial mucosa of ex-cigarette
smokers, depending upon the number of years between cessation of
smoking and death, although it usually remains above that found in
nonsmokers.

The cytologic studies included in this table (182, 198, 222) all
noted an increased percentage of sputum specimens showing meta-
plasia among smokers as compared with nonsmokers.

PULMONARYCARCINOGENESIS

General Aspects of Carcinogenesis

Agents found in cigarette smoke which have been identified as,
or are suspected of being carcinogenic, are listed in table 11. The
list includes certain compounds which most probably contribute to
the pathogenesis of the various cancers discussed in the other sec-
tions of this chapter. Many other agents have been identified in
tobacco and tobacco smoke. At the present time, they do not appear
to bear a direct relationship to carcinogenesis. Stedman (262) and
Wynder and Hoffmann (319) provide detailed listings and discus-
sions concerning these materials.

258


TABLE lO.-Pathologic and cytologic findings in the trachea-bronchial tree of smokers and nonsmokers
                    (Actual number of cases show" in parentheses)

Author.
Y==,
countrY,
reference

NuIu""`,";f
method of
selection

R.?sllIts                                   Comments

Chang.
1967,
U.S.A.
and
K0rell
(55).

105 males and
females 40-86
years of age.

          Percent of cases with brmachid basal cell hyperactivity
Nonsmokers  . . . . . . . . . . , . . .    23.6 (34)
smokers  . . . . . . . . . . . . .     43.7 (71)
Heavy smokers . . . . . . . . . . . . . . . , . . . . . . . . .    t61.3 (31)

Smokers included
pipe snd cigar
smokers.
t psO.01 in com-
parison with
nonsmokers.

Hamilton
et al..
1957.
U.S.A.
(117).

Selected
autopsy
material.

                Number     Age range
Smokers  . . . . . . . . . . . . . . . .  16         39-71
Nonsmokers    20         26-83

Percent of cues with:
Bad cell     SQuamoua
hyperplasia    metaplaaia
  86.6        20.0
  40.0        15.0

Tsmaitional
metaplaaia
  40.0
  36.0

No lung cancer
patienta included.

     Sanderud,   100 males                   Percent of case6 with bronchial ag~arno~n epithelial netaplaia         Nonsmokers in-
       1956.      autopsied at           Nonsmokers  . . . . . . . . . . . . . . . . .    64.0 (39)          elude those
      Norway    Gade Institute         Pipe . . . . . . . . . . . . . . . . . . . . . . . . .._.........._..................    80.6 (20)          smoking less
       (240).     on whom             All cigarette  . . . . . . . . . . . , . . . . . . . . .    79.0 (38)          than or equal to
              smoking data          Cigarettes per day:                                              6 grams per day.
               was available.            E&14  . . . , . . .     70.0 (23)
                                 16-26  . . . . . . . . . . , . . . . .    90.0 (10)
                                 >ZS . . . . . . . . . . . . . . . . , . . . . , . . . . . . , . . .    100.0 (6)

     Knudtaon,   100 persons                               Percent of cases with:               Atupical    Age, occupation,
       1960,      23-86 years                  No. of        NO       Basal cell     SQWtnOU8     proliferative    and site of
      U.S.A.     of age                       P+%WWd      change     hgperplasia    metapIa.&     ?"dWAlsia     residence were
       (1.47).     autopsied at  Nonsmokers . . . . . .  (21)         41.6         23.6        14.3         9.6       found to have no
               Seattle     Cigarettes/day:                                                          appreciable
               Veterans      1-9   . . , . . . . . . .   (9)        17.8         11.1        11.1         . .        effect.
               Hospital on    10-16  . . . . . . . . . . . . . . . . .  (11)         18.2         18.2        64.6         9.1
               whom       16-20 . . .._........._.. (44)        20.4         29.6        29.6        29.6
              smoking     >21  . . . . . . . . . , .   (9)        11.1         33.3        44.4        11.1

it               data was    Pipe or cigar  , . , . , .   (6)          . .        100.0         . .          
               available.
rg


TABLE lO.-Pathologic and cytologic findings in the trachea-bronchial tree of smokers and nonsmokevs (cont.)
                         (Actual "umber of cases shown in parentheses)

Author.
year,
country,
refrrenee

Results                                  COlllllle"tS

Auerbach   339 persons
et al..     22-m years
1961,      of age
U.S.A.     autopsied at
(f2).     East Orange
         Veterans
        Hospital
         (excludes
         lung
         Wl"C.X)

Nonsmokers:
<40 years of age
40-59  .
60-69  .
>70  . . . .
Smokers <l pack/day:
<40 years of age
40-59  
60-49  .
>70  . .
Smokers >l pack/day:
<40 years of age
4rk69  
6lL69  . . . . . .
>70  



.

........
........
........
........

........
........
........
........

. .   8
  11
  28
  18

  14
. . .  24
  36
  22

  17
._.. 63
. . . .  84
. . . .  15

Number of
sections
of bronchial
epithelium

333
560
1,463
918

727
1,240
1.772
1,101

880
3,027
4,136
756

Percent sectimla Percent sections
with cilia absent   with bone
and sntirel~   atypical cells
atypical cell8   and cilia absent

              0.3
               
              0.1
              0.6

   0.1          4.7
   1.0          16.9
   0.5          10.8
   0.6          9.4

   1.5          12.5
   4.5          17.4
   6.9         20.5
   9.8         23.7

The suthors noted a
dose-response re-
lation of smoking
to:
  a. loss of cilia,
  b. increase in
     number of
    atypical
     cells,
  c. carcinoma
     in situ.
Average "umber of
sections per case
equaled 62.3.

Cross
et al..
1961,
U.S.A.
(64).

140 persons                    Percent aectiom showing changes in bronchial epithcltum (number of sectiona) t The authors noted
autopsied at                                      Squamow   Atypicd   Carcinoma          that the differ-
Iowa City                      NW??tld   Hyperplmia   metapimia   ?fWtUplLISG    in situ   Carcinoma  ence between
Veterans    Nonsmokers (31) . . 61(562)     36(137)     8 (33)     t15 (68)             . . . .   smokers and "on-
Hospital    Smokers ( 109 ) . . . . . . . . . . . . . 44(570)     43(662)     16(197)     20(263)     l(12)     2.6(34)    smokers was
on whom                                                                       statistically
smoking                                                                       significant.
data was
available.


TABLE lO.-Pathologic and cytologic findings in the trachea-bronchial tree of smokers and nonsmokers (cont.)
                         (Actual "umber of cases show" in parentheses)

Author.
ye.8=,
c0u*t.rY,
reference

%:k;oaf
method of
selection

Results                                  comments

Auerbach
et al.,
1962.
U.S.A.
(14).

72 autopsied
former ciga-
rette smokers
who had been
smoking for
210 yc*lg
and had
ceased
25 years ago.

                        Number of     Percent sections Percent s&ions Percent sectiona Each a-smoker
                       sectimu of     with cilia absent with mmc atypi- with 50 percent   matched with a
                         brachial      and entirely    cd celk and   atypical eel&   current smoker
             Number       epithelium      atypical cells    cilia absent  and cilia preeent  plus "ever-smoker
Nonsmokers   72          3,166           0.0         0.1          0.6      for age. OCC"PB-
Rx-smokers .   12          3,436           0.2         0.9          2.5      tion. and resi-
Current smokers .   72          3,537           8.0        19.0         80.8      dence. There was
                                                                  an average of
                                                                  50.3 sections per
                                                                  subject and none
                                                                   had less than 18
                                                                   sections.


TABLE IO.--Pathologic and cytologic findings in the trachea-bronchial tree of smokers and nonsmokers (cont.)
                        (Actual number of cases shown in parentheses)

Author,    Number of
  Year,      cases and
country,    method of                                  ResU1t.S                                  COllUIl.Xlts
reference     selection

Auerbach   456 male and                                       Percent *ec-   Percent sec-   Percent *ec-    Major findings
et al..      302 female                           Number of      tima with     timw with    tiom with 50    noted:
1962.      smokers and                          wctiona of     cilia absent   wme atypi- percmt atypical    Urban nonsmokers
U.S.A.     nonsmokers                             bronchial     and entirely   cd cells and    ceUs and       showed more
(13).     autopsied and                 Number     epithelium    atypical cell.9   cilia absent   cilia present     lesion than rural.
         matched for   Males :                                                               Both lesions and
         rage. oceu-     Nonsmokers . . . . .  41         2,346                   0.1         0.7       atypical nuclei
        pation. and    Cigarette smokers  . . . . . .  75         3,393      6.9        21.2        78.6       were much less
         residence.    Females: . .                                                           frequent in non-
                   Nonsmokers . . . . . . . .  47         2,379          . .         0.1         0.5       smokers and less
                  Cigarette smokers .  76         3,607         2.5        13.3        62.6       frequent in pipe
                  Males :                                                               and cigar smokers
                   Nonsmokers . . .  36         1.106      0.3         0.2         0.6       than in cigarette
                   Cigar smokers  . . . . . . .  36         1,733                   10.0        10.7       smokers.
                   Cigarette smokers . . . . . .  35         1.626         12.8        27.3        83.1      57.1% of cases bad
                                                                           60-55 sections
                                                                           31.5% of eases had
                                                                           40-49 sections
                                                                           7.3% of cases had
                                                                           30-b9 sections
                                                                           4.6% of cases had
                                                                           16-29 sections

Robbins,
1966,
U.S.A.
(2.22).

103 students                          Percent in each cytologic clads                        Smokers defined as
17-24 years                                  Slight&     Moderat&       strmg1y      those having eon-
of age who                           Normal       atypicd      &p&l       atypical      sumd 210 ciga-
underwent   Nonsmokers (45)  . . . . . . . .  86.7          4.4          8.9           .         rettes a day for
WXOSOl     Smokers (58)  . . . . .  55.2         32.8         10.3          1.7         21 year.
sputum
induction.


TARI E lO.---Pathologic md cytologic findings in the trachea-bronchial tree of smokers and nonsmokers (cont.)
                          (Actual number of crises shown in parentheses)

Author.     Number of
year.      cases and
country,     method of
reference     selection

Results

Maltoni    1,000 healthy                                             Number    Percent ahowinp mctaplasia
et al.,      males who   Nonsmokers  . .      294            41.16
1968,      underwent   Smokers:
Italy      sputum       l-10 cigarettes/day _. . ".   189            47.09
(182).     induction.     11-20  .     385            51.43
                   21-30 . .      93            61.29
                   >30 . .    39            69.23            -~~- __
Nasiell,    50 nonsmoking                           Sputum crtologic changes              Percent with    t Regarded by
1968.      outpatients,                               Percent              Percent with    utupical       author 89 "real
SWdCn    39X smokers                   Number        M&S      Mean age   metaplasia    metap1naiat      premalignant
(198).        
         wrtmpatmg Nonsmokers    50           42         57.1        18           4        change."
         in general    Smokers  _. 393           73         46.6        62          27
         health exam-
         ination who
         underwent
         SPUtUm
         induction.

Spain
et nl.,
1970,
U.S.A.
(258).

15'7 males and
TX females
nutopsied fol-
lowing sudden
or accidentnl
death fol
whom smok-
ina data were
available (ex-
smokers ex-
cluded from
female data).

Males :

Nonsmokers .
Ex-smokers
<l pack
>l pack
Females:




Nonsmokers  
<l pack . .  
>l pack  

-









.........
.........

.........
.........
.........






........
.......


.



.


,...


........
........
........





Number

    36
.    21
    32
    6.8

    34
.    18
.    26

Percent with metaplasia  The authors found
                no evidence af
     50.0         carcinomn in situ
     67.7         or pwneoplastic
     62.5         atypicnl changes.
     73.5

34.1
33.3
46.1


In order to facilitate understanding of the relationships of the
various compounds to one another, the third column presents the
presently underst.ood relative importance of each of the various
groups of compounds. These compounds have been tested only in
animals or tissue cultures, and it should be stressed that the rela-
tive importance of one compound may not be the same in man as
it is in animals.

Table 11 is divided into two major sections. The first section
details those compounds which are considered to be or are suspected
of being cancer initiators. These are compounds which induce
irreversible changes in responsive cells. In the second section are
listed those compounds which are considered to be or are suspected
of being tumor promoters. These compounds promote the malrg-
nant reproduction of cells in which neoplastic changes have been
initiated. A number of these initiators may also act as complete
carcinogens in their own right. The evidence concerning the two
stage initiation-promotion mechanism is still rather limited for
respiratory tract carcinogenesis.

The pol~nuclear aromatic hydrocarbons (PAH) listed are pres-
ently considered to play a very significant role in pulmonary car-
cinogenesis due to tobacco smoking. These compounds act as tumor
initiators or complete carcinogens. The particular role of these
agents in environmental and occupational carcinogenesis has been
reviewed by Falk, et al. (93). That such hydrocarbons are pro-
duced from tobacco during human smoking has been shown by
Kiryu and Kuratsune (2-N). These authors reported the presence
of benz[ a] anthracene, chrysene, benzo[ alpyrene, and benzo-
[blfluoranthene in the "tar" produced by normal smoking and
measured in either filters or stubs.

Two hydrocarbons which have frequently appeared in the litera-
ture on experimental tobacco carcinogenesis may not actually be
present in tobacco smoke. They have been used as representatives
of carcinogenic PAH, a class which includes many constituents that
have been ident.ified in cigarette smoke condensate. They are
`Y,?C!-dimethy!benz[a]anthracene  and 3-methylcholanthrene and
have been frequently used as tumor initiators or complete carcino-
gens, particularly in skin painting and tracheal implantation
experiments.

The nitrosumine compounds listed are potent carcinogens affect-
ing many organ systems, including the respiratory tract (188,
199). Nagee and Barnes (181) have presented a detailed account
of experiments in this area. Xitrosamines have been identified in
trace amounts in tobacco "tar" and the conditions required for their
formation (the presence of secondary amines and nitric oxide) are

264


TABLE Il.-Identified or suspected tumorigenic agents in cigurette smoke'

Estimated
concentrs-
tion in 100
cigarettes
(85 mm.
"onfilter)

Presently understood relative
importance in experimental
  tobacco carcinogen&s

I. Complete carcinogens and tumor initiators:
Polynuclear aromatic hydrocarbons  ........
   1. Benzo (a) pyrene  ..................
  2. Dibe"z(a,hlanthracene   ..........
   3. Be"zo(b)fluora"thene  .............
  4,Benzo(j)fluoranthene  ..............
  6. Dibenzo(a,iJ pyrene  ...............
   6. Benz(a)anthracene  ..............
  7. Cbrysene  ..........................
  8. Indeno(l,2,3-cd),,yrene  ...........
  9. Be"zo(ciphenanthrene'  .............
  10. MethyIbenzo(a)pyre"es  ..........
  11. Methylchrysenes  ....................

N-heterocyclic hydrocarbons  ..........    l-2
1. Dibenz(a,h)acridine  ............    0.01
2,Dibenz(a,j)acridine  ................    1.0
3. `IH-dibenzo (c&z) carbazole  ...........    0.07

N-nitrosamines"                     l-10

1. Dimethylnitrosamine  .............    0.4
2. Diethyinitrosamine  ...............   TKXe
3. Methyl-n-butylnitrosamine  ..........   TlYWe
4. Nitrosopyrrolidine  ..................    0.4
5. Nitrosopiperidine  ..................   TP3C-Z

Epoxides, peroxy compounds. and la&ones:
1. Epoxides  ...........................
2. Peroxides  ...................
3. LarAones  ...........................
   a. a-Leva"re"olide  ................
  b. a-Levantenolide  ................

No data
PRSe"t


20.0
2.0

N-alkyl-heterocyclics:
1. I-methylindoie  .....................

Pesticides and fungicides :<
1. TDE  .............................
2.o,l;-DDD  .......................
3. DDT  ......................
4. Maleic hydrazide  .................

10-100
10.?OO
IO-IOF
10-100


2-3





1.5"

Beta-naphthyiamine  ..,.,,,,..

Polonium 210  

10-30 "I3
3.9
0.4
0.3
0.6
TlYSe
0.3
2.0
0.5
TCDX
0.1
2.0

Tumor initiators

Tumor initiators.

suspected carcinogens of possible
importance (presence in fresh
smoke possible).

Certain of these compounds 8~
know" carcinogens; presence in
smoke condensate not established.

Possib!e initiator.

No essentiai contribution suspected.

Suspected b!adder carcinogen:
of doubtf"i significance at
reported ievels.

Of some importance on!y in the

-;irocuries   case of relatively high conten-
       tration. but not important at
       reported levels.

Nickelcompounds  .  Present  Suspected carcinogens of some
                                 importance.

265


TABLE Il.-Identified or suspected tumorigenic agents in cigarette smoke'
                  (cont.)

Estimated
concentra-
tion in 100
cigarettes
(85 mm.
nonfilter)

Presently understood relative
importance in experimental
tobacco carcinogenesis

II. Tumor promoting agents:
Neutral promoters (polymers)
   (unknown structures.)

No data  Of possible importance.

Volatile phenols    20-30 mg.  Of possible importance.
  1. Phenol
2. Cresol

Nonvolatile fatty acids    20.100 mg. Of minor importance.
  1. Stearic acid
2. Oleic acid

N-alkyl heterocyelics:                      Of possible importance.
1. I)-methylcarbazole  . . . . . . . . . . .  Present

1 Modified and expanded from (319. 320) with reference to (52, 60, 89. Ill. 149. 402. 261.
299,494.295).
2 Has not been tested as an initiator, but is a known complete carcinogen.
3 See Neurath. (9X),
`See (112,128).

found in tobacco smoke (38). However, nitrosamines may be arti-
facts dependent on the method of smoke collection (201).

Neurath (202) considers the nitrosamines listed in table 11 as
being present in fresh cigarette smoke (253, 254). However, con-
clusive confirmation of their presence in fresh smoke is not available
(38,138,15.5,319).

Certain of the pesticides and fungicides presently in use on
tobacco have been found to be carcinogenic (91,273,280). A num-
ber of these, such as DDT, are now being phased out of regular
domestic use. The compounds listed have been shown to be present
in trace amounts in mainstream tobacco smoke (I 11,128). A recent,
extensive review by Guthrie (2 12 ) provides more detailed informa-
tion concerning these agents.

Radioactive isotopes can be found in tobacco and tobacco smoke
(105). Potassium-40, while present in tobacco leaf, is not trans-
mitted in any substantial amount to mainstream smoke (230).
Polonium-210 (PO,,,,), however, is transmitted into the mainstream
smoke (94, 123, 142, 145, 215, 217). A number of autopsy studies
(table A12) have shown that the bronchial epithelium of smokers
contains significantly more Po~,~ than that of nonsmokers. LitBe,
et al. (172, 173, 17s) have also noted that the concentration of
polonium was markedly higher at sites of bronchial bifurcation.
These authors stress the importance of this finding for pulmonary
carcinogenesis by noting that bronchogenic carcinomas are fre-

266


quently located at bifurcations and that the polonium levels which
they found in those regions probably have biologic significance
(~16). Other investigators (11.1, 217') have not observed this
excess at bifurcations, and in a recent discussion Wynder and Hoff-
mann (8.20) concluded that it appears unlikely that PO?,,, in the
amounts present in cigarette smoke plays a role in tobacco car-
cinogenesis.

Although not listed as a separate group, there are a number of
agents in cigarette smoke which are potent inhibitors of ciliary
movement. Their importance in cnrcinogenesis derives from the
increased amount of time which they afford the kno1v-n carcinogens
to be present on the surface of the bronchial epithelium. These
inhibitors include volatile aldehydes, hydrogen cyanide, nitrogen
oxides, volatile phenols, and certain volatile acids such as formic
and acetic (1.29).

In some respects, the animal and tissue culture studies detailed
below apply to neoplastic transformations, not only in the lung but
in ot,her tissues in which tobacco smoke, particularly cigarette
smoke, is believed to play a role. These general experiments will be
presented here, however, with the experiments which bear on lung
tissue directly.

Skin Painting a,nd Shxtaneous Injection

Numerous animal studies on rats, mice, and rabbits, have been
performed utilizing known carcinogens, whole tobacco "tar," and
various tobacco condensate subfractions, or compounds known to
be present in tobacco smoke. These experiments involve the single
or repeated painting of shaved or unshaved animal skin. A selected
number of these studies js presented in table A13. Numerous other
studies, performed prior to and following 19.5:3, are reviewed by
lvynder and Hoffmann (319).

The skin painting method is still considered to be a valid pro-
cedure for the identification of agents suspected of participating in
Pulmonary carcinogenesis, as well as for the quantification of the
reduction in tumorgenicity of specific agents,

The exposure of tissue and organ cultures to cigarette smoke, its
condensates, or its conhtituent compounds has been shown to sig-
nificantly alter patterns of cell growth and reproduction. Table A14
Presents an outline of these experiments. Once again, less severe
effects have been noted lvhen filtered smoke was used (165).

267


Tracheobronchial Implantation and Instillation.

More complex experiments concerning the carcinogenicity of
cigarette and tobacco smoke are represented by those which involve
the direct implantation, instillation, or fixation of suspected ma-
terials into the tracheobronchial tree of animals. Certain of these
experiments are outlined in table AX. Recent reviews by Saffiotti
(233,234) Laskin, et al. (159)) and Montesano, et al. (189) as well
as that by Wynder and Hoffmann (319) provide more detailed and
extensive accounts of these experiments.

Of note among the results outlined in this table are the following :
The enhanced carcinogenicity found when benzo[a]pyrene (B[a]P)
is combined with a carrier such as hematite dust (235)) and the
definite increase in bronchial epithelial preneoplastic and neo-
plastic changes among dogs treated with smoke condensate as com-
pared with those undergoing only physical bronchial stimulation
(224).

Inhalation

Various species, including mice, rats, hamsters, and dogs, have
been exposed to cigarette smoke or aerosols of its constituents.
These inhalation experiments are outlined in table A16. It must be
noted that the majority of the studies listed involve the passive
inhalation of the material presented usually in a chamber. Active
inhalation experiments, exemplified by the work of Rockey and
Speer (223) and Auerbach and his colleagues (11, 129) involved
animals which were trained to inhale voluntarily, thus more closely
simulating human smoking.

Results of note among these experiments include the following:
Miihlbock (195) observed that cigarette smoke inhalation en-
hances the already substantial rate of spontaneous alveolar cell
carcinoma format.ion in hybrid mice, and various investigators in-
duced adenomas in experimental animals (108, 168, 206). Harris
and Negroni (I 21) found that exposure to cigarette smoke achieved
some enhancement of adenocarcinoma formation in mice but did
not observe proven squamous cell carcinoma. Some of their mice
had also been exposed to Swine influenza virus aerosol. In a related
study, Boren (32) exposed hamsters to cigarette smoke at set inter-
vals over a 4%hour period. The author observed alterations in pul-
monary cell kinetics (the pattern of DNA synthesis) as demon-
strated by H"-thymidine autoradiography. The pattern of the label-
ing response to cigarette smoke was significantly different from
that of the response to high oxygen concentrations.

Auerbach, et al. (22) have reported the development of early

268


invasive squamous cell bronchogenic carcinoma in dogs following
a period of direct inhalation of cigarette smoke. These investiga-
tors trained beagle dogs to inhale cigarette smoke through a
tracheostoma (50) and divided the animals into groups according
to dosage as detailed in table 17. A number of dogs died during the
course of the experiment which ran for 875 days, or approximately
29 months. The causes of death are listed in table 18. All of the
remaining dogs, with the exception of group "h" (high exposure,
heavy weight), were sacrificed shortly after day 875 ; the survivors
among the heavier dogs are continuing to smoke.

Examination of the respiratory tree of the animals revealed a
number of tumors (table 19). Most of these were similar to the type
of tumor which in man is referred to as bronchiole-alveolar. This
tumor arises in the bronchiolar and alveolar epithelium and tends
to be multicentric. Two striking characteristics of these bronchiolo-
alveolar tumors were the existence of a histologic spectrum (from
a tumor resembling the benign condition of adenosis to frankly
malignant tumors with invasion of the pleura and surrounding
parenchyma) and the marked tendency to squamous change. Inva-
sive bronchiole-alveolar tumors were found in 12 dogs in the group
which had been exposed to the largest dosage of cigarette smoke.
Several had tumors of more than one category. Ten of these dogs
had invasive bronchiole-alveolar tumors which did not extend into
the pleura, one dog had an invasive bronchiole-alveolar tumor
which extended to the pleura, and four had invasive bronchiolo-
alveolar tumors extending into the pleura beyond the pleural-
pulmonary junctions. In addition, two bronchogenic squamous cell
carcinomas were found in this group (table 19). The dosage de-
pendence of tumor formation is shown in figures 2 and 3.

Major findings of the study were twofold. First, that smoking
filter-tip cigarettes was less harmful, both in terms of pulmonary
parenchymal damage and lung tumors, than smoking identical
cigarettes without filters. This supports the generally held view
that total particulate matter is a meaningful indicator of the car-
cinogenic potential of a cigarette, Second, lung cancer of two types
found in man was produced by the inhalation of cigarette smoke.
TWO of the dogs were found to have early invasive squamous cell
carcinoma of the bronchus, and both belonged to the high-dosage
group. These carcinomas were indistinguishable from early invasive
squamous cell carcinomas found in the bronchial tubes of human
beings who smoke cigarettes. The majority of tumors found in the
dogs were of a bronchiole-alveolar type, which although not as
common as squamous cell cancer in man, is not rare in humans.
This type is often included in the category of adenocarcinoma. A
number of studies have shown an excess of these tumors among

269


TABLE IT.-Datu on pedigreed m& beagle dogs of groups F, L, H, h, and N
         (Some of the figures apply only to dogs surviving 8'76 days or longer)

Filter
**O"p
F

NO
filter
gri?p

NO
filter
grour,
H

fE*       Nonsmokers
group         grO"P
h           N

Number of doss on day No. 67'
Weight at start (day No. 1) mean weight (pounds)
Cigar&e s per dog II, 875 days _. t..
Mcarr numlwr of c~ynrettes per day _. _.
Eauivalertt number of cigarettes per day for 150 pound man
Type of cigarettes:'

                                              ___-
12             12            24            38           R

25.0            26.1           26.0           31.9          30.7
6,143           3,103          6,129           6.129          none
  7.02            3.64            7.0            7.0         -
42.1            21.2            42.0           32.9

Milligrams of tar per cigarette .
Milligrams of nicotine per cigarette
Total dosage in 875 days:
Grams of tar per dog _.  
Grams of niecrtinp per dog  
Dosage in Xi5 days relative to starting weight:
Grams tar/pounds weight  
Grams nicotine/pounds weight _. _,

17.8
1.17


109.3
7.19

4.31            4.12            8.31
0.29            0.22            0.44

34.8            34.8           34.8         -
1.85            1.85           1.85

103.5           207.8
6.56           11.12

207.8         -
11.12         -


6.61         -
0.35         -

-_I          ____
' The smoking dogs were divided into CLOUDS F. L. H. and h on dav No. 67.
? Dogs of groups L, H. and h smoked filter-tip cigarettes during a training period at the start of ,the experiment, but smoked nonfilter cigarettes thereafter.
SOI'H~~~S: Adapted from Hammond, E. C. et al. (119).


TABLE I%-Swmnary of principal cause of death (days No. 57 through No. 875) in dogs of groups F, L, H, h, atztl N
        (Each death classified according to most severe condition-some dogs <liwl of n n>mbinnti<m <,f rauses list&

NO
filter

          Principal cause of death                         Group
                                                   IA                               _.
                                                              ~~~___
Pulmonary emphysema and fibrosis _,                           2                     -           2
Cc~r r)ulmonnle (pulmonnry emphysema and fibrosis with
right heart enlargement)                             3           5                      8
Pulmonary infarction  .      1           1           2           *5                      9
Bronchopneumonia       -                      3           I          -           4
Aspiration of food . . . . . . . . . . . . . . . . . . . . . . . . . .      1           1                                -           2
Uncertain _._.,..._,,,.,.,._.,.,,..,,,,........,....,.                           2           1                      3
Number of deaths __,.,.,........._..__.,.,,,,..__.___,      2           2          12          12          -          28
Number surviving 876 days . . . . .     10          10          12          2 R           8          66
Total number of dogs . . . . .     12          12          24          :3X           8          94

  SOURCE: Hammond, E. C. et al. (119).


TABLE lg.-lhtcc on dogs with lung tunlors indicating type of tumor and lobe in w'hich the tumor was found
                NTfber      Age at                              Early ssxuunous
Group           ",%if                 death     Lobes with bronchido-alveolar tumors     cd bronchial
                                 cigarettes     (Years)     Non-invasive        Invasive        carcinoma

Group N (nonsmokers)  . . . . . . . . . . . . . . N      904a
                         N      904b

Group F (filter-tip)  . F
                          F
                          F
                          F

878a        6,161
879a        6.170
885~s        6,224
X90a        6,269

Group L (no filter)  . . . . . . . . . . . . . L
                          L
                          L
                          L
                          L
                          L
                          L

347         1,055
812         2,847
87th        3,103
87'7a        3,107
xnza        3.127
896a        3,183
899a        3,195

Group H (no filter)   H
                         H
                         ii
                         H
                         H
                          H
                          H
                         H
                         H
                         H
                         H
                         H
                         H
                         H
                         H
                         H
                         H
                         H
                         H

135          518        2.5
259         1,343        3.3
563         3.404        4.1
716         4,689        5.0
753         5,030        3.x
760         5,088        4.2
868         5,970        5.3
R'ifia        6,129        4.9
R77a        6,138        5.4
R'78n        6,147        5.3
xa2a        6.183        6.4
883a        6,192        4.7
8858        6.210        5.0
889a        6,246        5.0
890a        6,255        4.9
892a        6,213        6.1
8!lZb        6,213        5.3
897a        6.318        5.2
X!)7b        6.318        4.5

5.1        LA
4.9        RA

6.1        LA
4.7        LA
5.2        LA
5.4        LA

3.x        LA, LC
5.1        RA
5.1        LA, RA
5.2        LA, LC
5.2        LA. LD
5.3        LA, RD
5.4        LA

RC
LA, RA, RD
LD. RA


RI
LA
LA



. .
RA
LA
RA. RD. RI

LA
LC, RA
RA
LC

1.A
LA, RA, RD

-
LA, LD. RA
LA
LA

LA
LA, RA
LA

-

-
LA, RA
-
LA

-

-
-

-

-

-

-

-
-
-
-

-

-
LABB
-
-
-
LMB
-
-

-
-
-


TABLE lg.-Data on. dogs with lung tumors indicating type of tumor and lobe in which the tumor was found (cont.)

Day of
death

Number
  of
cigarettes

Age at
death
(years )

                       Early squamous
I.ohrs with bronchiolo-alveolar tumors    cell bronchial
Non-invasive        Invasive       carcinoma

Group h (no filter)  .,,..,........... . . h      606         3.760        4.6        LA
                          h      626         3,928        4.4                      I,A, RI
                          h      649         4,143        5.0        RI             T.A. RA
                          h      794         5.400        5.1        LA, HA

LA, left apical lobe; LC, left cardiac; LD left disphragmatic: RA. right
apical; RC, right cardiac; RI, right intermediate; RD. right diaphragmatic;
LABB, left apical branch bronchus; LMB. left main bronchus.

start of smoking. The letter "a" or "b" follows the day of death of dogs
sacrificed after day 3875.

For smoking dogs, the day of death indicates the number of days since      Sorinc~: Auerbach. 0. et al. (II ).


80

58.3

TUMORS
DOGS

NONSMOKING

FILTER-TIP      NO FILTER
       (% as many cigarettes)
           as Group H

GROUP H:
NO FILTER

2            4            7           19
s        i?        -ii       24

FIGURE 2.-Percent of smoking dogs with tumors.
SOURCE: Adapted from Auerbach, O., et al. (11).

20.8

0
     GROUP N:      GROUP F:       GROUP L:     GRLu. 8,
    NONSMOKERS    FILTER-TIP      NO FILTER     NO FILTEI

4.8

TUMORS       2            4            12          35
LOBES     56       xi        s4      158

FIGURE S.-Percent of lung lobes with tumors in smoking dogs.
SOURCE: Adapted from Auerbach, O., et al. (11).

274


cigarette smokers (C, .i;?, II,`), but the magnitude of this relation-
ship is not as great as that with squamous cell cancer in man.

Reduction in Tumorigenicity

The importance of reducing total particulate matter in cigarette
smoke is reflected in the dose-dependent results of the Auerbach-
Hammond study. A major objective of experimenta tobacco car-
cinogenesis must be the reduction in the tumorigenicity of cigarette
smoke and other tobacco products. In a recent article (320),
Wynder and Hoffmann have reviewed the various methods applied
to achieve this goal. Among therje methods are the modification of
the tobacco itself, the modification of the conditions of tobacco
pyrolysis, the use of additives, and the use of filters. The use of
filters should produce a reduction of particulate matter as well as
of gas phase components.

Bross (44) studied 974 cases of lung cancer at Roswell Park
Memorial Institute and concluded that smokers who switched to
filter cigarettes showed a decreased risk of developing lung cancer.
However, even after switching, heavy smokers were still found to
have a mortality risk five times that, of nonsmokers.

More recently, Wynder, et al. (3.24) reported on an interview
study of 350 patients with histologically confirmed lung cancer and
552 age and sex-matched controls. They found that subjects who
had switched from nonfilter to filter cigarettes ten or more years
prior to the study incurred a lower relative risk of lung cancer at
all consumption levels than that incurred by those who continued to
smoke nonfilter cigarettes. The authors suggest that this difference
in relative risk may be due to the lower "tar" content in filter
cigarette smoke. Prospective studies concerning the effects of filter
cigarette smoking are presently being conducted.

Apart from variations in "tar" exposure due to filtration, it
appears that different patterns of smoking result in the inhalation
of varied amounts of "tar." Graham, et al. (103) simulated dif-
ferent inhalation patterns with the use of an analytic smoking ma-
chine. He found that smoking a given number of puffs over a long
period of time results in greater "tar" retrieval than smoking them
over a short period. Also, he observed that taking most of the puffs
at the end of the cigarette results in the highest retrieval while
taking most at the beginning results in the smallest retrieval.
Complementing these observations is the same author's case/con-
trol study (102) of 183 men with lung cancer and 161 men with
diseases not related to tobacco smoking. He found that the lung
cancer patients had significantly greater high "tar" yield cigarette
smoking patterns than the controls. The risk of lung cancer was
found to increase with the increase in mean number of puffs per

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