TABLE 4.—Smoking habits of 21 Navajo uranium miners
with lung cancer

 

 

Cigarettes/day Number of men
0.0 8
el 2
1-3 6
4-8 5

 

SOURCE: Adapted from Samet, Kutvirt et al. 11984)

 
  

9
| Smokers Nonsmokers

 

Attributable lung cancer/ 1,000 person-years

 

 

 

 

 

 

 

 

T T T T tT
<5 599 10-149 15-24.9 >25<5 599 10-149 15-249 >25

interval in years after start of mining

FIGURE 2.—Influence of age at observation and induction-
latent period on attributable lung cancer
deaths among U.S. uranium miners

NOTE: Error bars are 90 percent confidence intervals
SOURCE: Adapted from Roscoe et al. ‘in press.

birthdate, on year when their mining started, and on the magnitude
and rate of exposure to radon daughters. The mean I-L period was
23." and 18.5 years for nonsmokers and smokers, respectively

451
(p<0.001). The mean age at death was 54.7 and 50.2 years,
respectively (p< 0.001).

Two sophisticated analyses using Cox regression methods were
done of the U.S. uranium miner cohort in an attempt to determine
the relative contribution of various factors to the miners” lung
cancers. One of the analyses used a cohort approach (Hornung and
Samuels 1981); the other used a nested case-control approach
(Whittemore and McMillan 1983). Both concluded that the interac-
tion between smoking and radiation effects was multiplicative.

Swedish Miners

Axelson and Sundell (1978) conducted a case-control study of lung
cancer patients in the area around two adjacent lead-zinc mines that
had begun operating prior to 1920. Twenty-nine lung cancer cases
were identified from parish death register data; the controls were
the three individuals entered in the register just before and just after
each lung cancer case, but who had not died of lung cancer. Of the 29
cases, 21 had underground mining exposure in comparison with only
19 of the 174 controls. The mean radon daughter exposure of the
lung cancer cases was approximately 300 WLM. Smoking informa-
tion was obtained for both groups (some from relatives). Data on the
21 lung cancer deaths of miners were collected over a 20-year period
(1956-1976). The mean age at death was 70 and 59 years, respective-
ly, for nonsmokers and smokers with lung cancer. The mean I-L
period was 43 and 34 years, respectively, for nonsmokers and
smokers with lung cancer. The nonsmokers contributed 47 percent of
the lung cancers, whereas only 19 percent of the controls were
nonsmokers.

Damber and Larsson (1982; Larsson and Damber 1982) performed
a case-control study of 604 male lung cancer deaths in the three
northernmost counties of Sweden. Two control groups were selected
from among deceased and living populations. Decedent controls were
drawn from the national registry for causes of death and matched for
sex, year of death, and municipality to the lung cancer cases. Living -
controls were selected only for those lung cancer cases under the age
of 80 (467 cases) and were drawn from the national population
registry and matched for age, sex, and year of birth. Twenty-five of
the cases and only 10 of the controls had underground mining
exposure. The relative risks for smoking and underground mining
exposure were these: nonsmoking individuals with no underground
mining exposure, 1; nonsmokers with underground mining exposure
(2.4 decedent controls, 7.0 living controls); smokers with no under-
ground mining exposure (6.8 decedent, 7.4 living); and smoking
miners (18.2 decedent and 16.1 living). The mean age at death was 69
and 63 years, respectively, for nonsmokers and smokers among the |
miners with lung cancer. The mean I-L period was 43 and 35 years,

452
respectively, for nonsmokers and smokers among the miners with
lung cancer. The mean exposure was not given, but was probably
about 100 WLM, as many of the subjects were the individuals studied
by Radford and Renard (1984). This difference was considered to
represent a multiplicative effect of cigarettes and radon daughters,
but it was not possible to rule out an additive effect.

Case—control studies were done with a different group of Swedish
iron miners (Edling 1982; Edling and Axelson 1983). Cases were
deaths from lung cancer, and controls were miners who died from
nonmalignant causes, matched for birthdate, sex, and year of death.
Mean exposures were about 100 WLM. There were 44 cases among
miners, and a standardized mortality ratio (SMR) of 11.5 to 16.2 was
calculated for lung cancer. Of these 44 cases, 38 were smokers and 6
were nonsmokers. The risk ratio was 1.5 to 2 times greater among
smokers than among nonsmokers. The mean age at death was 67 and
61 for nonsmokers and heavy smokers, respectively. The mean I-L
period was 40 and 37 for nonsmokers and heavy smokers, respective-
ly. The authors concluded that the interaction was probably additive.

A retrospective cohort study was done of another group of workers
from two iron mines, one worked since 1890, the other since 1920
(Radford and Renard 1984). Death data were collected for a 26-year
period (1951-1976). There were 50 lung cancer deaths that occurred
10 or more years after start of mining. The mean exposure was about
94 WLM (84 WLM corrected for exposure immediately prior to
death). Smoking information was obtained from relatives for all lung
cancer deaths and by questionnaire from approximately half of those
study members alive in 1973. Using general population data on
smoking and mortality, a dose-response relationship for radon
daughter exposure was demonstrated. There were 18 lung cancer
deaths among nonsmokers versus 32 among smokers. The relative
risk due to radon daughter exposure was 10 for nonsmokers and 2.9
for smokers (p<0.001), and the radiation exposures were approxi-
mately equal for both groups. The absolute excess lung cancer risk
attributable to radon daughter exposures was slightly higher for
smokers than for nonsmokers. The mean I-L periods were 41.3 for
nonsmokers and 38.8 years for smokers. The mean age at death from
lung cancer was approximately 65 years, but was not calculated by
smoking status. The authors concluded that the interaction was
slightly more than additive.

Canadian Miners

In studies of a group of Canadian fluorspar miners there were only
2 lung cancer deaths among nonsmokers versus 76 among smokers
(Wright and Couves 1977; Morrison et al. 1981). Smoking data were
incomplete, but it was estimated that only 5 percent of the miners
were nonsmokers. The mean exposure was approximately 600 WLM.

453
The followup period was from 1933 to 1977, an interval of 44 years.
The mean I-L period was 25 years and declined with increasing age
at start of mining. The mean age at death was 52 years.

An analysis of sputum cytology results from 249 active Canadian
uranium miners found that the frequency of atypical cells in sputum
was related to both cigarette smoking and radiation exposure. Few
atypias were seen among nonsmokers, and this was interpreted as a
potentiation of the radiation effect by smoking (Band et al. 1980).

Other Epidemiological Studies Relating Radiation and Cancer

Because of the high cost of imported fuel, the Swedes were among
the first to emphasize the closing of cracks and adding insulation to
dwellings in order to conserve heating fuel. Sealing the indoor
environment also resulted in an elevation in the radon levels in the
indoor environment. These radon exposures have resulted in a
substantial interest in Sweden in the role of radon as well as in the
role of cigarette smoking on their lung cancer death rates.

A case-control study was conducted in rural areas of Sweden,
limited to people who had lived at the same address for 30 years
before death (Axelson 1983). Measurements of radon in different
types of houses led the researchers to classify wooden houses without
basements as low radon, and brick or concrete houses with base-
ments (especially those built on alum shale or granite deposits) as
high radon. Smoking histories were obtained on half of the cases
from questionnaires completed by relatives. In the high exposure
housing, smokers had a lung cancer crude risk ratio of 8.3; in the low
exposure houses the ratio was only 2.0. There was no difference in
smoking habits between inhabitants of the two types of houses. The
researchers felt that this indicated a multiplicative or synergistic
interaction. A second study of Swedish residents did not alter that
conclusion (Axelson 1983; Edling et al. 1984).

In a case-control autopsy study of 204 Japanese A-bomb survivors
with lung cancer who subsequently died, the relationship of smoking
to radiation exposure was examined (Ishimaru et al. 1975). An
increase in lung cancer risk was seen with increasing radiation
exposure and increasing amount smoked, but no interaction could be
discerned.

A cohort study of 40,000 A-bomb survivors studied the relationship
of cigarette smoking and radiation exposure to cancer mortality
(Prentice et al. 1983). Subjects were stratified by smoking and-
radiation categories, and multiplicative and additive models were
examined. There were 281 lung cancers. The lung cancer risk rose
with both increasing radiation and increasing smoking. Cancer of
some sites showed an absence of or a negative correlation, but both
esophageal and lung cancer risk rose with both increasing radiation

454
TABLE 5.—Interaction of radiation and cigarette smoking
among Japanese A-bomb survivors

 

Relative risk estimates

 

 

 

Number Nonsmokers Smokers
of
Cancer site cancers ~<10 rad 10-99 rad > 100 rad - 10 rad 10-99 rad >100 rad
Stomach 658 1 1.2 1.4 1.3 10 13
Esophagus 58 1 3.2 6.5 5.6 6.6 7.8
Lung 281 1 11 23 24 2.4 3.6

 

SOURCE: Adapted from Prentice et al. '1983)

and increasing smoking (Table 5). The use of Cox regression analysis
did not distinguish between an additive or a multiplicative interac-
tion.

Preliminary findings from a case-control study among A-bomb
survivors suggest that gamma radiation and cigarette smoking
combine in an additive fashion to increase lung cancer risk (Blot et
al. 1984).

Comment on Epidemiological Studies

With the exception of some of the U.S. studies with over 300 lung
cancer cases, most of the human studies were of relatively small
populations, with small numbers of lung cancers. Although confi-
dence in the risk estimates and the mean I-L periods derived is
decreased, there is no reason to suspect that the small population
sizes provided any qualitative distortion of the smoking-radiation
interaction. The studies varied in the quality of their radiation dose
estimates and of their smoking information. Some of the smoking
data was obtained by interview, some retrospectively from relatives,
and some at entry into the study with no consideration given to
subsequent changes in smoking habits. Because of the small num-
bers, pipe and cigar smokers and ex-smokers were sometimes
combined with other groups or light smokers and heavy smokers
were often combined. Some had smoking information on little more
than half of the population. The observations of protective, additive,
or multiplicative effects cannot be easily dismissed. These observed
differences could all be correct for specific groups at specific times
without violating any biological principles.

The mean I-L periods in the various studies differ considerably, as
do the relationships between nonsmoker and smoker I-L periods. It
should be noted that in all of the studies the I-L period was shorter
among smokers than among nonsmokers, although in some studies

455
the difference was small. In studies of radiation and cancer, it has
frequently been noted that the observed latent period is strongly
dependent on age at exposure and on the length of the followup
period. That is, subjects who are young at first exposure and who are
followed for most of their lives will exhibit a much longer mean
latent period than will a group first exposed during middle age and
followed for only 25 years. The intensity and magnitude of exposure
may also have an influence on the I-L period (Archer et al. 1979).
Longer I-L periods were noted among Europeans than among U.S.
miners. Longer followup periods and higher radiation dose rates and
doses are probably responsible for this difference.

Cigarette smoking habits may also influence the measured I-L
period for developing lung cancer following onset of radon daughter
exposure independent of any biologic interaction. Even without
significant radon daughter exposure, a number of smoking miners
would have developed lung cancer, and some may have done so prior
to the latent period required for radiation-induced cancers. This
phenomenon would be particularly important in those individuals
whose radiation exposure (but not their smoking exposure) began
late in life. The effect of this independent development of lung
cancer due to cigarette smoking would be to shorten the I-L time
calculated for radon daughter exposure in smokers compared with
nonsmokers, and for workers who joined the workforce later in life
compared with those whose exposure began at a younger age.

Differences in age at start of mining and years of followup between
the nonsmokers and smokers within a cohort might well influence
the relative risks calculated for the two subgroups within any study.
However, even if age at start, years of followup, and percentage
ultimately developing lung cancer are the same for nonsmoking and
smoking subgroups, their relative frequency of induced lung cancer
might vary considerably with time, as indicated in Figures 2 and 3.

Interaction of Radiation and Cigarette Smoke (or Its
Constituents) in the Generation of Animal Tumors

A number of animal experiments have explored the possible
interactions between cigarette smoke or cigarette smoke condensate
(CSC) and ionizing radiation. These experiments have used x-ray or
alpha or beta radiation. Some have used rat or mouse skin as the test
object; others have used the lungs of living animals.

Bock and Moore (1959) found that intense x-ray exposure of a
small portion of the mouse body increased the sensitivity of distant
areas of the skin to cancer induction by painting with CSC.

An experiment using CSC and beta radiation from *Sr on mouse
skin (400 mice) was reported at two separate time points (Suntzeff et
al. 1959; Cowdry et al. 1961). In this experiment both the beta

456
7
18 -
qooere-- Smoking uranium miners
o .
4 —— Nonsmoking uranium miners
@ 144 —
> —— US. white men a
§ —
5 o
° /
S 10-4 eos
: a ok
2 “ SN
od 4 “ x
8 a / y NL
> 67 > ~s
5 L 4 SL
y a “ mee

 

 

 

Age at observation (years)

FIGURE 3.—Hypothetical lung cancer distribution among
smoking and nonsmoking uranium miners
with uniform radon daughter exposure and
among U.S. white men

radiation and CSC were applied periodically (both separately and
together) so that large total doses of both were used. The first report
gave results at 18 months and considered the interaction to be
synergistic. Fifty-four percent of the mice with combined agents had
skin cancer versus 37 and 5 percent, respectively, when the agents
were used singly. However, when the study was completed by
following the mice until they died naturally, the sum of the skin
cancers among the groups treated with single agents was nearly as
large as the number found among the mice treated with both agents.
Cancers appeared 6 to 7 months earlier in mice treated with both
agents.

A preliminary experiment using CSC and beta particles on rat
skin (McGregor 1976) found a threefold increase in skin tumors over
that induced by beta radiation alone. The effect was attributed to
tumor promotion activity because the CSC applications were started
2 months after beta exposure and because the amount of CSC used
did not produce any tumors when used alone. This was followed by
further experiments (McGregor and Meyers 1982), using 916 rats.
CSC was applied immediately after exposure to 1,600 rad of beta

re _ _ A57T
particles in one group and 2 months after in another group. When
applied immediately, severe ulceration resulted, making-‘tumor yield
difficult to interpret. When applied 2 months after radiation,
malignant and nonmalignant yields were increased (p< 0.01). Again,
the levels of CSC used produced no significant increase in cancers by
themselves. The experiments were terminated at 14 and 18 months,
so the ultimate cancer yields were not determined, but at the end of
the experiment there were 2.5 times as many cancers in the beta-
plus-CSC group as in the beta-alone group. At 50 weeks, however, the
ratio was higher (3.4), indicating that tumors appeared earlier in the
group treated with both agents.

Nenot (1977) studied rats that inhaled cigarette smoke plus
americium 241, which delivered alpha radiation to the lungs. The
smoke increased the yield of lung cancers and made them appear
earlier. It was interpreted as a cancer-promoting effect by cigarette
smoke, because the smoke alone did not produce cancer at the doses
used.

The carcinogenic effects of radon daughters, uranium ore dust,
and cigarette smoke in dogs have been reported (Cross et al. 1978,
1982; NCRP 1984b). Dogs were exposed to radon daughters plus
uranium ore dust, to radon daughters plus ore dust plus cigarette -
smoke, to cigarette smoke alone, or to sham cigarettes with room air.
Daily cigarette smoking periods both preceded and followed the dust
plus radon daughter exposures. There were seven lung cancers
among the 20 nonsmoking dogs and none among the controls or the
dogs exposed to smoke alone. Although no dogs were exposed to dust
alone, other experiments suggest that they would not have developed
lung cancer. Exposure to 20 cigarettes per day resulted in pulmonary
emphysema and fibrosis. These two conditions, however, were much
more severe in the dogs exposed to mixtures that included radon
daughters and uranium ore dust. Two nasal carcinomas were found
in the dogs exposed to ore dust and radon daughters, and one in the
group exposed to these two agents plus smoke. There were none in -
the other two groups. In these studies, cigarette smoke appeared to -
be protective.

In an extensive series of experiments in France, cigarette smoke
was inhaled by rats, either before or after a series of radon daughter .
inhalations (Chameaud et al. 1980, 1981, 1982). The cigarette smoke
alone did not produce lung cancers at the levels used. When the
smoke was given in the weeks preceding radon daughter inhalation, .
it had no effect; when the exposure to smoke was delayed until after.
radon daughter exposure was completed, or given during radon.
daughter exposure, significantly higher numbers of lung cancers.
were observed. These features were considered to be characteristic of
cancer promotion by cigarette smoke, although the terms “cocarcino-
genesis” and “synergism” were at times applied by the researchers.

458
Interactions of Radiation and Chemical Carcinogens

A number of experiments tested the interaction of radiation and
chemical carcinogens. Some of these chemicals are constituents of
cigarette smoke or are chemically related to such constituents.
Although most carcinogens can also act as cancer-promoting agents,
in these experiments the additional tumor promoters in cigarette
smoke were absent, making them less pertinent to the topic of
radiation and cigarette smoke interaction than the experiments
reviewed in the preceding section. With this in mind, they are
summarized below. Benzo[alpyrene (BaP) and polonium 210 (Po-210)
were injected intratracheally in hamsters (McGandy et al. 1974;
Little and O’Toole 1974; Little et al. 1978). When given simulta-
neously, tumors appeared earlier, but the effects were additive.
When BaP was given 4 to 5 months after radiation, the effects
appeared to be synergistic, but because effects were small when BaP
was given first and saline injections had nearly the same effect, the
BaP action was considered to be mostly tumor promotion. A similar
study with intratracheal instillations of BaP and plutonium oxide
(PuO,) was done in rats (Metivier et al. 1984) and was considered to
show synergism. Both PuO, and Po-210 emit alpha particles.

BaP used with 150 roentgens of whole body x ray on mouse fetuses
resulted in more tumors (of al! types) than was obtained with x ray
alone, but fewer than was obtained with the BaP alone (Urso and
Gengozian 1982).

Dimethylbenz[aJanthracene (DMBA) and 0.8 MeV electrons were
administrated to rat skin at 28 days of age (Burns and Albert 1984).
Multistage analysis of the interaction suggests the existence of two
dose-dependent stages for single doses of radiation and multiple
doses of DMBA, and also that prolongation of the radiation dose
either adds four presumably non-dose-dependent stages or stimulates
clonal growth of an early stage cell.

Rats were given 600 WLM, then treated with 5-6 benzoflavone,
methylcholanthrene (MCA), or phenobarbital (Queval et al. 1979).
MCA is a carcinogen, the other two are not. Phenobarbital had no
effect. With both benzoflavone and MCA the number of tumors was
doubled. The latent period was greatly shortened with benzoflavone,
but only slightly with MCA. Benzoflavone suppresses tumor develop-
ment when used with BaP.

When rat fetuses were exposed to x ray and the mothers were
injected with ethylnitrosourea (ENU) 4 days later, as adults the rats
developed fewer neurogenic tumors than with ENU alone. This
reduction in tumors was not due to an increased mortality rate of the
fetally exposed animals (Kalter et al. 1980).

The administration of 1.25 gray (Gy) whole body x ray followed by
injection of ENU was used to induce nervous system tumors
(Knowles 1982). The incidence of these tumors was consistently and

459
significantly higher in the group given ENU alone than in any of the
irradiated groups. The histology of tumors in all groups resembled
those induced by ENU.

When mice were irradiated in utero (36 rad x ray) and then given
urethane at 21 days of age, the yield of lung tumors was enhanced
over urethane alone (Nomura 1984). X ray alone yielded no tumors.
The x-ray effect was seen during the first 14 days of gestation, but
not during the later fetal or neonatal stages.

Intraperitoneal application of tetradecanoylphorbol acetate (TPA)
(a strong tumor-promoting agent) had no influence on the incidence
of malignant lymphomas following four doses of 1.7 Gy of x ray
(Brandner et al. 1984).

When beta particles from phosphorus 32 were used with TPA and
high fat, high protein diets as potential tumor-promoting agents, no
evidence of tumor promotion was found on liver cell transformation
(Berry et al. 1984).

Comment on Animal Studies

Although the results of the animal studies indicate that the
interaction between radiation and cigarette smoke, or its compo-
nents, ranges from no interaction to protection, promotion, and
synergism, there are several features common to many of the
experiments. When cigarette smoke or BaP is administered before
the radiation, there is little or no interaction with respect to tumors.
When administered several months after the radiation, the interac-
tion is greater. In addition, as a general rule, tumors appear earlier
in animals when cigarette smoke is used. In some of the experiments,
the early appearance of cancers caused investigators to apply the
word “synergism” to the interaction, but further followup plus the
production of few or no cancers by the smoke or CSC alone, usually
led the investigators to conclude that the interaction was mainly one
of cancer promotion (Chameaud et al. 1981; McGregor and Meyers
1982). Some of the experiments with cigarette smoke components led
to the same conclusion (Little et al. 1978). This conclusion is
buttressed by the observation that the cancer-promoting activity of
cigarette smoke is greater than its initiating activity (Bock 1968,
1972; Van Duuren et al. 1971; Wynder 1983). Cancer promoters
sometimes increase the yield of cancers in animal experiments by
simply speeding up the appearance of the tumors. Nonspecific injury
sometimes promotes radiation-induced tumors.

Polonium 210 in Cigarette Smoke

Lead 210, which has a 22 year half life, is widely deposited on plant
foliage as a result of radon and radon daughter decay in the
atmosphere. It decays slowly to Po-210, which emits alpha particles

460
that are more dangerous than the beta particles emitted by lead 210.
Appreciable amounts of these two radioisotopes are found in tobacco
and in tobacco smoke, and may contribute to the cancer potential of
cigarette smoke (Radford and Hunt 1964; Kolb et ai. 1966; Stahlho-
fen 1968; Black and Bretthauer 1968). A major fraction of the
inhaled Po-210 was shown to be absorbed from the lung directly into
the bloodstream (Little and McGandy 1968). Intratracheal instilla-
tion of Po-210 into the lungs of hamsters resulted in cancer at levels
as low as 15 rad (Little et al. 1978). Calculations of the radiation dose
from the Po-210 in cigarettes have been made repeatedly. Doses to
small portions of the bronchial epithelium were found in man to be
about 1 rad per year (Cohen et al. 1980), 8 rem per year (Steinfeld
1980), and 80 to 100 rad per lifetime (Martell 1983). Average
exposures to the bronchial epithelium, however, are much less than
these calculated doses, which are administered to very small selected
spots. There has been considerable debate as to how much the
radiation from Po-210 contributes to the lung cancer that results
from smoking, ranging from no effect (Hickey and Clelland 1982) to
most of the cancers (Wagner 1982; Ravenholt 1982: Martell 1983;
Winters and Di Frenza 1983). The consensus appears to reflect a
middle ground—that the radiation in cigarette smoke contributes to
its carcinogenicity, but that the chemical agents in smoke also
contribute (Radford 1982; Cross 1984).

To the extent that Po-210 in cigarette smoke induces lung cancer,
its effect would be expected to be directly additive to the effect of the
short half-life radon daughters. To the extent that chemical agents
are involved (either as cancer initiators or as promoters), an
interaction might be expected to occur. Both the animal data and the
human data reviewed indicate at least some interaction, which
therefore reflects action by the chemical constituents of cigarette
smoke, particularly as promoters.

Hypothesis That Reconciles Discrepancies in Epidemiological
Data

A hypothesis that could reconcile the discrepancies in the epidemi-
ologic data has been presented (Archer 1985). Alpha radiation dose
from radon daughters may induce a finite number of lung cancers in
an irradiated group, with most of these cancers being expressed. In
the absence of cigarette smoking, these cancers could have a longer
latent period and may or may not be fully expressed among the
population, depending on the force of competing causes of death
among the older members of the population and the presence or
absence of promoting agents. In the presence of continuing exposure
to cigarette smoke, these radiation-induced cancers could appear at

461
an earlier date following exposure (and at younger ages) than among
groups not exposed to cigarette smoke.

The lung cancers that would normally be induced by cigarette
smoke would still be present, and added to those induced by
radiation in a mining population. Thus, on a lifetime basis, there
would appear to be an additive effect (radiation plus smoking), plus
perhaps a few extra cancers that would not have been expressed if
the latent period had not been shortened by smoking. The earlier
appearance of cancers among smokers would give an appearance of
synergism in studies conducted within 20 or 30 years after the start
of exposure.

This hypothesis is best understood by examining Figure 3. In this
hypothetical graph it is assumed that an equal number of smoking
and nonsmoking miners of the same age are exposed at age 30 to the
same amount of radon daughters. The resultant curves of lung
cancer incidence reflect the distribution in time of the appearance of
the induced cancers. The shape of the curves might vary somewhat
from the curves for people who are first exposed at older ages. It is
evident from these curves that investigators who examine lung
cancer mortality data at different points in time after the subjects
had begun mining could obtain data indicating synergism (at 40 to 60
years of age), or additivity (at 60 to 70 years of age), or protectiveness
(at 70 or more years of age). The “synergism” noted in the U.S.
uranium miner studies (mean age at death was 55 years for
nonsmokers) would thus be explained (Saccomanno et al. 1967), as
would the “protection” found in one of the Swedish studies (mean
age at death was 70 years for nonsmokers) (Axelson and Sundell
1978). The “additive” effect noted by another Swedish study (mean
age at death was 65 years) with deaths collected over a 26-year
period (Radford and Renard 1984) would also be explained. The long
data-gathering period resulted in a collection of deaths from young
as well as aged miners. The short collection period used in another
Swedish study (Damber and Larsson 1982) (mean age at death was 69
years), interpreted as “synergism,” may have resulted from a biased
sampling of deaths because they were from a 5-year period only, or
were from the entry into mining at different times or ages by
smokers and nonsmokers.

A mortality analysis of radon daughter-exposed miners within 25
years after they started mining would, according to the hypothesis,
give an early impression of synergism, just as early observations in
two of the animal studies did (Suntzeff et al. 1959; McGandy et al.
1974), even though lifetime studies would indicate otherwise.

According to some experts, even if the final incidence of lung
cancer in smoking and nonsmoking irradiated individuals were the
same, the net effect could be regarded as synergistic; this is because

462
smoking shortens the tumor-free life of those who develop cancer
‘UN Sci. Comm. 1982).

Interaction of Radiation and Cigarette Smoke on Other
Aspects of the Respiratory Tract

Larynx and Nasal Sinuses

The attachment of radon daughters to dust particles that are
deposited in the airways (along with unattached ions) of animals and
man means that the upper respiratory tract and bronchi receive
higher total doses of radiation than any other part of the body.
Excess cancers of the larynx have been reported in uranium miners
(Tichy and Janisch 1973). Although this cancer site has been
associated with cigarette smoking, the possible interaction of the two
agents on the larynx has not been evaluated. Cancer of the sinuses
has been attributed to the radon and radon daughters that collect in
the paranasai sinuses of people with elevated radium body burdens
(Rowland et al. 1978; Schlenker and Harris 1979). Cancer of these
sinuses has not been attributed to cigarette smoke in U.S. popula-
tions. The nasal and pharyngeal and tracheal epithelium in man
may be sufficiently thick and covered by enough protective mucus so
that the alpha particles from radon daughters rarely penetrate to
those cells where permanent injury can result (presumably the basal
germinal layer). The thin epithelium of the bronchial subdivisions
apparently may not provide similar protection.

Pulmonary Function and Fibrosis

Epidemiologic studies have demonstrated that the pulmonary
function of uranium miners is compromised (Archer, Carroll et al.
1964; Archer, Brinton et al. 1964; Trapp et al. 1970; Samet, Young et
al, 1984). The loss in pulmonary function is followed in time by
greatly elevated mortality rates from or with nonmalignant pulmo-
nary disease (Archer et al. 1976; Archer 1980; Waxweiler et al. 1981).
In these analyses several diseases were grouped together—cor
pulmonale, silicosis, pulmonary fibrosis, chronic obstructive lung
disease, emphysema, and related diagnoses—because diagnostic
criteria for them are known to vary greatly between physicians.
They usually reflect injury by inhaled toxic agents. Uranium miners
were also exposed to a third toxic agent, silica (alpha quartz), in ore
dust as well as to radon daughters and cigarette smoke.

Uranium ore dust and tobacco smoke, as well as radiation,
undoubtedly contribute to the nonmalignant pulmonary problems of
uranium miners. Both human studies and animal studies have
indicated that radiation contributes to the lung pathology and
functional loss (Archer, Brinton et al. 1964; Cross et al. 1978; Cross,
Filipy et al. 1981; Cross, Palmer et al. 1981). Very few of the uranium

463
miners disabled by shortness of breath had typical silicotic nodules
on x ray and were therefore unable to obtain workmen’s compensa-
tion for silicosis. Neither the relative roles nor the interactions of
these three agents (radon daughters, cigarette smoke, silica) in these
conditions is well characterized.

The pathology of radiation pneumonitis after larger acute radia-
tion doses is well known (Gross 1981). Following irradiation at high
doses, there is death of some of the epithelial and endothelial cells
within 3 to 6 months, resulting in increased capillary permeability
and leakage of plasma proteins into the alveolar surface. Within 1 to
3 years, the pneumonitis is followed by a fibrotic reaction, which
may represent a healing of the radiation pneumonitis, but has the
effect of reducing the functional capacity and compliance of the lung.

After relatively low chronic doses of alpha radiation, as occurs in
uranium miners, such changes have not been reported, but some
fibrotic change is implied by the aforementioned epidemiologic
studies. The high linear energy transfer of alpha radiation leads to
the belief that cellular injury and repair after chronic low doses of
alpha radiation could slowly lead to fibrotic changes. The injury
would be so diffuse, however, that fibrosis would be detectible only
after many years. Loss of pulmonary function, fibrosis, and other
changes have been observed in the lungs of rats, hamsters, and dogs
chronically exposed to radon daughters, cigarette smoke or diesel
exhaust, and uranium ore dust (Gaven et al. 1977; Stuart et al. 1977,
1978; Wehner et al. 1979; Cross, Palmer et al. 1981; Cross, Filipy et
al. 1981; Cross et al. 1982; NCRP 1984b). Although these experiments
were not designed to evaluate the degree of interaction of the
different agents, it was clear that the fibrotic and other pathologic
changes were much more severe when the animals were exposed to
two or three of the agents together than when exposed to a single
agent.

The relatively low radon daughter exposures at which pulmonary
function effects (possibly due to radiation) have been found in
uranium miners (Samet, Young et al. 1984) suggest that there may
be no threshold for such effects.

Research Recommendations

1. The possibility that alpha radiation from background radon
daughters in homes may contribute to lung cancer in human
populations (Axelson 1983; NCRP 1984a, b; Harley 1984;
Radford and Renard 1984) and the interaction of both active
and involuntary tobacco smoking on this possible effect of ©
radon daughters need further investigation. They may have
important implications for the ventilation of homes and for the -
effects of involuntary smoking.

464
2. The influence of tumor-promoting agents on radiation-induced
cancers has not been adequately explored. Further animal
studies of this interaction are indicated.

Summary and Conclusions

1. There is an interaction between radon daughters and cigarette
smoke exposures in the production of lung cancer in both man
and animals. The nature of this interaction is not entirely clear
because of the conflicting results in both epidemiological and
animal studies.

2. The interaction between radon daughters and cigarette smoke
exposures may consist of two parts. The first is an additive
effect on the number of cancers induced by the two agents. The
second is the hastening effect of the tumor promoters in
cigarette smoke on the appearance of cancers induced by
radiation, so that the induction-latent period is shorter among
smokers than nonsmokers and the resultant cancers are
distributed in time differently between smokers and nonsmok-
ers, appearing earlier in smokers.

465
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CHAPTER 12

SMOKING INTERVENTION
PROGRAMS
IN THE WORKPLACE
CONTENTS

 

Introduction

 

Criteria for Evaluating Worksite Programs
Changes in Participants’ Smoking Behavior
Worksitewide Program Effects
General Effects

 

General Review of Worksite Programs
Uncontrolled Studies
Controlled Studies
Remaining Issues

 

Special Issues Relevant to Worksite Programs
Social Support
Physician Advice
Incentives
High Risk Populations
Multiple Risk Factor Reduction Programs
Organizational Characteristics and Other Factors

 

Implementation of Worksite Smoking Programs
Promotion and Recruitment
Program Characteristics

 

Recommendations for Future Research
Methodological Issues
Substantive Areas

 

Summary and Conclusions

 

References

475