Massachusetts mortality survey (Dubrow and Wegman 19841, it must
be concluded that to the extent smoking effects were adequately
controlled by statistical design, certain occupations appear to be
associated with significant risks of cancer, independent of the role of
smoking. Unavoidably, the occupational classes used for this kind of
study are broad: the actual exposure circumstances within these
classes that might be conducive to cancer can only be speculated.

Viadana and colleagues (19761 studied 11,591 white male cancer
patients and controls who were hospitalized at Roswell Park
Memorial Institute between 1956 and 1965. They used occupational
histories to classify cases and controls as being exposed to "chemi-
cals" and "combustion products," and into specific groups within
these broad classifications, e.g., operatives in the chemical industry
or bus, cab, or taxi drivers. Operatives in the chemical industry had
an increased relative risk of having cancer of the stomach (RR 4.25,
p<O.O5). The relative risks for lung and laryngeal cancer were
slightly, but not significantly, increased.

Relative risks for larynx (RR 3.63, p<O.O5), pharynx (RR 3.38,
p< 0.051, and bladder (RR 6.77, p<O.O5) cancers were significantly
elevated for operatives in the leather industry. Relative risks were
altered after controlling for smoking, but the risks associated with
occupation appeared to be independent of smoking. The influence of
smoking on the risks associated with occupation were difficult to
assess, because the relative risks adjusted for age and smoking were
not tabulated. Instead, these results were discussed selectively.
Although the information needed to investigate the interaction
between smoking and occupation was available, this report did not
discuss this issue.

Lung Cancer

Stayner and Wegman (1983) used a case-control design to study
the relationship between smoking, lung cancer, and occupation,
based on a portion of the data from the Third National Cancer
Survey. The analysis was limited to men aged 30 to 84 when
diagnosed as having lung cancer who had responded to an int.erview
that included occupational and smoking histories. Occupation was
coded in broad categories defined for the 1970 census. Cases and
controls were grouped as "ever" or "never" users of tobacco to
control for smoking exposure. Controls were selected from survey
participants with other types of cancer, excluding those individuals
with the types of cancer that have been associated with occupation
or smoking (e.g., lip, mouth, pharynx, larynx, esophagus, pancreas,
bladder, liver, skin, brain, and blood and bone marrow). These
exclusions left 900 controls to be compared with 420 cases. Blue-
collar workers had an odds ratio (OR) of 1.24 (p < 0.05) for developing
lung cancer after adjustment for smoking status and age. This

376


difference was due in part to the increased odds for developing
squamous cell carcinoma (OR 2.11, p<O.O5) compared with average
odds for developing adenocarcinoma (OR 0.97) and small cell
carcinoma (OR 1.22). When the data were analyzed using more
narrowly defined occupational groups, no statistically significant
associations were found. However, when histologic types were
considered separately, laborers had higher odds ratios for small-cell
carcinoma (OR 2.47, p< 0.05) and squamous cell carcinoma (OR 1.97,
p < 0.05) after adjustment for smoking.
Stayner and Wegman reported positive associations between
smoking and all three histologic types of lung cancer. They did not
consider the potential interactions between smoking and occupation
in discussing their data. Their report did illustrate the importance of
considering histologic type when conducting etiologic studies of lung
cancer.
Few studies of occupational risk focus on women. Leung (1977)
reported an association between cooking with a kerosene stove and
lung cancer in Chinese women living in Hong Kong. This case-
control study was conducted to identify factors that might account
for the relatively high mortality rates for lung cancer experienced by
women in Hong Kong. In 260 consecutive cases of histologically
proven lung cancer, 92 percent (166/180) of the men and 56 percent
!45/80) of the women smoked cigarettes compared with 59 percent of
the male smokers and 11 percent of the female smokers in a
"nonrandom" popu!ation sample. In a second series of 44 lung cancer
cases in women. 91 percent i40/44) used a kerosene stove daily for
over 2 years compared with 36 percent of the families sampled in
seven areas of Hong Kong.
The sampling schemes used in this study could easily produce
biased results. Smoking prevalence in the community was based on a
convenience sample and might have underestimated the prevalence
of smoking by women. Kerosene stove usage could be associated with
many other environmental e::?3sures that might be related to lung
cancer. Nevertheless, strong ilssociations between smoking and
kerosene stove use and lung cancer were found among women. The
author concluded that the question of synergy between stove usage
and smoking requires further study.
In a case-control study of lung cancer, Pastorino and colleagues
(1984) estimated the proportions of lung cancer attribut.able to
smoking and occupational exposure to known or suspected carcino-
gens. Lung cancer cases were drawn from a well-defined geographic
area in northern Italy where a large proportion (74 percent) of
employed men work in industry. In this area, 240 incident cases of
lung cancer in men occurred between 1976 and 1979. Twenty-nine
cases were excluded because diagnostic criteria were not met and 7
cases could not be reached for interview, leaving 204 cases (85


percent of total) for analysis. Controls were selected at random from
the electoral rolls of men living in the same region and matched with
cases for age within 2 years. Of the 366 controls enrolled, 15 could
not be reached for interview. Interviews were conducted by two
occupational physicians and two public health nurses. Occupational
histories focused on specific exposure to asbestos, tars and mineral
oil, chromium, nickel, arsenic, bis-chloromethyl ether, chloromethyl
methyl ether, vinyl chloride, and polycyclic aromatic hydrocarbons
as contained in soot. "No exposure" was defined strictly as a work
situation where the subject could not have been exposed to these
materials. "Possible" and "probable" exposures were defined on the
basis of descriptions of specific job tasks. Ten percent of the control
interviews and 50 percent of the case interviews were with next of
kin.

The relative risk for lung cancer was strongly related to cigarette
smoking in a dose-related way. Relative risk ranged from 2.3 for
smokers of 1 to 9 cigarettes per day to 9.0 for smokers of 30 or more
cigarettes per day. Occupational exposures were also positively
associated with lung cancer. The relative risk for possible exposure
was 1.6, and for probable exposure, 2.7. The authors estimated that
81 percent of lung cancers could be attributed to smoking (95 percent
confidence interval, 69 to 93) and that 33 percent could be attributed
to occupational exposure to known carcinogens (95 percent conti-
dence interval, 19 to 47).

Pastorino and colleagues (1984) illustrated how relative risk varies
positively with occupational exposure and cigarette smoking. The
relative risk increased in men without occupational exposure from
1.0 in nonsmokers to 2.7,6.2, 9, and 11 in men who smoked 1 to 9, 10
to 19, 20 to 29, and 30 or more cigarettes per day, respectively. In
men with possible and probable occupational exposure, the relative
risk increased from 2.5 in nonsmokers to 3.8, 14, 19, and 20 in men
who smoked 1 to 9, 10 to 19,20 to 29, and 30 or more cigarettes a day,
respectively. Occupational exposure was subcategorized by exposure
to asbestos and PAH, the most common occupational exposures in
this study. Both were independently associated with lung cancer
risk. The relative risks associated with asbestos and PAH exposures
in combination with smoking were more consistent with additive
effects, but a specific analysis of the possible interactions was not
discussed.

Bladder Cancer

In the last 15 years, many case-control studies and analyses of
mortality statistics have been used to examine relationships between
occupation and bladder cancer. In only a few has enough historical
information been aggregated in detail sufficient to permit explora-
tion of interactive effects between occupation and smoking.


A case-control study of bladder cancer patients in the hospitals of
Leeds, England, failed to show that smoking was a risk factor for
bladder cancer, but did indicate that the prognosis was worse in
patients who continued to smoke (Anthony and Thomas 197OaJ
Controls for this study were lung cancer patients and surgical cases
interviewed 5 years previously at the same hospital. They were not
matched to cases by age. In an expansion of this study, Anthony and
Thomas (197Ob) matched cases to controls (again using previously
interviewed patients) with respect to age, sex, residence, and
smoking habit (never smoked, greatest amount ever smoked, cessa-
tion of smoking). They then calculated risk ratios for aggregates of
cases according to their "predominant occupations" and "employ-
ment in suspect environments." They identified significantly elevat-
ed risks of bladder cancer among workers in the chemical dye
industry, textile workers, tailors, engineering workers, and hairdres-
sers. Because cases and controls were matched for smoking habit,
risks were presumably attributable only to occupation.

In an extensive case-control study of bladder cancer in the
Boston-Brockton, Massachusetts, area in 1967-1968, Cole and col-
leagues (1971, 1972) examined occupation and smoking information
obtained by interviewing 470 incident cases and 500 age- and sex-
matched controls. Controls were selected at random from published
"resident lists." Smoking was taken into account with respect to
intensity (cigarettes per day) and also estimated total dose (pack-
years). Thirteen occupational exposure categories were used in
classifying patients and controls: dyestuffs, rubber, leather, printing,
paint, petroleum, other organic chemicals, other chemicals, fumes
and dust, manufacturing (not elsewhere classified), farming, service,
and office. From this study the authors calculated mean relative risk
ratios of 1.89 and 2.00 for bladder cancer in male and female
smokers, respectively, and demonstrated gradients of risk in both
sexes, based on numbers of cigarettes smoked per day. The maxi-
mum mean relative risk ratio (3.8) was for women who smoked more
than one and one-half packs per day. Standardization by occupation-
al categories did not alter the relative risk estimates for smoking.

When risks were analyzed by occupational categories (ever em-
ployed), significantly elevated ratios were found in only two catego-
ries: those working with rubber and rubber products (1.57) and those
working with leather and leather products (2.00). People exposed to
dyestuffs, paint, and other organic chemicals exhibited apparent
elevations of risk, but the number of cases available for study was too
small to yield statistically significant increases. Relative risks were
very similar whether or not controlled for smoking. Examined in
terms of "usual occupation" instead of "ever employed," risk
associations with occupation tended to be weaker, but rubber and
leather industries were again identified as those most likely to

379


involve an occupational hazard of bladder cancer, even when
controlled for smoking. Risk attributable to hazardous occupation
(work in industries involving exposure to chemicals) was estimated
to be 7 to 18 percent of the total bladder cancer risk, depending on
the basis used for specifying occupation. Relative risk ratios ranged
from 1.21 to 1.75.

The epidemiology of bladder cancer with respect to beverage
habits as well as smoking and occupation was addressed in three
Canadian studies. Miller (1977) conducted a case-control study of 349
bladder cancer cases from British Columbia, Nova Scotia, and
Newfoundland, matching each case to controls by age, sex, and
residence (but not by smoking). Control subjects were recruited from
the residential neighborhoods of the subjects. Questionnaires admin-
istered in the homes inquired into the occupations of the respon-
dents, as well as their smoking and coffee-consuming habits.
Significant relative risk ratios (2.0 to 10.5) were found for cigarette
smoking, and showed a substantial dependence on estimated lifetime
consumption of cigarettes. Occupational risks were evaluated only
with respect to seven categories: chemical, rubber, photography,
spray painting, petroleum, medicine, and "other." Risk ratios were
2.0 or more in all categories, and were statistically significant in two:
"chemical" (12.0) and `<other" (2.1). No details of the nature of
chemical exposures were offered, and no analysis of smoking habit
within occupational categories was presented. The number of case
control pairs within the six specific categories was small (total 78),
and no occupation-based risk ratios for nonsmokers were stated
explicitly. Population-attributable risk percentages calculated by the
authors for men were occupation (known and suspect), 35 percent;
cigarette smoking, 56 percent; coffee drinking, 27 percent; and total,
118 percent. For women the percentages were 1,29, and 13 percent,
respectively; the total was 43 percent.

An extension of this study on bladder cancer published in 1980
(Howe et al. 1980) included 632 case-control pairs from the same
Canadian provinces. Strong relative risks for smoking were con-
firmed in men and women, the magnitudes depending on daily
usage, duration, and estimated lifetime consumption. Associated
with significantly elevated bladder cancer risk in men were workers
in the chemical, rubber, petroleum, welding, and railroad industries,
guards and watchmen, nurserymen, metal machinists, material
recorders, and military personnel. Risk ratios for military personnel
and clerical workers declined when smoking was controlled for;
other risk ratios reportedly did not. This analysis was based on
responses to a query as to whether subjects had ever worked in the
specified jobs, not on usual occupation. Despite the size of the study,
the number of discordant matched pairs was relatively small: fewer
than 50 in all occupational categories except agriculture, military,

380


and mechanics. No excess risk was indicated for people engaged in
the dyeing of cloth or tanning, but the number of pairs available for
analysis was not sufficient to provide reliable estimates. Discordant
pair ratios of 4/3 and 5/l were recorded for past contacts with
benzidine and bis-chloromethyl ether, respectively, on the part of
male respondents. The numbers were too small to permit an
examination for the confounding effects of smoking. Very few
women were employed in the suspect industries, and no significant
risk elevations associated with occupation were identified among
women.

Miller and colleagues (1978) matched each of 265 incident bladder
tumor patients diagnosed at the Ottawa Civic Hospital Urology
Clinic to two control patients treated at the clinic who did not have
bladder tumors. Administered questionnaires inquired into previous
disease in self and family, occupational exposures, use of coffee,
tobacco, and sweeteners, exposure to radiation, and prior treatment
with antituberculosis drugs. Relative risk calculations and discrimi-
nant analysis identified the following significant risks, in apparent
order of importance: in men, a family history of allergy (1.8),
occupational exposure to radiation (1.6), occupational exposure to
chemicals (1.5), cigarette smoking (1.6), and a history of gout (1.7). In
women, coffee drinking (1.6) and a history of tuberculosis (2.0) were
identified as risks; a history of allergy in the patient appeared to be
protective (0.3). Chemical exposures were identified tentatively as
paints, varnishes, lacquers, gum and wood chemicals, and industrial
chemicals. Risk ratios derived from this study are uniformly low, and
those for factors traditionally regarded as important for bladder
cancer (smoking and occupation) are lower than a risk ratio having
no previously recognized association with the disease (family history
of allergy, in men only). This aspect of the findings casts a degree of
doubt on the soundness of the study design, particularly the use of
patients with urologic disease other than bladder cancer as controls.
Discriminant function analysis presumably identified both smoking
and occupational exposure to chemicals and radiation as indepen-
dent risk factors for bladder cancer. No data were offered from which
to determine whether these risks are additive or synergistic.

Calculating proportionate incidence ratios for bladder cancer
within broad occupational categories used by the Los Angeles
County/University of Southern California Cancer Surveillance Pro-
gram, Weinberg and colleagues (1983) examined incidence data for
Los Angeles County over the period 1972-1976. They found higher
relative risks of bladder cancer among managers and salesmen (high
on the socioeconomic scale) than among service workers, laborers,
and transportation workers (low on the socioeconomic scale). The
latter group have been reported to be the heavier smokers (CDC
1976; Bonham and Leaverton 1976). The authors argued that, at

381


least in the Los Angeles area, the occurrence of bladder cancer in
relation to social class corresponds more closely with coffee-drinking
habits (greater in the upper classes) than with smoking or occupa-
tion. The social class distribution of bladder cancer incidence in Los
Angeles contrasts sharply with the report of Adelstein (1980) in
England, who found from analysis of death certificate and census
data for 1970-1972 that cancer in general and bladder cancer in
particular were afflictions primarily of the lower socioeconomic
classes. The discrepant relationships to social class categories may be
attributable to the different parameters used in the two studies
(incidence versus mortality), to the disparate cultural and economic
circumstances of the populations examined, or specifically, to
different spectra of environmental carcinogens in the two regions.
Interestingly, the two studies are in essential agreement with
respect to lung cancer but not bladder cancer.

Glashan and Cartwright (1981) and colleagues (Cartwright et al.
19811, in a case-control study, matched 991 incident cases of bladder
cancer treated at three West Yorkshire clinics over 3 years to age-
and sex-matched controls "without malignant disease." The source
of the controls was not mentioned, but presumably they were clinic
patients. Elevated relative risk ratios for smoking (not quantitatively
defined) were found in men 0.8) and women (1.6). Significantly
elevated relative risks were found for chemical industry workers and
printers, but not for leather workers, hairdressers, or dye users.
Nonsmoking dye manufacture process workers experienced an
apparent increase in risk of bladder cancer (RR 1.9, not statistically
significant), but dye process workers who smoked were at highly
significant risk (RR 4.6). A similar relationship was found among
printers. The risk ratios for nonsmokers were admittedly based on
few subjects. Risk ratios for dye process workers increased strikingly
with duration of employment (>29 years, RR 10.5). The chemical
nature of the dyes to which workers were actually exposed was not
discussed.

A case+control study of 212 cases of bladder cancer in rural
Denmark drew upon general population controls matched to cases by
sex, age, and region of residence (Mommsen et al. 1982, 1983).
Multivariate logistic regression was used to identify factors (evalu-
ated by questionnaire) associated statistically with the malignancy.
Significant relative risk ratios were found for tobacco use (l&2.1),
work with petroleum, asphalt, oil, or gasoline (2.9-3.8), industrial
work (2.21, work with chemical materials (2.0), alcohol use (2.3), and
previous venereal disease (2.9). Farmers, who were presumably
exposed to pesticides, were at less than average risk of developing
bladder cancer. The report did not explore the interactive effects of
occupation and tobacco use.

392


A case-control study in the greater New Orleans area, wherein 82
patients with bladder cancer and 169 matched general population
controls were interviewed by telephone, was used to identify
smoking of filter cigarettes (but not of unfiltered cigarettes or other
tobacco products) as a risk factor for bladder cancer (Sullivan 1982).
Matching criteria were not specified. A large number of employment
categories and chemical exposures appeared to involve risks, most
prominently mechanical engineers and people exposed to paint
thinners, coal, petroleum, metals, welding materials, office supplies,
and industrial equipment.

In a study in northern New Jersey (Najem et al. 1982), 75 cases
were compared with 150 patient controls, matched by age, sex, race,
place of birth (in New Jersey or elsewhere), current residence, and
the clinic providing care. Occupations were recorded only when job
tenure was more than 1 year. Smoking habits were characterized as
never smoked, former smoker, or current smoker. Several criteria
were used to test the significance of associations, and significant
risks were analyzed to test for the confounding effects of smoking.
Significant risk ratios were identified for cigarette smoking (2.0) and
work in dye (3.1), petroleum (2.5), and plastics (3.4) industries, but
not for employment in rubber, textile, printing, rodenticide, or cable
industries, although some ratios did exceed 1. When the significant
occupational risk ratios were analyzed within the three strata of
smoking status, ratios for current smokers were essentially the same
as those calculated without controlling for smoking. Curiously, the
occupational risk ratios for nonsmokers in the dye, plastics, and
petroleum industries consistently exceeded the ratios for current
smokers, but the ratios for ex-smokers were consistently lower (1.3 to
1.5). Some ratios were based on only a single case in a smoking-
occupation cell.

In a recently reported case-control study at Turin, Italy, 512 male
bladder cancer patients diagnosed from 1978 to 1983 were compared
with 596 patient controls (225 urologic, 371 surgical) (Vineis et al.
1984). Smoking and occupational information was assembled by
interview. Highly significant relative risk ratios were found for
cigarette smoking, the magnitude depending on smoking intensity,
on age when smoking started, and possibly on brand of cigarettes
smoked. Occupational risk analysis was based on 64 patients
classified as "exposed": 14 cases and 2 controls employed more than
6 months in dye production (said to include exposure to benzidine
and betanaphthylamine), plus 28 cases and 20 controls employed in
the rubber industry. From this, the authors calculated risk ratios
strongly suggesting interactive effects of occupational exposure and
smoking, most striking in workers less than 50 years of age, and
dependent on smoking intensity (relative risk was 144.0 for hazar-
dously employed workers who smoked). The relative risk for

383


hazardous occupation among nonsmokers of all ages (there were only
five chemically exposed: two cases, three controls) was 3.7. The
relative risk for smoking among the nonexposed of all ages was 5.2.
The risk for the occupationally exposed who smoked was 11.6
relative to nonexposed nonsmokers. The risk ratio relationships
based on all age groups are more suggestive of an additive overall
effect than of synergy. The small number of occupat,ionally exposed
nonsmokers in the study limits the confidence that can be placed in
the analysis.

Smith and colleagues (1985) recently examined relationships of
occupational solvent exposure and smoking to incident cases of
bladder cancer in regions of the United States served by the National
Cancer Institute's Surveillance, Epidemiology, and End Results
(SEER) program and included in the National Bladder Cancer Study
(NBCS) of 1978. Controls selected from the NBCS study were
frequency-matched to the cases by age and sex. Among nonsmokers
reporting at least 6 month's exposure to chlorinated and simple
hydrocarbon solvents used in dry cleaning and in other industries,
the relative risk of bladder cancer was significantly elevated only in
women (RR 1.38), and this was not significantly related to duration
of exposure. In both men and women chemically exposed, however,
the risk of bladder cancer increased progressively and significantly
from nonsmokers to former smokers to current smokers. There was
no evidence of interaction between the effects of occupation and
smoking. The evidence of a smoking effect was consistent and
substantial in this study (highest RR 4.681, but indications of a
solvent exposure effect were weak and of borderline statistical
significance.

Inhalation of combustion effluents is thought to pose a risk of
cancer at various sites, including the bladder. For a case-control
study of 81 male bladder cancer patients in Quebec (1970-19751, age-
and sex-matched individuals living in the patients' neighborhoods
were recruited to serve as controls (Theriault et al. 1981). Detailed
histories were taken covering lifetime employment and residence,
medications, personal habits, and water supply. Smoking habit was
characterized qualitatively and quantitatively. Information on de-
ceased cases was received from next of kin. These authors calculated
a mean relative risk of bladder cancer of 5.70 among currently
smoking workers in the electrolysis department of an aluminum
reduction plant. Relative risk for smoking among other workers was
1.82, and risk associated with electrolysis department employment
alone was 1.90. (It was necessary to base the latter estimate on ex-
smokers because there were no nonsmokers so employed.) The
independent risk ratios are not statistically significant, but the
range of values for electrolysis workers who smoked extended from
2.0 to 12.30. To the extent that the ratio estimates can be relied

384


upon, they suggest a strong interaction between smoking and
occupational exposure.

Silverman and colleagues (19831, in a population-based case-
control study of 303 white male bladder cancer cases in Detroit
(1977-19781, explored occupational, dietary, and personal habit
associations. Controls under 65 years of age were chosen from the
Detroit population by random digit dialing, operating with a pool of
2,110 households. Controls of retirement age were selected at
random from Health Care Financing Administration lists. A total of
296 controls were recruited for home interviews. Analysis of
occupational associations relied on an "ever employed" query, and
responses were classified according to the industry identified and by
occupation. An apparent strong interaction involved truck driving as
an occupation and cigarette smoking. Among people who had never
been truck drivers, smoking one or two packs of cigarettes per day
increased the risk of bladder cancer by a factor of 1.6; smoking more
than two packs increased the risk ratio to 2.1. The ratio for truck
drivers smoking less than one pack per day was 1.3; for smokers of
one or two packs per day, the ratio was 6.8. The risk ratio for heavy
smokers could not be calculated because none of the controls
reported smoking more than two packs per day. A relationship with
the inhalation of diesel exhaust was suspected, but could not be
confirmed from the data.

Not unexpectedly, the case-control studies used to test a relation-
ship of pesticide exposure to urinary tract cancer are inconclusive.
Pesticides are chemically and toxicologically diverse; worker expo
sures to them are equally varied. It is unlikely that in epidemiologic
studies based on broad occupational categories carcinogenic risk
would be detected, if indeed it exists. Several case-control studies of
bladder cancer have indicated that as an occupational group, people
"working in agriculture" are at no more than average risk of urinary
tract cancer, or are actually at less than average risk (Anthony and
Thomas 1970b; Cole et al. 1972; Howe et al. 1980). In some studies of
exposures to pesticides, specifically, nonsignificantly elevated risk
ratios have been shown (Najem et al. 1982; McLaughlin et al. 1983).
In Canada, bladder cancer was found to be significantly associated
with crop spraying and nursery work as occupations (Howe et al.
1980). These associations were said to be unaffected by controlling
for smoking.

Other Specific Cancer Sites

Cancer of the kidney and upper urinary tract has received less
attention than bladder cancer. In a nationwide case-control study of
202 patients with renal adenocarcinoma (Wynder et al. 19741, the
past personal and occupational histories of the patients were
examined in relation to histories from other hospitalized patients.

385


Relative risk among heavy smokers (more than one pack per day)
under 50 years of age was 8.0, but only 2.1 in patients over age 50.
Moderate smokers (up to one pack per day) were at intermediate
risk. Except for a tentative identification of employment in textiles
as a risk factor, no associations with occupational exposures to
metals, dyes, or other organic chemicals were found.
In the Boston area, 43 cases of cancer of the renal pelvis and ureter
were studied in relation to bladder cancer cases and randomly
chosen general population controls (Schmauz and Cole 1974). Only
among smokers of more than two and one-half packs of cigarettes per
day did a significant risk appear (RR 10.0). Of the occupational
categories identified, only leather working exhibited a suspect
relationship to cancer at these sites.
Occurrences of renal cell carcinoma (495) and cancer of the renal
pelvis (74) in the Minneapolis-St. Paul area from 1974 to 1979 were
studied for heritable and environmental risk factors (McLaughlin et
al. 1983, 1984). Controls were chosen randomly from the metropoli-
tan area population. Because half of the cases were already deceased,
background data had to be obtained through next-of-kin interviews.
With respect to cancer of the renal pelvis, the risk of disease
increased steadily in both men and women in relation to smoking
intensity (maximum RR 10.7 in men, 11.1 in women). The only links
to occupation appeared in relation to exposures to hydrocarbons:
coal, natural gas, and mineral and cutting oils. There were not
enough cases to permit analyses for smoking risk within occupations.
Renal cell carcinoma also appeared to be related to cigarette
smoking, but relative risk ratios were much lower (2.3 in male, 2.1 in
female heavy smokers), and the dose-response relationship was not
as consistent as in the case of renal pelvis or bladder cancer.
Analysis for "usual industry of employment" failed to identify any
significant occupational associations.
Musicco and colleagues (1982), in a case-control study of brain
neoplasms in Italy, sought to associate the occurrence of gliomas
(various types and grades) with occupations of victims prior to
diagnosis during 1979 and 1980. Forty-two cases were matched with
nonglioma patients at the Neurological Institute C. Besta of Milan.
The controls were matched by age, sex, and area of residence. They
suffered from a variety of chronic diseases, some probably character-
ized by physical and or mental disability from a relatively early age.
Smoking was defined as a minimum l-year usage, and total lifetime
usage was estimated. More than 20 pack-years was considered heavy
smoking. The authors found a significantly elevated risk ratio (5.0)
for "agricultural work after 1960" when the data were analyzed
without stratification. When stratified by sex, age, and residence, the
ratio was 1.9 (not significant). The relative risk was 1.3 for smoking
and 1.6 for heavy smoking, neither statistically significant. No


occupational risk ratios for nonsmokers were calculated. Particular-
ly with respect to occupational risk calculations, the appropriateness
of neurologically afflicted patients as controls must be questioned.
Nonetheless, the authors were inclined to indict modern pesticides
and fertilizers as causal factors for gliomas.

Austin and Schnatter (19831, in a followup case-control study of 21
patients dying from a brain tumor in a Texas petrochemical worker
cohort, indicated that the tumors were of several different types.
Efforts to identify unique past chemical exposures of brain tumor
victims were not successful.

Using case-control methodology in reviewing 142 cases of pancre-
atic adenocarcinoma in several large U.S. clinical centers, Wynder
and colleagues (1973) demonstrated that cigarette smokers were at
increased risk of developing this disease. Risk ratios increased
progressively with the number of cigarettes smoked per day.
Controls for this study were patients in the same hospitals who had
been interviewed for other epidemiologic studies. Controls did not
include patients suffering from tobacco-related cancers (mouth,
larynx, lung, esophagus, bladder, kidney) or other tobacco-related
diseases (bronchitis, emphysema, coronary heart disease). Fifteen
male cancer patients reported having been occupationally exposed to
"dyes, chemicals, metal dust, saw dust, grease, oil, or gas fumes," but
there was no difference between cases and controls with respect to
the frequency with which this exposure was reported.

A case-control study in New Jersey (Stemhagen et al. 1983) of 265
victims of primary liver cancer occurring from 1975 to 1980 was
conducted by interview of family members. Controls were selected
from hospital records and death certificates, and were matched by
age, sex, race, and county of residence. No evidence was adduced to
indict smoking as a factor in causing this disease. Significantly
elevated risk ratios were derived for farm laborers but not for farm
owners or farm managers or for people engaged in manufacturing
pesticides. Other people apparently at risk were gasoline service
station employees, those employed at eating and drinking establish-
ments, and those providing laundry and dry cleaning services. It was
not possible to identify specific past chemical exposures that might
have contributed to the risk.

A recent study of 102 cases of primary liver cancer in Sweden
utilized controls matched by age, sex, race, year of death, and
municipality where the decedent had lived (Hardell et al. 1984). No
association with smoking history was found. Occupational exposure
to solvents appeared to double the risk of liver cancer. No other
occupations or chemical exposures were identified as risk factors,
although a strong association with alcoholism was indicated.

Investigation of 207 cases of large bowel cancer in a Quebec
community explored several risk factors in cases and controls, the

387


latter selected from the communities where the cases resided, and
matched by age and sex (Vobecky et al. 1983). Smoking was not
identified as a significant risk factor, although a slightly elevated
risk ratio (1.2) for smoking (alone) was calculated. Industrial
exposure at a local synthetic fiber factory did appear to be a
significant association (RR 2.2). When the risk of industrial exposure
and smoking were considered in combination, a higher risk was
evident (2.81, at a stronger level of significance. A moderate degree of
smoking+ccupation interaction is suggested.

Chronic Lung Disease

The likelihood that exposure to dusts and fumes in rubber product
manufacture plays a causative role in the chronic obstructive lung
disease encountered in this industry was examined in two studies.
Fine and Peters (1976) assessed symptomatology and pulmonary
function in 65 white male workers engaged an average of 7 years in
rubber processing at three Akron tire plants. Air sampling showed 1
to 3 mg/m3 of respirable dust in the work environments. Smoking
habits were classified as never smoker, former smoker, current
cigarette smoker, and current and former pipe and cigar smoker.
Controls (189) were chosen from plant workers not exposed to
polluted air. Processing workers reported a much higher prevalence
of cough and phlegm than controls; this was true among nonsmokers
as well as smokers in the various categories. Smoking nearly doubled
the frequency of this symptom complex in the processing workers.
However, dyspnea and wheeze, generally considered indicative of
chronic obstructive lung disease, were no more prevalent among
processing workers than among controls. Reported frequencies of
bronchitis, pneumonia, asthma, and winter colds were not signifi-
cantly greater among these workers than among controls. Pulmo-
nary function testing yielded important findings. In comparing all
workers with all controls, only the ratio of forced expiratory volume
in 1 second to forced vital capacity (FEV,/FVC) was significantly
lower in the particulate-exposed workers. However, the exposed
group and the control group were subdivided according to whether
they had been employed in their respective jobs for more or less than
10 years. Although the long-term processing workers were older and
had smoked longer than the controls, decrements in flow rates and
FEV, /FVC were not significantly correlated with years of cigarette
smoking. Using appropriate adjustments for age, the long-term-
exposed  employees  exhibited significant deficits in FEVI,
FEV,/FVC, and flow rates at 50 and 25 percent of FVC. Multiple
regression analysis confirmed that duration of employment in
rubber processing was a significant predictor of reduced FEV, and
FVC. Employment for more than 10 years appeared to cause a
significant decline in FEV,/FVC and the FVC-standardized flow rate


at 50 percent FVC. These results were independent of smoking
variables, ethnicity, socioeconomic status, and age. The absence of a
correlation between decrement in lung function and cigarette
smoking and the small number of workers in this study raise
questions about the generalizability of the data in this study.

Lednar and colleagues (1977) examined the work history and
smoking habit backgrounds of 73 former rubber workers who were
retired prematurely between 1964 and 1973 with medically docu-
mented, disabling pulmonary disease. They were members of a
cohort of 4,302 workers employed in 1964 at an Akron plant. Thirty-
nine were retired with emphysema, 10 with lung cancer, 8 with
asthma, and 16 with other pulmonary conditions. Work background
and likely exposure to dusts and fumes were determined from
company records; smoking histories were obtained from question-
naires mailed to retirees or relatives. The investigators utilized two
control groups, the first consisting of disabled employees retired
because of diseases other than pulmonary (disabled controls) and the
second of currently employed workers and early retirees free of
acknowledged pulmonary disease (nondisabled controls). Relative
risk ratios were calculated for smoking and for occupational
exposures to dusts and fumes. Relative risks for pulmonary disability
retirement in relation to smoking and various occupational titles
were also calculated. Risk ratios for smoking alone (based on
smokers and nonsmokers at worksites not otherwise contaminated)
were consistently greater than 1.0, but they were significant only in
the case of maintenance workers. For all workers combined, the
smoking risk ratio was 2.95 (p<O.O5). Ratios for occupational
exposure alone were remarkably elevated in some job classifications,
but none were significant. When the combination of smoking and
occupational exposure was considered, however, substantially and
significantly elevated risk ratios were found for workers engaged in
extrusion (15.81, finishing and inspection (7.81, curing (6.71, and other
tasks. Furthermore, combined exposure to dust and cigarette smoke
appeared to increase by tenfold to twelvefold the risk of pulmonary
disability. The data suggested interactive effects between smoking
and occupational pollutants, more in the range of potentiation than
simple addition.

Another suggestion of enhanced adverse effects from cigarette
smoke and irritating air pollutants has come from examination of
workers exposed to airborne contaminants from the milling of
rubber (Sparks et al. 1982). For the factory worker population as a
whole, productive cough was definitely more common among current
smokers than among nonsmokers: 35.5 percent of the smokers versus
6.5 percent of the nonsmokers in parts of the plant where dust
concentrations were minimal. Among workers exposed to irritating
dust, 8 percent of the nonsmokers experienced a productive cough

389


and 42.5 percent of the smokers were so affected. In a work area
where dust concentrations were highest, but did not generate
complaints of upper respiratory tract irritation, 3.3 of the nonsmok-
ers and 29.3 of the smokers reported productive cough. The
combination of irritating fumes or particles with cigarette smoke
may stimulate bronchial mucus secretion more than either factor
acting alone.

In a recent longitudinal study of 3,799 male coke oven workers,
Madison and colleagues (1984) examined relationships between a
series of risk variables (age, current smoking status, job location) and
indices of pulmonary function (FEV1, FVC, and detailed exfoliative
cytology of sputum). Covariance and multiple logistic regression
analyses were done to identify the principal factors predicting FEV,
and FEV,/FVC. Measurements were done in 1978 and in 1982.
Appropriate adjustments were made for height, weight, and years at
the coke oven. Data from Caucasians and blacks were analyzed
separately. Both smoking and job location (six categories) had
significant detrimental effects on FEV, and FEV,/FVC in Caucasian
workers. In blacks, smoking adversely affected FEV, and FEV,/FVC
but job location did not.

Sputum cytology included examination for various cells (reactive
bronchial epithelial cells, metaplastic epithelium, histiocytes, poly-
morphonuclear leukocytes); prominence in each specimen was
graded on a scale of 0 to 4, and atypical metaplasia was rated as
mild, moderate, or severe. The investigators found excessive promi-
nence of certain exfoliated cells well correlated with reduced FEV,
and FEV,/FVC, a result apparently not caused by smoking, because
the percentage of workers showing cells was equivalent in both
smoking categories. Multiple logistic regression was done to identify
factors principally responsible for metaplasia in Caucasians: age and
smoking were the strongest predictors, but job location was also a
significant factor. Among blacks, only smoking and age were
significantly predictive.

Madison and colleagues (1984) believe that their use of data from
two examinations, plus sputum cytology, identified work-related
pulmonary injury not demonstrated in earlier cross-sectional studies
and that the findings may portend pulmonary disability in some
workers. The interval between examinations was not considered long
enough to permit time trend analysis. These authors reported no
measurement of airborne particulate or fumes at the six job
locations.

Research Recommendations

1. Efforts to minimize workplace exposure to known and suspect-
ed carcinogens should continue and not be delayed in anticipa-

390


tion of definitive evidence of hazard from occupational or
environmental studies in humans.

2. Efforts to assist smokers in their efforts to quit smoking must
continue in all sectors of the population. Blue-collar workers
have a higher prevalence of smoking and a higher exposure to
materials that might interact with cigarette smoke to increase
disease risk. Because of these dual exposures, an intensive
effort should be made to reduce the smoking rates of these
workers.

3. Epidemiologic studies to assess the health impacts of smoking
or work exposures to noxious substances should take both
factors into account as potentially causative. Additionally, the
possibility of interaction should be kept in mind, and whenever
possible, tested for.

4. Laboratory animal studies designed to explore the health-
damaging effects of tobacco smoke should include experiments
capable of identifying interactions with major industrial pollu-
tants.

5. There should be continuing research aimed at identifying the
principal constituents of common industrial pollutants that act
as cancer initiators and promoters. There should also be
continuing efforts to demonstrate the mechanism of tissue
damage caused by cigarette smoke and various industrial
pollutants, alone and in combination.

6. Modern tissue culture techniques employed to identify carcino-
gens should be exploited as test systems for interactive effects
between tobacco smoke constituents and industrial pollutants.

Summary and Conclusions

1. The biotransformation of industrial toxicants can be modified
at least to some extent by the constituents of tobacco smoke
through enzyme induction or possibly inhibition. Both tobacco
smoke and some industrial pollutants contain substances
capable of initiating and promoting cancer and damaging the
airways and lung parenchyma. There is, therefore, an ample
biologic basis for suspecting that important interactive effects
between some workplace pollutants and tobacco smoke exist.
2. In mortality studies of coke oven workers and gas workers,
convincing evidence has indicated that work exposures to oven
effluents are causing an excess risk of lung cancer in spite of
the lack of adequate information on smoking. Other mortality
studies that suggest small increases in smoking-related dis-
eases, such as pancreatic cancer in refinery workers, cannot be
interpreted without more information on smoking.

391


3. For bladder cancer, the interactions between smoking and
occupational exposure are unclear, with both additive and
antagonistic interactions having been demonstrated.
4. The risk of pulmonary disability in rubber workers was
increased when smoking and occupational exposure to particu-
lates were combined. There are few empirical animal experi-
ments that demonstrate interactive effects between cigarette
smoking and various industrial chemicals for lung disease.

392


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CHAPTER 10

COTTON DUST EXPOSURE
AND CIGARETTE SMOKING