American Journal of Industrial Medicine 22511-520 (1992)
A Case-Control Study of Cancer of the Nose and Paranasal Sinuses and Occupational Exposures Pietro Comba, DSC, Giuseppe Battista, MD, Stefan0 Belll, D S ~ , Bruno de Capua, YD, Enzo Merler, MD, Daniela Orsi, D S ~ , Stefania Rodella, DSc, Carla Vindigni, YD, and Olav Axelson, MD
The association between nasal cancer and various occupations was investigated in a case-control study in the provinces of Verona and Vicenza (northeastern Italy) and Siena (central Italy). Cases of malignant epithelial neoplasm of the nasal cavities and paranasal sinuses diagnosed in the years 1982-1987 in the hospitals of Verona, Legnago, Bussolengo, Vicenza, and Siena comprised the study. Controls were patients admitted to the same hospitals as the cases, with any diagnosis except chronic rhino-sinusal disease and nasal bleeding. Age, gender, residency, and date of admission were taken into account by matching. Cases and controls, or their next of kin, were interviewed or required to fill in a mailed questionnaire; the overall response rate was 70%. Altogether, 78 cases and 254 controls provided information on occupational history. Significantly increased risks were associated (in males) with work in the wood industry (odds ratio [O.R.] : 5.8; 90% confidence interval [C.I.] : (2.2-16) and in the leather industry (6.8; 1.9-25). Textile workers, furnacemen, construction workers, and workers with possible exposure to organic dusts showed increased risks even if statistical significance was not reached. o 1992 Wiley-Liss, Inc. Key words: rhino-sin4 tumors, nasal bleeding, organic dust exposures, wood workers, leather industry, nasal cancer
INTRODUCTION
Cancer of the nose and paranasal sinuses has been shown to occur at an increased rate among workers exposed to a variety of agents. The etiologic role of chromium for this neoplasm was f i i t detected by Newman [ 18901; the first evidence of risk for nickel workers was presented by Bridge [1933], and the causal role of
Istituto Superiore di SanitA, Rome, Italy (P.C., S.B.). Unit of Workers’ Preventive Medicine, University of Siena, Siena, Italy (G.B., D.O.). Ear, Nose and Throat Clinic, University of Siena, Siena, Italy (B.d.C.). Centre for the Study and Prevention of Cancer, U.S.L. 10 E, Florence, Italy (E.M.). Institute of Pathology, University of Verona, Verona, Italy (S.R.). Institute of Pathology, University of Siena, Siena, Italy (C.V.). D e p m e n t of Occupational Medicine, University of Linkoping, Linkoping, Sweden (O.A.). Address reprint requests to Dr. Pietro Comba, Istituto Superiore di SanitB, Vide Regina Elena 299,00161 Rome, Italy. Accepted for publication December 17, 1991. 0 1992 Wiley-Liss, Inc.
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wood dust and leather dust was demonstrated by MacBeth [1965] and Acheson et al. [1968, 19701 in a series of investigations in the 1960s. A number of reports published in the 1970s and in the 1980s have shown associations between nasal cancer and various other occupations and exposures, even if no final conclusions have been reached so far in causal terms. These reports concern textile workers [Acheson et al., 1972; Brinton et al., 1985; Olsen, 19881, miners and quarrymen [Acheson et al., 19811, farmers [Wiklund and Steineck, 19881, and workers in the food industry [Olsen, 1988; Vaughan, 19891. Organic dusts [Engzell et al., 19781, cutting oils [Roush et al., 19801, and pesticides [Hardell et al., 19821 have been suggested as possible causative agents. Previous studies conducted in the provinces of Florence, Siena, and Pisa (central Italy) and Pavia (northern Italy) have confirmed an increased risk of nasal cancer caused by exposure to wood and leather dusts [Cecchi et al., 1980; Battista et al., 1983; Merler et al., 1986; Loi et al., 19891, and a case-control study performed at the National Cancer Institute in Milan corroborated these findings and provided evidence of an increased risk for metal workers, construction workers, textile workers, and farmers as well [Bimbi et al., 19881. The purpose of the present investigation was to further study the less clear but possible associations between nasal cancer and various occupational exposures, through a collaborative case-control approach in the provinces of Verona and Vicenza (northeasternItaly) and of Siena (central Italy). The province of Siena is mainly rural, and is characterized by agricultural activity and handicraft. Verona with its province, and the neighboring province of Vicenza have various types of industrial activities, including textile industry, leather industry, tanneries, and well developed agriculture. In the years 1980-1985, average annual standardized mortality rates from nasal cancer have been 0.12 per 100,000 person-years in Verona, 0.30 per 100,OOO personyears in Vicenza, and 0.10 per 100,000 person-years in Siena. MATERIALS AND METHODS The study population included the catchment area of the Hospitals of Verona, Legnago, Bussolengo, and Vicenza (Verona study) and Siena (Siena study), encompassing a population of about 1,750,000 individuals. The cases eligible for the study were those with malignant epithelial neoplasms of the nose and paranasal sinuses diagnosed in the years 1982-1987 by the Institute of Pathology and the Ear, Nose and Throat (EN") Clinic of the University of Verona, by the Ear, Nose and Throat Departments at the Hospitals of Vicenza, Bussolengo, and Legnago, and by the Institute of Pathology at the University of Siena. Only histologically confirmed diagnoses were accepted and the cases were classified according to the WHO guidelines [Shanmugaratnam and Sobin, 19781. Whenever a case was selected, six potential hospital controls were identified on the basis of the following criteria: 1. admission to the same hospital as the case, at the same date if possible, otherwise
obtained through a search backwards in time from the date of admission of the case; 2. all diagnoses were accepted among the control subjects except chronic rhinosinusal disease and acute nasal bleeding;
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3. the same sex as the case and a similar age, i.e., within 5 years of age, was required; and 4. the controls were selected by taking residence zones into account, regarding city, province, and region. Of the six controls per case, four were primarily enrolled in the study, while two were kept as substitutes; substitution occurred if a control had to be excluded from the study at a subsequent stage because of evidence of noncompliance with one of the admissibility criteria, or if he/she formally refused to be interviewed. No substitution took place if the subject could not be traced or simply did not respond to the mailed questionnaire. Information on occupational history was collected by trained interviewers if the person was in hospital or was resident in Verona or Siena. In the other areas covered by the study, a questionnaire was mailed to cases and controls; a second questionnaire was mailed in case of nonresponse, and finally, a telephone call was made, in order to ask subjects to join the study. If these contacts had no success, the subject was categorized as nonrespondent. Telephone interviews were conducted in order to improve the quality of information from the mailed questionnaires. For deceased subjects, the next of kin was contacted. The questionnaire used by the interviewers, as well as the mailed version, included a section on general occupational history and other specific questions concerning work in the following branches: mining and quarrying; chemical industry; metal industry; textile and garment industry; wood and furniture industry; leather industry; agriculture. Information on smoking habits was also collected. Subjects were categorized as exposed according to the criterion of “having ever worked as. . . .” with respect to wood, leather, metal, textile, mining and construction industry, farming, and other occupations entailing exposures to dusts and fumes. The reference category included subjects who had never been active in any of these occupations. Data were processed using Biomedical Data Program (BMDP) statistical package. Odds ratios (OR) were computed after stratification by age, according to the procedure by Mantel and Haenszel [ 19591; 90% confidence intervals (CI) were computed according to the approximate procedure suggested by Miettinen [ 19761. Logistic regression analysis was performed according to the program included in the BMDP package. Attributable fractions for the exposed and the reference groups were estimated according to the procedure described by Miettinen [ 19741. RESULTS
The initial group comprised 77 cases and 302 controls from Verona, and 19 cases and 76 controls from Siena. In Siena, 100% of cases and 93.4% of controls were interviewed; in Verona, the corresponding figures were 76.6% and 60.6%; the overall response rate was 70%. Table I shows the procedures adopted for the collection of information. The final study group was made up of 78 cases (55 males and 23 females) and 254 controls (184 males and 70 females). Table 11reports the distribution of these study subjects by age and sex. The histologic type of the neoplasms was known for all cases except three. Squamous cell carcinoma was found in 25 (47%) of male and 8 (36%) of female
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TABLE I. Distribution of Study Subjects (Cases and Controls) by Mode of Collection of Information in Study of Nasal Cancer and Occupational Exposures From Verona and Siena Hospitals, 1982-1987 Verona cases Eligible Interviewed Controls Eligible Interviewed (included after substitution) Questionnaire administered by interviewer Study subject Next of kin Mailed questionnaire" Study subject Next of kin Total
Siena
Total
77 59
19 19
96 78
302 183 (28)
76 71 (3)
378 254
30 33
48 13
92 (13.0%) 87 (21.8%)
15 (-)b 14 (-)
107 101
90
332
242
78
46
"In parentheses, the proportion of mailed questionnaires supplemented by telephone interview. b-, no mailed questionnaire was supplemented by telephone interviews. TABLE 11. Distribution of Cases and Controls by Age and Sex in Study of Nasal Cancer and Occupational Exposures From Verona and Siena Hospitals, 1982-1987 Verona Cases
Siena
Controls
Total
cases
Controls
cases
Controls
0 0
0 0
1 1
4 4
70
Males Females Total Males Females Total
cases, adenocarcinomas in 13 (25%) and in 3 (14%), respectively. The remaining cases were affected by transitional, mucoepithelial, and undifferentiated carcinomas. The number of cases and controls who reported having ever worked in a number of occupations is shown in Tables Ill and IV. Odds ratios were computed after
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515
TABLE 111. Odds Ratios (OR) and 90% Confidence Intervals (CI) Associated With Various Occupations* in Males (Age-Stratifed and Logistic Regression Analyses) in Study of Nasal Cancer From Verona and Siena Hospitals, 19821987
No. of cases Wood workers Leather workers Metal workers Chemical workers Furnacemen Construction workers Miners Textile workers‘ Garment workers Farmers Other occupations entailing exposure to inorganic dusts and fumes Other occupations entailing exposure to organic dusts All occupations known or suspected to be at risk Reference categoryd
14 5 5
No. of controls
OR (M-H)B
90% CI
OR (LR)b
90% CI
5.8 6.8 1.6
2.2-15 1.9-25 0.44-6.0
1.0
0.33-3.3
1.2-17 1.1-8.4 0.47-7.3 0.84-20
2.5 2.3 0.9 4.5
0.64-9.5 0.90-5.8 0.25-3.2 0.77-26
1.4
0.69-2.9
4.1
0.73-23
4 I1 3 2
19 7 18 2 7 30 13 4
-
-
-
24
83
2.5
0.95-6.4
13
51
2.0
0.74-5.5
2
6
3.9
0.73-21
51
151 33
2.8
-
4
-
4.5 3.0 I .9 4.1
1.o
1.2-6.7
1.o
*“Having ever worked as . . .” “M-H = Mantel-Haenszel. b~~ = Logistic regression. ‘No age stratification was possible because of small number of cases. dDenied “having ever worked as . . .”
TABLE IV. Odds Ratios (OR) and 90% Confidence Intervals (CI) Associated With Various Occupations* in Females (Age-Stratifledand Logistic Regression Analyses) in Study of Nasal Cancer From Verona and Siena Hospitals, 19821987
No. of cases
No. of controls
OR (M-H)
90% CI
3 2 8
5 17
3.2 0.8 1.3 1.5
1
1
3.2
0.32-32
12 I1
35 35
1.1
0.49-2.42
Wood workers Textile workers Garment workers Farmers Other occupations entailing exposure to inorganic dusts and fumes All occupations known or suspected to be at risk Reference categorya *“Having ever worked as . . .” ‘Denied “having ever worked as
. . .”
1
1 12
1.o
0.32-32 0.24-2.7 0.28-5.7 0.60-3.7
OR (LR)
90% CI
0.7 1.1
0.19-2.3 0.31-6.4 0.4-2.9
2.0
0.16-23
1.4
1.o
stratification by age in males; in females, stratification was not feasible because of the small number of exposed cases. The results shown in Table IIl c o n f m the role of wood and leather dusts for the development of nasal cancer. The odds ratio for work as a furniture maker, joiner, and carpenter was 6.5 (90% CI: 2.1-20), while lumberjacks had an odds ratio of 4.1 (1.1-15); none of the cases who had worked as lumberjacks had been furniture
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TABLE V. Attributable Fractions Relative to Various Occupations* Based on Odds Ratio Derived From Logistic Analysis, Exeept for Wood Workers and Leather Workers (Stratified Analysis) in Study of N d Cancer in Verona-Siena, 1982-1987 Attributable fractions 8
Wood workers Leather workers Metal workers Furnacemen Construction workers Miners Textile workers Garment workers Farmers Other occupations entailing exposure to inorganic dusts and fumes Other occupations entailing exposure to organic dusts All occwations known or susoected to be at risk *“Having ever worked as
Exposed
Population
83 85
21 8
-
-
60 56
4 11
-
78
-
3
-
-
30
13
22 76 64
5
3 60
. . .”
workers, joiners, or carpenters. Among leather workers, an odds ratio of 8.3 (1.9-36) was associated with shoemaking. Leather tanners had an odds ratio of 5.0 (0.92-28) based on two exposed cases, none of them ever having worked as shoemakers. A significantly increased risk appears in relation to the occupations of furnacemen and construction worker. Metal workers, miners, textile workers, farmers, and other workers with possible exposure to inorganic and organic dusts show increased risks of nasal cancer, even if statistical significance was not reached. Among females (Table IV), an increased risk appears associated with woodwork and with other occupations with exposure to dusts and fumes, even if the small sample size prevents any firm conclusions. It may be noted that the various occupational groups are considered against a reference category without any suspect type of exposure. The association between nasal cancer and various occupations with a moderate risk was further tested by using a logistic regression approach in order to take into account the possible confounding role of exposures in the wood and leather industries. To some extent, this regression analysis modified the results obtained through stratified analysis. A four-fold increased risk appeared to be associated with work in the textile industry and with occupations entailing exposure to organic dusts; a doubling of risk was associated with work in the construction industry and with the job title of furnacemen; and a slightly increased risk was associated with farming and with other occupations entailing exposures to dusts and fumes (Table III). In females, a nonsignificantly increased risk, based on two exposed cases, was associated with work in the garment industry (Table IV). The attributable fractions associated with various occupations are reported in Table V. The overall fractions, i.e., for all occupational exposures, in the male population, were 64% for the exposed and 60% for the total population. It was not possible to estimate these parameters among females, because of the few exposed cases.
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The odds ratio associated with smoking was 2.0 (90% CI: 0.9-4.3) for males, and 0.83 (0.32-2.2) for females. Analysis by histotype, in males, provided some findings of interest. The odds ratios associated with woodwork were 13.9 (3.10-62) for adenocarcinoma cases, and 1.7 (0.42-7.2) for squamous cell carcinomas. The corresponding figures for leather work were 14.1 (2.6-76) and 1.6 (0.21-12). All cases of adenocarcinoma, except two, had worked in the wood or leather industries. These two individuals were a marble dealer and a furnaceman employed in a factory for the production of tannic acid; this latter job also implied some exposure to wood dust in sawing chips. Prior to working as furnaceman, this subject had been in the packing department of a facility producing diatomaceous earth. DISCUSSION
The present study had the purpose of providing information on the associations between nasal cancer and various occupational exposures. Many of these have not yet been studied to such an extent that a causal role has been established. With regard to validity issues, selection bias can be reasonably excluded, because no differential admission to hospitals in relation to exposure should be expected for the cases and controls. The overall response rates appear to be complying with current standards only in Siena. The response rate in Verona is lower than originally expected, mainly because of the large catchment area of the hospitals, due to their high reputation. A relatively high proportion of subjects diagnosed and treated in Verona did not respond to the mailed questionnaires, but there is no evidence to think of a differential nonresponse, conditional upon exposure status. Until recent years, nasal cancer has rarely been compensated in Italy, and there is no evidence suggesting recall bias due to awareness of the occupational causes of this disease. Major interviewer bias can be excluded as well, since interviewers in Verona and Siena had been trained in order to avoid such errors; mail questionnaires, as well as the questionnaires filled in by the interviewers, were coded blindly with respect to caseness. The present investigation adopted the methodology of the hospital-based casecontrol study, the definition of the study base being secondary to the cases enrolled in the study. Controls have thus been extracted from hospital files taking into account sex, age, residence, and date of admission to hospital. Age and sex were taken into account in the analysis, while residence and date of admission were not further considered, since they were regarded as variables, “balancing” at a group level the cases and controls subgroups, rather than being true confounders. Confounding due to work in wood and leather industries could be taken into account by use of logistic regression analysis. Considering the findings of the present study, the well known association of nasal cancer with wood industries was confirmed. Furniture makers, joiners, carpenters, and lumberjacks had a significantly increased risk of nasal cancer. The latter finding is of some relevance, since the evidence of carcinogenicity associated with work in lumber and sawmill industries has up to now been evaluated as “inadequate” by the International Agency for Research on Cancer [IARC,1987al. It may be noted that the types of wood used by the cases included birch, fir,poplar, beech, maple, cherry tree, oak, mahogany, walnut, chestnut, briar, samba, obeche, mansonia, and basa, i.e., both “soft” and “hard” woods.
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The increased risk associated with work as shoemaker is consistent with the findings of previous studies reviewed by IARC [ 1987bl. The increased risk associated with work as a tanner is consistent with the presence of nasal carcinogens in tanning work, presumably leather dusts, tannins, and chromates, even if no excess risk of nasal cancer in tanners has so far been demonstrated [IARC, 1987bl. This study also indicated an increased risk associated with work in the textile industry; the two exposed cases were a manufacturer of clothes and blankets, and a cotton baler. Exposure to cotton dust has been shown to be associated with nasal cancer by Acheson et al. [ 19721; subsequently Brinton et al. [ 1984, 19851 reported an increased risk of nasal cancer among textile workers employed in dusty occupations, mainly entailing exposure to cotton. An increased risk of nasal cancer in textile workers has been consistently demonstrated by findings from Sweden [Malker et al., 19861, Hong Kong [Ng, 19861, Denmark [Olsen, 19881, Italy [Bimbi et al., 19881, and France [Leclerc et al., 19901. An increased risk from exposure to other organic dusts was indicated by two cases: a baker and an entrepreneur who produced zootechnic feed and flour. Bakers and flour workers seem to have an increased risk of nasal cancer, as initially shown by Acheson et al. [1970] and subsequently confirmed by Engzell et al. [1978], Acheson et al. [1981], and Leclerc et al. [1990]. Furnacemen also appeared to be at risk, based on four exposed cases; two of them had been employed in the manufacture of bricks, one was a kier worker, and one was the aforementioned worker of the tannic acid plant. An increased incidence of nasal cancer in furnacemen was originally reported by Acheson et al. [1981] with respect to work in metal industries. It can be assumed that furnacemen, regardless of the industrial sector they are employed in, inhale mineral dust particles of various sizes carrying polycyclic aromatic hydrocarbons. Hence, there is a similarity with gas production workers who also seem to be at risk [Bruusgaard, 1959; Gustavsson and Reutewall, 19901. An increased risk was associated with work in the construction industry. High relative risks of nasal cancer among construction workers have been reported by Bross et al. [1978], Roushet al. [1980], Ng [1986], andLeclerc et al. [1990]. Various mineral dusts, tar, and oils have been mentioned as exposures of possible etiologic importance; furthermore, some established risk factors for nasal cancer can also be present in construction work, namely chromates (in cement) and wood dust. A moderate excess risk of nasal cancer appeared as associated with farming; the odds ratio increased when the evaluation was limited to squamous cell carcinoma (1.63; 90%C.I.: 0.58-4.60). Although respiratory malignancies in principle occur at a lower rate among farmers than in other occupations [Blair et al., 19851, an excess of nasal cancer in farmers has been reported from Canada, at borderline of statistical significance [Gallagher et al., 19841, Denmark, in females only, [Olsen, 19881, Italy, Sweden (in 1974-1979 only), and France with respect to squamous cell carcinoma [Bimbi et al., 1988; Wiklund and Steineck, 1988; Leclerc et al., 19901. Hardell et al. [1982] had suggested the possible role of chlorophenols and phenoxyacids in the induction of nasal cancer, which is in agreement with the excess of nasal cancer among a subgroup of 2-methyl-4 chlorophenoxyacetic acid (MCPA) manufacturers, highly exposed only, reported from Great Britain [Coggon et al., 19861. The attributable fractions estimated in the present study have to be considered with some caution, since the study base was secondary to the definition of cases
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(‘ ‘hospital-based’’ case-control). In principle, though, it seems reasonable to suggest that these estimates essentially reflect the underlying attributable fractions in the population of the provinces of interest. The present study would then demonstrate that as many as 60% of the cases of nasal cancer in the male population of the provinces of Verona, Vicenza, and Siena could be attributed to occupational exposures. It seems as if the etiological share of nasal cancer relative to occupation is larger than for most other cancer types. It should be noted though, that because of the rarity of this disease, most studies are of small size, and thus both relative risks and attributable fractions are affected by imprecision. Therefore, reduction of ambient levels of dusts and fumes in the activities associated with increased risks of nasal cancer seems important, even though the understanding of relevant pathogenetic mechanisms is still incomplete [Weed et al., 1988; Weed and Trock, 19881.
ACKNOWLEDGMENTS
The authors wish to thank Mr. Cera and Mr. Guarise from the Hospital of Vicenza and Mr. Uber from the Hospital of Verona for their kind cooperation in data retrieval. This study was supported by the Italian National Research Council Finalized Project “Oncology” section on Head and Neck Tumors. REFERENCES Acheson ED, Cowdell RH, Hadfield E, Macbeth RG (1968): Nasal cancer in woodworkers in the furniture industry. Br Med J 2587-596. Acheson ED, Cowdell RH, Jolles B (1970): Nasal cancer in the Northamptonshireboot and shoe industry. Br Med J 1:385-393. Acheson ED, Cowdell RH, Rang E (1972): Adenocarcinoma of the nasal cavity and sinuses in England and Wales. Br J Ind Med 29:21-30. Acheson ED, Cowdell RH, Rang EH (1981): Nasal cancer in England and Wales: An occupational survey. Br J Ind Med 38:218-224. Battista G, Cavallucci F, Comba P, Quercia A, Yindigni C, Sartorelli E (1983): A case-referent study on nasal cancer and exposure to wood dust in the province of Siena, Italy. Scand J Work Environ Health 9:25-29. Bimbi G, Battista G, Belli S, Berrino F, Comba P (1988): Nasal cancer and occupational exposures: A case-referent study. In Hogstedt C, Reuterwall C (eds): “Progress in Occupational Epidemiology.” Amsterdam: Elsevier, pp. 99-102. Blair A, Malker H, Cantor KP, Burmeister L, Wiklund K (1985): Cancer among farmers: A review. Scand J Work Environ Health 11:397-407. Bridge JC (1933): “Annual Report of the Chief Inspector of Factories for the Year 1932.” London: His Majesty’s Stationery Office, pp 103-104. Brinton LA, Blot WJ, Becker JA, Winn DM, Browder JP, Farmer JC, Fraumeni JF (1984): A casecontrol study of cancers of the nasal cavity and paranasal sinuses. Am J Epidemiol 119:896-906. Brinton LA, Blot WJ, Fraumeni JF (1985): Nasal cancer in the textile and clothing industries. Br J Ind Med 42:469-474. Bross IDJ, Viadana E, Houten L (1978): Occupational cancer in men exposed to dust and other environmental hazards. Arch Environ Health 33:300-307. Bmusgaard A (1959): Opptreden av visse kreftformer blant gassverkarbeidere. Tidsskr Nor Laegeforen 79:755-756. Cecchi F, Buiatti E, Kriebel D, Nastasi L, Santucci M (1980): Adenocarcinoma of the nose and paranasal
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sinuses in shoemakers and woodworkers in the province of Florence, Italy (1963-77). Br J lnd Med 37:222-225. Coggon D, Pannett B, Winter PD, Acheson ED, Bonsall J (1986): Mortality of workers exposed to 2-methyl4 chlorophenoxyacetic acid. Scand J Work Environ Health 12:448-454. Engzell U, Englund A, Westerholm P (1978): Nasal cancer associated with occupational exposure to organic dust. Acta Otolaryngol. 86:437-442. Gallagher RP, Threlfall WJ, Jeffries E, Band PR, Spinelli J, Coldman AJ (1984): Cancer and aplastic anemia in British Columbia fanners. J Natl Cancer Inst 72:1311-1315. Gustavsson P, Reuterwall C (1990): Mortality and incidence of cancer among Swedish gas workers. Br J h d Med 47:169-174. Hardell L, Johansson B, Axelson 0 (1982): Epidemiological study of nasal and nasopharyngeal cancer and their relation on phenoxy acid or chlorophenol exposure. Am J Ind Med 3:247-257. International Agency for Research on Cancer (IARC) (1987a): “Overall Evaluations of Carcinogenicity: An Updating.” Lyon: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Supplement 7, pp 378-387. International Agency for Research on Cancer (IARC) (1987b): “Overall Evaluations of Carcinogenicity: An Updating.” Lyon: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Supplement 7, pp 232-237. Leclerc A, Luce D, Gerin M, Casal A (1990): Case-control study on occupational risk factors in nasal cancer. In Sakurai H, Okazaki I, Omae K (eds): “Occupational Epidemiology.” Amsterdam: Elsevier Science Publisher, pp 93-96. Loi AM, Amram DL, Bramanti L, Roselli MG, Giacomini G,Simi U, Belli S, Comba P (1989): Nasal cancer and exposure to wood and leather dust. A case-control study in Pisa area. J Exp Clin Cancer Res 8:13-19. Macbeth R (1965): Malignant disease of the paranasal sinuses. J Laryngol 79592-612. Maker HSR, McLaughlin JK. Blott WJ, Weiner JA, Maker BK, Ericcson JLE, Stone BJ (1986): Nasal cancer and occupation in Sweden, 1961-1979. Am J Ind Med 9:477-485. Mantel N, Haenszel W (1959): Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 23:719-748. Merler E, Baldasseroni A, Laria R, Faravelli P, Agostini R, Pisa R, Benino F (1986): On the causal association between exposure to leather dust and nasal cancer: Further evidence from a casecontrol study. Br J Ind Med 43:91-95. Miettinen 0 (1974): Proportion of disease caused or prevented by a given exposure, trait or intervention. Am J Epidemiol 99:325-332. Miettinen 0 (1976): Estimability and estimation in case-referent studies. Am J Epidemiol 103:226-235. Newman D (1890): A case of adeno-carcinomaof the left inferior turbinated body, and perforation of the nasal septum, in the person of a worker in chrome pigments. Glasgow Med J 33:469-470. Ng TP (1986): A case-referent study of cancer of the nasal cavity and sinuses in Hong Kong. Int J Epidemiol 15171-175. Olsen JH (1988): Occupational risks of sinonasal cancer in Denmark. Br J Ind Med 45:329-335. Roush GC, Meigs JW, Kelly J, Flannery JT, Burdo H (1980): Sinonasal cancer and occupation: A case-control study. Am J Epidemiol 111:183-193. Shanmugaratnam K, Sobin LH (1978): Types histologiques des tumeurs des voies akriennes sup6rieures. Organisation Mondiale de la Santk, Geneve. Vaughan TL (1989): Occupation and squamous cell cancers of the pharynx and sinonasal cavity. Am J Ind Med 16:493-510. Weed DL, Selmon M, Sinks T (1988): Links between categories of interaction. Am J Epidemiol 127: 17-27. Weed DL, Trock B (1988): Interactions and public health decisions. J Clin Epidemiol 41:207-209. Wiklund K, Steineck G (1988): Cancer in the respiratory organs of Swedish farmers. Cancer 61:10551058.
A Case-Control Study of Cancer of the Nose and Paranasal Sinuses and Occupational Exposures Pietro Comba, DSC, Giuseppe Battista, MD, Stefan0 Belll, D S ~ , Bruno de Capua, YD, Enzo Merler, MD, Daniela Orsi, D S ~ , Stefania Rodella, DSc, Carla Vindigni, YD, and Olav Axelson, MD
The association between nasal cancer and various occupations was investigated in a case-control study in the provinces of Verona and Vicenza (northeastern Italy) and Siena (central Italy). Cases of malignant epithelial neoplasm of the nasal cavities and paranasal sinuses diagnosed in the years 1982-1987 in the hospitals of Verona, Legnago, Bussolengo, Vicenza, and Siena comprised the study. Controls were patients admitted to the same hospitals as the cases, with any diagnosis except chronic rhino-sinusal disease and nasal bleeding. Age, gender, residency, and date of admission were taken into account by matching. Cases and controls, or their next of kin, were interviewed or required to fill in a mailed questionnaire; the overall response rate was 70%. Altogether, 78 cases and 254 controls provided information on occupational history. Significantly increased risks were associated (in males) with work in the wood industry (odds ratio [O.R.] : 5.8; 90% confidence interval [C.I.] : (2.2-16) and in the leather industry (6.8; 1.9-25). Textile workers, furnacemen, construction workers, and workers with possible exposure to organic dusts showed increased risks even if statistical significance was not reached. o 1992 Wiley-Liss, Inc. Key words: rhino-sin4 tumors, nasal bleeding, organic dust exposures, wood workers, leather industry, nasal cancer
INTRODUCTION
Cancer of the nose and paranasal sinuses has been shown to occur at an increased rate among workers exposed to a variety of agents. The etiologic role of chromium for this neoplasm was f i i t detected by Newman [ 18901; the first evidence of risk for nickel workers was presented by Bridge [1933], and the causal role of
Istituto Superiore di SanitA, Rome, Italy (P.C., S.B.). Unit of Workers’ Preventive Medicine, University of Siena, Siena, Italy (G.B., D.O.). Ear, Nose and Throat Clinic, University of Siena, Siena, Italy (B.d.C.). Centre for the Study and Prevention of Cancer, U.S.L. 10 E, Florence, Italy (E.M.). Institute of Pathology, University of Verona, Verona, Italy (S.R.). Institute of Pathology, University of Siena, Siena, Italy (C.V.). D e p m e n t of Occupational Medicine, University of Linkoping, Linkoping, Sweden (O.A.). Address reprint requests to Dr. Pietro Comba, Istituto Superiore di SanitB, Vide Regina Elena 299,00161 Rome, Italy. Accepted for publication December 17, 1991. 0 1992 Wiley-Liss, Inc.
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wood dust and leather dust was demonstrated by MacBeth [1965] and Acheson et al. [1968, 19701 in a series of investigations in the 1960s. A number of reports published in the 1970s and in the 1980s have shown associations between nasal cancer and various other occupations and exposures, even if no final conclusions have been reached so far in causal terms. These reports concern textile workers [Acheson et al., 1972; Brinton et al., 1985; Olsen, 19881, miners and quarrymen [Acheson et al., 19811, farmers [Wiklund and Steineck, 19881, and workers in the food industry [Olsen, 1988; Vaughan, 19891. Organic dusts [Engzell et al., 19781, cutting oils [Roush et al., 19801, and pesticides [Hardell et al., 19821 have been suggested as possible causative agents. Previous studies conducted in the provinces of Florence, Siena, and Pisa (central Italy) and Pavia (northern Italy) have confirmed an increased risk of nasal cancer caused by exposure to wood and leather dusts [Cecchi et al., 1980; Battista et al., 1983; Merler et al., 1986; Loi et al., 19891, and a case-control study performed at the National Cancer Institute in Milan corroborated these findings and provided evidence of an increased risk for metal workers, construction workers, textile workers, and farmers as well [Bimbi et al., 19881. The purpose of the present investigation was to further study the less clear but possible associations between nasal cancer and various occupational exposures, through a collaborative case-control approach in the provinces of Verona and Vicenza (northeasternItaly) and of Siena (central Italy). The province of Siena is mainly rural, and is characterized by agricultural activity and handicraft. Verona with its province, and the neighboring province of Vicenza have various types of industrial activities, including textile industry, leather industry, tanneries, and well developed agriculture. In the years 1980-1985, average annual standardized mortality rates from nasal cancer have been 0.12 per 100,000 person-years in Verona, 0.30 per 100,OOO personyears in Vicenza, and 0.10 per 100,000 person-years in Siena. MATERIALS AND METHODS The study population included the catchment area of the Hospitals of Verona, Legnago, Bussolengo, and Vicenza (Verona study) and Siena (Siena study), encompassing a population of about 1,750,000 individuals. The cases eligible for the study were those with malignant epithelial neoplasms of the nose and paranasal sinuses diagnosed in the years 1982-1987 by the Institute of Pathology and the Ear, Nose and Throat (EN") Clinic of the University of Verona, by the Ear, Nose and Throat Departments at the Hospitals of Vicenza, Bussolengo, and Legnago, and by the Institute of Pathology at the University of Siena. Only histologically confirmed diagnoses were accepted and the cases were classified according to the WHO guidelines [Shanmugaratnam and Sobin, 19781. Whenever a case was selected, six potential hospital controls were identified on the basis of the following criteria: 1. admission to the same hospital as the case, at the same date if possible, otherwise
obtained through a search backwards in time from the date of admission of the case; 2. all diagnoses were accepted among the control subjects except chronic rhinosinusal disease and acute nasal bleeding;
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3. the same sex as the case and a similar age, i.e., within 5 years of age, was required; and 4. the controls were selected by taking residence zones into account, regarding city, province, and region. Of the six controls per case, four were primarily enrolled in the study, while two were kept as substitutes; substitution occurred if a control had to be excluded from the study at a subsequent stage because of evidence of noncompliance with one of the admissibility criteria, or if he/she formally refused to be interviewed. No substitution took place if the subject could not be traced or simply did not respond to the mailed questionnaire. Information on occupational history was collected by trained interviewers if the person was in hospital or was resident in Verona or Siena. In the other areas covered by the study, a questionnaire was mailed to cases and controls; a second questionnaire was mailed in case of nonresponse, and finally, a telephone call was made, in order to ask subjects to join the study. If these contacts had no success, the subject was categorized as nonrespondent. Telephone interviews were conducted in order to improve the quality of information from the mailed questionnaires. For deceased subjects, the next of kin was contacted. The questionnaire used by the interviewers, as well as the mailed version, included a section on general occupational history and other specific questions concerning work in the following branches: mining and quarrying; chemical industry; metal industry; textile and garment industry; wood and furniture industry; leather industry; agriculture. Information on smoking habits was also collected. Subjects were categorized as exposed according to the criterion of “having ever worked as. . . .” with respect to wood, leather, metal, textile, mining and construction industry, farming, and other occupations entailing exposures to dusts and fumes. The reference category included subjects who had never been active in any of these occupations. Data were processed using Biomedical Data Program (BMDP) statistical package. Odds ratios (OR) were computed after stratification by age, according to the procedure by Mantel and Haenszel [ 19591; 90% confidence intervals (CI) were computed according to the approximate procedure suggested by Miettinen [ 19761. Logistic regression analysis was performed according to the program included in the BMDP package. Attributable fractions for the exposed and the reference groups were estimated according to the procedure described by Miettinen [ 19741. RESULTS
The initial group comprised 77 cases and 302 controls from Verona, and 19 cases and 76 controls from Siena. In Siena, 100% of cases and 93.4% of controls were interviewed; in Verona, the corresponding figures were 76.6% and 60.6%; the overall response rate was 70%. Table I shows the procedures adopted for the collection of information. The final study group was made up of 78 cases (55 males and 23 females) and 254 controls (184 males and 70 females). Table 11reports the distribution of these study subjects by age and sex. The histologic type of the neoplasms was known for all cases except three. Squamous cell carcinoma was found in 25 (47%) of male and 8 (36%) of female
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TABLE I. Distribution of Study Subjects (Cases and Controls) by Mode of Collection of Information in Study of Nasal Cancer and Occupational Exposures From Verona and Siena Hospitals, 1982-1987 Verona cases Eligible Interviewed Controls Eligible Interviewed (included after substitution) Questionnaire administered by interviewer Study subject Next of kin Mailed questionnaire" Study subject Next of kin Total
Siena
Total
77 59
19 19
96 78
302 183 (28)
76 71 (3)
378 254
30 33
48 13
92 (13.0%) 87 (21.8%)
15 (-)b 14 (-)
107 101
90
332
242
78
46
"In parentheses, the proportion of mailed questionnaires supplemented by telephone interview. b-, no mailed questionnaire was supplemented by telephone interviews. TABLE 11. Distribution of Cases and Controls by Age and Sex in Study of Nasal Cancer and Occupational Exposures From Verona and Siena Hospitals, 1982-1987 Verona Cases
Siena
Controls
Total
cases
Controls
cases
Controls
0 0
0 0
1 1
4 4
70
Males Females Total Males Females Total
cases, adenocarcinomas in 13 (25%) and in 3 (14%), respectively. The remaining cases were affected by transitional, mucoepithelial, and undifferentiated carcinomas. The number of cases and controls who reported having ever worked in a number of occupations is shown in Tables Ill and IV. Odds ratios were computed after
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TABLE 111. Odds Ratios (OR) and 90% Confidence Intervals (CI) Associated With Various Occupations* in Males (Age-Stratifed and Logistic Regression Analyses) in Study of Nasal Cancer From Verona and Siena Hospitals, 19821987
No. of cases Wood workers Leather workers Metal workers Chemical workers Furnacemen Construction workers Miners Textile workers‘ Garment workers Farmers Other occupations entailing exposure to inorganic dusts and fumes Other occupations entailing exposure to organic dusts All occupations known or suspected to be at risk Reference categoryd
14 5 5
No. of controls
OR (M-H)B
90% CI
OR (LR)b
90% CI
5.8 6.8 1.6
2.2-15 1.9-25 0.44-6.0
1.0
0.33-3.3
1.2-17 1.1-8.4 0.47-7.3 0.84-20
2.5 2.3 0.9 4.5
0.64-9.5 0.90-5.8 0.25-3.2 0.77-26
1.4
0.69-2.9
4.1
0.73-23
4 I1 3 2
19 7 18 2 7 30 13 4
-
-
-
24
83
2.5
0.95-6.4
13
51
2.0
0.74-5.5
2
6
3.9
0.73-21
51
151 33
2.8
-
4
-
4.5 3.0 I .9 4.1
1.o
1.2-6.7
1.o
*“Having ever worked as . . .” “M-H = Mantel-Haenszel. b~~ = Logistic regression. ‘No age stratification was possible because of small number of cases. dDenied “having ever worked as . . .”
TABLE IV. Odds Ratios (OR) and 90% Confidence Intervals (CI) Associated With Various Occupations* in Females (Age-Stratifledand Logistic Regression Analyses) in Study of Nasal Cancer From Verona and Siena Hospitals, 19821987
No. of cases
No. of controls
OR (M-H)
90% CI
3 2 8
5 17
3.2 0.8 1.3 1.5
1
1
3.2
0.32-32
12 I1
35 35
1.1
0.49-2.42
Wood workers Textile workers Garment workers Farmers Other occupations entailing exposure to inorganic dusts and fumes All occupations known or suspected to be at risk Reference categorya *“Having ever worked as . . .” ‘Denied “having ever worked as
. . .”
1
1 12
1.o
0.32-32 0.24-2.7 0.28-5.7 0.60-3.7
OR (LR)
90% CI
0.7 1.1
0.19-2.3 0.31-6.4 0.4-2.9
2.0
0.16-23
1.4
1.o
stratification by age in males; in females, stratification was not feasible because of the small number of exposed cases. The results shown in Table IIl c o n f m the role of wood and leather dusts for the development of nasal cancer. The odds ratio for work as a furniture maker, joiner, and carpenter was 6.5 (90% CI: 2.1-20), while lumberjacks had an odds ratio of 4.1 (1.1-15); none of the cases who had worked as lumberjacks had been furniture
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TABLE V. Attributable Fractions Relative to Various Occupations* Based on Odds Ratio Derived From Logistic Analysis, Exeept for Wood Workers and Leather Workers (Stratified Analysis) in Study of N d Cancer in Verona-Siena, 1982-1987 Attributable fractions 8
Wood workers Leather workers Metal workers Furnacemen Construction workers Miners Textile workers Garment workers Farmers Other occupations entailing exposure to inorganic dusts and fumes Other occupations entailing exposure to organic dusts All occwations known or susoected to be at risk *“Having ever worked as
Exposed
Population
83 85
21 8
-
-
60 56
4 11
-
78
-
3
-
-
30
13
22 76 64
5
3 60
. . .”
workers, joiners, or carpenters. Among leather workers, an odds ratio of 8.3 (1.9-36) was associated with shoemaking. Leather tanners had an odds ratio of 5.0 (0.92-28) based on two exposed cases, none of them ever having worked as shoemakers. A significantly increased risk appears in relation to the occupations of furnacemen and construction worker. Metal workers, miners, textile workers, farmers, and other workers with possible exposure to inorganic and organic dusts show increased risks of nasal cancer, even if statistical significance was not reached. Among females (Table IV), an increased risk appears associated with woodwork and with other occupations with exposure to dusts and fumes, even if the small sample size prevents any firm conclusions. It may be noted that the various occupational groups are considered against a reference category without any suspect type of exposure. The association between nasal cancer and various occupations with a moderate risk was further tested by using a logistic regression approach in order to take into account the possible confounding role of exposures in the wood and leather industries. To some extent, this regression analysis modified the results obtained through stratified analysis. A four-fold increased risk appeared to be associated with work in the textile industry and with occupations entailing exposure to organic dusts; a doubling of risk was associated with work in the construction industry and with the job title of furnacemen; and a slightly increased risk was associated with farming and with other occupations entailing exposures to dusts and fumes (Table III). In females, a nonsignificantly increased risk, based on two exposed cases, was associated with work in the garment industry (Table IV). The attributable fractions associated with various occupations are reported in Table V. The overall fractions, i.e., for all occupational exposures, in the male population, were 64% for the exposed and 60% for the total population. It was not possible to estimate these parameters among females, because of the few exposed cases.
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The odds ratio associated with smoking was 2.0 (90% CI: 0.9-4.3) for males, and 0.83 (0.32-2.2) for females. Analysis by histotype, in males, provided some findings of interest. The odds ratios associated with woodwork were 13.9 (3.10-62) for adenocarcinoma cases, and 1.7 (0.42-7.2) for squamous cell carcinomas. The corresponding figures for leather work were 14.1 (2.6-76) and 1.6 (0.21-12). All cases of adenocarcinoma, except two, had worked in the wood or leather industries. These two individuals were a marble dealer and a furnaceman employed in a factory for the production of tannic acid; this latter job also implied some exposure to wood dust in sawing chips. Prior to working as furnaceman, this subject had been in the packing department of a facility producing diatomaceous earth. DISCUSSION
The present study had the purpose of providing information on the associations between nasal cancer and various occupational exposures. Many of these have not yet been studied to such an extent that a causal role has been established. With regard to validity issues, selection bias can be reasonably excluded, because no differential admission to hospitals in relation to exposure should be expected for the cases and controls. The overall response rates appear to be complying with current standards only in Siena. The response rate in Verona is lower than originally expected, mainly because of the large catchment area of the hospitals, due to their high reputation. A relatively high proportion of subjects diagnosed and treated in Verona did not respond to the mailed questionnaires, but there is no evidence to think of a differential nonresponse, conditional upon exposure status. Until recent years, nasal cancer has rarely been compensated in Italy, and there is no evidence suggesting recall bias due to awareness of the occupational causes of this disease. Major interviewer bias can be excluded as well, since interviewers in Verona and Siena had been trained in order to avoid such errors; mail questionnaires, as well as the questionnaires filled in by the interviewers, were coded blindly with respect to caseness. The present investigation adopted the methodology of the hospital-based casecontrol study, the definition of the study base being secondary to the cases enrolled in the study. Controls have thus been extracted from hospital files taking into account sex, age, residence, and date of admission to hospital. Age and sex were taken into account in the analysis, while residence and date of admission were not further considered, since they were regarded as variables, “balancing” at a group level the cases and controls subgroups, rather than being true confounders. Confounding due to work in wood and leather industries could be taken into account by use of logistic regression analysis. Considering the findings of the present study, the well known association of nasal cancer with wood industries was confirmed. Furniture makers, joiners, carpenters, and lumberjacks had a significantly increased risk of nasal cancer. The latter finding is of some relevance, since the evidence of carcinogenicity associated with work in lumber and sawmill industries has up to now been evaluated as “inadequate” by the International Agency for Research on Cancer [IARC,1987al. It may be noted that the types of wood used by the cases included birch, fir,poplar, beech, maple, cherry tree, oak, mahogany, walnut, chestnut, briar, samba, obeche, mansonia, and basa, i.e., both “soft” and “hard” woods.
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The increased risk associated with work as shoemaker is consistent with the findings of previous studies reviewed by IARC [ 1987bl. The increased risk associated with work as a tanner is consistent with the presence of nasal carcinogens in tanning work, presumably leather dusts, tannins, and chromates, even if no excess risk of nasal cancer in tanners has so far been demonstrated [IARC, 1987bl. This study also indicated an increased risk associated with work in the textile industry; the two exposed cases were a manufacturer of clothes and blankets, and a cotton baler. Exposure to cotton dust has been shown to be associated with nasal cancer by Acheson et al. [ 19721; subsequently Brinton et al. [ 1984, 19851 reported an increased risk of nasal cancer among textile workers employed in dusty occupations, mainly entailing exposure to cotton. An increased risk of nasal cancer in textile workers has been consistently demonstrated by findings from Sweden [Malker et al., 19861, Hong Kong [Ng, 19861, Denmark [Olsen, 19881, Italy [Bimbi et al., 19881, and France [Leclerc et al., 19901. An increased risk from exposure to other organic dusts was indicated by two cases: a baker and an entrepreneur who produced zootechnic feed and flour. Bakers and flour workers seem to have an increased risk of nasal cancer, as initially shown by Acheson et al. [1970] and subsequently confirmed by Engzell et al. [1978], Acheson et al. [1981], and Leclerc et al. [1990]. Furnacemen also appeared to be at risk, based on four exposed cases; two of them had been employed in the manufacture of bricks, one was a kier worker, and one was the aforementioned worker of the tannic acid plant. An increased incidence of nasal cancer in furnacemen was originally reported by Acheson et al. [1981] with respect to work in metal industries. It can be assumed that furnacemen, regardless of the industrial sector they are employed in, inhale mineral dust particles of various sizes carrying polycyclic aromatic hydrocarbons. Hence, there is a similarity with gas production workers who also seem to be at risk [Bruusgaard, 1959; Gustavsson and Reutewall, 19901. An increased risk was associated with work in the construction industry. High relative risks of nasal cancer among construction workers have been reported by Bross et al. [1978], Roushet al. [1980], Ng [1986], andLeclerc et al. [1990]. Various mineral dusts, tar, and oils have been mentioned as exposures of possible etiologic importance; furthermore, some established risk factors for nasal cancer can also be present in construction work, namely chromates (in cement) and wood dust. A moderate excess risk of nasal cancer appeared as associated with farming; the odds ratio increased when the evaluation was limited to squamous cell carcinoma (1.63; 90%C.I.: 0.58-4.60). Although respiratory malignancies in principle occur at a lower rate among farmers than in other occupations [Blair et al., 19851, an excess of nasal cancer in farmers has been reported from Canada, at borderline of statistical significance [Gallagher et al., 19841, Denmark, in females only, [Olsen, 19881, Italy, Sweden (in 1974-1979 only), and France with respect to squamous cell carcinoma [Bimbi et al., 1988; Wiklund and Steineck, 1988; Leclerc et al., 19901. Hardell et al. [1982] had suggested the possible role of chlorophenols and phenoxyacids in the induction of nasal cancer, which is in agreement with the excess of nasal cancer among a subgroup of 2-methyl-4 chlorophenoxyacetic acid (MCPA) manufacturers, highly exposed only, reported from Great Britain [Coggon et al., 19861. The attributable fractions estimated in the present study have to be considered with some caution, since the study base was secondary to the definition of cases
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(‘ ‘hospital-based’’ case-control). In principle, though, it seems reasonable to suggest that these estimates essentially reflect the underlying attributable fractions in the population of the provinces of interest. The present study would then demonstrate that as many as 60% of the cases of nasal cancer in the male population of the provinces of Verona, Vicenza, and Siena could be attributed to occupational exposures. It seems as if the etiological share of nasal cancer relative to occupation is larger than for most other cancer types. It should be noted though, that because of the rarity of this disease, most studies are of small size, and thus both relative risks and attributable fractions are affected by imprecision. Therefore, reduction of ambient levels of dusts and fumes in the activities associated with increased risks of nasal cancer seems important, even though the understanding of relevant pathogenetic mechanisms is still incomplete [Weed et al., 1988; Weed and Trock, 19881.
ACKNOWLEDGMENTS
The authors wish to thank Mr. Cera and Mr. Guarise from the Hospital of Vicenza and Mr. Uber from the Hospital of Verona for their kind cooperation in data retrieval. This study was supported by the Italian National Research Council Finalized Project “Oncology” section on Head and Neck Tumors. REFERENCES Acheson ED, Cowdell RH, Hadfield E, Macbeth RG (1968): Nasal cancer in woodworkers in the furniture industry. Br Med J 2587-596. Acheson ED, Cowdell RH, Jolles B (1970): Nasal cancer in the Northamptonshireboot and shoe industry. Br Med J 1:385-393. Acheson ED, Cowdell RH, Rang E (1972): Adenocarcinoma of the nasal cavity and sinuses in England and Wales. Br J Ind Med 29:21-30. Acheson ED, Cowdell RH, Rang EH (1981): Nasal cancer in England and Wales: An occupational survey. Br J Ind Med 38:218-224. Battista G, Cavallucci F, Comba P, Quercia A, Yindigni C, Sartorelli E (1983): A case-referent study on nasal cancer and exposure to wood dust in the province of Siena, Italy. Scand J Work Environ Health 9:25-29. Bimbi G, Battista G, Belli S, Berrino F, Comba P (1988): Nasal cancer and occupational exposures: A case-referent study. In Hogstedt C, Reuterwall C (eds): “Progress in Occupational Epidemiology.” Amsterdam: Elsevier, pp. 99-102. Blair A, Malker H, Cantor KP, Burmeister L, Wiklund K (1985): Cancer among farmers: A review. Scand J Work Environ Health 11:397-407. Bridge JC (1933): “Annual Report of the Chief Inspector of Factories for the Year 1932.” London: His Majesty’s Stationery Office, pp 103-104. Brinton LA, Blot WJ, Becker JA, Winn DM, Browder JP, Farmer JC, Fraumeni JF (1984): A casecontrol study of cancers of the nasal cavity and paranasal sinuses. Am J Epidemiol 119:896-906. Brinton LA, Blot WJ, Fraumeni JF (1985): Nasal cancer in the textile and clothing industries. Br J Ind Med 42:469-474. Bross IDJ, Viadana E, Houten L (1978): Occupational cancer in men exposed to dust and other environmental hazards. Arch Environ Health 33:300-307. Bmusgaard A (1959): Opptreden av visse kreftformer blant gassverkarbeidere. Tidsskr Nor Laegeforen 79:755-756. Cecchi F, Buiatti E, Kriebel D, Nastasi L, Santucci M (1980): Adenocarcinoma of the nose and paranasal
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sinuses in shoemakers and woodworkers in the province of Florence, Italy (1963-77). Br J lnd Med 37:222-225. Coggon D, Pannett B, Winter PD, Acheson ED, Bonsall J (1986): Mortality of workers exposed to 2-methyl4 chlorophenoxyacetic acid. Scand J Work Environ Health 12:448-454. Engzell U, Englund A, Westerholm P (1978): Nasal cancer associated with occupational exposure to organic dust. Acta Otolaryngol. 86:437-442. Gallagher RP, Threlfall WJ, Jeffries E, Band PR, Spinelli J, Coldman AJ (1984): Cancer and aplastic anemia in British Columbia fanners. J Natl Cancer Inst 72:1311-1315. Gustavsson P, Reuterwall C (1990): Mortality and incidence of cancer among Swedish gas workers. Br J h d Med 47:169-174. Hardell L, Johansson B, Axelson 0 (1982): Epidemiological study of nasal and nasopharyngeal cancer and their relation on phenoxy acid or chlorophenol exposure. Am J Ind Med 3:247-257. International Agency for Research on Cancer (IARC) (1987a): “Overall Evaluations of Carcinogenicity: An Updating.” Lyon: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Supplement 7, pp 378-387. International Agency for Research on Cancer (IARC) (1987b): “Overall Evaluations of Carcinogenicity: An Updating.” Lyon: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Supplement 7, pp 232-237. Leclerc A, Luce D, Gerin M, Casal A (1990): Case-control study on occupational risk factors in nasal cancer. In Sakurai H, Okazaki I, Omae K (eds): “Occupational Epidemiology.” Amsterdam: Elsevier Science Publisher, pp 93-96. Loi AM, Amram DL, Bramanti L, Roselli MG, Giacomini G,Simi U, Belli S, Comba P (1989): Nasal cancer and exposure to wood and leather dust. A case-control study in Pisa area. J Exp Clin Cancer Res 8:13-19. Macbeth R (1965): Malignant disease of the paranasal sinuses. J Laryngol 79592-612. Maker HSR, McLaughlin JK. Blott WJ, Weiner JA, Maker BK, Ericcson JLE, Stone BJ (1986): Nasal cancer and occupation in Sweden, 1961-1979. Am J Ind Med 9:477-485. Mantel N, Haenszel W (1959): Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 23:719-748. Merler E, Baldasseroni A, Laria R, Faravelli P, Agostini R, Pisa R, Benino F (1986): On the causal association between exposure to leather dust and nasal cancer: Further evidence from a casecontrol study. Br J Ind Med 43:91-95. Miettinen 0 (1974): Proportion of disease caused or prevented by a given exposure, trait or intervention. Am J Epidemiol 99:325-332. Miettinen 0 (1976): Estimability and estimation in case-referent studies. Am J Epidemiol 103:226-235. Newman D (1890): A case of adeno-carcinomaof the left inferior turbinated body, and perforation of the nasal septum, in the person of a worker in chrome pigments. Glasgow Med J 33:469-470. Ng TP (1986): A case-referent study of cancer of the nasal cavity and sinuses in Hong Kong. Int J Epidemiol 15171-175. Olsen JH (1988): Occupational risks of sinonasal cancer in Denmark. Br J Ind Med 45:329-335. Roush GC, Meigs JW, Kelly J, Flannery JT, Burdo H (1980): Sinonasal cancer and occupation: A case-control study. Am J Epidemiol 111:183-193. Shanmugaratnam K, Sobin LH (1978): Types histologiques des tumeurs des voies akriennes sup6rieures. Organisation Mondiale de la Santk, Geneve. Vaughan TL (1989): Occupation and squamous cell cancers of the pharynx and sinonasal cavity. Am J Ind Med 16:493-510. Weed DL, Selmon M, Sinks T (1988): Links between categories of interaction. Am J Epidemiol 127: 17-27. Weed DL, Trock B (1988): Interactions and public health decisions. J Clin Epidemiol 41:207-209. Wiklund K, Steineck G (1988): Cancer in the respiratory organs of Swedish farmers. Cancer 61:10551058.
