a Institut Municipal d'Investigació Mèdica (IMIM), Barcelona, Spain.
b Universitat Autònoma de Barcelona, Spain.
c Universitat Pompeu Fabra, Barcelona, Spain.
d Institut Català d'Oncologia, Barcelona, Spain.
e Hospital General de Elche, Spain.
f Hospital Son Dureta, Palma de Mallorca, Spain.
g Hospital Vall d'Hebron, Barcelona, Spain.
h Centres and members of the PANKRAS II Study Group. Institut Municipal d'Investigació Mèdica, Universitat Autònoma de Barcelona and Universitat Pompeu Fabra (Co-ordinating Centre): M Porta,1 FX Real,1 N Malats,2 J Alguacil,S Costafreda, L Ruiz, M Jariod, I Cortès,3 E Fernandez,3 L Gavaldà,3 JL Piñol,3 E Carrillo,3 A Maguire, M Soler, A García de Herreros, A Serrat, M Torà. Hospital General de Elche: A Carrato,2 E Gómez,3 V Barberà, JM Barón, M de Diego, R Guaraz, FJ Lacueva, JA Maruenda, A Orduña, J Ruiz, C Sillero,A Teruel. Hospital del Mar, Barcelona: M Andreu,2 JM Corominas,4 S Coll,M Conangla, JM Gubern, T Maristany, A Panadès, R Solà, F Tous. Hospital de Son Dureta, Mallorca: J Rifà,2 M Marrugat,3 J Calafell, P de Miguel, J Forteza, N Matamoros, A Obrador, O Pons, C Saus, T Terrasa. Hospital de la Vall d'Hebron, Barcelona: L Guarner,2 A Alvarez, J Bellmunt, I de Torre, M García, E Murio, A Nadal, V Puig-Diví, N Tallada. Hospital Mútua de Terrassa:A Salas,2,4 E Cugat, JC Espinós, E García-Olivares, M García. 1Principal investigator, 2Centre coordinator-investigator, 3Monitor, 4Study reference pathologist.
Reprint requests: Prof. M Porta, Institut Municipal d'Investigació Mèdica, Universitat Autònoma de Barcelona, Carrer del Doctor Aiguader 80, E-08003 Barcelona, Catalonia, Spain. E-mail: mporta{at}imim.es
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Abstract |
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Methods Incident cases of pancreatic cancer and hospital controls were prospectively identified and interviewed during their hospital stay. Occupational history was obtained by direct interview with the patient and was available for 164 (89%) of 185 pancreatic cancer cases and for 238 (90%) of 264 controls. Occupations were coded according to the Spanish version of the International Standard Classification of Occupations 1988.
Results A significant increased odds ratio (OR) was observed in men for physical, chemistry and engineering science technicians. Elevated risks were also found for metal moulders, sheet-metal workers, structural metal workers, welders and related workers, painters and varnishers and machinery mechanics and fitters. Agricultural workers did not present an increased risk for pancreas cancer in men. In women, however, high OR were observed for agricultural workers and for textile and garment workers. Most associations remained unchanged after considering long duration of the exposure and the period 515 years before diagnosis.
Conclusions Few occupations were at increased risk for pancreatic cancer, and the associations observed are in accordance with previous studies. The increases in risk observed for women in agricultural and textile jobs, and for men in the manufacture of dyes and pigments may deserve further attention.
Keywords Neoplasms, pancreas, chemistry, textile industry, agriculture, dyes, Spain
Accepted 10 May 2000
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Introduction |
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In Spain, uncertainties surrounding occupational cancers are especially large, since few studies exist; none is available for pancreatic cancer.41 Although this neoplasm does not represent one of the major causes of cancer mortality in Spain, its mortality has increased dramatically over the last 40 years, showing the steepest upward trend of all Europe.42 It is unknown to what extent such an increase is related to the accuracy of death certification, changes in lifestyle or other environmental factors.42,43
The purpose of the present study was to identify occupations that, in Spain, may be associated with an increased risk of pancreatic cancer.
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Material and Methods |
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Trained monitors conducted interviews with patients during the hospital stay. The questions concerned clinical history, symptoms preceding admission, occupation and lifestyle. Most interviews were conducted with the patient (88% with the patient alone and 6% with the patient plus a relative). To assess the reliability of responses, a sample of 110 relatives was concurrently and separately interviewed, and high agreement between the two sets of responses was found.44 The study protocol was approved by the Ethics Committee of the participating hospitals, and patients gave their informed consent prior to their inclusion in the study.
Occupational exposures
Patients were asked if they had ever worked in any of ten activities a priori defined as potentially related to pancreas and biliary cancers, according to a review of the literature. These were pesticide use, handling of petroleum derivatives, the chemical industry, the metal industry, rubber industry, graphic arts, jewellery, manufacture or repair of automobiles, leather tanning, and the textile industry. When the patient reported having worked in any of such activities, he/she was asked for the duration of exposure, particular activity, and products to which he/she had been exposed. In addition, they were asked about any other activity performed for at least 6 years. The occupations obtained were coded according to the Spanish National Classification of Occupations 1994 (CNO94), which is adapted from the International Standard Classification of Occupations 1988.
Statistical analysis
The risk for pancreatic cancer was estimated for any occupation held for at least one year. Job titles were initially examined based on one-digit major occupational groups and two-digit subcategories. Risks for the a priori high-risk occupations were further assessed by duration of exposure and by applying a period analysis.
Univariate statistics were computed as customary.4451 Odds ratios (OR) were calculated to estimate the magnitude of associations between each occupational exposure and pancreatic cancer. The associations were explored separately for men and women. Multivariate-adjusted OR and 95% CI were estimated by unconditional logistic regression. The following potential confounders were included in the models: age (quartiles), hospital, smoking (five categories: non-smoker and quartiles for pack-years), coffee consumption (number of weekly cups during the year prior to the first symptom), and alcohol use (non-drinker, occasional, low consumption, high consumption and heavy drinker).52 Allowance for other potential confounding variables (e.g. schooling, diabetes) did not substantially modify any of the estimates. If the observed number of people in one cell of the contingency table was zero, the Woolf-Haldane correction was applied.53 The level of statistical significance was set at 0.05 and all tests were two-tailed.
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Results |
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Table 2 shows the risk estimators for pancreatic cancer according to gender for all major occupational groups (one-digit), and for subgroups (two-digit) with at least four exposed subjects. In men, a 2.6-fold increase in risk of pancreatic cancer was found for general managers and government administrators. This association was stronger within the subgroup working proprietors (wholesale and retail trade) (OR = 12, 95% CI : 0.9157). For the major group support technicians and professionals an OR of 2.1 was observed (95% CI : 0.76.0), which rose to 20 (95% CI : 1.8228) within the subgroup of physical, chemistry and engineering science technicians, the only subgroup whose increase in risk was statistically significant. Non-significant twofold increased risks were found for support professionals in financial and commercial operations, supervisor of stationary machinery operators, and machinery fitters and machine assemblers. Slight increases were observed among skilled workers in agricultural activities, unskilled workers in agriculture and fishing, and unskilled construction workers. In women, OR were elevated in skilled workers in agricultural activities (OR = 2.2, 95% CI : 0.86.2) and unskilled manufacturing industry workers (OR = 4.2, 95% CI : 0.629) (Table 2
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Results by duration of employment are shown in Table 3. In men, the association observed for physical, chemistry and engineering science technicians remained unchanged (all exposed subjects had worked for at least 20 years). Job titles associated with a higher socioeconomic status (general managers and government administrators and trade agents) showed increased OR when considering long duration of the activity. The same pattern was apparent for construction-related occupations (structural building workers, construction machinery operators, and unskilled construction workers), and among painters, supervisors of stationary machinery operators, and machinery mechanics and fitters. High increases in risk were found when working less than 20 years as metal moulders, sheet-metal workers, structural metal workers, welders and related workers, or as machinery operators in the manufacture of dyes and pigments. While self-employed skilled workers in agricultural activities did not show any increase in risk, there were some indications of an association among those who performed their activity as employees. In women, increased OR were observed for any duration of exposure among skilled workers in agriculture and only for longer than 20 years of duration in textile and garment work (OR = 11, 95% CI : 1.0135).
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Discussion |
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The increased risk of pancreatic cancer in agricultural workers was more consistent among women than among men, since among the latter an association was observed only among those who carried out their activity as employees but not among men who were self-employed. Lack of this association cannot be attributed to low statistical power, since the probability of detecting an OR of 2.5 among men was 90%.
Some authors have reported statistically significant risks of pancreatic cancer in agricultural and related occupations. In 1976 and in 1983, Milham23 observed such risk among nurserymen in Washington. Alavanja et al.14 found an OR of 2.2 in workers employed in flour mills. And in 1992, Garabrant et al.13 reported a dose-response relationship in a cohort of workers manufacturing DDT. Later, several other studies have reported associations between pancreatic cancer and pesticide exposure,6,1517,1922 although most lacked information about the specific type of pesticide used. Other studies found non-significant increases in the risk of pancreatic cancer in agricultural workers.18,24 A recent meta-analysis4 reported a meta-risk ratio of 1.5 (95% CI : 0.63.7) for organochlorine insecticides. A different meta-analysis evaluating cancer risk among farmers reported a slightly increased meta-relative risk for pancreatic cancer only when considering proportional mortality studies and case-control studies.54 Several studies5560 among workers manufacturing pesticides did not find increased risks, although none had a substantial number of cases with histological confirmation. Diagnostic misclassification for pancreatic cancer has been shown to seriously bias risks.13,6166 The prospective identification of cases and the in-depth review of diagnoses performed in our study45,49 greatly reduced the potential for diagnostic misclassification. Some epidemiological studies on pesticides may also have underestimated risks because of the difficulty of estimating cumulative personal exposure. Serum levels may provide accurate estimates of individual internal dose for persistent compounds.67,68 Thus, our findings on organochlorine compounds46 may also deserve attention from an occupational perspective; we reported that cases of pancreatic cancer were more likely to have serum concentrations of p,p-DDE than controls (multivariate-adjusted OR for upper versus lower tertile: 5.6 [95% CI : 1.324.6], P for trend 0.025).46
In agreement with other reports, the other important association found among women in our study was for textile workers.6,23,28,32,38,39
Physical, chemistry and engineering science technicians, and machinery operators in the manufacture of dyes and pigments showed the strongest associations among men in the present study. The latter group included workers potentially exposed to pigments and anilines. Some of these compounds are aromatic amines, known to be pancreatic carcinogens in animal models, and it has been suggested that they may play a role in human pancreatic cancer as well.69 Mack et al.5 also reported an RR above 2 (95% CI : 0.95.2) in workers handling dyes and, within a cohort of workers processing synthetic resins,70 an OR of 7 (P < 0.05) was detected among those employed for more than 16 years in vinyl and polyethylene production. Furthermore, in a Finnish study,6 a cluster of six cases (and no referents: indeterminate OR, P = 0.0004) was observed when pooling the similar branch categories synthetic resins, plastic materials and synthetic rubber and plastic products not elsewhere classified. Male and female Finnish hairdressers may also be at increased risk.71
We also observed an association with metal moulders and welders and related workers. A recent case-control study in China38 reported a threefold increased risk for pancreatic cancer among plumbers and welders. Similarly, Norell et al.31 found an increased OR for pancreatic cancer in individuals exposed to welding materials, although not in welders. The association found among painters in our study could be due to exposure to some pigments or to solvents. Some studies6,31 have seen an excess of pancreatic cancer among painters, whereas others have not.72,73
Weak associations were apparent for different job titles related to building construction. Other studies have reported increased risks among cement finishers,6,74 bricklayers,34 cranemen and derrickmen,23,34,75 and construction workers.38,76 Another association observed in the present study, although weak, concerns general managers. Studies that made similar observations have invoked chance or methodological caveats,6,28 since no explanation was forthcoming.
Occupations that showed an increased risk when considering long duration of exposure were also found to increase risk in the period 515 years before the diagnosis. This period is deemed critical in pancreatic carcinogenesis.1,911,46
The presence of heterogeneous exposures to agents in relatively broad occupational groups is another limitation of job title-based studies. Analyses based on an assessment of occupational histories by industrial hygienists are the subject of a separate report.77
Additional methodological issues should be considered in the interpretation of the results. Most pancreatitis is due to alcohol abuse or to obstruction of the pancreatic ducts.78 Occupation plays a small or null role in the aetiology of the pathologies of controls,7781 more than half of whom suffered from chronic or acute pancreatitis. The possibility that pancreatitis increases the risk of pancreas cancer or that the two entities share some risk factors,1,9,8284 would tend to mask the associations. However, after excluding from the referent group patients with pancreatitis, risk estimators were hardly modified. Also, the main results were adjusted for alcohol and smoking. The main advantages8587 of using subjects with other pathologies included in the PANKRAS II Study as a referent group are: (1) a decrease in potential interviewer bias, (2) economic efficiency, and (3) an increase in the specificity of the relationship between the exposure of interest and pancreatic cancer (versus other pancreatic diseases). Furthermore, because of the diagnostic suspicion criterion for entry into the study, all cases and referents followed a highly similar referral and diagnostic pathway; this maximized the likelihood that all subjects stemmed from a common study base. Other important case-control studies on pancreatic cancer and occupation used hospital controls,32 cancer controls,16,22 or both.28
A main strength of the study is that around 90% of subjects had occupational data. In addition, over 90% of interviews in cases and controls were performed directly with the patient. These figures are seldom achieved in pancreatic cancer, and are a consequence of the prompt identification of cases with putative diagnoses.
The diversity of occupations assessed may raise two concerns. First, in some occupations the number of exposed cases was low, which yielded some imprecise estimates and precluded examination of exposures related to the aluminium industry35,36 and dry cleaning.9 It was also impracticable to explore interactions among occupations and lifestyle factors. Interactions may be particularly relevant for occupational compounds with a potential to act as tumour promoters.43,46 The second concern is multiple testing. To minimize this, our analyses were closely linked to substantive hypotheses and results from previous studies.
This report stems from the first study investigating the role of occupation in pancreatic cancer in Spain. The observed associations are in accordance with results from previous studies. In spite of the study limitations, the increases in risk observed in agricultural and textile workers in women, and for men working in the manufacture of dyes and pigments may deserve further attention.
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Acknowledgments |
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