Risk of pancreatic cancer and occupational exposures in Spain

PII: S0003-4878(99)00119-2

Ann. occup. Hyg., Vol. 44, No. 5, pp. 391±403, 2000 7 2000 British Occupational Hygiene Society Published by Elsevier Science Ltd. All rights reserved Printed in Great Britain. 0003±4878/00/$20.00

Risk of Pancreatic Cancer and Occupational Exposures in Spain JUAN ALGUACIL$, TIMO KAUPPINEN%, MIQUEL PORTA$}*, TIMO PARTANEN%, NUÂRIA MALATS$}, MANOLIS KOGEVINAS$}, FERNANDO G. BENAVIDES$k, JORDI OBIOLS}, FEÂLIX BERNAL}, JULI RIFAÁ$$ and ALFREDO CARRATO%%, PANKRAS II Study Group, }} $Institut Municipal d'Investigacio MeÁdica, Carrer del Dr. Aiguader 80, E-08003 Barcelona, Spain; %Finnish Institute of Occupational Health, Helsinki, Finland; }Universitat AutoÁnoma de Barcelona, Barcelona, Spain; kUniversitat Pompeu Fabra, Barcelona, Spain; }Instituto Nacional de Seguridad e Higiene en el Trabajo, Barcelona, Spain; $$Hospital Son Dureta, Mallorca, Spain; %%Hospital General de Elche, Alicante, Spain. The objective of the study was to analyse the relationship between occupational exposures and risk of pancreatic cancer. Incident cases of pancreatic cancer and hospital controls were prospectively identi®ed and interviewed during the hospital stay. Occupational history was obtained by direct interview with the patient, and was available for 164 (89%) of 185 pancreatic cancer cases, and 238 (90%) of 264 controls. Two industrial hygienists evaluated exposures to 22 suspected carcinogens previously associated with pancreatic cancer. Occupational exposures were also assessed using the Finnish job-exposure matrix (FINJEM). For each type of pesticide group, moderately increased odds ratios (OR) were apparent in the high-intensity category, highest for arsenical pesticides …OR ˆ 3:4; 95% CI 0.9±12.0), and `other pesticides' …OR ˆ 3:17; 95% CI 1.1±9.2). ORs for aniline derivatives, and dyes and organic pigments, were also higher for high-intensity exposure, and increased when lagged and restricted to long duration of exposure. ORs above 3 were observed for the following agents evaluated by FINJEM: pesticides, benzo[a ]pyrene, lead, volatile sulphur compounds, and sedentary work. Whilst generally negative, results lend moderate support to the hypothesis of an association between exposure to some pesticides and pancreatic cancer. Larger studies could address the potential for these compounds to modify the carcinogenic risk of other environmental exposures. Suggestive increases in risk from aniline derivatives, dyes and organic pigments, and benzo[a ]pyrene may also deserve further attention. 7 2000 British Occupational Hygiene Society. Published by Elsevier Science Ltd. All rights reserved. Keywords: neoplasms; pancreas; FINJEM; pesticides; dyes; solvents; benzo[a ]pyrene; cancer

INTRODUCTION

The aetiology of exocrine pancreatic cancer remains Received 18 June 1999; in ®nal form 3 November 1999. *Author to whom correspondence should be addressed. Tel.: +34-93-225-7553/+34-93-221-1009; fax: +34-93221-3237; e-mail: [email protected] }}Members of the Multicentre Prospective Study on the Role of the K-ras and other Genetic Alterations in the Diagnosis, Prognosis and Etiology of Pancreatic and Biliary Diseases (PANKRAS II) Study Group are listed in the Appendix. 391

very poorly understood, with smoking being the only ®rmly established risk factor. Factors suspected of slightly increasing susceptibility or of causing moderate increases in risk include diabetes, chronic pancreatitis and some dietary components. Although occupational cancer studies have suggested a number of associations, most ®ndings are non-speci®c or inconsistent (Anderson et al., 1996; Weiderpass et al., 1998). Garabrant et al. (1992) reported a strong relationship between pancreatic cancer and pesticides in a cohort of workers involved in the production of DDT. Subsequently,

392

J. Alguacil et al.

several studies (Blair et al., 1993; Forastiere et al., 1993; Friedman and Van den Eeden, 1993; Partanen et al., 1994; Kauppinen et al., 1995; Fryzek et al., 1997; Cerhan et al., 1998; Cantor and Silberman, 1999) have reported statistically signi®cant excesses of pancreatic cancer in occupations entailing exposure to pesticides. Recent reviews have argued a link with pancreatic cancer for hydrocarbon solvents (Weiderpass et al., 1998; OjajaÈrvi et al., 2000), and for metal-working ¯uids (Calvert et al., 1998). In Spain the age-standardized mortality rate for pancreatic cancer is 8.92 deaths per 100 000 in men and 5.71 in women (LoÂpez-Abente et al., 1997). Between 1955 and 1989, these rates increased 279% in men and 164% in womenÐthe steepest change throughout Europe (Fernandez et al., 1994). Knowledge of the occupational determinants of pancreatic cancer is especially scant in Spain, where few studies have explored occupation as a risk factor for cancer in general and, to date, there are no studies on pancreatic cancer in particular. Spanish workers, along with Greeks and Portuguese, work under the least favourable conditions in the European Union, including inhaling and handling many hazardous substances (EFILWC, 1997). The primary purpose of the present study was to analyse the association between risk of pancreatic cancer and occupational exposures previously associated with this neoplasm. Occupational histories and occupational exposure information were obtained from direct interviews of patients, and were further evaluated by industrial hygienists. We also explored the association for some additional agents and exposures through the Finnish job-exposure matrix (FINJEM). MATERIAL AND METHODS

Subjects The PANKRAS II study was conducted between 1992 and 1995 at ®ve general hospitals in the eastern part of Spain. Incident cases of pancreatic cancer …N ˆ 185† and hospital controls …N ˆ 264† were prospectively identi®ed and interviewed during their hospital stays (Porta et al., 1999a, 1999b; Soler et al., 1998, 1999; GavaldaÁ et al., 1995). Controls were subjects free of pancreatic cancer who had been admitted to the same hospitals as cases with an initial diagnostic suspicion of pancreatic cancer, biliary cancer or chronic pancreatitis. Cases and controls were recruited concurrently. After completion of patient recruitment, the diagnosis of all patients was reviewed by a panel of experts using all clinical and pathological information available (Soler et al., 1998). Occupational histories were obtained for 164 (88.6%) of cases and for 238 (90.2%) of controls. Controls included 93 patients with chronic pancreatitis, 34 with acute pancreatitis,

70 with other benign pathologies (mainly, biliary pathology), and 41 with other cancers: lymphoma …N ˆ 8), periampullary neoplasm (7), abdominal digestive neoplasm of unspeci®ed origin (6), stomach (5), metastasis (5), colon (4), lung (2), liver (2), small intestine (1) and oesophagus (1). Trained monitors conducted interviews with patients during their hospital stays. The questions concerned clinical history, symptoms preceding admission, occupational history, and life-style. 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 relatives was concurrently and separately interviewed, and agreement between the two sets of responses was compared …N ˆ 110 pairs) (GavaldaÁ et al., 1995). Main characteristics of cases and controls are shown in Table 1. Pancreatic cancer cases were on average about six years older than controls. Women constituted 42% of the pancreatic cancer group and less than 30% of controls, whereas education was similar in the two groups. Alcohol consumption …P < 0:05† and smoking …P ˆ 0:09† were lower in pancreatic cancer cases. The consumption of co€ee was fairly similar. These distributions remained practically unchanged after strati®cation by gender. Occupational exposures Participants were asked if they had ever worked in any of ten activities a priori de®ned to be potentially related with pancreas and biliary cancers, according to a review of the literature: pesticide use, handling of petroleum derivatives, chemical industry, metal industry, rubber industry, graphic arts, jewellery, manufacture or repair of automobiles, leather tanning, and textile industry. Participants who reported having worked in any of such activities were asked for the duration of employment, speci®c activity, and products to which they had been exposed. Two additional questionnaire sections were reserved for any other activity performed for at least six years. The industrial hygienists were also given information about the ages at which subjects started and stopped schooling, and about the calendar year and the place of residence. The median numbers of occupations reported by men and women were 2 and 1, respectively …P < 0:01). Among cases, 46% of participants reported having worked as `unskilled workers' (45% among controls), 27% as `skilled workers' (controls, 33%), almost one-third as `machinery operators' (controls, 39%), and over 25% as farmers (20% of controls). Among women, almost one-third of cases had exclusively been housewives (18% among controls). Di€erences in the distribution of age, gender and study centre between participants who provided occupational information and those who did not were negligible.

Occupation and pancreatic cancer in Spain

Using all the information about occupational exposures collected in the questionnaire, two industrial hygienists of the National Institute of Occupational Safety and Hygiene (INSHT) of Barcelona evaluated exposures to 22 suspected carcinogens (see Table 2). They coded exposure as exposed, unexposed, or unknown. Exposed required a substantiated source of exposure. If exposure was unsubstantiated but possible, the category `unknown' was used. The intensity of the exposure was coded as high, low, unknown, or none. The industrial hygienists developed algorithms for the exposure assessment. Two occupational epidemiologists evaluated and accepted the algorithms. In addition, we used the FINJEM (Kauppinen et al., 1998) to explore occupational exposure to 21 chemical agents, four physical exposures, and two ergonomic exposures. Twelve of the chemical agents and one physical exposure were in the list of agents

393

covered by the Spanish hygienists. The exposure categories used were substantial, low, and unexposed. The cut-o€ point between low and substantial was set as close as possible to the 75th percentile of the distribution of the product of the probability of exposure (range 0.06±1) and the intensity of exposure (mostly in mg mÿ3 or in ppm). Statistical analysis Univariate statistics were computed as customary (Armitage and Berry, 1994; Porta et al., 1999a). Odds ratios were calculated to estimate the magnitudes of associations between each occupational exposure and pancreatic cancer. Multivariate-adjusted odds ratios (OR) and 95% con®dence intervals (CI) were estimated by unconditional logistic regression. The following potential confounders were included

Table 1. Socio-demographic characteristics and life-style factors of cases and controls Exocrine pancreatic cancer N Number of subjects

(%)

164

Controls N

(%)

238

Age Mean [SD]

66.9

[12.5]

Gender Men Women

96 68

(58.5) (41.5)

167 71

(70.2) (29.8)

Hospital Elche Hospital del Mar Mallorca Vall d'Hebron MuÂtua de Terrassa

27 18 47 43 29

(16.5) (11.0) (28.7) (26.2) (17.7)

29 72 22 79 36

(12.2) (30.3) (9.2) (33.2) (15.1)

Education Unknown Illiterate Able only to read and write Up to 10 years of schooling Schooling for >10 years

2 19 43 85 15

(1.2) (11.6) (26.2) (51.8) (9.1)

4 29 46 131 28

(1.7) (12.2) (19.3) (55.0) (11.8)

Smoking Never 1±25 pack-years 26±40 pack-years 41±60 pack-years > 60 pack-years

72 27 24 21 20

(43.9) (16.5) (14.6) (12.8) (12.2)

77 34 43 49 34

(32.5) (14.3) (18.1) (20.7) (14.3)

Alcohol Non-drinker Occasional drinker Low consumption High consumption Heavy drinker

24 19 54 31 36

(14.6) (11.6) (32.9) (18.9) (22.0)

30 10 48 43 106

(12.7) (4.2) (20.3) (18.1) (44.7)

24 140

(14.6) (85.4)

27 210

(11.4) (88.6)

Co€ee Non-regular drinkers Regular co€ee drinkers

61.0

[15.4]

394

J. Alguacil et al.

in the models: age (four-category ordinal scale), gender, hospital (®ve), smoking (®ve categories: non-smoker and quartiles for pack-years), and alcohol use (non-drinker, occasional, low consumption, high consumption and heavy drinker) (Paton and Saunders, 1981). Allowance for other potential confounding variables (that is schooling, co€ee, and diabetes) did not substantially modify the estimates. Strati®ed analysis for gender was performed when the ensuing number of exposed cases was three or higher. The level of statistical signi®cance was set at 0.05, and all tests were two-tailed. RESULTS

Results based on the exposure assessment by hygienists are presented in Table 2. Some agents previously found associated with pancreatic cancer showed indications of an elevated risk. This was so for each type of pesticides, the highest increases in risk being for arsenical pesticides (88%) and `other pesticides' (86%). There was a high correlation between exposure to di€erent pesticides. Among

cases, 63% of those exposed to any pesticide were also exposed to all pesticides (33% among controls), and 92% of those exposed to arsenical pesticides were also exposed to the rest of pesticides (100% among controls). Most subjects exposed to organophosphate pesticides were also exposed to organochlorine pesticides used in the treatment of fruit, vineyards and cotton, and in dry farming and orcharding. The main organochlorine pesticides used were the insecticides lindane and endosulphan, and the acaricide dicofol, while the most common organophosphate pesticides were glyphosate, chlorpyrifos, dimethoate, and azinphos methyl. In the past, arsenical compounds were mainly used as insecticides (arsenates) for fruit crop protection and antifungics (arsenites, even at present) for vine protection and as rodenticides. `Other pesticides' included paraquat, diquat, carbamates, and inorganic copper compounds. When both genders were considered together, no excess was found for any organic solvent. Among women, however, excesses were found for aromatic and for aliphatic hydrocarbon solvents …OR ˆ 2:84,

Table 2. Occupational exposures and risk of exocrine pancreatic cancer. Estimates based on industrial hygienists assessment of exposure

Agent Any pesticideb Organochlorine pesticides Organophosphate pesticides Arsenical pesticides Other pesticides All pesticidesc Hydrocarbon solventsd Aliphatic hydrocarbon solvents Aromatic hydrocarbon solventse Benzene Chlorinated hydrocarbon solvents Other organic solvents Aluminium Hexavalent chromium compounds Trivalent chromium compounds Nickel compounds Lead Dyes and organic pigments Aniline derivatives Other inorganic pigments Asbestos Ionizing radiation Polycyclic aromatic hydrocarbons (PAH) Cotton dust Cutting oils

Pancreatic cancer

Controls

NEPa

NEPa

ORa

95% CIa

19 16 17 13 16 12 39 32 33 22 2 12 2 19 17 1 8 10 6 2 1 1 13 9 4

21 17 19 7 14 7 68 62 65 34 2 32 3 26 25 0 28 11 5 9 2 0 34 22 8

1.23 1.20 1.27 1.88 1.86 1.78 0.93 0.90 0.80 0.93 2.23 0.68 2.14 1.47 1.32 ± 0.56 1.13 1.35 0.60 1.34 ± 0.81 0.59 0.73

(0.58±2.64) (0.53±2.74) (0.57±2.83) (0.66±5.35) (0.77±4.47) (0.62±5.15) (0.54±1.61) (0.50±1.59) (0.46±1.41) (0.47±1.83) (0.21±23.9) (0.31±1.46) (0.29±16.1) (0.68±3.18) (0.60±2.95) ± (0.22±1.42) (0.42±3.04) (0.36±5.11) (0.11±3.17) (0.09±19.6) ± (0.37±1.76) (0.24±1.44) (0.19±2.77)

a NEP: number of exposed patients; OR: odds ratio; CI: con®dence interval. Adjusted for sex, age, hospital, and consumption of alcohol and of tobacco. b Includes exposure to any of the following types of pesticides: organochlorine, organophosphate, arsenical, other pesticides. c Includes exposure to each one of the following types of pesticides: organochlorine, organophosphate, arsenical, other pesticides. d Includes chlorinated hydrocarbon solvents, aromatic hydrocarbon solvents and aliphatic hydrocarbon solvents. e Except benzene.

147 16 151 12 148 14 152 11 125 18 21 152 9

Organophosphate pesticides Non-exposed High

Arsenical pesticides Non-exposed High

Other pesticides Non-exposed High

All pesticidesd Non-exposed High

Hydrocarbon solventse Non-exposed Low High

Other organic solvents Non-exposed High

Chromium compounds Non-exposed Low High 145 17 2

148 15

Organochlorine pesticides Non-exposed High

f

145 17

Pancreatic cancer NP

Any pesticideb Non-exposedc High

Agent and intensity

211 25 1

205 27

169 28 40

230 3

223 7

230 4

218 13

220 11

216 14

Controls NP

1 1.32 4.49

1 0.69

1 0.92 0.94

1 3.57

1 3.17

1 3.35

1 1.80

1 1.75

1 1.73

OR

Ever exposed at least 6 monthsa

(0.59±2.95) (0.37±54.3)

(0.29±1.64)

(0.44±1.94) (0.48±1.85)

(0.91±14.0)

(1.09±9.18)

(0.94±12.0)

(0.75±4.30)

(0.70±4.39)

(0.74±4.04)

95% CI

145 13 0

152 6

125 12 16

152 8

148 9

151 9

147 9

148 10

145 10

Pancreatic cancer NP

211 15 0

205 17

169 18 29

230 3

223 5

230 4

218 8

220 8

216 8

Controls NP

(0.57±4.00) ±

(0.26±2.20)

(0.35±2.05) (0.38±1.78)

(0.46±8.05)

(0.56±6.79)

(0.50±7.42)

(0.39±3.68)

(0.41±3.69)

(0.43±3.86)

95% CI

(continued on next page)

1 1.51 ±

1 0.76

1 0.85 0.83

1 1.92

1 1.95

1 1.92

1 1.20

1 1.23

1 1.28

OR

Exposed at least 10 years, 10 years before diagnosisa

Table 3. Risk estimates by intensity of occupational exposure. Based on industrial hygienists' assessment of exposures

Occupation and pancreatic cancer in Spain 395

154 5 5 158 5 151 10 3 155 7

Dyes and organic pigments Non-exposed Low High

Aniline derivatives Non-exposed High

Polycyclic aromatic hydrocarbons (PAH) Non-exposed Low High

Cotton dust Non-exposed High 215 19

203 28 6

232 3

226 6 5

209 22 6

1 0.46

1 0.74 1.11

1 1.77

1 1.00 1.30

1 0.58 0.47

OR

(0.17±1.22)

(0.31±1.77) (0.24±5.21)

(0.36±8.57)

(0.27±3.71) (0.32±5.27)

(0.21±1.59) (0.05±4.40)

95% CI

155 3

151 8 2

158 5

154 3 4

156 5 1

Pancreatic cancer NP

215 13

203 17 2

232 2

226 1 2

209 13 4

Controls NP

1 0.29

1 1.08 1.73

1 2.58

1 2.95 2.20

1 0.74 0.57

OR

(0.07±1.13)

(0.39±3.00) (0.22±13.8)

(0.43±15.3)

(0.27±32.1) (0.35±13.7)

(0.21±2.53) (0.06±5.77)

95% CI

Exposed at least 10 years, 10 years before diagnosisa

a NP: number of patients; OR: odds ratio; CI: con®dence interval. Ind.: Indeterminate. Adjusted for sex, age, hospital, and consumption of alcohol and tobacco. ORs for low intensity are not reported if the number of cases and controls exposed was less than 5. b Includes exposure to any of the following types of pesticides: organochlorine, organophosphate, arsenical, other pesticides. c Reference category …OR ˆ 1). d Includes exposure to each one of the following types of pesticides: organochlorine, organophosphate, arsenical, other pesticides. e Includes chlorinated hydrocarbon solvents, aromatic hydrocarbon solvents and aliphatic hydrocarbon solvents. f Includes hexavalent and trivalent chromium compounds.

156 7 1

Controls NP

Ever exposed at least 6 monthsa

Pancreatic cancer NP

Lead Non-exposed Low High

Agent and intensity

Table 3 (continued )

396 J. Alguacil et al.

56% of working hours 70% of working hours

Ergonomic exposures Perceived physical workload Sedentary workd

26 4

30 9 0 6

1 3 12 6 0 0 4 4 8 0 4 6 0 3 3 3 2 3 2 6 0

NEP

29 2

30 10 0 8

7 2 14 4 3 0 8 4 14 0 4 4 0 5 8 6 3 9 5 4 5

NEP

Controlsa

1.00 3.19

1.44 0.97 ± 1.30

0.36 3.15 1.57 3.10 0.00 ± 0.71 2.39 1.24 ± 2.42 3.25 ± 1.44 0.48 0.47 0.78 0.64 0.46 4.34 0.00

OR

c

b

NEP: number of exposed patients; OR: odds ratio; CI: con®dence interval. Ind.: Indeterminate. Adjusted for sex, age, hospital, and consumption of alcohol and of tobacco. Includes aliphatic, alicyclic, aromatic, or chlorinated hydrocarbon solvents. Includes exposure to any of the following types of pesticides: insecticides, herbicides and fungicides. d Work done in seated posture, measured by subjective rating in questionnaire surveys.

a

15% of working hours 3% of working hours ± 0.39 mT

12.58 ppm 0.02 mg mÿ3 0.19 ®bres cmÿ3 0.01 mg mÿ3 0.49 mg mÿ3 0.41 mg mÿ3 10.67 mg mÿ3 0.47 mg mÿ3 0.04 ppm 0.10 ppm 6.92 mg mÿ3 0.25 mmol l.ÿ1 ± 1.03 mg mÿ3 1.80 mg mÿ3 11.49 ppm 0.35 mg mÿ3 0.52 mg mÿ3 1.00 mg mÿ3 0.37 ppm 1.00 mg mÿ3

Cut-o€ point between the `low' and `substantial' exposure categories

Physical exposures Cold Heat Ionizing radiation Low-frequency magnetic ®elds

Chemical agents Any hydrocarbon solventb Any pesticidec Asbestos Benzo(a )pyrene Bitumen fumes Cadmium Chromium compounds Diesel engine exhaust Formaldehyde Gasoline Gasoline engine exhaust Lead Leather dust Nickel Oil mist Other organic solvents Polycyclic aromatic hydrocarbons (PAH) Synthetic polymer dust Textile dust Volatile sulphur compounds Wood dust

Agents and exposures

Pancreatic cancera

(0.50±2.01) (0.53±19.4)

(0.74±2.80) (0.34±2.71) ± (0.38±4.41)

(0.04±3.40) (0.35±28.4) (0.58±4.25) (0.73±13.2) (0.00±Ind.) ± (0.18±2.73) (0.50±11.4) (0.45±3.42) ± (0.51±11.6) (0.73±14.4) ± (0.29±7.24) (0.11±2.08) (0.09±2.44) (0.12±5.18) (0.15±2.69) (0.08±2.63) (0.92±20.5) (0.00±Ind.)

95% CI

Table 4. Risk estimates for exocrine pancreatic cancer and substantial exposure during at least 10 years, 10 years before the diagnosis. Based on exposure assessment by FINJEM

Occupation and pancreatic cancer in Spain 397

398

J. Alguacil et al.

95% CI 0.47±17.2; and OR ˆ 6:7, 95% CI 0.67± 67.4, respectively). Among all participants (cases and controls combined, since there were no major di€erences), 29% of those exposed to `hydrocarbon solvents' were also exposed to `any pesticide' (25% to organochlorine pesticides), while 78% of those exposed to `any pesticide' were also exposed to `hydrocarbon solvents'. Almost 95% of participants exposed to aromatic hydrocarbon solvents were also exposed to the aliphatic hydrocarbon solvents. Occupations involving use of solvents in our study were: farmers, machine and engine mechanics, sheet-metal workers, service station attendants, machine-tool setters and painters. ORs for chromium compounds were increased, men being most exposed. The main source of exposure to chromium compounds was dermal contact with the impurities of cement in construction work (17 of 19). Exposure to hexavalent and trivalent chromium compounds was highly correlated. Small increases in risk were apparent for aniline derivatives and for dyes and organic pigments. Ten of the eleven participants exposed to aniline derivatives were included among the 21 individuals exposed to dyes and organic pigments. Job titles among cases exposed to aniline derivatives were: manufacture of dyes, textile workers, dry cleaners, and shoemakers. For dyes and organic pigments, jobs included textile ironing, leather tanning, a hairdresser and a ceramic decorator. Several agents previously reported to be associated with pancreatic cancer (lead, cotton dust, cutting oils) did not show increased ORs. Few cases and controls had been exposed by industrial hygienists to chlorinated hydrocarbon solvents, aluminium, nickel, asbestos, and ionizing radiation. Table 3 shows the results according to the intensity of occupational exposure. Agents with fewer than ®ve exposed cases were excluded from this analysis. ORs for low intensity are not reported if the number of exposed cases was less than ®ve. Table 4 shows the ORs for substantial exposure to agents and exposures evaluated by FINJEM, with allowance for latency and duration of the exposure. For each type of pesticide increased risks were observed for the high-intensity category (the ORs were above three for `all pesticides', arsenical pesticides, and `other pesticides') (Table 3). The OR for pesticides from FINJEM was also above three for the substantial exposure category (Table 4). When patients with chronic or acute pancreatitis were excluded from the control group, the associations tended to decrease slightly, increasing only for hydrocarbon solvents (values close to unity). In the analysis for both genders combined, the relative risk for each type of solvent was consistently slightly less than one. There were no di€erences between the ORs for high and low intensity, with and without allowance for latency and duration.

The excess for hydrocarbon solvents in women disappeared when exposures where lagged by ten years. The results for solvents by FINJEM (Table 4) indicated no association with pancreatic cancer. ORs for aniline derivatives, and dyes and organic pigments were higher for high-intensity exposure, and increased when lagged and restricted to long duration of exposure (ORs > 2, Table 3). A threefold increased risk for benzo[a ]pyrene for the FINJEM substantial exposure category was observed (Table 4). Job titles among cases for this category of exposure were: machine and engine mechanics, smiths, and foundry moulders. While estimates based on the assessment of industrial hygienists were close to one for lead compounds, the FINJEM approach resulted in a threefold increase in men when exposures where lagged by ten years. No excess was observed for either cotton dust by hygienists or textile dust by FINJEM. While the Spanish hygienists considered only three subjects as exposed to asbestos, the FINJEM classi®ed 15 cases and 23 controls in the substantial exposure category. This may re¯ect di€erent sources of exposure to asbestos among Spanish and Finnish workers, and di€erences in sensitivity between the approaches. Among the exposures evaluated only with FINJEM, an association was apparent for volatile sulphur compounds (Table 4). Among the ergonomic factors, sedentary work (work done in a seated posture) showed an increased OR for substantial exposure, mainly among women …OR ˆ 3:19, 95% CI 0.53±19.4); the ®gure remained unchanged after lagging for 20 and 30 years.

DISCUSSION

The results of this study lend only moderate support to the hypothesis of an association between exposure to some pesticides and pancreatic cancer. There were indications of an elevated risk among workers exposed to aniline derivatives, dyes and organic pigments, and benzo[a ]pyrene. No association was apparent for any organic solvent or cutting oils. However, the number of subjects was small, and caution should be used in the interpretation of all estimates. A moderate number of occupational exposures was assessed; they had been chosen a priori based on the available scienti®c evidence. Most subjects exposed to pesticides were farmers, and confounding from other potentially carcinogenic agents in farming is conceivable. However, no excess was evident for fuels, engine exhaust, and solvents. Adding these three agents to multivariate models did not materially change the ORs for any group of pesticides. The strongest associations were found for arsenical pesticides and for `other pesticides'. Only one study appears to have assessed

Occupation and pancreatic cancer in Spain

pancreatic cancer and arsenical pesticides, and the association was weak (Tollestrup et al., 1995). Some studies reported signi®cant excesses of pancreatic cancer in agricultural and related occupations, but most lacked information on the speci®c type of pesticide used (Milham, 1983; Alavanja et al., 1990; Garabrant et al., 1992; Blair et al., 1993; Forastiere et al., 1993; Friedman and Van den Eeden, 1993; Partanen et al., 1994; Kauppinen et al., 1995; Fryzek et al., 1997; Cerhan et al., 1998; Cantor and Silberman, 1999). Other studies found remarkable increases in pancreatic cancer risk among agricultural and related workers (Falk et al., 1990; Siemiatycki et al., 1991; FigaÁ-Talamanca et al., 1993; Zhong and Rafnsson, 1996; Zahm, 1997). The ®nding of a signi®cant ecologic correlation between incidence rates for pancreatic cancer and amount of garden refuse suggested pesticide exposure as a possible explanation (Schwartz et al., 1998). A recent meta-analysis evaluating cancer among farmers reported slightly increased meta-RR for pancreatic cancer when considering only PMR studies or case-control studies, while the meta-RR for cohort studies was clearly below unity (Acquavella et al., 1998). Furthermore, there are at least six studies among workers manufacturing pesticides that did not ®nd an increased risk (Wong et al., 1984; Ribbens, 1985; Coggon et al., 1986, 1991; Amoateng-Adjepong et al., 1995; Sathiakumar et al., 1992). There is one caveat, howeverÐnone of the six studies had substantial histological con®rmation, contrary to the reanalysis of Garabrant et al. (1993). Diagnostic misclassi®cation has been shown to seriously bias risk estimates for pancreatic cancer (Garabrant et al., 1993; Malats et al., 1993; Porta et al., 1996). The prospective identi®cation of cases and the in-depth review of diagnoses performed in our study greatly reduced the potential for diagnostic misclassi®cation (Soler et al., 1998). There is `sucient evidence' that inorganic arsenic compounds are skin and lung carcinogens in humans (IARC, 1980). IARC (1991) has also concluded that occupational exposure in spraying and application of non-arsenical insecticides entails exposures that are probably carcinogenic to humans (group 2A), while most herbicides and fungicides evaluated have been classi®ed as possibly carcinogenic to humans (group 2B) or not classi®able as to its carcinogenicity to humans. Blair et al. (1992) observed that since several of the tumours seen in immunocompromised subjects appear to be excessive among farmers, it is possible that agricultural exposures a€ect cancer risks through immunologic perturbations. Laboratory evidence supports the hypothesis that some pesticides (for example, dichlorvos, nitrofen) may be pancreatic carcinogens (Blair et al., 1990). It is also possible that some pesticides act as tumour promoters, thus enhancing the e€ect

399

of other carcinogens (Blair et al., 1992; Weiderpass et al., 1998; Porta et al., 1999b). We found a statistically non-signi®cant positive association with pancreatic cancer among workers exposed to aniline derivatives, and dyes and organic pigments. 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 (Anderson et al., 1997). An excess of pancreatic cancer has been reported in some studies entailing exposure to dyes and aniline derivatives (Mancuso and El-Attar, 1967; Depue et al., 1985; Mack et al., 1985; Magnani et al., 1987) and among leather tanners (She€et et al., 1982; Edling et al., 1986; Constantini et al., 1989; Pietri et al., 1990; Mikoczy et al., 1994, 1996). However, this was not so in other cohorts of exposed workers (Delzell et al., 1989; Bulbulyan et al., 1995). The carcinogenic properties of benzo[a ]pyrene are widely known; considering its presence in tobacco smoke (the only well-established risk factor for pancreatic cancer) we ®nd this excess credible, even when exposure to benzo[a ]pyrene was evaluated only by FINJEM. An enhanced risk for benzo[a ]pyrene but not for the rest of PAH is not necessarily in contradiction, since the sources of benzo[a ]pyrene may be di€erent from the rest of PAH. Nadon et al. (1995) found a signi®cant association for pancreatic cancer and benzo[a ]pyrene but a weak association for the total PAH. The review of the epidemiologic evidence of cancer in aluminium reduction plant workers by Ronneberg and Langmark (1992) suggested an association between pancreatic cancer and potroom workers. Sulphur dioxide is deemed `not classi®able as to its carcinogenicity to humans' (group 3) by IARC (1992). Most cases exposed to volatile sulphur compounds were workers in the chemical industry, metal industry or foundries, workplaces entailing exposure to anilines or PAH. Exposure to chromium was mostly due to dermal contact with cement in construction workers. A Finnish study reported an odds ratio of 11 for cement and building materials (Partanen et al., 1994). Sedentary work was consistently associated with excess risk during di€erent periods of latency time and duration of the exposure. Most sedentary workers were women, and in the absence of any other exposure this association might indicate a role for obesity in pancreatic cancer (Friedman and Van den Eeden, 1993; Anderson et al., 1996). Contrary to reported associations between pancreatic cancer and cutting oils (Calvert et al., 1998), and hydrocarbon solvents (Weiderpass et al., 1998; OjajaÈrvi et al., 2000), our data did not show an excess in workers exposed to these compounds. Among the controls there were four patients (1.7%)

400

J. Alguacil et al.

with rectal cancer, a disease perhaps related with exposure to metalworking ¯uids, but only one of them was exposed to cutting oils. A link between solvents and chronic pancreatitis has been reported by some (Foster et al., 1993; McNamee et al., 1994), but not other studies (Orbaek et al., 1985; Hotz et al., 1990). A meta-analysis of cancer among individuals exposed to solvents (Chen and Seaton, 1996) reported increased risks for lymphoma and biliary tract cancer. In our control group, patients with pancreatitis, lymphoma or periampullary malignancies were more exposed to hydrocarbon solvents than the rest of controls. This would tend to dilute a possible association between these compounds and pancreatic cancer. Using subjects included in the PANKRAS II Study as controls resulted in decreased interviewer bias and increased speci®city of the estimates. Because of the diagnostic suspicion criterion for entry into the study, all cases and controls followed the same referral and diagnostic pathway, maximizing the likelihood that all subjects arose from a common study base. A remarkable strength of the study is the high percentage of subjects with occupational histories (around 90%). Other studies on pancreatic cancer relying on personal interviews have achieved response rates of 40±60% (Silverman et al., 1994, 1995; Boyle et al., 1996). In addition, over 90% of our interviews were performed directly with the study subject. The occupational exposures were assessed by industrial hygienists, which is one of the most valid approaches (Siemiatycki et al., 1991). Since cases were interviewed and assessed in the same way as controls, misclassi®cation of exposure would be non-di€erential. The potential for selection bias when using hospital controls is well known in pancreatic cancer. Occupational exposures play a negligible role in the aetiology of diseases a€ecting the controls of our study, most of whom had chronic or acute pancreatitis. It is unclear whether pancreatitis may slightly increase susceptibility to pancreas cancer (Fernandez et al., 1995), or if the two processes share some risk factors (Foster et al., 1993; McNamee et al., 1994); if true, this would tend to dilute the associations. None the less, when patients with chronic or acute pancreatitis (which comprised most of the controls who regularly drank and smoked) were excluded from the control group, the associations decreased only slightly, probably because the main statistical analyses already adjusted for alcohol and smoking. Furthermore, subdividing the control group into `other neoplasms', `pancreatitis', and `other benign pathology' revealed no di€erences among these three groups in the distribution of the occupational exposures, except for exposure to hydrocarbon solvents. Some neoplasms in the controls (lymphomas, stomach cancer) may be associated with agricultural ex-

posures (Acquavella et al., 1998); this might also tend to dilute the observed association for pesticides. Some important case-control studies on the risk of pancreatic cancer associated with occupational exposures have used hospital controls (Falk et al., 1990), cancer controls (Kauppinen et al., 1995; Partanen et al., 1994), or both (Pietri et al., 1990). CONCLUSION

Results lend moderate support to the hypothesis of an association between exposure to some pesticides and pancreatic cancer. Larger studies could address the potential for these compounds to modify the carcinogenic risk of other environmental exposures (Porta et al., 1999b). Suggestive increases in risk from aniline derivatives, dyes and organic pigments, and benzo[a ]pyrene may also deserve further attention. AcknowledgementsÐWe gratefully acknowledge scienti®c advice provided by F.X. Real, L. Guarner, D.J. MacFarlane, A. OjajaÈrvi, A.M. Garcõ a, A. `t Mannetje E. CastejoÂn, J. Guasch and E. Orts. We are also indebted to the following members of our supporting sta€ who were associated with the study: S. Costafreda, J. Gomez, E. Fernandez, L. Ruiz, E. Carrillo, P. Barbas and L. EspanÄol. Partly funded by research grants from Fondo de InvestigacioÂn Sanitaria (92/0007, 95/0017 and 97/1138), FundacioÂn Salud 2000, MSD Spain and Generalitat de Catalunya (CIRIT 1999 SGR 000241 and 1998 / BEAi 400011).

REFERENCES Acquavella, J., Olsen, G., Cole, P., Ireland, B., Kaneene, J., Schuman, S. and Holden, L. (1998) Cancer among farmers: a meta-analysis. Annals of Epidemiology 8, 64± 74. Alavanja, M. C. R., Blair, A. and Masters, M. N. (1990) Cancer mortality in the US ¯our industry. Journal of the National Cancer Institute 82, 840±849. Amoateng-Adjepong, Y., Sathiakumar, N., Delzell, E. and Cole, P. (1995) Mortality among workers at a pesticide manufacturing plant. Journal of Occupational and Environmental Medicine 37, 471±478. Anderson, K. E., Potter, J. D. and Mack, T. M. (1996) Pancreatic cancer. In Cancer Epidemiology and Prevention, 2nd ed, eds D. Schottenfeld and J. F. Fraumeni Jr, pp. 725±771. Oxford University Press, New York. Anderson, K. E., Hammons, G. J., Kadlubar, F. F., Potter, J. D., Kaderlik, K. R., Ilett, K. F., Minchin, R. F., Teitel, C. H., Chou, H.-C., Martin, M. V., Guengerich, F. P., Barone, G. W., Lang, N. P. and Peterson, L. A. (1997) Metabolic activation of aromatic amines by human pancreas. Carcinogenesis 18, 1085± 1092. Armitage, P. and Berry, G. (1994) Statistical Methods in Medical Research, 3rd. ed. Blackwell, Oxford. Blair, A., Axelson, O., Franklin, C., Paynter, O. E., Pearce, N., Stevenson, D., Trosko, J. E., Vainio, H., Williams, G., Woods, J. and Zahm, S. M. (1990) Carcinogenic e€ects of pesticides. In The E€ect of Pesticides on Human Health, eds S. R. Baker and C. F.

Occupation and pancreatic cancer in Spain Wilkinson, Advances in Modern Environmental Toxicology, Vol. 18. Princeton Scienti®c, Princeton, NJ. Blair, A., Zahm, S. H., Pearce, N. E., Heineman, E. F. and Fraumeni, J. F. Jr (1992) Clues to cancer etiology from studies of farmers. Scandinavian Journal of Work and Environmental Health 18, 209±215. Blair, A., Dosemeci, M. and Heineman, E. F. (1993) Cancer and other causes of death among male and females farmers from twenty-three states. American Journal of Industrial Medicine 23, 729±742. Boyle, P., Maisonneuve, P., Bueno de Mesquita, B., Ghadirian, P., Howe, G. R., Zatonski, W., Baghurst, P., Moerman, C. J., Simard, A., Miller, A. B., Przewoniak, K., McMichael, A. J., Hsieh, C.-C. and Walker, A. M. (1996) Cigarette smoking and pancreas cancer: A case-control study of the SEARCH programme of the IARC. International Journal of Cancer 67, 63±71. Bulbulyan, M. A., Figgs, L. W., Zahm, S. H., Savitskaya, T., Goldfarb, A., Astashevsky, S. and Zaridze, D. (1995) Cancer incidence and mortality among betanaphthylamine and benzidine dye workers in Mocow. International Journal of Epidemiology 24, 266±275. Calvert, G. M., Ward, E., Schnorr, T. M. and Fine, L. J. (1998) Cancer risk among workers exposed to metalworking ¯uids: a systematic review. American Journal of Industrial Medicine 33, 282±292. Cantor, K. P. and Silberman, W. (1999) Mortality among aerial applicators and ¯ight instructors: followup from through 1988. American Journal of Industrial Medicine 36, 239±247. Cerhan, J. R., Cantor, K. P., Williamson, K., Lynch, C. F., Torner, J. C. and Burmeister, L. F. (1998) Cancer mortality among Iowa farmers: recent results, time trends, and lifestyle factors (United States). Cancer Causes Control 9, 311±319. Chen, R. and Seaton, A. (1996) A meta-analysis of mortality among workers exposed to organic solvents. Occupational Medicine 46, 337±344. Coggon, D., Pannett, B. and Winter, P. D. (1986) Mortality of workers exposed to 2-methyl-4-chlorophenoxyacetic acid. Scandinavian Journal of Work and Environmental Health 12, 448±454. Coggon, D., Pannett, B. and Winter, P. D. (1991) Mortality and incidence of cancer at four factories making phenoxy herbicides. British Journal of Industrial Medicine 48, 173±178. Constantini, A., Paci, E. and Miligi, L. (1989) Cancer mortality among workers in the Tuscan tanning industry. British Journal of Industrial Medicine 46, 384±388. Delzell, E., Macaluso, M. and Cole, P. (1989) A follow-up study of workers at a dye and resin manufacturing plant. Journal of Occupational Medicine 31, 273±278. Depue, R. H., Kagey, B. T. and Heid, M. F. (1985) A proportional mortality study of the acting profession. American Journal of Industrial Medicine 8, 57±66. Edling, C., Kling, H., Flodin, U. and Axelson, A. (1986) Cancer mortality among leather tanners. British Journal of Industrial Medicine 43, 494±496. European Foundation for the Improvement of Living and Working Conditions (1997) Second European Survey on Working Conditions. EFILWC, Dublin. Falk, R. T., Pickle, L. W. and Fontham, E. T. (1990) Occupation and pancreatic cancer risk in Louisiana. American Journal of Industrial Medicine 18, 565±576. Fernandez, E., La Vecchia, C., Porta, M., Negri, E., Lucchini, F. and Levis, F. (1994) Trends in pancreatic cancer mortality in Europe, 1955±1989. International Journal of Cancer 57, 786±792. Fernandez, E., La Vecchia, C., Porta, M., Negri, E., D'Avanzo, B. and Boyle, P. (1995) Pancreatitis and the risk for pancreatic cancer. Pancreas 11, 185±189.

401

FigaÁ-Talamanca, I., Mearelli, I., Valente, P. and Bascherini, S. (1993) Cancer mortality in a cohort of rural licensed pesticide users in the province of Rome. International Journal of Epidemiology 22, 579±583. Forastiere, F., Quercia, A., Miceli, M., Settimi, L., Terenzoni, B., Rapiti, E., Faustini, A., Borgia, P., Cavariani, F. and Perucci, C. A. (1993) Cancer among farmers in central Italy. Scandinavian Journal of Work and Environmental Health 19, 382±389. Foster, J. R., Idle, J. R., Hardwick, J. P., Bars, R., Scott, P. and Braganza, J. M. (1993) Induction of drug-metabolizing enzymes in human pancreatic cancer and chronic pancreatitis. Journal of Pathology 169, 457±463. Friedman, G. D. and Van den Eeden, S. (1993) Risk factors for pancreatic cancer: an exploratory study. International Journal of Epidemiology 22, 30±37. Fryzek, J. P., Garabrant, D. H., Harlow, S. D., Severson, R. K., Gillespie, B. W., Schenk, M. and Schottenfeld, D. (1997) A case-control study of self-reported exposures to pesticides and pancreas cancer in southeastern Michigan. International Journal of Epidemiology 72, 62±67. Garabrant, D. H., Held, J., Langholz, B., Peters, J. M. and Mack, T. M. (1992) DDT and related compounds and risk of pancreatic cancer. Journal of the National Cancer Institute 84, 764±771. Garabrant, D. H., Held, J. and Homa, D. (1993) DDT and pancreatic cancer. Response to Malats et al.. Journal of the National Cancer Institute 85, 328±329. GavaldaÁ, L., Porta, M., Malats, N., PinÄol, J. L., FernaÂndez, E., Maguire, A., CorteÂs, I., Carrillo, E., Marrugat, M., RifaÁ, J. and Carrato, A. (1995) Concordancia entre la informacioÂn facilitada por el paciente y un familiar sobre antecedentes patoloÂgicos, consumo de tabaco, de alcohol, de cafeÂ, y dieta en el caÂncer de paÂncreas exocrino y del sistema biliar extrahepaÂtico. Gaceta Sanitaria 9, 334±342. Hotz, P., Pilliod, J., Bourgeois, R. and Boillat, M. A. (1990) Hydrocarbon exposure, pancreatitis, and bile acids. British Journal of Industrial Medicine 47, 833±837. International Agency for Research on Cancer (1980) Some Metals and Metallic Compounds. In IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans, Vol. 23. IARC, Lyon. International Agency for Research on Cancer (1991) Occupational Exposures in Insecticide Application, and Some Pesticides. In IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans, Vol. 53. IARC, Lyon. International Agency for Research on Cancer (1992) Occupational Exposures to Mists and Vapours from Strong Inorganic Acids; and Other Industrial Chemicals. In IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans, Vol. 54. IARC, Lyon. Kauppinen, T., Partanen, T., Degerth, R. and Ojajarvi, A. (1995) Pancreatic cancer and occupational exposures. Epidemiology 6, 498±502. Kauppinen, T., Toikkanen, J. and Pukkala, E. (1998) From cross-tabulations to multipurpose exposure information systems: A new job-exposure matrix. American Journal of Industrial Medicine 33, 409±417. LoÂpez-Abente, G., Pollan, M., Ruiz, M. and AragoneÂs, N. (1997) Mortalidad por caÂncer en EspanÄa. AnÄo 1994. BoletõÂn EpidemioloÂgico Semanal 5, 177±184. Mack, T. M., Peters, J. M., Yu, M. C., Hanisch, R., Wright, W. E. and Henderson, B. E. (1985) Pancreas cancer is unrelated to the workplace in Los Angeles. American Journal of Industrial Medicine 7, 253±266. McNamee, R., Braganza, J. M., Hogg, J., Leck, I., Rose, P. and Cherry, N. M. (1994) Occupational exposure to hydrocarbons and chronic pancreatitis: a case-referent

402

J. Alguacil et al.

study. Occupational and Environmental Medicine 51, 631±637. Magnani, C., Coggon, D., Osmond, C. and Acheson, D. E. (1987) Occupation and ®ve cancers: A case-control study using death certi®cates. British Journal of Industrial Medicine 44, 769±776. Malats, N., Real, F. X. and Porta, M. (1993) DDT and pancreatic cancer. Journal of the National Cancer Institute 85, 328. Mancuso, T. F. and El-Attar, A. (1967) A cohort study of workers exposed to betanaphthylamine and benzidine. Journal of Occupational Medicine 9, 277±285. Mikoczy, Z., SchuÈltz, A. and Hagmar, L. (1994) Cancer incidence and mortality among Swedish leather tanners. Occupational and Environmental Medicine 51, 530±535. Mikoczy, Z., SchuÈltz, A., StroÈmberg, U. and Hagmar, L. (1996) Cancer incidence and speci®c occupational exposures in the Swedish leather tanning industry: A cohort based case-control study. Occupational and Environmental Medicine 53, 463±467. Milham, S. Jr (1983) Occupational Mortality in Washington State. In NIOSH Pub. no. 83-116. Government Printing Oce, Washington, DC. Nadon, L., Siemiatycki, J., Dewar, R., Krewski, D. and GeÂrin, M. (1995) Cancer due to occupational exposure to polycyclic aromatic hydrocarbons. American Journal of Industrial Medicine 28, 303±324. OjajaÈrvi, I. A., Partanen, T. J., Ahlbom, A., Bo€etta, P., Hakulinen, T., Jourenkova, N., Kauppinen, T. P., Kogevinas, M., Porta, M., Vainio, H. U., WeiderpassPetersen, E. and Wesseling, C. H. (2000) Occupational exposures and pancreatic cancer: a meta-analysis. Occupational & Environmental Medicine (in press). Orbaek, P., Risberg, J., Rosen, I., Haeger-Aronsen, B., Hagstadius, S., Hjortsberg, U., Regnell, G., Rehnstrom, S., Svensson, K. and Welinder, H. (1985) E€ects of long-term exposure to solvents in the paint industry. Scandinavian Journal of Work and Environmental Health 11(suppl 2), s1±s28. Partanen, T., Kauppinen, T., Degerth, R., Moneta, G., Mearelli, I., OjajaÈrvi, A., Hernberg, S., Koskinen, H. and Pukkala, E. (1994) Pancreatic cancer in industrial branches and occupations in Finland. American Journal of Industrial Medicine 25, 851±866. Paton, A. and Saunders, J. B. (1981) ABC of alcohol. British Medical Journal 283, 1248±1250. Pietri, F., Clavel, F. and Auquier, A. (1990) Occupational risk factors for cancer of the pancreas: A case-control study. British Journal of Industrial Medicine 47, 425± 428. Porta, M., Malats, N., PinÄol, J. L., Real, F. X. and RifaÁ, J. (1996) Relevance of misclassi®cation of disease status in epidemiologic studies of pancreatic cancer. Response to Silverman et al.. Journal of Clinical Epidemiology 49, 602±603. Porta, M., Malats, N., Guarner, L., Carrato, A., RifaÁ, J., Salas, A., Corominas, J. M., Andreu, M. and Real, F. X. (1999a) Association between co€ee drinking and Kras mutations in exocrine pancreatic cancer. Journal of Epidemiology & Community Health 53, 702±709. Porta, M., Malats, N., Jariod, M., Grimalt, J. O., RifaÁ, J., Carrato, A., Guarner, L., Salas, A., Santiago-Silva, M., Corominas, J. M., Andreu, M. and Real, F. X. (1999b) Serum concentrations of organochlorine compounds and K-ras mutations in exocrine pancreatic cancer. The Lancet 1999; 354, 2125±2129. Ribbens, P. H. (1985) Mortality study of industrial workers exposed to aldrin, dieldrin and endrin. International Archives of Occupational and Environmental Health 56, 75±79. Ronneberg, A. and Langmark, F. (1992) Epidemiologic evidence of cancer in aluminium reduction plant

workers. American Journal of Industrial Medicine 22, 573±590. Sathiakumar, N., Delzell, E., Austin, H. and Cole, P. (1992) A follow-up study of agricultural chemical production workers. American Journal of Industrial Medicine 21, 321±330. Schwartz, G. G., Skinner, H. G. and Duncan, R. (1998) Solid waste and PC: An ecologic study in Florida, USA. International Journal of Epidemiology 27, 781±787. She€et, A., Thind, I., Miller, A. M. and Louria, D. B. (1982) Cancer mortality in a pigment plant utilizing lead and zinc chromates. Archives of Environmental Health 37, 44±52. Siemiatycki, J., Gerin, M., Dewar, R., Nadon, L., Lakhani, R., Begin, D. and Richardson, L. (1991) Associations between occupational circumstances and cancer. In Risk Factors for Cancer in the Workplace, ed. J. Siemiatycki, pp. 141±295. CRC Press, Boca Raton, FL. Silverman, D. T., Dunn, J. A., Hoover, R. N., Schi€man, M., Lillemoe, K. D., Schoenberg, J. B., Brown, L. M., Greenberg, R. S., Hayes, R. B., Swanson, G. M., Wacholder, S., Schwartz, A. G., Li€, J. M. and Pottern, L. M. (1994) Cigarette smoking and pancreas cancer: A case-control study based on direct interviews. Journal of the National Cancer Institute 86, 1510±1516. Silverman, D. T., Brown, L. M., Hoover, R. N., Schi€man, M., Lillemoe, K. D., Schoenberg, J. B., Swanson, G. M., Hayes, R. B., Greenberg, R. S., Bienichou, J., Schwartz, A. G., Li€, J. M. and Pottern, L. M. (1995) Alcohol and pancreatic cancer in blacks and whites in the United States. Cancer Research 55, 899±905. Soler, M., Porta, M., Malats, N., Guarner, L., Costafreda, S., Gubern, J. M., Garcõ a-Olivares, E., Andreu, M. and Real, F. X. (1998) Learning from case-reports: Diagnostic issues in an epidemiologic study of pancreatic cancer. Journal of Clinical Epidemiology 51, 1215± 1221. Soler, M., Malats, N., Porta, M., Fernandez, E., Guarner, L., Maguire, A., PinÄol, J. L., RifaÁ, J. and Carrato, A. Study Group (1999) Medical conditions in patients with pancreatic and biliary diseases: Validity and agreement between data from questionnaires and medical records. Digestive Diseases & Sciences 44, 2469±2477. Tollestrup, K., Daling, J. R. and Allard, J. (1995) Mortality in a cohort of orchard workers exposed to lead arsenate pesticide spray. Archives of Environmental Health 50, 221±229. Weiderpass, E., Partanen, T., Kaaks, R., Vainio, H., Porta, M., Kauppinen, T., OjajaÈrvi, A., Bo€etta, P. and Malats, N. (1998) Pancreatic cancer: Occurrence, trends, and environmental etiology. A review. Scandinavian Journal of Work and Environmental Health 24, 165±174. Wong, O., Brocker, W. and Davis, H. V. (1984) Mortality of workers potentially exposed to organic and inorganic brominated chemicals, DBCP, TRIS, PBB, and DDT. British Journal of Industrial Medicine 41, 15±24. Zahm, S. H. (1997) Mortality study of pesticide applicators and other employees of a lawn care service company. Journal of Occupational and Environmental Medicine 39, 1055±1067. Zhong, Y. and Rafnsson, V. (1996) Cancer incidence among Icelandic pesticide users. International Journal of Epidemiology 25, 1117±1124.

Occupation and pancreatic cancer in Spain APPENDIX

Centres and members of the PANKRAS II study group Institut Municipal d'Investigacio MeÁdica, Universitat AutoÁnoma de Barcelona and Universitat Pompeu Fabra (Coordinating Centre): F.X. Real [Principal investigator], M. Porta [Principal investigator], N. Malats [Centre CoordinatorInvestigator], J. Alguacil, S. Costrafreda, L. Ruiz, M. Jariod, E. Carrillo [Monitor], I. CorteÁs [Monitor], E. Fernandez [Monitor], L. GavaldaÁ [Monitor], J.L. PinÄol [Monitor], A. Garcõ a de Herreros, A. Maguire, A. Serrat, M. Soler, M. ToraÁ. Hospital General de Elche: A. Carrato [Centre Coordinator-Investigator], E. GoÂmez [Monitor], V. BarberaÁ, J.M. BaroÂn, M. de Diego, R. Guaraz, F.J.

403

Lacueva, J.A. Maruenda, A. OrdunÄa, J. Ruiz, C. Sillero, A. Teruel. Hospital del Mar, Barcelona: M. Andreu [Centre Coordinator-Investigator], J.M. Corominas [Study Reference Pathologist], S. Coll, M. Conangla, J.M. Gubern, T. Maristany, A. PanadeÁs, R. SolaÁ, F. Tous. Hospital de Son Dureta, Mallorca: J. RifaÁ [Centre Coordinator-Investigator], M. Marrugat [Monitor], 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 [Centre CoordinatorInvestigator], A. Alvarez, J. Bellmunt, I. de Torre, M. GarcõÂ a, E. Murio, A. Nadal, V. Puig-DivõÂ , N. Tallada. Hospital MuÂtua de Terrassa: A. Salas [Centre Coordinator-Investigator and Study Reference Pathologist], E. Cugat, J.C. EspinoÂs, E. GarcõÂ a-Olivares, M. GarcõÂ a.