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Original article
Workplace
Occupation and occupational exposure to endocrine disrupting chemicals in male breast cancer: a case–control study in Europe
  1. Sara Villeneuve1,2,
  2. Diane Cyr1,2,
  3. Elsebeth Lynge3,
  4. Laurent Orsi1,2,
  5. Svend Sabroe4,
  6. Franco Merletti5,
  7. Giuseppe Gorini6,
  8. Maria Morales-Suarez-Varela7,8,9,
  9. Wolfgang Ahrens10,
  10. Cornelia Baumgardt-Elms11,
  11. Linda Kaerlev12,
  12. Mikael Eriksson13,
  13. Lennart Hardell14,
  14. Joëlle Févotte15,16,
  15. Pascal Guénel1,2,16
  1. 1CESP – INSERM (National Institute of Health and Medical Research), Villejuif, France
  2. 2University Paris 11, Paris, France
  3. 3Institute of Public Health, University of Copenhagen, Copenhagen, Denmark
  4. 4Department of Epidemiology, School of Public Health, University of Aarhus, Aarhus, Denmark
  5. 5Unit of Cancer Epidemiology, University of Turin, CERMS and CPO, Piemonte, Italy
  6. 6Epidemiology and Public Health, Environmental and Occupational Epidemiology Unit, ISPO Cancer Prevention and Research Institute, Florence, Italy
  7. 7Unit of Public Health and Environmental Care, Department of Preventive Medicine, Valencia University, Valencia, Spain
  8. 8Research Group CIBER CB06/02/0045, CIBER Actions – Epidemiology and Public Health, Valencia, Spain
  9. 9Research Foundation, University Hospital Dr. Peset, Valencia, Spain
  10. 10Bremen Institute for Prevention Research and Social Medicine, Bremen, Germany
  11. 11Hamburg Cancer Registry, Hamburg, Germany
  12. 12Center for National Clinical Databases South, Department of Research and HTA, Odense University Hospital, Odense, Denmark
  13. 13Department of Oncology, Lund University Hospital, Lund, Sweden
  14. 14Department of Oncology, Orebro University Hospital, Orebro, Sweden
  15. 15UMRESTTE (Université Claude-Bernard Lyon 1 – InVS – INRETS), Lyon, France
  16. 16InVS (Institute of Health Surveillance), Department of Occupational Health (DST), Saint-Maurice, France
  1. Correspondence to Pascal Guénel, CESP – Inserm U1018, 16 avenue Paul Vaillant-Couturier, 94807 Villejuif Cedex, France; pascal.guenel{at}inserm.fr

Abstract

Objectives Male breast cancer is a rare disease of largely unknown aetiology. In addition to genetic and hormone-related risk factors, a large number of environmental chemicals are suspected of playing a role in breast cancer. The identification of occupations or occupational exposures associated with an increased incidence of breast cancer in men may help to identify mammary carcinogens in the environment.

Methods Occupational risk factors for male breast cancer were investigated in a multi-centre case–control study conducted in eight European countries which included 104 cases and 1901 controls. Lifetime work history was obtained during in-person interviews. Occupational exposures to endocrine disrupting chemicals (alkylphenolic compounds, phthalates, polychlorinated biphenyls and dioxins) were assessed on a case-by-case basis using expert judgement.

Results Male breast cancer incidence was particularly increased in motor vehicle mechanics (OR 2.1, 95% CI 1.0 to 4.4) with a dose–effect relationship with duration of employment. It was also increased in paper makers and painters, forestry and logging workers, health and social workers, and furniture manufacture workers. The OR for exposure to alkylphenolic compounds above the median was 3.8 (95% CI 1.5 to 9.5). This association persisted after adjustment for occupational exposures to other environmental oestrogens.

Conclusion These findings suggest that some environmental chemicals are possible mammary carcinogens. Petrol, organic petroleum solvents or polycyclic aromatic hydrocarbons are suspect because of the consistent elevated risk of male breast cancer observed in motor vehicle mechanics. Endocrine disruptors such as alkylphenolic compounds may play a role in breast cancer.

  • Case-control studies
  • occupations
  • occupational exposures
  • breast neoplasms
  • male
  • endocrine disruptors
  • epidemiology
  • cancer
  • endocrine disrupters

https://doi.org/10.1136/oem.2009.052175

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    What this paper adds

    • Environmental exposures may play a role in breast cancer occurrence but have not been studied extensively.

    • The study of male breast cancer may help to identify occupational risk factors, as occupational exposures to most potential carcinogens occur more frequently in men than in women.

    • The incidence of male breast cancer was increased in motor vehicle mechanics, pointing to a possible role of occupational exposures to petrol and petroleum solvents.

    • The incidence of male breast cancer was associated with occupational exposures to endocrine disrupting chemicals such as alkylphenolic compounds.

    • These results suggest that some occupational chemicals are mammary carcinogens, and may offer new clues for cancer prevention.

    Introduction

    Male breast cancer is a rare disease, representing less than 1% of all breast cancers, with incidence rates of approximately 1 per 100 000 men per year in Europe.1 Factors linked to hormonal or reproductive function in women have been studied extensively as aetiological factors in female breast cancers, but little is known about the aetiology of male breast cancer. The risk factors reported for this disease include mutations in the BRCA2 gene, the presence of an extra X chromosome (Klinefelter syndrome), infertility, cryptorchidism, mumps orchitis and alcohol consumption.2

    Certain environmental exposures, such as organic solvents3 or endocrine disrupting chemicals that interfere with hormonally mediated processes and can stimulate the growth of breast cancer cells in laboratory studies, are also suspected risk factors for breast cancer.4–6 Many studies have been conducted on female breast cancer risk in the community in relation to a few endocrine disrupting chemicals such as dichlorodiphenyltrichloroethane (DDT) or polychlorinated biphenyls (PCBs), with mainly negative results.7 8 However, only a few occupational studies on female breast cancer where exposures are higher and better characterised compared with community settings, have been conducted. These studies have shown associations between female breast cancer and exposure to certain organic solvents,9 10 pesticides,11 12 PCBs13 and other endocrine disruptors.14 There is also growing evidence that disruption of circadian rhythm during night shift work increases the risk of female breast cancer.15 For the purpose of identifying mammary carcinogens in occupational settings, the study of male breast cancer offers several advantages over the investigation of female breast cancer for identifying environmental mammary carcinogens, because exposures to the occupational agents of interest, such as polycyclic aromatic hydrocarbons (PAHs), occur more frequently in jobs held by men than by women. In addition, confounding from female reproductive risk factors is not a concern in men. Occupational studies have inconsistently reported associations between male breast cancer and exposure to heat,16–19 petrol, PAHs or combustion products,19 20 and electromagnetic fields.19 21–23 None of these studies has specifically investigated the role of exposure to endocrine disrupting chemicals.

    The first objective of this study was to examine the risk of male breast cancer by occupation to identify potential occupational carcinogens. A second objective was to test the hypothesis that exposure to environmental oestrogens present in occupational settings24 25 increased the risk of male breast cancer. More specifically, we investigated occupational exposures to alkylphenolic compounds,14 phthalates,26 27 PCBs and dioxins,28 and pesticides.12

    Material and methods

    We conducted a European multi-centre case–control study of seven sites of rare cancers (gallbladder and extra-hepatic bile ducts, small intestine, bone, eye melanoma, thymus, mycosis fungoides and male breast). Cases and controls were recruited in selected areas of eight European countries (appendix). The recruitment was population based in Denmark, France, Germany, Italy and Sweden, and hospital based in Latvia, Portugal and Spain. Findings on alcohol consumption in relation to male breast cancer have been reported previously for the countries that used a population based design.29 The study design and the data collection procedures have been described in detail earlier30 and are summarised below.

    The study was approved by the local ethics committees in each participating country.

    Recruitment of cases and controls

    Cases were men living in the participating study areas who were diagnosed with a breast cancer between 1 January 1995 and 30 June 1997. Only men aged 35–70 years at diagnosis were eligible because the study focused on occupations and because earlier occupational exposures among older subjects may be hard to recall and difficult to assess by study investigators due to changes in work processes. Case ascertainment was based on regular contacts with clinical and pathology departments in each study area. For each case an expert pathologist reviewed the pathology report and one slide representative of the tumour. In total, 122 male breast cancer patients were eligible for the study. Eighteen cases could not be contacted because the doctor did not give permission or the patient refused to participate. Therefore, 104 cases (85%) were interviewed and were available for the analysis (table 1).

    View this table:
    Table 1

    Number of men eligible for the study and number of respondents by country (European study on male breast cancer)

    Controls were selected randomly during case recruitment and were frequency matched to the cases by year of birth (5-year strata), sex and study area. Controls were selected from population registers in Denmark, Italy and Sweden, from electoral rolls in France and from municipality registers in Germany. Colon cancer patients were regarded as appropriate alternatives to population controls in some cases, as no occupational exposure to chemicals is known to play a role in colon cancer. Hospital based cancer controls were selected randomly among incident colon cancer patients in Latvia and Spain, and among the colon and a few stomach cancer patients in Portugal. The controls served as a common pool of controls for each of the seven groups of rare cancer cases included in the European study. For the present study we selected only control men in study areas with at least one male breast cancer patient. The participation rate among population controls was high in France (81%) and Italy (74%) but lower (<60%) in Denmark, Germany and Sweden. In countries using a hospital based design, the participation rate among cancer controls was above 95%. The overall participation rate in controls was 67%, and 1901 controls were available for the analysis (table 1).

    Data collection

    A structured questionnaire was first developed in English, translated into the language of each participating country and then back-translated into English for quality control. This questionnaire was used during a face-to-face or a telephone (Denmark, Sweden) interview by a trained interviewer. We obtained information on sociodemographic characteristics, previous medical conditions, lifestyle factors, anthropometric characteristics, and alcohol and tobacco consumption. A detailed occupational questionnaire was used for each job held for more than 6 consecutive months during the interviewee's lifetime. Questionnaires specific to 27 work tasks such as welding or painting, were also used whenever relevant to identify particular occupational exposures.

    Coding of jobs and occupational exposures

    Each job held for more than 6 months was coded for occupation and industry by trained coders. Occupation was coded according to the International Standard Classification of Occupations (ISCO) of the International Labour Organization, 1968 revision. Industry was coded according to the Statistical Classification of Economic Activities in the European Community (NACE), 1996 revision.

    Exposure to endocrine disrupting chemicals was assessed for each job held during the subject’s work history by an expert in occupational hygiene. Exposure assessment was conducted by individually reviewing the job-specific questionnaires to collect information on plant production, the work tasks performed, and the type of equipment and chemical products used by the worker. In order to decrease the total number of jobs to be reviewed by the expert, we selected job questionnaires based on their ISCO and NACE codes and discarded those where job exposure to endocrine disrupting chemicals was extremely unlikely. Based on the expert's judgement and a literature review, exposure to alkylphenolic compounds, phthalates, PCBs and dioxins was coded using semi-quantitative indicators for exposure probability (0: not exposed; 1: possibly exposed; 2: probably exposed; 3: definitely exposed), exposure frequency (1: <30% of working hours; 2: 30–70%; 3: >70%) and exposure intensity, based on the expert's judgement concerning airborne concentration or dermal contact (1: low; 2: medium; 3: high). Coding of exposure was blind as to case–control status. Exposure to pesticides was assessed in the same way, but a detailed assessment by type of pesticide was beyond the scope of the present paper.

    We calculated an exposure score for each job in the subject's work history as the product of exposure probability, frequency and intensity and the duration of the job period in years. The lifetime cumulative exposure of each study subject consisted of the sum of the job-specific exposure scores over the entire work history.

    Statistical analysis

    ORs were calculated for workers ever employed in an occupation or industry, using workers who were never employed in that occupation or industry as a reference group. Occupations and industries were defined by the two- or three-digit ISCO codes and by the two-digit NACE code, respectively. Only job groups with at least five cases are presented.

    In the analyses by occupational exposure to endocrine disrupting chemicals, we categorised ever-exposed subjects into two groups according to the median of the cumulative exposure distribution among controls, and used never exposed subjects as the reference category. For pesticides, exposed workers were divided according to exposure tertiles.

    All analyses were conducted using unconditional logistic regressions using the SAS v 9. ORs were adjusted for age (5-year age group), country and the stratification variables, as well as for potential confounders coded as categorical variables, including alcohol consumption, body mass index (BMI) and education.

    We also conducted several rounds of analyses (i) restricting to countries that used a population based design and no colon cancer controls, (ii) restricting to the cases with know oestrogen positive receptor status (48 out of 54 cases with known status), and for the occupational exposure analyses (iii) calculating cumulative exposure scores with a lag time of 5, 10 or 15 years before diagnosis or interview for the controls, (iv) excluding jobs with low exposure probability from the cumulative exposure scores. These sensitivity analyses did not modify our findings and are not shown.

    Results

    Study sample

    The distribution of cases and controls by age, alcohol consumption and education are presented in table 2. The age distribution of cases and controls did not differ significantly. As reported earlier, alcohol consumption was strongly associated with male breast cancer.29 Lower education was associated with some increase in risk, although the ORs did not reach statistical significance. No statistically significant excess risk was observed in any BMI category. Because BMI was weakly associated with male breast cancer in some countries,29 we adjusted for this variable in further analyses.

    View this table:
    Table 2

    Comparison of cases and controls by selected characteristics (European study on male breast cancer)

    Occupations and industries

    ORs for male breast cancer were increased in wood preparation workers and paper makers (OR 2.4, 95% CI 0.9 to 6.5), motor vehicle mechanics (OR 2.1, 95% CI 1.0 to 4.4) and painters (OR 2.3, 95% CI 1.0 to 5.2) (table 3). The OR increased markedly for workers employed for 10 or more years as motor vehicle mechanics (OR 5.9, 95% CI 2.4 to 14.6) (not shown). Conversely, a non-significantly decreased OR was observed for farmers and agricultural workers.

    View this table:
    Table 3

    ORs* by occupation (ISCO codes†) (European study on male breast cancer)

    Table 4 presents ORs associated with specific industries. Increased ORs were observed in forestry and logging (OR 2.4, 95% CI 1.0 to 5.6), health and social work (OR 2.3, 95% CI 1.1 to 5.1) and the sale and repair of motor vehicles (OR 1.8, 95% CI 1.0 to 3.2). This latter increase (NACE code 50) was explained by the increased OR in motor vehicle mechanics (ISCO code 8-43), with nine cases and 57 controls being classified in both NACE code 50 and ISCO code 8-43. ORs in the manufacture of rubber and plastic (OR 1.9, 95% CI 0.8 to 4.6), manufacture of electrical machinery (OR 2.0, 95% CI 0.8 to 5.3) and manufacture of furniture (OR 1.8, 95% CI 0.9 to 3.7) were also increased but did not reach statistical significance.

    View this table:
    Table 4

    ORs* by industry (NACE code†) (European study on male breast cancer)

    Occupational exposures

    In table 5, the OR adjusted for non-occupational risk factors was elevated for alkylphenolic compounds above the median (ORa 3.8, 95% CI 1.5 to 9.5) and a dose–response trend was apparent (p<0.01). The OR for exposure to PCBs and dioxins above the median was also increased (ORb 2.1, 95% CI 1.0 to 4.5) and at the limit of statistical significance. When adjusting further for exposures to other endocrine disruptors (ORb in table 5), that is including all occupational exposure variables in a single model, male breast cancer incidence remained associated with alkylphenolic compounds for exposure above the median (OR 3.3, 95% CI 1.1 to 9.9), but the dose–response trend was not statistically significant. No increased risk was observed for phthalates, or for PCBs and dioxins. Exposure to pesticides was not associated with male breast cancer in either model. Confounding between occupational exposures is thus apparent from table 5, indicating that multiple exposures to endocrine disruptors occurred among workers in our data.

    View this table:
    Table 5

    ORs associated with occupational exposure to environmental oestrogens (European study on male breast cancer)

    Discussion

    We found that the incidence of male breast cancer was increased in wood preparation workers and paper makers, motor vehicle mechanics and painters as well as in forestry and logging workers and health and social workers, and in workers involved in the manufacture of furniture, and in the sale and repair of motor vehicles. We also investigated occupational exposures to endocrine disrupting chemicals, and found that male breast cancer incidence was more particularly associated with alkylphenolic compounds.

    Study strengths and limitations

    This is a relatively large study on male breast cancer conducted in eight European countries. Despite the large study base, the high participation rate among male breast cancer patients30 and the large number of controls, some analyses were based on relatively low statistical power. For example, we calculated that a twofold increased OR was detectable with a statistical power of 80% (α=5%, two-sided) if the exposure prevalence among controls was at least 15%, a condition that was not met in all calculations. Chance findings due to multiple testing are also possible. Nevertheless, if the observed associations are real, they may have been difficult to detect in epidemiological studies on female breast cancer based on higher numbers of cases but much lower exposure prevalence.

    The overall participation rate among controls was 67%, with large disparities across countries. A selection bias, for example according to socioeconomic status or education, was thus possible, but should be controlled for, at least in part, by adjusting for education. Restricting to countries with high participation rates among controls such as France and Italy did not alter the findings, providing reassurance that selection bias is not a major problem.

    Using colon cancer controls in countries with a hospital based design could have biased our results if colon cancer was associated with the occupational risk factors of interest. However, with the exception of low physical activity,31 there is no recognised occupational risk factor for colon cancer. Our results were unchanged when the analyses were conducted separately in countries that did not use colon cancer controls.

    Occupational exposures to oestrogenic chemicals were assessed by expert judges reviewing the job-specific questionnaires blindly as to case–control status. This case-by-case exposure assessment method may lead to non-differential exposure misclassification errors, but it is considered to be more efficient than a job–exposure matrix, since the exposure is evaluated for individual workers rather than for groups of workers with the same job.32 Exposures to oestrogenic chemicals arising from the general environment could not be evaluated in our study. This should not be a major problem considering that environmental exposures occur at lower levels than in occupational settings, and that they should be equally distributed among occupationally and non-occupationally exposed subjects.

    Occupations and industries

    Few studies have investigated male breast cancer risk in relation to occupational risk factors, and most of them have several drawbacks, including low statistical power,16–18 the use of a mortality rather than an incidence register to recruit male breast cancer patients,19 or information on occupation known from census data at only one point in time instead of lifetime occupational history.20 23 33

    We found a twofold increased incidence of male breast cancer in motor vehicle mechanics, with an indication of a dose–response relationship with duration of employment (OR 5.9 in men employed for 10 or more years in that occupation). Similarly, a registry based case–control study in Denmark20 reported an increased incidence of male breast cancer in workers employed in service stations, vehicle maintenance, the wholesale petrol trade, or car repair workshops. Exposure to solvents, petrol and vehicle combustion products containing suspected mammary carcinogens such as benzene and polycyclic aromatic hydrocarbons (PAHs), may explain these associations,3 34 and previous studies on female breast cancer provided some evidence of a link with exposure to solvents.9 10 This link is of interest and needs to be investigated further in male and in female breast cancer studies.

    We reported an increased incidence of male breast cancer in painters (OR 2.3, 95% CI 1.0 to 5.3), suggesting a potential adverse effect of solvents again, or paint additives. The elevated incidence in wood preparation workers and paper makers, and in men employed in forestry and logging, also suggests that chemicals with endocrine disrupting properties, such as volatile organic compounds in wood,35 could play a role in breast cancer.

    Conversely, no increased incidence of male breast cancer was detected in our study among metal processors (ISCO code 7-2; table 3) or among men employed in the metal manufacturing industry (NACE code 27; table 4). These findings do not confirm the elevated risks of male breast cancer reported in workers employed in blast furnaces, steel work and rolling mills,16–19 and hence do not support the hypothesis that exposure to heat,36 which is common in these industries, may be carcinogenic to the breast. Neither do our results point towards a role of electromagnetic fields in male breast cancer, as suggested by other investigators,21 37 38 since workers in occupations with potentially high exposures such as electricians or welders were not at increased risk in our data.

    Occupational exposures to endocrine disrupting chemicals

    This is the first study to examine a possible association between male breast cancer and exposure to endocrine disrupting chemicals. Many hormonally active compounds suspected of affecting breast cancer due to their oestrogenic or anti-oestrogenic properties were identified in laboratory studies,39 but only a few have been investigated in epidemiological studies. We examined oestrogenic compounds that can be found in occupational settings,24 25 and excluded chemicals with very low exposure prevalence in the study, such as bisphenol A or parabens.

    Exposure to alkylphenolic compounds was associated with male breast cancer in our data. Alkylphenol polyethoxylates surfactants and alkylphenols are used in a broad range of occupations and industries, but are mainly used as detergents and in plastics, rubber products and cosmetics,24 25 and in the textile industry.40 The workers exposed to alkylphenolic compounds in the present study can be better characterised by their industry, and were mainly employed in finishing of textiles, in the manufacture of leather clothes, and in the pulp and paper, plastics, paints and varnishes, soap and detergents, and rubber products industries. To our knowledge, only one study in women has examined the relationship between exposure to alkylphenolic compounds and breast cancer.14 In this population based case–control study, the possibility of exposure to 18 xenoestrogens was determined using a job–exposure matrix derived from the US National Occupational Exposure Survey database. Probable exposure to 4-octylphenol, an alkylphenolic compound, was associated with an OR of 2.9 (95% CI 0.8 to 10.8) after adjustment for potential confounders. Overall, our findings provide some support for the hypothesis that alkylphenolic compounds may play a role in breast cancer incidence. It should be noted, however, that multiple exposures to endocrine disruptors occurred in our data, and that confounding made it difficult to disentangle the effects of individual compounds. It is thus possible that the main association observed between male breast cancer and alkylphenolic compounds could be accounted for by multiple exposure to different classes of oestrogenic compounds, which can have synergistic effects.41

    The OR associated with exposure to dioxins and PCBs above the median was increased twofold, although this association was not apparent after adjusting for alkylphenolic compounds. PCBs and dioxins are two groups of persistent organochlorine compounds. PCBs were used as dielectric fluids in electrical capacitors, and also for miscellaneous uses in adhesives, oils and paint.28 Most studies on the association between breast cancer and environmental exposure to PCBs, based on measurements in the blood or fat of cases or controls, reported no increased risk of female breast cancer.8 In a cohort study of women employed in capacitor facilities, no overall increase in breast cancer incidence was detected after exposure to PCBs, as estimated from a job–exposure matrix.13 Several studies, however, point to a possible role of PCBs in breast cancer for the subgroup of potentially predisposed women who carry a genetic variant in the CYP1A1 gene.42–45 There also remain uncertainties concerning the role of certain PCB subgroups, such as dioxin-like PCBs.8 Dioxins have been investigated less frequently in relation to breast cancer. In the cohort of women exposed to 2,3,7,8-TCDD (the main dioxin) following the explosion of a trichlorophenol manufacturing plant near Seveso, Italy, an increase in female breast cancer incidence was observed in the most contaminated areas46 and among women with higher TCDD serum levels.47 Increased mortality from breast cancer in both women and men was also reported in an international cohort of workers exposed to phenoxy herbicides contaminated with dioxins.48 Overall, these data provide some support for the hypothesis that some PCBs and dioxins may increase the risk of breast cancer, and require further attention.

    Phthalates have been widely used as plasticisers in soft plastics or cosmetics,49 but they have never been investigated thoroughly in relation to breast cancer incidence in an epidemiological study. We found no significant association between male breast cancer and exposure to phthalates, possibly because of confounding by alkylphenolic compounds. Because of their widespread use, their effects in hormone-related cancers deserve further attention. The role of environmental exposures to persistent organochlorine pesticides, such as DDT, was investigated in many studies, with mainly negative findings.7 Other studies in female farmers reported increased breast cancer risk in women likely exposed to pesticides,11 or living close to pesticide application areas.12 Our data provide no support for an association between pesticide exposure and breast cancer in men, but the lack of information on specific pesticides may account for these negative findings.

    Conclusion

    The elevated risk of male breast cancer in certain occupations suggested possible environmental mammary carcinogens. The elevated risk of male breast cancer among motor vehicle mechanics points to a role of PAH and petrol or petroleum solvents in breast carcinogenesis, which needs to be investigated further in studies of male or female breast cancer. For the first time in male breast cancer, we have shown that endocrine disrupting chemicals could affect breast cancer risk. These results support growing evidence that breast cancer may be linked to exposure to environmental pollutants, and should encourage further studies on this issue.

    Appendix

    The European Study Group on Occupational Causes of Rare Cancers

    Denmark: Herman Autrup, Henrik Kolstad, Linda Kaerlev, Elsebeth Lynge, Jorn Olsen, Lisbeth Norum Pedersen, Svend Sabroe, Preben Johansen, Stein Poulsen, Peter Stubbe Teglbjaerg, Mogens Vyberg. France: Pascal Guénel, Joëlle Févotte, Diane Cyr and the members of the FRANCIM association: Patrick Arveux, Antoine Buemi, Paule-Marie Carli, Gilles Chaplain, Jean-Pierre Daurès, Jean Faivre, Pascale Grosclaude, Anne-Valérie Guizard, Michel Henry-Amar, Guy Launoy, Francois Ménégoz, Nicole Raverdy, Paul Schaeffer. Germany: Wolfgang Ahrens, Cornelia Baumgardt-Elms, Sibylle Gotthardt, Ingeborg Jahn, Karl-Heinz Jöckel, Hiltrud Merzenich, Andreas Stang, Christa Stegmaier, Antje Timmer, Hartwig Ziegler. Italy: Terri Ballard, Franco Bertoni, Giuseppe Gorini, Sandra Gostinicchi, Giovanna Masala, Enzo Merler, Franco Merletti, Lorenzo Simonato, Paola Zambon. Latvia: Irena Rogovska, Galina Sharkova, Aivars Stengrevics. Lithuania: Jolita Gibaviciene, Laimonas Jazukevicius, Juozas Kurtinaitis, Poma Pociute. Portugal: Noemia Alfonso, Altamiro Costa-Pereira, Sonia Doria, Carlos Lopes, José Manuel Lopes, Ana Miranda, Cristina Santos. Spain: M Adela Sanz Aguado, Juan J Aurrekoetxea, Concepción Brun, Alicia Córdoba, Miguel Angel Martínez González, Francisco Guillén Grima, Rosa Guarch, Agustin Llopis González, Blanca Marín, Amparo Marquina, María M Morales Suárez-Varela, Inés Aguinaga Ontoso, JM Martínez Peñuela, Ana Puras, Francisco Vega, Maria Aurora Villanueva Guardia. Sweden: Mikael Eriksson, Lennart Hardell, Irene Larsson, Hakan Olson, Monica Sandström, Gun Wingren. Switzerland: Jean-Michel Lutz. United Kingdom: Janine Bell, Ian Cree, Tony Fletcher, Alex JE Foss.

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    Footnotes

    • Funding The study ‘Occupational Risk Factors for Rare Cancers of Unknown Etiology’ was financially supported by the European Commission, DGXII, grants no BMH1 CT 931630 and ERB CIPD CT 940285, and the following national funding agencies. Denmark: The Strategic Environment Programme. France: Ligue Nationale contre le Cancer, Fondation de France (grant no 955368); Institut National de la Santé et de la Recherche Médicale (INSERM) (grant ‘Réseau en Santé Publique’); French Ministry for the Environment. Germany: Federal Ministry for Education, Science, Research and Technology (BMBF), grant no 01-HP-684/8. Italy: MURST, Region Piedmont; Ministry of Labour; Italian Association for Cancer Research; Compagnia SanPaolo/FIRMS. Portugal: Junta Nacional de Investidacäo Cientifica e Tecnológica, Praxis XXI, no 2/2.1/SAU/1178/95. Spain: Fondo de Investigación de la Sanitarie, Ministerio de Sanidad y Consumo, Unidad de Investigación Clinico-Epidemiológica, Hospital Dr. Peset, Generalitet Valenciana; Departmento de Sanidad y Consumo, Gobierno Vasco; Fondo de Investigación de la Sanitaria (FIS), Ministerio de Sanidad y Consumo, Ayuda a la Investigación del Departamento de Salud del Gobierno de Navarra. Sweden: Swedish Council for Work Life Research; Research Foundation of the Department of Oncology in Umeå; Swedich Society of Medicine; Lund University Hospital Research Foundation; Gunnar, Arvid and Elisabeth Nilsson Cancer Foundation; Örebro County Council Research Committee, Örebro Medical Center Research Foundation; John and Augusta Persson Foundation for Scientific Medical Research; Berta Kamprad Foundation for Cancer Research.

    • Competing interests None.

    • Ethics approval This study was conducted with the approval of the ethics committee of each European country participating in the study (Denmark, France, Germany, Italy, Latvia, Portugal, Spain and Sweden).

    • Provenance and peer review Not commissioned; externally peer reviewed.