Cancer risk among farmers in the Province of VercelliAnn Ig () 2014; 26: 255-263 doi:10.7416/ai.2014.1983255 Cancer risk among farmers in the Province of (Italy) from 2002 to 2005: an ecological study C. Salerno*, S. Sacco**, M. Panella*, P. Berchialla***, K. Vanhaecht****, L.A. Palin*

Key words: Farmers, pesticides, cancer risk, Province of Vercelli, Italy Parole chiave: Coltivatori diretti, pesticidi, rischio di cancro, Provincia di Vercelli, Italia

Abstract Background: As the link between agricultural pesticides and numerous types of human cancers is well- known. Farmers living in the Province of Vercelli (Italy) were observed to verify if they have a higher cancer risk than the rest of the local employed population. Literature showed a well-known excess of cancer morbidity and mortality in the Province of Vercelli, but only few studies focused on cancer incidence in local farmers. Studying farmers could allow to assess the causal importance respectively of environmental pressure and professional exposure factors in explaining cancer excesses in the above-mentioned area. Materials and methods: The present ecological study considered all cancer new cases recorded among the mean employed population with a range of age from 25 to 84 years and resident in the Province of Vercelli during the four-year period 2002-2005. Cancer odds ratios, by gender and type of cancer, between farmers and non-farmers were calculated. Results: Farmers showed a higher risk for the following tumors: colorectal (OR 2.38, IC95%: 1,76-2,87), leaukaemia (OR 2.65, IC95%:2,12-2,89), digestive system (OR 2.16, IC95% 1,92-2,33), lymphoma OR 2.08, IC95%:1,99-2,23), melanoma (OR 2.90, IC95%:2,54-3,15), myeloma OR 3.55, IC95%:3,23-3,70), pancreas OR 3.38, IC95%:3,14-3,61), lung (1.59, IC95%:1,12-2,38) and kidney (2.70, IC95%:2,41-2,99). Males showed a higher risk for lung cancer, females for liver neoplasm, melanoma and lymphoma. Conclusions: Farmers showed a higher risk for several cancers. Further studies are needed, in order to examine in detail the issue, to encourage the use of personal protective equipment and to promote a more responsible pesticides use.

Introduction ever-increasing and ever-changing use in agriculture made pesticide exposure a major Pesticides are considered as one of the environmental health issue in agricultural main factors involved in environmental communities (2). contamination of today’s world (1): their Agricultural pesticides are mostly

* Department of Translational Medicine, University of Eastern “Amedeo Avogadro”, , Italy ** Department of Brain and Behavioural Sciences, Section of Biostatistics, Neurophysiology and Psychiatry, Unit of Medi- cal Statistics and Computational Genomics - Clinical Epidemiology and Health Planning Laboratory, University of Pavia, Italy *** Department of Clinical and Biological Sciences, , Orbassano, Turin, Italy **** Health Services Research Group, School of Public Health, Faculty of Medicine, University of Leuven, Belgium Sources of Funding: None. Conflicts of Interest: the Authors declare that they have no conflict of interest. 256 C. Salerno et al. constituted by toxic, persistent and bio- (1). Several pesticides were associated accumulative substances, which affect the with various cancers: many national and soil physical and chemical properties: they international researches confirmed the link can be found in about the half of fruits between the use of pesticides in agriculture and vegetables eaten every day and they and numerous types of human tumours (see extensively pollute environmental matrices, Table 1 and related references in Appendix) including surface water and groundwater (6, 7). The mechanisms by which pesticides (3). A recent research by the Italian Higher may be linked to cancer in humans are Institute for the Environmental Protection unclear: potential mechanisms include and Research (Istituto Superiore per la oxidative stress, DNA damage, chromosome Protezione e la Ricerca Ambientale, ISPRA) aberration, immune response abnormality found 166 pesticides in Italian water, some of and chronic inflammation (8). which (e.g. atrazine) were forbidden a long In the present ecological study, a specific time ago: 34.4% of surface water samples workers’ group (the farmers) resident in the and 12.3% of groundwater ones resulted to Province of Vercelli (Italy) was observed in be polluted by pesticides whose quantity order to verify if its occupational exposure exceeded law limits for drinking water (4). to pesticides could be linked to cancer Agricultural pesticides are extremely incidence. harmful to environmental health and to The Province of Vercelli has a strong several very useful living organisms (3): it is agricultural tradition: agriculture, especially enough to mention the recent bees murrain based on rice-growing, is the main economic due to neonicotinoid pesticides based on activity in this area. On the other hand, imidacloprid (5). several important sources of environmental Long-term contact to pesticides can harm pressure are concentrated in this small area: human life and can disturb the function a municipal solid waste incinerator near of different organs in the body, including the town of Vercelli and two nuclear sites, nervous, endocrine, immune, reproductive, one near the town of Vercellese (the renal, cardiovascular and respiratory systems nuclear power plant “Enrico Fermi”, active

Table 1 - Studies about the association between pesticides exposure and cancer (104 studies were found and 83 were included: complete references are reported in Appendix A) Modified and adapted from: Bassil KL, Vakil C, Sanborn M, Cole DC, Kaur JS, Kerr KJ. Cancer health effects of pesticides: systematic review. Can Fam Physician 2007; 53 (10): 1704-11.

Type of cancer No. of No. of Summary of results studies found studies included Lung 4 4 2/4 found positive associations 5/6 found positive associations; Breast 12 6 1 found decreased risk with exposure Pancreatic 3 3 All found positive associations Non-Hodgkin lymphoma 32 27 23/27 found positive associations Leukemia 23 16 14/16 found positive associations Brain 11 11 All found positive associations Prostate 10 8 All found positive associations Stomach 1 1 Found a positive association Ovarian 1 1 Failed to find an association Kidney 7 6 All found positive associations Cancer risk among farmers in the Province of Vercelli (Italy) 257 until 1986) and one near the town of cases) recorded in the reference population (deposit of 80% of national nuclear waste). during the four-year period 2002-2005. Literature showed a well-known excess The Province of Vercelli is not served of cancer morbidity and mortality in the by a cancer registry (10). Therefore, to Province of Vercelli (9-13), but only few estimate the number of cases included intra- studies focused on cancer incidence in extra Regional passive mobility, Hospital local farmers and on the possible role of Discharge Forms (Schede di Dimissione their professional exposure to pesticides Ospedaliera, SDO) were used (16). SDOs (14). Studying farmers could allow to also contained information about age, assess the causal importance respectively gender, profession and type of diagnosed of environmental pressure and professional cancer. SDOs were consulted in the Local exposure factors in explaining cancer Health Unit of Vercelli (Azienda Sanitaria morbidity and mortality excesses in the Locale Vercelli, ASL VC) (17). above-mentioned area. Prevalent cases (admissions after the first hospitalization) were identified by consulting the SDOs of ASL VC concerning the period Objectives 2000-2001 and were excluded. Only cancer cases confirmed by the The present research aimed to discover if histopathology report (about 70% of those in a greater number of cancer cases among local the SDOs) were considered. Histopathology farmers could support the hypothesis that this reports were consulted at the Service of specific workers’ group have a higher risk to Pathological Anatomy of ASL VC (17). develop cancer diseases than the rest of the Cancer cases were then divided in cases resident employed population. The Authors recorded in farmers and non-farmers. tried to determine in a preliminary way if their This division was done according to the data were consistent with literature studies profession indicated on SDOs and confirmed (6-8), in order to delve into such results and by patients at hospitalization moment. to validate them with further researches. Patients who did not write their profession were excluded. Profession of patients who self declared Materials and methods farmers in SDOs was verified by consulting data about social security contributions Reference population paid during the period 1965-2005: only In the present ecological study, the patients who paid at least one year of social mean employed population with a range security contributions as farmers were of age from 25 to 84 years and resident in considered. Their occupational history the Province of Vercelli (Piedmont Region, was then controlled: farmers who also paid Italy) during the four-year period 2002-2005 any social security contributions for job was chosen as reference population. Farmers activities associated with higher cancer vs. non-farmers were considered. risk (e.g. textile workers) were excluded. Data were obtained from the Statistics Data about social security contributions Office of the Vercelli Chamber of Commerce were taken from Italian National Institute (15). of Social Security (Istituto Nazionale di Previdenza Sociale, INPS) (18). It was not Cancer cases possible to perform these contributions The present study considered all the first checks for non-farmers because data were hospital admissions for cancer (incident new not available. 258 C. Salerno et al.

The Authors decided to use new clinical resident in the Province of Vercelli during cases instead of prevalent ones, in order the four-year period 2002-2005 amounted to to avoid profession redundancy and to be 74,000 workers (42,000 males and 32,000 sure that every worker (and his profession) females). Farmers represented 5,81% of was counted only once. In the few cases the reference population, with about 4,300 of multiple cancer in the same person, operators (2,494 males and 1,806 females), profession was counted one single time. while non-farmers amounted to 69,700 In order to have data as similar as possible individuals (39,506 males and 30,194 to the employed population of the Province females). Stratification for age (five-year of Vercelli, all cases from 25 to 84 years old classes of age) proved that both farmers and were taken in account: in this way, on the one non-farmers had the same age distribution hand paediatric and youth cases (in which (data not shown). professional exposure is not significant) were not taken into consideration, on the other hand Main outcomes a 10-15-year latency period between exposure Data analysis including both genders (see end and cancer appearance was considered Table 2) showed that farmers, compared (19), given the farmers’ well-established habit to non-farmers, had a higher risk for the to go on working over the age of 70. following cancer types: oncohematologic, liver, pancreas, intestine, melanoma, lung Statistical Methods and kidney tumours. Calculated odds ratios The number of cancer cases recorded in for most of these pathologies showed highly farmers and non-farmers and the number significant P-values. of farmers and non-farmers present in the Data analysis divided by gender (see reference population were used in order to Table 3) demonstrated that both males and calculate the cancer odds ratio between the females in farmers, compared to males two professional categories. Cancer odds and females in non-farmers, had a higher ratios between the two groups were also risk for the following cancers: colorectal, calculated by gender and type of cancer. leukaemia, myeloma, pancreas and kidney The significance of the comparison between tumours. Lung cancer risk appeared to be the two workers’ groups was evaluated with higher only for males in farmers, while Pearson’s chi-squared test and Yates’ chi- liver neoplasm, melanoma and lymphoma squared test (20). Differences were considered demonstrated higher risks only for female statistically significant if P-value < 0.05. farmers. Calculated odds ratios for prostate Analyses were not age adjusted because (male farmers vs. male non-farmers) farmers and non-farmers belonging to the and udder cancer (female farmers vs. reference population showed the same female non-farmers) appeared to be highly age distribution (see Results: Reference significant. population). Calculations were carried out using the Discussion statistical software R, version 3.0.1 (21). The present study highlights that, in the reference population of the Province of Results Vercelli during the four-year period 2002- 2005, farmers, compared to non-farmers, Reference population showed a higher incidence for several The mean employed population with types of cancer, according to International a range of age from 25 to 84 years and Scientific Literature findings (6-8). Cancer risk among farmers in the Province of Vercelli (Italy) 259

Table 2 - Cancer odds ratios, by type of cancer, between farmers and non-farmers in the reference population (i.e the mean employed population with a range of age from 25 to 84 years and resident in the Province of Vercelli -Piedmont Region, Italy- during the four-year period 2002-2005)

No. of cancer cases No. of cancer cases Cancer odds ratio IC 95% Type of cancer P* in farmers a in non-farmers b (farmers vs. non-farmers) Colorectal 69 434 2.38 0.005 1,76-2,87 Leukaemia 13 91 2.65 0.0001 2,12-2,89 Oesophagus 4 29 2.30 n.s. 0,91-3,56 Liver + Biliary 18 139 2.16 0.0029 1,92-2,33 system Lymphoma 17 130 2.08 0.0061 1,99-2,23 Larynx 5 46 1.81 n.s 0,88-2,93 Melanoma 12 69 2.90 0.0009 2,54-3,15 Myeloma 10 47 3.55 0.0003 3,23-3,70 Pancreas 16 79 3.38 0.0001 3,14-3,61 Lung 35 366 1.59 0.01 1,12-2,38 Kidney 17 105 2.70 0.0002 2,41-2,99 Stomach 7 95 1.23 n.s 0,85-1,87 Bladder 22 299 1.23 n.s 0,91-2,12 Thyroid 4 34 1.96 n.s 0,90-3,11 a = number of farmers in the reference population: 4,300 subjects b = number of non-farmers in the reference population: 69,700 subjects * = differences are considered “statistically significant” if P < 0.05 and “highly statistically significant” if P < 0.001 (n.s. = not significant, i.e. P > 0.05)

As far as single tumour risk excesses feeding, fetal life, childhood and puberty are concerned, there are many hypothesis are key periods in which exposure to such supported by scientific studies. For instance, substances can cause serious damages: much for tumours involving specific hormones such more attention must be paid since such as breast, prostate, ovary and pancreas cancer, effects can be transgenerational (3, 22). it is possible to mention a specific pesticide It is by now proved that occupational category named “endocrin disruptors” (3, exposure to pesticides is linked to several 22). They are hormone mimetic molecules types of cancer, such as brain, breast, capable of interfering, even at very low pancreas, lung and testicular cancer, doses, with endocrine system, in particular malignant tumours and above all leukaemias, with thyroid and sexual steroids homeostasis not Hodgkin lymphomas and myelomas (3, (3). Results usually appear belatedly 23). The genetic damage mechanism, called (after decades) and vary according to chromosome translocation, was showed in the exposure moment: for example it has French peasants exposed to pesticides (24). been recently shown that exposure to A group of peasants exposed to pesticides DichloroDiphenylTrichloroethane (DDT; an was observed for 9 years: the group showed insecticide used in the 50s, prohibited many a dramatic increase of lymphoid cells clones years ago, but still present in environmental through chromosome translocation, which matrices) is linked to a higher risk of is the first step of the following lymphoma breast cancer if the exposure takes place evolution (24). This study is very important in prepubertal age (3). Pregnancy, breast- because demonstrated for the first time the 260 C. Salerno et al. ------IC95% 3,98-4,27 3,11-3,56 2,22-3,15 2,68-3,12 2,11-4,12 1,59-2,91 4,56-5,23 0,88-2,99 0,77-2,54 1,76-2,25 0,90-3,86 0,87-2,12 0,53-1,85 0,44-1,32 2,99-3,53 P ------n.s. n.s. n.s. n.s. n.s. n.s. 0.006 0.007 0.0026 0.0012 0.0001 0.09** 0.0001 0.0001 0.024** b ------4.18 2.84 2.97 3.18 3.22 2.33 4.85 1.52 1.57 1.93 2.39 1.43 1.04 0.74 3.25 (female farmers vs. (female farmers female non-farmers) female non-farmers) Cancer odds ratio for females ------IC95% 0,93-3,12 0,76-3,10 0,65-2,32 0,70-2,98 3,23-4,10 1,91-2,21 0,91-3,78 2,12-2,54 1,83-2,78 1,11-1,85 0,75-2,80 1,55-2,09 0,80-2,12 0,61-2,10 2,56-2,99 P ------n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. 0.031 0.0007 0.0002 0.0006 0.0002 0.033** 0.033** a ------2.11 3.66 2.07 2.31 1.66 1.40 1.84 2.31 2.35 1.55 1.96 2.70 1.38 1.20 1.32 (male farmers vs. (male farmers male non-farmers) male non-farmers) Cancer odds ratio for males Type of cancer Type Melanoma Myeloma Colorectal Leukaemia + Biliary system Liver Lymphoma Larynx Pancreas Oesophagus Lung Uterus Ovary Breast Prostate Thyroid Kidney Nervous system Nervous Bladder Stomach Table 3 - Cancer odds ratios, by gender and type of cancer, between farmers and non-farmers in the reference population (i.e. the mean employed population with a with population employed mean the (i.e. population reference the in non-farmers and farmers between cancer, of type and gender by ratios, odds Cancer - 3 Table period 2002-2005) Italy- during the four-year - Piedmont Region, of Vercelli range of age from 25 to 84 years and resident in the Province a = number of farmers, by gender, in the reference population: 2,494 males and 1,806 females by gender, a = number of farmers, in the reference population: 39,506 males and 30,194 females by gender, b = number of non-farmers, are considered “statistically significant” if P < 0.05 and “highly statistically 0.001 (n.s. = not significant, i.e. > 0.05) * = differences confirm this statistically significant P-value chi-squared test doesn’t ** = Yates Cancer risk among farmers in the Province of Vercelli (Italy) 261 molecular mechanism linking pesticides pollutants: among them there were factories exposure to blood diseases. workers exposed to substances as dangerous Literature showed a well-known excess as pesticides. of cancer morbidity and mortality in the Further studies may also use an extension Province of Vercelli (9-13), but only few of cancer cases dataset up to 2009: on the studies focused on cancer incidence in local one hand, this is supposed to strengthen farmers and on the possible role of their indications already emerged in the present professional exposure to pesticides (14). research, on the other hand it could highlight The present study, even if completely partial risk excesses for other types of cancer, e.g. and hypothetical, has the merit to address thyroid and nervous system cancers, not the issue of occupational cancer risk in an detectable with the present limited cases at important workers’ category for the Province disposal. Since observational studies so far of Vercelli, which has a strong agricultural conducted in the Province of Vercelli (9-13) tradition. Agriculture in the considered area always showed high frequencies of some is essentially based on rice-growing: this oncological diseases (i.e. colorectal, nervous could allow further studies to find out the system, thyroid cancer and leukaemias), it is molecules involved in the frequency excess advised to go on with researches about these of some types of cancer. target organs.

Study limitations The present study didn’t take in account Conclusions socio-demographic and behavioural characteristics of the two considered Further complete and comprehensive workers’ groups (e.g. place of birth, place studies are needed to examine in detail the of residence, income, voluptuary habits, issue of pesticides use and cancer excesses etc.). Some of them (e.g. place of residence recorded among farmers in the Province of close to health-risky sites, tobacco smoking, Vercelli. This will allow to set up a series of alcohol drinking) could be responsible interventions to sensitize farmers, in order for part of the observed cancer incidence to increase their awareness, to encourage excesses and therefore may be deepened the use of personal protective equipment in further studies. On the other hand, some and to promote a more responsible use of considerations lead to the suspect that, in pesticides. the present study, cancer risk excesses due to agricultural occupational exposure may be underestimated. Farmers were in fact exposed Thanks : We thank you for your precious collaboration Professor Maria Teresa Tenconi, Director of Hygiene to potentially dangerous substances such as and Public Health of Pavia pesticides, but most of them lived in the countryside and therefore were less exposed to pollutants produced by industrial waste and vehicles. In this regard, it is necessary Riassunto to consider that benzene, diffusely present Il rischio di cancro tra i coltivatori diretti della in cars but also in agricultural vehicles Provincia di Vercelli (Italia) dal 2002 al 2005: uno fuels, is a strong carcinogen involved in studio ecologico hematologic tumours aetiopathogenesis Obiettivo: verificare se i coltivatori diretti residenti (25). Non-farmers instead worked mainly in nella Provincia di Vercelli presentano un più alto rischio urban centres, with an undoubtedly higher di sviluppare un cancro rispetto al resto della popolazione exposure to non-occupational environmental attiva locale. 262 C. Salerno et al.

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Corresponding author: Dr. Sara Sacco, M.D., Ph.D. student, Department of Brain and Behavioural Sciences, Section of Biostatistics, Neurophysiology and Psychiatry, Unit of Medical Statistics and Computational Genomics - Clinical Epidemiology and Health Planning Laboratory, University of Pavia, Via Agostino Bassi 21, 27100 Pavia, Italy e-mail: [email protected]