Cancer risks in a population-based study of 70,570 agricultural workers: results from the Canadian census health and Environment cohort (CanCHEC)

Agricultural workers represent a unique population. While these individuals are employed in a range of occupations associated with exposure to a number of potential carcinogens, they also have a lower prevalence of cigarette smoking and increased levels of physical activity [ 1]. As a result, individuals employed in agriculture tend to experience lower overall morbidity and mortality compared to the general population, and also exhibit distinctive cancer risk profiles [ 1– 4]. Studies of cancer incidence and mortality in farmers have consistently reported reduced risks of tobacco-related cancers, such as lung and bladder [ 2, 3, 5– 7]. Lower incidence of colorectal cancer has also been attributed to this favourable risk factor profile that includes higher levels of physical activity [ 3, 5, 7– 9].

However, studies of agricultural workers also point to a number of elevated cancer risks in this population, especially for lymphatic and hematopoietic cancers, melanoma, lip cancer, prostate cancer and brain tumors [ 2, 3, 5, 7]. This pattern is consistent with hazards associated with occupational exposure to pesticides, solvents, sunlight, dusts, and biological agents, such as zoonotic viruses, fungi and bacteria. Recent reports from the Agricultural Health Study (AHS), a large cohort of pesticide applicators and their spouses, also confirm many previous findings and implicate certain pesticides as key determinants of the cancer risks observed in agricultural populations [ 10].

Despite the accumulating evidence for a unique pattern of cancer incidence among agricultural workers and farmers, the last meta-analysis of studies in this area, conducted in 1998, reported inconsistent and highly heterogeneous results [ 3]. In addition to the multiplicity of exposures in agriculture, a possible explanation for these findings is that many earlier studies of agricultural populations have used mortality as the primary outcome, making it difficult to disentangle factors that influence cancer development from prognosis. Since then, few large-scale population-based occupational studies have been conducted, with one notable exception being the Nordic Occupational Cancer Study (NOCCA), which reported cancer incidence patterns among farmers and other occupational subgroups have been carried out in Denmark, Finland, Iceland, Norway and Sweden [ 5, 7]. However, similar comprehensive studies were lacking in Canada, despite the fact that agriculture has historically been one of the largest sectors of the Canadian economy.

A narrative review of the literature on cancer among farmers and an editorial dedicated to the NOCCA project, both published in 2009, called for future studies focusing on specific exposures, as well as the need for continued occupational cancer surveillance to document cancer incidence in agricultural workers and other occupational subgroups. [ 11, 12]. Furthermore, a consortium of agricultural cohort studies, AGRICOH, has been formed in 2010 to promote research efforts in this area, such as pooling of data across prospective studies to enable large-scale analyses of specific exposure-disease associations [ 13].

The Canadian Census Health and Environment Cohort (CanCHEC) was assembled to investigate cancer incidence patterns in specific socio-demographic and occupational groups in Canada. The aim of the present study was to address an important gap in Canadian occupational cancer surveillance by providing a comprehensive analysis of cancer risks among men and women employed in agriculture, by using data from a representative sample of the Canadian population. To our knowledge, this is the first and largest study of its kind in Canada, enabling a systematic analysis of cancer incidence by occupational subgroup, on a scale not previously possible in a single study.

This analysis of a large, population-based cohort study of Canadian agricultural workers has confirmed many established patterns of cancer risk, and uncovered several novel associations. As expected, overall cancer risk was significantly lower for both men and women employed in agricultural occupations, in comparison with the rest of the working population. The incidence of main tobacco- and alcohol-related cancers, such as lung, liver and larynx was also significantly reduced for both men and women working in agriculture.

However, a cautious interpretation of our findings is warranted since this cohort was designed for the purposes of cancer surveillance, with the primary goal of identifying meaningful patterns in cancer incidence by occupation. Therefore, while this analysis sacrifices some detail and specificity compared to exposure assessments in studies designed to evaluate specific agricultural exposures, linkage projects such as this one provide a unique opportunity to examine cancer patterns by occupation for a large, nationally representative sample of the population. Although our findings do not elucidate specific exposure-response relationships, the associations identified in this cohort provide leads regarding exposures that may be implicated in cancer risk and warrant follow-up in other studies.

Pesticides, several of which have been classified as known (Group 1) or probable (Group 2A) human carcinogens by the International Agency for Research on Cancer and several regulatory agencies in the United States [ 23– 25], are among the most prevalent and studied agricultural exposures [ 26]. Exposure to pesticides is often considered a major factor underlying increased risks of NHL, multiple myeloma, and leukemia observed in agricultural populations [ 3, 11]. A meta-analysis of 13 case-control studies observed a significantly increased risk of NHL associated with occupational pesticide exposure, and suggestive associations were reported for other hematopoietic cancers [ 27]. This pattern of results is consistent with the findings of population-based case-controls studies of pesticide exposure in Canada [ 28– 30] and the United States [ 31– 33], as well as results from the AHS cohort [ 10].

Our findings of increased leukemia risk among female farmers and managers, and specifically crop farmers, are also supported by recent studies of farming and pesticide exposure. The Iowa Women’s Health Study, a large cohort created by linkage to the Iowa Cancer Registry, reported increased risks of acute myeloid leukemia (AML) among women living on farms [ 34]. Furthermore, a large multi-site prospective cohort of postmenopausal women in the United States also reported increased risks of chronic lymphocytic leukemia/small lymphocytic lymphoma and AML associated with insecticide exposure [ 35]. Therefore, while the excess risks of hematological cancers observed in our study cannot be directly attributed to a specific exposure, the existing epidemiologic literature is suggestive of pesticides as a contributing factor.

The increased risk of pancreatic cancer observed among women employed in agriculture is a noteworthy finding of this study. A Spanish case-control study observed similarly increased risks of pancreatic cancer among female, but not male, agricultural workers [ 36]. However, a later analysis of a similar population-based case-control study in Spain observed a non-significant suggestive increase in risk male agricultural workers only [ 37]. A meta-analysis of occupational risk factors for pancreatic cancer identified several positive but weak associations, with the strongest evidence observed for nickel compounds based on results in four populations [ 38].

Pesticide exposure has been linked to prostate cancer [ 39, 40], however, the overall evidence for an increased risk of prostate cancer in farmers remains weak [ 41] and is unlikely to account for the modestly increased risks observed in our study. The observed associations may reflect a multitude of factors, including genetic predisposition and screening behavior, and should be interpreted with caution since the etiology of prostate cancer is poorly understood. Currently, the only established risk factors for prostate cancer are age, ethnicity, and a positive family history of prostate cancer [ 42]. Despite extensive research into lifestyle factors, the epidemiological evidence remains mixed. Early observations of increased prostate cancer risk associated with reduced sunlight exposure prompted investigations into the protective effects of vitamin D [ 43]. Although it was initially promoted for prostate cancer prevention [ 44], the accumulation of convicting findings, and recent reviews and meta-analyses of vitamin D do not support a convincing causal relationship with prostate cancer incidence [ 45– 47].

The inverse risk estimates observed for kidney, colon, rectal and bladder cancers are suggestive of a favourable risk factor profile in agricultural workers with respect to physical activity and body weight, which are recognized modifiable risk factors for these cancers [ 48, 49]. The decreased risks of bladder cancer observed consistently among male agricultural workers may also be related to the low prevalence of cigarette smoking in this population [ 50]. However, the impact of other environmental and occupational bladder cancer risk factors, such as contamination of drinking water with arsenic, exposure to polycyclic aromatic hydrocarbons (PAHs), aromatic amines, and diesel and gasoline emissions cannot be discounted [ 51– 53].

In addition to a low prevalence of tobacco smoking, endotoxin exposure may also contribute to the lower risk of lung cancer observed in agricultural workers. Endotoxin, or lipopolysaccharide (LPS), is a component of the outer membrane of Gram-negative bacteria, and is released during cell replication. These molecules are ubiquitous and inhalation of endotoxins present in dust is the main route of exposure. High levels of endotoxin exposure have been documented in agricultural settings, especially for activities involving animal breeding and handling [ 54]. Although the epidemiologic studies do not provide strong causal evidence, some mechanistic studies suggest that endotoxins can inhibit tumor initiation and growth, and LPS may stimulate the production of endogenous antineoplastic mediators [ 55– 57]. A systematic review of cohort and case control studies of lung cancer in cotton textile production and agriculture found significant inverse associations for endotoxin exposure among livestock farmers [ 58], suggesting that it may partly contribute to the lower risk of lung cancer observed for some agricultural occupations.

Our findings of statistically significant increases in the risk of lip cancer and melanoma among men implicate exposure to sunlight and ultraviolet (UV) radiation as a putative risk factor. Studies have identified UV exposure as a major determinant of both melanoma and non-melanoma skin cancers, including cancers of the facial skin [ 59]. Due to the small number of lip cancers in women this association could not be estimated, although excesses in melanoma risk, especially among female crop farmers, are compatible with this hypothesis. Overall, it appears that occupations associated high socioeconomic status, as well as jobs that involve outdoor work and potential for exposure to industrial chemicals tend to show increased risks of skin and lip cancer, compared with the general population [ 7, 60]. However, increased melanoma risk among agricultural workers may also be related to pesticide exposure, with studies reporting associations both with occupational [ 61] and residential use [ 62].

Cancers of the oral cavity are a diverse group of tumours arising from the epithelium lining the oral cavity and pharynx, with distinct risk factor profiles. The increased risks observed for lip cancer specifically, rather than all oral cavity cancers, is likely to reflect the interplay between risk factors shared common to all oral carcinomas, such as alcohol consumption and tobacco smoking, and more specific causal factors, such as human papillomavirus infection, a susceptibility factor for oropharyngeal carcinoma [ 63, 64].

Our analysis of more refined agricultural subgroups also revealed a 3-fold increased risk of thyroid cancer among male crop farmers. There are few known thyroid cancer risk factors with the exception of female sex and ionizing radiation. Although thyroid hormone excretion and metabolism can be disrupted by a number of chemicals found in the workplace, such as organochlorine pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers, the link with thyroid cancer remains tenuous. An analysis of predominantly male atrazine users in the AHS found an elevated risk of thyroid cancer for the highest compared to the lowest category of intensity-weighted use, but the trend was not monotonic and not statistically significant [ 65].

Several limitations of this analysis should be acknowledged. Given the retrospective nature of this cohort and its creation using linkage between existing health and administrative data sources, we did not have information on duration of employment in agriculture prior to the 1991 Census. We were also unable to track changes in occupation over the course of the follow-up period. This relatively crude approach is likely to reduce the specificity and sensitivity of our exposure assessment, resulting in exposure misclassification. However, since these limitations apply to all occupational groups within the cohort, and errors in exposure ascertainment are independent of cancer status, comparisons between agricultural workers and other groups may lead to imprecise risk estimates, but are unlikely to produce spurious associations [ 66]. Furthermore, classifying individuals with a short duration of employment in agriculture as exposed, would be expected to bias associations towards the null.

A second limitation concerns the possibility that some participants were diagnosed with cancer prior to cohort inception in 1991. Failure to account for a past history of cancer would only bias our analyses if agricultural workers as a group were enriched for cancer survivors, compared to all other occupations. However, since this is unlikely, a more relevant concern is that some prevalent cancer cases in the cohort were classified as outcome-free. This would be expected to bias the observed associations towards the null if the misclassification of disease status is non-differential with respect to occupation. While we acknowledge that a pre-1991 cancer diagnosis may affect the participant’s subsequent employment trajectory and occupation reported on census day, these effects are unlikely to have a differential impact on workers in agriculture compared to other industries [ 67].

Furthermore, our sensitivity analyses demonstrate that most of the observed associations persisted after the exclusion of individuals diagnosed with cancer within 10 years of cohort inception. The excess risks of lip cancer, melanoma and NHL in men were also observed in the sub-cohort, along with the inverse associations for lung, liver, bladder and larynx cancers. Similarly, the array of increased and decreased risks observed for female agricultural workers in the main analysis were also observed in the sensitivity analyses. Therefore, the stable pattern of associations emerging in both the full CanCHEC cohort and the cancer-free sub-cohort suggests that the inclusion of pre-1991 cancer cases is unlikely to bias the observed cancer risks or create spurious associations.

Confounding by lifestyle-related cancer risk factors is often a concern in occupational studies, as well as in studies relying on linkages between cancer registries and existing databases. Although smoking information was not available in CanCHEC, previous studies, in addition to analyses using the same linked 1991 Census data show that major determinants of smoking status include age, sex, level of education and occupation [ 21, 22]. Therefore, although confounding by smoking cannot be excluded, adjustment for key determinants of smoking status in our analysis helps mitigate the impact of this residual confounding. Furthermore, the magnitude of confounding by tobacco smoking or high levels of alcohol consumption may be further minimized in our study due to the low prevalence of both of these risk factors in agricultural populations, contemporaneous to CanCHEC inception [ 68, 69].

Other limitations of this study include limited power for investigating less common cancers, especially within more refined agricultural subgroups. In addition, given the large number of cancer sites and occupational subgroups that were tested, some of the observed associations may be chance findings due to multiple comparisons.

Our study has a number of important strengths. CanCHEC is the largest population-based cohort in Canada, and one of the largest studies of its kind worldwide. Although it is smaller than the previously mentioned NOCCA cohort of 15 million [ 7], the 2.1 million participants in CanCHEC, including 70,570 agricultural workers are broadly representative of the Canadian population due to the high response rate for the 1991 Census [ 15]. Although the exposure assessment is less detailed than in studies such as the AHS, CanCHEC provides a powerful resource for examining cancer patterns in specific population groups and represents a valuable addition to the cancer literature by demonstrating that disparities in cancer risk by occupation status continue to persist and should be investigated using more targeted studies. The updated linkage to the Canadian Cancer Registry allows for a long follow-up period, which is important for cancer outcomes that have long latency periods. Together, the large sample size and length of follow-up allow for a large number of events, which results in improved statistical power for the investigation of detailed occupational subgroups and specific cancer sites. Importantly, relatively few studies focus on women employed in agriculture, and even fewer have systematically reported estimates of cancer risk across multiple sites and occupational subgroups.

In the beginning twentieth century, agriculture was the single most common occupation, employing over 1 million Canadians and accounting for one-third of all jobs. Over the course of our follow-up period, between 1991 and 2011, the total number of Canadian farms fell by over 74,000 and now represents less than 1% of the labour force. However, if agricultural populations experience higher incidence for certain types of cancer, understanding the magnitude of these increased risks represents an important step towards developing preventive efforts targeting these populations.

Despite the changing profile of Canadian agricultural workers, studies of this population continue to be relevant by providing insight into cancer risks associated with common exposures that are often found outside of agricultural settings. For instance, the large magnitude of UV-related risks, especially for lip cancer, underscores the substantial impact that may be achieved by preventive efforts in this area. Therefore, studies of agricultural workers can inform preventive interventions aimed at reducing the cancer burden in the general population.

In summary, the results of the present analysis point to excess risks for certain cancers among agricultural workers. A wide range of exposures is possible in agriculture, including pesticides, solvents, engine exhaust emission, UV light, dust, as well as zoonotic viruses and bacteria. Exposures can vary considerably between occupations, and even between farms, therefore future research must focus on specific exposures to identify and clarify which risk factors may contribute to the observed pattern of cancer incidence.