In this case-control study in France, increases in the risk of central nervous system tumors were observed in relation to various occupational pesticide exposures in agriculture but also outside agriculture. In the most exposed individuals, the risk of glioma was non-significantly trebled in open field and in fruit-growing and multiplied by 1.68 in vine-growing. Elevated risks of glioma were also observed for non-agricultural use of pesticides, especially in workers in green spaces and in the wood industry, and to a lesser extent in pest control workers. No increase in risk was seen for meningioma, nor in indirectly exposed individuals in agriculture. Although the total number of cases included was quite large, most of the elevated risks we found did not reach the statistical significance because of limited numbers when considering tumor subtypes together with specific types of pesticide exposures. Thus, these results can only be interpreted as trends, but they are important to consider because of the strength of some associations that we observed. Moreover, these results were globally consistent, showing higher risks in gliomas and in most exposed individuals for almost all the types of pesticide use.
The main strengths of this study include the enrolment of incident cases supported by population-based cancer registries, face-to-face interviews, the analysis of sub-types of tumors (gliomas, meningiomas), accurate pesticide exposure assessment (exploring agricultural and non-agricultural jobs, direct and indirect exposures). Considering the 73% participation rate in cases and 45% in controls, we cannot rule out selection bias. However, the lower participation of subjects with gliomas and elderly people, more frequently exposed to pesticides as shown by observations of participants, is likely to have decreased our risk estimates and biased our results toward the null. Apart from this, we do not see any clear reasons why the participation would be related to pesticide exposures especially as the study was presented to participants as dealing with environmental and occupational factors and CNS health in general, without mentioning the hypothesis on pesticides. Recall bias is a concern in our study as in any retrospective study. However, we believe that this bias was limited by the review of exposure data by experts, who considered job titles as well as responses to specific questionnaires to ensure exposure assessment consistency.
One of the lessons from our study, as already raised by results from a previous study, is the difficulty of highlighting associations when histological types of CNS tumors and kind of exposures are not analyzed separately. This could explain why studies using imprecise metrics for pesticide exposure, such as job titles, have failed to demonstrate an association (Fincham et al. 1992; Forastiere et al. 1993). In our study, the highest risks were observed for gliomas in open field farmers. Wheat and corn were the main crops they had treated in their occupational lives, sometimes in combination with other crops, such as potato, sunflower, rape or beet. Some of them have also raised livestock and may have used insecticides on them. This open field context implies the use of a wide variety and combination of pesticides during a given season and even more life-long, leading to complex toxicological issues. Our result is not in line with those of studies developed in the US in open field farming: associations between pesticide use and risk of brain tumors were unclear in the Upper Midwest Study (Carreón et al. 2005; Ruder et al. 2004) and so far limited to chlorpyrifos in applicators (Lee et al. 2004) and organochlorines (lindane and chlordane) in spouses in the Agricultural Health Study (Louis et al. 2017), while these two studies covered areas (Iowa, South Carolina, Michigan, Minnesota, Wisconsin) devoted to open field farming (wheat, corn, beet, etc.). However, American farming differs from French, by larger and more frequently monocultural farms, that may be associated with different practices, work organization and equipment, all factors that can influence pesticide exposures. But our result in open field farming is consistent with those from the French Agrican cohort that found elevated risks for CNS tumors in farmers using pesticides, more pronounced in those growing peas, beets and potatoes (Piel et al. 2017). Even if not significant, we also found elevated risk of gliomas in relation with the longest pesticide exposures in vine-growing, consistent with the historical case-control study by Mussico in Italy (Musicco et al. 1988), with an ecological analysis performed on vine-growing at the national scale in France (Viel et al. 1998), and with a previous case-control study we conducted in the Bordeaux area (Provost et al. 2007). Results on fruit and vegetable growing are less conclusive, but indicated a trend towards an increased risk of glioma in the most exposed, for which no other evidence in the literature has been found. Few studies have explored the association of CNS tumors with pesticide exposures outside agriculture. We observed a significant doubling in risk in green space workers, consistent with a study in golf course workers that found an elevated mortality for CNS tumors compared to the USA general population (Kross et al. 1996). The non-significant doubling of risk that we found in workers exposed in the wood industry is in line with a case-control study on gliomas that showed a raised risk among wood workers, attributed to exposure to organochlorine wood preservative and solvents (Cordier et al. 1988). Our conclusions on pest control workers are limited because of small numbers, but the slight increase in risk we found in the most exposed is in line with a study in Roma that found an excess in CNS tumor mortality in a retrospective cohort of pest control workers (Figà-Talamanca et al. 1993).
In this study, we have not explored the role of specific active ingredients, as people generally cannot remember them life-long. However, the increases in risk we observed across several crops and also outside agriculture, suggest either of the role of a large range of pesticides or of the role of pesticides that have been indicated for multiple uses. Carbamates, that have been pointed out by several studies (Carreón et al. 2005; Navas-Acién et al. 2002; Piel et al. 2019a, 2019a), fulfill the second hypothesis as they have been used as insecticides on crops (including seed treatment) and animals, as well as herbicides and fungicides (mainly dithiocarbamates), but we cannot rule out the possibility that several other molecules, among the more than 1,000 that have been marketed since 1950, could play a role.