Pesticides expenditures by farming type and incidence of Parkinson disease in farmers: A French nationwide study.

BACKGROUND: Professional pesticides exposure is associated with PD risk, but it remains unclear whether specific products, which strongly depend on farming type, are specifically involved. We performed a nationwide ecological study to examine the association of pesticides expenditures for the main farming types with PD incidence in French farmers. METHODS: We used the French National Health Insurance database to identify incident PD cases in farmers (2010-2015). We combined data on pesticides expenditures with the agricultural census to compute pesticides expenditures for nine farming types in 2000 in 3571 French cantons. The association between pesticides expenditures and PD age/sex standardized incidence was examined using multilevel Poisson regression, adjusted for smoking, neurologists' density, and deprivation index. RESULTS: 10,282 incident PD cases were identified. Cantons with the highest pesticides expenditures for vineyards without designation of origin were characterized by 16% (95% CI = 6-28%) higher PD incidence (p-trend corrected for multiple testing = 0.006). This association was significant in men and older farmers. There was no association with pesticides expenditures for other farming types, including vineyards with designation of origin. CONCLUSIONS: PD incidence increased significantly with pesticides expenditures in vineyards without designation of origin characterized by high fungicide use. This result suggests that agricultural practices and pesticides used in these vineyards may play a role in PD and that farmers in these farms should benefit from preventive measures aiming at reducing exposure. Our study highlights the importance of considering farming type in studies on pesticides and PD and the usefulness of pesticides expenditures for exposure assessment.

Domestic use of pesticides during early periods of development and risk of testicular germ cell tumors in adulthood: a French nationwide case-control study.

BACKGROUND: Testicular germ cell tumours (TGCT) are the most frequent cancers in young men in developed countries and their incidence rate has doubled worldwide over the past 40 years. Early life exposures to pesticides are suspected to increase TGCT risk. Our research aimed at estimating adult TGCT risk associated with parental domestic use of pesticides during early periods of child development. METHODS: We conducted a case-control study of 304 TGCT cases, aged 18-45 years old, recruited in 20 French university hospitals, and 274 controls frequency-matched on hospital and birth year. Participants' mothers provided information on their domestic use of pesticides from 1 year before start of pregnancy to 1 year after their son's birth, for gardening activities, treatment of indoor plants, pets, wood and mold, and pest control. Odds ratios (OR) for TGCT (overall and by histological subtype) and 95% confidence intervals (CI) were estimated using conditional logistic regression. RESULTS: Prevalence of reported domestic use of pesticides was 77.3% for insecticides, 15.9% for fungicides and 12.1% for herbicides. While no association was found for any use of insecticides (OR = 1.27, CI = 0.80-2.01) or herbicides (OR = 1.15, CI = 0.67-2.00), elevated risks of TGCT overall (OR = 1.73, CI = 1.04-2.87) and non-seminoma subtype (OR = 2.44, CI = 1.26-4.74) were observed for any use of fungicides. When specific purposes were examined, using fungicides and/or insecticides for woodwork (OR = 2.35, CI = 1.06-5.20) and using insecticides on cats and dogs (OR = 1.95, CI = 1.12-3.40) were associated with increased risk of non-seminoma subtype. We found no association for seminoma subtype. CONCLUSIONS: Although recall bias may partially explain the elevated ORs, our study provides some evidence of a positive association between domestic use of pesticides during early periods of development, particularly fungicides and risk of adult TGCT and non-seminoma. Given the common domestic use of pesticides in France, further research on TGCT risk is warranted.

Agricultural activities and the incidence of Parkinson's disease in the general French population.

Most studies on pesticides and Parkinson's disease (PD) focused on occupational exposure in farmers. Whether non-occupational exposure is associated with PD has been little explored. We investigated the association between agricultural characteristics and PD incidence in a French nationwide ecologic study. We hypothesized that persons living in regions with agricultural activities involving more intensive pesticide use would be at higher risk. We identified incident PD cases from French National Health Insurance databases (2010-2012). The proportion of land dedicated to 18 types of agricultural activities was defined at the canton of residence level. We examined the association between agricultural activities and PD age/sex-standardized incidence ratios using multivariable multilevel Poisson regression adjusted for smoking, deprivation index, density of neurologists, and rurality (proportion of agricultural land); we used a false discovery rate approach to correct for multiple comparisons and compute q-values. We also compared incidence in clusters of cantons with similar agricultural characteristics (k-means algorithm). We identified 69,010 incident PD cases. Rurality was associated with higher PD incidence (p < 0.001). Cantons with higher density of vineyards displayed the strongest association (RRtop/bottom quartile = 1.102, 95% CI = 1.049-1.158; q-trend = 0.040). This association was similar in men, women, and non-farmers, stronger in older than younger persons, and present in all French regions. Persons living in the cluster with greatest vineyards density had 8.5% (4.4-12.6%) higher PD incidence (p < 0.001). In France, vineyards rank among the crops that require most intense pesticide use. Regions with greater presence of vineyards are characterized by higher PD risk; non-professional pesticides exposure is a possible explanation.

Combining crop-exposure matrices and land use data to estimate indices of environmental and occupational exposure to pesticides.

BACKGROUND: Exposure assessment represents a major challenge for studies on the relation between pesticides and health. OBJECTIVE: We developed a method combining information from crop-exposure matrices (CEMs) and land use data, in order to compute indices of environmental and occupational pesticide exposure. We illustrate our approach using French data (1979-2010). METHODS: We used CEMs for five crops (straw cereals, grain corn, corn fodder, potatoes, vineyards) that describe use (annual probability, frequency, intensity) of pesticide subgroups, chemical families, and active substances by region and time since 1960. We combined these data with land use data from agricultural censuses (1979, 1988, 2000, 2010) to compute indices of environmental and occupational pesticide exposure in cantons (small French administrative units). Indices of environmental exposure were calculated based on the area of each crop in the cantons, while indices of occupational exposure depended on combinations of crops in each farm from the cantons. To illustrate our approach, we selected a pesticide group (herbicides), chemical family of herbicides (phenoxyacetic acids), and active substance from the phenoxyacetic acids chemical family (2,4-D). RESULTS: The estimated proportion of the area of crops with CEMs and of farms sprayed with herbicides was close to 100% between 1979-2010, but the estimated average annual number of applications increased. There were decreasing time-trends for phenoxyacetic acids and 2,4-D over the same period for all indices of exposure. There was a high use of herbicides throughout France in 2010, except in the South coast. For phenoxyacetic acids and 2,4-D, the spatial distribution was heterogeneous for all indices of exposure, with the highest values in the Centre and North regions. IMPACT STATEMENT: Assessment of pesticide exposure is a key issue for epidemiological studies on their association with health outcomes. However, it presents some unique challenges, particularly for retrospective exposure and the investigation of chronic diseases. We present a method to compute indices of exposure by combining information from crop-exposure matrices for five crops and land use data. Specificities of environmental and occupational exposure are addressed using different methods. These methods are applied to pesticides used in agriculture in France for five crops (3 groups, 91 chemical families, 197 active substances) to produce indices at a small geographic scale from 1979 to 2010 for the whole metropolitan France. Besides using these indices in French epidemiological studies, our approach could be relevant for other countries.

Changes in the European Union definition for endocrine disruptors: how many molecules remain a cause for concern? The example of crop protection products used in agriculture in France in the six last decades.

Background: The endocrine-disrupting effects of phytopharmaceutical active substances (PAS) on human health are a public health concern. The CIPATOX-PE database, created in 2018, listed the PAS authorized in France between 1961 and 2014 presenting endocrine-disrupting effects for humans according to data from official international organizations. Since the creation of CIPATOX-PE, European regulations have changed, and new initiatives identifying substances with endocrine-disrupting effects have been implemented and new PAS have been licensed. Objectives: The study aimed to update the CIPATOX-PE database by considering new 2018 European endocrine-disrupting effect identification criteria as well as the new PAS authorized on the market in France since 2015. Methods: The endocrine-disrupting effect assessment of PAS from five international governmental and non-governmental initiatives was reviewed, and levels of evidence were retained by these initiatives for eighteen endocrine target organs. Results: The synthesis of the identified endocrine-disrupting effects allowed to assign an endocrine-disrupting effect level of concern for 241 PAS among 980 authorized in France between 1961 and 2021. Thus, according to the updated CIPATOX-PE data, 44 PAS (18.3%) had an endocrine-disrupting effect classified as "high concern," 133 PAS (55.2%) "concern," and 64 PAS (26.6%) "unknown effect" in the current state of knowledge. In the study, 42 PAS with an endocrine-disrupting effect of "high concern" are similarly classified in CIPATOX-PE-2018 and 2021, and 2 new PAS were identified as having an endocrine-disrupting effect of "high concern" in the update, and both were previously classified with an endocrine-disrupting effect of "concern" in CIPATOX-PE-2018. Finally, a PAS was identified as having an endocrine-disrupting effect of "high concern" in CIPATOX-PE-2018 but is now classified as a PAS not investigated for endocrine-disrupting effects in CIPATOX-PE-2021. The endocrine target organs associated with the largest number of PAS with an endocrine-disrupting effect of "high concern" is the reproductive system with 31 PAS. This is followed by the thyroid with 25 PAS and the hypothalamic-pituitary axis (excluding the gonadotropic axis) with 5 PAS. Discussion: The proposed endocrine-disrupting effect indicator, which is not a regulatory classification, can be used as an epidemiological tool for occupational risks and surveillance.

Parental occupations at birth and risk of adult testicular germ cell tumors in offspring: a French nationwide case-control study.

Background: Testicular germ cell tumors (TGCT) are the most frequent cancer in young men in developed countries. Parental occupational exposures during early-life periods are suspected to increase TGCT risk. The objective was to estimate the association between parental occupations at birth and adult TGCT. Methods: A case-control study was conducted, including 454 TGCT cases aged 18-45 from 20 French university hospitals, matched to 670 controls based on region and year of birth. Data collected from participants included parental jobs at birth coded according to the International Standard Classification of Occupation-1968 and the French nomenclature of activities-1999. Odds ratios (OR) for TGCT and 95% confidence intervals (CI) were estimated using conditional logistic regression, adjusting for TGCT risk factors. Results: Paternal jobs at birth as service workers (OR = 1.98, CI 1.18-3.30), protective service workers (OR = 2.40, CI 1.20-4.81), transport equipment operators (OR = 1.96, CI 1.14-3.37), specialized farmers (OR = 2.66, CI 1.03-6.90), and maternal jobs as secondary education teachers (OR = 2.27, CI 1.09-4.76) or in secondary education (OR = 2.35, CI 1.13-4.88) were significantly associated with adult TGCT. The risk of seminoma was increased for the above-mentioned paternal jobs and that of non-seminomas for public administration and defence; compulsory social security (OR = 1.99, CI 1.09-3.65); general, economic, and social administration (OR = 3.21, CI 1.23-8.39) for fathers; and secondary education teacher (OR = 4.67, CI 1.87-11.67) and secondary education (OR = 3.50, CI 1.36-9.01) for mothers. Conclusion: Some paternal jobs, such as service workers, transport equipment operators, or specialized farmers, and maternal jobs in secondary education seem to be associated with an increased risk of TGCT with specific features depending on the histological type. These data allow hypotheses to be put forward for further studies as to the involvement of occupational exposures in the risk of developing TGCT, such as exposure to pesticides, solvents, or heavy metals.

The relation between type of farming and prevalence of Parkinson's disease among agricultural workers in five French districts.

Retrospective assessment of pesticide exposure is complex; however, patterns of pesticide use strongly depend on farming type, which is easier to assess than pesticide exposure. Our aim was to estimate Parkinson's disease (PD) prevalence in five French districts in 2007 among affiliates of Mutualité Sociale Agricole (MSA) and to investigate the relation between PD prevalence and farming type. We identified PD cases from administrative files as persons who used levodopa and/or benefited from free health care for PD. Densities of 16 farming types were defined at the canton of residence level (1988 French agricultural census). We used logistic regression to study the relation between PD prevalence and density of farming types and a semi-Bayes approach to deal with correlated exposures. We identified 1,659 PD cases, yielding an age- and sex-standardized PD prevalence of 3.01/1,000. Prevalence increased with age and was higher in men than women. We found a higher PD prevalence among affiliates living in cantons characterized by a higher density of farms specialized in fruits and permanent crops (multivariable semi-Bayes model: OR(4+5 vs 1+2+3 quintiles) = 1.21, 95% CI = 1.08-1.36; test for trend, P = 0.035). In France, farms specialized in fruits and permanent crops rank first in terms of insecticide use per hectare. Our findings are consistent with studies reporting an association between PD and insecticide use and show that workers in farms specialized in fruits or permanent crops may be an occupational group at higher PD risk.

The ED/TEG Indicator for the Identification of Endocrine Disrupting or Toxic Effects on Endocrine Glands of Crop Protection Products Used in Organic and Conventional Agriculture in France.

Studying the human health impacts of pesticides and their endocrine disruptor (ED) effects is a public health concern. The aim of this study is to identify phytopharmaceutical active substances (PAS) that are an ED or are toxic on endocrine glands (TEG), and to propose an ED/TEG effect indicator. Five international official databases were analyzed to identify the occurrence of health outcomes for 458 PAS. Health outcomes targeting seven endocrine systems were selected. For each substance, the level of evidence of the collected information and the number of outcomes were used to affect a level of concern about ED/TEG effects. Among the substances studied, 10% had a global ED/TEG effect classified as 'high concern', 55% as 'medium concern', 9% as 'low concern', and 26% as 'unknown'. Ten of the high ED/TEG concern substances and 170 medium or low concern substances were licensed in 2018 in France. The outcomes were mainly on the reproductive organs, thyroid, and adrenal glands. Eight of the 41 biocontrol products studied were classified: 5 were 'high' or 'medium concern' and 3 had 'unknown effect'. Although the proposed ED/TEG indicator is not an official classification, it can be used as an epidemiological tool for classifying the occupational and environmental risks of substances in retrospective population studies and be useful for occupational health physicians.

Medico-administrative data combined with agricultural practices data to retrospectively estimate pesticide use by agricultural workers.

This work is part of a global project aiming to use medico-administrative big data from the whole French agricultural population (~3 millions), collected through their mandatory health insurance system (Mutualité Sociale Agricole), to highlight associations between chronic diseases and agricultural activities. At the request of the French Agency for Food, Environmental and Occupational Health & Safety (ANSES), our objective was to estimate which pesticides were probably used by each agricultural worker, in order to include this information in our analyses and search for association with diseases. We selected five databases to achieve this objective: the Graphical Land Parcel Registration (RPG), the French Agricultural Census, "Cultivation Practice" surveys from the Agriculture ministry, the MATPHYTO crop-exposure matrix and the Compilation of Phytosanitary Indexes from the French Public Health Agency. A geographical grid was designed to use geographical location while maintaining worker anonymity, dividing France into square tracts of variable surface each containing a minimum of 1500 agricultural workers. We developed an automated algorithm to predict each individual potential exposure by crossing her/his occupational activity, the geographical grid and the RPG to deduce cultivation practices and use it as a gateway to estimate pesticides use. This approach allowed drawing, from administrative data, a list of substances potentially used by each agricultural worker throughout France. Results of the algorithm are illustrated at collective level (descriptive statistics for the whole population), as well as at individual level (some workers taken as examples). The generalization of this method in other national contexts is discussed. By linking this information with the health insurance databases, this approach could contribute to the agricultural workers health surveillance.

Association of Parkinson's Disease and Its Subtypes with Agricultural Pesticide Exposures in Men: A Case-Control Study in France.

BACKGROUND: Pesticides have been associated with Parkinson's disease (PD), but there are few data on important exposure characteristics such as dose-effect relations. It is unknown whether associations depend on clinical PD subtypes. OBJECTIVES: We examined quantitative aspects of occupational pesticide exposure associated with PD and investigated whether associations were similar across PD subtypes. METHODS: As part of a French population-based case-control study including men enrolled in the health insurance plan for farmers and agricultural workers, cases with clinically confirmed PD were identified through antiparkinsonian drug claims. Two controls were matched to each case. Using a comprehensive occupational questionnaire, we computed indicators for different dimensions of exposure (duration, cumulative exposure, intensity). We used conditional logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs) among exposed male farmers (133 cases, 298 controls). We examined the relation between pesticides and PD subtypes (tremor dominant/non-tremor dominant) using polytomous logistic regression. RESULTS: There appeared to be a stronger association with intensity than duration of pesticide exposure based on separate models, as well as a synergistic interaction between duration and intensity (p-interaction = 0.04). High-intensity exposure to insecticides was positively associated with PD among those with low-intensity exposure to fungicides and vice versa, suggesting independent effects. Pesticide exposure in farms that specialized in vineyards was associated with PD (OR = 2.56; 95% CI: 1.31, 4.98). The association with intensity of pesticide use was stronger, although not significantly (p-heterogeneity = 0.60), for tremor-dominant (p-trend < 0.01) than for non-tremor-dominant PD (p-trend = 0.24). CONCLUSIONS: This study helps to better characterize different aspects of pesticide exposure associated with PD, and shows a significant association of pesticides with tremor-dominant PD in men, the most typical PD presentation. CITATION: Moisan F, Spinosi J, Delabre L, Gourlet V, Mazurie JL, Bénatru I, Goldberg M, Weisskopf MG, Imbernon E, Tzourio C, Elbaz A. 2015. Association of Parkinson's disease and its subtypes with agricultural pesticide exposures in men: a case-control study in France. Environ Health Perspect 123:1123-1129; http://dx.doi.org/10.1289/ehp.1307970.