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International audience; Biomonitoring can be relevant for assessing pesticides exposure of residents living close to vineyards (LCTV). However, because xenobiotics are generally present at low levels in human biological matrices and the sources of pesticide exposure are multiple, several challenges need to be overcome to reliably assess exposure in residents LCTV. This includes particularly identifying the most appropriate exposure biomarkers, the biological matrices in which they should be measured, and analytical methods that are sufficiently sensitive and specific to quantify them. The aim of the present study was to develop a tiered approach to identify relevant biomarkers and matrices for assessing pesticide exposure in residents LCTV. We used samples from a biobank for 121 adults and children included in a national prevalence study conducted between 2014 and 2016 who lived near or far from vineyards. We analyzed five priority pesticides (folpet, mancozeb, tebuconazole, glyphosate, and copper) and their metabolites in urine and hair samples. We identified relevant biomarkers according to three criteria related to: i) the detection frequency of those pesticides and metabolites in urine and hair, ii) the difference in concentrations depending on residence proximity to vineyards and, iii) the influence of other environmental and occupational exposure sources on pesticide levels. This tiered approach helped us to identify three relevant metabolites (two metabolites of folpet and one of tebuconazole) that were quantified in urine, tended to be higher in residents LCTV than in controls, and were not significantly influenced by occupational, dietary, or household sources of pesticide exposure. Our approach also helped us to identify the most appropriate measurement strategies (biological matrices, analytical methods) to assess pesticide exposure in residents LCTV. The approach developed here was a prerequisite step for guiding a large-scale epidemiological study aimed at comprehensively measuring pesticides exposures in French residents LCTV with a view to developing appropriate prevention strategies.

There is increasing evidence that people living near crops are exposed to the pesticides used on these crops, particularly through drift and volatilization of pesticides beyond the treated areas. However, these data are difficult to generalize to the French agricultural context and it is therefore necessary to produce objective measurements of non-occupational exposure to pesticides in people living near crops in France, in particular near vineyards. Measuring biomarkers of exposure in biological matrices is a relevant approach to produce such data. However, there are several challenges in estimating pesticide exposure from biological measurements, in particular the selection of exposure biomarkers that reliably reflect specific exposure to environmental pollutants, including in the context of multisource exposures. The objective of this thesis is to develop an approach to identify relevant biomarkers of exposure to measure exposure to pesticides used specifically in vineyards and to identify the most appropriate biological matrices for their measurement and interpretation. This approach is based on ad hoc bioassays performed on biological samples (urine and hair) from 121 adults and children included in the Esteban study, between 2014 and 2016, and living near or far from vineyard plots. These analyses concerned five priority pesticides selected for the study (folpet, mancozeb, tebuconazole, glyphosate, copper) and their metabolites. This approach allowed the identification of three relevant biomarkers of exposure (metabolites of folpet and tebuconazole) that are both specific to the priority pesticides used in wine-growing crops in France and relevant to previous studies aimed at specifically assessing exposure in a wine-growing context. The work carried out in the framework of the thesis also allowed the identification of the most appropriate analytical strategies (biological matrices, analytical methods) to evaluate pesticide exposures in people living near vineyards. This work is a preliminary step to provide guidance on the requirements and practical implications of a large-scale study to characterize pesticide exposure in people living near vineyards in France. This is an essential step for conducting large-scale epidemiological studies and assessments of the associated health risks, but also for developing prevention strategies and appropriate public policies., Il existe de plus en plus de données indiquant que les personnes vivant près de cultures sont exposées aux pesticides utilisés sur ces cultures à travers notamment de phénomènes de dérive et de volatilisation des pesticides au-delà des zones traitées. Toutefois, ces données sont difficilement généralisables au contexte agricole français et il est donc nécessaire de produire des mesures objectives de l’exposition non professionnelle aux pesticides chez les personnes vivant près de cultures en France, en particulier près de vignes. La réalisation de mesures de biomarqueurs d’exposition dans des matrices biologiques est une approche pertinente pour produire de telles données. Toutefois, il existe plusieurs défis pour estimer l'exposition aux pesticides à partir de mesures biologiques, en particulier la sélection de biomarqueurs d’expositions permettant de refléter de manière fiable une exposition spécifique à des polluants de l’environnement, y compris dans un contexte d’expositions multisources. L'objectif de la thèse est de développer une approche d’identification des biomarqueurs d’exposition pertinents pour mesurer l’exposition aux pesticides utilisés spécifiquement dans les cultures viticoles et identifier les matrices biologiques les plus adaptées à leur dosage et à leur interprétation. Cette approche est basée sur des dosages biologiques ad hoc réalisés à partir d’échantillons biologiques (urines et cheveux) de 121 adultes et enfants inclus dans l’étude Esteban, entre 2014 et 2016, et vivant près ou loin de parcelles viticoles. Ces analyses ont concerné cinq pesticides prioritaires sélectionnés pour l’étude (folpel, mancozèbe, tébuconazole, glyphosate, cuivre) et leurs métabolites. Cette approche a permis d'identifier trois biomarqueurs d’exposition pertinents (métabolites du folpel et du tébuconazole) à la fois spécifiques des pesticides prioritaires utilisés dans les cultures viticoles en France et pertinents au regard des études antérieures visant à évaluer spécifiquement les expositions dans un contexte viticole. Les travaux réalisés dans le cadre de la thèse ont également permis d'identifier les stratégies analytiques les plus appropriées (matrices biologiques, méthodes analytiques) pour évaluer les expositions aux pesticides chez les personnes vivant près de vignes. Ces travaux sont une étape préalable pour fournir des indications sur les exigences et les implications pratiques d’une étude à grande échelle visant à caractériser l’exposition aux pesticides chez les riverains de vignes en France. Il s’agit d’une étape essentielle pour conduire des études épidémiologiques à grande échelle et des évaluations des risques sanitaires associés, mais également pour développer des stratégies de prévention et des politiques publiques appropriées.