GlyCin - Understanding the toxicokinetics of glyphosate and its metabolite in occupational and environmental exposure scenarios

Glyphosate (GLY) is the third most sold Plant Protection Products (PPP) in Switzerland, and conventional farmers (CF) use glyphosate-based herbicides (GBH) in various crops. Despite the widespread use of GBH, there is limited understanding of the toxicokinetics of GLY associated with occupational exposure among farm workers. In addition, the difference in toxicokinetics between occupational exposure and environmental exposure to GLY through contaminated diet remains inadequately characterized. 

The present study aims to address this lack of knowledge by characterizing both occupational and environmental exposure to GLY and its metabolite, aminomethylphosphonic acid (AMPA), in Swiss farmers working in orchards and vineyards, while also investigating environmental exposure through food sources and its impact on the general population. Specifically, our objectives are to: 

1. to determine the toxicokinetics of GLY and AMPA by quantifying the internal dose of GLY and AMPA in urine samples from CF using GBH over a 3-day post-exposure period, and to compare these doses with those quantified in urine samples from organic farmers (OF) and the Swiss Health Study pilot study (SHeS-pilot), a population-based sample of adults exposed to glyphosate through environmental sources
2. identify the primary routes of occupational exposure to GLY and determine the key exposure determinants in farmers
3. characterize both occupational and environmental exposure to GLY and its metabolite AMPA by developing a Physiologically Based Pharmacokinetic (PBPK) model that will integrate urine concentrations measured in CF, OF, and SHeS-pilot population and data from a food diary

We will recruit 100 CF from orchards or vineyards, using GBH routinely in their agricultural practice overall in Switzerland. These two cultures represent the most intensive GBH use per hectares. As controls, we will recruit unpaired 50 OF living in the same area and working in similar conditions (i.e., same crops) than CF. OF and data from the general adult population (SHeS-pilot) will be used to assess GLY environmental exposure. Initially, CF and OF will collect their 24-h urines over one day for GLY and AMPA analysis. Food diary will be recorded using a mobile application to estimate the intake of contaminated food. During a GBH application, CF will collect their urines for 3-consecutive day to determine the urinary elimination kinetics of GLY and AMPA and complete a questionnaire on their tasks relative to GBH application (e.g., concentration of the preparation, duration of the application, use of personal protective equipment). In addition, a subsample of 40 CF will be monitored using the video exposure monitoring (VEM) for three days to characterize work exposure situation. Air and handwashing samples will be added to the VEM to estimate the exposure dose through inhalation and dermal contact. 

The combination of biomonitoring results (urine), air and handwashing measurements, work activity records using self-reporting documents, food diary and VEM will enable us to estimate the overall exposure and the kinetics of elimination of GLY in Swiss farmers. These data will help to identify the major routes of entry for occupational exposure. The collection of these data will be synthetized to characterize both occupational and environmental GLY exposure in a PBPK model. 

This study will close the knowledge gaps on urinary elimination kinetics of GLY and AMPA according to the route of entry in the body (i.e., inhalation, dermal contact or ingestion) and allow quantifying the GLY exposure of Swiss farmers. The identification of exposure determinants will be of importance to promote safer GLY use, support regulatory decision-making and improve risk assessment strategies adapted to the Swiss context.