Étude de la cinétique des pesticides pyréthrinoïdes en conditions contrôlées et en milieu de travail dans un objectif de biosurveillance

Pyrethroids are widely used insecticides. The general population is exposed to these compounds through the diet while agricultural workers are exposed during various tasks in the fields. Pyrethroids are compounds of interest given their neurotoxic, immune and endocrine disruptor effects; they should thus be monitored to ensure the health of the population. Measurement of biomarkers of exposure, which consists of quantifying concentrations of a substance or its metabolites in accessible biological matrices, allows estimating absorbed doses. Biomarkers can also be endogenous molecules that respond to a physiological stress and identified as biomarkers of effects. To refine biomonitoring of exposure strategies , one must be familiar with the toxicokinetics of xenobiotics; to date, biomonitoring studies rarely consider temporal variability, hence intra- and inter-individual variability, which may influence estimation of exposure The aim of the thesis was to apply a kinetic approach for the assessment of exposure to pyrethroids in controlled conditions and in the workplace. In an ancillary study, the effect of pyrethroid exposure on early metabolic changes was also evaluated. Three final metabolites (cis-DCCA, trans-DCCA and 3-PBA) of two of the most used pyrethroids, permethrin and cypermethrin, were measured in plasma and urine of six volunteers orally exposed to a dose similar to the reference dose, as analyzed by mass spectrometry. After oral exposure to cypermethrin, the mean apparent elimination half-life (t½) of trans-DCCA, cis-DCCA and 3-PBA in plasma was 5.1, 6.9 and 9.2 h, respectively,  as compared to 7.1, 6.2 and 6.5 hours after permethrin exposure. In urine, the mean apparent elimination half-life (t½) of trans-DCCA, cis-DCCA and 3-PBA was 6.3, 6.4 and 6.4 h, respectively, after the administration of cypermethrin compared to 5.4, 4.5 and 5.7 h after permethrin exposure. The time profiles were similar following exposure to cypermethrin and permethrin. The data help to interpret the significance of biological measurements and optimal sampling strategies.  Later, a biomonitoring study in agricultural workers was conducted for the assessment of their exposure and refinement of biomonitoring strategies. Within-subject variability in biomonitoring data of several workers was more important than inter-subject variability.  Urine samples were also used to identify changes in the metabolome and hence potentially identify new biomarkers of early effects. In particular, an increased urinary excretion of hippurate (p <0.0001) was observed in workers exposed following an exposure episode to pyrethroid, a biomarker of the conjugation of benzoic acid.  In conclusion, this study allowed to better document the toxicokinetics of key biomarkers of exposure to pyrethroids, in order to refine biomonitoring of exposure strategies. It has also provided more information on agricultural exposure in Quebec workers and professional parameters associated with high exposure. This project is part of a risk assessment in occupational health.

Keyphrases: DCCA, 3-PBA, Pyrethroids, Permethrin, Cypermethrin, Biomonitoring, Biomarker, Toxicokinetics, Risk assessment, Occupational health, Metabolomics