Summary

Pyrethroid exposure is of mounting concern in the workplace. This class of pesticides is now extensively used in agriculture on a wide variety of crops and is replacing organophosphorus insecticides. Pyrethroids are used because of their neurotoxic effect on insects, but they can cause the same effects in humans. Exposure to these insecticides has been linked to changes to the immune and endocrine systems. Workers may be heavily exposed to pyrethroids when spreading the insecticide or working in treated areas. However, it is not always easy to determine the doses that are actually absorbed in the workplace, given the varied and potentially combined exposure conditions, notably through the respiratory tract and skin, to which agricultural workers are exposed. Biological monitoring using urinary measurements of metabolites is now recognized by the scientific community as the best approach to assess exposure to that type of product. However, the interpretation of biological monitoring data requires thorough knowledge of what happens (toxicokinetic behaviour) to the priority substance in the human organism in order to make a link between biomarker levels in workers and the doses that have actually been absorbed. In the case of pyrethroids, human kinetic data and actual exposure of workers remain two aspects that are still not well documented. The general objective of this project is to refine, validate and apply a toxicokinetic approach to assess pyrethroid exposure in agricultural workers.

This project was divided into three parts: (1) a controlled kinetic study using volunteers acutely exposed to a low dose (standard oral dose) of two of the most commonly used pyrethroids, permethrin and cypermethrin; (2) refining a toxicokinetic model for these pyrethroids using data from the controlled kinetic study, to be used as a front-line tool to reconstitute the doses absorbed in workers; (3) biological monitoring of agricultural workers (vegetable crops) following an episode of pyrethroid exposure and reconstruction of the doses absorbed using toxicokinetic modelling and serial urinary measurements.

The study of volunteers exposed to pyrethroids in a controlled manner made it possible to acquire new urinary and blood profiles to reduce uncertainty in a toxicokinetic model of permethrin and cypermethrin. The modeling confirmed that the kinetic parameters were similar for both substances. A single model was therefore used to predict temporal profiles for both permethrin and cypermethrin metabolites following different single or combined exposure pathways (oral, dermal or respiratory routes) and various temporal exposure scenarios (single or repeated, continuous or intermittent). The modeling also suggests that the model could be adapted to simulate the kinetics of other pyrethroids and their metabolites and thus serve as a generic tool to reconstruct the doses absorbed and predict the main exposure pathways for all pyrethroids.

The study of agricultural workers also enabled us to better characterize the temporal urinary profiles typical of biomarkers of exposure to permethrin and cypermethrin in agricultural workers involved in vegetable production in Québec, according to their tasks (spreading, inspection, harvesting, weeding), and to assess intra-and inter-subject variability. It also led to pinpointing certain factors that could have an impact on the biological levels observed and to document appropriate sampling strategies for routine biomonitoring. In particular, the primary work task was a predictor of the levels of biomarkers of exposure observed. Pesticide applicators generally presented with higher biological values than workers doing tasks such as weeding, harvesting or inspecting the fields. Special attention should therefore be paid to this first group of agricultural workers in future studies or for routine follow-up. Nevertheless, the results also show that working in a treated area (inspection, harvesting or weeding) could increase pyrethroid exposure, which indicates that working practices, as well as the wearing of individual protection equipment, should be more systematically assessed for all agricultural workers.

The biological data gathered in this study also shows the importance of measuring a number of metabolites, in particular, trans-DCCA and 3-PBA, and to carry out serial collections to establish the level of work-related exposure, the main exposure routes and the corresponding doses absorbed by the targeted individuals. Based on the temporal profiles of DCCA and 3-PBA observed in the volunteers and the most exposed workers, the alternative for routine biological monitoring within a group or to compare the levels among homogeneous exposure groups would be to collect urine pre-exposure (after at least 48 hours without pesticide exposure) and to collect it again at the end of the work shift after the start of exposure, followed by collection of the first urine the next morning.  This would enable an exposure baseline level to be drawn, and would make it possible to identify the maximal post-exposure excretion levels, given that the profiles observed in the volunteers showed a peak a few hours after exposure and that those of the most exposed workers showed that maximal excretion was reached 18 to 32 hours after the start of a period of application or work in a treated area.

The toxicokinetic modeling done for this study has proven useful for making inferences about the main exposure routes in workers and for establishing the corresponding doses absorbed by adjusting the urinary profiles observed in these workers. In particular, it showed inadvertent work-related oral exposure to pyrethroids should be more closely evaluated as it is directly related to work practices and hygiene. The modeling was also used to derive the biological reference values that must not be exceeded to prevent adverse health effects. Although several workers presented with biological levels that were higher than the concentrations observed among the general Canadian population, these values were all below the thresholds not to be exceeded to limit health risks. The same was true when the absorbed doses reconstructed with a model were compared to the standard absorbed doses not to be exceeded to prevent adverse health effects (i.e., the absorbed dose corresponding to the standard dose established by the US Environmental Protection Agency or the “Acceptable Operator Exposure Level” (AOEL)) established by the European Commission.