Department of Environmental and Occupational Health, Chair in Toxicological Risk Assessment and Management, and Public Health Research Center (CReSP), University of Montreal, Roger-Gaudry BuildingMain Station, P.O. Box 6128, Montreal, QC, U424H3C 3J7, Canada.
Faculty of Health - Pharmacy, HERA Team (Health Environment Risk Assessment), INSERM UMR1153-CRESS (Research Center in Epidemiology and StatisticS), University of Paris, 4 Avenue de l Observatoire, 75006, Paris, France.
Arch Toxicol. 2020 Sep;94(9):3045-3058. doi: 10.1007/s00204-020-02810-6. Epub 2020 Jun 23.
This study aimed at gaining more insights into the impact of pesticide coexposure on the toxicokinetics of biomarkers of exposure. This was done by conducting an in vivo experimental case-study with binary mixtures of lambda-cyhalothrin (LCT) and captan and by assessing its impact on the kinetic profiles of LCT biomarkers of exposure. Groups of male Sprague-Dawley rats were exposed orally by gavage to LCT alone (2.5 or 12.5 mg/kg bw) or to a binary mixture of LCT and captan (2.5/2.5 or 2.5/12.5 or 12.5/12.5 mg/kg bw). In order to establish the temporal profiles of the main metabolites of LCT, serial blood samples were taken, and excreta (urine and feces) were collected at predetermined intervals up to 48 h post-dosing. Major LCT metabolites were quantified in these matrices: 3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-cyclopropane carboxylic (CFMP), 3-phenoxybenzoic acid (3-PBA), 4-hydroxy-3-phenoxybenzoic acid (4-OH3PBA). There was no clear effect of coexposure at the low LCT dose on the kinetics of CFMP and 3-PBA metabolites, based on the combined assessment of temporal profiles of these metabolites in plasma, urine and feces; however, plasma levels of 3-PBA were diminished in the coexposed high-dose groups. A significant effect of coexposure on the urinary excretion of 4-OH3PBA was also observed while fecal excretion was not affected. The temporal profiles of metabolites in plasma and in excreta were further influenced by the LCT dose. In addition, the study revealed kinetic differences between metabolites with a faster elimination of 3-PBA and 4-OH3BPA compared to CFMP. These results suggest that the pyrethroid metabolites CFMP and 3-PBA, mostly measured in biomonitoring studies, remain useful as biomarkers of exposure in mixtures, when pesticide exposure levels are below the reference values. However, the trend of coexposure effect observed in the benzyl metabolite pathway (in particular 4-OH3BPA) prompts further investigation.
本研究旨在深入了解农药共暴露对暴露生物标志物毒代动力学的影响。为此，进行了一项体内实验性病例研究，采用氯氟氰菊酯（LCT）和克菌丹的二元混合物，并评估其对暴露生物标志物 LCT 动力学特征的影响。雄性 Sprague-Dawley 大鼠经灌胃暴露于单独的 LCT（2.5 或 12.5mg/kg bw）或 LCT 和克菌丹的二元混合物（2.5/2.5、2.5/12.5 或 12.5/12.5mg/kg bw）。为了建立 LCT 主要代谢物的时间曲线，在给药后至 48 小时内，每隔一定时间采集系列血样，并收集尿液和粪便。在这些基质中定量测定了主要的 LCT 代谢物：3-（2-氯-3,3,3-三氟丙-1-烯基）-2,2-二甲基环丙烷羧酸（CFMP）、3-苯氧基苯甲酸（3-PBA）、4-羟基-3-苯氧基苯甲酸（4-OH3PBA）。根据这些代谢物在血浆、尿液和粪便中的时间曲线的综合评估，低剂量 LCT 共暴露对 CFMP 和 3-PBA 代谢物的动力学没有明显影响；然而，共暴露高剂量组的血浆 3-PBA 水平降低。共暴露对尿液中 4-OH3PBA 排泄的影响也很显著，而粪便排泄不受影响。代谢物在血浆和排泄物中的时间曲线还受到 LCT 剂量的影响。此外，研究还揭示了代谢物之间的动力学差异，3-PBA 和 4-OH3PBA 的消除速度比 CFMP 快。这些结果表明，在混合物中，当农药暴露水平低于参考值时，作为暴露生物标志物的拟除虫菊酯代谢物 CFMP 和 3-PBA 仍然有用，尤其是生物监测研究中测量的代谢物。然而，苯甲酯代谢途径中观察到的共暴露效应趋势（特别是 4-OH3PBA）促使进一步研究。
