Biomarkers of Exposure to Pyrimethanil After Controlled Human Experiments

Abstract

Pyrimethanil (PYM) is a fungicide used pre- and post-harvest on many crops. It has a low acute toxicity but is of toxicological concern because of its antiandrogenic properties. The aim of the current work was to investigate some metabolism and estimate elimination kinetics of PYM in humans after experimental oral and dermal exposure. A liquid chromatography triple quadrupole mass spectrometry (LC–MS-MS) method was developed and validated for the analysis of PYM and its metabolite 4-hydroxypyrimethanil (OH–PYM) in human urine. The method was applied to analyze urine obtained from two volunteers experimentally exposed to PYM. The elimination of OH–PYM seemed to follow first-order kinetics and a two-phase excretion. After the oral exposure, the elimination half-life of OH–PYM in the rapid phase was 5 and 3 h for the female and male volunteer, respectively. In the slower phase, it was 15 h in both volunteers. After the dermal exposure, the half-life in the rapid phase was 8 h in both volunteers. In the slower phase, it was 30 and 20 h, respectively. About 80% of the oral dose was recovered as urinary OH–PYM in both volunteers. The dermal dose recovered as urinary OH–PYM was 9.4% and 19%, in the female and male volunteer, respectively. OH–PYM was mainly found as a conjugate of sulfonate and glucuronic acid. No free PYM was found. The analytical method showed good within-run, between-run and between-batch precision with a coefficient of variation between 6% and 12%. A limit of detection of 0.1 ng/mL and a limit of quantification of 0.4 ng/mL were achieved for both the analytes. The method was applied to biomonitor PYM exposure in populations in Sweden. OH–PYM was detected in nearly 50% and 96% of samples from the environmentally and occupationally exposed populations, respectively.

Filaggrin Polymorphisms and the Uptake of Chemicals through the Skin—A Human Experimental Study

“…The chemicals included in this study are common among environmental, consumer, and occupational exposures. Pyrimethanil is a fungicide used in conventional fruit agriculture, and both workers and consumers can be exposed (Faniband et al 2019). Pyrimethanil has been found to be an aryl hydrocarbon receptor agonist in vitro (Medjakovic et al 2014) and has been shown to disrupt liver metabolism and thyroid hormones in rodents at high concentrations, 13-1,000 mg=kg=d (Hurley 1998).…”

“…In humans, pyrimethanil is mainly metabolized by oxidation to OH-pyrimethanil, after which conjugation (mainly with sulfonate) occurs. After oral exposure, 80% of the compound was found in urine as OH-pyrimethanil (Faniband et al 2019). Pyrimethanil is not considered of toxicological concern to humans below the ADI of 0:17 mg=kg=d and has low acute toxicity (https://efsa.onlinelibrary.wiley.com/doi/pdf/10.2903/ j.efsa.2006.61r).…”

Concentrations and temporal trends in pesticide biomarkers in urine of Swedish adolescents, 2000–2017

“…The analyses were performed using a liquid chromatography system (UFLC RX ; Shimadzu Corporation, Kyoto, Japan) coupled with triple quadrupole linear ion trap mass spectrometer equipped with TurboIonSpray source (QTRAP 5500 and 6500+; AB Sciex, Foster City, CA, USA). The analyzed exposure biomarkers of the parent pesticides were 3-phenoxybenzoic acid A modified method based on Faniband et al [38] was applied for the simultaneous analysis of 3-PBA, 4F-3-PBA, CFCA, DCCA, TCPy, OH-PYM, OH-TBZ, OH-TEB, 2,4-D, and MCPA. In short, urine samples were enzymatically treated overnight with β-glucuronidase/arylsulfatase and extracted on 96-well solid phase extraction (SPE) plates before LC-MS/MS analysis.…”

“…The measured concentrations only reflect exposure within the past 24 h and are probably associated with very recent intake of food, since these compounds have short biological half-lives [ 38 , 48 ]. Furthermore, the absolute measured urinary concentrations of each compound can be difficult to compare because the metabolism and toxicokinetic parameters of the compounds vary.…”

“…A modified method based on Faniband et al [ 38 ] was applied for the simultaneous analysis of 3-PBA, 4F-3-PBA, CFCA, DCCA, TCPy, OH-PYM, OH-TBZ, OH-TEB, 2,4-D, and MCPA. In short, urine samples were enzymatically treated overnight with β-glucuronidase/arylsulfatase and extracted on 96-well solid phase extraction (SPE) plates before LC–MS/MS analysis.…”