Toxicokinetics of captan and folpet biomarkers in dermally exposed volunteers

Abstract

To better assess biomonitoring data in workers exposed to captan and folpet, the kinetics of ring metabolites [tetrahydrophthalimide (THPI), phthalimide (PI) and phthalic acid] were determined in urine and plasma of dermally exposed volunteers. A 10 mg kg(-1) dose of each fungicide was applied on 80 cm(2) of the forearm and left without occlusion or washing for 24 h. Blood samples were withdrawn at fixed time periods over the 72 h following application and complete urine voids were collected over 96 h post-dosing, for metabolite analysis. In the hours following treatment, a progressive increase in plasma levels of THPI and PI was observed, with peak levels being reached at 24 h for THPI and 10 h for PI. The ensuing elimination phase appeared monophasic with a mean elimination half-life (t(½) ) of 24.7 and 29.7 h for THPI and PI, respectively. In urine, time courses PI and phthalic acid excretion rate rapidly evolved in parallel, and a mean elimination t(½) of 28.8 and 29.6 h, respectively, was calculated from these curves. THPI was eliminated slightly faster, with a mean t(½) of 18.7 h. Over the 96 h period post-application, metabolites were almost completely excreted, and on average 0.02% of captan dose was recovered in urine as THPI while 1.8% of the folpet dose was excreted as phthalic acid and 0.002% as PI, suggesting a low dermal absorption fraction for both fungicides. This study showed the potential use of THPI, PI and phthalic acid as key biomarkers of exposure to captan and folpet.

A Detailed Urinary Excretion Time Course Study of Captan and Folpet Biomarkers in Workers for the Estimation of Dose, Main Route-of-Entry and Most Appropriate Sampling and Analysis Strategies

“…Based on current results and those of a previous study in volunteers dermally exposed to captan and folpet (Berthet et al, 2011d), one alternative is to collect first morning void, end-of-shift sample, and last evening void during three consecutive days. Spot samples collected on several days are still needed to properly assess exposure as peak levels of THPI and PI in blood were reached only 24 and 10 h after a dermal exposure to captan and folpet in volunteers, respectively, with ensuing mean elimination half-lives (t 1 / 2 ) of 24.7 and 29.7 h, respectively (Berthet et al, 2011d). An approach more amenable to routine Mean THPI levels calculated from data of both workers.…”

Toxicokinetic modeling of folpet fungicide and its ring‐biomarkers of exposure in humans

“…Model development was based on available published metabolism data (Gordon et al ., ) along with the human time‐course data newly collected in volunteers (Berthet et al ., , ). In this controlled experiment of Berthet et al .…”

“…In this controlled experiment of Berthet et al . (, ), healthy volunteers were exposed orally to 1 mg kg −1 of folpet or dermally to 10 mg kg −1 of folpet. The detailed time courses of PI in plasma and in urine were determined during a 96 h period post‐dosing.…”

“…When looking at the data of Berthet et al . (, ) on the elimination rate of PI in blood and urine as a function of time considering a given route of exposure (oral or dermal), it was also shown that elimination slopes were similar for blood and urine, as expected. Therefore, the transfer rate of PI from blood to urine, k BU , can straightforwardly be computed directly from each of the observed blood and urinary time courses of Berthet et al .…”

“…Recently, the human time courses of PI in blood and urine of volunteers orally and dermally exposed to folpet were documented (Berthet et al ., , ). The objective of the present study was to use these new data to develop a biomathematical model to describe and better understand the toxicokinetics of folpet and its ring metabolites in humans.…”