Toxicokinetic modeling of captan fungicide and its tetrahydrophthalimide biomarker of exposure in humans

Measurement of tetrahydrophthalimide (THPI) in urine has been used for the biomonitoring of exposure to the widely used captan fungicide in workers. To allow a better understanding of the toxicokinetics of captan and its key biomarker of exposure, a human multi-compartment model was built to simulate the transformation of captan into THPI and its subsequent excretion while accounting for other non-monitored metabolites. The mathematical parameters of the model were determined from best-fits to the time courses of THPI in blood and urine of five volunteers administered orally 1 mg/kg and dermally 10 mg/kg of captan. In the case of oral administration, the mean elimination half-life of THPI from the body (either through faeces, urine or metabolism) was found to be 13.43 h. In the case of dermal application, mean THPI elimination half-life was estimated to be 21.27 h and was governed by the dermal absorption rate. The average final fractions of administered dose recovered in urine as THPI were 3.6% and 0.02%, for oral and dermal administration, respectively. Furthermore, according to the model, after oral exposure, only 8.6% of the THPI formed in the GI reaches the bloodstream. As for the dermal absorption fraction of captan, it was estimated to be 0.09%. Finally, the average blood clearance rate of THPI calculated from the oral and dermal data was 0.18 ± 0.03 ml/h and 0.24 ± 0.6 ml/h while the predicted volume of distribution was 3.5 ± 0.6 l and 7.5 ± 1.9 l, respectively. Our mathematical model is in complete accordance with both independent measurements of THPI levels in blood (R2 = 0.996 for oral and R2 = 0.908 for dermal) and urine (R2 = 0.979 for oral and R2 = 0.982 for dermal) as well as previous experimental data published in the literature.

► Tetrahydrophthalimide (THPI) in urine has been used for the biomonitoring of exposure to the widely used captan fungicide.
► A human multi-compartment model was built to simulate the transformation of captan into THPI and its subsequent kinetics.
► Kinetics of captan and its ring-metabolites were modeled for different routes-of-exposure: oral, dermal and inhalation.
► Only first-order transitions were required to simulate in vivo kinetics of captan ring-metabolites.
► The model is in accordance with published experimental data.