title: Toxicokinetic modeling of captan fungicide and its tetrahydrophthalimide biomarker of exposure in humans.
abstract: 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 1mg/kg and dermally 10mg/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 ± 0.6l and 7.5 ± 1.9l, respectively. Our mathematical model is in complete accordance with both independent measurements of THPI levels in blood (R(2)=0.996 for oral and R(2)=0.908 for dermal) and urine (R(2)=0.979 for oral and R(2)=0.982 for dermal) as well as previous experimental data published in the literature.
authors: Department of Environmental and Occupational Health, University of Montreal, Quebec, Canada.
authors: Roberto
authors: R
authors: Heredia-Ortiz
authors: Michèle
authors: M
authors: Bouchard
mesh_terms: D000279:Administration, Cutaneous; D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000652:urine; D002215:Captan / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity / Q000652:urine*; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity / Q000652:urine*; D006207:Half-Life; D006801:Humans; D008954:Models, Biological; D010797:Phthalimides / Q000652:urine*
chemical_list: D015415:Biomarkers; D005659:Fungicides, Industrial; D010797:Phthalimides; C009417:tetrahydrophthalimide; D002215:Captan