title: A toxicokinetic model of malathion and its metabolites as a tool to assess human exposure and risk through measurements of urinary biomarkers.
abstract: A toxicokinetic model is proposed to predict the time evolution of malathion and its metabolites, mono- and dicarboxylic acids (MCA, DCA) and phosphoric derivatives (dimethyl dithiophosphate [DMDTP], dimethyl thiophosphate [DMTP], and dimethyl phosphate [DMP]) in the human body and excreta, under a variety of exposure routes and scenarios. The biological determinants of the kinetics were established from published data on the in vivo time profiles of malathion and its metabolites in the blood and urine of human volunteers exposed by intravenous, oral, or dermal routes. In the model, body and excreta compartments were used to represent the time varying amounts of each of the following: malathion, MCA, DCA, DMDTP, DMTP, and DMP. The dynamic of intercompartment exchanges was described mathematically by a differential equation system that ensured conservation of mass at all times. The model parameters were determined by statistically adjusting the explicit solution of the differential equations to the experimental human data. Simulations provide a close approximation to kinetic data available in the published literature. When simulating a dermal exposure to malathion, the main route of entry for workers, the model predicts that it takes an average of 11.8 h to recover half of the absorbed dose of malathion eventually excreted in urine as metabolites, compared to 3.2 h following an intravenous injection and 4.0 h after oral administration. This shows that following a dermal exposure, the absorption rate governs the urinary excretion rate of malathion metabolites because the dermal absorption rate is much slower than biotransformation and renal clearance processes. The model served to establish biological reference values for malathion metabolites in urine since it allows links to be made between the absorbed dose of malathion and the time course of cumulative amounts of metabolites excreted in urine. From the no-observed-effect level (NOEL) of 0.61 micromol/kg/day derived from the data of Moeller and Rider (1962), the model predicts corresponding biological reference values for MCA, DCA, and phosphoric derivatives of 44, 13, and 62 nmol/kg, respectively, in 24-h urine samples. The latter were used to assess the health risk of workers exposed to malathion in botanical greenhouses, starting from urinary measurements of MCA and DCA metabolites.
authors.affiliation: Département de Santé Environnementale et Santé au Travail, Faculté de Médecine, Université de Montréal, C. P. 6128, Succursale Centre-ville, Québec, Canada H3C 3J7.
authors.forename: Michèle
authors.initials: M
authors.lastname: Bouchard
authors.forename: Nathalie H
authors.initials: NH
authors.lastname: Gosselin
authors.forename: Robert C
authors.initials: RC
authors.lastname: Brunet
authors.forename: Onil
authors.initials: O
authors.lastname: Samuel
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Dumoulin
authors.forename: Gaétan
authors.initials: G
authors.lastname: Carrier
mesh_terms: D000042:Absorption; D000328:Adult; D000465:Algorithms; D015415:Biomarkers; D001711:Biotransformation; D003198:Computer Simulation; D005260:Female; D006801:Humans; D007306:Insecticides / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine; D008294:Malathion / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine; D008297:Male; D008954:Models, Biological; D019055:No-Observed-Adverse-Effect Level; D016273:Occupational Exposure / Q000009:adverse effects; D012016:Reference Values; D015203:Reproducibility of Results; D018570:Risk Assessment; D012869:Skin Absorption; D013997:Time Factors
chemical_list: D015415:Biomarkers; D007306:Insecticides; D008294:Malathion