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ToxSci Advance Access published online on March 25, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg061
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received December 19, 2002; accepted February 10, 2003
© 2003 Society of Toxicology

Risk Assessment

A Toxicokinetic Model of Malathion and Its Metabolites as a Tool to Assess Human Exposure and Risk through Measurements of Urinary Biomarkers

Michèle Bouchard 1, Nathalie H. Gosselin 1, Robert C. Brunet 2, Onil Samuel 3, Marie-Josée Dumoulin 1, Gaétan Carrier 1*

1 Chaire en analyse des risques toxicologiques pour l'humain and Département de santé environnementale et santé au travail, Faculté de Médicine, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, Québec, Canada, H3C 3J7
2 Département de Mathématiques et de Statistique and Centre de Recherches Mathématiques, Faculté des arts et des sciences, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, Québec, Canada, H3C 3J7
3 Institut national de santé publique du Québec. Direction de la toxicologie humaine. Centre de toxicologie, 945 avenue Wolfe, Ste-Foy, Québec, Canada, G1V 5B3

* To whom correspondence should be addressed. E-mail: gaetan.carrier{at}umontreal.ca.


  Abstract

A toxicokinetic model is proposed to predict the time evolution of malathion and its metabolites, mono- and di-carboxylic 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 and 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 inter-compartment exchanges was described mathematically by a differential equation system that ensures conservation of mass at all times. The model parameters were determined by adjusting statistically 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 on average 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 µmol/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.

malathion, mono-carboxylic acids, di-carboxylic acids, phosphoric derivatives, toxicokinetics, risk assessment .


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