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.

Acetylcholinesterase Activity and Neurodevelopment in Boys and Girls

“…5,9 There is limited information regarding the association between AChE activity and neurodevelopment in children; most studies have focused on metabolite or direct quantification of pesticides in blood or urine. Because organophosphates have short half-lives in blood (,1 day) [10][11][12] and exposure varies by day and season, quantification of their metabolites in urine has greater daily variability within children than between children, 13,14 which increases the likelihood of exposure misclassification. In addition, urinary measurements may overestimate exposures to the parent compound because metabolite elevations also reflect exposure to less toxic ambient metabolites.…”

A Comparison of Two Exposure Systems to Apply Malathion to Lumbricus terrestris L

“…Detoxification of malathion and malaoxon in mammals occurs by cleavage of the carboxyl groups by A-esterases and carboxylesterases resulting in mono-and di-acids, which are rapidly excreted in the urine (Eto 1974;Bouchard et al 2003). The presence of carboxylesterases is considered to be a relevant factor in insect resistance to malathion (Devonshire et al 2003) and may be an important factor in the apparent resistance in L. terrestris.…”

The Red Blood Cell Acetylcholinesterase Levels of Depressive Patients with Suicidal Behavior in an Agricultural Area

“…One of them is OPs residues in the urine of subjects which could not be measured simultaneously. However short half-lives of OPs in blood (approximately 1 day) and variations in daily and seasonal exposure lead to great daily variability of OPs metabolites in urine [38,39]. Measurement of AChE activity may overcome these problems.…”