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Toxicokinetic Modeling of Parathion and its Metabolites in Humans for the Determination of Biological Reference Values

Abstract A multi-compartment kinetic model was developed to describe the kinetics of parathion and its metabolites, p-nitrophenol (p-NP) and alkyl phosphates (AP), in order to assess worker exposure and health risks. Model compartments represent body burdens and excreta of parathion and its metabolites; to minimize the number of compartments and free parameters, regrouping was carried out on the basis of the time scales of the kinetic processes involved. Burden variations in time were described mathematically by differential equations that ensure conservation of mass on a mole basis. Model parameter values were determined from statistical fits to published in vivo kinetic data in humans. Except for the dermal absorption fraction and absorption rate, which are known to be subject to wide intra- and inter-individual variability, a single set of parameter values for the internal body kinetics enabled the model to simulate accurately the available kinetic data. For dermal exposure to parathion, with a typical absorption rate of 0.085 h−1, model simulations show that it takes 20 h to recover half of the total amounts of p-NP eventually excreted in urine and 30 h for the AP. The model can be used to estimate the dose of parathion absorbed under different exposure routes and temporal scenarios, based on measurements of amounts of metabolites accumulated in urine over given time periods. Using the above dose-excreta links and the human no-observed-effect level for parathion reported in the literature for the inhibition of cholinesterase activities, biological reference values are proposed in the form of specific amounts of urinary metabolites excreted over chosen time periods.