title: Physiological modeling and derivation of the rat to human toxicokinetic uncertainty factor for the carbamate pesticide aldicarb.
abstract: Aldicarb (ALD, 2-methyl-2-(methylthio)-propionalaldehyde O-(methyl-carbamoyl) oxime, Temik) is widely used as an insecticide, nematocide and acaricide and it is oxidized to aldicarb sulfoxide (ALX) and aldicarb sulfone (ALU). Neither a toxicokinetic model nor an estimate of the target tissue dose of ALD and its metabolites in exposed organisms is available. The objective of this study was: (i) to develop a physiologically based toxicokinetic (PBTK) model for ALD in the rat and humans, and (ii) to determine the interspecies toxicokinetic uncertainty factor (UF(AH-TK)) of ALD. The model consists of a series of mass balance differential equations that describe the time course behavior of ALD in blood, liver, kidney, lungs, brain, fat, and rest of the body compartments. The physiological parameters of the model (blood flow rates, cardiac output, and tissue volumes) were obtained from the literature, while the maximum velocity (mg/kg/min) and the Michaelis constant (mg/l) for ALD oxidation in rats and humans were determined by in vitro AH-TK microsomal assays. The estimation of the tissue:blood partition coefficient was accomplished within the PBTK model by representing the tissues as a composite of neutral lipids, phospholipids and water, and providing the vegetable oil:water partition coefficient as input parameter. The validity of the rat PBTK model was assessed by comparing the model simulations of ALX time course blood concentrations and the inhibition patterns of acetylcholinesterase (AChE) in erythrocytes and plasma obtained by administering rats ALD (0.1 and 0.4 mg/kg, iv). The human PBTK model was validated by comparing the simulations of AChE inhibition patterns in blood with human experimental data obtained from oral administrations of ALD. The UF(AH-TK) for ALD was determined by dividing the areas under the blood and brain concentration vs time curve (AUCCV, AUCCBR) for ALD and ALX in the rat and in human exposed to the same dose. The results indicate that with respect to parent chemical, equivalent applied doses in rats and humans result in a 9.5-fold difference in the AUC(CV) and AUC(AH-TK) respectively, in the two species, and 17-fold difference in the AUC(CV) and AUC(CBR) with respect to the metabolite. In other words, in order to have toxicokinetic equivalence in rats and humans, the former species must be exposed to a dose that is 9.5 and 17 times higher than the human with respect to the parent chemical and the metabolite respectively. Overall, the present study demonstrates the applicability of PBTK models in the quantitative evaluation of UH(AH-TK), and shows that their current default values are inaccurate, at least with respect to ALD, which has potential negative implications in the alleged protection of risk estimates derived from them.
authors.affiliation: Pelekis Group, P.O. Box 415, Nazareth, PA 18064, USA. pelekism@aol.com
authors.forename: M
authors.initials: M
authors.lastname: Pelekis
authors.forename: C
authors.initials: C
authors.lastname: Emond