Abstract
The objectives of this study were twofold: (1) to characterize the toxicokinetics and dose-dependent systemic/tissue distribution of deltamethrin (DLM) over a range of doses in adult Sprague-Dawley (S-D) rats; (2) to provide comprehensive time course blood and tissue data for development of a physiologically based toxicokinetic (PBTK) model for DLM. DLM is one of the more neurotoxic members of a relatively new and commonly used class of insecticides, the pyrethroids. Despite widespread exposure of the general population to pyrethroids, there is little basic toxicokinetic (TK) data to use in health risk assessments or in development of PBTK models. Male S-D rats were dosed orally with 0.4, 2, or 10 mg DLM/kg dissolved in glycerol formal (GF). Another group received 2 mg/kg iv. Serial blood and tissue samples were taken at sacrifice and analyzed by high-performance liquid chromatography for their DLM content, in order to obtain comprehensive time course data sets for estimation of classical TK, as well as PBTK parameters (e.g., tissues:blood partition coefficients). Gastrointestinal (GI) absorption of DLM was rapid but incomplete. Bioavailability was just 18%. Some 83% of DLM in blood was present in the plasma. Just 0.1-0.3% of systemically absorbed doses reached the brain, the target organ of the bioactive parent compound. Fat, skin and surprisingly, skeletal muscle, accumulated large amounts of the highly lipophilic chemical and served as slow-release depots. Tissue distribution was dose dependent, though generally not proportional to dose. Clearance was dose independent in this dosage range. The time-profiles were used by A. Mirfazaelian et al. (2006, Toxicol. Sci. 93, 432-442) to construct and adjust a PBTK model. Much remains to be learned about physiological/biochemical processes and barriers that govern the GI absorption, transport, brain deposition, and elimination of DLM and other pyrethroids in laboratory animals and humans.
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