Deltamethrin toxicokinetics in rats
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Deltamethrin (DLM) is a widely-used Type II pyrethroid insecticide and a relatively potent neurotoxicant. Previous studies have shown that immature rats are more susceptible to acute DLM neurotoxicity than adults. The main objectives of this study were: (1) to characterize the absorption, systemic/tissue distribution and elimination of DLM over a range of doses in adult rats; (2) to characterize the age- and dose-dependency of DLM toxicokinetics (TK) and tissue distribution in developing rats. New analytical method for DLM quantification in plasma and various tissues was developed and validated prior to TK studies. The limits of detection (LOD) and quantification (LOQ) were 0.01 and 0.05 µg DLM/ml or g, respectively. Selection of proper vehicles for DLM administration was an issue. To assess the influence of two common ®®vehicles, Alkamuls (AL, formerly Emulphor) and glycerol formal (GF), on the bioavailability and toxicokinetics (TK) of DLM, adult Sprague-Dawley (S-D) male rats were administered DLM iv or po, either by dissolving it in GF or in AL. Bioavailability and target organ (brain) levels were significantly higher when the insecticide was given orally to rats in GF rather than as an unstable aqueous suspension in AL. To characterize the TK of DLM, adult male S-D rats were dosed orally with 0.4, 2 or 10 mg DLM/kg dissolved in GF. Another group received 2 mg DLM/kg iv. Oral bioavailability was low, and very small proportions of systemically-absorbed doses reached the brain, the target organ of DLM. Fat, skin and muscle accumulated relatively large amounts of the highly lipophilic chemical and served as slow-release depots during elimination. Tissue deposition was dose-dependent, though not directly proportional to dose. Elimination kinetics were linear in this dosage range. To determine whether the susceptibility of immature rats to acute DLM neurotoxicity was due to age-dependent TK, DLM was administered via gavage at 0.4, 2 or 10 mg DLM/kg to male S-D rats of postnatal days (PND) 10, 21, and 40. Plasma and target organ (brain) DLM levels, like the magnitude of acute neurotoxicity, were inversely related to age. Inadequate metabolic detoxification capacity in the youngest pups was an important contributor to their susceptibility to DLM poisoning. These TK plasma and tissue time-course data will be invaluable in developing physiological models to use in predicting children’s target organ dosimetry and risks for different exposure scenarios.