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Tissue time course and bioavailability of the pyrethroid insecticide bifenthrin in the Long-Evans rat
Hughes, M., D. Ross, B. Edwards, M. DeVito, AND J. Starr. Tissue time course and bioavailability of the pyrethroid insecticide bifenthrin in the Long-Evans rat. XENOBIOTICA. Taylor & Francis, Inc., Philadelphia, PA, 46(5):430-438, (2016).
What is the study? This study examined the tissue time course and bioavailability of bifenthrin. Bifenthrin is a pyrethroid insecticide. We administered bifenthrin at two dose levels by the oral route and one dose level by the intravenous route. In one study we examined the tissue time course of bifenthrin in blood, liver, brain and fat after oral administration. In a second study we determined the bioavailability of bifenthrin using jugular vein cannualted rats and serially collecting blood samples following oral or intravenous administration. Why was it done? We wanted to examine the tissue dosimetry and bioavailability of bifenthrin. This type of data can be used for PBPK model development for bifenthrin. Our previous work with other pyrethroids (deltamethrin, permethrin) indicated that the pyrethroids the compounds are distributed widely and tended to remain in fat. We examined fat out to 21 days and bifenthrin was detected in this tissue at this time after oral administration. We also wanted to examine the bioavailability of bifenthrin. This will let us know the amount of bifenthrin that reaches the systemic circulation after oral exposure. What is the impact to the field and Agency? One impact is that the bioavailability of bifenthrin is <40% in the rat. This means that <40% of an oral dose reaches the systemic circulation. The remainder is either not absorbed or rapidly metabolized in the liver. Bifenthrin is retained in fat at least out to 21 days. However, it is unlikely that bifenthrin in fat mobilizes to other organs such as the brain, because the levels in brain started to decrease after 24 h post-exposure.
Bifenthrin is a pyrethroid insecticide and human exposure to it can occur by oral, pulmonary and dermal routes. Pyrethroids are neurotoxic agents and it is generally believed that the parent pyrethroid is the toxic entity. This study evaluated the oral disposition and bioavailability of bifenthrin in the adult male Long-Evans rat. In one experiment, rats were administered bifenthrin (0.3 or 3 mg/kg) by oral gavage and serially sacrificed (0.25 h to 21 days) after dosing. Blood, liver, brain and adipose tissue were removed from these animals. In a second experiment, bioavailability of bifenthrin was assessed by serially sampling blood from jugular vein cannulated rats (0.25 to 24 h) following oral (0.3 or 3 mg/kg) or intravenous (0.3 mg/kg) administration of chemical. Tissues were extracted and analyzed for bifenthrin by HPLC-tandem mass spectrometry. Results from the first experiment show that concentrations of bifenthrin in blood and liver peaked 1-2 h post-administration and for both doses the area under the curve (AUC) was 40-80% greater in liver than blood. Brain concentrations peaked later (4-6 h) and were lower than in blood at both doses, although the brain and blood AUC was similar for the 0.3 mg/kg dose and 60% greater in brain than blood at the 3 mg/kg dose. Bifenthrin in adipose tissue peaked at 8 and 24 h for the 0.3 and 3 mg/kg doses, respectively, and was retained at higher concentrations (about 500-fold) than in blood. Following iv administration, the blood bifenthrin concentration decreased bi-exponentially, with a distribution half-life of 0.2 h and an elimination half-life of 8 h. The bioavailability of bifenthrin was 25% at the 0.3 mg/kg dose and 38% for the 3 mg/kg dose. Therefore, these disposition and kinetic bifenthrin data may decrease uncertainties in the risk assessment for this pyrethroid pesticide.
BIFENTHRIN KINETICS 051515.DOCX