Chan Melissa P L, Morisawa Shinsuke, Nakayama Aki, Kawamoto Yuko, Sugimoto Miki, Yoneda Minoru
Department of Global Environment Engineering, Graduate School of Engineering, Kyoto University, Yoshida-honmachi, Sakyo-ku, Kyoto City 606-8501, Japan.
Environ Toxicol. 2006 Oct;21(5):464-78. doi: 10.1002/tox.20209.
Endosulfan, an organochlorine (OC) insecticide belonging to the cyclodiene group, is one of the most commonly used pesticides to control pests in vegetables, cotton, and fruits. To date, no physiologically based pharmacokinetic (PBPK) model has been located for endosulfan in animal species and humans. The estimation by a mathematical model is essential since information on humans can scarcely be obtained experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of (14)C-Endosulfan to male Sprague-Dawley rats. The model was parameterized by using reference physiological parameter values and partition coefficients that were determined in the experiment and optimized by manual adjustment until the best visual fit of the simulations with the experimental data were observed. The model was verified by simulating the disposition of (14)C-Endosulfan in vivo after single and multiple oral dosages and comparing simulated results with experimental results. The model was further verified by using experimental data retrieved from the literature. The present model could reasonably predict target tissue dosimetries in rats. Simulation with three-time repeated administration of (14)C-Endosulfan and experimental data retrieved from the literature by the constructed model fitted fairly well with the experimental results; thus suggesting that the newly developed PBPK model was developed. Sensitivity analyses were used to determine those input parameters with the greatest influence on endosulfan tissue concentrations.
