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DEVELOPMENT OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR DELTAMETHRIN IN DEVELOPING SPRAGUE-DAWLEY RATS
Citation:
MIRFAZAELIAN, A., K. KIM, S. S. ANAND, S. LEE, H. J. KIM, R. TORNERO-VELEZ, J. V. BRUCKNER, AND J. W. FISHER. DEVELOPMENT OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR DELTAMETHRIN IN DEVELOPING SPRAGUE-DAWLEY RATS. Presented at Society of Toxicology, San Diego, CA, March 05 - 09, 2006.
Impact/Purpose:
Model Development
The overall goal of this work is to develop a modeling system that will enable risk assessors to apply PBPK/PD models to research and regulatory problems. The specific aim is to achieve Agency recognition of PBPK/PD modeling systems, such as ERDEM, as computational tools for risk characterization, research design, and diagnosis of resource allocation.
The key aspects of this research are to:
1. Add a multi-run graphical-user-interface (GUI) in the ERDEM "Front End" to assist the user in defining model input and to improve multi-run capability so that suites of parameter values can be run to speed up the parameter fitting process. Add intra-cellular and uncertainty analysis capability to the graphical-user-interface (GUI) in the ERDEM "Front End." Add the interface for additional compartments and subsystems as needed.(Sub-Task: Model Graphical User Interface and Development GUI)
2. Develop a repository in the ERDEM Front End database to store exposure time histories for processing ERDEM model runs. This Exposure/Time History Repository/Bio-monitoring Interface is expected to help users input various exposure model parameters into a generic PBPK model to process ADME functions simultaneously with a pharmacodynamic (PD) component to determine target tissue dose and effects, e.g., acetyl cholinesterase (AChE) inhibition (Sub-Task: Model Exposure/Time History Repository).
3. Generate Quantitative Structure Activity Relationship (QSAR) databases for chemicals of interest to test ADME and PD mechanisms and make predictions about activity for chemicals where data is lacking. These QSARs may be used to probe the in silico biological layers in ERDEM to examine ADME and PD mechanisms at the organism (e.g., body burden and lethality), tissue and organ, and cellular and sub-cellular levels (Sub-Task: QSAR and Intracellular modeling).
4. Provide exposure and risk assessment specialist's computational modeling tools to establish commonality among dermal exposure and dose related algorithms used in risk assessment. Recognition of the need for a "harmonization" of approaches arose through publication of international reports on dermal absorption (OECD, 2004a, 2004b, 2004c and WHO, 2005) and national colloquiums EPA, 2005 and AIHA, 2005) on dermal exposure methods comparisons (Sub-Task: Dermal Exposure to Dose Harmonization).
5. Develop symbolic solutions to PBPK models for application to risk assessment.
Description:
This work describes the development of a physiologically based pharmacokinetic (PBPK) model of deltamethrin, a type II pyrethroid, in the developing male Sprague-Dawley rat. Generalized Michaelis-Menten equations were used to calculate metabolic rate constants and organ weights of rats of different ages. The PBPK model predictions compared favorably with experimental blood, brain and fat DLT profiles over the range of doses. The model will aid in our understanding of the processes affecting the disposition of pyrethroids in humans.