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CONSTRUCTION OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC/PHARMACODYNAMIC (PBPK/PD) MODEL FOR CARBOFURAN USING THE EXPOSURE RELATED DOSE ESTIMATING MODEL (ERDEM)
Citation:
ZHANG, X., A. M. TSANG, M. S. OKINO, F. W. POWER, J. B. KNAAK, AND C. C. DARY. CONSTRUCTION OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC/PHARMACODYNAMIC (PBPK/PD) MODEL FOR CARBOFURAN USING THE EXPOSURE RELATED DOSE ESTIMATING MODEL (ERDEM). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R-06/135 (NTIS PB2007-100680), 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:
Carbofuran, known as 2, 3-dihydro-2, 2-dimethyl-7-benzofuranyl-N-methylcarbamate, is a broad spectrum N-methyl carbamate pesticide. Carbofuran and its metabolite, 3-hydroxycarbofuran, exert their toxicity by reversibly inhibiting acetylcholinesterase (AChE). Carbofuran is widely used in agriculture for pest control. Agricultural workers and the general population may be exposed to it by dermal contact, inhalation, or ingestion as a result of its application or by food intake. To better characterize the human health risk caused by carbofuran exposure, a physiologically-based pharmacokinetic/ pharmacodynamic (PBPK/PD) model was developed in the Exposure Related Dose Estimating Model (ERDEM) system in order to facilitate an understanding of carbofuran's absorption, distribution, metabolism, elimination (ADME) processes, and AChE inhibition effects for the rat. To obtain relevant experimental measurements and the estimates of physiological, biochemical, and physicochemical parameters for the model, literature reviews were conducted. The focus was placed on oral exposure and modeling carbofuran metabolism in the liver to 16 known metabolites, the enterohepatic circulation of glucuronide conjugates, and the excretion to urine and feces. Cholinesterase inhibition by carbofuran and 3-hydroxycarbofuran is modeled in the blood and brain.
Generally, the model simulated results were consistent with available experimental measurements. Following an oral exposure of 50 µg/kg carbofuran, the model predicted that the minimum blood AChE activity occurred at 22 minutes as the enzyme activity was inhibited by 40%, comparing with 15 minutes (37%) reported by Ferguson et al., (1984). The model also suggested that carbofuran had a short half-life of 5.2 hrs; the inhibition capability of carbofuran (ki = 1.6 x 105 L mmol-1 H-1) was about 2.7 times that of 3-hydroxycarbofuran (ki = 6 x 104 L mmol-1 H-1); and a NOAEL value for acute single oral exposure in the rat was about 10 µg/kg using the blood AChE activity as the toxicological endpoint. To identify parameters that had the greatest impact on the simulated dose metrics in urine and blood for the oral exposure scenario, global relative ratios from a sensitivity analysis were calculated based on the boundary values (i.e., 5th and 95th percentiles of each model parameter). Ultimately, thirty sensitive parameters, which included major compartment blood flows and volumes, main metabolic reactions, partition coefficients of major metabolites in main compartments, and the urinary excretion of major metabolites, were found and chosen for constructing Monte Carlo simulations. Results of the simulation runs indicated that following oral exposure to 50 µg/kg carbofuran the minimum AChE activity in the blood ranged from 29.3% to 79.0% (as 5th and 95th percentiles) with a mean of 55.9% (SD = 15.1%); and the minimum AChE activity in the brain ranged from 8.6% to 61.3% (as 5th and 95th percentiles) with a mean of 32.0% (SD = 16.2%). The results of this carbofuran study, and the resulting rat PBPK/PD model, provide a good framework for future risk assessment activities.