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MODEL DEVELOPMENT - DOSE MODELS
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:
Model Development
Humans are exposed to mixtures of chemicals from multiple pathways and routes. These exposures may result from a single event or may accumulate over time if multiple exposure events occur. The traditional approach of assessing risk from a single chemical and a single route of exposure does not provide a realistic description of exposures and the cumulative risks that result from real-world exposures. Risk assessments within EPA are now evolving toward "cumulative assessments" as mandated by legislation including the Food Quality Protection Act (FQPA) and the Safe Drinking Water Act (SDWA). However, there are considerable uncertainties associated with assessing aggregate exposures and cumulative risks. State-of-the-art predictive models can be used to reduce these uncertainties in describing the physical, chemical, and biological processes that lead to exposure and dose of chemical contaminants. Dose models describe how pollutants are absorbed into the body, distributed to various organs what the may or may not be metabolized and contribute to health problem. The goal of this research is to refine NERL's Exposure Related Dose Estimating Model to improve both ease of use and provide additional modeling capabilities. Models developed in this task are being designed to address the narrow definition of cumulative risk as defined by FQPA, namely risk from mixtures of chemicals with a common "mode of action."
The Exposure Related Dose Estimating Model (ERDEM) is a physiologically based pharmacokinetic (PBPK) modeling system that describes internal doses resulting from human exposure to chemicals. Recently a physiologically based pharmacokinetic physiologically based pharmacokinetic (PBPK/PD) model has been added to provide predictions of actual organ level doses for single chemicals and mixtures. ERDEM has been used to estimate doses resulting from aggregate exposure scenarios to MTBE, TCE, chlorpyrifos, malathion, and carbaryl. Planned research will provide enhancements that improve both ease of operation and additional modeling capabilities. The ERDEM front end will be modified to include an exposure time history repository that will take inputs from various exposure models such as SHEDS so that a Monte Carlo simulation can be run. The system will also be modified to provide the user with an uncertainty analysis interface that will enable researchers to perform sensitivity and Monte Carlo analyses including correlated parameters such as volumes and blood flows. ERDEM components will be modified or new ones added as necessary to meet the Agencies needs. These include intracellular modeling approaches, multiple compartment organs, and the development of Quantitative Structure Activity Relationship (QSAR) databases to make predictions for chemicals where data are lacking.
The outcome of this research will be a state-of-the science PBPK/PD modeling tool that can be used by risk assessor and risk managers to improve regulatory decision making. ERDEM is fundamental to studies of aggregate exposure and cumulative risk because it allows for the examination of multiple exposure routes (e.g. oral, dermal and respiratory) simultaneously. The model features developed under this task will be applied in support of OPP's risk assessment of pyrethroids and n-methyl carbamates.