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PREDICTIVE ORGANOPHOSPHORUS (OP) PESTICIDE QSARS AND PBPK/PD MODELS FOR RISK ASSESSMENT OF SUSCEPTIBLE SUB-POPULATIONS
Citation:
Dary, C C., J. B. Knaak, F W. Power, C. B. Thompson, AND J N. Blancato. PREDICTIVE ORGANOPHOSPHORUS (OP) PESTICIDE QSARS AND PBPK/PD MODELS FOR RISK ASSESSMENT OF SUSCEPTIBLE SUB-POPULATIONS. Presented at Society of Toxicology, Las Vegas, NV, September 26-27, 2002.
Impact/Purpose:
Research will be conducted to develop and apply integrated microenvironmental, and physiologically-based pharmacokinetic (PBPK) exposure-dose models and methods (that account for all media, routes, pathways and endpoints). Specific efforts will focus on the following areas:
1) Develop the Exposure Related Dose Estimating Model (ERDEM) System.
Includes: Updating the subsystems and compartments of the ERDEM models with those features needed for modeling chemicals of interest to risk assessors;
Designing and implementing the graphical user interface for added features.
Refining the exposure interface to handle various sources of exposure information;
Providing tools for post processing as well as for uncertainty and variability analyses;
Research on numerical and symbolic mathematical/statistical solution methods and computational algorithms/software for deterministic and stochastic systems analysis.
2) Apply ERDEM and other quantitative models to understand pharmacokinetics (PK) and significantly reduce the uncertainty in the dosimetry of specific compounds of regulatory interest.
Examples of the applications are:
exposure of children to pesticides
study design
route-to-route extrapolation
species extrapolation
experimental data analysis
relationship between parametric uncertainty and the distribution of model results
validity of scaling methods within species
validity of scaling methods from one species to another species
reduction of uncertainty factors for risk assessment
Description:
Successful use of the Exposure Related Dose Estimating Model (ERDEM) in risk assessment of susceptible human sub-populations, e.g., infants and children, requires input of quality experimental data. In the clear absence of quality data, PBPK models can be developed and possibly enhanced through the judicious use of predictive Quantitative Structure Activity Relationships (QSAR). A thorough review of the available physicochemical and biological data revealed substantial data gaps and variances among experimental protocols. Published OP rat liver P450 microsomal Vmax, Km values on oxon formation were reviewed and compared with current studies with human liver microsomal P450 CYPs. Information on the inhibition of B-esterases (kis) by oxons, hydrolysis of the oxons (Vmax, Km) by plasma and liver A-esterases were reviewed along with conjugation reactions involving leaving groups. Deficiencies were evident for certain PBPK model parameters related to percutaneous absorption, i.e., Kp (cm/h), and tissue/blood partition coefficients and metabolic parameter such as Vmax and Km). From an understanding of the limitations of the available data, a predictive scenario-based PBPK/PD model was generated for 31 OP insecticides of interest to EPA from provisional QSAR estimates. New research is needed to obtain the necessary data for continued model construction and validation.
This work has been funded (wholly) or (in part) by the United States Environmental Protection Agency under Interagency Assistance Agreement (DW 47944301) to GSA. It has been subjected to Agency review and approved for publication.