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USE OF EXPOSURE-RELATED DOSE ESTIMATING MODEL (ERDEM) FOR ASSESSMENT OF AGGREGATE EXPOSURE OF INFANT AND CHILDREN TO N-METHYL CARBAMATE INSECTICIDES
Citation:
POWER, F. W., J. B. KNAAK, M. S. OKINO, R. TORNERO-VELEZ, J. N. BLANCATO, AND C. C. DARY. USE OF EXPOSURE-RELATED DOSE ESTIMATING MODEL (ERDEM) FOR ASSESSMENT OF AGGREGATE EXPOSURE OF INFANT AND CHILDREN TO N-METHYL CARBAMATE INSECTICIDES. Presented at Society of Toxicology Annual Meeting, New Orleans, LA, March 06 - 10, 2005.
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:
A physiologically based pharmacokinetic (PBPK) model was developed within the Exposure Related Dose Estimating Model (ERDEM) framework to investigate selected exposure inputs related to recognized exposure scenarios of infants and children to N-methyl carbamate pesticides as specified under the Food Quality Protection Act (FQPA). Conservative assumptions underlying residential exposure and cumulative risk were examined as inputs for particular exposure scenarios using residential dermal transfer coefficients, ambient air concentrations, and dietary intake. Physiological, pharmacokinetic and pharmacodynamic parameters describing the fate and effects of carbaryl, aldicarb, and propoxur in rats were scaled to establish the model structure for exposure to humans. Adjustments were made for differences in metabolism and physiology between children and adults. Michaelis-Menten kinetics were used to describe metabolism, where the chemical species compete for the catalytic enzymes. Bimolecular rate constants, ki (pM-1 hr-1), were used to describe inhibition of acetyicholinesterase by the parent compounds, where the effects are assumed to be additive. The simulation results over a day reveal the effects of residential exposure on cholinesterase activity, and highlight the scenarios and biological pathways where chemical interactions are important. The interactions are a cause for differences in risk between cumulative and single-chemical exposures.
Although this work was reviewed by EPA and approved for publication, it may not necessarily reflect official Agency policy.