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PROPOSED SUITE OF MODELS FOR ESTIMATING DOSE RESULTING FROM EXPOSURES BY THE DERMAL ROUTE
Citation:
CohenHubal, E A., A. Bunge, L. M. Hanna, J. N. McDougal, AND A M. Jarabek. PROPOSED SUITE OF MODELS FOR ESTIMATING DOSE RESULTING FROM EXPOSURES BY THE DERMAL ROUTE. Presented at Society for Risk Analysis 2000 Annual Meeting, Arlington, VA, December 3-6, 2000.
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:
Recent risk assessment guidance emphasizes consideration of mechanistic factors for influencing disposition of a toxicant. To incorporate mechanistic information into risk assessment, a suite of models is proposed for use in characterizing and quantifying dosimetry of toxic agents absorbed by the dermal route. The model suite was developed by identifying mass-transfer resistances in the dermal system. The most general (and most complex) model in the suite includes all potentially relevant resistances. The model treats the stratum corneum (SC), viable epidermis (VE), and subcutaneous fat as distributed-parameter compartments. Two-dimensional diffusion resulting from biphasic properties of the SC is also considered. The dermis is treated as a lumped-parameter compartment leading to systemic circulation. Irreversible binding is modeled in the SC; metabolism in theVE and the dermis. For most cases the full realization of this model will not be required, nor will data be available to implement it. Therefore, a series of reduced structures are also presented. These range from a distributed parameter model that only considers resistance in the SC to a model that treats the entire skin system as one well-stirred compartment linked to a systemic PBPK model. The model suite provides the flexibility required to conduct risk assessment on a wide variety of compounds. This is the first work that has addressed dermal dose-response dosimetry. Incorporating the dermal dosimetry model suite along with parallel suites for inhalation and ingestion routes into the risk characterization process will improve the mechanistic basis of assessments and, as a result, provide a platform for quantitative route-to-route extrapolation and calculation of aggregate estimates.
This work has been funded wholly or in part by the United States Environmental Protection Agency under contract no. 68-D-99-012 to Research Triangle Institute. It has been subjected to Agency review and approved for publication.