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CHEMOMORPHIC ANALYSIS OF MALATHION IN SKIN LAYERS OF THE RAT: IMPLICATIONS FOR THE USE OF DERMATOPHARMACOKINETIC (DPK) TAPE STRIPPING IN EXPOSURE ASSESSMENT TO PESTICIDES
Citation:
Dary, C C., J N. Blancato, AND M. A. Saleh. CHEMOMORPHIC ANALYSIS OF MALATHION IN SKIN LAYERS OF THE RAT: IMPLICATIONS FOR THE USE OF DERMATOPHARMACOKINETIC (DPK) TAPE STRIPPING IN EXPOSURE ASSESSMENT TO PESTICIDES. REGULATORY TOXICOLOGY AND PHARMACOLOGY 34(3):234-248, (2001).
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:
The dermatopharmacokinetic (DPK) method of dermal tape stripping may prove to be a valuable addition to risk assessment protocols for toxic substances as it has been for the assessment of bioequivalence and bioavailability of topical dermatologic drugs. The measurement of drug penetration into stratum corneum (SC) with respect to time is thought to be comparable with drug distribution in underlying tissues. To examine this possibility, the dermal penetration and absorption characteristics of [14C]malathion in the Sprague-Dawley rat was examined by three analytical techniques. [14C]Malathion was applied in different vehicles for 30-min and 1-h periods of exposure. Penetration into the SC was assessed by tape stripping followed by instant electronic autoradiography (IEA). Also, the 14C activity retained in three successive 16 um sections of the skin application site was determined by IEA and malathion was identified by Fourier transform infrared microscopy (FTIR microscopy). Absorbed [14C]malathion was measured in selected tissues, organs, and the residual carcass by liquid scintillation counting (LSC). Penetration into the SC followed a linear trend. The capacity of the SC reservoir for malathion amounted to approximately 1% of the dermal dose, while approximately 6% of the dose was absorbed. Results from this study support the view that LSC remains the method of choice to efficiently and reliably quantify absorption of a radiolabeled test substance. IEA offers the ability of the user to visualize the extent and profile of dermal absorption. When IEA is combined with FTIR microscopy, an effectual tool for studying the penetration of chemicals into layers of the skin emerges. The combined use of the three analytical techniques can be used to test the validity of the DPK method in hazard evaluation and exposure assessment of the organophosphorus insecticides.
This work was partially supported by the National Institutes of Health research centers in minority institution (RCMI) under grant #RR03045-12A. Additional funding was provided by the U.S. Environmental Protection Agency (U.S. EPA) through the Office of Research and Development (ORD) under cooperative agreement #CR818220-02-5.