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Predicting dermal penetration for ToxCast chemicals using in silico estimates for diffusion in combination with physiologically based pharmacokinetic (PBPK) modeling.
Citation:
Evans, M., M. Sawyer, K. Isaacs, AND J. Wambaugh. Predicting dermal penetration for ToxCast chemicals using in silico estimates for diffusion in combination with physiologically based pharmacokinetic (PBPK) modeling. Society of Toxicology, New Orleans, LA, March 13 - 17, 2016.
Impact/Purpose:
The principal exposure route considered in this project will be dermal, and the primary goal is to expand its current description in HT-SHEDS. The skin is a multi-layered organ, one that is both complex to describe mathematically and covers a large surface of the body. There are several constants used to describe dermal absorption: diffusion across the top layer of skin, chemical partitioning between vehicle and topical chemical, lipophilicity of the chemical, and partitioning into blood. Despite the potential importance of the skin as a route of exposure, dermal exposure has not been systematically quantitated. The goal of this work is to calculate dermal absorption for a subset of chemicals having dermal experimental measurements. These results can be generalized to rules that can be then tested using HT experimental setups. The chemicals listed in the current ToxCast list (~2,000) will be used to select candidates from the literature or to guide necessary experiments (which will be covered under a separate IRP if conducted). Once the chemicals with experimental measurements are selected, a regression will be performed to obtain equations relating chemical weight and dermal constants.
Description:
Predicting dermal penetration for ToxCast chemicals using in silico estimates for diffusion in combination with physiologically based pharmacokinetic (PBPK) modeling.Evans, M.V., Sawyer, M.E., Isaacs, K.K, and Wambaugh, J.With the development of efficient high-throughput (HT) in vitro techniques, a strategy has been outlined to correlate in vivo toxicity with HT measurements. ToxCast is an EPA research program for screening environmental chemicals with HT hazard tests. Under the analogous ExpoCast program, predictive models are being developed to estimate exposures and target doses to allow, in combination with ToxCast hazard predictions, risk-based chemical prioritization. Dermal exposure may be a major route of exposure for many ToxCast chemicals, such as those found in consumer products. Mathematical diffusion models allow for in silico calculation of dermal diffusion constants using empirical equations that include physico-chemical characteristics. Lag time (Tlag) is a constant defining the length of time needed for dermal penetration to start. Tlag is related to the diffusion constant and molecular weight. Estimating diffusion and lag time constants with established mathematical models, we calculated Tlag values for about 2,000 chemicals listed as part of Toxcast Phase I and II. Values in Tlag ranged from 0.1 hours to 2663 hours in length. The shorter Tlag values indicate that this chemical can be rapidly absorbed, therefore shorter Tlag chemicals could be prioritized for study due to their ability to cross the skin barrier rapidly. The application of Tlag as a prioritization tool will depend on activity patterns and other lifestyle data. Ultimately, this in silico approach can be used for characterization of dermal absorption processes in forward exposure-dose PBPK and reverse dosimetry models in ExpoCast and elsewhere. Future research will compare diffusion constants and dermal parameters generated in silico with in vivo or in vitro dermal kinetic datasets. (The views expressed in this presentation are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency if you end up short on space, this can be changed to This abstract does not reflect U.S. EPA policy.)