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Application of a high throughput physiology based pharmacokinetic/toxicokinetic (httk) dermal route using human in vivo caffeine exposure data
Citation:
Evans, M., A. Meade, G. Lian, B. Deacon, T. Chen, AND J. Wambaugh. Application of a high throughput physiology based pharmacokinetic/toxicokinetic (httk) dermal route using human in vivo caffeine exposure data. SOT, Nashville, TN, March 19 - 23, 2023. https://doi.org/10.23645/epacomptox.22207225
Impact/Purpose:
Chemical Safety and health assessment is an important area of research due to the large number of chemicals being used. The dermal route is one of the major routes of exposure and needs to be included in high-throughput approaches such as httk (high troughput toxicokinetic ) model, an open sourced PBPK model developed for public use. This work evaluates the development of a dermal route of exposure using general principles and experimental data.
Description:
Dermal absorption represents an important route of exposure with chemicals from multiple sources: environmental, pharmaceutical, occupational, and consumer products. Due to the lack of toxicity information and large number of chemicals applied dermally, a high throughput approach is well suited for estimation of potential health risk for this exposure type. A dermal route has been added to a high throughput, generic, and physiologically based toxicokinetic (httk) model to predict systemic dose due to dermal absorption. Dermal permeability (Kp) is a key chemical-specific parameter needed to quantify dermal absorption. We used two different methods to calculate dermal permeability for caffeine, both based on quantitative structure activity relationships (QSAR). The Potts-Guy QSAR equation is the default approach used by the US EPA to calculate dermal absorption permeability. The UK Surrey model combines the QSAR approach with a diffusion-based “brick and mortar” model representative of the stratum corneum (SC). Realistic dimensions are used to represent the SC and sequential layers underneath the SC, assumed to behave as sinks (rapid diffusion). The combination of a QSAR and mechanistic approach allow for the distinction between subsequent layers. Both the Potts-Guy and UK Surrey QSAR approaches use molecular weight and the octanol/water partition coefficient to calculate Kp. The UK Surrey model estimated permeability for caffeine to be 6.36e-05 cm/h, while the Potts-Guy permeability estimate doubled in value. Both Potts-Guy and the UK Surrey permeability methods have been incorporated into httk and can be chosen by the user. Our work concentrates on the application of the UK Surrey hybrid approach, with httk dermal simulations used to predict an in vivo clinical dataset applying 1.25 mg in a 25 cm2 area on the chest (Otberg et al, 2008). The experimental data indicates that elimination is larger than accounted by the model, indicating than an additional mechanism needs to be added to the model. We first considered increasing metabolic clearance and doing so lead to an improvement in the fit of the peak value. However, metabolic clearance alone was not sufficient to explain the experimental elimination. Preliminary inclusion of evaporation from the SC is being explored as an additional factor necessary to explain the experimental elimination observed. In summary, a hybrid approach combining QSAR and mechanistic concepts have been applied using caffeine as an example chemical. Continued evaluation of the hybrid model Is expected to provide additional insights into mechanisms needed to explain the data. (This abstract does not reflect US EPA policy).
URLs/Downloads:
DOI: Application of a high throughput physiology based pharmacokinetic/toxicokinetic (httk) dermal route using human in vivo caffeine exposure data
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