NORA Manufacturing Sector Strategic Goals
R017529 - 021H: Mechanistically-Based In Silico Estimation of Dermal Absorption in the Workplace (7529)Start Date: 9/1/2007
End Date: 8/31/2012
Principal Investigator (PI)Name: Joan Karr
Funded By: NIOSH
Primary Goal Addressed
Secondary Goal Addressed
Attributed to Manufacturing
To develop and apply to occupational risk assessment a sophisticated, yet accessible mathematical model that closely mimics percutaneous penetration, tissue concentrations and clearance of chemicals in human skin in vivo.
The investigators propose to further develop and apply to occupational risk assessment a sophisticated, yet accessible mathematical model that closely mimics percutaneous penetration, tissue concentrations and clearance of chemicals in human skin in vivo. The working model, developed during the previous period of support, will be calibrated by means of new experiments and extended to include a wider range of chemicals. Initial development of a transient swelling and shrinkage model for skin decontamination and a thermodynamically-based model for interacting chemical mixtures will be undertaken. The skin decontamination model will be supported by human in vivo and in vitro studies with DEET. Single component, multicomponent and swelling models wll be used to interpret complex skin absorption phenomena found in occupational health practice. Model software will be packaged in a spreadsheet format to provide accessibility to the occupational health and safety/industrial hygiene communities. Key technical features in the skin absorption model include: (1) a hydration-dependent, microscopically-based model for stratum corneum permeability; (2) a dermal vascular model that allows accurate prediction of permeant concentrations and clearance in the viable skin layers; (3) quantitative estimation of the evaporation rates of volatile permeants; (4) incorporation of convective flow and surfactant and organic solvent effects for skin decontamination; (5) a detailed microscopic model for permeant transport in the epidermis; and (6) a thermodynamic activity-based model for interactions in chemical mixtures contacting the skin. The primary routes by which occupatational exposures occur are inhalation and dermal exposure (skin contact). Effective dermal risk assessment for workers involved with hazardous chemicals (solvents, pesticides, cleaning fluids, etc.) requires accurate methods for estimating exposure to and absorption of the chemical, and the probable biological response to this event. Evaluation of the potential effectiveness of washing for purposes of mitigating dermal risk is an essential part of this process. Completion of the proposed project will provide a significant improvement to current methods for estimating absorption of chemicals subsequent to dermal exposures in the workplace.
The specific aims are:
Aim 1. To refine the microscopic skin permeability model constructed in our laboratories over the past period of support and improve its calibration by comparison with new laboratory skin partitioning and absorption data.
Aim 2. To apply the skin permeability model to real-world scenarios of immediate relevance to occupational health practice, thereby testing the utility of the developed model, and to implement a probabilistic version of he calculations. A version of the model incorporating transient swelling and wash-off, supported by a forearm wash study with DEET, will be developed to test the impact of various decontamination approaches on skin absorption.
Aim 3. To develop advanced components for the skin permeability model to improve its accuracy, extend the range of applicability to a broader set of compounds and mixtures thereof, and achieve a next-generation understanding of penetration transients.
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