title: A framework incorporating the impact of exposure scenarios and application conditions on risk assessment of chemicals applied to skin.
abstract: OBJECTIVE
  1. To develop a framework for exposure calculation via the dermal route to meet the needs of 21st century toxicity testing and refine current approaches; 2. To demonstrate the impact of exposure scenario and application conditions on the plasma concentration following dermal exposure.
  
  
  METHODS
  A workflow connecting a dynamic skin penetration model with a generic whole-body physiologically-based pharmacokinetic (PBPK) model was developed. The impact of modifying exposure scenarios and application conditions on the simulated steady-state plasma concentration and exposure conversion factor was investigated for 9 chemicals tested previously in dermal animal studies which did not consider kinetics in their experimental designs.
  
  
  RESULTS
  By simulating the animal study scenarios and exposure conditions, we showed that 7 studies were conducted with finite dose exposures, 1 with both finite and infinite dose exposures (in these 8 studies, an increase in the animal dose resulted in an increase in the simulated steady-state plasma concentrations (C p,ss)), while 1 study was conducted with infinite dose exposures only (an increase in the animal dose resulted in identical C p,ss). Steady-state plasma concentrations were up to 30-fold higher following an infinite dose scenario vs. a finite dose scenario, and up to 40-fold higher with occlusion vs. without. Depending on the chemical, the presence of water as a vehicle increased or decreased the steady-state plasma concentration, the largest difference being a factor of 16.
  
  
  CONCLUSIONS
  The workflow linking Kasting's model of skin penetration and whole-body PBPK enables estimation of plasma concentrations for various applied doses, exposure scenarios and application conditions. Consequently, it provides a quantitative, mechanistic tool to refine dermal exposure calculations methodology for further use in risk assessment.
authors.affiliation: The Procter & Gamble Company, Temselaan 100, Strombeek-Bever, 1853 Belgium.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Dancik
authors.affiliation: The Procter & Gamble Company, Cincinnati, OH 45253 USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Troutman
authors.affiliation: The Procter & Gamble Company, Temselaan 100, Strombeek-Bever, 1853 Belgium.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jaworska
keywords: Dermal exposure; Forward and reverse dosimetry; PBPK; Skin penetration kinetics