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A framework incorporating the impact of exposure scenarios and application conditions on risk assessment of chemicals applied to skin.

Dancik Y, Troutman JA, Jaworska J - In Silico Pharmacol (2013)

Bottom Line: A workflow connecting a dynamic skin penetration model with a generic whole-body physiologically-based pharmacokinetic (PBPK) model was developed.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.

View Article: PubMed Central - PubMed

Affiliation: The Procter & Gamble Company, Temselaan 100, Strombeek-Bever, 1853 Belgium.

ABSTRACT

Purpose: 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.

Method: 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.

No MeSH data available.


Related in: MedlinePlus

2-Methoxyethanol (2-ME) a) steady-state plasma concentrations and (b) exposure conversion factors in logarithmic scale. Dose, exposures scenarios and application conditions are described in Tables 1 and 2.
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Fig8: 2-Methoxyethanol (2-ME) a) steady-state plasma concentrations and (b) exposure conversion factors in logarithmic scale. Dose, exposures scenarios and application conditions are described in Tables 1 and 2.

Mentions: The effect of adding or removing an aqueous vehicle on the ECF varies with the chemical and the dilution. Addition of 50% water alters the Cp, ss and ECFs significantly only for BR (Figure 1(a), (b)) with a 3-fold increase in the values across the doses, and for DGMME (Figure 3 (a), (b)) with a 2-fold decrease in the values. The 90% water dilution has a more diverse effect, increasing the BR Cp, ss and ECF values by the same amount as the 50% dilution, but decreasing those of DGMME, DMF (Figure 5(a), (b)) and 2-ME (Figure 8(a), (b)) 8- to 16-fold. Removal of the vehicle used in the DGMBE and TGA animal studies increases the Cp, ss and ECF values up to 3-fold (Figure 4(a), (b) and 9(a), (b)).Figure 8


A framework incorporating the impact of exposure scenarios and application conditions on risk assessment of chemicals applied to skin.

Dancik Y, Troutman JA, Jaworska J - In Silico Pharmacol (2013)

2-Methoxyethanol (2-ME) a) steady-state plasma concentrations and (b) exposure conversion factors in logarithmic scale. Dose, exposures scenarios and application conditions are described in Tables 1 and 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230815&req=5

Fig8: 2-Methoxyethanol (2-ME) a) steady-state plasma concentrations and (b) exposure conversion factors in logarithmic scale. Dose, exposures scenarios and application conditions are described in Tables 1 and 2.
Mentions: The effect of adding or removing an aqueous vehicle on the ECF varies with the chemical and the dilution. Addition of 50% water alters the Cp, ss and ECFs significantly only for BR (Figure 1(a), (b)) with a 3-fold increase in the values across the doses, and for DGMME (Figure 3 (a), (b)) with a 2-fold decrease in the values. The 90% water dilution has a more diverse effect, increasing the BR Cp, ss and ECF values by the same amount as the 50% dilution, but decreasing those of DGMME, DMF (Figure 5(a), (b)) and 2-ME (Figure 8(a), (b)) 8- to 16-fold. Removal of the vehicle used in the DGMBE and TGA animal studies increases the Cp, ss and ECF values up to 3-fold (Figure 4(a), (b) and 9(a), (b)).Figure 8

Bottom Line: A workflow connecting a dynamic skin penetration model with a generic whole-body physiologically-based pharmacokinetic (PBPK) model was developed.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.

View Article: PubMed Central - PubMed

Affiliation: The Procter & Gamble Company, Temselaan 100, Strombeek-Bever, 1853 Belgium.

ABSTRACT

Purpose: 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.

Method: 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.

No MeSH data available.


Related in: MedlinePlus