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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

Diethylene glycol mono-n-butyl ether (DGMBE) (a) steady-state plasma concentrations and (b) exposure conversion factors in logarithmic scale. Doses, exposures scenarios and application conditions are described in Tables 1 and 2.
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Fig4: Diethylene glycol mono-n-butyl ether (DGMBE) (a) steady-state plasma concentrations and (b) exposure conversion factors in logarithmic scale. Doses, exposures scenarios and application conditions are described in Tables 1 and 2.

Mentions: Figures 1(a), 2(a), 3(a), 4(a), 5(a), 6(a), 7(a), and 9(a) show that Cp, ss either increases with the applied dose, meaning the kinetics of skin penetration are dose-dependent, or remains constant. It is constant for BR (Figure 1(a)), DGMME at the two highest doses (Figure 3(a)), 2-EH (Figure 6(a)) and MPA (Figure 7(a)). In the cases of BR and DGMME, the exposure scenario lacks a removal step. Scenario A is equivalent to scenario B and yields infinite dose kinetics at all (BR) or the highest (DGMME) doses (see comparison of scenario A and B results below). In the cases of 2-EH and MPA, infinite dose kinetics are reached after each daily application, but due to the removal step, the average steady-state flux () and Cp, ss values are less than from an infinite dose.Figure 1


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)

Diethylene glycol mono-n-butyl ether (DGMBE) (a) steady-state plasma concentrations and (b) exposure conversion factors in logarithmic scale. Doses, 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

Fig4: Diethylene glycol mono-n-butyl ether (DGMBE) (a) steady-state plasma concentrations and (b) exposure conversion factors in logarithmic scale. Doses, exposures scenarios and application conditions are described in Tables 1 and 2.
Mentions: Figures 1(a), 2(a), 3(a), 4(a), 5(a), 6(a), 7(a), and 9(a) show that Cp, ss either increases with the applied dose, meaning the kinetics of skin penetration are dose-dependent, or remains constant. It is constant for BR (Figure 1(a)), DGMME at the two highest doses (Figure 3(a)), 2-EH (Figure 6(a)) and MPA (Figure 7(a)). In the cases of BR and DGMME, the exposure scenario lacks a removal step. Scenario A is equivalent to scenario B and yields infinite dose kinetics at all (BR) or the highest (DGMME) doses (see comparison of scenario A and B results below). In the cases of 2-EH and MPA, infinite dose kinetics are reached after each daily application, but due to the removal step, the average steady-state flux () and Cp, ss values are less than from an infinite dose.Figure 1

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