Ana M. Barbero

Tissue Binding Affects the Kinetics of Theophylline Diffusion Through the Stratum Corneum Barrier Layer of Skin

New data sets on both (i) equilibrium theophylline (TH) partitioning/binding in stratum corneum and (ii) transient TH diffusion through human epidermis are explained by an extended partition-diffusion model with reversible binding. Data conform to a linear binding isotherm within the tested concentration range (0-2000 μg/mL) with an equilibrium ratio of bound-to-free solute of approximately 1.4. The permeability coefficient for TH is 4.86 × 10(-5) cm/h, and the lag time is 20.1 h. Binding occurs as a slow process, significantly affecting the kinetics of dermal penetration.

A paired comparison between human skin and hairless guinea pig skin in vitro permeability and lag time measurements for 6 industrial chemicals

The purpose of the present study was to measure and compare permeability coefficients (kp) and lag times (τ) in human skin and hairless guinea pig (HGP) skin. Paired experiments employed heat-separated epidermal membranes from human and HGP sources mounted on static in vitro diffusion cells. Infinite-dose, saturated aqueous solutions of 6 industrial chemicals were used as donors: aniline, benzene, 1,2- dichloroethane, diethyl phthalate, naphthalene, and tetrachloroethylene. No significant differences were found between human and HGP skin for either kp or τ for any of these chemicals (p ≥ .24). HGP vs. human kp measurements, and HGP vs. human τ measurements, were highly correlated. For kp, the slope of the linear correlation was close to unity (1.080 ± 0.182) and the intercept close to 0 (0.015 ± 0. 029 cm/h), with a correlation coefficient (r2) = 0.898. For τ, the slope was also close to unity (0.818 ± 0.030) and the intercept close to 0 (–0.014 ± 0.023 h), with r2 = 0.994. These results suggest that HGP skin may serve as an excellent surrogate for human skin in in vitro dermal penetration studies.

Application of numerical methods for diffusion-based modeling of skin permeation.

The application of numerical methods for mechanistic, diffusion-based modeling of skin permeation is reviewed. Methods considered here are finite difference, method of lines, finite element, finite volume, random walk, cellular automata, and smoothed particle hydrodynamics. First the methods are briefly explained with rudimentary mathematical underpinnings. Current state of the art numerical models are described, and then a chronological overview of published models is provided. Key findings and insights of reviewed models are highlighted. Model results support a primarily transcellular pathway with anisotropic lipid transport. Future endeavors would benefit from a fundamental analysis of drug/vehicle/skin interactions.

Skin Penetration And Lag Times Of Neat And Aqueous Diethyl Phthalate, 1,2-Dichloroethane And Naphthalene

Cutaneous exposures to occupational chemicals may cause toxic effects. For any chemical, the potential for systemic toxicity from dermal exposure depends on its ability to penetrate the skin. Most laboratory studies measure chemical penetration from an aqueous solution through isolated human or laboratory animal skin, although most exposures are not from pure aqueous solutions. The US EPA Interagency Testing Committee (ITC) mandated by the Toxic Substances Control Act, has required industry to measure the in vitro penetration of 34 chemicals in their pure or neat form (if liquid). The goal of the present study was to measure skin permeability and lag time for three neat chemicals of industrial importance, representing the general types of chemicals to be studied by the ITC (non-volatile liquids, volatile liquids, and solids), and to examine interlaboratory variation from these studies. Steady state fluxes and lag times of diethyl phthalate (DEP, slightly volatile), 1,2-dichloroethane (DCE, highly volatile), and naphthalene (NAP, solid) were studied in two different laboratories using different analytical methods. One lab also measured fluxes and lag times from saturated aqueous vehicle. Static diffusion cells, dermatomed hairless guinea pig skin, and gas chromatography were used to measure skin penetration. In the two laboratories, the steady state fluxes (mean±SD; µg cm−2hour−1) of DEP applied neat were: 11.8±4.1 and 23.9±7.0; fluxes of DCE (neat) were 6280±1380 and 3842±712; fluxes of NAP from powder were 30.4±2.0 and 7.5±4.7. Compared with neat fluxes measured in the same laboratory, flux from saturated aqueous solution was higher with DEP (1.9 ×) but lower with DCE (0.17 ×) and NAP (0.45 ×). The three chemicals studied including a dry powder, demonstrate the potential for significant dermal penetration.

Dermal permeation of 2-hydroxypropyl acrylate, a model water-miscible compound: Effects of concentration, thermodynamic activity and skin hydration

UNLABELLED The goal of these studies was to measure and interpret the skin permeability characteristics of 2-hydroxypropyl acrylate (HPA) as a model compound that is completely miscible with water. METHODS In vitro permeation from HPA-H2O binary mixtures through human epidermis and silicone membranes was measured. Thermodynamic activities of HPA and H2O in these mixtures were determined. Permeation was also measured through epidermis and silicone from donor solutions with constant HPA activity but different H2O activities. Water uptake into desiccated human stratum corneum (SC) equilibrated with HPA-H2O mixtures was determined. RESULTS Steady-state flux of HPA through silicone was a linear function of HPA activity but not HPA concentration. For epidermis on the other hand, flux increased with HPA activity only for HPA activities ≤ 0.35. At constant HPA activity, flux decreased 4.5-fold as water activity decreased from 1 to 0.8. Incubation of SC with HPA-H2O mixtures resulted in substantial changes in SC water content, dependent on the water activity of the mixture and consistent with measured SC water sorption data. CONCLUSIONS These experiments provide unequivocal evidence of a substantial increase in epidermal barrier function resulting from SC dehydration. Dehydration-related alterations in the SC appear responsible for the observed flux characteristics.

Dermal Penetration Potential of Perfluorooctanoic Acid (PFOA) in Human and Mouse Skin

Recent data, using a murine model, have indicated that dermal exposure to perfluorooctanoic acid (PFOA) induces immune modulation, suggesting that this may be an important route of PFOA exposure. To investigate the dermal penetration potential of PFOA, serum concentrations were analyzed in mice following topical application. Statistically significant and dose-responsive increases in serum PFOA concentrations were identified. In vitro dermal penetration studies also demonstrated that PFOA permeates both mouse and human skin. Investigation into the mechanisms mediating PFOA penetration demonstrated that dermal absorption was strongly dependent upon the ionization status of PFOA. In addition, PFOA solid, but not 1% PFOA/acetone solution, was identified as corrosive using a cultured epidermis in vitro model. Despite its corrosive potential, expression of inflammatory cytokines in the skin of topically exposed mice was not altered. These data suggest that PFOA is dermally absorbed and that under certain conditions the skin may be a significant route of exposure.

In vitro Human Epidermal Penetration of 1-Bromopropane

1-Bromopropane (1-BP; CAS number 106-94-5), also known as n-propyl bromide, is a halogenated short-chain alkane used as an organic solvent with numerous commercial and industrial applications, including garment dry cleaning and vapor degreasing of metals. The purpose of this study was to determine the dermal absorption characteristics and corrosivity of 1-BP. Heat-separated human epidermal membranes were mounted on static diffusion cells. Different exposure scenarios were studied (infinite dose, finite dose, and transient exposure) using neat 1-BP and saturated aqueous solution as donor. Steady-state fluxes for infinite-dose neat 1-BP exposure averaged 625 to 960 μg cm−2 h−1. The finite-dose (10 μl/cm2 = 13.5 mg/cm2) unoccluded donor resulted in penetration of <0.2% of the applied dose (22 μg/cm2). A 10-min transient exposure to infinite dose resulted in total penetration of 179 μg/cm2. Steady-state 1-BP fluxes from neat application of a commercial dry cleaning solvent were similar (441 to 722 μg cm−2 h−1). The permeability coefficient of 1-BP in water vehicle was 0.257 ± 0.141 cm/h. The absorption potential of 1-BP following dermal exposure is dependent upon the type and duration of exposure. Donor losses due to evaporation were approximately 500-fold greater than dermal absorption flux; evaporation flux was 420 mg cm−2 h−1. 1-BP is cytotoxic but not corrosive, based on results from a cultured reconstructed human epidermal model (EpiDerm Skin Corrosivity Test).

In Vitro Dermal Penetration of 4-Chloro-3-Methylphenol from Commercial Metal Working Fluid and Aqueous Vehicles

The biocide 4-chloro-3-methylphenol (CMP, CAS number 59-50-7) is a common additive to metal-working fluids (MWF) and building materials. National Institute for Occupational Safety and Health (NIOSH) researchers previously identified and quantified CMP in a commercial water-soluble MWF, TRIM VX, and demonstrated irritancy and sensitization potential of both TRIM VX and CMP alone after dermal exposure in a murine model. In the current study, the in vitro human epidermal permeability of CMP contained in a working dilution of TRIM VX (20% in water) was evaluated and, for comparison, permeability from an aqueous buffer was also assessed. CMP penetration was also measured from transient exposures to 20% TRIM VX. To address differences in penetration rates from 20% TRIM VX and from buffer, the role of thermodynamic activity of CMP in the 2 vehicles on dermal penetration was investigated. Static headspace gas chromatography was used to measure vapor pressures and infer fractional thermodynamic activities of CMP in the mixtures. Permeability coefficient (kp ) of CMP from 20% TRIM VX was (4.1 ± 0.8) × 10−3 cm/h (mean ± SD, n = 5), and CMP was found at a concentration of 3555 ± 191 μg/ml in this donor. In contrast, kp was 0.18 ± 0.03 cm/h (n = 5) at a similar concentration (3919 ± 240) from buffer donor. Steady-state fluxes from 20% TRIM VX and buffer were comparable when expressed as functions of thermodynamic activity of CMP in the donor, rather than as concentrations. Transient (20 or 40 min) exposures of epidermal membranes to 20% TRIM VX (n = 4) resulted in total penetration of 4.2 ± 1.2 and 7.3 ± 0.8 μg/cm2, respectively; these amounts are comparable to amounts predicted using a simple algebraic equation.

In vitro human epidermal permeation of nicotine from electronic cigarette refill liquids and implications for dermal exposure assessment

Nicotine plus flavorings in a propylene glycol (PG) vehicle are the components of electronic cigarette liquids (e-liquids), which are vaporized and inhaled by the user. Dermal exposure to nicotine and e-liquids may occur among workers in mixing and filling of e-cigarettes in the manufacturing process. Inadvertent skin contact among consumers is also a concern. In vitro nicotine permeation studies using heat-separated human epidermis were performed with surrogate and two commercial e-liquids, neat and aqueous nicotine donor formulations. Steady-state fluxes (Jss), and lag times (tlag) were measured for each formulation. In addition, transient (4 h) exposure and finite dose (1–10 μl/cm2) experiments were undertaken using one commercial e-liquid. Average Jss (μg/cm2/h) from formulations were: nicotine in PG (24 mg/ml): 3.97; commercial e-liquid containing menthol (25 mg/ml nicotine): 10.2; commercial e-liquid containing limonene (25 mg/ml nicotine): 23.7; neat nicotine: 175. E-liquid lag times ranged from 5 to 10 h. Absorbed fraction of nicotine from finite doses was ≈0.3 at 48 h. The data were applied to transient exposure and finite dose dermal exposure assessment models and to a simple pharmacokinetic model. Three illustrative exposure scenarios demonstrate use of the data to predict systemic uptake and plasma concentrations from dermal exposure. The data demonstrate the potential for significant nicotine absorption through skin contact with e-cigarette refill solutions and the neat nicotine used to mix them.

Effect of stratum corneum heterogeneity, anisotropy, asymmetry and follicular pathway on transdermal penetration

Abstract The impact of the complex structure of the stratum corneum on transdermal penetration is not yet fully described by existing models. A quantitative and thorough study of skin permeation is essential for chemical exposure assessment and transdermal delivery of drugs. The objective of this study is to analyze the effects of heterogeneity, anisotropy, asymmetry, follicular diffusion, and location of the main barrier of diffusion on percutaneous permeation. In the current study, the solution of the transient diffusion through a two‐dimensional‐anisotropic brick‐and‐mortar geometry of the stratum corneum is obtained using the commercial finite element program COMSOL Multiphysics. First, analytical solutions of an equivalent multilayer geometry are used to determine whether the lipids or corneocytes constitute the main permeation barrier. Also these analytical solutions are applied for validations of the finite element solutions. Three illustrative compounds are analyzed in these sections: diethyl phthalate, caffeine and nicotine. Then, asymmetry with depth and follicular diffusion are studied using caffeine as an illustrative compound. The following findings are drawn from this study: the main permeation barrier is located in the lipid layers; the flux and lag time of diffusion through a brick‐and‐mortar geometry are almost identical to the values corresponding to a multilayer geometry; the flux and lag time are affected when the lipid transbilayer diffusivity or the partition coefficients vary with depth, but are not affected by depth‐dependent corneocyte diffusivity; and the follicular contribution has significance for low transbilayer lipid diffusivity, especially when flux between the follicle and the surrounding stratum corneum is involved. This study demonstrates that the diffusion is primarily transcellular and the main barrier is located in the lipid layers. Graphical abstract Figure. No Caption available.