Last data update: Sep 23, 2024. (Total: 47723 publications since 2009)
Records 1-15 (of 15 Records) |
Query Trace: Frasch HF [original query] |
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Spectral reflectance measurement of evaporating chemical films: Initial results and application to skin permeation
Frasch HF , Lee L , Barbero AM . J Pharm Sci 2018 107 (8) 2251-2258 The current study has two aims. First the method of spectral reflectance was used to measure evaporation rates of thin ( approximately 25-300 mum) films of neat liquid volatile organic chemicals exposed to a well-regulated wind speed u. Gas phase evaporation mass transfer coefficient (kevap) measurements of 10 chemicals, 9 of which were measured at similar u, are predicted (slope of log-log data = 1.01; intercept = 0.08; R(2) = 0.996) by a previously proposed mass transfer correlation. For one chemical, isoamyl alcohol, the dependence of kevap on u(0.52) was measured, in support of the predicted exponent value of (1/2). Second, measured kevap of nicotine was used as an input in analytical models based on diffusion theory to estimate the absorbed fraction (Fabs) of a small dose (5 muL/cm(2)) applied to human epidermis in vitro. The measured Fabs was 0.062 +/- 0.023. Model-estimated values are 0.066 and 0.115. Spectral reflectance is a precise method of measuring kevap of liquid chemicals and the data are well-described by a simple gas phase mass transfer coefficient. For nicotine under the single exposure condition measured herein, Fabs is well-predicted from a theoretical model that requires knowledge of kevap, maximal dermal flux and membrane lag time. |
In vitro human skin permeation of benzene in gasoline: Effects of concentration, multiple dosing and skin preparation
Frasch HF , Barbero AM . J Expo Sci Environ Epidemiol 2017 28 (2) 193-201 In vitro human skin benzene permeation was measured from gasoline formulations with benzene concentrations ranging from 0.8 to 10 vol% and from neat benzene. Steady-state fluxes (JSS), permeability coefficients (kp) and lag times (tlag) were calculated from infinite dose exposures. Permeation of benzene from small gasoline doses administered over a two-day period was also studied. The thermodynamic activity of benzene in gasoline at 30 degrees C was determined and the solution is near-ideal over the range from 0.8 to 100 vol%. JSS through human epidermal membranes were linear (R2=0.92) with concentration over the range from 0.8 to 10 vol%. JSS (mug/cm2/h) from gasoline (0.8 vol% benzene=6.99 mg/ml) through epidermis and full-thickness skin were 9.37+/-1.41 and 1.82+/-0.44, respectively. Neat benzene JSS was 566+/-138. Less than 0.25% of the total applied benzene mass from finite doses (10 mul/cm2) of gasoline was detected in receptor cells, and a small reduction of barrier function was observed from six total doses administered over 2 days. Application of these results to dermal exposure assessment examples demonstrates a range of systemic benzene uptakes that can be expected from occupational and consumer dermal exposures to gasoline, depending on the type and extent of exposure. |
In vitro human epidermal permeation of nicotine from electronic cigarette refill liquids and implications for dermal exposure assessment
Frasch HF , Barbero AM . J Expo Sci Environ Epidemiol 2016 27 (6) 618-624 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 mul/cm2) experiments were undertaken using one commercial e-liquid. Average Jss (mug/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 approximately 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.Journal of Exposure Science and Environmental Epidemiology advance online publication, 7 December 2016; doi:10.1038/jes.2016.68. |
Effect of frozen human epidermis storage duration and cryoprotectant on barrier function using two model compounds
Barbero AM , Frasch HF . Skin Pharmacol Physiol 2015 29 (1) 31-40 Skin is commonly stored frozen and then thawed prior to use for in vitro permeation experiments. Does frozen storage of skin alter its barrier property? Numerous studies have found contradictory answers to this question. In this study, the steady-state flux and lag time of diethyl phthalate (DEP) were measured for fresh human skin and skin frozen at -85 degrees C for 1, 2, 3, 6, 9, 12, and 18 months with 10% glycerol as a cryoprotective agent. No significant differences in steady-state flux were found between fresh and previously frozen samples (p = 0.6). For lag time, a significant (p = 0.002) difference was found among all groups, but comparisons with fresh skin were not significant. Does glycerol have a cryoprotective effect? The steady-state flux and lag time of DEP and caffeine were measured through human skin stored at -85 degrees C for up to 12 months with and without 10% glycerol. No significant differences in steady-state flux or lag time were found between samples stored with or without glycerol for either DEP or caffeine (p ≥ 0.17). These findings support the use of frozen skin to measure the passive permeation of chemicals in studies unconcerned with viability and metabolism. Published by S. Karger AG, Basel. |
The transient dermal exposure II: post-exposure absorption and evaporation of volatile compounds
Frasch HF , Bunge AL . J Pharm Sci 2015 104 (4) 1499-507 The transient dermal exposure is one where the skin is exposed to chemical for a finite duration, after which the chemical is removed and no residue remains on the skin's surface. Chemical within the skin at the end of the exposure period can still enter the systemic circulation. If it has some volatility, a portion of it will evaporate from the surface before it has a chance to be absorbed by the body. The fate of this post-exposure "skin depot" is the focus of this theoretical study. Laplace domain solutions for concentration distribution, flux, and cumulative mass absorption and evaporation are presented, and time domain results are obtained through numerical inversion. The Final Value Theorem is applied to obtain the analytical solutions for the total fractional absorption by the body and evaporation from skin at infinite time following a transient exposure. The solutions depend on two dimensionless variables: chi, the ratio of evaporation rate to steady-state dermal permeation rate; and the ratio of exposure time to membrane lag time. Simple closed form algebraic equations are presented that closely approximate the complete analytical solutions. Applications of the theory to the dermal risk assessment of pharmaceutical, occupational, and environmental exposures are presented for four example chemicals. |
Dermal permeation of 2-hydroxypropyl acrylate, a model water-miscible compound: effects of concentration, thermodynamic activity and skin hydration
Frasch HF , Barbero AM , Dotson GS , Bunge AL . Int J Pharm 2014 460 240-7 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. |
Analysis of finite dose dermal absorption data: implications for dermal exposure assessment
Frasch HF , Dotson GS , Bunge AL , Chen CP , Cherrie JW , Kasting GB , Kissel JC , Sahmel J , Semple S , Wilkinson S . J Expo Sci Environ Epidemiol 2013 24 (1) 65-73 A common dermal exposure assessment strategy estimates the systemic uptake of chemical in contact with skin using the fixed fractional absorption approach: the dermal absorbed dose is estimated as the product of exposure and the fraction of applied chemical that is absorbed, assumed constant for a given chemical. Despite the prominence of this approach there is little guidance regarding the evaluation of experiments from which fractional absorption data are measured. An analysis of these experiments is presented herein, and limitations to the fixed fractional absorption approach are discussed. The analysis provides a set of simple algebraic expressions that may be used in the evaluation of finite dose dermal absorption experiments, affording a more data-driven approach to dermal exposure assessment. Case studies are presented that demonstrate the application of these tools to the assessment of dermal absorption data. (Journal of Exposure Science and Environmental Epidemiology advance online publication, 29 May 2013; doi:10.1038/jes.2013.23.) |
Dermal absorption of finite doses of volatile compounds
Frasch HF . J Pharm Sci 2012 101 (7) 2616-9 Laplace domain solutions to a previously published finite dose skin diffusion model are presented. The purpose of the current analysis is to derive a simple algebraic expression quantifying the total mass that is systemically absorbed at infinite time after exposure, relative to the applied mass. The resulting expression is a function of two dimensionless parameters: f, the fractional depth within the skin surface through which the permeant is initially deposited, and chi, the ratio of maximum evaporation flux to maximum dermal flux. The result may be useful for dermal risk assessment as well as in the evaluation of cosmetic and pharmaceutical product performance. ((c) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.) |
Application of numerical methods for diffusion-based modeling of skin permeation
Frasch HF , Barbero AM . Adv Drug Deliv Rev 2012 65 (2) 208-20 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. |
Mathematical models of skin permeability: an overview
Mitragotri S , Anissimov YG , Bunge AL , Frasch HF , Guy RH , Hadgraft J , Kasting GB , Lane ME , Roberts MS . Int J Pharm 2011 418 (1) 115-29 Mathematical models of skin permeability play an important role in various fields including prediction of transdermal drug delivery and assessment of dermal exposure to industrial chemicals. Extensive research has been performed over the last several decades to yield predictions of skin permeability to various molecules. These efforts include the development of empirical approaches such as quantitative structure-permeability relationships and porous pathway theories as well as the establishment of rigorous structure-based models. In addition to establishing the necessary mathematical framework to describe these models, efforts have also been dedicated to determining the key parameters that are required to use these models. This article provides an overview of various modeling approaches with respect to their advantages, limitations and future prospects. |
Dermal penetration potential of perfluorooctanoic acid (PFOA) in human and mouse skin
Franko J , Meade BJ , Frasch HF , Barbero AM , Anderson SE . J Toxicol Environ Health A 2012 75 (1) 50-62 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. |
Tissue binding affects the kinetics of theophylline diffusion through the stratum corneum barrier layer of skin
Frasch HF , Barbero AM , Hettick JM , Nitsche JM . J Pharm Sci 2011 100 (7) 2989-95 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 mcg/mL) with an equilibrium ratio of bound-to-free solute of approximately 1.4. The permeability coefficient for TH is 4.86 x 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. |
In vitro human epidermal penetration of 1-bromopropane
Frasch HF , Dotson GS , Barbero AM . J Toxicol Environ Health A 2011 74 (19) 1249-60 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 mcg cm(-2) h(-1). The finite-dose (10 mcl/cm(2) = 13.5 mg/cm(2)) unoccluded donor resulted in penetration of <0.2% of the applied dose (22 mcg/cm(2)). A 10-min transient exposure to infinite dose resulted in total penetration of 179 mcg/cm(2). Steady-state 1-BP fluxes from neat application of a commercial dry cleaning solvent were similar (441 to 722 mcg 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). |
Dynamics of diffusion with reversible binding in microscopically heterogeneous membranes: general theory and applications to dermal penetration
Nitsche JM , Frasch HF . Chem Eng Sci 2011 66 (10) 2019-2041 Essentially all biological membranes and tissues exhibit microscopic heterogeneity in the form of cellular, lamellar or other organization, and molecular diffusion in these materials is frequently slowed by binding to elements of the microstructure ("trapping"). This paper addresses situations where binding is describable as a linear reversible process at the microscale, with forward ("on") and reverse ("off") rate constants kf(x) and kr(x) that vary with position. Very commonly it is tacitly assumed that the macroscopically observable binding behavior should follow the same rate law with the substitution of appropriate effective (tissue-average) rate constants and . This assumption is probed theoretically for spatially periodic microstructures using a judicious application of numerical calculations and asymptotic analysis to prototypical one-dimensional transport problems. We find that smooth microscopic variations produce an anomalous macroscopic exchange between free and bound solute populations that is not well described by a single pair of forward and reverse rate constants, i.e., violates the usual paradigm. In contrast, discontinuous variations (as in two-phase composite media) are evidently well described by the usual paradigm. For the latter case we derive simple and general algebraic equations giving and , and generalize them to any three-dimensional unit cell representing the tissue microstructure. Validity of the formulas is demonstrated with reference to a concrete example describing molecular diffusion through the stratum corneum (barrier) layer of skin, comprising lipid (intercellular) and corneocyte (cellular) phases. Our analysis extends coarse-graining (homogenization, effective transport) theory for irreversible trapping systems to the reversible case. |
A paired comparison between human skin and hairless guinea pig skin in vitro permeability and lag time measurements for 6 industrial chemicals
Frasch HF , Barbero AM . Cutan Ocul Toxicol 2009 28 (3) 107-13 The purpose of the present study was to measure and compare permeability coefficients (k(p)) and lag times (tau) 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 k(p) or tau for any of these chemicals (p ≥ .24). HGP vs. human k(p) measurements, and HGP vs. human tau measurements, were highly correlated. For k(p), 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 (r(2)) = 0.898. For tau, the slope was also close to unity (0.818 +/- 0.030) and the intercept close to 0 (-0.014 +/- 0.023 h), with r(2) = 0.994. These results suggest that HGP skin may serve as an excellent surrogate for human skin in in vitro dermal penetration studies. |
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