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Introduction: 'Soak and smear' method, water soaking to induce skin hydration followed by topical corticoids application suggests effectiveness in clinical dermatological practice. We investigate one possible mechanism of soaking times effect on drug partitioning and diffusion rates in skin and its proposed efficacy., Methods: Utilizing an in vitro flow-through diffusion system to evaluate efficacy of the 'soak and smear' method following 0.5, 8, and 20 min water soaking and [ 14 C]-hydrocortisone topical application on human skin to probe the possibility of percutaneous penetration enhancement., Results: In water-soak groups, more [ 14 C]-hydrocortisone was absorbed and retained in stratum corneum and epidermis, whereas, in the control (no soak) more was in the deep skin-dermis and receptor fluid. These differences between water-soak groups and the control are statistically significant ( p  < .05)., Conclusion: Effect of 'soak and smear' on skin absorption and penetration depends on interaction of individual drug's physicochemical property, stratum corneum hydration, and stratum corneum-epidermoid barrier status. Water soaking ( ≤ 20 min) induced skin hydration increases [ 14 C]-hydrocortisone absorption and retention into the upper skin layer but not deep layers. This could support the proposed hypothesis of clinical dermatological treatment of hydrocortisone to local skin inflammations should the epidermis be found to be a key target for atopic dermatitis therapy.

Introduction: Skin care products are often utilized in conjunction with topical treatment for skin disease. However, these appears insufficient body of experimental data to advise the health care worker or patient. Examine penetration effect (hence potential for altering efficacy and toxicity) - dosing with one topical after another and how quickly such a potential phenomenon might occur., Methods: A marketed moisturizer applied on human skin with an in vitro diffusion system. At 1, 15, and 30 min post application, [ 14 C]-benzoic acid dosed the same skin site for 24 h. Amounts of chemical retained in skin and permeation flux rats were measured to determine penetration effect of the prior moisturizer application., Results: Exposure of a water-enriched moisturizer before a hydrophilic chemical immediate application favors the chemical penetration, especial in 1 and 15 min moisturizer exposure groups. The enhancement effect was expressed as an earlier lag time and a rapid absorption peak when compared to related non-moisturizer control., Conclusion: This experiment opens up a large door: what would be the result with many complex topical products and different tracers was used here, of varying hydrophilicity and lipophilicity. We do not wish to overgeneralize until such studies are confirmed in vivo .

This study compared the efficiency for in vitro human skin decontamination using DDGel and RSDL when applied at different timepoints (5 min and 90 min). Experiments were performed using in vitro human skin models, in which skin was mounted onto Flow-Through diffusion cells. The mass of 14 -C DIMP removed from skin surface after decontamination was quantitated by measuring radioactivity with a liquid scintillation spectrometer. Both decontaminants removed more than 90% recovery dose of DIMP from skin compared to control group (p < 0.05). DDGel skin decontamination reduced more toxicant amount when compared to RSDL. DDGel showed slight higher decontamination ability of DIMP than RSDL and efficiently removed chemicals from the skin surface, also reduced the amount of DIMP in receptor fluid. A similar decontamination regimen with RSDL and DDGel at 90 min showed that both were still might effectively increase the time window of opportunity for treatment. Thus, DDGel can offer a potential as a next generation skin decontamination platform technology for military and civilian applications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This study compared the efficiency for in vitro human skin decontamination using DDGel and RSDL. Experiments were performed using in vitro human skin models, in which skin was mounted onto Flow-Through diffusion cells. The mass of 14 -C CEES removed from skin surface after decontamination was quantitated by measuring radioactivity with a liquid scintillation spectrometer. Both decontaminants removed more than 82% of CEES from skin. DDGel skin decontamination significantly reduced toxicant amount when compared to RSDL. Mean CEES remaining in stratum corneum (SC), viable epidermis, dermis, and systemic absorption of DDGel and RSDL were, 0.12 and 0.55% (P < 0.01), 0.31 and 0.95% (p < 0.01), 1.08 and 2.92% (p < 0.05), 3.13 and 6.34% (p < 0.05), respectively. DDGel showed higher decontamination efficiency (twice decontamination efficacy factor, DEF) than RSDL and efficiently removed chemicals from the skin surface, importantly back-extracted from the SC, and significantly reduced both chemical penetration into skin and systemic absorption. Thus, DDGel can offer a potential as a next generation skin decontamination platform technology for military and civilian applications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: With rapid development of nanotechnology, there is increasing interest in nanoparticle (NP) application and its safety and efficacy on human skin. In this study, we utilized confocal laser scanning microscopy to estimate NP skin penetration., Methods: Three different-sized polystyrene NPs marked with red fluorescence were applied to human skin, and Calcium Green 5N was used as a counterstain. Dimethyl sulfoxide (DMSO) and ethanol were used as alternative vehicles for NPs. Tape stripping was utilized as a barrier-damaged skin model. Skin biopsies dosed with NPs were incubated at 4°C or 37°C for 24 hours and imaged using confocal laser scanning microscopy., Results: NPs were localized in the stratum corneum (SC) and hair follicles without penetrating the epidermis/dermis. Barrier alteration with tape stripping and change in incubation temperature did not induce deeper penetration. DMSO enhanced NP SC penetration but ethanol did not., Conclusion: Except with DMSO vehicle, these hydrolyzed polystyrene NPs did not penetrate intact or barrier-damaged human "viable" epidermis. For further clinical relevance, in vivo human skin studies and more sensitive analytic chemical methodology are suggested., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

This study evaluated the effects of three vehicles-ethanol (EtOH), isopropyl alcohol (IPA), and isopropyl myristate (IPM)-on stratum corneum (SC) absorption and diffusion of the [ 14 C]-model compounds benzoic acid and butenafine hydrochloride to better understand the transport pathways of chemicals passing through and resident in SC. Following application of topical formulations to human dermatomed skin for 30 min, penetration flux was observed for 24 h post dosing, using an in vitro flow-through skin diffusion system. Skin absorption and penetration was compared to the chemical-SC (intact, delipidized, or SC lipid film) binding levels. A significant vehicle effect was observed for chemical skin penetration and SC absorption. IPA resulted in the greatest levels of intact SC/SC lipid absorption, skin penetration, and total skin absorption/penetration of benzoic acid, followed by IPM and EtOH, respectively. For intact SC absorption and total skin absorption/penetration of butenafine, the vehicle that demonstrated the highest level of sorption/penetration was EtOH, followed by IPA and IPM, respectively. The percent doses of butenafine that were absorbed in SC lipid film and penetrated through skin in 24 h were greatest for IPA, followed by EtOH and IPM, respectively. The vehicle effect was consistent between intact SC absorption and total chemical skin absorption and penetration, as well as SC lipid absorption and chemical penetration through skin, suggesting intercellular transport as a main pathway of skin penetration for model chemicals. These results suggest the potential to predict vehicle effects on skin permeability with simple SC absorption assays. As decontamination was applied 30 min after chemical exposure, significant vehicle effects on chemical SC partitioning and percutaneous penetration also suggest that skin decontamination efficiency is vehicle dependent, and an effective decontamination method should act on chemical solutes in the lipid domain.

The stratum corneum (SC), a permeable membrane, limits percutaneous penetration. As SC chemical and structural properties responsible for skin barrier function appear depth-related, we conducted an in vitro dermatopharmacokinetic study on intact and adhesive tape-stripped skin samples to clarify whether SC is a homogeneous barrier for chemical transport. SC concentration-thickness profiles were determined for four C-14 labeled model chemicals, panthenol, benzoic acid, paraoxon and butenafine, using the tape-stripping approach. Data analysis with the unsteady-state diffusion equation of Fick's second law permitted a chemical diffusion coefficient in SC. To evaluate the consistency of SC permeability from its surface to lower levels, the skin was tape-stripped five to 10 times to remove the upper cell layers before chemical application, such that diffusion coefficients could be determined from three SC depth levels (0, 5 and 10 tape strips). Results suggested the depth-dependency of SC permeability to panthenol, benzoic acid and butenafine; the diffusion coefficient of panthenol decreased significantly after the first five tape strips and subsequently remained consistent. A progressive increase in diffusion coefficients of benzoic acid and butenafine was observed as tape-stripping levels increased. The removal of superficial SC did not result in a significant difference in the paraoxon diffusion coefficient. For individual chemicals, a variation in the diffusion coefficient from SC surface to deeper layers agreed with the change of the diffusion coefficient over time in intact skin. Characterization of the SC properties contributing to the depth-dependent SC permeability will hopefully provide further insight to skin penetration/decontamination. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Skin decontamination is a primary interventional method used to decrease dermal absorption of hazardous contaminants, including chemical warfare agents, pesticides and industrial pollutants. Soap and water wash, the most common and readily available decontamination system, may enhance percutaneous absorption through the "wash-in effect." To understand better the effect of soap-water wash on percutaneous penetration, and provide insight to improving skin decontamination methods, in vitro human epidermal penetration rates of four C(14) -labeled model chemicals (hydroquinone, clonidine, benzoic acid and paraoxon) were assayed using flow-through diffusion cells. Stratum corneum (SC) absorption rates of these chemicals at various hydration levels (0-295% of the dry SC weights) were determined and compared with the results of the epidermal penetration study to clarify the effect of SC hydration on skin permeability. Results showed accelerated penetration curves of benzoic acid and paraoxon after surface wash at 30 min postdosing. Thirty minutes after washing (60 min postdosing), penetration rates of hydroquinone and benzoic acid decreased due to reduced amounts of chemical on the skin surface and in the SC. At the end of the experiment (90 min postdosing), a soap-water wash resulted in lower hydroquinone penetration, greater paraoxon penetration and similar levels of benzoic acid and clonidine penetration compared to penetration levels in the non-wash groups. The observed wash-in effect agrees with the enhancement effect of SC hydration on the SC chemical absorption rate. These results suggest SC hydration derived from surface wash to be one cause of the wash-in effect. Further, the occurrence of a wash-in effect is dependent on chemical identity and elapsed time between exposure and onset of decontamination. By reducing chemical residue quantity on skin surface and in the SC reservoir, the soap-water wash may decrease the total quantity of chemical absorbed in the long term; however, the more immediate accelerated absorption of chemical toxins, particularly chemical warfare agents, may be lethal. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

Interaction between drug and proteins and lipids in stratum corneum (SC) is an important pharmacokinetic parameter in early steps of absorption. Previous in vivo studies showed that the total amount of compound, regardless of properties, penetrating over a 96 h period could be predicted by the amount present in SC 30 min after application by a linear relationship. Validating this linear relationship through in vitro study would facilitate testing of transdermal drug delivery platforms. We aimed to determine in vitro penetration behavior across SC of humans by determining the relationship between quantity present in SC reservoir 30 min after application with 24 h skin absorption and penetration. In this study, use of the SC reservoir effect to predict absorption and penetration of topical compounds is reaffirmed with in vitro models involving human skin. These results indicate the amount in short-term (30 min) SC reservoir predict long-term (24 h) skin absorption and penetration, as characterized by statistically significant linear relationships determined via regression. This may be explained by the fact that SC is a rate-limiting barrier to percutaneous drug transport. After molecules diffuse through SC barrier, passage into deeper dermal layers and systemic uptake occur relatively quickly. These results enable one to measure quantity in SC reservoir shortly after topical application as a proxy for absorption and penetration over longer periods. With respect to drug development and risk assessment of toxic substances, this may simplify assays attempting to quantitate penetration capacity. Further investigation with a larger range of compounds is needed to clarify the observations recorded here. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

Compounds with varying physical and chemical properties may have different affinities to the stratum corneum (SC) and/or its intercellular lipids, keratin protein, and possible water domains. To better understand the mechanism of percutaneous absorption, we utilized 21 carbon-14 labeled chemicals, with wide hydrophilicity (log P = -0.05 to 6.17), and quantified their absorption/adsorption properties for a short incubation time (15 min) with regards to intact SC membrane, delipidized SC membrane and SC lipid. A facile method was developed for SC/lipid absorption, providing a more equivalent procedure and comparable data. SC lipid absorption of chemical solutes positively correlated with the octanol/water partition coefficient (log P). Differences between the percent dose of chemical absorption to intact SC and the total percent dose contributed by the protein and lipid domains suggest the possibility and significance of a water domain. Absorption rate experiments showed a longer lag time for intact SC than for delipidized SC or SC lipid, suggesting that the water domain may delay chemical binding to protein and lipid domains, and may be a factor in the resistance of many chemicals to current decontamination methods. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

Context: Occlusion is widely utilized to enhance the percutaneous penetration of applied drugs in clinical practice; however, occlusion does not increase the penetration of all chemicals., Objective: This study determines: (1) whether occlusion enhances the percutaneous penetration of the lipophilic salicylic acid or the hydrophilic formaldehyde when compared to non-occlusion, (2) evaluate whether occlusion duration affects the penetration of compounds and (3) establish to what extent occlusive films in clinical practice interact with topically-applied chemicals and possibly hinder penetration., Materials and Methods: Separately, single doses of [14C]-formaldehyde and [14C]-salicylic acid were applied onto human skin overlying diffusion cells under non-occlusion as well as various occlusive time periods (1, 4 and 8 h). The percent dose penetrating into each compartment as well the percent dose adhering to the plastic wrap were determined., Results: The radioactivity recovery as percent of applied dose of [14C]-salicylic acid was significantly higher under occlusion versus non-occlusion in the epidermis, dermis and receptor fluid after 24 h (p < 0.05). For [14C]-formaldehyde, no significant statistical differences were observed between occlusion versus non-occlusion. The plastic wrap often used to enhance the penetration of topically applied drugs does not itself substantially adhere to the tested chemicals., Conclusion: Occlusion duration, previously undocumented for in vitro studies, impacted the percutaneous penetration of the lipophilic salicylic acid more so than the hydrophilic formaldehyde. A strong correlation between occlusion-enhanced penetration and partition coefficients was observed, but we do not wish to overgeneralize these results until more compounds of varying physical--chemical properties are studied.

Skin decontamination is the primary intervention needed in chemical, biological and radiological exposures, involving immediate removal of the contaminant from the skin performed in the most efficient way. The most readily available decontamination system on a practical basis is washing with soap and water or water only. Timely use of flushing with copious amounts of water may physically remove the contaminant. However, this traditional method may not be completely effective, and contaminants left on the skin after traditional washing procedures can have toxic consequences. This article focuses on the principles and practices of skin decontamination.

Since the advent of World War II, governments and laboratories have made a concerted effort to improve prophylactic and therapeutic interventions counteracting cutaneously directed chemical warfare agents (CWA), and by inference, common industrial and consumer dermatotoxicants. In vitro percutaneous penetration assays, first utilized by Tregear in the 1940s and presently in various modifications, have been fundamental to this effort. Percutaneous penetration, often considered a simple one-step diffusion process, consists of at least 15 steps. The first part of this review covers the initial steps related to absorption and excretion kinetics, vehicle characteristics, and tissue disposition. Importantly, the partitioning behavior and stratum corneum (SC) diffusion by a wide physicochemical array of compounds shows that many compounds have similar diffusion coefficients determining their percutaneous absorption in vivo. After accounting for anatomical SC variation, the penetration flux value of a substance depends mainly on its SC/vehicle partition coefficient. Additionally, the SC acts as a 'reservoir' for topically applied molecules and application of tape stripping has been found to quantify the chemical remaining in the SC which can predict total molecular penetration in vivo. Decontamination is of particular concern and even expediting standard washing procedures after dermal chemical exposure often fails to remove chemicals. This overview summarizes knowledge of percutaneous penetration extending insights into the complexities of penetration, decontamination and potential newer assays that may be of practical importance., (Copyright © 2012 John Wiley & Sons, Ltd.)

Cutaneously directed chemical warfare agents can elicit significant morbidity and mortality. The optimization of prophylactic and therapeutic interventions counteracting these agents is crucial, and the development of decontamination protocols and methodology of post dermal exposure risk assessments would be additionally applicable to common industrial and consumer dermatotoxicants. Percutaneous (PC) penetration is often considered a simple one-step diffusion process but presently consists of at least 15 steps. The systemic exposure to an agent depends on multiple factors and the second part of this review covers absorption and excretion kinetics, wash and rub effects, skin substantivity and transfer, among others. Importantly, the partitioning behavior and diffusion through the stratum corneum (SC) of a wide physicochemical array of compounds shows that many compounds have approximately the same diffusion coefficient which determines their percutaneous absorption in vivo. After accounting for anatomical variation of the SC, the penetration flux value of a substance depends mainly on its SC/vehicle partition coefficient. Additionally, the SC acts as a 'reservoir' for topically applied molecules, and tape stripping methodology can quantify the remaining chemical in the SC which can predict the total molecular penetration in vivo. The determination of ideal decontamination protocols is of utmost importance to reduce morbidity and mortality. However, even expeditious standard washing procedures post dermal chemical exposure often fails to remove chemicals. The second part of this overview continues to review percutaneous penetration extending insights into the complexities of penetration, decontamination and potential newer assays that may be of practical importance., (Copyright © 2012 John Wiley & Sons, Ltd.)

This study evaluated pH effects on [(14)C] d-methamphetamine hydrochloride ([(14)C]-meth HCl) percutaneous penetration in vitro and volatility and stability in aqueous solution, on solid surface, or human skin using the finite dose technique and flow through diffusion cells. Results show that when the pH level exceeds 4 or 5, the nonvolatile [(14)C]-meth HCl salt becomes unstable, likely converting to its volatile freebase form. Additionally, contaminated smooth, dense surfaces retain and transfer more [(14)C]-meth HCl than those with rough, loose surfaces, especially under acidic conditions. Skin surface pH is a critical factor affecting the rate and magnitude of dermal absorption. [(14)C]-Meth HCl penetrates into and through the human cadaver skin quickly following exposure. [(14)C]-Meth HCl retained in the skin layer is released into the receptor fluid even if the contact material has been removed. Future exploration of decontaminant and removal procedure efficacies and their effect on dermal penetration of [(14)C]-meth HCl is recommended., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Aims: This study measures the dynamic change of the trans-epidermal water loss (TEWL) rate and in vitro skin permeation data of tritiated water and [(14) C]-clonidine HCl in order to refine our knowledge in the relationship between percutaneous penetration and TEWL., Measures: TEWL values were measured before and during the experimental period. Single application of tritiated water and [(14) C]-clonidine HCl were dosed at the same time on dermatomed human skin samples collected from 12 donors in a flow through diffusion cell system. Radioactivity of absorbed dose: stratum corneum, epidermis, dermis, receptor fluid collected every 4 hours, as well as removable dose residue was counted to determine accountability, percent dose, μg equivalent, and flux rate. These data were further combined with TEWL values to analyze their possible relationship., Results: Results showed that baseline TEWL values correlated with the thickness of dermatomed skin (r=-0.44, P=0.007), and with tritiated water fluxes (r=0.34, P=0.04) and [(14) C]-clonidine HCl (r=0.36; P=0.03). The fluxes of tritiated water and [(14) C]-clonidine HCl were correlated (r=0.67, P<0.001). When TEWL and permeation data were compared, the pattern of tritiated water expressed as a percent dose permeated in receptor fluid resembled the TEWL pattern., Conclusion: The methodology described provides evidences of the correlation of TEWL and skin integrity and skin permeation and further demonstrates to be a rapid alternative to tritiated water permeation for measuring skin barrier functions in vitro. To develop TEWL measurement as a possible predictive model to assess in vitro percutaneous absorption, however more chemicals with various physical-chemical properties need to be examined, and the relationships to TEWL and tritiated water flux better defined., (© 2011 John Wiley & Sons A/S.)

The purpose of this study is to investigate the transdermal delivery characteristics of Gentiana macrophylla complex components system through different parts of the skin under micro-needles conditions. Two-chamber diffusion cells were used, different parts of isolated skin and micro-needle pretreated isolated mouse skin were applied separately, high performance liquid chromatography (HPLC) similarity evaluation methods were used to evaluate transdermal delivery characteristics of Gentiana macrophylla complex components system on receiving pool and the permeation rate and penetration amount of Gentiopicroside at different parts of mouse skin. In the 24 h, the similarity between receiving fluid which was on passive transdermal delivery and micro-needle transdermal delivery conditions and original fluid were ranged from 83.0% to 98.9%; By the micro-needle pretreatment with different parts of the mouse skin, the time that Gentiana macrophylla complex components system though abdominal skin to the receiving fluid which reached 90% similarity compared with that of original fluid was 4 h, which was 18 h at back skin and 12 h at neck skin separately. Micro-needles can be used as the ideal ingredients for traditional Chinese medicine complex transdermal delivery; transdermal absorption time delay could be greatly reduced and its bioavailability was improved. The permeation rate and similarity to original liquid of Chinese medicine complex components increased significantly in the abdominal skin relative to the neck and back skin under micro-needle conditions.

Aim: This study investigates the relationship between transepidermal water loss (TEWL) and skin permeability to tritiated water as a rapid assessment of the integrity of the barrier properties of skin as part of in vitro skin permeation studies., Methods: TEWL values before and during the experimental period were measured using three evaporimeters (A, B, and C) representing different measuring principles and technologies. Single application of tritiated water was dosed on dermatomed human skin samples in a flow-through diffusion cell system. Radioactivity of the absorbed dose and the removable dose residues was counted to determine percent dose and flux rate. These data were further combined with TEWL values to analyze the correlation., Results: Evaporimeter C, a closed chamber-condenser technology, had higher measurement capacity than other instruments, evaporimeter A, an open chamber, and evaporimeter B, a closed chamber (P<0.001). The baseline TEWL value correlated with tritiated water flux (r=0.34, P=0.04). The pattern of tritiated water expressed as percent dose permeated into receptor fluid was similar to that of TEWL values., Conclusion: These data indicate that TEWL can be ascribed to be a measure of skin water barrier function. Further work should be conducted to interpret the significance of measuring TEWL by evaporimetry.

Background: Geraniol and citronellol are commonly used fragrance components in consumer products. Both are listed as alleged fragrance allergens that should be declared in the European Union when used in cosmetics and consumer products. Such allergenic potential is determined largely by effects on the skin once these materials penetrate and elicit an immune response. Few data demonstrate their penetration abilities or their effects on percutaneous absorption. We wanted to determine the effects of these materials on skin absorption. Skin penetration characterization via flow-through diffusion study serves as a reasonable model for determining dermal dosing for fragrance materials. Such characterization can be used for more accurate safety exposure calculations and regulatory determinations. Extensive comparisons to in vivo data in humans or closely related animals will be required before accepting flow-through diffusion methods as in vivo alternatives by industry and regulatory bodies., Objective: To evaluate the penetration abilities of geraniol and citronellol when they are used in a typical vehicle in consumer products., Methods: In vitro skin penetration of radiolabeled geraniol and citronellol was studied under occlusion in human cadaver skin, using flow-through diffusion cells for scintillation counting to determine the percentage of dose absorbed. For comparison, two doses of each material were used: 2% and 5% in 3:1 diethyl phthalate/ethanol., Results: After 24 hours, geraniol and citronellol had relatively low skin absorption rates; 3.8% +/- 2.1% of 2% citronellol, 4.7% +/- 1.9% of 5% citronellol, 3.5% +/- 1.9% of 2% geraniol, and 7.3% +/- 1.1% of 5% geraniol were recovered from skin and receptor fluid compartments. These materials showed good mass-balance recovery. The majority of the dose was recovered in the skin washes (a minimum of 64.7% +/- 4.6% recovered for 2% citronellol and a maximum of 79.3% +/- 3.9% recovered for 5% geraniol). Receptor fluid collection points over time showed a linear increase in the amounts of citronellol and geraniol that penetrated the skin, although overall absorption values were quite small., Conclusion: In vitro results indicate that geraniol and citronellol have low potentials for skin penetration, which has implications for their ability to induce allergenicity and for more predictive toxicologic profiling of these materials. In vivo studies should be done to correlate the in vitro results.

Use of the percutaneous route may avoid some of the undesirable side effects that occur following oral administration in estrogen replacement therapy. At present, knowledge of estradiol transdermal properties relating to delivery of drugs in the skin is lacking. One reason is that in the existing transport models of estradiol, the skin is regarded as a single layer. This study revealed a significant difference of effects on estradiol delivery in the 3 sublayers of the skin and has caused us to believe that if we can obtain information about the transfer properties of estradiol in human skin (3 sublayers), we will not only increase our understanding of the estradiol biotransport mechanism, but also benefit clinical application. Accordingly, radioactive 17beta-estradiol was used to clarify the percutaneous absorption of estradiol into the 3 sublayers of the skin (stratum corneum, epidermis, and dermis) and to evaluate the effect of drugs delivered in each sublayer. Based on data thereby obtained, mathematical models were built to further obtain transport parameters (diffusivity, permeability, lag time, and partition coefficients) for the 3 layers of the skin.

The in vitro percutaneous absorption of carbon-14-labeled benzene ([(14)C]benzene) in dermatomed human skin was determined using 2 cleaning products containing benzene. This study utilized cleaning solutions commonly used in the workplace. As Environmental Protection Agency (EPA) guidelines cover dose occlusion for volatile chemicals, the treatments were both nonoccluded and occluded, with low (10 microL/cm(2)), high (30 microL/cm(2)), and multiple (10 microL/cm(2) x 3 at 0, 30, and 60 min) doses. In an open-to-air test, the benzene quickly evaporated, and only 0.5%-1.4% of the original dose remained after 30 minutes. In the diffusion studies, human skin absorption of benzene peaked in the first few hours without occlusion, but was sustained for 24 hours with occlusion. The absorption of a high single dose was 1.2 +/- 0.16 times (mean +/- standard deviation) greater than that of a multiple dose, whereas theory would predict 1.0. The low-dose to high- or multiple-dose ratio was 3.6 +/- 2.2, so there was a clear dose response. The effect of occlusion was significant. In this study occlusion increased absorption by 40.1 +/- 24.6 times. These data place into partial perspective the role of occlusion in benzene flux, but should not be generalized until other volatile substances are studied in the experimental system and further validated with in vivo systems.

Background/purpose: Percutaneous permeation is a frequently used approach in drug delivery, but the detailed physics process in the patch--stratum corneum (SC)--viable epidermis system remains unclear: the influence of the interphases in the multilayered structure has been little studied., Methods: This paper applied the finite-element method to develop a contact algorithm with an interphase element to account for the interphase barrier on drug diffusion and chemical absorption during a transdermal drug delivery process. A more realistic multilayer structure, including the patch, SC and viable epidermis, are incorporated into the algorithm. Both interphases between the patch and SC, and between SC and viable epidermis are considered., Results: Our study confirms that the interphase transfer coefficients have a direct connection with drug concentration and flux distribution along the diffusion paths. The simulation results suggested a potential for the optimal control of drug diffusion. The partition coefficients and other interphase barrier factors can be incorporated into the model., Conclusions: The algorithm can deal with complicated geometrical conditions, which is difficult using classical analytical approaches. Furthermore, calibrated against experiments, the model may predict more realistically the drug delivery process and drug distribution profiles so as to assist in the patch and even drug design.

Decontamination of a chemical from skin is often an emergency measure. This study utilized an in vitro model to compare the decontamination capacity of three model decontaminant solutions (tap water, isotonic saline, and hypertonic saline). Human cadaver skin was dosed (approximately 0.25 microg on 3 cm(2) per skin) with radio-labeled [(14)C]-formaldehyde. After a defined exposure time (1, 3, and 30 min post-dosing, respectively), the surface skin was washed three times (4ml per time) with each solution. After washing, the skin was stripped with tape discs twice. Lastly, the wash solutions, strippings, receptor fluid, and remainder of skin were liquid scintillation analyzer counted to determine the amounts of formaldehyde. Additionally, an evaporation test at different exposure times (1min, 3min, 15min, 30min, and 60min, respectively) was conducted to monitor formaldehyde % evaporation. There were no statistical differences among these groups except isotonic saline, at 3min post-exposure (in wash solutions), showed a significantly difference (p<0.05) when compared to tap water. Formaldehyde % evaporation increased linearly with extending application times, and were 7.7%, 13.6%, 19.7%, 24.4%, and 35.9% (1min, 3min, 15min, 30min, and 60min, respectively). This data suggests that isotonic saline may be effective in removing formaldehyde from skin. However, results from this model need validation in vivo. The model may provide a facile and robust method of accelerating knowledge of decontamination mechanism and lead to enhanced efficacy.

This study determined the in vivo human bioavailability of topical estradiol, and the transfer of drug between dosed subject and naive recipient. In vivo bioavailability was determined in human volunteers by (14)C urinary excretion following topical [(14)C]-estradiol (0.06%) dose administration and were adjusted by intravenous human excretion amounts to give absolute bioavailability amounts. Drug transfer was determined by volunteer skin contact/rubbing for 15 minutes, 1 hour after topical dosing. [(14)C]-estradiol bioavailability as percent dose absorbed (n=6) was 7.5+/-4.1 from protected dose site, 8.2+/-6.3 from non-protected dose site, 6.6+/-7.6 from dosed volunteers subjected to skin contact/rub and 4.3+/-3.8 from non-dosed volunteers subjected to skin contact/rub. Between these small groups, the values were not statistically different. Under experimental conditions, a measurable dose of radioactive 17beta-estradiol dose was delivered to naive recipient volunteers through skin contact/rub with other volunteers previously topically dosed. Any residual topical bioactive chemical which resides on the open skin surface can transfer by skin contact to another individual. It is important for prescribing physicians and patients to understand that clinically significant transfer of topical bioactive drugs can occur. This may be particularly important for substances which may produce inadvertent effects.

This study was conducted to evaluate the dermal absorption of arsenic from residues present on the surface of wood preserved with chromated copper arsenate (CCA). The research reported herein used methods parallel to those of earlier research on the dermal absorption of radiolabeled arsenic (R. C. Wester et al., 1993, Fund. Appl. Toxicol. 20, 336-340), with modifications to allow use of environmental matrices that are not radiolabeled. These modifications include the surface area of application and dietary intake of arsenic, thus maximizing the potential for detection of dermally absorbed arsenic in exposed animals above diet-associated background levels of exposure. Two forms of arsenic were administered in this work. The first, arsenic in solution, was applied to the skin of monkeys to calibrate the model against prior absorption research and to serve as the basis of comparison for absorption of arsenic from CCA-treated wood residues. The second substrate was residue that resides on the surface of CCA-treated wood. Results from this research indicate that this study methodology can be used to evaluate dermally absorbed arsenic without the use of a radiolabel. Urinary excretion of arsenic above background levels can be measured following application of soluble arsenic, and absorption rates (0.6-4.4% absorption) are consistent with prior research using the more sensitive, radiolabeled technique. Additionally, the results show that arsenic is poorly absorbed from CCA-treated wood residues (i.e., does not result in urinary arsenic excretion above background levels).

Perchloroethylene (PCE) is a widely used volatile organic chemical. Exposures to PCE are primarily through inhalation and dermal contact. The dermal absorption of PCE from a soil matrix was compared in rats and humans using real-time MS/MS exhaled breath technology and physiologically based pharmacokinetic (PBPK) modeling. Studies with rats were performed to compare the effects of loading volume, concentration, and occlusion. In rats, the percutaneous permeability coefficient (K(P)) for PCE was 0.102 +/- 0.017, and was independent of loading volume, concentration, or occlusion. Exhaled breath concentrations peaked within 1 h in nonoccluded exposures, but were maintained over the 5 h exposure period when the system was occluded. Three human volunteers submerged a hand in a container of PCE-laden soil for 2 h and their exhaled breath was continually monitored during and for 2.5 h following exposure. The absorption and elimination kinetics of PCE were slower in these subjects than initially predicted based upon the PBPK model developed from rat dermal kinetic data. The resulting K(P) for humans was over 100-fold lower than for the rat utilizing a single, well-stirred dermal compartment. Therefore, two additional PBPK skin compartment models were evaluated: a parallel model to simulate follicular uptake and a layered model to portray a stratum corneum barrier. The parallel dual dermal compartment model was not capable of describing the exhaled breath kinetics, whereas the layered model substantially improved the fit of the model to the complex kinetics of dermal absorption through the hand. In real-world situations, percutaneous absorption of PCE is likely to be minimal.

The development and validation of noninvasive techniques for estimating the dermal bioavailability of solvents in contaminated soil and water can facilitate the overall understanding of human health risk. To assess the dermal bioavailability of trichloroethylene (TCE), exhaled breath was monitored in real time using an ion trap mass spectrometer (MS/MS) to track the uptake and elimination of TCE from dermal exposures in rats and humans. A physiologically based pharmacokinetic (PBPK) model was used to estimate total bioavailability. Male F344 rats were exposed to TCE in water or soil under occluded or nonoccluded conditions by applying a patch to a clipper-shaved area of the back. Rats were placed in off-gassing chambers and chamber air TCE concentration was quantified for 3-5 h postdosing using the MS/MS. Human volunteers were exposed either by whole-hand immersion or by attaching patches containing TCE in soil or water on each forearm. Volunteers were provided breathing air via a face mask to eliminate inhalation exposure, and exhaled breath was analyzed using the MS/MS. The total TCE absorbed and the dermal permeability coefficient (K(P)) were estimated for each individual by optimization of the PBPK model to the exhaled breath data and the changing media and/or dermal patch concentrations. Rat skin was significantly more permeable than human skin. Estimates for K(P) in a water matrix were 0.31 +/- 0.01 cm/h and 0.015 +/- 0.003 cm/h in rats and humans, respectively. K(P) estimates were more than three times higher from water than soil matrices in both species. K(P) values calculated using the standard Fick's Law equation were strongly affected by exposure length and volatilization of TCE. In comparison, K(P) values estimated using noninvasive real-time breath analysis coupled with the PBPK model were consistent, regardless of volatilization, exposure concentration, or duration.

Realistic estimates of percutaneous absorption following exposures to solvents in the workplace, or through contaminated soil and water, are critical to understanding human health risks. A method was developed to determine dermal uptake of solvents under non-steady-state conditions using real-time breath analysis in rats, monkeys, and humans. The exhaled breath was analyzed using an ion-trap mass spectrometer, which can quantitate chemicals in the exhaled breath stream in the 1-5 ppb range. The resulting data were evaluated using physiologically-based pharmacokinetic (PBPK) models to estimate dermal permeability constants (Kp) under various exposure conditions. The effects of exposure matrix (soil versus water), occlusion versus non-occlusion, and species differences on the absorption of methyl chloroform, trichloroethylene, and benzene were compared. Exposure concentrations were analyzed before and at 0.5-hour intervals throughout the exposures. The percentage of each chemical absorbed and the corresponding Kp were estimated by optimization of the PBPK model to the medium concentration and the exhaled-breath data. The method was found to be sufficiently sensitive for animal and human dermal studies at low exposure concentrations over small body surface areas, for short periods, using non-steady-state exposure conditions.

In the home and workplace, decontamination of a chemical from skin is traditionally done with a soap-and-water wash, although some workplaces may have emergency showers. It has been assumed that these procedures are effective, yet workplace illness and even death occur from chemical contamination. Water, or soap and water, may not be the most effective means of skin decontamination, particularly for fat-soluble materials. This study was undertaken to help determine whether there are more effective means of removing methylene bisphenyl isocyanate (MDI), a potent contact sensitizer, from the skin. MDI is an industrial chemical for which skin decontamination, using traditional soap and water and nontraditional polypropylene glycol, a polyglycol-based cleanser (PG-C), and corn oil were all tried in vivo on the rhesus monkey, over 8 h. Water, alone and with soap (5% and 50% soap), were partially effective in the first h after exposure, removing 51-69% of the applied dose. However, decontamination fell to 40-52% at 4 h and 29-46% by 8 h. Thus, the majority of MDI was not removed by the traditional soap-and-water wash; skin tape stripping after washing confirmed that MDI was still on the skin. In contrast, polypropylene glycol, PG-C, and corn oil all removed 68-86% of the MDI in the first h, 74-79% at 4 h, and 72-86% at 8 h. Statistically, polypropylene glycol, PG-C, and corn oil were all better (p < 0.05) than soap and water at 4 and 8 h after dose application. These results indicate that a traditional soap-and-water wash and the emergency water shower are relatively ineffective at removing MDI from the skin. More effective decontamination procedures, as shown here, are available. These procedures are consistent with the partial miscibility of MDI in corn oil and polyglycols.

Literature from the first half of this century reports concern for toxicity from topical use of boric acid, but assessment of percutaneous absorption has been impaired by lack of analytical sensitivity. Analytical methods in this study included inductively coupled plasma-mass spectrometry, which now allows quantitation of percutaneous absorption of 10B in 10B-enriched boric acid, borax, and disodium octaborate tetrahydrate (DOT) in biological matrices. This made it possible, in the presence of comparatively large natural dietary boron intakes for the in vivo segment of this study, to quantify the boron passing through skin. Human volunteers were dosed with 10B-enriched boric acid, 5.0%, borax, 5.0%, or disodium octaborate tetrahydrate, 10% in aqueous solutions. Urinalysis, for boron and changes in boron isotope ratios, was used to measure absorption. Boric acid in vivo percutaneous absorption was 0.226 (SD = 0.125) mean percent dose, with flux and permeability constant (Kp) calculated at 0.009 microg/cm2/h and 1.9 x 10(-7) cm/h, respectively. Borax absorption was 0.210 (SD = 0.194) mean percent dose, with flux and Kp calculated at 0.009 microg/cm2/h and 1.8 x 10(-7) cm/h, respectively. DOT absorption was 0.122 (SD = 0.108) mean percent, with flux and Kp calculated at 0.01 microg/cm2/h and 1.0 x 10(-7) cm/h, respectively. Pretreatment with the potential skin irritant 2% sodium lauryl sulfate had no effect on boron skin absorption. These in vivo results show that percutaneous absorption of boron, as boric acid, borax, and disodium octaborate tetrahydrate, through intact human skin is low and is significantly less than the average daily dietary intake. This very low boron skin absorption makes it apparent that, for the borates tested, the use of gloves to prevent systemic uptake is unnecessary. These findings do not apply to abraded or otherwise damaged skin.

The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), used for control of weeds in agriculture, forestry, and rights of way, can accumulate as a residual chemical in soil. The objective was to determine percutaneous absorption of 2,4-D from soil, with emphasis on soil load and skin contact time. With control acetone vehicle, in vivo absorption of 2,4-D in the rhesus monkey was 8.6 +/- 2.1% of the dose, which compared closely to published human absorption of 6.0 +/- 2.4%. Percutaneous absorption from soil loads of 1 and 40 mg/cm2 were 9.8 +/- 4.0 and 15.9 +/- 4.7%, respectively, values similar to acetone vehicle. In vitro absorption in human skin calculated from skin contact accumulation over 24 h was 1.8 +/- 1.7, 1.7 +/- 1.3, and 1.4 +/- 1.2% for soil loads of 5, 10, and 40 mg/cm2, respectively. Thus, soil load did not affect 24-h percutaneous absorption. Current Environmental Protection Agency (EPA) recommended calculated reductions due to soil load are not supported by these results with 2,4-D. Percutaneous absorption of 2,4-D from acetone vehicle for 8 h dosing period was 3.2 +/- 1.0%, one-third the value of 8.6 +/- 2.1% over 24 h. With soil vehicle, absorption for 8 h was only 0.03 +/- 0.02% for 40 mg/cm2 soil load and 0.05 +/- 0/.004% for 1 mg/cm2 soil load. Absorption for 16 h was 2.2 +/- 1.2%. Absorption over time was linear for acetone vehicle, where total dose is deposited on skin, but not linear for soil vehicle, which had an 8-h delay (lag time). This equates with a normal 8-h work day where most of the contaminated soil can be washed off the skin. The apparent partition coefficient of 2,4-D between soil and water changed over time. This suggests there is a "mobility" phase for 2,4-D in soil that will change with time. For soil vehicle, percutaneous absorption of 2,4-D was not linear in respect to soil load or to skin contact time. Calculation based on assumed linearity can falsely estimate potential human health hazard. Clearly, the dermatokinetics with soil and skin represent complex interactive forces that require detailed evaluation before overgeneralizing rules for interpretation in terms of risk assessment.

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