[Skin absorption and skin metabolism].
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Balneology↗
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Skin absorption of solvent mixtures--effect of vehicles on skin absorption of toluene.
The skin absorption rates of toluene in various solvent mixtures were investigated in mice. The skin absorption rate of toluene in toluene/methanol mixtures exhibited a parabolic relationship to the mixed ratio. The maximum rate was obtained at a mixed ratio of 50% (V/V). The skin absorption rate of toluene at this point (50%) was about 4.7 times higher than that of pure toluene. The permeability coefficient (Kp) of toluene increased as the mixed ratio of methanol increased. Methanol enhanced skin absorption of toluene. The skin absorption rate of toluene in a toluene/benzene mixture was inversely proportional to the concentration of benzene. The Kp of toluene is kept constant through the mixed ratios of benzene, and benzene does not have an enhancing effect on the skin absorption of toluene contained in the toluene/benzene mixture. We examined the effects of various vehicles on the skin absorption rates of toluene in mixtures containing 50% (v/v) of toluene. Methanol was a good penetration enhancer for toluene, and its effect is similar to the effect of well-known skin penetration enhancers like DMSO, N,N-Dimethylacetamide, and N,N-Dimethylformamide. Therefore, it is necessary to take special precautions against the skin absorption of toluene when handing thinners that contain methanol.
Animals↗
[Skin absorption (conditions of permeability, penetration, absorption of the skin)].
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Androgens↗
Comparative in vitro skin absorption and metabolism of coumarin (1,2-benzopyrone) in human, rat, and mouse.
The in vitro percutaneous absorption and skin metabolism of coumarin (1,2-benzopyrone) was studied in metabolically viable human, rat (F344), and mouse (CD1 and DBA/2) skin. Following application of [14C]coumarin (3.7 microg/cm2; 0.02% in ethanol) to unoccluded skin in flow-through diffusion cells of a skin absorption model (SAM), the absorption through the skin into the receptor fluid at 72 hr was rapid and extensive in all species, reaching (mean +/- SD) 50.4 + 9.1% of the applied dose in human, 51.3 +/- 7.3% in rat, and 44.9 +/- 13.5% in mouse. When the skin was occluded immediately after exposure, the extent of absorption at 72 hr was enhanced in all species. At 72 hr, substantial amounts of [14C]coumarin were found in unoccluded mouse skin (31.7 +/- 13.6%), with less in human (10.2 +/- 6.5%) and rat (12.7 +/- 5.0%) tissue. When occluded, the skin residues at 72 hr were 10.4 +/- 11.7% (mouse), 8.5 +/- 3.9% (human), and 11.9 +/- 7.5% (rat). The absorption of coumarin through rat skin into the receptor fluid over 72 hr was linearly related to the applied dose (r2 = 0.998 unoccluded skin; r2 = 0.999 occluded skin) over the dose range 3.7 to 378.7 microg/cm2. The nature and extent of cutaneous metabolism was studied following (i) topical application for 24 hr to human, rat, and mouse skin in the SAM system; (ii) incubation at 37 degrees C for up to 6 hr with human, rat, and mouse whole skin homogenates; and (iii) incubation at 37 degrees C for up to 24 hr with freshly isolated and cultured human epidermal keratinocytes. HPLC and GCMS analyses of skin extracts and receptor fluid confirmed that, in all three species, only the parent compound, coumarin, was present at all times from 10 min to 24 hr. These data indicate that topically applied coumarin is rapidly and extensively absorbed through human, rat, and mouse skin, and that the compound remains metabolically unchanged during absorption. These observations may have implications for the safe and effective use of coumarin in consumer products which come into contact with the skin and as a topical therapeutic agent.
Aged↗
A new technology to measure skin absorption of vapors.
Skin vapor absorption is one of the major exposure routes for some widely used chemicals (e.g., 2-methoxy ethanol), but a good apparatus with which exposure can be measured is currently unavailable. In this study, a polished stainless-steel chamber-combined with computer-controlled auto-feedback software and hardware, real-time gas sensors, and an auto-injection microsyringe-was proposed as new technology. In addition, the machines had activated-charcoal tubes and cold traps, both of which simulated the skin uptake and validated the reliability of the proposed system. The exposure concentrations, relative humidity, and temperature were effectively controlled at 25+/-0.5 ppm (or 300+/-10 ppm), 80+/-2%, and 27.5+/-0.5 degrees C, respectively. The relative errors between the quantity of 2-methoxy ethanol collected in either the charcoal tubes or the cold traps and the quantity of ME injected to maintain a constant exposure were less than 5%. The authors also used this new technology to successfully measure skin absorption of ME vapor in 6 volunteers. The authors concluded that this new technology is a direct, continuous, noninvasive, and simple tool with which to measure skin absorption of vapors.
Air Pollutants, Occupational↗
The isolated perfused bovine udder as an in vitro model of percutaneous drug absorption. Skin viability and percutaneous absorption of dexamethasone, benzoyl peroxide, and etofenamate.
Using udders from slaughtered cows as a new in vitro model of percutaneous drug absorption, the tissue viability and the percutaneous absorption of dexamethasone, benzoyl peroxide, and etofenamate were studied. The organ was perfused with gassed tyrode solution for up to 6 hr. As shown by measurement of glucose consumption, lactate production, lactate dehydrogenase activity, and pH in the perfusate, the tissue was viable over a 6-hr period. This was confirmed by a histological examination. Determination of the udder skin-fold thickness demonstrated that no edema developed within the perfusion period. A maximum skin penetration of dexamethasone was found after administration of dexamethasone dissolved in acetone with dimethyl sulfoxide, followed by ointment with salicylic acid, ointment without salicylic acid, and acetone solution. Experiments with benzoyl peroxide and etofenamate demonstrated that the perfused udder skin was capable of metabolizing drugs in vitro. In conclusion, the isolated perfused bovine udder is a new in vitro model, which maintains bovine udder skin with an isolated vasculature in a viable state. Using this in vitro model, we note it is possible to compare the dermal penetration, metabolism, and absorption of substances after topical administration of different drug formulations.
Animals↗
Skin absorption from patch test systems.
The development of topical drug products requires testing for skin toxicology reactions. A variety of patch test systems are available with which chemicals are applied to skin. The purpose of this study was to determine the skin absorption of paraphenylenediamine (PPDA) from a variety of such systems. [14C]-PPDA (1% pet., USP) was placed in a variety of patch test systems at a concentration normalized to equal surface area (2 mg/mm2). Skin absorption was determined in the guinea pig by urinary excretion of 14C. There was a six-fold difference in the range of skin absorption (p less than 0.02). In decreasing order, % skin absorption from the systems were Hill Top Chamber (53.4 +/- 20.6) greater than Teflon Control patch (48.6 +/- 9.3) greater than Small Finn Chamber with paper disc insert (34.1 +/- 19.8) greater than Small Finn Chamber (29.8 +/- 9.0) greater than Large Finn Chamber (23.1 +/- 7.3) greater than AL-Test Chamber (8.0 +/- 0.8). Thus, the choice of patch system could produce a false negative error if the system inhibits skin absorption, with a subsequent skin toxicology reaction.
Administration, Cutaneous↗
Skin absorption of inorganic lead (PbO) and the effect of skin cleansers.
OBJECTIVE: The aim of this study was to investigate the percutaneous penetration of lead oxide (PbO) powder and the effect of rapid skin decontamination with two different detergents. METHODS: Franz cells were used to study in vitro PbO skin penetration through human skin during a 24-hour period. The tests were performed without or with decontamination using either Ivory Liquid soap or a new experimental cleanser 30 minutes after the start of exposure. RESULTS: We confirm that PbO can pass through the skin with a median penetration of 2.9 ng/cm (25-75th percentiles 0.35-6). The cleaning procedure using Ivory Liquid soap significantly increased skin penetration with a median value of 23.6 ng/cm (25-75th percentiles 12-47.1; Mann-Whitney U test, P = 0.0002), whereas the new experimental cleanser only marginally increased penetration (7.1 ng/cm). CONCLUSIONS: Our results indicate that it is necessary to prevent skin contamination from occurring because a short contact can increase skin content and penetration even if quickly followed by washing. This study demonstrated that PbO powder can pass through the skin and that skin decontamination done after 30 minutes of exposure did not decrease skin absorption occurring over 24 hours and stresses the need to prevent skin contamination when using toxic substances.
Detergents↗
Permeation and skin absorption: reproducibility of various industrial reconstructed human skin models.
Human reconstructed skin models could be very useful tools to quantify percutaneous permeation and absorption. Before using such models, the reproducibility in the same batch and/or various batches, i.e. the relevance of the results obtained, must be verified. The reproducibility of 3 industrial models--EpiDerm, Episkin and SkinEthic--was tested regarding the permeation and skin absorption of 3 topically applied compounds (with a large range of physicochemical properties): lauric acid, caffeine and mannitol. For all the models, the intrabatch reproducibility was greater than the interbatch reproducibility. According to the batches tested, the larger difference in terms of reproducibility between the 3 models was observed in the case of mannitol, a very poor permeant. In this case, the best reproducibility was observed with EpiDerm and Episkin. Moreover, the rank order of the 3 compounds applied, in terms of permeation and skin absorption, was the same as that expected from ex vivo human skin. Such results revealed human skin models as a promising means to test in vitro permeation and percutaneous absorption of topical products.
Drug Evaluation, Preclinical↗
Skin absorption of organic solvent vapors in nude mice in vivo.
Nude mice each attached to a respirator to avoid pulmonary uptake were exposed in a glass exposure chamber to 200, 1000 or 3000 ppm of benzene, toluene or tetrachloroethylene (perclene) for 2, 4 or 6 h. The animals were killed at the end of the study and the amount of each solvent retained in the whole body was determined by gas chromatography. Skin absorption rates were calculated from the amount retained in the whole body using the single compartment model (elimination rate constant) obtained in a previous experiment. There was a linear relationship between the amount of skin absorption and exposure time, and also a linear relationship between the skin adsorption rate and concentration of exposed vapors. Skin absorption of solvent vapors occurs by passive diffusion as defined by Fick's law. The skin absorption coefficient (cm/h) of each solvent vapor was calculated by dividing the skin absorption rate by exposure concentration; the values were 1.24 for toluene, 1.00 for perclene and 0.619 for benzene. The coefficient may be useful for evaluating the amount of skin absorption (ng) was calculated by multiplying the skin absorption coefficient (cm/h), concentration of solvent vapor (ng/cm3), exposure time (h) and exposed skin area (cm2).
Animals↗
High-performance liquid chromatography method for the quantification of non-radiolabelled cinnamic compounds in analytes derived from human skin absorption and metabolism experiments.
An isocratic high-performance liquid chromatography method has been developed for the quantification of the skin sensitisers trans-cinnamaldehyde and trans-cinnamic alcohol, and their cinnamic metabolites. The relative standard deviations (RSDs) between the gradients of eight sets of standard curves were 2.8, 3.1 and 1.9% for cinnamic alcohol, cinnamaldehyde and cinnamic acid, respectively. Sample analytes were derived from two series of experiments: in vitro full-thickness human skin absorption and metabolism studies and metabolism studies using human skin homogenates, with non-radiolabelled cinnamic compounds. Skin absorption and metabolism experiments were performed in the absence and presence of the alcohol dehydrogenase inhibitor, pyrazole. Samples from full-thickness skin absorption studies were analysed without extraction; cinnamic compounds from within skin were extracted into methanolic solutions using newly developed methods. The intra-assay RSDs ranged from 0.17 to 2.52% for cinnamic alcohol, 0.24 to 9.14% for cinnamaldehyde and 0.26 to 6.43% for cinnamic acid. The inter-assay RSDs for cinnamic alcohol, cinnamaldehyde and cinnamic acid, respectively, as determined from n=20 HPLC runs, were 2.10, 4.16 and 2.26%.
Acrolein↗
An FTIR investigation of isocyanate skin absorption using in vitro guinea pig skin.
Isocyanates may cause contact dermatitis, sensitization and asthma. Dermal exposure to aliphatic and aromatic isocyanates can occur in various exposure settings. The fate of isocyanates on skin is an important unanswered question. Do they react and bind to the outer layer of skin or do they penetrate through the epidermis as unreacted compounds? Knowing the kinetics of these processes is important in developing dermal exposure sampling or decontamination strategies, as well as understanding potential health implications such exposure may have. In this paper the residence time of model isocyanates on hairless guinea pig skin was investigated in vitro using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectrometry. Model isocyanates tested were octyl isocyanate, polymeric hexamethylene diisocyanate isocyanurate (pHDI), polymeric isophorone diisocyanate isocyanurate (pIPDI) and methylenediphenyl diisocyanate (MDI). Isocyanates in ethyl acetate (30 microL) were spiked directly on the skin to give 0.2-1.8 micromol NCO cm(-2) (NCO = -N=C=O), and absorbance of the isocyanate group and other chemical groups of the molecule were monitored over time. The ATR-FTIR findings showed that polymeric isocyanates pHDI and pIPDI may remain on the skin as unreacted species for many hours, with only 15-20% of the total isocyanate group disappearing in one hour, while smaller compounds octyl isocyanate and MDI rapidly disappear from the skin surface (80+% in 30 min). Isocyanates most likely leave the skin surface by diffusion predominantly, with minimal reaction with surface proteins. The significance of these findings and their implications for dermal exposure sampling and isocyanate skin decontamination are discussed.
Animals↗
The role of skin absorption as a route of exposure for volatile organic compounds (VOCs) in drinking water.
Assessments of drinking water safety rely on the assumption that ingestion represents the principal route of exposure. A review of the experimental literature revealed that skin penetration rates for solvents are remarkably high, and that the stratum corneum is a less effective barrier to penetration than traditionally assumed. Based on published skin absorption rates, we used Fick's law (Jos = Kop delta Cos) to determine permeability constants for selected compounds. We then calculated dose per kilogram for nine different exposure situations and compared this to the oral dose per kilogram. We found that skin absorption contributed from 29-91 per cent of the total dose, averaging 64 per cent. Dose per kilogram body weight ranged from .0002 mg/kg-.18 mg/kg, with an average of .03 mg/kg. In weak aqueous solutions, flux of the solute is directly proportional to concentration. Laboratory approaches differ markedly from environmental exposures and can underestimate absorption. We conclude that skin absorption of contaminants in drinking water has been underestimated and that ingestion may not constitute the sole or even primary route of exposure.
Administration, Oral↗
In vivo skin absorption and distribution of the nerve agent VX (O-ethyl-S-[2(diisopropylamino)ethyl] methylphosphonothioate) in the domestic white pig.
The purpose of this study was to characterize the skin absorption and distribution of VX (O-ethyl-S-[2 (diisopropylamino)ethyl] methylphosphonothioate) in the domestic pig in order to evaluate the animal as a potential model for assessing pretreatments against toxic anti-cholinesterase compounds. A liquid droplet (equivalent to a 2 x LD50 dose) of radiolabelled VX was applied to the inner ear-skin of each anaesthetized animal. Blood and tissue samples (liver, lung, kidney, heart and skin exposure sites) were obtained post-mortem. The amount of radioactivity in each sample was measured by liquid scintillation counting, from which the skin absorption rate and dose distribution of VX were calculated. A substantial proportion (22 +/- 3%) of the applied dose remained within the skin at the site of application. It is conceivable that strategies to minimize or remove this reservoir may be of benefit in the early treatment of VX-exposed casualties. Image analysis of autoradiographs of exposed skin sites indicated that each milligram of radioactive VX covered an area of 1.2 +/- 0.5 cm2. The average skin absorption rate of 14C-VX was 661 +/- 126 microg/cm2 per hour. Comparison of these data with previous studies suggests that human skin is less permeable to VX than pig skin, but VX spreads over a greater surface area when applied to human skin. Thus, paradoxically, while pig-ear skin is more permeable than human skin, the difference in skin surface spreading may lead to the absorption of an equivalent systemic dose.
Administration, Cutaneous↗
Reconstructed epidermis versus human and animal skin in skin absorption studies.
European chemical policy in general and the REACH initiative in particular will increase the number of chemical substances submitted to toxicological evaluation by several orders of magnitude compared to the current status. To limit animal exposure the resulting enormous increase in testing, however, asks for validated in vitro test systems. While the OECD favours in vitro testing for cutaneous absorption using viable human and animal skin (Guideline 428) the availability of viable human skin is already limited today. We present a comparison of various in vitro techniques suitable for routine skin absorption studies including commercially available reconstructed human epidermis which may be a reliable alternative to excised human and animal skin. In order to develop a protocol for the subsequent transfer to partner laboratories the experimental set-up was analysed stepwise using the OECD reference compounds caffeine and testosterone. Franz cell type, the donor and receptor media for hydrophilic/lipophilic substances, albumin and tensid addition, and storage conditions of the excised skins were systematically varied. A protocol has been developed which now allows to proceed to the pre-validation process.
Administration, Topical↗
Skin absorption of some vaporous solvents in volunteers.
OBJECTIVES: To determine the dermal absorption rates of vaporous 1,1,1-trichloroethane (111TRI), trichloroethene (TRI), tetrachloroethene (TETRA), hexane (HEX), toluene (TOL) and m-xylene (XYL) in humans. The determined absorption data were used for the validation of two published models for prediction of non-steady-state skin absorption. METHODS: Five volunteers were dermally exposed on an area of about 1,000 cm2 (forearm and hand) for 20 or 30 min. An inhalation exposure with a known dose rate served as a reference. Using the solvent concentrations in exhaled air, measured after both inhalation and dermal exposure, we calculated the maximum absorption rate into the blood, and the average absorption rates into the skin throughout the exposure, using the linear system dynamics method. RESULTS: The absorption rates into the skin, normalised for exposure concentration, amounted to 0.021 cm/h (111TRI), 0.049 cm/h (TRI), 0.054 cm/h (TETRA), 0.013 cm/h (HEX), 0.14 cm/h (TOL), and 0.12 cm/h (XYL). The maximum absorption rates into the blood ranged from 0.005 nmol/h for 111TRI and HEX to 0.050 nmol/hr for TOL. The ratios between the predicted and experimental values of the absorption rates into the skin ranged, for the model of Cleek and Bunge [4], from 0.3 (HEX) to 1.1 (TRI and TETRA), and for the model of Wilschut and Ten Berge [22], from 1.1 (HEX) to 4.7 (XYL). CONCLUSION: The linear system dynamics method allowed us to calculate not only the total amount absorbed by the skin but also the maximum absorption rate into the blood. The steady-state absorption rate, usually described by a permeability constant, will be below the absorption rate into the skin and above the maximum absorption rate into the blood. The skin absorption rates predicted by the models showed a good agreement with the experimental values. A comparison of the estimated whole-body skin uptake with the inhalatory uptake from the same atmosphere, revealed that the dermal uptake contributed from 0.1% (HEX) to 1% (TOL and XYL) to the total uptake.
Administration, Cutaneous↗
[Skin absorption of surface-active substances and their effect on the skin resorption of cations].
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Cations, Divalent↗
Human skin absorption of Bis-2-(chloroethyl)sulphide (sulphur mustard) in vitro.
The purpose of this study was to measure the absorption and intra-epidermal fate of 35S-radiolabelled sulphur mustard (35SM) in human breast skin in vitro. Skin (full-thickness or heat-separated epidermis) was placed into static diffusion cells and was exposed to droplets of liquid 35SM or saturated 35SM vapour. Amounts of 35SM penetrating the skin were measured from which skin absorption rates were calculated. Unbound radiolabel was washed from the surface, extracted from the skin and analysed to determine the identity of the radiolabelled species in order to measure the extent of hydrolysis of sulphur mustard. Penetration rates of liquid 35SM measured in vitro (71-294 microg cm(-2) h(-1)) were in agreement with those measured previously in vivo using human volunteers (60-240 microg cm(-2) h(-1)). Rates of liquid 35SM skin absorption under occluded, infinite dose conditions were highest through heat-separated epidermal membranes (294+/-58 microg cm(-2) h(-1)) and lowest through full-thickness skin (71+/-14 microg cm(-2) h(-1)). Fluxes of saturated 35SM vapour (110+/-75 microg cm(-2) h(-1)) through heat-separated membranes were similar to those previously measured through human forearm skin in vivo (162 microg cm(-2) h(-1)). Although hydrolysis of 35SM did occur, both on the surface and within the skin, it accounted for only a small percentage of the total applied dose (<2.7+/-1.2%). The difference in total amount of liquid 35SM penetrated between occluded and unoccluded conditions in vitro (79+/-14%) was similar to that lost as vapour from unoccluded skin in vivo (80%). A substantial reservoir of 35SM (14-36% of the applied dose) was measured within heat-separated epidermal membranes for up to 24 h which may have significant implications for the management of personnel exposed to sulphur mustard.
Autoradiography↗