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PubMed1991

The effects of zwitterionic surfactants on skin barrier function.

The action of five zwitterionic surfactants on the barrier function of hairless mouse skin has been studied in vitro. The surfactants considered were dodecylbetaine and hexadecylbetaine (C12BET and C16BET, respectively), hexadecylsulfobetaine (C16SUB), N,N-dimethyl-N-dodecylamine oxide (C12AO), and dodecyltrimethylammonium bromide (C12TAB). Excised skin was pretreated with each surfactant, at various concentrations, for 16 hr, following which the permeation of a model compound, nicotinamide, was measured. The action of the surfactants was assessed by comparing nicotinamide flux through surfactant-pretreated skin with that across control membranes which were exposed to buffer alone for 16 hr. All surfactants decreased skin barrier function to some extent. The degree of nicotinamide penetration enhancement induced was correlated with the ratio of the surfactant pretreatment concentration to the surfactant critical micelle concentration, suggesting that solubilization of stratum corneum lipids may be an important mechanism in explaining the effects observed. More detailed studies with 14C-radiolabeled C12BET and C16BET showed that the dodecyl analog was itself well absorbed, whereas the C16 compound partitioned into the skin favorably but then transferred only very slowly into the receptor phase. These observations were consistent with toxicity studies (albeit at much higher concentrations in a different animal model, the rat) which indicated that the dermal LD50 of C12BET was significantly less than that of C16BET (the value for which was so large that it could not be reliably determined). Overall, this study provides, we believe, useful information pertinent to the potential dermal toxicity of the surfactants considered following occupational or environmental exposure.

Administration, Oral↗
PubMed1984

Observable tumours, risk assessment and experimental design.

The first goal of this article is to outline a design for an efficient experiment for testing each of many chemicals for carcinogenic potential by dermal exposure, including a risk assessment when appropriate. The second is to validate a general mathematical model for the dose-response function in this situation by using the results from a large experiment in skin painting done by the Oak Ridge National Laboratory. These two goals are related because the general model is used as a guide in the choice of an efficient design for testing the many chemicals on which information is required.

Animals↗
PubMed1988

Two-year carcinogenicity study on three aromatic epoxy resins applied cutaneously to CF1 mice.

The cutaneous and systemic carcinogenic potentials of pure and two technical diglycidyl ethers of bisphenol A, DGEBPA, EPON 828 and EPIKOTE 828, respectively, have been investigated in six groups each of 50 male and 50 female CF1 mice. Twice weekly over a period of 2 yr, 0.2 ml of a 1 or 10% (w/v) solution of one of the epoxy resins in acetone was applied to the dorsal skin. A group of 50 male and 50 female CF1 mice was similarly treated treated with 2% (w/v) beta-propiolactone in acetone (the positive control) while a group of 100 male and 100 female mice was treated with acetone alone (negative control). Survival of the CF1 mice to 2 yr was unaffected by cutaneous exposure to each epoxy resin. The compounds proved to be mildly irritant to murine skin, the response in males being greater than in females. There was a very low incidence of benign and malignant tumours of the skin and subcutis after exposure to any of these compounds. The number of systemic lymphoreticular/haematopoietic tumours was increased only in females treated with EPIKOTE 828 or DGEBPA. In male mice, treated with 10% EPON 828, there was a slight increase in the number of renal tumours. The incidence of other systemic tumours in either sex was not increased following cutaneous application of the purified or the two technical DGEBPA resins (1 to 10% in acetone). The significance of all these findings is fully discussed.

Administration, Topical↗
PubMed1995

An alternative strategy to the use of guinea pigs for the identification of skin sensitization hazard.

For over half a century, guinea pig methods have dominated the field of toxicology concerned with the identification of skin sensitizers. Specific protocols, for example the guinea pig maximization test (GPMT), have been pre-eminent in the identification of skin sensitization hazard for regulatory purposes. However, there are increasingly several forces driving change, not least animal use/welfare considerations. In response to this and to address the need for a rapid screen for chemical allergens, an alternative strategy has been developed. In the first instance, a chemical is assessed by a computer-based expert system. This system is constructed from some 50 rules describing the key chemically reactive substructures of known skin sensitizers. The output from the expert system is also evaluated in the light of the understanding of the skin penetration characteristics of the chemical. In this way, and without use of animals, the likelihood that a chemical represents a skin sensitization hazard is assessed based on the two key characteristics of a skin sensitizer: (1) its direct or indirect ability to react with skin protein (i.e. does it contain a structural alert?); and (2) the ability of the chemical to partition into the appropriate epidermal compartment. When the chemical does possess a structural alert and has the capacity to penetrate skin sufficiently, then it may be regarded as a potential skin sensitizer. Subsequent to this screening phase, if necessary the chemical may be assessed in the murine local lymph node assay. This assay is quicker and cheaper than traditional guinea pig assays and importantly is less stressful to the fewer animals that it requires. The assay is well validated and produces objective results which are equivalent to the GPMT in terms of identifying significant skin sensitization hazard. In this paper, the above strategy is described in more detail, focusing on its relevance to hazard identification and its value in animal welfare terms. It is concluded that the strategy provides an important opportunity for both substantial reduction and refinement of animal use in a manner which will not compromise the existing standard of classification and labelling of skin sensitization hazard in the European Union.

Animal Testing Alternatives↗
PubMed1987

Short-term changes in natripheric and hydrosmotic water fluxes across the skin and in urine production due to increases in the osmolarity of the external environment in the toad.

1. Sudden decreases in the osmotic gradient across the skin due to the replacement of water of the bath by 115 mM NaCl had no effect on water uptake of intact or hypophysectomized toads. 2. A concomitant decrease in the urine production was observed in intact but not in hypophysectomized animals. 3. Addition of amiloride chlorydrate (0.25 mM) to the 115 mM NaCl bath induced a significant decrease in water uptake both in intact and in hypophysectomized toads. 4. The osmotic permeability coefficient (LPD) increased significantly during the osmotic gradient reduction with 115 mM NaCl plus 0.25 mM amiloride or 230 mM sucrose in both groups. 5. No changes in the plasmatic osmolarity were detected during the development of these responses to the osmotic gradient reduction. 6. These results are consistent with the hypothesis of short-term changes in the natripheric and hydrosmotic fluxes of water across the skin and in urine production triggered by the osmotic gradient reduction. The possible participation of arginine vasotocin in these responses is discussed.

Acclimatization↗
PubMed1993

Effects of feeding on water balance and cutaneous drinking in the toad (Bufo bufo L.).

1. Toads fed mealworms ad libitum for 24-hr periods once a week retained water in the body in amounts that varied with meal size, as well as temporally. 2. The ratio between masses of water retained and mealworms eaten increased from about 0.5 in May to about 1.3 by mid-July, and declined again at the end of the seasonal feeding period. 3. It is argued that this pattern reflects seasonal variation in the secretion of digestive (gastric) juice in response to meal size. 4. The cutaneous drinking response, reflected in number of visits to the water source, increased in strength with successive feedings. 5. It is suggested that the drinking response to feeding included a secondary, behavioural component, superimposed upon a primary response to feeding.

Animals↗
PubMed1996

Imaging of fluorescent molecule and small ion transport through human stratum corneum during high voltage pulsing: localized transport regions are involved.

During the application of high-voltage pulses across the skin, transport of two negatively charged fluorescent molecules through the stratum corneum is highly localized. The apparent size of these localized transport regions (LTR's) is initially 10 microns in diameter for both calcein and sulforhodamine. Appearance of LTR's occurred at or above transdermal voltages of 75 V. In the range of 75 to 160 V, the number of LTR's increases with voltage, but their initial size is the same at all voltages; with additional pulses LTR's increase in size, reaching diameters of approximately 40-80 microns. Small ion currents across the skin are also localized and include the LTR's; however, the areas of current flux appeared to be larger. There was no visible damage to the structure of the skin seen at 100 x magnification for any of the voltages used (< 170 V across the skin). Significantly, LTR's are not sweat ducts or hair follicles.

Adult↗
PubMed1986

Dermal exposure and urinary metabolite excretion in farmers repeatedly exposed to 2,4-D amine.

Following multiple exposures to 2,4-D amine salts under normal field conditions in which ground rigs were used, farmers who sprayed once or twice had an average dermal exposure of 655 micrograms 2,4-D acid equivalents (a.e.)/kg a.e. sprayed and an average cumulative urinary metabolite excretion of 10.9 micrograms 2,4-D a.e./kg a.e. sprayed. One very high outlier value was excluded from these averages (F). Following 4 to 7 exposures, the average cumulative dermal exposure was 1,077 micrograms 2,4-D a.e./kg a.e. sprayed and the average cumulative urinary metabolite excretion was 21.5 micrograms 2,4-D a.e./kg a.e. sprayed. The amount of 2,4-D metabolite in urine was significantly correlated with the amount of herbicide sprayed and the time required for the urinary metabolite excretion to return to background concentration was related to the amount sprayed and the number of exposures.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1996

Biomonitoring of diesel exhaust-exposed workers. DNA and hemoglobin adducts and urinary 1-hydroxypyrene as markers of exposure.

Diesel exhaust-exposed workers have been shown to have an increased risk of lung cancer. A battery of biomarkers were evaluated for their ability to assess differences in exposure to genotoxic compounds in bus garage workers and mechanics and controls. Lymphocyte DNA adducts were analyzed using the 32P-postlabelling method with butanol and P1 enrichment procedures. Hydroxyethylvaline (HOEtVal) adducts in hemoglobin were measured by gas chromatography-mass spectrometry (GC-MS) and 1-hydroxypyrene (HPU) in urine determined using HPLC analysis. The exposed workers had significantly higher levels of all three biomarkers compared to the controls. Total DNA adduct levels were 0.84 fmol/micrograms DNA vs 0.26 in controls (butanol) and 0.65 fmol/micrograms DNA vs. 0.08 (P1 nuclease). Median HOEtVal adduct level in exposed workers was 33.3 pmol/g hemoglobin vs. 22.1 in controls. HOEtVal adducts correlated with HPU but not with DNA adducts. The levels of HPU in urine were 0.11 micromol/mol creatinine compared to 0.05 in controls. All three assays applied were sensitive enough to evaluate a low level of exposure to environmental pollutants, with postlabelling and GC-MS as the most sensitive assays. The study indicated that skin absorption of polycyclic aromatic hydrocarbons (PAH) might be an important factor to consider when studying PAH exposure from air pollution sources.

Adult↗
PubMed1994

Determination of enantiomeric purity of nicotine in pharmaceutical preparations by 13C-NMR in the presence of a chiral lanthanide shift reagent.

A method for the determination of enantiomeric composition of nicotine samples, based on 13C-NMR spectroscopy in the presence of the chiral lanthanide shift reagent, tris[3-(trifluoromethylhydroxymethylene)-(+)-camphorato]ytte rbium [Yb(tfc)3], was developed. Observation at 100.6 MHz of the C2' resonance of nicotine in the presence of 0.15-0.20 mol of the ytterbium complex, either in ordinary 13C[1H]-NMR spectra or in carbon spectra enhanced by polarization transfer (refocused INEPT), allowed precise determination of the ratios of (S)- to (R)-nicotine. At least 1% of (R)-nicotine could be determined in samples of (S)-nicotine, milligram amounts being required for the analysis. Use of the 13C-NMR spectra is more advantageous than use of 1H-NMR spectra. Thus, Yb(tfc)3 induced separation of the proton resonances of the enantiomers of nicotine, and the shifted resonances of nicotine enantiomers could be assigned by use of 1H-13C heteronuclear chemical shift correlation, but the proton resonances were broad, their chemical shifts were sensitive to small variations of the ratio between Yb(tfc)3 and nicotine, and signals of the enantiomer present in small amounts were easily obscured by impurities. Therefore, although 13C-NMR is more time consuming, this method is more suitable for routine analysis. The method was applied for the determination of enantiomeric purity of (S)-nicotine in pharmaceutical formulations, including chewing gums, skin absorption patches, inhalators, and nasal sprays.

Magnetic Resonance Spectroscopy↗
PubMed1992

Subdermal penetration of topically applied clobetasol propionate in ointment base through intact human skin: lack of effect on subcutaneous adipose tissue blood flow.

Some data have demonstrated a substantial subdermal accumulation of topically applied drugs in animals. The aim of this study was to evaluate a possible effect of epicutaneously applied clobetasol propionate on blood flow in human subcutaneous adipose tissue. Nine healthy subjects were studied. The 133Xenon wash-out method was used for the measurement of subcutaneous blood flow. Resting blood flow and the local blood flow regulatory mechanisms, autoregulation of blood flow and the veno-arteriolar reflex, were assessed prior to treatment and were measured following 24, 48 and 72 h of treatment. The results demonstrated no effect of clobetasol propionate on resting subcutaneous blood flow or the local regulatory mechanisms.

Adipose Tissue↗
PubMed2006

Preparation and characterization of a stratum corneum substitute for in vitro percutaneous penetration studies.

The intercellular stratum corneum (SC) lipids form the main barrier for diffusion of substances through the skin. A porous substrate covered with synthetic SC lipids would be an attractive model to study percutaneous penetration, hereby replacing native human SC. Prerequisite is that this stratum corneum substitute (SCS) is prepared with a uniform lipid composition and layer thickness. Furthermore, the lipid organization and orientation should resemble that in SC. The objective of this study was to investigate the utility of an airbrush spraying device to prepare a SCS composed of cholesterol, ceramides and free fatty acids on a polycarbonate filter. The results demonstrate that a proper choice of solvent mixture and lipid concentration is crucial to achieve a uniform distribution of the applied lipids over the filter surface. A smooth and tightly packed lipid layer is only obtained when the equilibration conditions are appropriately chosen. The SCS possesses two crystalline lamellar phases with periodicities similar to those present in native SC. The orientation of these lamellae is mainly parallel to the surface of the polycarbonate filter, which resembles the orientation of the intercellular SC lipids. In conclusion, the airbrush technique enables generation of a homogeneous SCS, which ultimately may function as a predictive in vitro percutaneous penetration model.

Chromatography, Thin Layer↗
PubMed2004

The use of polymers for dermal and transdermal delivery.

The use of polymers for skin preparations is manifold. Requirements of such polymers are dependent on the formulation types. The most applied polymers on skin belong to various classes, for example to cellulose derivatives, chitosan, carageenan, polyacrylates, polyvinylalcohol, polyvinylpyrrolidone and silicones. They are gelating agents, matrices in patches and wound dressings, anti-nucleants and penetration enhancers. Correlations between commercially available products and results of new scientific investigations are often difficult or not possible, because of the lack of comparative data especially for transdermal patches. Finally, two promising future trends of polymeric systems, gene delivery and tissue engineering, are discussed.

Adjuvants, Pharmaceutic↗
PubMed2004

Skin deep.

Over the past 30 or so years there has been a considerable advance in our knowledge of the mechanisms of skin permeation. This has largely been brought about by the development of sophisticated biophysical techniques and increased computing powers. The advanced technology has clearly provided indications, at a molecular level, about routes of permeation and how the barrier function can be modulated by excipients with which actives are formulated. This publication reviews some of the advances that have been made and mathematical models that have been constructed to predict percutaneous penetration and transdermal delivery. The models also indicate the various enhancement strategies that can be used in dermal penetration. In the past, it has been difficult to identify precise mechanisms of action of the different classes of enhancer but a combination of appropriate biophysical techniques, mathematical modelling and chemometric analysis can help identify the contributing processes. The models can also be used to indicate rate control in transdermal delivery, whether it is in the applied delivery device or in the skin.

Administration, Cutaneous↗
PubMed2006

Effect of selected fluorinated drugs in a "ringing" gel on rheological behaviour and skin permeation.

The purpose of the present study was to investigate the influence of different drugs exhibiting different solubility on the viscoelastic properties and on the skin diffusion profile of a ringing gel. In a preliminary rheology study with the placebo gel predominating elastic properties were confirmed and a temperature influence was indicated. Fluconazole, fludrocortisone-acetate, flumethasone-pivalate, flutamide and flufenamic-acid each 1% (w/w) were incorporated into the preparation and oscillatory measurements were performed at temperatures of 25, 28, 32 and 37 degrees C. In all drug containing formulations a high elastic G' value predominated the viscous G'' value. The highest G' value could be obtained with the incorporated flumethasone-pivalate. Additionally in almost all cases the G' values decreased with increasing temperature compared to the placebo gel. Additionally in vitro standard diffusion experiments using Franz-type cells and porcine skin were performed. Following rank order of the cumulative drug release after 48 h was obtained: fluconazole>flufenamic-acid>flumethasone-pivalate>flutamide>fludrocortisone-acetate. Furthermore an excellent chemical stability of all incorporated drugs was confirmed over 10 weeks.

Animals↗
PubMed2005

Percutaneous penetration of diethanolamine through human skin in vitro: application from cosmetic vehicles.

Concern has been raised over the safety of diethanolamine (DEA) which may be present as a minor component of alkanolamide ingredients of cosmetic formulations. Skin penetration data were therefore generated for a range of typical formulations under in-use conditions. Seven rinse-off formulations (A-E, G and H), a leave-on emulsion (F), representing prototype cosmetic formulations and containing representative levels of DEA were prepared. Target levels of DEA were attained by inclusion of DEA as either (14)C-DEA or a combination of (14)C-DEA and unlabeled DEA. Skin permeation and distribution were evaluated using human skin in vitro, static diffusion cells and phosphate buffered saline (pH 7.4) as the receptor phase. At least 12 replicate epidermal membranes were prepared from a minimum of four donors for each test group. Receptor phase samples were taken at appropriate time intervals. At the end of the test period, radioactivity remaining on the skin surface and on the diffusion cell donor cap was determined before the skin samples were tape-stripped. The remaining tissue was solubilized and radioactivity determined. Permeation was very low from all vehicles applied under in-use conditions (range 1-48 ng/cm(2) over 24 h). Comparison was also made between permeation and distribution of DEA from an infinite dose of a simple aqueous solution and the leave-on formulation (F) through paired samples of fresh and frozen full thickness skin from the same donors. When applied as an infinite dose in aqueous solution DEA permeation at 24 h was greater through frozen than through fresh skin. From the leave-on formulation, permeation was similar and very low for both fresh and frozen skin. Recovery of DEA after application of the aqueous solution to fresh human skin and subsequent aqueous and organic extraction of the epidermal and dermal tissue indicated that the majority (>98%) of DEA was in the aqueous extract, suggesting that DEA was in the free state and not associated with the lipid fraction. These data provide a basis for the estimation of the potential systemic exposure and safety margins for DEA in representative cosmetic formulations.

Administration, Cutaneous↗