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Methanol absorption rate through the human skin has been examined by the use of modified direct method, and a value of 0.192 mg/cm2/min was determined. The excretion of unchanged methanol with urine and exhaled air, after the absorption through the skin and administration "per os of identical doses, were also examined.
A simple non-invasive ultra-violet/visible (UV/vis) diffusive reflectance spectroscopy combined with fiber-optics was investigated to elicit the dynamics of skin penetration in vivo of a pharmaceutical, aminolevulinic acid polyethylene glycol cream (5-ALA-PEG cream). Temporal data of the reflectance, R(lambda), were measured from a bare skin region and from a skin region treated with 5-ALA cream. The difference in apparent optical density [(DeltaAOD)=Deltalog[1/R(lambda)]] between the treated and untreated regions of the skin was gradually increased to a local maximum value with an increasing time of measurement, and then it was decreased in an oscillatory manner. This temporal increase in DeltaAOD was interpreted as a diminution of total reflectance by an increased scattering inside the skin tissue as topically applied materials penetrated gradually and temporally accumulated into the skin. A following decrease in DeltaAOD was attributed to diminished scattering effects as the penetrated materials gradually cleared out by cellular uptake of 5-ALA and circulation by epidermal capillary. In conclusion, it was possible to measure the skin absorption kinetics of the topically treated materials, including the penetration time and clearing out from the temporal course of the differential AOD.
Theoretically percutaneous absorption comprises two components: the transepidermal route and the transappendageal route, so-called 'shunt' diffusion. The relative importance of 'shunt' diffusion was investigated with a model of appendage-free skin. After treatment with 60 degrees C water for exactly 1 min, hairless dorsal rat skin regrows as a continuous epidermis. We present preliminary results of hydrocortisone diffusion in vitro, in appendage-free skin relative to normal skin. With intact skin under our experimental conditions, the steady-state flux and the total diffusion in 24 h were 50-fold larger.
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OBJECTIVES: The increased use of glycol ethers (GEs) for water-based paints and cleaning products, combined with a lack of information about many of these products, particularly with regard to the effects of percutaneous exposure, led us to evaluate the skin absorption rates of a group of glycol ethers in vitro. METHODS: Skin permeation was calculated using the Franz cell method with human skin. A physiological solution was used as the receiving phase. The amount of solvent passing through the skin was analysed with a gas chromatographic technique employing flame ionization detection. A permeation profile was obtained and steady state, lag time and permeation constant flux was calculated for each of the following solvents: ethylene glycol monoethyl ether (EGMEE), propylene glycol mono-methyl ether (PGMME); propylene glycol mono-methyl ether acetate (PGMMEac); 2-propylene glycol 1-butyl ether (2PG1BE), ethylene glycol dimethyl ether (EGDME), ethylene glycol diethyl ether (EGDEE) and diethylene glycol dimethyl ether (DEGDME). All solvents were tested in their pure form and with 70% acetone. RESULTS: For all solvents tested the lag time was less than 2 h, and for the majority of them was about 60 min. Flux at steady state ranged between 0.017 +/- 0.005 and 3.435 +/- 1.897 mg/cm(2)/h and permeation rate was from 0.0192 to 1.02 x 10(-3) cm/h. The presence of acetone in the solution caused a reduction in lag time and an increase in permeation rate, higher for EGMEE, lower for EGDEE, indicating the enhancing effect of this mixture of solvents. CONCLUSIONS: Our results confirm the high percutaneous absorption of the GEs tested. The Franz method might be helpful for obtaining a grading of skin notation for hydrophilic substances: in the case of glycol ethers, it can give us precise information about permeation risk, particularly important in the evaluation of exposure. In the case of solvents with high dermal absorption, the air concentration is no longer a sufficient measure of the total exposure to workers, and therefore merely respecting threshold limit values (TLVs) in the air is not necessarily enough to protect them.
Ingestion of paraquat is the most common cause of fatal pesticide poisoning. Liver involvement in acute paraquat poisoning is self-limited and usually consists of cholestasis. However, long-term hepatic effects after paraquat exposition have not been described up to now, probably because of the high mortality rate of this acute poisoning. We report the case of an agricultural worker who developed persistent cholestasis after an episode of acute paraquat poisoning through skin absorption.
OBJECTIVES: The aims of the study were three-fold: to assess the skin uptake of the industrial catalyst dimethylethylamine (DMEA) (a) in vitro from water solutions by fresh guinea-pig and human skin specimens, (b) in gaseous form in vivo in human volunteers, and (c) to estimate the relevance of the uptake as an occupational hazard. METHODS: Specimens from the in vitro and in vivo experiments were analysed by gas chromatography using a nitrogen-sensitive detector. DESIGN: DMEA, diluted with water or isotonic saline solution was applied to fresh human or guinea-pig skin, mounted in Teflon flow-through cells with a perfusion fluid flow rate of 1.5 ml/h, samples being collected at 2-h intervals for 48 h. Three healthy male volunteers each had their right forearm exposed (in a Plexiglass chamber) for 4 h to DMEA at each of three different levels (250, 500 and 1000 mg/m3 air). Urine was collected up to 24 h after the start of each experiment. RESULTS: DMEA penetrated both guinea-pig and human skin. The median steady-state flux and permeability coefficient (Kp) values, were 0.009 mg/cm2 x h and 0.001 cm/h, respectively, for guinea-pig skin, and 0.017 mg/cm2 x h and 0.003 cm/h, respectively, for human skin. The median uptake in the three volunteers at the different DMEA exposure levels (250, 500 or 1000 mg/m3) was 44, 64 and 88 micrograms, respectively. The median Kp for all experiments was 0.037 cm/h. CONCLUSION: Uptake of DMEA through the skin is of far less importance than simultaneous uptake via the airways. Thus, the amount of DMEA excreted in urine is a variable of limited use for the purposes of biological monitoring. Although a wide range of Kp values was obtained in the in vitro experiments, both for guinea-pig and human skin, there was no marked difference in median Kp values between the two types of skin. The Kp values were lower than those obtained for human forearm skin in vivo. However, future studies of other tertiary aliphatic amines may show the in vitro method to yield values predictive of those obtained in in vivo studies.
To obtain better insight into the robustness of in vitro percutaneous absorption methodology, the intra- and inter-laboratory variation in this type of study was investigated in 10 European laboratories. To this purpose, the in vitro absorption of three compounds through human skin (9 laboratories) and rat skin (1 laboratory) was determined. The test materials were benzoic acid, caffeine, and testosterone, representing a range of different physico-chemical properties. All laboratories performed their studies according to a detailed protocol in which all experimental details were described and each laboratory performed at least three independent experiments for each test chemical. All laboratories assigned the absorption of benzoic acid through human skin, the highest ranking of the three compounds (overall mean flux of 16.54+/-11.87 microg/cm(2)/h). The absorption of caffeine and testosterone through human skin was similar, having overall mean maximum absorption rates of 2.24+/-1.43 microg/cm(2)/h and 1.63+/-1.94 microg/cm(2)/h, respectively. In 7 out of 9 laboratories, the maximum absorption rates of caffeine were ranked higher than testosterone. No differences were observed between the mean absorption through human skin and the one rat study for benzoic acid and testosterone. For caffeine the maximum absorption rate and the total penetration through rat skin were clearly higher than the mean value for human skin. When evaluating all data, it appeared that no consistent relation existed between the diffusion cell type and the absorption of the test compounds. Skin thickness only slightly influenced the absorption of benzoic acid and caffeine. In contrast, the maximum absorption rate of testosterone was clearly higher in the laboratories using thin, dermatomed skin membranes. Testosterone is the most lipophilic compound and showed also a higher presence in the skin membrane after 24 h than the two other compounds. The results of this study indicate that the in vitro methodology for assessing skin absorption is relatively robust. A major effort was made to standardize the study performance, but, unlike in a formal validation study, not all variables were controlled. The variation observed may be largely attributed to human variability in dermal absorption and the skin source. For the most lipophilic compound, testosterone, skin thickness proved to be a critical variable.
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A patient had extensive blunt trauma from a high-speed crash in which nitromethane fuel erupted from the fuel tank and soaked into his protective multilayer jumpsuit. The clinical diagnosis was complicated because the absorption of nitromethane fuel through the skin and by inhalation falsely increased the serum creatinine value when a modified Jaffe reaction was used in the laboratory. This spurious value was "unmasked" by the use of an enzymatic method to measure the serum creatinine level. A high serum creatinine value disproportionate to the level of BUN and recent skin exposure to nitromethane were the clinical indications that suggested the differentiation of massive rhabdomyolysis from spurious hypercreatinemia. This spurious value was a confounding factor in the diagnosis of crush syndrome and rhabdomyolysis.
Dermal penetration and absorption of jet fuels in general, and JP-8 in particular, is not well understood, even though government and industry, worldwide, use over 4.5 billion gallons of JP-8 per year. Exposures to JP-8 can occur from vapor, liquid, or aerosol. Inhalation and dermal exposure are the most prevalent routes. JP-8 may cause irritation during repeated or prolonged exposures, but it is unknown whether systemic toxicity can occur from dermal penetration of fuels. The purpose of this investigation was to measure the penetration and absorption of JP-8 and its major constituents with rat skin, so that the potential for effects with human exposures can be assessed. We used static diffusion cells to measure both the flux of JP-8 and components across the skin and the kinetics of absorption into the skin. Total flux of the hydrocarbon components was 20.3 micrograms/cm(2)/h. Thirteen individual components of JP-8 penetrated into the receptor solution. The fluxes ranged from a high of 51.5 micrograms/cm(2)/h (an additive, diethylene glycol monomethyl ether) to a low of 0.334 micrograms/cm(2)/h (tridecane). Aromatic components penetrated most rapidly. Six components (all aliphatic) were identified in the skin. Concentrations absorbed into the skin at 3.5 h ranged from 0.055 micrograms per gram skin (tetradecane) to 0.266 micrograms per gram skin (undecane). These results suggest: (1) that JP-8 penetration will not cause systemic toxicity because of low fluxes of all the components; and (2) the absorption of aliphatic components into the skin may be a cause of skin irritation.
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One parameter equation connected skin-resorptive toxicity of pesticides and its solubility in water was maintained. For defoliants, insecticides, acaricides, nematocides and zoocides a good correlation between calculated and experimental values of skin-resorptive toxicity for rats was shown.
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A case of chronic lead poisoning is described in a woman presenting with abdominal pain due to cutaneous absorption of a lead soap. We have found no other case of intoxication by this route in the literature.
The aim of this study was to investigate the cutaneous penetration and metabolism of the new vitamin E prodrug delta-tocopherol glucoside (delta-TG), as compared to those of common vitamin E acetate, in vitro, both in reconstituted human epidermis and in viable human skin. Better diffusion was observed with alpha-tocopherol acetate (alpha-TAc) than with delta-tocopherol glucoside in both skin models, at 0.1% and 0.05% in a myritol solution; however, no metabolism was detected with alpha-tocopherol acetate. In all conditions tested (two skin models, two concentrations, three test times, and compartmental analysis) the delta-tocopherol glucoside was metabolized into free tocopherol. In the reconstituted human epidermis, after 18 h, over 90% of the delta-tocopherol glucoside was bioconverted. In the viable human skin, the extent of metabolism was about 20%, with 0.12 and 0.10 microg/cm2 of delta-tocopherol glucoside in the stratum corneum and epidermis, respectively. After topical application, the delta-tocopherol glucoside had a considerable reservoir effect, associated with gradual delivery of free tocopherol. The use of this gluco-conjugated vitamin E at a low concentration shows the capability of the skin to metabolize the prodrug in a slow and prolonged manner, making this gluco-conjugated vitamin E an excellent candidate for continuous reinforcement of antioxidants in the skin.
When we try to maximize drug flux through the skin, we usually meet major difficulties because of the impervious nature of the stratum corneum. A popular solution incorporates penetration enhancers into transdermal products. Such materials ideally possess the sole property of reversibly reducing the barrier resistance of the horny layer, allowing the drug to reach the living tissues at a greater rate. This article considers examples of accelerant action that support a general concept explaining enhancer activity in human skin. The core of the proposal is that enhancers usually work by one or more of three main mechanisms: alteration of the lipid or protein domains of the stratum corneum or increase in tissue partitioning of a drug, a coenhancer, water, or any combination of these three chemicals. We may usefully refer to the overall hypothesis as the lipid-protein-partitioning (LPP) concept.