[Effect on the skin and absorption of chlorinated diphenyl (sovol)].
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Biphenyl Compounds↗
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Results for “Skin Absorption”
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Percutaneous absorption and metabolism of dinitrochlorobenzene in vitro.
Dinitrochlorobenzene (DNCB) absorption through mouse and rat dorsal skin, pig ear skin and human abdominal skin in vitro was determined, and local metabolism to the glutathione conjugate was related to glutathione transferase activities and glutathione status in the skin. Absorption studies were conducted using skin mounted in a flow-through diffusion cell with tissue culture medium as receptor fluid. DNCB applied to the surface of skin in acetone penetrated through 26-day-old rat skin better than through the skin of the other species investigated. The amounts of absorption through pig and human skin and conjugation formation were similar. In general, occlusion resulted in increased penetration of DNCB but no change in conjugation. Human skin showed the highest gluta-thione-S-transferase activity towards DNCB, followed by 26-day-old rat, pig, mouse and neonatal rat skin. Levels of glutathione were highest in mouse skin, followed by neonatal rat, 26-day-old rat, pig and human skin, with pig and human skin showing similar levels. These studies indicated that the glutathione level in skin was the determining factor influencing the degree of DNCB conjugation during percutaneous absorption, and this was greatly depleted during percutaneous penetration of DNCB.
Administration, Cutaneous↗
Percutaneous penetration and metabolism of 2-butoxyethanol.
2-Butoxyethanol (2-BE) is widely used as an industrial solvent, which may result in human dermal exposure within the workplace. This study compares in vivo and in vitro skin absorption of 2-BE using similar application regimes and determines the potential of skin to metabolise this chemical prior to entering the systemic blood circulation. Following topical application of undiluted [1-14C] 2-BE to occluded rat skin in vivo, 28% of the dose was absorbed after 24 h. The major routes of excretion included the urine (19%), expiration as carbon dioxide (6%) and faeces (0.4%) whilst little of the dose remained in the carcass (1.3%). Free 2-BE (0.5%), butoxyacetic acid (8%), glucuronide conjugate (3%), sulphate conjugates (0.7%) and ethylene glycol (0.6%) were detected in urine. Permeation rates of 2-BE through unoccluded rat dermatomed skin (16%) were greater than rat whole skin (8%) whilst absorption through human dermatomed skin (4%) was lower than the rat. Absorption of undiluted 2-BE through occluded rat dermatomed skin in vitro (18%) most accurately predicted absorption through rat skin in vivo. However, 2-BE absorption (23%) was enhanced by application in methanol. Distribution analysis and microautoradiography demonstrated the lack of 2-BE accumulation within the skin in vitro or in vivo. This was reflected in the absence of first pass metabolism of 2-BE during percutaneous penetration through viable human or rat skin in vitro or rat skin in vivo, despite rat skin cytosol having the potential to metabolise 2-BE. In conclusion, the in vitro system provided a reasonable estimate of dermal absorption in vivo for the rat. Therefore, by extrapolation of the comparative in vitro data for human and rat skin in vitro, dermal absorption of 2-BE in man was about one-fifth of that in the rat. However, the rapid penetration through skin in vitro prevented local metabolism and systemic exposure after skin contact with 2-BE in vivo was likely to be to the parent compound. Thus, in vitro skin systems can be used to model dermal absorption of volatile glycol ethers, to predict how much compound enters the circulation and allows the toxicologist to evaluate the body burden of a chemical and potential systemic toxicity.
Administration, Cutaneous↗
In vitro and in vivo percutaneous absorption of catechol.
The Cosmetic Ingredient Review Expert Panel found insufficient data to conclude that catechol could be used safely in permanent hair dye products. Information was lacking on the extent of oxidation and skin absorption of remaining catechol. In vitro percutaneous absorption studies were conducted in human and rat skin using a consumer permanent hair dye spiked with 0.6% catechol. A 30-min application demonstrated 0.4% of the applied dose was absorbed through human skin and 0.2% through rat skin. The minimal absorption observed was due to the short exposure time and to partial oxidation of catechol by the dye developer. The fate of catechol remaining in rat skin after exposure in vitro and in vivo was investigated with additional absorption studies using catechol in ethanol. At 72 h, 24-h application of 4% catechol resulted in skin absorption of 81% of the applied dose in vitro and 53% in vivo. Skin levels measured at 24 h remained unchanged after 72 h. Therefore the skin reservoir did not contribute to the estimated systemic absorption. A deconvolution technique employed to predict skin absorption using plasma levels from intravenous and dermal administration overestimated in vivo skin absorption due to volatility of catechol in an ethanolic vehicle.
Administration, Cutaneous↗
The use of sweat to monitor lead absorption through the skin.
It is usually assumed that lead can be absorbed through the skin only if it is present as an organolead compound such as tetraethyllead or lead naphthanate. It has been found, however, that finely-powdered lead metal or lead nitrate solution placed on the skin results in rapid absorption of lead, and transport of the metal around the body. The absorbed lead appears in sweat and saliva, but not in blood or urine. The application of 6 mg of lead as 0.5 M lead nitrate to the left arm resulted in an increase in lead concentration in pilocarpine-induced iontophoresis sweat samples taken from the right arm, from an initial value of 15-25 micrograms Pbl-1 to greater than 300 micrograms Pbl-1 after 2 days. Saliva lead increased from 2.5 to 15 micrograms Pbl-1 in the same period. The rate of lead absorption through the skin increases with increased sweating of the skin. Since no measurable increase in blood lead has been found, the lead must be transported in the plasma and rapidly concentrated into the extracellular fluid pool (sweat and saliva), without significant uptake by the erythrocytes, and with a very low transient concentration in the plasma. Workers occupationally exposed to lead have extremely high levels of lead in sweat even though their lead in blood is only moderately elevated. Lead absorbed through the skin may be eliminated via sweat and other extracellular fluids, and hence not be as great a health hazard as ingested lead, but this will need to be proved by further studies.
Environmental Pollution↗
[Changes in the bactericidal function of the skin and absorptive capacity of the reticuloendothelial system under the influence of vitamin B12].
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Humans↗
Skin penetration flux and lag-time of steroids across hydrated and dehydrated human skin in vitro.
To study the effect of hydration on skin absorption, we investigated penetration across human skin of twelve model chemicals having steroidal structure but different molecular weight and compared the steady-state penetration rate (J) and lag-time (t) across hydration intact skin (Jh and th) with that across dehydrated intact skin (Jd and td). Stratum corneum (SC) thickness of hydrated (52 microm) is 3.3 times that of dehydrated skin (16 microm). Transepidermal water loss (TEWL) of hydrated (7.6+/-2.1 g/m2/h) is twice that of dehydrated skin (3.4+/-1.6 g/m2/h, p<0.05) which are similar to in vivo values, suggesting the SC barrier function was recovered. The ratio of Jh/Jd ranged between 0.7 and 3.6 (average of 1.9). On the other hand, the ratio of th/td was almost constant (average of 0.8). Ratios of Jh/Jd and th/td were independent of MW and Ko/w. In percutaneous absorption experiments in vitro, skin was preserved in culture medium until use and SC might swell during that time. Therefore, we consider the possibility that J and t varied between hydrated and dehydrated skin. We confirmed the difference of J and t between hydrated and dehydrated skin in vitro and now need to define these results under in vivo condition.
Adult↗
Modulation of the barrier function of the skin.
Transport of xenobiotics across the stratum corneum, the rate-controlling membrane of skin, is slow and the mechanism appears complex. However, the basic transfer is controlled by fundamental physicochemical concepts, the predominant of which are partition (K), diffusion (D) and solubility (C(s)). In order to change the rate of penetration it is therefore clear that it is these parameters that should be targeted. In most instances enhancement strategies are adopted to improve D, K or C(s), however there are instances in which permeation reduction may be beneficial. Examples include the topical application of sunscreens or insect repellents. This publication demonstrates the way in which modulation effects can be assessed and the difficulties involved in determining which of the physicochemical parameter(s) are being affected. If the formulation influences more than one, synergism can often be seen. Advances in computer modelling have provided an insight into the mechanisms of action of some of the chemical enhancers at a molecular level. Enhanced skin absorption has been reported for the delivery of macromolecules such as insulin (associated with transfersomes) or DNA (as a DOTAP complex). The barrier property of the skin must be modulated for this to be achieved. However the precise mechanisms of action have not been elucidated.
Animals↗
A model for quantifying absorption through abnormal skin.
Techniques are available for quantitatively studying factors governing absorption through normal skin (in vivo and in vitro) but relatively little is known about the permeability of abnormal skin. We have designed and evaluated an in vivo model for quantifying absorption through abnormal skin. Absorption of [3H]mannitol and [14C]octyl benzoate was studied through altered rat skin. [3H]Mannitol penetrated normal skin much more slowly than did [14C]octyl benzoate. Abnormal skin was more permeable to [3H]mannitol and [14C]octyl benzoate, absorption was greater than 100X and greater than 2X greater, respectively, than normal. The in vivo model has been successfully used to quantify absorption through abnormal skin.
Animals↗
Mercury, not sulphur dioxide, poisoning as cause of smelter disease in industrial plants producing sulphuric acid.
Several episodes of "smelter disease", previously assumed to be caused by sulphur dioxide (SO2) poisoning, have been reported in workers replacing pipes in sulphuric acid manufacturing plants. One such incident, affecting 20 men, was recorded in Akita, Japan, in July, 1993, but the protection these workers used suggested that some cause other than SO2 needed to be looked for. 10 workers were affected despite wearing respirators with SO2 cartridges, the symptoms including dyspnoea, diarrhoea, colicky pain, muscle pain and eczema with erythema. Subsequently 10 other workers using face masks with supplied air were affected, though without respiratory symptoms. Sludge in the piping contained mercuric sulphate, and mercury fumes resulted when pipes were cut with gas burners. Blood and urine measurements confirmed heavy exposure to the metal, and simulation experiments in rats showed that skin absorption was likely too. The masks with supplied air ought to have excluded both SO2 and mercury fumes. The only way to avoid smelter disease reliably is to wear an encapsulated suit that prevents inhalation and skin absorption of industrial toxins.
Acute Disease↗
Partition coefficients for benzene in human skin.
The contribution of benzene to body burden after skin absorption compared with that due to inhalation absorption is of potential interest in the setting and interpretation of benzene (inhalation) exposure standards. However, an understanding of the quantitative relationship between skin and inhalation absorption, under different exposure conditions, is required. Such knowledge may be gained through physiological based pharmacokinetic (PBPK) modeling. The intake of benzene to the body via inhalation has been studied extensively. Physiological parameters enabling the calculation of amounts of benzene entering the blood stream per unit time are readily available for use in a PBPK model. Unfortunately, some data (i.e., partition coefficients) that would enable biologically plausible calculation of amounts of benzene entering the blood stream via skin absorption in a PBPK model are not available. Hence, the aim of this research was to determine partition coefficients across the epidermal and dermal layers of human skin so that these could be used within a PBPK model to determine quantitatively the flow rate of benzene per unit time through intact skin into the blood stream. The partition coefficients found for blood substitute: viable epidermis and blood substitute: dermis were, respectively, 2.4 and 11.2. Partition coefficients for benzene : stratum corneum (4.2), whole skin : blood substitute (2.2), benzene : water (109/126), and benzene : blood substitute (55/59) also were determined for the purposes of validating the blood substitute: viable epidermis and blood substitute : dermis partition coefficients.
Benzene↗
Percutaneous absorption of hair dyes: correlation with partition coefficients.
A homologous series of hair dyes was selected for percutaneous absorption studies with excised human skin. The permeability constants obtained for the dyes were compared with octanol/water and skin membrane/water partition coefficients. The compounds examined were: p-phenylenediamine, o-phenylenediamine, 2-nitro-p-phenylenediamine, 2-amino-4-nitrophenol, 4-chloro-m-phenylenediamine, and 4-amino-2-nitrophenol. Skin absorption of the dyes was observed when they were applied in an aqueous solution. With one exception, the octanol/water partition coefficients were in the same rank order as the permeability constants. The determination of the partitioning of the hair dyes between water and either stratum corneum or epidermis was more complex. Preliminary stratum corneum/water partition studies resulted in values that were in the reverse order of skin permeation. When binding of the compounds to components of the membrane was saturated, the partition values more closely duplicated the rank order of permeability of the dyes. Prediction of percutaneous absorption of substances based on their partition coefficients may be confounded if these compounds are capable of binding to skin.
Cell Membrane Permeability↗
Interactions of skin thickness and physicochemical properties of test compounds in percutaneous penetration studies.
OBJECTIVES: To determine the effect of skin thickness on the percutaneous penetration and distribution of test compounds with varying physicochemical properties using in vitro systems. Studies were carried out in accordance with OECD guidelines on skin absorption tests. METHODS: Percutaneous penetration of caffeine (log P -0.01), testosterone (log P 3.32), propoxur (log P 1.52) (finite dose in ethanol to water vehicle ratio) and butoxyethanol (log P 0.83) (undiluted finite dose or as an infinite dose 50% [v/v] aqueous solution) through skin of varying thicknesses under occluded conditions was measured using flow through cells for 8-24 h. Saline (adjusted to pH 7.4) was used as receptor fluid, with BSA added for studies with testosterone and propoxur. Following exposure, the remaining surface dose was removed by swabbing and the skin digested prior to scintillation counting. RESULTS: The maximum flux of caffeine was increased with decreasing skin thickness, although these differences were found to be non-significant. The presence of caffeine in the skin membrane was not altered by skin thickness. Maximum flux and cumulative dose absorbed of testosterone and butoxyethanol (in both finite and infinite doses) were markedly reduced with full thickness (about 1 mm thick) skin compared with split thickness skin (about 0.5 mm). Maximum flux of propoxur (dissolved in 60% ethanol) was clearly higher through skin of 0.71 mm than through skin of 1.36 mm, but no difference was found between 0.56 and 0.71 mm. The proportion of propoxur present in the membrane after 24 h increased significantly over the complete range of thicknesses tested (0.56-1.36 mm). CONCLUSIONS: A complex relationship exists between skin thickness, lipophilicity and percutaneous penetration and distribution. This has implications for risk assessment studies and for the validation of models with data from different sources.
2,4-Dichlorophenoxyacetic Acid↗
Stability and transdermal absorption of topical amphotericin B liposome formulations.
The aim os this study was to characterize the stability and transdermal absorption of amphotericin B (AMB: 0.05 mg/mg lipid) in hydrogenated soya phosphatidylcholine/cholesterol/charged lipid [dicetyl phosphate (-) or stearylamine (+)] liposomes at molar ratios of 1:1:0, 7:2:0, 7:2:1(-) and 7:2:1(+). The AmB contents in liposomes were determined by HPLC with UV detection at 382 nm. Stabilities of AmB in liposome formulations were compared with those in solution and powder forms, during storage at 4, 30 and 45 degrees C for 90 days. Absorption studies of AmB across the rat skin were conducted, using vertical Franz diffusion cells at 37 degrees C for 24 h. The slowest degradation was observed in the positive liposome (7:2:1(+)AmB), with shelf life of approximately 1 year (30 degrees C). In comparison, the shelf lives of AmB in solution and powder were 4 and 14 days, respectively. AmB in positive liposomes seemed to demonstrate the highest flux in stratum corneum (58 ng/cm(2)/h), while the highest flux in viable epidermis (23 ng/cm(2)/h) was observed in negative liposomes. AmB entrapped in charged liposomes showed sustained skin absorption. The positively charged liposome might be the best formulation for AmB, due to its higher stability than other formulations.
Administration, Cutaneous↗
Percutaneous absorption of explosives and related compounds: an empirical model of bioavailability of organic nitro compounds from soil.
The percutaneous absorption potentials of (14)C-labeled 2,4,6-trinitrotoluene (TNT), trinitrobenzene, 2,4-dinitrotoluene (2,4-DNT), 2,6-dinitrotoluene (2,6-DNT), 2-amino-4,6-dinitrotoluene, 4-amino-2,6-dinitrotoluene, 2,4-diamino-6-nitrotoluene, 2,6-diamino-4-nitrotoluene, N-methyl-N,2,4,6-tetranitrobenzamine, hexahydro-1,3,5-trinitro-1,3,5-triazine, octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine, and 2,2-thiobis(ethanol) were determined from two soil types, Yolo having 1.9% carbon and Tinker having 9.5% carbon. TNT skin absorption from another low-carbon soil (Umatilla) was also determined. Approximately 10 microg/cm(2) of radiolabeled compound was applied in 5 microl of acetone or 10 mg/cm(2) of soil to excised pigskin mounted in skin penetration-evaporation chambers. Absorption from acetone served as a control. Radiolabel recovered from the dermis and tissue culture media (receptor fluid) was summed to determine the percentage of absorption from the soils. For each compound, percentage absorptions of radiolabel were highest from acetone solution and lowest from Tinker soil, with the results from Yolo soil being intermediate. Skin absorptions of TNT from Yolo and Umatilla soils were similar. For TNT in all vehicles, the penetration rate of radiolabel into the receptor fluid was highest during the 1- to 2-h interval after dosing. HPLC analysis of TNT radiolabel in receptor fluid at maximum flux indicated extensive conversion to monoamino derivatives and other metabolites. For 2,4-DNT and 2,6-DNT applications in Yolo soil, percentage absorptions approached those obtained from acetone applications. After 2,4-DNT and 2,6-DNT applications (acetone and soils), HPLC analysis of radiolabel in receptor fluid during the period of maximum flux revealed no significant metabolites. Skin absorption of the nitro compounds from soils was found to correlate with the compound's water solubility and vapor pressure. These findings formed the basis of an empirical model to predict skin bioavailability.
Animals↗
Comparison of six respirator fit-test methods with an actual measurement of exposure in a simulated health care environment: Part I--Protocol development.
Quantitative fit tests (QNFT) have been assumed to be predictive of the protection respirators would provide to a wearer in the workplace. Workplace studies have consistently found no correlation between quantitative fit factors and workplace protection factors. This article is the first in a series of three describing a study designed to compare the fit factors from six QNFT methods against the actual dose of 1,1,2 trichloro-1,2,2 trifluoroethane (Freon-113) received under the same laboratory conditions. Five preliminary studies conducted to develop the protocol to assess the respirator wearer's dose through end-exhaled air analysis are described in this article: (1) chamber characterization, (2) end-exhaled air sampling, (3) skin absorption testing, (4) pharmacokinetic modeling, and (5) subject characterization. It was established that the concentration of corn oil aerosol and Freon-113 could be generated simultaneously in the chamber. It was ascertained that the optimum time to sample the exhaled breath was 30 minutes after the subject exited the chamber. It was also found that in a chamber concentration of 500 ppm, without any respiratory exposure, Freon-113 was still present in the end-exhaled air. This was attributed to skin absorption. The end-exhaled air of subjects exposed to 0.5, 3, 5, 25, 50, and 100 ppm (30 minute time-weighted average) of Freon-113 was evaluated at 30 minutes postexposure. This characterization was then used to predict the actual dose of Freon-113 received during the method comparison and validation testing to be described in subsequent articles.
Adult↗
Measuring performance of a half-mask respirator in a styrene environment.
A workplace protection factor (WPF) study was conducted with a half-mask air-purifying respirator during fiber glass boat production. Styrene was the measured analyte, and the geometric mean WPF found was 39.7. Analytical detection limits, sample contamination, and pulmonary elimination from previous exposures or from skin absorption were identified as important considerations that can bias the WPFs measured. There were significant differences in the mean concentrations found inside the respirator when analyzed by time period. An increase in the concentration found inside the facepiece cavity and a decrease in the WPF over time was found for people with three or four measurements. This indicates either a change in performance of the respirator over time or a bias from low-level exposures during the day or skin absorption.
Air Pollutants, Occupational↗
Absorption through human skin of ibuprofen and flurbiprofen; effect of dose variation, deposited drug films, occlusion and the penetration enhancer N-methyl-2-pyrrolidone.
The penetration of ibuprofen and flurbiprofen, non-steroidal anti-inflammatory agents, was investigated from drug films deposited by acetone evaporation on cadaver skin in an open cell 'in-vivo mimic' design. Increased dosage did not produce a proportional increase in the permeation and maximizing the skin-drug contact did not increase penetration: both factors indicate that absorption from deposited drug films was dissolution rate-limited. Occlusion of the skin did not increase the dissolution rate of the deposited drug film, but did elevate the penetration of drug already present within the skin at the time of occlusion. The diffusion coefficients for both drugs were calculated by two methods, yielding 1.8 +/- 1.3 X 10(-11) cm2 s-1 and 1.0 +/- 0.56 X 10(-11) cm2 s-1 for ibuprofen and 1.9 +/- 0.59 X 10(-11) cm2 s-1 and 0.77 +/- 0.23 X 10(-11) cm2 s-1 for flurbiprofen. Increasing the acetone-skin contact time from 2 min to 2 h did not significantly alter the permeability of the skin. Absorption of flurbiprofen was similar from 10 and 100% saturated aqueous solutions, suggesting that the skin has a limited capacity for flurbiprofen transport beyond which further increase in drug penetration may be difficult. N-Methyl-2-pyrrolidone enhanced the penetration flux of ibuprofen sixteenfold and flurbiprofen, over threefold. The 'in-vivo mimic' design for permeation experiments has thus proved to be useful for evaluating the kinetics of topical therapy and the mechanism of action of potential penetration enhancers.
Acetone↗