Percutaneous permeation and skin irritation of JP-8+100 jet fuel in a porcine model

JP-8 is the major jet fuel used by US Air Force. JP-8+100 is a new jet fuel recently introduced by the US Air Force, which contains JP-8 plus three performance additives [butylated hydroxytoluene (BHT), metal deactivator (MDA) and 8Q405]. The purpose of the present study was to investigate the percutaneous permeation of JP-8+100 across pig ear skin in vitro and to study the effect of JP-8+100 exposure on the skin barrier function, moisture content and irritation in Yucatan minipigs. The influence of performance additives on the permeation of JP-8 was studied by adding each additive individually to JP-8. The percutaneous permeation and skin irritation data obtained with JP-8+100 were compared with that of JP-8. JP-8+100 spiked with 5.0 microCi of radiolabeled [14C]tridecane, nonane, naphthalene or toluene (selected components of JP-8+100) was used for the in vitro percutaneous permeation studies. For skin irritation studies, 250 microl of JP-8+100 was placed in a Hill top chamber and affixed over the marked treatment area for 24 h. The components of JP-8+100 such as tridecane, nonane, naphthalene and toluene permeated readily through pig ear skin without any apparent lag time. Compared to JP-8, the permeation of tridecane, toluene and nonane from JP-8+100 was significantly lower (P<0.05). However, the permeation of naphthalene from JP-8+100 was significantly higher than from JP-8. When BHT was added to JP-8, the permeation of all four chemicals were significantly decreased (P<0.05). Though the addition of 8Q405 to JP-8 decreased the permeation of all four chemicals, the values were not significantly different (P>0.05) from that of JP-8. Addition of MDA did not show any significant change in the permeation of the selected chemicals from JP-8. Application of JP-8+100 increased the transepidermal water loss (TEWL) about three times compared to the baseline level. The skin moisture content decreased consistently after the application of JP-8+100, though it was not significantly different (P>0.05) from the baseline level. JP-8+100 caused a moderate erythema (score: 1.60) and a moderate to severe edema (score: 2.60). These results suggest that JP-8+100 produces significant changes in the barrier function of the skin and a local irritant effect upon occlusive dermal exposure. However there was no significant difference in the skin irritation data observed from JP-8 and JP-8+100.     

Percutaneous absorption, biophysical, and macroscopic barrier properties of porcine skin exposed to major components of JP-8 jet fuel

JP-8 has been associated with toxicity in animal models and humans. There is a great potential for human exposure to JP-8. Quantitation of percutaneous absorption of JP-8 is necessary for assessment of health hazards involved in its occupational exposure. In this study, we selected three aliphatic (dodecane, tridecane, and tetradecane) and two aromatic (naphthalene and 2-methylnaphthalene) chemicals, which are major components of JP-8. We investigated the changes in skin lipid and protein biophysics, and macroscopic barrier perturbation from dermal exposure of the above five chemicals. Fourier transform infrared (FTIR) spectroscopy was employed to investigate the biophysical changes in stratum corneum (SC) lipid and protein. FTIR results showed that all of the above five components of JP-8 significantly (P<0.05) extracted SC lipid and protein. Macroscopic barrier perturbation was determined by measuring the rate of transepidermal water loss (TEWL). All of the five JP-8 components studied, caused significant (P<0.05) increase in TEWL in comparison to control. We quantified the amount of chemicals absorbed assuming 0.25 m(2) body surface area exposed for 8 h. Our findings suggest that tridecane exhibits greater permeability through skin among aliphatic and naphthalene among aromatic JP-8 components. Amount of chemicals absorbed suggests that tridecane, naphthalene and its methyl derivatives should be monitored for their possible systemic toxicity.     

Dermal toxicity and microscopic alterations by JP-8 jet fuel components in vivo in rabbit

In this study, we investigated the skin irritation, macroscopic and microscopic barrier alteration in vivo in rabbits from aliphatic and aromatic components of jet propellant-8 (JP-8) jet fuel. Macroscopic barrier properties were evaluated by measuring transepidermal water loss (TEWL), skin capacitance, and skin temperature; microscopic changes were observed by light microscopy. Draize visual scoring system was used to measure skin irritation. We found significant (P<0.05) increase in temperature at the site of all chemically saturated patches immediately after patch removal in comparison to the control site. Tridecane (TRI) produced a greater increase in temperature and capacitance at all time points than all the other components of JP-8. Both the aliphatic and aromatic components increased the TEWL at all time points. Tridecane produced greater increase in TEWL followed by naphthalene (NAP), 1-methylnaphthalene (1-MN), 2-metylnaphthalene (2-MN), tetradecane (TET), and dodecane (DOD). All of the above components of JP-8 caused moderate to severe erythema and edema, which were not resolved to the baseline even after 24 h of patch removal. Light microscopy revealed an increase in epidermal thickness (ET), and decrease in length and thickness of collagen fibers’ bundle by the above components of JP-8. These results suggest potential dermatotoxicity from the JP-8 components.     

In Vivo Percutaneous Absorption,Skin Barrier Perturbation,and Irritation from JP-8 Jet Fuel Components

Abstract

JP-8 jet fuel has been reported to cause systemic and dermal toxicities in animal models and humans. There is a great potential for human exposure to JP-8. In this study, we determined percutaneous absorption and dermal toxicity of three components of JP-8 (i.e., xylene, heptane, and hexadecane) in vivo in weanling pigs. In vivo percutaneous absorption results suggest a greater absorption of hexadecane (0.43%) than xylene (0.17%) or heptane (0.14%) of the applied dose after 30 min exposure. Transepidermal water loss (TEWL) provides a robust method for assessing damage to the stratum corneum. Heptane showed greater increase in TEWL than the other two chemicals. No significant (p<0.05) increase in temperature was observed at the chemically treated site than the control site. Heptane showed greater TEWL values and erythema score than other two chemicals (xylene and hexadecane). We did not observe any skin reactions or edema from these chemicals. Erythema was completely resolved after 24 h of the patch removal in case of xylene and hexadecane.     

Effect of jet fuels on the skin morphology and irritation in hairless rats

Jet A and JP-8 are the major jet fuels used in civilian and military (US Air Force) flights, respectively. JP-8+100 is a new jet fuel recently introduced by US Air Force in some of its locations. The purpose of this study was to investigate the effects of dermal exposure of jet fuels (Jet A, JP-8, and JP-8+100) on the skin morphology, barrier function, moisture content, blood flow, and skin irritation (erythema and edema) in hairless rats. Jet fuels were applied by both occlusive and unocclusive methods. The skin of treated and control (untreated) sites were excised and analyzed by magnetic resonance imaging (MRI) (500 MHz, 11.7 Tesla). Unocclusive application of JP-8, Jet A, and JP-8+100 increased the transepidermal water loss (TEWL) gradually and the values at 120 h were significantly greater than the baseline value (P<0.05). Both occlusive and unocclusive application of jet fuels decreased the skin moisture content significantly (P<0.05). Unocclusive application of JP-8, Jet A, and JP-8+100 increased the skin blood flow, though the values returned to the baseline levels within 24 h. Occlusive application of jet fuels (8 h/day for 2 days) caused a substantial increase in the skin blood flow and the values at 48 h were about 6-fold greater than the baseline value. Occlusive application of jet fuels caused a moderate to severe erythema and a moderate edema. MRI was used to obtain proton images and water self-diffusion maps of hairless rat skin exposed to jet fuel. Exposure to JP-8 showed the largest difference from the control with regards to visual observations of the stratum corneum and hair follicles, while JP-8+100 appeared to affect the hair follicle region. The results of the present study demonstrate that exposure to jet fuels can disrupt the skin barrier function, cause skin irritation, and alter the skin structure (stratum corneum and viable epidermis) and MRI can be used as a tool to investigate the alterations in the skin morphology after exposure to toxic chemicals.     

Effects of short-term high-dose and low-dose dermal exposure to Jet A, JP-8 and JP-8 + 100 jet fuels.

Occupational and environmental exposures to jet fuel recently have become a source of public and regulatory concern. This study investigates the cutaneous toxicity of three fuels used in both civilian and military aircraft. Pigs, an accepted animal model for human skin, were exposed to low-dose (25 microl or 7.96 microl cm(-2)) or high-dose (335 microl or 67 microl cm(-2)) Jet A, JP-8 and JP-8 + 100 under occluded (Hill Top) chamber or cotton fabric) and non-occluded conditions for 5 h, 24 h and 5 days. To mimic occupational exposure, fuel-soaked fabric (high dose) was used. Erythema, edema, transepidermal water loss (TEWL) and epidermal thickness were quantified. High-dose fabric occluded sites had slight erythema at 5 h with increased erythema at 5 days. No erythema was noted in any of the occluded (Hill Top) or non-occluded sites at any of the time points. Morphological assessments depicted slight intracellular epidermal edema at all time points. An increase in change in TEWL (DeltaTEWL) was observed at the 5-h and 24-h fabric and Hill Top occluded treatments and a decrease at the 5-day fabric and Hill Top occluded sites. In all 5-day JP-8 + 100 fabric sites, intracorneal microabscesses filled with inflammatory cells were observed. Epidermal thickening was significant (P < 0.05) in all three jet fuels at the high-dose fabric sites, with JP-8 + 100 being the thickest. The epidermal rete peg depth increased significantly (P < 0.05) at 24 h and 5 days with Jet A, JP-8, and JP-8 + 100 in the fabric sites. No significant differences were noted in the 5-day non-occluded fabric and Hill Top occluded and non-occluded sites. Jet fuel JP-8 + 100 tended to have the greatest proliferative response. In conclusion, the high-dose fabric-soaked exposure at 5 days to Jet A, JP-8 and JP-8 + 100 fuels caused the greatest increase in cutaneous erythema, edema, epidermal thickness and rete peg depth compared with high-dose non-occluded or low-dose exposure under Hill Top occluded and non-occluded conditions.     

Dermal toxicity: effect of jet propellant-8 fuel exposure on the biophysical, macroscopic and microscopic properties of porcine skin

The effect of jet propellant-8 (JP-8) fuel exposure on the biophysical, macroscopic and microscopic changes in vitro in porcine skin has been investigated. Fourier transform infrared (FTIR) spectroscopy was employed to investigate the biophysical changes in stratum corneum (SC) lipid and protein. FTIR results showed that the treatment of the SC with JP-8 to increasing exposure time caused correspondingly greater percent decrease in the peak heights and areas under the absorbance curve of methylene and amide absorbances, suggesting greater loss of lipid and protein from SC layers. In vitro transepidermal water loss (TEWL) studies allowed an investigation into the macroscopic barrier properties of the skin. TEWL results were in consonance with that of FTIR. There was a significant increase (P<0.05) in TEWL through 8 and 24 h JP-8 exposed skin in comparison to the control. Light microscopy provided direct, corroborative, visual evidences of epidermal and dermal alterations. Epidermal swelling, dermal matrix granulation, mast cell granules, shortened collagen fibers were observed in the skin exposed with JP-8. Thus, it is concluded that JP-8 exposure causes appreciable biophysical and histological changes along with increased TEWL values in vitro in pig skin which may lead to skin irritation and dermal toxicity in vivo.     

In vivo percutaneous absorption,skin barrier perturbation,and irritation from JP-8 jet fuel components

JP-8 jet fuel has been reported to cause systemic and dermal toxicities in animal models and humans. There is a great potential for human exposure to JP-8. In this study, we determined percutaneous absorption and dermal toxicity of three components of JP-8 (i.e., xylene, heptane, and hexadecane) in vivo in weanling pigs. In vivo percutaneous absorption results suggest a greater absorption of hexadecane (0.43%) than xylene (0.17%) or heptane (0.14%) of the applied dose after 30 min exposure. Transepidermal water loss (TEWL) provides a robust method for assessing damage to the stratum corneum. Heptane showed greater increase in TEWL than the other two chemicals. No significant (p < 0.05) increase in temperature was observed at the chemically treated site than the control site. Heptane showed greater TEWL values and erythema score than other two chemicals (xylene and hexadecane). We did not observe any skin reactions or edema from these chemicals. Erythema was completely resolved after 24 h of the patch removal in case of xylene and hexadecane.     

Effect of in vivo jet fuel exposure on subsequent in vitro dermal absorption of individual aromatic and aliphatic hydrocarbon fuel constituents

The percutaneous absorption of topically applied jet fuel hydrocarbons (HC) through skin previously exposed to jet fuel has not been investigated, although this exposure scenario is the occupational norm. Pigs were exposed to JP-8 jet fuel-soaked cotton fabrics for 1 and 4 d with repeated daily exposures. Preexposed and unexposed skin was then dermatomed and placed in flow-through in vitro diffusion cells. Five cells with exposed skin and four cells with unexposed skin were dosed with a mixture of 14 different HC consisting of nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, ethyl benzene, o-xylene, trimethyl benzene (TMB), cyclohexyl benzene (CHB), naphthalene, and dimethyl naphthalene (DMN) in water + ethanol (50:50) as diluent. Another five cells containing only JP-8-exposed skin were dosed solely with diluent in order to determine the skin retention of jet fuel HC. The absorption parameters of flux, diffusivity, and permeability were calculated for the studied HC. The data indicated that there was a two-fold and four-fold increase in absorption of specific aromatic HC like ethyl benzene, o-xylene, and TMB through 1- and 4-dJP-8 preexposed skin, respectively. Similarly, dodecane and tridecane were absorbed more in 4-d than 1-dJP-8 preexposed skin experiments. The absorption of naphthalene and DMN was 1.5 times greater than the controls in both 1- and 4-d preexposures. CHB, naphthalene, and DMN had significant persistent skin retention in 4-d preexposures as compared to 1-d exposures that might leave skin capable of further absorption several days postexposure. The possible mechanism of an increase in HC absorption in fuel preexposed skin may be via lipid extraction from the stratum corneum as indicated by Fourier transform infrared (FTIR) spectroscopy. This study suggests that the preexposure of skin to jet fuel enhances the subsequent in vitro percutaneous absorption of HC, so single-dose absorption data for jet fuel HC from naive skin may not be optimal to predict the toxic potential for repeated exposures. For certain compounds, persistent absorption may occur days after the initial exposure.     

Assessment of skin absorption and penetration of JP-8 jet fuel and its components.

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.     

Assessment of skin irritation and molecular responses in rat skin exposed to nonane, dodecane and tetradecane

Aliphatic hydrocarbons constitute a major portion of jet fuels, kerosene and other solvents. This study investigated the effects of dermal exposures of selected aliphatic hydrocarbons (nonane, dodecane and tetradecane) on the skin irritation (erythema), transepidermal waterloss (TEWL) and expression of interleukin-1alpha (IL-1alpha), tumor necrosis factor (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1) in the skin and blood of hairless rats. Dermal exposures were carried out by occlusive application of chemicals (230 microl for 1 h, using Hill Top Chambers) for 1 h. The expression of IL-1alpha, TNF-alpha and MCP-1 was measured by enzyme immunoassay (EIA), and the regulatory proteins NFkappaB and IkappaBalpha were measured by Western blot analysis. The skin irritation and TEWL data indicate that the irritation was in the following decreasing order: nonane > dodecane > tetradecane. Likewise, nonane significantly increased the expression of IL-1alpha, TNF-alpha and MCP-1 in skin and blood as compared to control at different time points. Dodecane and tetradecane did not show any increase in the expression of IL-1alpha and MCP-1 as compared to control (P > 0.05), but the expression of TNF-alpha by dodecane and tetradecane was significantly higher than control at all time points. The release of cytokines by nonane exposure was further supported by activation of NFkappaB p65 and corresponding degradation of IkappaBalpha in the skin. In conclusion, this study demonstrates that the biophysical parameters (TEWL and erythema scores) were correlated to the biomarker expressions after dermal exposures with nonane but not with dodecane and tetradecane. Dodecane produced only mild irritation in response to experimental conditions of the present study and further did not show significant differences in IL-1alpha and MCP-1 levels in skin and blood. However, TNF-alpha was well expressed in response to all the chemicals. Tetradecane did not show any visible signs of skin irritation and also did not produce any significant difference in IL-1alpha and MCP-1 release profiles as compared with control. The expression of TNF-alpha in skin due to tetradecane support the fact that visually indistinguishable skin irritation reactions can induce significant changes in the biological marker profile.     

In vitro and in vivo comparison of dermal irritancy of jet fuel exposure using EpiDerm (EPI-200) cultured human skin and hairless rats

The purpose of this study was to evaluate an in vitro EpiDerm human skin model (EPI-200) to study the irritation potential of jet fuels (JP-8 and JP-8+100). Parallel in vivo studies on hairless rats on the dermal irritancy of jet fuels were also conducted. Cytokines are an important part of an irritation and inflammatory cascade, which are expressed in upon dermal exposures of irritant chemicals even when there are no obvious visible marks of irritation on the skin. We have chosen two primary cytokines (IL-1alpha and TNF-1alpha) as markers of irritation response of jet fuels. Initially, the EPI-200 was treated with different quantities of JP-8 and JP-8+100 to determine quantities which did not cause significant cytotoxicity, as monitored using the MTT assay and paraffin embedded histological cross-sections. Volumes of 2.5-50 microl/tissue (approximately 4.0-78 microl/cm2) of JP-8 and JP-8+100 showed a dose dependent loss of tissue viability and morphological alterations of the tissue. At a quantity of 1.25 microl/tissue (approximately 2.0 microl/cm2), no significant change in tissue viability or morphology was observed for exposure time extending to 48 h. Nonetheless, this dose induced significant increase in IL-1alpha and TNF-alpha release versus non-treated controls after 24 and 48 h. In addition, IL-1alpha release for JP-8+100 was significantly higher than that observed for JP-8, but TNF-alpha release after 48 h exposure to these two jet fuels was the same. These findings parallel in vivo studies on hairless rats, which indicated higher irritation levels due to JP-8+100 versus JP-8. In vivo, transepidermal water loss (TEWL) and IL-1alpha expression levels followed the order JP-8+100 > JP-8 > control. Further, in vivo TNF-alpha levels for JP-8 and JP-8+100 were also elevated but not significantly different from one another. In aggregate, these findings indicate that EPI-200 tissue model can be utilized as an alternative to the use of animals in evaluating dermal irritation.     

In vitro permeability and binding of hydrocarbons in pig ear and human abdominal skin

Human skin has continual exposure to chemicals due to various occupational activities. Chemicals that get on skin have the potential to be absorbed. Hence, the potential human health hazards of a chemical must include an estimate for percutaneous absorption. An inexpensive, easy, and adequate model for the quantitative measurement of skin penetration of chemicals from JP-8 is absent. Cutaneous penetration studies in vitro through human skin are severely limited due to the lack of availability of the human skin. In this study, we have shown that pig ear skin can be used as a model for risk assessment from the percutaneous absorption of chemicals. We determined flux and permeability coefficient (Kp) of three chemicals--heptane, hexadecane, and xylene--from their permeation profile through porcine and human skin. Binding of these chemicals to porcine stratum corneum (SC) and human SC were also determined. Factors of difference (FOD) in the permeability of pig and human skin were 1.71, 1.28, and 1.16, respectively, for heptane, hexadecane, and xylene. FOD in binding of heptane, hexadecane, and xylene to pig and human SC were found to be 1.04, 0.76, and 1.31, respectively. Since, FOD for permeability and binding parameters were less than 2, hence, we conclude that pig ear skin can be used as model for humans for risk assessment from percutaneous absorption of chemicals.     

Skin permeation enhancement effect and skin irritation of saturated fatty alcohols

Though the skin permeation enhancement effect of chemical penetration enhancers has been studied extensively, their skin irritation potential has not been adequately investigated. The objective of this study was to evaluate the skin permeation enhancement effect and skin irritation of saturated fatty alcohols using melatonin as a model compound. A saturated solution of melatonin in a mixture of water and ethanol (40:60) containing 5% w/v of saturated fatty alcohol was used in the skin permeation studies using Franz diffusion cells. For skin irritation studies, 230 microl of fatty alcohol solution was applied on the dorsal surface of the hairless rats using Hill top chamber. The skin irritation was evaluated by visual scoring method and bioengineering methods such as measurement of transepidermal water loss (TEWL) and skin blood flow. The flux of melatonin across hairless rat skin was found to be dependent on the carbon chain length of the fatty alcohols, with decanol showing the maximum permeation of melatonin. All fatty alcohols increased the TEWL and skin blood flow significantly compared with the vehicle. The fatty alcohols (decanol, undecanol and lauryl alcohol), which showed greater permeation of melatonin, also produced greater TEWL, skin blood flow and erythema. Tridecanol and myristyl alcohol showed lower permeation enhancement effect but caused greater skin irritation. Octanol and nonanol may be the most useful enhancers for the transdermal delivery of melatonin considering their lower skin irritation and a reasonably good permeation enhancement effect. However, further studies are needed to ascertain their safety as skin penetration enhancers. Skin permeation and skin irritation in experimental animals such as rats are generally higher compared with human skin. Further studies in human volunteers using fatty alcohols at the concentrations of 5% or lower may provide useful information on the utility of these fatty alcohols as permeation enhancers.     

Effect of methyl substitution of benzene on the percutaneous absorption and skin irritation in hairless rats

The permeation rate and skin retention of benzene and methylbenzenes were assessed in vitro using hairless rat skin. The effects of unocclusive dermal exposures of these chemicals (15 microl every 2h for 8h a day for 4 days) on the transepidermal water loss (TEWL), erythema and skin histopathology were measured in CD hairless rats. The expression of IL-1 alpha and TNF-alpha in the skin and blood were measured at the end of dermal exposures. The flux of benzene was about 1.5-, 2.5- and 80-fold higher than toluene, xylene and tetramethyl benzene isomers (TMB), respectively, and the values were inversely correlated with molecular weight (r(2)=0.7455) and logoctanol-water partition coefficient (r(2)=0.7831). The retention of chemicals in stratum corneum (SC) was in the order of TMB>xylene>toluene approximately benzene. The TEWL and erythema data demonstrated that the irritation was in the following order: TMB>xylene>benzene. The histo-pathological examination showed that xylene and TMB induced granulocyte infiltration, swelling of the epidermis, and extensive disruption and damage of stratum corneum. Likewise, the expression of IL-1 alpha in the blood and TNF-alpha in the skin after dermal exposures was higher for TMB followed by xylene and benzene compared to control. In conclusion, the aromatic hydrocarbon chemicals induced cumulative irritation upon low-level repeat exposures for a 4-day period and the irritation increased with the number of methyl groups of benzene. The affinity of the chemical to SC and their gradual accumulation in the skin in the present study is the reason for the differences in the skin irritation profiles of different aromatic chemicals. Our ultimate goal is to develop a biologically based model that connects skin retention of chemical to the skin irritation response. The findings of the present study will be helpful in understanding the role of these chemicals in the jet fuel and various petroleum based fuels in inducing skin irritation response.     

Dermal absorption and penetration of jet fuel components in humans

Jet propulsion fuel 8 (JP-8) is the largest source of chemical exposures on military bases. Dermal exposure to JP-8 has been investigated in vitro using rat or pig skin, but not in vivo in humans. The purpose of this study was to investigate the absorption and penetration of aromatic and aliphatic components of JP-8 in humans. A surface area of 20 cm2 was delineated on the forearms of human volunteers and 1 ml of JP-8 was applied to the skin. Tape-strip samples were collected 30 min after application. Blood samples were taken before exposure (t=0 h), after exposure (t=0.5 h), and every 0.5 h for up to 4 h past exposure. The tape-strip samples showed evidence of uptake into the skin for all JP-8 components. The blood data was used to estimate an apparent permeability coefficient (Kp). The rank order of the apparent Kp was naphthalene>1-methyl naphthalene=2-methyl naphthalene>decane>dodecane>undecane. This rank order is similar to results from rat and pig-skin studies. However, this study demonstrates that rat and pig models of the skin over predict the internal dose of JP-8 components in humans.     

Dermal absorption and distribution of topically dosed jet fuels jet-A, JP-8, and JP-8(100).

Dermal exposure to jet fuels has received increased attention with the recent release of newer fuels with novel performance additives. The purpose of these studies was to assess the percutaneous absorption and cutaneous disposition of topically applied (25 microl/5 cm(2)) neat Jet-A, JP-8, and JP-8(100) jet fuels by monitoring the absorptive flux of the marker components 14C naphthalene and (3)H dodecane simultaneously applied nonoccluded to isolated perfused porcine skin flaps (IPPSF) (n = 4). Absorption of 14C hexadecane was estimated from JP-8 fuel. Absorption and disposition of naphthalene and dodecane were also monitored using a nonvolatile JP-8 fraction reflecting exposure to residual fuel that might occur 24 h after a jet fuel spill. In all studies, perfusate, stratum corneum, and skin concentrations were measured over 5 h. Naphthalene absorption had a clear peak absorptive flux at less than 1 h, while dodecane and hexadecane had prolonged, albeit significantly lower, absorption flux profiles. Within JP-8, the rank order of absorption for all marker components was (mean +/- SEM % dose) naphthalene (1.17 +/- 0.07) > dodecane (0.63 +/- 0.04) > hexadecane (0.18 +/- 0.08). In contrast, deposition within dosed skin showed the reverse pattern. Naphthalene absorption into perfusate was similar across all fuel types, however total penetration into and through skin was highest with JP-8(100). Dodecane absorption and total penetration was greatest from JP-8. Absorption of both markers from aged JP-8 was lower than other fuels, yet the ratio of skin deposition to absorption was greatest for this treatment group. In most exposure scenarios, absorption into perfusate did not directly correlate to residual skin concentrations. These studies demonstrated different absorption profiles for the three marker compounds, differential effects of jet fuel types on naphthalene and dodecane absorption, and uncoupling of perfusate absorption from skin disposition.     

血余炭纳米纤维膜皮肤刺激性和过敏性实验研究

目的:观察血余炭纳米纤维膜外用对皮肤的刺激性和过敏性反应,为评价其安全性提供参考。方法:采用家兔皮肤刺激实验,分完整皮肤组和损伤皮肤组,分别在给药1 d、连续给药7 d后,观察皮肤有无红斑、水肿等刺激反应;采用豚鼠皮肤过敏实验,每周贴敷血余炭纳米纤维膜致敏1次,连续3周,于首次致敏后的第28天皮肤再次给药进行攻击,观察皮肤有无红斑、水肿等过敏反应。结果:血余炭纳米纤维膜对家兔的完整皮肤和破损皮肤,经单次给药或多次给药24 h后去除敷料,分别于1、24、48、72 h观察,均未见红斑及水肿,刺激反应平均分值均<0.5,无刺激性;豚鼠皮肤过敏实验中,未出现皮肤明显红斑、水肿等皮肤过敏反应及其他全身性过敏反应。结论:血余炭纳米纤维膜对家兔完整皮肤和损伤皮肤不会引起刺激性反应,对豚鼠皮肤无过敏性反应,具有良好的皮肤用药安全性。     

复方九节茶乳膏的抗炎镇痛及皮肤安全性的初步研究

目的初步评价复方九节茶乳膏的抗炎、镇痛作用及其使用安全性。方法采用醋酸扭体法和小鼠耳廓肿胀模型观察镇痛、抗炎作用,并进行家兔皮肤刺激实验和豚鼠皮肤过敏实验。结果复方九节茶乳膏能显著性减少冰醋酸引起的小鼠扭体次数;抑制由二甲苯所致小鼠耳廓肿胀。复方九节茶乳膏对家兔完整皮肤无刺激性,单次给药破损皮肤组1只家兔出现轻度水肿,24h后恢复正常;豚鼠实验未出现变态反应。结论复方九节茶乳膏具有明显的镇痛、抗炎作用;复方九节茶乳膏对家兔皮肤无明显刺激性作用,对豚鼠皮肤无明显致变态反应作用。     

An in vivo investigation of the rabbit skin responses to transdermal iontophoresis

To optimize the benefits of transdermal iontophoresis, it is necessary to develop a suitable animal model that would allow for extensive assessments of the biological effects associated with electro-transport. Rabbit skin responses to iontophoresis treatments were evaluated by visual scoring and by non-invasive bioengineering parameters and compared with available human data. In the current density range 0.1–1.0 mA/cm² applied for 1 h using 0.9% w/v NaCl and 0.5 mA/cm² for up to 4 h, no significant irritation was observed. 2 mA/cm² applied through an area of 1 cm² for 1 h resulted in slight erythema at both active electrode sites but without significant changes in transepidermal water loss (TEWL) and laser Doppler velocimetry (LDV). A value of 4 mA/cm² under similar conditions caused moderate erythema at the anode and cathode with TEWL and LDV being significantly elevated at both sites; 1 mA/cm² current applied for 4 h, caused moderate erythema at both anode and cathode; and 1 mA/cm² applied for 1 h caused no irritation when the area of exposure was increased from 1 to 4.5 cm². When significant irritation and barrier impairment occurred, the erythema was resolved within 24 h with barrier recovery complete 3–5 days post-treatment. Rabbit skin thus shows promise as an acceptable model for iontophoresis experiments.