Percutaneous absorption and skin irritation of JP-8 (jet fuel)

JP-8 is the major jet fuel used by US Army and Air Force. The purpose of the present study was to investigate the percutaneous absorption of JP-8 across pig ear skin and human skin in vitro and to study the effect of JP-8 exposure on the skin barrier function and irritation in Yucatan minipigs. JP-8 spiked with 5.0 microCi of radiolabeled (14C) tridecane, nonane, naphthalene or toluene (selected components of JP-8) was used for the in vitro percutaneous absorption studies with excised pig ear skin and human skin. For in vivo studies, 250 microl of JP-8 or two of its components (toluene or nonane) was placed in a Hill top chamber(R) and affixed over the marked treatment area for 24 h. Transepidermal water loss (TEWL), skin capacitance (moisture content) and skin irritation (erythema and edema) were evaluated before treatment and at 1,2 and 24 h after removal of the patches. The components of JP-8 such as tridecane, nonane, naphthalene and toluene permeated significantly through pig ear skin and human skin and the permeation rates were found to be proportional to their composition in JP-8. The steady state flux values of tridecane across pig ear skin and human skin did not differ significantly (P>0.05). Though the steady state flux values of nonane, naphthalene and toluene were statistically different between porcine and human skin (P<0.01), the values were close considering the large variations usually observed in the percutaneous absorption studies. Application of toluene, nonane or JP-8 increased the TEWL, JP-8 being the highest (3.5 times at 24 h compared to baseline level). The skin moisture content decreased after the application of JP-8, though it was not significantly different (P>0.05) from the baseline level. JP-8 caused a moderate erythema and a moderate to severe edema. Though the edema decreased after 24 h, the degree of erythema remained about the same until 24 h. The skin irritation caused by JP-8 was greater than neat toluene or nonane. The TEWL data of toluene, nonane and JP-8 correlated well with the skin irritation data (erythema and edema). Exposure of JP-8, which contains hundreds of aliphatic and aromatic hydrocarbons, caused significant changes in the barrier function of the skin as indicated by an increase in TEWL and produced a significant erythema and edema in minipigs. Furthermore, the disruption of barrier function of skin, as indicated by increased TEWL after exposure to JP-8 might result in increased permeation of its own components and/or other chemicals exposed to skin. The present study provides further evidence that pig ear skin may be used as a model for predicting the rates of permeation of chemicals through human skin.     

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: 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.     

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.     

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.     

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.     

Effect of saline iontophoresis on skin barrier function and cutaneous irritation in four ethnic groups.

The effect of saline iontophoresis on skin barrier function and irritation was investigated in four ethnic groups (Caucasians, Hispanics, Blacks and Asians). Forty healthy human volunteers were recruited according to specific entry criteria. Ten subjects, five males and five females, were assigned to each ethnic group. Skin barrier function was examined after 4 hours of saline iontophoresis at a current density of 0.2 mA/cm(2) on a 6.5 cm(2) area in terms of the measured responses: transepidermal water loss (TEWL), skin capacitance, skin temperature and visual scores. There were significant differences in TEWL among the ethnic groups prior to patch application. TEWL at baseline in ethnic groups was in the rank order: Caucasian>Asian>Hispanic>Black. Iontophoresis was generally well tolerated, and skin barrier function was not irreversibly affected by iontophoresis in any group. There was no significant skin temperature change, compared to baseline, in any ethnic groups at any observation point. Edema was not observed. At patch removal, the erythema score was elevated in comparison to baseline in all ethnic groups; erythema resolved within 24 hours. Thus, saline iontophoresis produced reversible changes in skin barrier function and irritation in healthy human subjects.     

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 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.     

Regional variations in skin barrier function and cutaneous irritation due to iontophoresis in human subjects.

The effect of saline iontophoresis on skin barrier function and irritation was investigated on three body sites (abdomen, chest and upper arm) in order to select an appropriate site for iontophoretic delivery of drugs. Thirty healthy human volunteers were recruited according to specific entry criteria. Ten subjects, five males and five females, were assigned to each body site group. Skin barrier function and irritation was examined after 4 h of saline iontophoresis at a current density of 0.2 mA/cm(2) on a 6.5 cm(2) area in terms of the measured responses: transepidermal water loss (TEWL), skin capacitance, skin temperature and visual scores. Alterations in TEWL due to iontophoresis were not observed in the upper arm and chest; however, changes in TEWL at the abdomen were observed and returned to baseline 2 h after patch removal. Similarly, changes in capacitance due to iontophoresis returned to baseline (P>0.05) at the three body sites 2 h after patch removal except under the anode at the abdomen (P<0.05). There was a significant increase in skin temperature due to iontophoresis at the anode and the cathode (P<0.05) at the upper arm. Edema was not observed. At patch removal, the erythema score was significantly (P<0.001) elevated in comparison to baseline at the three body sites. Erythema resolved within 24 h except at the chest under the anode, where the erythema score was still higher (P<0.01) than the baseline. Papules appeared in five subjects at the active anode site on the chest. In three of the subjects, these papules did not resolve until 24 h post patch removal. Thus, there was regional variation in the function of the skin and irritation due to iontophoresis. Irritation was greater at the chest than at the abdomen or upper arm.     

The effect of damaged skin barrier induced by subclinical irritation on the sequential irritant contact dermatitis

Skin damage caused by a single specific stimulus has been extensively studied. However, many additional mild skin irritants are experienced every day before obvious irritant contact dermatitis (ICD) appears. The effect that these previously experienced mild irritations have on the incidence and severity of sequential ICD remains undefined. The purpose of this work was to explore whether the effects of skin barrier damage induced by either the open patch test with 1% sodium lauryl sulfate (SLS), tape stripping test (TAP) (10×), or irradiation with 0.75 median erythemal dose UVB (MED) will affect the severity of sequential irritant dermatitis induced by a 0.5% SLS occlusive patch test (PT). Nine treatments were applied to nine different locations of the ventral forearm of each subject at random. The nine treatment types were as follows: open patch test with 1% SLS; 10× TAP; UVB irradiation with 0.75 MED; open patch test with 1% SLS + PT with 0.5% SLS (SLSPT); 10× TAP + PT with 0.5% SLS (TAPPT); UVB irradiation with 0.75 MED + PT with 0.5% SLS (UVPT); PT with distilled water (DISPT); PT with 0.5% SLS (PT); and the CONTROL (no treatment). After 5 days of subclinical irritation, the PT was applied on day 6. Transepidermal water loss (TEWL), capacitance (CAP), and skin color (a*) were measured at baseline and on days 6, 7, and 8. After the PT, indices of irritancy of PT, UVPT, SLSPT, and TAPPT were 60, 80, 87 and 100%, respectively. The index of irritancy of TAPPT and SLSPT were significantly higher than that of PT (p < 0.05). Clinical scores of SLSPT and TAPPT were also significantly higher than PT (p < 0.05). After 5 days of irritation, TEWL of SLS, TAP, SLSPT, and TAPPT were increased significantly compared to that of baseline. After the PT, D-value of TEWL between day 8 and day 6 ((≥6-8)TEWL) of SLSPT and TAPPT were greater than that of PT, and D-value of TEWL between day 8 and day 7 ((≥7-8)TEWL) of SLSPT and TAPPT were less than that of PT values. After the PT, a* values of SLSPT, TAPPT and PT all increased. The D-value of a* between day 8 and day 6 ((≥6-8)a*) of SLSPT and TAPPT were significantly greater than that of PT. After the PT, D-value of CAP between day 8 and day 6 ((≥6-8)CAP) of SLSPT was significantly different as compared to PT. The open patch test with 1% SLS and 10× TAP destroys the skin barrier and is able to significantly increase the irritancy and severity of sequential ICD by 0.5% SLS PT, and therefore influences the recovery speed of inflammation. The open patch test with 1% SLS, 10× TAP, and UVB irradiation with 0.75 MED affects the skin barrier to different degrees. TEWL is a sensitive biophysical parameter that can reflect mild damage to the skin barrier induced by subclinical irritation.     

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.     

Mixture effects of JP-8 additives on the dermal disposition of jet fuel components

Aliphatic and aromatic components in formulated jet fuels can cause occupational dermatitis. However, the influence of JP-8 performance additives (DIEGME, 8Q21, and Stadis450) on the dermal disposition of fuel components is not well understood. These additives are formulated with commercial Jet-A to form military JP-8 fuel. The purpose of this study is to assess the influence of these additives on the dermal disposition of marker aromatic and aliphatic components, naphthalene and dodecane, respectively. Porcine skin sections in an in vitro system were used to characterize chemical-biological interactions that modulate diffusion of jet fuel components and isolated perfused porcine skin flaps (IPPSFs) were used to evaluate diffusion in a viable skin model with an intact microvasculature. In these 5-h studies, Jet-A, Jet-A + DIEGME, Jet-A + 8Q21, and Jet-A + Stadis450, Jet-A + DIEGME + 8Q21, Jet-A + DIEGME + Stadis450, Jet-A + 8Q21 + Stadis450, and JP-8 mixtures were tested. In general, naphthalene absorption (0.76-2.39% dose) was greater than dodecane absorption (0.10-0.84% dose), while the IPPSFs alone demonstrated that dodecane absorption was significantly greater in JP-8 than in Jet-A. Synergistic interactions with 8Q21 + Stadis450 appear to enhance systemic absorption of either naphthalene or dodecane, while DIEGME + Stadis450 increased naphthalene (1.88% dose) and dodecane (2.02% dose) penetration into the skin and fat tissues of IPPSFs. These findings were supported by the fact that 8Q21 + Stadis450 significantly increased dodecane flux and permeability in porcine skin sections, but 8Q21 alone reduced marker diffusion in both membrane systems. Furthermore, dodecane is more likely than naphthalene to remain in the stratum corneum and skin surface at 5 h, and DIEGME mixtures played a significant role in skin and surface retention of both markers. In summary, the data suggest that various combinations of these three performance additives in JP-8 can potentially alter the dermal disposition of aromatic and aliphatic fuel components in skin. More importantly, products of two-factor interactions were not predictable from single-factor exposures and, by extension, cannot be extrapolated to three-factor interactions.     

Skin toxicity of jet fuels: ultrastructural studies and the effects of substance P

Topical exposure to jet fuel is a significant occupational hazard. Recent studies have focused on dermal absorption of fuel and its components, or alternatively, on the biochemical or immunotoxicological sequelae to exposure. Surprisingly, morphological and ultrastructural analyses have not been systematically conducted. Similarly, few studies have compared responses in skin to that of the primary target organ, the lung. The focus of the present investigation was 2-fold: first, to characterize the ultrastructural changes seen after topical exposure to moderate doses (335 or 67 microl/cm2) of jet fuels [Jet A, Jet Propellant (JP)-8, JP-8+100] for up to 4 days in pigs, and secondly, to determine if co-administration of substance P (SP) with JP-8 jet fuel in human epidermal keratinocyte cell cultures modulates toxicity as it does to pulmonary toxicity in laboratory animal studies. The primary change seen after exposure to all fuels was low-level inflammation accompanied by formation of lipid droplets in various skin layers, mitochondrial and nucleolar changes, cleft formation in the intercellular lipid lamellar bilayers, as well as disorganization in the stratum granulosum-stratum corneum interface. An increased number of Langerhans cells were also noted in jet fuel-treated skin. These changes suggest that the primary effect of jet fuel exposure is damage to the stratum corneum barrier. SP administration decreased the release of interleukin (IL)-8 normally seen in keratinocytes after JP-8 exposure, a response similar to that reported for SP's effect on JP-8 pulmonary toxicity. These studies provide a base upon which biochemical and immunological data collected in other model systems can be compared.     

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.     

Past, present and emerging toxicity issues for jet fuel

The US Air Force wrote the specification for the first official hydrocarbon-based jet fuel, JP-4, in 1951. This paper will briefly review the toxicity of the current fuel, JP-8, as compared to JP-4. JP-8 has been found to have low acute toxicity with the adverse effects being slight dermal irritation and weak dermal sensitization in animals. JP-4 also has low acute toxicity with slight dermal irritation as the adverse effect. Respiratory tract sensory irritation was greater in JP-8 than in JP-4. Recent data suggest exposure to jet fuel may contribute to hearing loss. Subchronic studies for 90 days with JP-8 and JP-4 showed little toxicity with the primary effect being male rat specific hydrocarbon nephropathy. A 1-year study was conducted for JP-4. The only tumors seen were associated with the male rat specific hydrocarbon nephropathy. A number of immunosuppressive effects have been seen after exposure to JP-8. Limited neurobehavioral effects have been associated with JP-8. JP-8 is not a developmental toxicant and has little reproductive toxicity. JP-4 has not been tested for immune, neurobehavioral or reproductive endpoints. JP-8 and JP-4 were negative in mutagenicity tests but JP-4 showed an increase in unscheduled DNA synthesis. Currently, JP-8 is being used as the standard for comparison of future fuels, including alternative fuels. Emerging issues of concern with jet fuels include naphthalene content, immunotoxicity and inhalation exposure characterization and modeling of complex mixtures such as jet fuels.     

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.