Toxicity and occupational exposure assessment for Fischer-Tropsch synthetic paraffinic kerosene

Fischer-Tropsch (FT) Synthetic Paraffinic Kerosene (SPK) jet fuel is a synthetic organic mixture intended to augment petroleum-derived JP-8 jet fuel use by the U.S. armed forces. The FT SPK testing program goal was to develop a comparative toxicity database with petroleum-derived jet fuels that may be used to calculate an occupational exposure limit (OEL). Toxicity investigations included the dermal irritation test (FT vs. JP-8 vs. 50:50 blend), 2 in vitro genotoxicity tests, acute inhalation study, short-term (2-week) inhalation range finder study with measurement of bone marrow micronuclei, 90-day inhalation toxicity, and sensory irritation assay. Dermal irritation was slight to moderate. All genotoxicity studies were negative. An acute inhalation study with F344 rats exposed at 2000 mg/m³ for 4 hr resulted in no abnormal clinical observations. Based on a 2-week range-finder, F344 rats were exposed for 6 hr per day, 5 days per week, for 90 days to an aerosol-vapor mixture of FT SPK jet fuel (0, 200, 700 or 2000 mg/m³). Effects on the nasal cavities were minimal (700 mg/m³) to mild (2000 mg/m³); only high exposure produced multifocal inflammatory cell infiltration in rat lungs (both genders). The RD₅₀ (50% respiratory rate depression) value for the sensory irritation assay, calculated to be 10,939 mg/m^3, indicated the FT SPK fuel is less irritating than JP-8. Based upon the proposed use as a 50:50 blend with JP-8, a FT SPK jet fuel OEL is recommended at 200 mg/m³ vapor and 5 mg/m³ aerosol, in concurrence with the current JP-8 OEL.     

Comparative electrophysiological evaluation of hippocampal function following repeated inhalation exposures to JP-8, Jet A,JP-5, and the synthetic Fischer Tropsch fuel

Exposure to fuels continues to be a concern in both military and general populations. The aim of this study was to examine effects of in vivo rat repeated exposures to different types of jet fuel utilizing microelectrode arrays for comparative electrophysiological (EP) measurements in hippocampal slices. Animals were exposed to increasing concentrations of four jet fuels, Jet Propellant (JP)-8, Jet A, JP-5, or synthetic Fischer Tropsch (FT) fuel via whole-body inhalation for 20 d (6 hr/d, 5 d/week for 28 d) and synaptic transmission as well as behavioral performance were assessed. Our behavioral studies indicated no significant changes in behavioral performance in animals exposed to JP-8, Jet A, or JP-5. A significant deviation in learning pattern during the Morris water maze task was observed in rats exposed to the highest concentration of FT (2000 mg/m³). There were also significant differences in the EP profile of hippocampal neurons from animals exposed to JP-8, Jet A, JP-5, or FT compared to control air. However, these differences were not consistent across fuels or dose dependent. As expected, patterns of EP alterations in brain slices from JP-8 and Jet A exposures were more similar compared to those from JP-5 and FT. Further longitudinal investigations are needed to determine if these EP effects are transient or persistent. Such studies may dictate if and how one may use EP measurements to indicate potential susceptibility to neurological impairments, particularly those that result from inhalation exposure to chemicals or mixtures.     

Systemic molecular and cellular changes induced in rats upon inhalation of JP-8 petroleum fuel vapor

Limited information is available regarding systemic changes in mammals associated with exposures to petroleum/hydrocarbon fuels. In this study, systemic toxicity of JP-8 jet fuel was observed in a rat inhalation model at different JP-8 fuel vapor concentrations (250, 500, or 1000?mg/m³, for 91 days). Gel electrophoresis and mass spectrometry sequencing identified the α-2 microglobulin protein to be elevated in rat kidney in a JP-8 dose-dependent manner. Western blot analysis of kidney and lung tissue extracts revealed JP-8 dependent elevation of inducible heat shock protein 70 (HSP70). Tissue changes were observed histologically (hematoxylin and eosin staining) in liver, kidney, lung, bone marrow, and heart, and more prevalently at medium or high JP-8 vapor phase exposures (500–1000?mg/m³) than at low vapor phase exposure (250?mg/m³) or non-JP-8 controls. JP-8 fuel-induced liver alterations included dilated sinusoids, cytoplasmic clumping, and fat cell deposition. Changes to the kidneys included reduced numbers of nuclei, and cytoplasmic dumping in the lumen of proximal convoluted tubules. JP-8 dependent lung alterations were edema and dilated alveolar capillaries, which allowed clumping of red blood cells (RBCs). Changes in the bone marrow in response to JP-8 included reduction of fat cells and fat globules, and cellular proliferation (RBCs, white blood cells-WBCs, and megakaryocytes). Heart tissue from JP-8 exposed animals contained increased numbers of inflammatory and fibroblast cells, as well as myofibril scarring. cDNA array analysis of heart tissue revealed a JP-8 dependent increase in atrial natriuretic peptide precursor mRNA and a decrease in voltage-gated potassium (K+) ion channel mRNA.     

Effects of repeated exposure of rats to JP-5 or JP-8 jet fuel vapor on neurobehavioral capacity and neurotransmitter levels

The U.S. Naval Service is anticipating transition from the nearly exclusive use of JP-5 jet fuel to predominant use of JP-8, consistent with the primary utilization by the U.S. Army, U.S. Air Force, and the militaries of most NATO countries. To compare the relative risk of repeated exposure to JP-5 versus JP-8 vapor, groups of 32 male Sprague-Dawley rats each were exposed for 6 h/d, 5 d/wk for 6 wk (180 h) to JP-8 jet fuel vapor (1,000 +/- 10% mg/m3), IP-5 vapor (1,200 +/- 10% mg/m3), or room air control conditions. Following a 65-d rest period, rats completed 10 tests selected from the Neurobehavioral Toxicity Assessment Battery (NTAB) to evaluate changes in performance capacity. Repeated exposure to JP-5 resulted in significant effects on only one test, forelimb grip strength (FGS), while exposure to JP-8 vapor resulted in a significant difference versus controls on appetitive reinforcer approach sensitization (ARAS). Rats were further evaluated for concentrations of major neurotransmitters and metabolites in five brain regions and in the blood serum. Levels of dopamine, the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), and the serotonin metabolite homovanillic acid (HVA) were significantly modulated in various brain regions, as measured 85+ d postexposure. Similarly, serum levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were differentially modulated following JP-8 or JP-5 exposure. Results are compared to previously published research evaluating the neurotoxicity of repeated exposure to other hydrocarbon fuels and solvents.     

Nasal Toxicity of Manganese Sulfate and Manganese Phosphate in Young Male Rats Following Subchronic (13-Week) Inhalation Exposure

Growing evidence suggests that nasal deposition and transport along the olfactory nerve represents a route by which inhaled manganese and certain other metals are delivered to the rodent brain. The toxicological significance of olfactory transport of manganese remains poorly defined. In rats, repeated intranasal instillation of manganese chloride results in injury to the olfactory epithelium and neurotoxicity as evidenced by increased glial fibrillary acidic protein (GFAP) concentrations in olfactory bulb astrocytes. The purpose of the present study was to further characterize the nasal toxicity of manganese sulfate (MnSO₄) and manganese phosphate (as hureaulite) in young adult male rats following subchronic (90-day) exposure to air, MnSO₄ (0.01, 0.1, and 0.5 mg Mn/m³), or hureaulite (0.1 mg Mn/m³). Nasal pathology, brain GFAP levels, and brain manganese concentrations were assessed immediately following the end of the 90-day exposure and 45 days thereafter. Elevated end-of-exposure olfactory bulb, striatum, and cerebellum manganese concentrations were observed following MnSO₄ exposure to ≥0.01, ≥0.1, and 0.5 mg Mn/m³, respectively. Exposure to MnSO₄ or hureaulite did not affect olfactory bulb, cerebellar, or striatal GFAP concentrations. Exposure to MnSO₄ (0.5 mg Mn/m³) was also associated with reversible inflammation within the nasal respiratory epithelium, while the olfactory epithelium was unaffected by manganese inhalation. These results confirm that high-dose manganese inhalation can result in nasal toxicity (irritation) and increased delivery of manganese to the brain; however, we could not confirm that manganese inhalation would result in altered brain GFAP concentrations.     

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.     

In vivo comparison of epithelial responses for S-8 versus JP-8 jet fuels below permissible exposure limit

This study was designed to characterize and compare the pulmonary effects in distal lung from a low-level exposure to jet propellant-8 fuel (JP-8) and a new synthetic-8 fuel (S-8). It is hypothesized that both fuels have different airway epithelial deposition and responses. Consequently, male C57BL/6 mice were nose-only exposed to S-8 and JP-8 at average concentrations of 53mg/m(3) for 1h/day for 7 days. A pulmonary function test performed 24h after the final exposure indicated that there was a significant increase in expiratory lung resistance in the S-8 mice, whereas JP-8 mice had significant increases in both inspiratory and expiratory lung resistance compared to control values. Neither significant S-8 nor JP-8 respiratory permeability changes were observed compared to controls, suggesting no loss of epithelial barrier integrity. Morphological examination and morphometric analysis of airway tissue demonstrated that both fuels showed different patterns of targeted epithelial cells: bronchioles in S-8 and alveoli/terminal bronchioles in JP-8. Collectively, our data suggest that both fuels may have partially different deposition patterns, which may possibly contribute to specific different adverse effects in lung ventilatory function.     

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.     

Inhalation toxicity study of disk-shaped potassium octatitanate particles (Terracess TF) in rats following 90 days of aerosol exposure

Since fibrous particles such as asbestos and some man-made fibers (MMF) have been known to produce carcinogenic or fibrogenic effects, disk-shaped potassium octatitanate (POT) particles (trade name: Terracess TF) were manufactured as nonfibrous particles. A 90-day inhalation toxicity study of Terracess TF was performed to evaluate comparative inhalation toxicity of the disk shape with a fibrous shape that was previously evaluated. Four groups of 20 male and 15 female rats each were exposed to Terracess TF aerosols at concentrations of 0, 2, 10, or 50?mg/m³ for 90 days. Ten male and 10 female rats per group were sacrificed at 90 days of exposure. After 90 days of exposure, 5 male rats per group were sacrificed at 3 wk of recovery period and 4–5 male rats per group or 5 female rats per group were sacrificed at 15?wk of recovery for lung clearance and histopathology. The mass median aerodynamic equivalent diameter (MMAED) of the aerosols of test materials ranged from 2.5 to 2.9?μm. There were no test-substance-related adverse effects on clinical observations. At the end of the 90-day exposure, a slight increase in lung-to-body weight ratios was observed at 50?mg/m³ in male but not in female rats. However, lung weights were within normal limits after 3- or 15-wk recovery periods. Microscopically, inhaled Terracess TF particles were mostly phagocytized by free alveolar macrophages (AMs) in the alveolar airspaces and alveolar walls maintained normal structure at 2 and 10?mg/m³. At 50?mg/m³, some alveoli were distended and filled with aggregates of particle-laden AMs. The alveolar walls showed slight type II pneumocyte hyperplasia, but neither proliferative inflammation nor alveolar fibrosis was present at 50?mg/m³. The clearance half-times for Terracess TF were estimated to be in the order of 6 to 9?mo for the 50-mg/m³ group and 2 to 3?mo for the 10- and 2-mg/m³ groups. The lung responses and lung clearance rate were comparable to those of “nuisance” type dusts at these concentrations. Based on interpretation that aggregated particle-laden AMs in alveoli was considered to be an early histopathological sign of lung overloading, an effect level was considered to be 50?mg/m³ and no-observed-adverse-effect level (NOAEL) was 10?mg/m³. This experiment clearly demonstrated that particle morphology was considered to be an important factor to determine inhaled particle toxicity.     

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.     

The Toxicologic and Oncogenic Potential of JP-4 Jet Fuel Vapors in Rats and Mice: 12-Month Intermittent Inhalation Exposures

Three-hundred Fischer 344 rats and 300 C57BL/6 mice of eachsex were divided into three treatment groups and exposed intermittently(6 hr/day, 5 days/week) to JP-4 jet fuel vapors at concentrationsof 0, 1000, and 5000 mg/m³ for 12 months. At exposure termination,10% of the animals were killed and those remaining were heldfor a 12-month postexposure tumorigenesis observation period.Pathologic findings in male rats revealed treatment-relatedrenal toxicity and neoplasia consistent with the male rat unique_2µ-globulin nephropathy syndrome. Distinct JP-4-inducedrespiratory toxicity was not observed, and pulmonary neoplasmswere not significantly increased in any treatment group. Benignhepatocellular adenomas were slightly increased in high-dosefemale mice, but the trend was reversed in male mice. Otherpathologic findings were regarded as equivocal or compatiblewith expected biologic variation. The study did not demonstratetarget organ toxicity or carcinogenesis which could be extrapolatedto other species.     

A 90-Day Inhalation Toxicity Study with Benomyl in Rats

A 90-Day Inhalation Toxiaty Study with Benomyl in Rats. WARHEIT,D. B., KELLY, D. P., CARAKOSTAS, M. C., AND SINGER, A. W. (1989).Fundam Appl Toxicol./ 12, 333-345. Benomyl [methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate,CAS Registry No. 17804-35-2] is a fungicide and the possibilityfor inhalation exposure exists for field workers. To assessthe toxicity of benomyl, groups of 20 male and 20 female CDrats were exposed nose-only 6 hr a day, 5 days a week, to concentrationsof 0, 10, 50 or 200 mg/m³ of a benomyl atmosphere. At the midpoint(approximately 45 days on test) and at the end of the exposureperiod, blood and urine samples for clinical evaluation werecollected from 10 rats/group/sex, and these animals were sacrificedfor pathological examination. Similar evaluations were performadon all remaining rats at the end of the 90-day test period.After approximately 45 days on test, compoundrelated degenerationof the olfactory epithelium was observed in all males and in8 of 10 female rats exposed to 200 mg/m³ benomyl. Two male ratsexposed to 50 mg/m³ had similar, although less severe, areasof olfactory epithelial degeneration. After approximately 90days of exposure, the remaining 10 rats/group/sex were sacrificedand examined. Of these rats, all of the males and females exposedto 200 mg/m³ had olfactory degeneration, along with 3 malesexposed to 50 mg/m³ of benomyl. No other observed lesions wereinterpreted to have been caused by the benomyl exposure. Inaddition, male rats exposed to 200 mg/m³ benomyl had depressedmean body weights compared to controls and this finding correlatedwith a reduction in food consumption. Based on pathologicalobservations, 10 mg/m³ represents the no-observable-effect level(NOEL) for the male rats, and 50 mg/m³ is the NOEL for the femalerats.     

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.     

Evaluation of skin sensitization potential of jet fuels by murine local lymph node assay

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 the US Air Force. Besides lung exposure, skin is the potential route of exposure to jet fuels. The purpose of the present study was to investigate the skin sensitization potential of jet fuels (Jet A, JP-8 and JP-8+100) using murine Local lymph node assay (LLNA). Female CBA/Ca mice (8-12-weeks-old) were used in the study. Dinitrochlorobenzene (DNCB, 0.25% w/v) and paraaminobenzoic acid (PABA, 2.5% w/v) were used as positive and negative control, respectively and acetone: olive oil (4:1, AOO) was used as the vehicle (control). All three jet fuels caused a proliferative activity significantly greater than the control (P<0.01). Our results demonstrate that JP-8 is a weak skin sensitizer [stimulation index (SI)=3.17]. The SI of Jet A and JP-8+100 were 2.44 and 2.38, respectively, hence are not considered as skin sensitizers. Interestingly, the SI of JP-8 with butylated hydroxytoluene (BHT) was consistently lower than JP-8, though the difference was not statistically significant (P>0.05). BHT, which is an antioxidant additive of JP-8+100, reduced the skin sensitization potential of JP-8. Furthermore, the lower SI of JP-8+100 could be partially attributed to the presence of BHT. The findings reported here suggest that care should be taken to minimize dermal exposure to jet fuels especially JP-8 to avoid skin sensitization.     

Biological and health effects of exposure to kerosene-based jet fuels and performance additives

Over 2 million military and civilian personnel per year (over 1 million in the United States) are occupationally exposed, respectively, to jet propulsion fuel-8 (JP-8), JP-8 +100 or JP-5, or to the civil aviation equivalents Jet A or Jet A-1. Approximately 60 billion gallon of these kerosene-based jet fuels are annually consumed worldwide (26 billion gallon in the United States), including over 5 billion gallon of JP-8 by the militaries of the United States and other NATO countries. JP-8, for example, represents the largest single chemical exposure in the U.S. military (2.53 billion gallon in 2000), while Jet A and A-1 are among the most common sources of nonmilitary occupational chemical exposure. Although more recent figures were not available, approximately 4.06 billion gallon of kerosene per se were consumed in the United States in 1990 (IARC, 1992). These exposures may occur repeatedly to raw fuel, vapor phase, aerosol phase, or fuel combustion exhaust by dermal absorption, pulmonary inhalation, or oral ingestion routes. Additionally, the public may be repeatedly exposed to lower levels of jet fuel vapor/aerosol or to fuel combustion products through atmospheric contamination, or to raw fuel constituents by contact with contaminated groundwater or soil. Kerosene-based hydrocarbon fuels are complex mixtures of up to 260+ aliphatic and aromatic hydrocarbon compounds (C(6) -C(17+); possibly 2000+ isomeric forms), including varying concentrations of potential toxicants such as benzene, n-hexane, toluene, xylenes, trimethylpentane, methoxyethanol, naphthalenes (including polycyclic aromatic hydrocarbons [PAHs], and certain other C(9)-C(12) fractions (i.e., n-propylbenzene, trimethylbenzene isomers). While hydrocarbon fuel exposures occur typically at concentrations below current permissible exposure limits (PELs) for the parent fuel or its constituent chemicals, it is unknown whether additive or synergistic interactions among hydrocarbon constituents, up to six performance additives, and other environmental exposure factors may result in unpredicted toxicity. While there is little epidemiological evidence for fuel-induced death, cancer, or other serious organic disease in fuel-exposed workers, large numbers of self-reported health complaints in this cohort appear to justify study of more subtle health consequences. A number of recently published studies reported acute or persisting biological or health effects from acute, subchronic, or chronic exposure of humans or animals to kerosene-based hydrocarbon fuels, to constituent chemicals of these fuels, or to fuel combustion products. This review provides an in-depth summary of human, animal, and in vitro studies of biological or health effects from exposure to JP-8, JP-8 +100, JP-5, Jet A, Jet A-1, or kerosene.     

Biological And Health Effects Of Exposure To Kerosene-Based Jet Fuels And Performance Additives

Over 2 million military and civilian personnel per year (over 1 million in the United States) are occupationally exposed, respectively, to jet propulsion fuel-8 (JP-8), JP-8 +100 or JP-5, or to the civil aviation equivalents Jet A or Jet A-1. Approximately 60 billion gallons of these kerosene-based jet fuels are annually consumed worldwide (26 billion gallons in the United States), including over 5 billion gallons of JP-8 by the militaries of the United States and other NATO countries. JP-8, for example, represents the largest single chemical exposure in the U.S. military (2.53 billion gallons in 2000), while Jet A and A-1 are among the most common sources of nonmilitary occupational chemical exposure. Although more recent figures were not available, approximately 4.06 billion gallons of kerosene per se were consumed in the United States in 1990 (IARC, 1992). These exposures may occur repeatedly to raw fuel, vapor phase, aerosol phase, or fuel combustion exhaust by dermal absorption, pulmonary inhalation, or oral ingestion routes. Additionally, the public may be repeatedly exposed to lower levels of jet fuel vapor/aerosol or to fuel combustion products through atmospheric contamination, or to raw fuel constituents by contact with contaminated groundwater or soil. Kerosene-based hydrocarbon fuels are complex mixtures of up to 260+ aliphatic and aromatic hydrocarbon compounds (C 6 -C 17+ ; possibly 2000+ isomeric forms), including varying concentrations of potential toxicants such as benzene, n-hexane, toluene, xylenes, trimethylpentane, methoxyethanol, naphthalenes (including polycyclic aromatic hydrocarbons [PAHs], and certain other C 9 -C 12 fractions (i.e., n-propylbenzene, trimethylbenzene isomers). While hydrocarbon fuel exposures occur typically at concentrations below current permissible exposure limits (PELs) for the parent fuel or its constituent chemicals, it is unknown whether additive or synergistic interactions among hydrocarbon constituents, up to six performance additives, and other environmental exposure factors may result in unpredicted toxicity. While there is little epidemiological evidence for fuel-induced death, cancer, or other serious organic disease in fuel-exposed workers, large numbers of self-reported health complaints in this cohort appear to justify study of more subtle health consequences. A number of recently published studies reported acute or persisting biological or health effects from acute, subchronic, or chronic exposure of humans or animals to kerosene-based hydrocarbon fuels, toconstituent chemicals of these fuels, or to fuel combustion products. This review provides an in-depth summary of human, animal, and in vitro studies of biological or health effects from exposure to JP-8, JP-8 +100, JP-5, Jet A, Jet A-1, or kerosene.     

Pulmonary Toxicity Assessments Of Inhaled Ethylene Oxide/Propylene Oxide Copolymer Lubricants In Rats

Abstract

The pulmonary toxicities of 5 different ethylene oxide/propylene oxide (EO/PO) copolymer commercial lubricant candidates were assessed by exposing groups of rats for 3 consecutive days (6 hlday) to aerosols of the different EO/PO test materials and evaluating pulmonary parameters at selected postexposure time periods. Because all 5 compounds could not be evaluated simultaneously, these studies were conducted over a period of 2 wk. During wk 1 of the study, rats were exposed either to 22 mg/m³ (mean value for the 3 days) of UCON 50-HB-5100 (50-HB-5100), to 110 mg/m³ of Pluronic L31 (131), or to 99.4 mg/m³ of Pluronic L64 (L64). The mass median aerodynamic diameters (MMADs) for all 3 compounds were < 2.6 μm. In the second group of studies, rats were exposed to 42 mg/m³ of UCON 50-HB-2000 (50-HB-2000), or to 111 mg/m³ of UCON 75-H-1400 (75-H-1400), with MMADs < 1.8 μm. Sham controls were exposed to room air. One rat in the UCON 50-HB-5W0 group died within 7 days postexposure. Similarly, 1 rat in the UCON 50-HB-2000 group died within 8 days postexposure. Within 48 h after exposure, the lungs of rats exposed to UCON 50-HB-5W0 and 50-HB-2000 were edematous. The lungs of rats were lavaged at 0 h (i.e., immediately after), 2 days, 1 wk, 1 and 3 mo postexposure. Cellular and biochemical data on samples recovered from bronchoalveolar lavage (BAD demonstrated a substantial pulmonary inflammatory response concomitant with increases in BAL fluid levels of lactate dehydrogenase (LDH), protein, alkaline phosphatase, and N-acetylglucosaminidase in the lungs of rats exposed to UCON 50-HB-5100. Similarly, the BAL biochemical and pulmonary cell differential data for 50-HB-2000-exposed rats were similar but less severe to that previously measured in 50-HB-5100-exposed rats. In contrast, the lungs of rats exposed to Pluronic 131 and L64 and UCON 75 H-1400 demonstrated only slight and reversible pulmonary inflammatory effects. The results from this study validate this inhalation bioassay technique for predicting the pulmonary toxicity of inhaled aerosols by confirming the effects measured in a previous 2-wk inhalation toxicity study with these same compounds. In the earlier study, UCON 50-HB-5W0 and UCON 50-HB-2000 produced severe pulmonary toxicity in rats. The cellular and biochemical results presented here confirm the earlier findings of significant pulmonary toxicity produced by inhalation of the UCON 50-HB-5W0 and UCON 50-HB-2000 compounds. In contrast, the three other compounds (Pluronic L31, Pluronic L64, UCON 75-H-1400) produced only weak pulmonary inflammatory effects following 3-day exposures at high aerosol concentrations.     

Subchronic JP-8 jet fuel exposure enhances vulnerability to noise-induced hearing loss in rats

Both laboratory and epidemiological studies published over the past two decades have identified the risk of excess hearing loss when specific chemical contaminants are present along with noise. The objective of this study was to evaluate the potency of JP-8 jet fuel to enhance noise-induced hearing loss (NIHL) using inhalation exposure to fuel and simultaneous exposure to either continuous or intermittent noise exposure over a 4-wk exposure period using both male and female Fischer 344 rats. In the initial study, male (n?=?5) and female (n?=?5) rats received inhalation exposure to JP-8 fuel for 6 h/d, 5 d/wk for 4 wk at concentrations of 200, 750, or 1500 mg/m3. Parallel groups of rats also received nondamaging noise (constant octave band noise at 85 dB(lin)) in combination with the fuel, noise alone (75, 85, or 95 dB), or no exposure to fuel or noise. Significant concentration-related impairment of auditory function measured by distortion product otoacoustic emissions (DPOAE) and compound action potential (CAP) threshold was seen in rats exposed to combined JP-8 plus noise exposure when JP-8 levels of 1500 mg/m3 were presented with trends toward impairment seen with 750 mg/m3 JP-8?+?noise. JP-8 alone exerted no significant effect on auditory function. In addition, noise was able to disrupt the DPOAE and increase auditory thresholds only when noise exposure was at 95 dB. In a subsequent study, male (n?=?5 per group) and female (n?=?5 per group) rats received 1000 mg/m3 JP-8 for 6 h/d, 5 d/wk for 4 wk with and without exposure to 102 dB octave band noise that was present for 15 min out of each hour (total noise duration 90 min). Comparisons were made to rats receiving only noise, and thosereceiving no experimental treatment. Significant impairment of auditory thresholds especially for high-frequency tones was identified in the male rats receiving combined treatment. This study provides a basis for estimating excessive hearing loss under conditions of subchronic JP-8 jet fuel exposure.     

Acute,Subchronic, and Mutagenicity Studies with Norbornene Fluoroalcohol

The object of this study was to evaluate the toxicity of norbornene fluoroalcohol (NBFOH), which is used as an intermediate in the production of fluorinated monomers and polymers. NBFOH was evaluated for acute oral, dermal, and inhalation toxicity, dermal sensitization using the Local Lymph Node Assay (LLNA), mutagenesis by the Ames assay, and subchronic toxicity in a 4-week inhalation rat study. NBFOH demonstrated slight acute toxicity in oral, dermal, and inhalation studies. Approximate lethal doses of 3400 and > 5000 mg/kg for the oral and dermal routes, respectively, and an approximate lethal concentration of 4300 mg/m³ were determined. NBFOH demonstrated moderate skin irritation, was a severe eye irritant, produced dermal sensitization, but did not cause bacterial mutagenicity either in the presence or absence of S9 activation. Male and female rats were exposed nose only to airborne NBFOH at levels of 0, 410, 1400, and 1500 mg/m³, 6 h/day, 5 days/week for 4 weeks with clinical and histopathology specimens collected 1 day after the final exposure. Due to the vapor pressure of NBFOH, the 1500 mg/m³ atmosphere was 27% aerosol and 73% vapor; the 1400 mg/m³ atmosphere was 5% aerosol and 95% vapor, and the 410 mg/m³ level was only vapor. No test substance–related mortality or clinical signs of toxicity were observed over the course of the study, and male rats demonstrated significant weight loss and decreased food consumption at 1400 mg/m³. Male rats from the 1500 mg/m³ group demonstrated an 11% increase in prothrombin time that was significantly higher than the control value. Examination of fluoride in the urine did not demonstrate a concentration–response relationship, with minimal elevations observed in male rats at all exposure levels and sporadic increases in females. Both male and female rats exposed to 1400 mg/m³ or greater had squamous metaplasia of the laryngeal mucosa and degeneration of the nasal olfactory and respiratory mucosa. Based on the above findings, NBFOH demonstrates the potential to produce allergic contact dermatitis, and subchronic inhalation studies indicate a no-observed-adverse-effect-level (NOAEL) of 410 mg/m³.     

JP-8 jet fuel can promote auditory impairment resulting from subsequent noise exposure in rats.

We report on the transient and persistent effects of JP-8 jet fuel exposure on auditory function in rats. JP-8 has become the standard jet fuel utilized in the United States and North Atlantic Treaty Organization countries for military use and it is closely related to Jet A fuel, which is used in U.S. domestic aviation. Rats received JP-8 fuel (1000 mg/m(3)) by nose-only inhalation for 4 h and half of them were immediately subjected to an octave band of noise ranging between 97 and 105 dB in different experiments. The noise by itself produces a small, but permanent auditory impairment. The current permissible exposure level for JP-8 is 350 mg/m(3). Additionally, a positive control group received only noise exposure, and a fourth group consisted of untreated control subjects. Exposures occurred either on 1 day or repeatedly on 5 successive days. Impairments in auditory function were assessed using distortion product otoacoustic emissions and compound action potential testing. In other rats, tissues were harvested following JP-8 exposure for assessment of hydrocarbon levels or glutathione (GSH) levels. A single JP-8 exposure by itself at 1000 mg/m(3) did not disrupt auditory function. However, exposure to JP-8 and noise produced an additive disruption in outer hair cell function. Repeated 5-day JP-8 exposure at 1000 mg/m(3) for 4 h produced impairment of outer hair cell function that was most evident at the first postexposure assessment time. Partial though not complete recovery was observed over a 4-week postexposure period. The adverse effects of repeated JP-8 exposures on auditory function were inconsistent, but combined treatment with JP-8 + noise yielded greater impairment of auditory function, and hair cell loss than did noise by itself. Qualitative comparison of outer hair cell loss suggests an increase in outer hair cell death among rats treated with JP-8 + noise for 5 days as compared to noise alone. In most instances, hydrocarbon constituents of the fuel were largely eliminated in all tissues by 1-h postexposure with the exception of fat. Finally, JP-8 exposure did result in a significant depletion of total GSH that was observable in liver with a nonsignificant trend toward depletion in the brain and lung raising the possibility that the promotion of noise-induced hearing loss by JP-8 might have resulted from oxidative stress.