4
Effects of Jet-Propulsion Fuel 8 on the Respiratory Tract

In this chapter, the subcommittee reviews studies in humans and experimental animals that examined potential respiratory tract effects of jet-propulsion fuel 8 (JP-8), related fuels, and kerosene. The subcommittee uses that information to assess the potential respiratory toxicity of JP-8 in humans. The National Research Council report Permissible Exposure Levels for Selected Military Fuel Vapors (NRC 1996) did not include a review of the effects of JP-8 on the respiratory tract.

EFFECTS OF EXPOSURE TO JET FUELS AND KEROSENE IN HUMANS

Few studies have directly or systematically addressed the potential for adverse effects of JP-8 or other jet fuels on the human respiratory tract. Available studies of respiratory tract toxicity of jet fuels and kerosene are described below and summarized in Table 4-1.

Tunnicliffe et al. (1999) reported the effect of occupational exposure to aircraft fuel (type not specified) and jet-stream exhaust on pulmonary function and respiratory symptoms in airport workers. Two hundred twenty-two full-time airport employees were divided into groups with essentially no exposure



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4 Effects of Jet-Propulsion Fuel 8 on the Respiratory Tract In this chapter, the subcommittee reviews studies in humans and experimental animals that examined potential respiratory tract effects of jet-propulsion fuel 8 (JP-8), related fuels, and kerosene. The subcommittee uses that information to assess the potential respiratory toxicity of JP-8 in humans. The National Research Council report Permissible Exposure Levels for Selected Military Fuel Vapors (NRC 1996) did not include a review of the effects of JP-8 on the respiratory tract. EFFECTS OF EXPOSURE TO JET FUELS AND KEROSENE IN HUMANS Few studies have directly or systematically addressed the potential for adverse effects of JP-8 or other jet fuels on the human respiratory tract. Available studies of respiratory tract toxicity of jet fuels and kerosene are described below and summarized in Table 4-1. Tunnicliffe et al. (1999) reported the effect of occupational exposure to aircraft fuel (type not specified) and jet-stream exhaust on pulmonary function and respiratory symptoms in airport workers. Two hundred twenty-two full-time airport employees were divided into groups with essentially no exposure

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TABLE 4-1 Effects of Jet Fuel Exposure on the Respiratory Tract in Humans Exposure Concentration Exposure Duration Results Reference Not reported 222 full-time airport employees divided into three exposure groups; high-exposure group, 56 participants exposed for most of day; moderate-exposure group, 83 participants exposed for 1 hr/day; no-exposure group, 86 participants Adjusted odds ratios for cough with phlegm (3.5) and for runny nose (2.9) significantly associated with frequent exposure; adjusted odds ratios for symptoms of watering eyes, stuffy nose, wheezing, shortness of breath not significant Tunnicliffe et al. 1999 Exposed group (5,706) had potential occupational exposure to JP-8; control group (5,706) did not work in occupations in which exposure to JP-8 would occur; all subjects were active duty members of US Air Force Not reported Analysis of medical records showed that subjects in all groups had similar health-care visit rates; no differences among groups in respiratory illnesses Gibson et al. 2001aa Measurements taken in breathing zones of subjects; median concentration of naphthalene, 1.9 μg/m3 (low-exposure group), 10.4 μg/m3 (moderate-exposure group), 447 μg/m3 (high-exposure group); median concentration of benzene, 3.1 μg/m3 (low-exposure group), 7.45 μg/m3 (moderate-exposure High- and moderate-exposure groups had persistent exposure to JP-8 (defined as at least 1 hr twice per wk for at least 9 mo); low-exposure group had no significant exposure to jet fuel or solvents Analysis of self-assessment questionnaire did not report differences among groups in measures related to respiratory tract, such as difficulty in breathing Gibson et al. 2001ba

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group), 242 μg/m3 (high-exposure group)   Overall average concentration 300 mg/m3 (range, 85-974 mg/m3) Average employment duration, 17 yr Undefined respiratory tract symptoms, palpitations, and feeling of pressure in chest may have been associated with exposure Knave et al. 1978 Three families (six adults, three children) exposed to kerosene in their homes at 5.6-79.7 mg/m3 4-8 mo as result of spill near their homes; exposure estimated at 100 hr/wk Three children, one adult developed asthma that persisted for more than 2 yr; other adults developed other respiratory tract symptoms, such as sore throat, cough, watery eyes, stuffed noses, chest tightness Todd and Buick 2000 aAdditional background information about these studies can be found in Appendix B.

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(86 participants), occasional exposure (83 participants exposed about 1 hr/day), and frequent exposure (56 participants exposed for “most of the day”). Participants filled out a self-administered questionnaire regarding respiratory symptoms, were skin-tested for allergies, and underwent spirometry to assess pulmonary function. Because of differences in demographic makeup of the exposure groups (low representation of females and socioeconomic stratification between the unexposed and exposed groups), logistic regression analyses on study data were performed only to compare men in the occasional- and frequent-exposure groups. Analyses were corrected for age and smoking habits and, where appropriate, for the presence of self-reported hay fever or asthma. The adjusted odds ratios (ORs) for cough with phlegm (3.5) and for runny nose (2.9) were significantly associated with frequent jet exhaust exposure. ORs for symptoms of watering eyes, stuffy nose, wheezing, and shortness of breath were not significantly different between the frequently and occasionally exposed groups. The investigators stated that increased adjusted ORs in the frequent-exposure group likely reflected a true association between symptoms and occupational settings, although bias and residual confounding could not be discounted. The investigators also stated that the symptoms suggested exposure to a respiratory irritant; the effects were more closely related to exposure to jet exhaust than to exposure to jet fuel. The Tunnicliffe et al. (1999) study is limited by lack of quantitative exposure assessment, elimination of evaluation of the unexposed group, limited end-point evaluation, lack of correction for subject bias, and the relatively small number of participants. The hypothesis that symptoms of respiratory irritation were due more to jet exhaust than to fuel should be taken with caution; more-recent studies have determined that JP-8 vapor can cause upper respiratory tract irritation in mice (U.S. Department of the Air Force 2001). Gibson et al. (2001a) examined the medical records of Air Force personnel occupationally exposed to aircraft fuel and compared them with records of unexposed (control) personnel. The exposed group consisted of 5,706 people (242 women and 5,464 men), and the control group consisted of 5,706 people (2,853 women and 2,853 men) randomly selected from a cohort of 20,244 Air Force unexposed personnel. Preliminary results showed that the total numbers of medical visits and visits for specific reasons, including respiratory problems, were not markedly different among the exposed and unexposed groups. Specific diseases, including respiratory illnesses, were examined, but no marked differences were found between the groups. This study is limited by many factors, including limited information on potential confounders, completeness of health-event recording, differences among personnel in availability of health care, consequences of taking sick leave for health-

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care visits, differences in health-care-seeking behavior, and differences in amount of self-care or sensitivity to symptoms of illness. Gibson et al. (2001b) conducted a health survey of 328 Air Force personnel (276 men and 52 women) with a self-assessment questionnaire. The subjects’ exposures were categorized as high (performed duties associated with aircraft fuel systems), moderate (may have come into contact with jet fuel in the course of their duties), or low (did not normally come into contact with jet fuel or other solvents while performing their duties). Only one of the several measures evaluated, “difficulty breathing,” was related to the effects of jet fuel on the respiratory tract. Preliminary results showed no statistical differences (adjusted for age, gender, and smoking history) between the high- and moderate-exposure groups compared with the low-exposure group in the reported symptom of “difficulty breathing.” This study is limited by the fact that the symptoms were self-reported, allowing for bias. In a study of sensory threshold of deodorized kerosene in humans, six volunteers 20 to 63 years (yr) old, were exposed to kerosene at 140 mg/m3 (20 ppm) for 15 min. No eye, nose, or throat irritation was reported during or after exposures. Three volunteers reported slight olfactory fatigue (Carpenter et al. 1976). Recent case reports suggest that prolonged exposure to kerosene vapors may result in development of asthma and other respiratory tract symptoms (Todd and Buick 2000). Three families (six adults, three children) were exposed to kerosene vapors for 4-8 months as a result of a spill near their homes. Exposures occurred for an estimated 100 hr/wk. Concentrations in one home were measured at 5.6-79.7 mg/m3. Three of the children and one adult developed asthma that persisted for more than 2 yr. The remaining adults developed other respiratory tract symptoms, such as sore throat, cough, watery eyes, stuffed noses, and chest tightness. That study is limited because only a small group of people (n = 9) were exposed. EFFECTS OF EXPOSURE TO JET FUELS AND KEROSENE IN EXPERIMENTAL ANIMALS Several animal inhalation toxicity studies have been conducted on various jet fuels (summarized in Table 4-2). In one study, male F344 rats were exposed to shale-oil-derived JP-4 continuously for 90 days by inhalation at 1,000 mg/m3. The exposure resulted in no effects on lung volumes, dynamic resistance and compliance, quasistatic compliance, partial and full forced vital capacities, carbon monoxide diffusion capacity, and closing volume. There

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TABLE 4-2 Effects of Jet Fuel Exposure on the Respiratory Tract in Experimental Animals Fuel Type Species or Cell Line Exposure Concentration Exposure Duration Effects Reference JP-4 F344 rats 1,000 mg/m3 90 days continuously Exposure resulted in no effects on lung volumes, dynamic resistance and compliance, quasistatic compliance, partial and full forced vital capacities, carbon monoxide diffusion capacity, and closing volume; no effects on deposition or clearance of inhaled 51Cr-labeled microspheres; no evidence of pulmonary disease in control and exposed rats Newton et al. 1991 JP-8 F344 rats, C57BL/6 mice 500, 1,000 mg/m3 (vapor) 90 days No respiratory tract effects attributed to JP-8; results well characterized with regard to concentration and chemical composition Mattie et al. 1991 JP-8 F344 rats 495-520, 813-1,094 mg/m3 (aerosol-vapor mixture) 1 hr/day, 5 days/wk for 7, 28, 56 days Pulmonary resistance increased in 7- and 28-day exposure groups; lung-permeability data indicated lung injuries peaking at 28 d of exposure; all groups had interstitial edema resulting from endothelial damage; all groups had activated thickening of alveolar septa and alveolar macrophages Hays et al. 1995; Pfaff et al. 1995 JP-8 C57BL/6, B6.A.D. (Ahrd/Nats knockout) Up to 118 mg/m3 aerosol; vapor concentration 1 hr/day for 7 days Exposures resulted in increases in total protein and LDH among groups at high concentrations; minimal morphologic changes after inhalation; damage to bronchiolar Robledo and Witten 1998; Robledo et al. 2000; Wang et

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  mice not reported   epithelium resulting in perivascular edema and damaged Clara cells at highest concentrations al. 2001 JP-4, JP-8, and JP-8 +100 Swiss-Webster mice JP-4:685-11,430 mg/m3, JP-8:681-3,613 mg/m3, JP-8 + 100:777-2,356 mg/m3 (vapor and aerosol) 30 min Exposure to jet fuels caused breathing patterns characteristic of upper airway sensory irritation at all concentrations but no apparent deep lung irritation at any concentration; RD50 determined to be 4,842 mg/m3 for JP-4, 2,876 mg/m3 for JP-8, 1,629 mg/m3 for JP-8 +100 US Department of the Air Force 2001 Deodorized kerosene Rats, beagles 20, 48, 100 mg/m3 (vapor) 6 hr/day, 5 days/wk for up to 67 days No pulmonary lesions observed in either species Carpenter et al. 1976 Kerosene Rabbits, guinea pigs 31,000-35,000 mg/m3 (aerosol) 15 min/day for 21 days Short-term exposures resulted in significant increases in total pulmonary resistance, increased tracheal resistance in rabbits; tracheas of exposed guinea pigs showed enhanced susceptibility to acetylcholine immediately and 24 hr after exposure; damage to tracheal ciliated cells in guinea pigs observed; increased numbers of nucleated and epithelial cells recovered in BALF Casacó et al. 1982; Casacó et al. 1985a,b; Noa and Sanabria 1984; Noa et al. 1985

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Fuel Type Species or Cell Line Exposure Concentration Exposure Duration Effects Reference JP-8 In vitro cell lines: rat lung alveolar type II epithelial cells, human histocytic lymphoma cells, T-cell leukemia cells 80 μg/ml 24 hr Rat lung cell line induced biochemical and morphologic markers of apoptotic cell death; T-cell leukemia cell lines resistant to cytotoxic effects of JP-8 Stoica et al. 2001 JP-8 Swiss-Webster mice 1,000, 2,500 mg/m3 (vapor-aerosol mixture) 1 hr/day for 7 days Of 796 proteins analyzed, 42 were altered by exposure to JP-8 at 2,500 mg/m3. 8 were increased, 34 were decreased in abundance; 1 of 42 proteins altered at 2,500 mg/m3 was also altered at 1,000 mg/m3 Witzmann et al. 1999 Abbreviations: BALF, bronchoalveolar lavage fluid; LDH, lactate dehydrogenase; RD50, dose that causes 50% decrease in respiratory rate; 99mTc-DTPA, technetium-99m diethylenetriamine pentaacetic acid.

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were no effects on deposition or clearance of 51Cr-labeled microspheres inhaled later. Lungs of the control and JP-4-exposed rats showed no evidence of pulmonary disease (Newton et al. 1991). Continuous inhalation of JP-8 vapor by F344 rats and C57BL/6 mice at 500 and 1,000 mg/m3 for 90 days resulted in no respiratory tract effects that could be attributed to JP-8 (Mattie et al. 1991). The exposures were well characterized with regard to concentration and chemical composition. Studies were conducted on the effects of JP-8 inhalation on the rat lung (Hays et al. 1995; Pfaff et al. 1995). Male F344 rats were exposed to an aerosol and vapor mixture of JP-8 at 495-520 mg/m3 (lower concentration) or 813-1,094 mg/m3 (higher concentration) for 1 hr/day, 5 days/wk for 7, 28, and 56 days. The aerosol particles were respirable and tended to be monodisperse (mass median aerodynamic diameter, 1.08-1.51; geometric standard deviation, 1.5-2.2). The aerosol:vapor ratio was reported at 1.2-1.8 (mean, 1.5). Control groups were sham-exposed for 7, 28, and 56 days. The lower-exposure concentration caused an increase in dynamic compliance after 7 days, but the effect did not persist with continued exposure to 28 days (Pfaff et al. 1995). Pulmonary resistance was increased in both the 7- and 28-day fuel-exposed groups. Pulmonary function was not measured in the low-exposure group at 56 days or in the high-exposure group at any time (Hays et al. 1995). Lung epithelial permeability, as determined by pulmonary clearance of technetium-99mlabeled diethylenetriamine pentaacetate (99mTcDTPA), was measured in all rats. Clearance rates were significantly increased above the corresponding time-control value among the low-exposure group after 7 days (Pfaff et al. 1995), the low- and high-exposure groups after 28 days, and the high-exposure group after 56 days (Hays et al. 1995). Lung-permeability data indicated that lung injuries peaked at 28 days of fuel exposure. Although no treatment-related pulmonary lesions observable by light microscopy were reported in rats exposed to JP-8 at 500 mg/m3 for up to 28 days (Pfaff et al. 1995), electron micrographs showed that all groups had interstitial edema resulting from endothelial damage. There was an apparent thickening of the alveolar septa, and alveolar macrophages were activated in all groups (Hays et al. 1995). Lung-permeability data correlated with histology data. In followup experiments, the pulmonary effects of JP-8 inhalation in mice were evaluated (Robledo and Witten 1998; Robledo et al. 2000; Wang et al. 2001). Groups of C57BL/6 and B6.A.D. (Ahrd/Nats knockout) mice were exposed 1 hr/day for 7 days to ambient air or aerosolized JP-8 at 0-118 mg/m3. JP-8 vapor was also present; however, the concentration of the vapor in the exposure atmosphere was not reported. Exposure had no effect on dynamic compliance or resistance. Lung epithelial permeability, as determined with 99mTcDTPA, was affected in C57BL/6 mice exposed at 50 and 113

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mg/m3 and in B6.A.D. (Ahrd/Nats) mice exposed at 48 (but not 50), 113, and 118 mg/m3. Exposures resulted in increases in total protein, an indicator of pulmonary edema, and lactate dehydrogenase (LDH), an indicator of pulmonary cell damage or death, among groups exposed at the higher JP-8 concentrations, but results varied between mouse strains and experiments. Conflicting effects of exposure on N-acetyl-b-D-glucosaminidase and on numbers of nucleated cell numbers and profiles recovered with bronchoalveolar lavage were reported for the two sets of experiments. For example, significant increases in nucleated cell counts were reported for C57Bl/6 and B6A.D. (AhrdNars) mice exposed to JP-8 at 113 mg/m3 (Robledo and Witten 1998), but significant decreases were reported for B6A.D. (AhrdNars) mice exposed to JP-8 at 48 and 118 mg/m3 (Robledo et al. 2000). Minimal morphologic changes observed with light microscopy were reported after JP-8 inhalation, but ultrastructural evaluations revealed damage to bronchiolar epithelium resulting in perivascular edema and damage to Clara cells in mice exposed at the highest concentrations. Early work on the effects of JP-8 inhalation in rats showed an inverse relationship between increases in airway epithelial permeability (99TcDTPA clearance) and decreased concentrations of the tachykinin substance P in bronchoalveolar lavage fluid (BALF) (Hays et al. 1995). Substance P has a strong affinity for the neurokinin receptor NK1, one of a family of plasma-membrane-bound neurokinin receptors that mediate protective reflex responses—such as bronchoconstriction, increased vascular permeability, vasodilatation, mucus secretion, and enhanced mucociliary activity—to airway exposure to mechanical or chemical irritants. Robledo and Witten (1999) further examined the role of substance P and receptor NK1 in mediating JP-8-induced lung injury. Groups of Ahrd/Nats mice were exposed to JP-8 at 50 mg/m3 for 1 hr/day for 7 days. End points included of pulmonary function, biochemical and cellular changes in BALF, 99mTcDPTA lung-clearance rates, and pulmonary morphology (based on light and electron microscopic evaluations). The effects of administration of an aerosol of (Sar9,Met[O2]11) substance P daily immediately after JP-8 inhalation and the effects of daily injection of the NK1 receptor antagonist CP-96345 on the end points were determined in additional groups of mice. JP-8 inhalation had no effect on pulmonary dynamic compliance or resistance. Exposure significantly increased 99mTc-DTPA clearance rate and total protein and LDH in lavage fluid. Exposure significantly decreased N-acetyl-b-D-glucosamine and total numbers of nucleated cells and macrophages in BALF. Morphologically, JP-8 induced marked focal areas of alveolar septal thickening and collapsed air spaces. Distal airways were characterized by the appearance of swollen and exfoliated bronchiolar epithelial cells. Areas of vacuolization between bronchioles and venules suggestive of subendothelial edema were

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also observed. Mice given substance P by inhalation showed none of the adverse functional, biochemical, or morphologic changes induced by JP-8 inhalation. However, the JP-8-induced adverse effects were exacerbated by administration of the NK1 antagonist CP-96345. Results of the studies suggest that JP-8 inhalation triggers a protective response in the lung, mediated by a substance P/NK1 receptor that may become overwhelmed by repeated inhalation of the fuel at high concentrations. The results of the pulmonary effects of inhaled JP-8 in mice and rats should be viewed with caution because exposure atmospheres are not well defined with respect to the concentration of vapor coexisting with aerosols. Morphologic evaluations were conducted in only a few animals per exposure group and were not reported quantitatively with regard to incidence or semiquantitatively with respect to severity. Pulmonary function measurements were not performed with conventional methods. Furthermore, conflicting results were obtained in replicated experiments with mice. The sensory-irritation potential of JP-4, JP-8, and JP-8+100 were evaluated in groups of four male Swiss-Webster mice exposed, head-only, for 30 min to atmospheres of each material containing both vapor and aerosol phases (U.S. Department of the Air Force 2001). The three test materials evoked breathing patterns characteristic of upper airway sensory irritation at all exposure concentrations. Examination of the breathing patterns revealed no apparent pulmonary (deep lung) irritation at any concentration. The calculated values for concentrations of JP-4, JP-8, and JP-8+100 that caused a 50% decrease in respiratory rate (RD50) were 4,842, 2,876, and 1,629 mg/m3 (total aerosol + vapor concentration), respectively. The relative irritancy ranking of the three fuels was JP-8+100 > JP-8 > JP-4. In contrast, respiratory rates of mice exposed to deodorized kerosene vapor by inhalation at 6,900 mg/m3 were not decreased by 50% or more from control values (Carpenter et al. 1976). To determine the effects of repeated inhalation of deodorized kerosene vapor, groups of 25 male rats and four male beagles were exposed at 20, 48, or 100 mg/m3 for 6 hr/day, 5 days/wk for up to 67 days. Characteristics examined included histopathologic findings, serum chemistry, and electrocardiograms (dogs only). No pulmonary lesions were observed in either species. No histopathologic evaluation of the upper respiratory tract was performed (Carpenter et al. 1976). Studies on the effects of short-term inhalation of kerosene aerosol (about 8 mm in diameter) at 3,100-3,500 mg/m3 have been conducted. Short-term exposures resulted in significance increases in total pulmonary resistance and increased tracheal resistance in rabbits (Casacó et al. 1982). Tracheas from exposed guinea pigs showed enhanced susceptibility to acetylcholine immediately and 24 hr after exposure (Casacó et al. 1985b). Repeated inhalation by

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guinea pigs (15 min/day for 21 days) resulted in damage to tracheal ciliated cells (Noa and Sanabria 1984) and pulmonary inflammatory responses and toxicity, as indicated by increases in numbers of nucleated and epithelial cells recovered in BALF (Noa et al. 1985). The effects of JP-8 inhalation on protein expression in mouse lung were evaluated in Swiss-Webster mice (Witzmann et al. 1999). Mice were exposed to an aerosol and vapor mixture of JP-8 at 1,000 or 2,500 mg/m3 for 1 hr/day for 7 days. Lung cytosol was prepared and analyzed. An average of 796 proteins were resolved in each sample pattern and matched reproducibly to a reference pattern. Of the 796 proteins, 42 were significantly altered (p < 0.001) by exposure to JP-8 at 2,500 mg/m3. Eight proteins were increased and 34 decreased in abundance. One of the 42 proteins altered at 2,500 mg/m3 was altered at 1,000 mg/m3, but 11 were altered significantly (p < 0.01). The observed alterations suggested four general effects: impaired synthetic and processing machinery, ultrastructural damage, toxic and metabolic stress and detoxification systems, and functional responses to CO2 handling, acid-base homeostasis, and fluid secretion. The effects were considered to be consistent with morphologic and functional alterations observed in mice after JP-8 exposure. The relevance of the findings to evaluating the scientific basis of the interim permissible exposure level (PEL) of 350 mg/m3 is questionable considering the high JP-8 concentration used in the study and the fact that the vapor concentration was not characterized. EFFECTS OF IN VITRO EXPOSURE TO JP-8 Stoica et al. (2001) investigated apoptosis as the molecular mechanism responsible for the cellular toxicity induced by JP-8 in several cell lines. JP-8 exposure of a rat lung alveolar type II epithelial cell line (RLE-6TN) induced biochemical and morphologic markers of apoptotic cell death, including caspase-3 activation, poly (ADP-ribose) polymerase cleavage, chromatin condensation, membrane blebbing, cytochrome c release from mitochondria, and genomic DNA cleavage into both oligonucleosomal (DNA ladder) and high-molecular-weight fragments. Similar responses to JP-8 were seen in the human histocytic lymphoma cell line (U937) and the T-cell leukemia cell line (Jurkat). Jurkat cells stably transfected with a plasmid encoding the antiapoptotic protein Bcl-xL or pretreated with the pan-caspase inhibitor Boc-D-frnk were resistant to the cytotoxic effects of JP-8. The results suggested that apoptotic cell death was at least partially responsible for the cytotoxic effects of JP-8. The apoptotic effects were seen with JP-8 dilutions of 1 × 10-4. Assuming a JP-8 density of 1 g/mL, that translates into concentrations of approximately 100 mg/mL of cell incubation medium. The physiologic rele-

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vance of that high concentration is questionable, so it is difficult to determine the relevance of the results to human exposure. CONCLUSIONS AND RECOMMENDATIONS Preliminary comparison of medical records of Air Force personnel occupationally exposed to JP-8 with records of unexposed (control) personnel showed that numbers of medical visits related to respiratory problems were not markedly different between the exposed and unexposed groups. Specific diseases, including respiratory illnesses, were examined, but no marked differences were found between the groups. No respiratory-tract effects were found in F344 rats and C57BL/6 mice exposed to JP-8 vapor at 500 or 1,000 mg/m3 for 90 days. However, several animal studies conducted in F344 rats and C57BL/6 mice suggest that mixtures of JP-8 vapors and aerosols can result in pulmonary inflammation and alterations in pulmonary functions. Toxic effects have been reported in C57BL/6 mice exposed at concentrations as low as 50 mg/m3 for 1 hr per day for 7 days. The results from those studies suggest that JP-8 aerosol is more toxic to the respiratory tract than JP-8 vapor. The subcommittee reviewed the methods used to generate the exposure atmospheres in the studies using mixtures of vapors and aerosols and suspects that the JP-8 concentrations in the atmosphere may have been underreported. However, even if the actual concentration was 20 times as high (i.e., if exposure was at a concentration of 1,000 mg/m3), the observation of positive effects from a short exposure duration (1 hr/day for 7 days) at that concentration leads the subcommittee to conclude that the interim PEL of 350 mg/m3 might be too high to be protective of human health (assuming the application of commonly used uncertainty factors). Because there are concerns about the characterization of the exposure atmospheres in the studies using mixtures of vapors and aerosols, the subcommittee recommends an examination of the methods of characterizing the exposure atmosphere. Future studies involving exposures to aerosols should be designed in collaboration with scientists knowledgeable in aerosol generation, aerosol physics, and quantification of vapors and aerosols to ensure accurate characterization of exposure atmospheres. The subcommittee recommends that respiratory-system toxicity be evaluated in experimental animals exposed to JP-8 vapors and mixtures of vapors and aerosols by the inhalation route. Because the composition of JP-8 varies from batch to batch, scientists with expertise in petroleum toxicology should be consulted to design the best approach for testing the respiratory-system toxicity of JP-8 (e.g., testing JP-8 samples at the extremes of their composition ranges or testing JP-8 samples

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