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5 Effects of Jet-Propulsion Fuel 8 on the Nervous System This chapter summarizes the findings on potential neurotoxicity from expo- sure to jet-propulsion fuel 8 (JP-8) presented in the National Research Council report Permissible Exposure Levels for Selected Military Fuel Vapors (NRC 1996) and reviews additional studies, most of which were completed after the 1996 re- port was published. Since the 1996 report was released, additional epidemio- logic studies associated with occupational JP-8 exposure and experimental animal studies examining the neurotoxic potential of kerosene-based jet fuels, including JP-8, and kerosene via the dermal and inhalation routes have been conducted. The subcommittee used the available information on JP-8 to assess the potential for toxic effects of JP-8 on the nervous system in humans. SUMMARY OF STUDIES DISCUSSED IN THE 1996 NATIONAL RESEARCH COUNCIL REPORT The National Research Council Subcommittee on Permissible Exposure Levels for Military Fuels reviewed studies on the potential toxic effects of JP- 5, JP-8, and diesel fuel marine (DFM) on the nervous system (NRC 1996). The vapors from those fuels contain a mixture of volatile hydrocarbons, 56
Effects of Jet-Propulsion Fuel 8 on the N ervous System 57 which at high concentrations are central nervous system (CNS) depressants and can produce anesthesia or asphyxia at high absorbed doses (Andrews and Snyder 1986; Marshall and Wollman 1985). The effectiveness of vapors as CNS depressants depends principally upon the volatility of their component hydrocarbons. The Subcommittee on Permissible Exposure Levels for Military Fuels found that data on potential nervous system effects of jet fuels are sparse. In several Swedish studies conducted by Knave and his colleagues, acute CNS symptoms were reported in workers who were employed in jet factories where they were potentially exposed to jet fuels designated Jet A-1 and JP-1 (Knave et al. 1976, 1978, 1979). Industrial-hygiene measurements of up to 3,200 mg/m3 were reported for a variety of job activities. Although the one-time air measurements reflected various activities, the exposures were not well charac- terized over time or by individual. In a study of 30 Swedish workers potentially exposed to jet fuels at a motor factory for an average of 17 years (yr), workers reported acute symp- toms of exposure to vapors and performance degradation associated with long-term exposure (Knave et al. 1978). The study reported an approximate time-weighted average (TWA) of 300 mg/m3. The findings of performance degradation said to be attributable to long-term exposure were considered unreliable for a number of reasons, including weak and inconsistent evidence of impairment, inadequate methods of evaluation, inadequate consideration of confounding, a small cohort of workers, and a lack of quantitative informa- tion on exposure over time. EFFECTS OF EXPOSURE TO JP-8 IN HUMANS Acute exposure to jet fuels has been associated with neurologic effects in humans, including headache, nausea, vomiting, dizziness, fatigue, in coordina- tion, irritability, problems with attention and memory, narcosis, and gait dis- turbances (Knave et al. 1976; Knave et al. 1978; Porter 1990; Anger and Storzbach 2001; Gibson et al. 2001b) (see Table 5-1). Persistent effects can include peripheral neuropathy and behavioral changes, such as reduced perfor- mance on tests of attention and psychomotor speed. In a preliminary assessment of data, Anger and Storzbach (2001) reported significant behavioral disturbances characterized by impaired performance on digit-span (forward), digit-symbol, and finger-tapping tests among workers who had high JP-8 exposure at the beginning of their workshifts compared with workers who had no significant JP-8 exposure. Exposure was deter- mined by median breathing-zone concentrations of two components of JP-8,
58 TABLE 5-1 Effects of JP-8 on the Nervous System in Humans Reference Exposure Concentration Exposure Duration Study Results Knave et al. Overall average concentration, 300 Average 21 of 30 workers re ported recurrent ac ute 1976; 1978; mg/m 3 (range, 85-974 mg/m 3) employment symptoms on exposure; expo sed workers 1979 a duration of 17 yr reported higher prevalence of neurasthenic symptoms, greater irregularity of performance on test of complex reaction time, greater perform ance de crement over time in sim ple reaction-time task, poorer performance in task of perceptual speed than control group Anger and Measurements taken in breathing High-exp osure Subjects were given seven neu robehavioral tests Storzbach zones of subjects; median group had persistent in Behavioral Assessment and Research System; 2001 b concentration of n aphthalene, 1.9 exposure to JP-8 before exposure, high-exposure group had :g/m 3 (low-exposure group), 447 (defined as 1 hr significantly lower performance on digit-span :g/m 3 (high-exposure group); median twice per wk for at forward and backward test, symbol digit-latency concentration of benzene, 3.1 :g/m 3 least 9 mo); low- test, and tap ping test than low -exp osure group ; (low-exposure group), 242 :g/m 3 exposure group had results of tests did not correlate with breath or (high-exposure group) no significant passive naphthalene or benzene exposure; effe cts exposure to jet fuel may be result of carryover from previous or solvents exposure; when pre- and post-exposu re test results were compared, passive naphthalene exposure w as significantly associated with performance on Oregon Dual Task Procedure, Match to Sample, and Tapping Trial 2
Bekkedal et Measurements taken in breathing High-exp osure Subjects were given eye-blink conditioning al. 2001 b zones of subjects; median group had persistent response test; morning session showed that high- concentration of n aphthalene, 1.9 exposure to JP-8; exposure group had statistically significant :g/m 3 (low-exposure group), 447 low-exposure group differences in percentage CR, CR peak latency, :g/m 3 (high-exposure group); median had no significant and C R onset latency; high-exp osure group also concentration of benzene, 3.1 :g/m 3 exposure to jet fuel had fewer CRs than low-exposure group; no (low-exposure group) and 242 :g/m 3 or solvents statistically significant exposure-based differences (high-exposure group) afternoon session showed Bhattacharya Measurements taken in breathing High- and Subjects were given postural sway tests; post-log et al. 2001b zones of subjects; median mod erate-exposure sway length, based on ANCOV A analysis after concentration of n aphthalene, 1.9 groups had controlling for cofac tors, w as sign ificantly :g/m 3 (low-exp osure group ), 10.4 persistent exposure associated with passive naphthalene exposure for :g/m 3 (moderate-exposure group ), to JP-8; low- âeyes closed no foamâ and âeyes closed bendingâ 447 :g/m 3 (high-exposure grou p); exposure group had tests median concentration of benzene, 3.1 no significant :g/m 3 (low-exposure group), 7.45 exposure to jet fuel :g/m 3 (moderate-exposure group ), or solvents 242 :g/m 3 (high-exposure group) Gibson et al. Exposed group (5,706) had potential Not reported Review of medical records showed no differences 2001a b occupational exposure to JP-8; betw een exposed and control group s in control group (5,706) did no t work in neurologic and mental illnesses occupations in which exposure to JP- 8 would occur; all subjects were active duty members of U.S. Air Force (Continued) 59
60 TABLE 5-1 Continued Reference Exposure Concentration Exposure Duration Study Results Gibson et al. Measurements taken in breathing High- and In self-assessment questionnaire, subjects in high- 2001b b zones of subjects; median mod erate-exposure and m oderate-exp osure groups reported m ore concentration of n aphthalene, 1.9 groups had headaches, dizziness, trouble concentrating, :g/m 3 (low-exp osure group ), 10.4 persistent exposure balance prob lems, walking difficulties, :g/m 3 (moderate-exposure group ), to JP-8; low- forgetfu lness, and trouble in gripping objects 447 :g/m 3 (high-exposure grou p); exposure group had median concentration of be nzene, 3.1 no significant :g/m 3 (low-exposure group), 7.45 exposure to jet fuel :g/m 3 (moderate-exposure group ), or solvents 242 :g/m 3 (high-exposure group) a Jet factory workers were exposed to Jet A-1 and JP-1, Swedish militaryâs equivalent of JP-4. b Data w ere collected from volunteers (m ale and fem ale active-duty Air Force personn el) at six Air F orce bases in United S tates. Volunteers were divided into three exposure groups: high, moderate, and low. High-exposure group performed tasks associated with repairing aircraft fuel systems; moderate-exposure group performed tasks associated with fuel handling, distribution, recovery, and testing; and low-exposure group did not routinely come into contact with jet fuel or solvents. Data were collected in morning before subjects went to work and after they completed their work for that day. Reported results are from a preliminary analysis of data . Addition al background information can be fo und in Appendix B. Abbreviations: ANC OVA , analysis of covariance; CR, conditioned response.
Effects of Jet-Propulsion Fuel 8 on the N ervous System 61 naphthalene and benzene (see Table 5-1). The low-exposure group had no specific source of exposure to JP-8, but the high-exposure group had been exposed to JP-8 occupationally for at least 9 months. The findings indicate that attention and executive function, working memory, and psychomotor function may be affected by exposure to JP-8 and that the acute effects of JP- 8 on cognitive function persist in people who have relatively high exposure. The association between exposure to jet fuels and the incidence of peripheral neuropathy has been identified in reports by Knave et al. (1976, 1978). That particular finding is consistent with the proposed mechanism of action of 2,5- hexanedione and its derivatives and supports the hypothesis that exposure to jet-fuel constituents may affect nervous system functioning because of the formation of a metabolite that can react with cellular macromolecules to in- duce neuropathy (Anthony et al. 1983a; Anthony et al. 1983b; Graham et al. 1995). Preliminary data analyses show disturbances of balance among subjects exposed to jet fuels that may reflect reversible depression of CNS function and disturbances of peripheral sensory perception due to neuropathy and disruption of cerebellar function (see Table 5-1 and the section in Appendix C on posturograms) (Bhattacharya 2001). A preliminary analysis of data by Bekkedal et al. (2001) suggests that the eyeblink conditioning response may be affected by exposure to JP-8 (see Table 5-1 and the section in Appendix C on blink-reflex classical conditioning). Several constituents of JP-8âtoluene and xyleneâare known to have neurotoxicologic effects in humans. It is not known whether exposure to such chemicals at the concentrations found in JP- 8 will cause adverse neurologic effects and whether their presence in the mix- ture produces additive, synergistic, or antagonistic effects. EFFECTS OF EXPOSURE TO JP-8 IN EXPERIMENTAL ANIMALS This section describes experimental-animal studies that have assessed the neurotoxic potential of JP-8 and related fuels. The studies are summarized in Table 5-2. Baldwin et al. (2001) exposed 6-month-old Fischer 344 rats to room air or JP-8 aerosols alone or to JP-8 and then aerosolized substance P, which has been shown to attenuate the effects of JP-8-induced pulmonary dysfunction and immunotoxicity in animals. Inhalation exposures were nose-only and performed 1 hr/day, 5 days/wk for 28 days. Aerosolized JP-8 with a mass mean aerodynamic diameter (MMAD) of 1.7-1.9 :m (M. Witten, University of Arizona, personal communication, 2002) was administered to the rats at
62 TABLE 5-2 Effects of Jet Fuel on Nervous System in Experimental Animals Exposu re Exposu re Fuel Type Species Concentration Duration Effec ts Reference 3 JP-8 F344 rats 1,059 mg/m 1 hr/day, 5 Neurologic me asures were assessed with Baldwin et al. (aerosol) for first 25 days/wk for 28 functional observation battery; exposed rats 2001 days, 2,491 days had significant differences in spontaneous mg/m 3 for activity and CN S excitability from controls; final 3 days exposed rats exhibited greater velocity of swimm ing in Morris swim ming task JP-8 Sprague- 1,000 or 5,000 6 hr/day, 5 High-dose group was significantly impaired Ritchie et al. (vapor) Dawley rats mg/m 3 days/w k for 6 relative to low-dose grou p in difficult task 2000, 2001a,b wk, followed involving pressing one or more levers after by no exp osure auditory cue and in task involving for 64 days complicated repeated acquisition; no diffe rences o bserved betw een two grou ps in simple autoshaping and fixed -ratio or spatial- reversal tasks; low-dose group exhibited superior performance relative to control group in test requiring three or four lever presses in three-lever array JP-8, JP-5 Sprague- 1,000 (JP-8) or 6 hr/day, 5 Significant differences were observed in JP-8- Rossi et al. (vapor) Dawley rats 1,200 (JP-5) days/w k for 6 exposed group in appetitive reinforcer 2001 mg/m 3 wk, followed approach sensitization compared with JP-5- by no exp osure exposed group and control group; JP-5- for 65 days exposed group showed increased forelimb grip strengths compared with JP-8-exposed
group and the control group; neurotransm itter concentrations were also measured; JP-8 exposure w as associated w ith decreased concentrations of 3,4- dihydroxyphenylacetic in cerebellum and brainstem; JP -5 exposure was associated with increased concentrations of dopamine and 3,4-d ihyd roxyphenyl-acetic acid in hippocampus and cortex, respectively, and with decreased concentrations of homovanillic acid in hippocampus; blood samples contained increased and decreased concentrations of 5-hy droxyindoleacetic acid in JP-5 and JP -8 expose d group s, respectively JP-4 (vapor) Sprague- 2,000 mg/m 3 6 hr/day for 14 Significant increase in appetitive reinforcer Nordholm et Dawley rats days, followed approach se nsitization w as observed for in al. 1999 by no exp osure short-recovery-period group, but not long- for 14 days or recovery-period group; long-recovery-period 60 days grou p exhibited sign ificant differences in prepulse inhibition trial and treadm ill response compared with controls and decrease in total locomotor activity compared with short-recovery-period group; no other differences in neu rologic measures were observed; blood serotonin concentrations were increased in short-recovery-period (Continued) 63
64 TABLE 5-2 Continued Exposu re Exposu re Fuel Type Species Concentration Duration Effec ts Reference group; blood 5-hydroxyindoleacetic acid was significantly increased in short- and long- recovery-period groups; serotonin and 5- hydroxyindoleacetic acid c oncentrations we re increased in short- and long-recovery-period groups in cerebellum, brainstem, and hippocam pal regions; those chem icals were also increased in striated region in short- recovery-period group and in cortical regions in long-recovery-period group Hydro- Rat 165, 330, 495 5 days/wk for Animals were evaluated immediately after Koschier desulfurized mg/kg 13 wk exposure period ended and after 4-wk 1999 kerosene (dermal) recovery period; no significant differences were ob served in functional observed b attery and motor activity, startle response, and histologic evaluations Abbreviations: CNS, central nervous system
Effects of Jet-Propulsion Fuel 8 on the N ervous System 65 1,059 mg/m3 for the first 25 days and 2,491 mg/m3 for the final 3 days. Sub- stance P was administered at 1 :M concentration in normal saline with a nebulizer for 15 min immediately after JP-8 exposure. Neurobehavioral mea- sures were based on functional observation battery (FOB) composed of caged and open-field observations to assess sensory, autonomic, and neuromuscular function. Spatial and visual discrimination and memory were evaluated with variations of the Morris swim task. No significant differences between the two JP-8 exposure groups were observed except in body weight. The JP-8- alone group displayed mild but significant weight loss early in the exposures but returned to pre-exposure weights by the last exposure. Because of the absence of differences in neurobehavioral measures between the JP-8 expo- sure groups, they were considered together and compared with controls. The JP-8-exposed rats exhibited more rearing (17 versus seven rears) for one of the five assessments performed and a greater arousal score (4.5 and 4.7 in exposed rats versus 3.8 in controls on a scale ranging from 1 to 6 with 4 con- sidered normal) for two of the five assessments performed. Differences in the swim-task measurement were limited to greater swimming velocity in the exposed groups. Rossi et al. (2001) exposed Sprague-Dawley rats to filtered air, JP-5 vapor at 1,200 mg/m3, or JP-8 vapor at 1,000 mg/m3 for 6 hr/day, 5 days/wk for 6 wks and then assessed neurobehavioral measures after a 65-day period during which there were no exposures. The neurologic tests included the acoustic- startle response, prepulse inhibition of the acoustic-startle response, appetitive-reinforcer approach sensitization, forelimb grip strength, locomotor activity, tail-flick response, conspecific approach, passive avoidance, Porsalt forced-swim test, and Morris water maze. After the neurobehavioral testing, concentrations of norepinephrine, dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, serotonin, and 5-hydroxyindoleacetic acid in several regions of the brain and in blood were analyzed. Significant differences were observed between the JP-8 group and the JP-5 exposure group and controls in appetitive-reinforcer approach sensitization, and JP-5-exposed animals dis- played greater forelimb grip strengths than the other two groups. Significant differences in neurotransmitter concentrations were recorded relative to con- trols, although the perturbations in neurotransmitter concentrations were not identical in the JP-5 and JP-8 groups. The JP-5-exposed rats had increased dopamine and 3,4-dihydroxyphenylacetic acid concentrations in the hippocam- pus and cortex, respectively. In addition, JP-5 exposure was associated with lower concentrations of homovanillic acid in the hippocampus. In compari- son, JP-8 exposure was associated with decreased 3,4-dihydroxyphenylacetic concentrations in the cerebellum and brainstem. Blood 5-hydroxyindoleacetic acid was increased and decreased in the JP-5 and JP-8 groups, respectively.
66 Toxicologic A ssessment of Jet-Propulsion F uel 8 Nordholm et al. (1999) performed a study similar to that of Rossi et al. (2001). They examined the effects of repeated exposure to JP-4 on several neurobehavioral measures. Rats received whole-body exposure to JP-4 vapor at 2,000 mg/m3 for 6 hr/day for 14 days and were then tested after a short recovery period (14 days) or a long recovery period (60 days). Neurobehav- ioral measures assessed were forelimb grip strength, photosensitivity, appetitive-reinforcer approach sensitization, total locomotor activity, acoustic startle and prepulse inhibition, tail-flick response, and treadmill physical fa- tigue. Routine histologic tests were performed on the major organs, and the same set of neurotransmitters were examined as in the Rossi et al. (2001) study. A significant increase in the appetitive-reinforcer approach sensitization was observed in the short-recovery group but not the long-recovery group relative to controls. Total locomotor activity was decreased in the long-recov- ery group, but not the short-recovery group relative to controls. Similarly, only the long-recovery group displayed significant differences from controls in prepulse inhibition and treadmill response relative. No other significant differences in neurobehavioral assessments were reported. Blood serotonin was higher in the short-recovery group and blood 5-hydroxyindoleacetic acid significantly higher in the short- and long-recovery group than in controls. Serotonin and 5-hydroxyindoleacetic acid were higher in the cerebellum, brainstem, and hippocampal regions in the short-recovery group and long- recovery group. Serotonin and 5-hydoxyindoleacitic acid were higher in the striated and cortical regions in the short-recovery group and the long-recovery group, respectively, than in controls. Ritchie et al. (2000, 2001a,b) studied neurobehavioral effects of JP-8 vapor at 1,000 and 500 mg/m3 for 6 hr/day, 5 days/wk for 6 wk followed by no exposure for 64 days. No differences were observed in simple autoshaping, fixed-ratio, or spatial-reversal tasks between exposure groups and controls. On two of 15 assessments, the high-dose group was significantly impaired relative to the low-dose group regarding a difficult task that required one or more lever presses after an auditory cue. Similarly, in the more complicated incremental repeated-acquisition task, the high-dose group exhibited signifi- cant impairment relative to the low-dose group in two of six assessments. In contrast, the low-dose group demonstrated superior performance relative to controls in a test requiring three to four lever presses in a three-lever array. This investigation suggests decreased performance in operant tasks at the highest exposure, but the significance of the findings is questionable for sev- eral reasons. There are relatively few significantly different outcomes; and, when observed, these differences occur only between the high-dose and low- dose groups and not between low-dose and control groups or high-dose and control groups. Significant differences also are observed only for one or two
Effects of Jet-Propulsion Fuel 8 on the N ervous System 67 evaluations in a series of evaluations that otherwise demonstrate no significant differences. No dose-response relationships were demonstrated for either the neurobehavioral or the neurotransmitter measurements, and a conclusion of hormesis for the superior performance observed in the low-dose group ap- pears premature given that only two exposure concentrations were examined. Koschier (1999) reviewed the potential of dermal exposure to kerosene to cause adverse health effects. The author described a study in which rats were exposed to hydrodesulfurized kerosene dermally at 0, 165, 330, and 495 mg/kg for 5 days/wk for 13 wk. The rats were assessed with a FOB, and motor activity, startle response, and histologic characteristics were measured. All groups were examined after the 13-wk exposure, and the control and high- dose groups were also examined after a 4-wk recovery period. No significant differences were observed in any of the measures in any of the exposure groups. CONCLUSIONS AND RECOMMENDATIONS To evaluate the potential for JP-8 to cause adverse neurologic effects, the subcommittee reviewed the available data on the neurotoxicity of JP-8, related jet fuels, and kerosene in humans and experimental animals. The database on potential neurotoxicity of jet fuels is sparse, especially with regard to human studies. In an epidemiologic investigation, workers exposed to jet fuels at a Swedish jet-motor factory for an average of 17 yr were studied for possible adverse health effects. The overall TWA exposure concentration in one-time measurements was 300 mg/m3; peak exposures were about 1,200-3,200 mg/m3. Significant differences between exposed and unexposed workers were found with respect to nervous system effects. Most of the exposed workers reported acute symptoms, such as dizziness, headache, nausea, and fatigue. Chronic symptoms included a greater incidence of neurasthenic symptoms, such as depressed mood, lack of initiative, sleep disturbances, memory impair- ment, headache, dizziness, and fatigue. However, the findings of nervous system effects attributable to long-term exposure were considered question- able for a number of reasons, including weak and inconsistent evidence of impairment, inadequate methods of evaluation, inadequate consideration of confounding factors, a small cohort of workers, and a lack of quantitative information on exposure. Preliminary results of a recent epidemiologic study on Air Force personnel occupationally exposed to JP-8 indicated that JP-8 exposure for 1 hr per day, 2 times per wk for 9 months may produce neurotoxic effects. In a self-assess- ment questionnaire, JP-8-exposed Air Force personnel reported more head-
68 Toxicologic A ssessment of Jet-Propulsion F uel 8 aches, dizziness, trouble concentrating, balance problems, walking difficulties, forgetfulness, and trouble with gripping objects than an unexposed (control) group. In that study, JP-8-exposed Air Force personnel also showed lower performance than a control group on several neurobehavioral tests and distur- bances of balance and altered eye-blink conditioning response. The lack of exposure information makes it difficult to determine the extent of the health risk. Animal studies have investigated the effects of several jet fuels on a num- ber of neurobehavioral end points. Several studies showed neurobehavioral effects in F344 and Sprague-Dawley rats exposed to JP-8 and JP-5 vapors at concentrations of about 1,000 mg/m3 for 6 hr per day, 5 days per week for 6 wk or to JP-8 aerosols at concentrations of 1,059 mg/m3 for 1 hr per day, 5 days per week for 4 wk. No dose-response relationships were demonstrated in the studies. Furthermore, the relevance of the observed neurobehavioral effects to humans is not known, and these positive findings need to be vali- dated against other well-established neurotoxicity end points. However, the findings provide an indication that the interim PEL of 350 mg/m3 might be too high to be protective of human health. The subcommittee recommends additional research to measure ambient and breathing-zone concentrations of JP-8 and its constituents (such as naph- thalene and toluene) and to determine body burden through assays of biologic samples for JP-8 constituents and metabolites. The findings should be corre- lated with acute and chronic symptoms and signs experienced by JP-8-exposed people. Preliminary positive findings reported in two neurologic tests (eye- blink and postoral-sway tests) conducted as part of a recent Air Force human study should be validated with standard neurologic tests. The subcommittee also recommends studies in experimental animals to examine the potential neurotoxic effects of JP-8. Specifically, the subcommit- tee recommends that neurologic (histologic, physiologic, and behavioral) measures be included in inhalation-toxicity tests with JP-8 vapors and mixtures of vapors and aerosols. 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 neurotoxicity of JP-8 (e.g., testing JP-8 samples at the extremes of their composition ranges or testing JP-8 sam- ples so that the concentrations of component classes can be correlated with toxic end points). REFERENCES Andrews, L.S., and R. Snyder. 1986. Toxic effects of solvents and vapors. Pp. 636- 668 in Casarett and Do ullâs Toxicology: The Basic S cience of Poisons, 3rd Ed.,
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