7

Effects of Military Fuel Vapors on the Central Nervous System

All volatile hydrocarbons are central-nervous-system (CNS) depressants and can produce anesthesia or asphyxia at sufficiently high concentrations (Andrews and Snyder, 1986; Marshall and Wollman, 1985). The extent to which vapors from JP-5, JP-8, and DFM are effective as CNS depressants depends on the volatility of their component hydrocarbons. The vapors from these fuels contain a mixture of volatile hydrocarbons. The achievable depth of anesthesia and the rate at which anesthesia occurs are related to the minimum alveolar concentration (MAC). MAC, expressed as percent of air in the alveolus, is the concentration necessary to produce anesthesia for the components of the vapor and their blood/air partition coefficients. If the MAC is low (e.g., halothane = 0.75% and methoxyflurane = 0.16%), the chemical is a highly potent anesthetic. If the MAC is high (e.g., nitrous oxide = 105%), the chemical is not a potent anesthetic. However, if the blood/gas partition ratio is high (e.g., methoxyflu



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Permissible Exposure Levels for Selected Military Fuel Vapors 7 Effects of Military Fuel Vapors on the Central Nervous System All volatile hydrocarbons are central-nervous-system (CNS) depressants and can produce anesthesia or asphyxia at sufficiently high concentrations (Andrews and Snyder, 1986; Marshall and Wollman, 1985). The extent to which vapors from JP-5, JP-8, and DFM are effective as CNS depressants depends on the volatility of their component hydrocarbons. The vapors from these fuels contain a mixture of volatile hydrocarbons. The achievable depth of anesthesia and the rate at which anesthesia occurs are related to the minimum alveolar concentration (MAC). MAC, expressed as percent of air in the alveolus, is the concentration necessary to produce anesthesia for the components of the vapor and their blood/air partition coefficients. If the MAC is low (e.g., halothane = 0.75% and methoxyflurane = 0.16%), the chemical is a highly potent anesthetic. If the MAC is high (e.g., nitrous oxide = 105%), the chemical is not a potent anesthetic. However, if the blood/gas partition ratio is high (e.g., methoxyflu

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Permissible Exposure Levels for Selected Military Fuel Vapors rane = 12), the rate of anesthesia is slow; if the blood/gas partition ratio is low (e.g., halothane = 2.3 and nitrous oxide = 0.47), the rate of anesthesia is rapid. Volatility also remains a key factor among the fuels. The maximum vapor concentration achievable with methoxyflurane is only 3%, whereas halothane can achieve a concentration of 32%. Thus, the degree to which the components of the fuel can volatilize, their potency as CNS depressants, and their blood/air partition coefficients are the determining factors in their ability to depress the CNS. These values have not been reported for JP-5, JP-8, and DFM. NEUROPHYSIOLOGICAL AND PSYCHOLOGICAL EFFECTS OF FUEL VAPORS Many organic solvents, including those that are components of military fuels, have the potential to cause narcosis and death after acute exposure. Workers acutely exposed to high concentrations of solvents typically show signs of CNS disturbance. Effects of acute high-level exposure include disorientation, euphoria, giddiness, confusion, tremor, and convulsions. Recovery from CNS effects is rapid and complete in the majority of subjects following removal from exposure. For example, Davies (1964) described a jet pilot who experienced exposure to JP-4 from a fuel leak in the cockpit during flight. It was estimated that the vapor concentration to which he was exposed reached 3,000-7,000 ppm (24,000-56,000 mg/m3). He reported feeling groggy and weak and was forced to land his aircraft. Upon landing, he demonstrated a staggering gait, slurring of speech, and a number of signs indicative of early anesthesia. Physical examination revealed an odor of fuel on his flying suit; a slight stagger to his gait; slurring of speech; peripheral sensory loss (positive Romberg); generalized, mild muscular weak

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Permissible Exposure Levels for Selected Military Fuel Vapors ness; and possible decreased sensation to pain on the surface of his arm. The pilot had previous experience with hypoxia and denied that it resembled the present episode. He reported that he did not feel "normal" for 36 hr after exposure but appeared in good condition during the next few days and 5 months later. Porter (1990) described the effects experienced by two aviators after acute exposure to JP-5 fuel vapor. Symptoms included headache, nausea, euphoria, memory defects, wobbly gait, impaired hand-eye coordination, runny nose, sneezing, anorexia, and excessive fatigue. The examination of blood and urine from both aviators was negative for aromatic hydrocarbons and carbon monoxide (<1%). Abnormalities on physical examination included ill appearance, conjunctivitis, and mild hypertension. Neurological examination was normal. Symptoms disappeared over the next 4 days. Other aviators in the same squadron reported similar symptoms after exposure to JP-5 in their cockpits. Volatilization of JP-8 and DFM would likely produce effects similar to those observed for JP-5. However, volatility for each fuel would be different, resulting in different vapor concentrations and, therefore, differences in severity of the effects. Data on the effects of chronic exposure to jet fuels are sparse. Knave and co-workers reported on two groups of aircraft factory workers exposed to jet fuels (Knave et al., 1976a,b, 1978, 1979; Struwe et al., 1983). The first study group consisted of 29 workers at an aircraft factory in Sweden (Knave et al., 1976a,b). The workers were selected from employer records and interviews and were identified as those “considerably exposed to fuel fumes from 1955 on.” No control group was used in the study. Workers were exposed to jet fuels designated Jet A-1 and JP-1, which Knave et al. (1976a) described as having “raw gasoline and kerosene as their principal components.” Exposure occurred during the construction, testing, and installation of fuel systems in aircraft. No measurements of exposure concentrations were made during this study. However, the workers were divided into two groups of “heavily” exposed (n = 13) and “less heavily” exposed

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Permissible Exposure Levels for Selected Military Fuel Vapors workers (n = 16). The heavily exposed group (group A) had exposure described as “continuous exposure for several hours daily to high concentrations of jet fuel fumes in the fuel rig or the test cells or intermittent exposure to high concentrations for at least 20-30 min each time with an average frequency of at least every second or third week.” Exposure of the less heavily exposed group (group B) was characterized as “less frequent intermittent exposure that group A.” A multicomponent evaluation of neurological and psychiatric factors was made. The workers were questioned about personal history and the occurrence of symptoms of neurasthenia and polyneuropathy. They were given neurological examinations designed to evaluate peripheral nerve function. Finally, measurements were made of conduction velocities in peripheral motor nerves and sensation thresholds of vibration in the extremities. The results of the evaluation were as follows. All workers in group A and 7 of 16 workers in group B reported repeated experience of acute symptoms of exposure during work, including dizziness, headache, nausea, respiratory tract symptoms, palpitations, and a feeling of pressure on the chest. They reported that on such occasions they needed to interrupt their work to “get a breath of fresh air.” One or more chronic symptoms described as indicative of neurasthenia and psychasthenia were reported by 12 of 13 workers in group A and by 9 of 16 workers in group B. Ten workers in group A and seven in group B had consulted a physician about these symptoms. One or more symptoms indicative of polyneuropathy (restless legs, muscle cramps, diffuse pain in extremities, distal paresthesia and numbness, or paresis) were reported by 11 of 13 workers in group A and 6 of 16 in group B. The clinical examination of peripheral nerve function revealed one or more of the neurological signs at the mildest level in 10 of 13 workers in group A and 7 of 16 in group B. Because no control group was evaluated in this study, the nerve conduction velocity and vibration threshold findings were com

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Permissible Exposure Levels for Selected Military Fuel Vapors pared with a reference group from another study of an industrial population by the same authors. No remarkable differences were found between the jet-fuel-exposed groups and the reference group. Knave and co-workers compared the prevalence of symptoms of neurasthenia, psychasthenia, and polyneuropathy and signs of polyneuropathy with symptoms and signs observed in reference populations from their previous studies of industrial populations. Based on the results from the reference groups, the authors concluded that the jet-fuel-exposed workers exhibited higher prevalence of those symptoms and signs than expected. Knave and co-workers noted the need for further blind controlled studies of workers chronically exposed to jet fuels. To obtain more information on chronic neurological effects of jet fuels, Knave et al. (1978) conducted another study of workers in a jet-motor factory. Workers in manufacturing sections where they were not exposed to jet fuels were used as controls for the workers exposed in areas of the factory where jet motors were assembled and tested. Exposed workers were selected by a committee consisting of representatives of management, trade unions, and the health department of the factory. The committee selected 30 of the most heavily exposed workers from all the employees who had regular or intermittent contact with jet fuels. Average and median employment duration was 17.7 and 19 years, respectively. The original control group of 30 was matched by age only. Later, a more rigorous procedure was used to assemble a final control group of 30, which was matched by age, duration of employment, educational level, and trade-union activity. The original control group was evaluated for some of the end points, most notably the psychiatric evaluations, but most results were reported only for the final control group. In their 1979 report, Knave et al. reported findings on neurasthenia for both the original and the final control group; in the 1978 report, results were generally reported only for the final control group. Exposure was evaluated quantitatively using personal air sam

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Permissible Exposure Levels for Selected Military Fuel Vapors plers attached to workers during regular working activities. Exposure concentrations varied widely, with some measurements exceeding 3,200 mg/m3. The authors calculated time averages for various activities. The resulting average concentrations ranged from 85 to 974 mg/m3. The authors reported that the overall average exposure concentration was approximately 300 mg/m3. The average exposure concentrations for specific tasks were 423 mg/m3 for component testers, 128 mg/m3 for engine testers, and 185-248 mg/m3 for mechanics. Exposed and control subjects were evaluated via medical history, standardized interview for neurasthenic symptoms, clinical neurological examination, psychiatric interviews and ratings, psychological tests, and neurophysiological examinations including EEGs, nerve conduction velocities, and vibration sensation thresholds. The results of these evaluations were reported by Knave et al. (1978). More detailed findings on the neurasthenic symptoms were described in a later report (Knave et al., 1979). Finally a detailed psychiatric followup on a subset of the exposed workers was reported by Struwe et al. (1983). Knave et al. (1978) reported that 21 of the 30 exposed workers reported that they had experienced recurrent acute symptoms upon exposure. Important differences between the exposed the control groups also were higher prevalence of neurasthenic symptoms, greater irregularity of performance on a test of complex reaction time, greater performance decrement over time in a simple reaction-time task, and poorer performance in a task of perceptual speed. There are several problems with these studies, however. Even though reviewers might have been blind to exposure status, the exposed subjects almost certainly knew their status, which might

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Permissible Exposure Levels for Selected Military Fuel Vapors introduce information bias in a situation where acute symptoms had been experienced. The Knave studies cannot distinguish the psychological effects of acute symptoms or knowledge of exposure from the chronic effects of generally intermittent exposure. Moreover, the control group reported relatively high prevalence of certain symptoms of neurasthenia, anxiety, or mental depression. In part, this might be because the authors relied on a diagnosis of neurasthenia that is not consistent with the diagnostic criteria usually described for neurasthenia, e.g., dysthymia. The results of three tests cited by Knave et al. (reaction time, simple reaction time, and perceptual speed) showed a difference between exposed and control groups. The authors attribute that difference to a greater variation in individual performance among present workers than in previous studies. Knave et al. (1978) stated that the examined groups were more heterogeneous with respect to education. In contrast to the psychiatric findings, the neurophysiological measurements indicated that nearly all subjects were clinically normal and provided only suggestive evidence of polyneuropathy. These neurophysiological measurements were technically crude and would not meet currently accepted methods for defining polyneuropathy and peripheral neuropathy (e.g., see Sweeney et al., 1993). Thus, the meaning of the neurophysiological findings is not clear. For example, the statistically significant differences in electroencephalograms (EEGs) suggested functional deficits to the authors, even though the EEGs were considered clinically normal in almost all the subjects, and certain analyses were "contradictory to an EEG change acutely induced" (Knave et al., 1978). The authors concluded that the data suggest a psycho-organic syndrome from chronic exposure. However, the data provide evidence of acute symptoms only. A major stumbling block in evaluating the neuropsychological effects of environmental exposures is the lack of a standardized test battery that can be administered in a relatively short time

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Permissible Exposure Levels for Selected Military Fuel Vapors and scored in a reliable fashion. The Knave et al. (1976a,b, 1978, 1979) and Struwe et al. (1983) studies used several tests to measure sensory, cognitive, affective, and motor symptoms. A modified version of the Comprehensive Psychopathological Ratings Score was administered to evaluate psychiatric symptoms. Knave et al. reported that the exposed workers were significantly different from the unexposed controls with regard to the incidence and prevalence of psychiatric symptoms. These tests can be considered to be a standard battery and reliably scored. Typical instruments used currently to assess personality, mood, and symptoms are self-administered checklists with rating scales (see Ehle and McKee, 1990, p. 254). Knave and co-workers used an interview technique that might have been susceptible to interviewer bias. Interpreting the results of these tests is difficult because of the lack of consideration of possible confounding factors (such as workers ' overall health, work conditions, and job satisfaction), and possible sources of bias in the testing procedures and selection factors. Knave et al. (1978) also reported significant differences between the exposed and unexposed groups in the results of psychological tests that focus on attention and sensorimotor speed. Two psychomotor tests administered in the study evaluated reaction time. Because tests that measure reaction time can be influenced by the subject's age, alertness, and motivation, the results of such tests at the least are hard to interpret and might lack meaning. Interestingly, the results of a test also measuring visuomotor and psychomotor performance, the Santa Ana test of manual dexterity, were not significantly different in the two groups in the Knave studies. A neuropsychological test based on a modified version of the Bourdon-Wiersma test was also administered. The Bourdon-Wiersma test is designed to measure more-complex cognitive function, such as attention, discrimination of perceived details, and visuomotor reaction time. Even though Knave and co-workers reported significant differences between the groups in that test, the tests of memory (recognition and reproduction) were not different.

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Permissible Exposure Levels for Selected Military Fuel Vapors Attribution of a chronic neurological syndrome to solvent or other organic chemical exposures has been a controversial issue. In 1986, participants of an International Consensus Workshop (ICW) published a paper designed to bring some rigor and adequate criteria to studies investigating psychiatric and psychological effects of hydrocarbon exposures (ICW, 1986). The ICW (1986) suggested a preliminary classification system to describe the symptoms and results of psychiatric and psychological tests used in evaluating long-term damage to the CNS. Workshop participants suggested that neuropsychologists need to provide data to document the presence and degree of impairment in subjects and to assist in separating solvent poisoning from other disorders or conditions. These kinds of data were not adequately provided in the Knave studies, which had been conducted nearly 10 years earlier. The ICW (1986) also stated that tests administered to determine impairments should be psychometrically sound and have adequate normative data from the relative population. Further, evaluations should ensure that low test scores are not simply a function of poor cooperation or low motivation. The variables cited by the ICW (1986) for consideration as confounders, interferences with testing, or modifiers of the effects of solvents included age, gender, ethnicity, previous head trauma, hobby exposures, alcohol consumption, drug use, genetic factors, exposure to other chemicals, and preexisting diseases or conditions. The ICW concluded that the validity, reliability, sensitivity, specificity, and predictive value of various neurological and psychological tests needed to be established as a basis for screening exposed workers for neurotoxic effects. Many of the more recent standards were not met in the Knave studies. Finally, the bulk of the work in the Knave studies was performed on a single cohort of 30 persons. Additional studies of other populations would be useful in evaluating and interpreting the findings presented by Knave et al. (1978). In animal studies, Bogo et al. (1984) investigated the effects of petroleum- and shale-oil-derived JP-5 in Sprague-Dawley rats ex

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Permissible Exposure Levels for Selected Military Fuel Vapors posed by inhalation at concentrations below those resulting in anesthesia. An airborne concentration of 1,600 mg/m3 was generated, and the rats were exposed 6 hr per day, 5 days per week for 30 days. There was a significant increase in water intake in exposed rats, but no other alterations in behavior were observed. Kinkead et al. (1993) investigated the acute toxicity of petroleum-derived JP-4 in six male Sprague-Dawley rats exposed to JP-4 vapor at a concentration of 38.3 mg/L for 6 hr. The coordination of the rats was affected after 10 min of exposure, followed by convulsions, which occurred sporadically throughout the exposure. There were no deaths during the exposure or for 14 days after the exposure. RELATIONSHIP BETWEEN STEL AND MINIMUM ALVEOLAR CONCENTRATIONS Establishment of a 15-min STEL for the volatile components of military fuels involves determining an air concentration of vapor, exposure to which will not lead to a loss of ability of the average worker to perform the tasks expected for up to 15 min. In theory, all organic vapors are potential anesthetics that differ primarily in potency. Therefore, the minimum alveolar concentrations (MACs) for the volatile components of military fuels may be used to help establish STELs. Exposure at the MAC of an anesthetic results in lack of movement in an average patient challenged with a standardized surgical incision. Selection of a dose that ensures that 100% of the population of patients will exhibit anesthesia can usually be accomplished by multiplying the MAC value by 1.3, i.e., about 30% higher than the MAC. If the dose-response curve for these agents is symmetrical, then a value that is approximately 30% below the MAC would not be expected to produce anesthesia in any patient. The actual distribution of patient sensitivities is usually not known, however. Establishment of a STEL also involves defining an exposure

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Permissible Exposure Levels for Selected Military Fuel Vapors level that will not reduce acceptable work activity. However, exposures just below the MAC divided by 1.3 might result in other signs of vapor intoxication, such as unsteadiness, inability to concentrate, and impaired motor coordination. For most vapors, a dose that is 10-50 times lower than the MAC will not impair working ability. The subcommittee's estimate of dose levels for known anesthetics that would not impair performance are shown in Table 7-1. In addition to knowing the concentration of vapor necessary to produce anesthesia, it is important to factor in the partition coefficient because it is directly related to the time necessary to establish anesthesia. The calculation of the coefficient is discussed in detail in Chapter 3. For the anesthetics mentioned above the partition coefficients are Cyclopropane 0.41 Diethyl ether 12.1 Enflurane 1.8 Halothane 2.3 Methoxyflurane 12.0 As stated in Chapter 3, the higher the partition coefficient (i.e., the more soluble the gas is in blood), the slower the onset of anesthesia regardless of the relative potencies of the gases. Thus, in establishing the STEL for vapors having a high partition coefficient, application of a 10-fold safety factor might be appropriate, whereas a 50-fold safety factor might be more appropriate for vapors displaying a low partition coefficient because of the rapid onset of anesthesia. CONCLUSIONS In one epidemiological investigation, 30 workers exposed to jet fuel at a Swedish jet-motor factory for an average of 17 years

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Permissible Exposure Levels for Selected Military Fuel Vapors TABLE 7-1 Percentages of MACs of Known Anesthetics     Expected Dose for 100% Response (1.3 × MAC) Expected Dose for Zero Response (0.7 × MAC) Estimated NOELsa Anesthetic MAC, %     1/10b 1/50c Cyclopropane 9.2 11.96 6.44 0.64 0.13 Diethyl ether 1.92 2.50 1.34 0.13 0.03 Enflurane 1.68 2.18 1.18 0.12 0.02 Halothane 0.75 0.98 0.53 0.05 0.01 Methoxyflurane 0.16 0.21 0.11 0.01 0.002 a NOELs, no-observed-effect levels. b Expected zero-response level divided by 10. c Expected zero-response level divided by 50.

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Permissible Exposure Levels for Selected Military Fuel Vapors were studied for possible adverse health effects. The TWA exposure concentrations from one-time measurements of workers in different job categories were calculated to be 420 mg/m3 for component testers, 130 mg/m3 for engine testers, and 190-250 mg/m3 for mechanics. The overall TWA concentration from one-time measurements was 300 mg/m3; peak exposures ranged from approximately 1,200 to 3,200 mg/m3. Significant differences between the exposed and nonexposed workers were found with respect to CNS effects. The majority of the exposed workers reported acute symptoms of dizziness, headache, nausea, and fatigue. Chronic symptoms included greater incidence of neurasthenic symptoms (depressed mood, lack of initiative, sleep disturbances, memory impairment, headache, dizziness, and fatigue). The exposed workers also showed higher performance degradation in a variety of performance tests than the nonexposed workers. The neurophysiological examination with electroencephalograms showed greater incidence of abnormalities in jet-fuel exposed workers than in nonexposed workers. However, the findings of CNS effects attributable to long-term exposure were considered questionable 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.