Review of Tests Assessing Neurologic Function in Persons Exposed to Jet Fuels
This appendix described four types of tests that have been used to assess the neurotoxicity potential of jet-propulsion fuel 8 and related fuels in humans: clinical neurological examinations, posturograms, nerve conduction studies, vibration sensation studies, and blink reflex classical conditioning studies. For each test, a critical analysis of its use in assessing neurotoxicity from exposure to jet fuels is presented. Limitations of these tests are also presented.
CLINICAL NEUROLOGIC EXAMINATIONS
Neurological examinations of 29 aircraft factory workers chronically exposed to jet fuel vapors revealed findings consistent with central and peripheral nervous system involvement (Knave et al. 1976). The exposed subjects were classified into two groups: heavily exposed (n = 13) and less heavily exposed (n = 16). Subjects from both groups (all of the heavily exposed workers and 7 of the 16 less heavily exposed workers) reported having repeatedly experienced acute effects of jet fuel exposure such as dizziness, headache, nausea, respiratory tract symptoms, heart palpitations, and a feeling of pressure on the chest. Symptoms indicative of peripheral neuropathy included muscle cramps, distal paresthesias, numbness, and paresis. Signs indicative of peripheral neuropathy on clinical neurological examination included re-
duced sensory perception particularly of pain and temperature sense among the subjects from the heavily exposed group. A high rate of symptoms indicative of CNS involvement (neurasthenia and psychasthenia) was also observed in the two exposed groups on comparison with the reference groups.
Posturogram measures spontaneous body sway, which is considered to be a quantitative version of the Romberg test, which is a simple clinical test of the integrated postural pathways and mechanisms (i.e., peripheral nerve fibers, spinal cord pathways, vestibular system components, and the cerebellum). The posturogram is a way of measuring a person's ability to maintain an up-right posture against variable perturbations. Performance on posturogram is a function of gender, age, and vision (Kollegger et al. 1992; Black et al. 1982; Thyssen et al. 1982). Various posturography techniques are available to provide quantitative measures. Posturogram performance deficits have been associated with exposures to various solvents including toluene, xylene, and jet fuel (Smith et al. 1997; Yokoyama et al. 1997).
The validity and reliability of the posturogram as a measure of central and peripheral nervous system function has been demonstrated in various studies. Posturogram findings have been shown to positively correlate with other measures of vestibular function such as positional nystagmus demonstrating the validity of this test (Kubo et al. 1990). Studies in subjects who consumed ethanol immediately before testing showed disturbances in body sway that correlated with the amount of ethanol consumed indicating that this test is a sensitive and valid measure of CNS dysfunction induced by neurotoxicants that are known to affect balance and the severity of the deficit can reflect the exposure dose (Mills and Bisgrove 1983; Lukas et al. 1989; Kubo et al. 1989). Studies by Benvenuti et al. (1999) demonstrated the consistency of posturogram findings on test-retest among geriatric subjects with disequilibrium demonstrating the reliability of this test as well as its validity.
Although the results of a study by Uimonen et al. (1995) indicate that the posturogram of a malingerer can be differentiated from that of a subject with vestibular neuritis by body sway velocity, these findings should be interpreted with caution. The administration of neuropsychological tests sensitive to malingering and motivation such as the Test of Memory and Motivation (TOMM) can be administered along with the posturogram and other conventional tests of neurological function to further differentiate those patients with a true performance deficit from those with deficits induced by factors such as secondary gain. Patients involved in litigation who have abnormal TOMM
scores and abnormal posturograms may have motivational influences that are affecting their performances.
Unfortunately, although the sensitivity of posturography is relatively high, the specificity of this test as a measure of neurotoxicant exposure-induced effects is relatively low as it reveals deficits due to many factors (e.g., diabetes and head injury). Thus, the findings on posturogram must also be interpreted in light of their correlation with other measures of neurophysiological and neuropsychological function as well as with the patient’s medical history and his or her history of neurotoxicant exposure to parse out the locus of the lesion (i.e., central v. peripheral). For example, the Digit Symbol Test is a neuropsychological measure of psychomotor function that has been shown to positively correlate with posturography findings among patients exposed to ethanol and central acting pharmaceuticals (Lukas et al. 1989; Allen and Lader 1992). Nerve conduction studies have been shown to positively correlate with posturography findings among patients with diabetic neuropathy (Uccioli et al. 1995).
In conclusion, posturography is a reasonable test to use to corroborate with data from neurophysiological and neuropsychological tests but performance on this test cannot be relied upon exclusively to establish exposure limits for neurotoxicants encountered in the workplace.
NERVE CONDUCTION STUDIES
Peripheral neuropathy has been reported in subjects exposed to various solvents including n-hexane and jet fuels. Neurological and neurophysiological examinations of 29 aircraft factory workers chronically exposed to jet fuel vapors findings consistent with peripheral neuropathy (Knave et al. 1976). The exposed subjects were classified into two groups: heavily exposed (n = 13) and less heavily exposed (n = 16). Clinical neurological examinations, nerve conduction velocities studies, and assessments of vibration sensation thresholds were performed on all subjects. All subjects in the heavily exposed group and 7 of 16 from the less heavily exposed reported having repeatedly experienced acute effects such as dizziness, headache, nausea, respiratory tract symptoms, heart palpitations, a feeling of pressure on the chest during exposures to jet fuel vapors in their inhaled air. A high rate of symptoms indicative of neurasthenia and psychasthenia and symptoms and signs indicative of polyneuropathy was observed both in the heavily exposed group and in the two groups combined in comparison with reference groups.
Nerve conduction studies have been used extensively to study peripheral nerve function. These tests have been shown to be valid marker of nerve damage and a correlated with pathological findings. These tests have been
shown to be reliable with good retest reliability and good interrator reliability due to established normal values and stringent testing procedures and protocols (Kimura 2001). Based on its review of the literature, the subcommittee concludes that nerve conduction studies are a good marker of neurological injury due to exposures to neurotoxicants and that the findings from this test can be relied upon to establish occupational and environmental exposure limits.
Vibration sensation thresholds were used to assess functioning in 29 aircraft factory workers chronically exposed to jet fuel vapors and who reported symptoms consistent with peripheral neuropathy (Knave et al. 1976). The exposed subjects were classified into two groups: heavily exposed (n = 13) and less heavily exposed (n = 16) and were compared with unexposed controls. Comparison of the subjects from the high-exposure group with controls revealed significant differences on vibration sensation thresholds.
The vibration sensation test is purported to be a quantitative measure of perception of a vibrating stimulus. It is used to see if a person can volitionally tell the examiner when a stimulus is first perceived. It is intended to reveal impairment in the ability of a peripheral nerve to conduct an impulse. If the subject has a high threshold for this test, it is suggested by the amount of time the subject requires for acknowledging his/her perception of the stimulus. This test is subject to embellishment by the examinee and to observer bias by the test administrator. Such impairments detected on screening tests such as this must be correlated with other more objective tests for evidence of peripheral neuropathy such as nerve conduction velocities, tendon reflex responses, and patterns of sensory loss detected by pin prick perception.
In conclusion, the subcommittee’s review of the literature suggests that the use of this test to assess peripheral nerve function among persons exposed to neurotoxicants is reasonable if corroborated with data from conventional validated neurophysiological tests. However, performance on this test cannot be relied upon by itself to establish exposure levels for neurotoxicants.
BLINK REFLEX CLASSICAL CONDITIONING
The use of blink reflex classical conditioning to investigate motor learning in subjects exposed to neurotoxicants has been suggested. Bekkedal et al. (2001) reported that the blink reflex conditioning response may be affected by exposure to JP-8. It has been shown that the cerebellum is involved in the
acquisition of motor skills and procedural learning (Corkin 1968; Sanes et al. 1990; Laforce and Doyon 2001). The data reviewed indicate that the blink reflex classical conditioning test is a valid marker of cerebellar function (Bracha et al. 1997; Glocker et al. 1999; Sears et al. 2000; Sommer et al. 2001). However, there are few comprehensive studies supporting the validity of this test by showing that it correlates positively with other measures of motor function and does not correlate positively with irrelevant measures (Sommer et al. 2001). Furthermore, the interrator reliability and test-retest reliability have not been fully established for this test. In addition, it has not been shown that this test would be practical to use from both a cost and risk versus benefits perspective in research studies.
The subcommittee concludes that the use of this test to assess cerebellar function among persons exposed to neurotoxicants is reasonable, but the data should not be relied upon exclusively and must be corroborated with data from conventional validated neuropsychological and neurophysiological tests particularly if it is to be used to establish exposure levels for neurotoxicants.
Allen, D., and M. Lader. 1992. The interactions of ethanol with single and repeated doses of suriclone and diazepam on physiological and psychomotor functions in normal subjects. Eur. J. Clin. Pharmacol. 42(5):499-505.
Bekkedal, M.Y.V., S.M. McInturf, G.D. Ritchie, and J. Rossi III. 2001. Eyeblink conditioning response test used to assess performance in JP-8 exposed air force personnel. Pp. 69-71 in JP8 Final Risk Assessment. The Institute of Environmental and Human Health (TIEHH), Lubbock, TX. August 2001.
Benvenuti, F., R. Mecacci, I. Gineprari, S. Bandinelli, E. Benvenuti, L. Ferrucci, A. Baroni, M. Rabuffetti, M. Hallett, J.M. Dambrosia, and S.J. Stanhope. 1999. Kinematic characteristics of standing disequilibrium: Reliability and validity of a posturographic protocol. Arch. Phys. Med. Rehabil. 80(3):278-287.
Black, F.O., C. Wall III, H.E. Rockette Jr., and R. Kitch. 1982. Normal subject postural sway during the Romberg test. Am. J. Otolaryngol. 3(5):309-318.
Bracha, V., L. Zhao, D.A. Wunderlich, S.J. Morrissy, and J.R. Bloedel. 1997. Patients with cerebellar lesions cannot acquire but are able to retain conditioned eyeblink reflexes. Brain120(Pt 8):1401-1413.
Corkin, S.1968. Acquisition of motor skill after bilateral medial temporal-lobe excision. Neuropsycologia6(3):255-265.
Glocker, F.X., M. Lauk, D. Foll, B. Koster, B. Guschlbauer, J. Timmer, G. Deuschl, and C.H. Lucking. 1999. Classical conditioning of the electrically elicited blink reflex in humans: A new method of data analysis. J. Neurosci. Methods89(2): 133-140.
Kimura, J.2001. Electrodiagnosis in Diseases of Nerve and Muscle: Principles and Practice, 3rd Ed. New York: Oxford University Press.
Kollegger, H., C. Baumgartner, C. Wober, W. Oder, and L. Deecke. 1992. Spontaneous body sway as a function of sex, age, and vision: Posturographic study in 30 healthy adults. Eur. Neurol.32(5):253-259.
Knave, B., H.E. Persson, J.M. Goldberg, and P. Westerholm. 1976. Long-term exposure to jet fuel: An investigation on occupationally exposed workers with special reference to the nervous system. Scand. J. Work Environ. Health2(3):152-164.
Kubo, T., Y. Sakata, T. Matsunaga, A. Koshimune, S. Sakai, K. Ameno, and I. Ijiri. 1989. Analysis of body sway pattern after alcohol ingestion in human subjects. Acta Otolaryngol. 468(Suppl):247-252.
Kubo, T., Y. Sakata, A. Koshimune, S. Sakai, K. Ameno, and I. Ijiri. 1990. Positional nystagmus and body sway after alcohol ingestion. Am. J. Otolaryngol. 11(6):416-419.
Laforce Jr., R., and J. Doyon. 2001. Distinct contribution of the striatum and cerebellum to motor learning. Brain Cogn.45(2):189-211.
Lukas, S.E., B.W. Lex, J.P. Slater, N.E. Greenwald, and J.H. Mendelson. 1989. A microanalysis of ethanol-induced disruption of body sway and psychomotor performance in women. Psychopharmacology (Berl)98(2):169-175.
Mills, K.C., and E.Z. Bisgrove. 1983. Body sway and divided attention performance under the influence of alcohol: Dose-response differences between males and females. Alcohol Clin. Exp. Res.7(4):393-397.
Sanes, J.N., B. Dimitrov, and M. Hallett. 1990. Motor learning in patients with cerebellar dysfunction. Brain113(Pt 1):103-120.
Sears, L.L., N.C. Andreasen, and D.S. O'Leary. 2000. Cerebellar functional abnormalities in schizophrenia are suggested by classical eyeblink conditioning. Biol. Psychiatry48(3):204-209.
Smith, L.B., A. Bhattacharya, G. Lemasters, P. Succop, E. Puhala II, M. Medvedovic, and J. Joyce. 1997. Effect of chronic low-level exposure to jet fuel on postural balance of US Air Force personnel. J. Occup. Environ. Med.39(7):623-632.
Sommer, M., J. Grafman, I. Litvan, and M. Hallett. 2001. Impairment of eyeblink classical conditioning in progressive supranuclear palsy. Mov. Disord.16(2):240-251.
Thyssen, H.H., J. Brynskov, E.C. Jansen, and J. Munster-Swendsen. 1982. Normal ranges and reproducibility for the quantitative Romberg's test. Acta Neurol. Scand66(1):100-104.
Uccioli, L., P.G. Giacomini, G. Monticone, A. Magrini, L. Durola, E. Bruno, L. Parisi, S. Di Girolamo, and G. Menzinger. 1995. Body sway in diabetic neuropathy. Diabetes Care18(3):339-344.
Uimonen, S., K. Laitakari, H. Kiukaanniemi, and M. Sorri. 1995. Does posturography differentiate malingerers from vertiginous patients?J. Vestib. Res.5(2):117-124.
Yokoyama, K., S. Araki, K. Murata, M. Nishikitani, K. Nakaaki, J. Yokota, A. Ito, and E. Sakata. 1997. Postural sway frequency analysis in workers exposed to n-hexane, xylene, and toluene: Assessment of subclinical cerebellar dysfunction. Environ Res.74(2):110-115