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Effects on human performance from acute and chronic exposure to organic solvents: A short review
Toxicology, 49 (1988) 349--358 Elsevier ScientificPublishers Ireland Ltd.
E F F E C T S ON H U M A N P E R F O R M A N C E F R O M ACUTE AND CHRONIC E X P O S U R E TO O R G A N I C SOLVENTS: A SHORT R E V I E W
ANDERS IREGREN Research Unit of Psychophysiology, National Institute of Occupational Health, S-171 84 Solna (Sweden)
SUMMARY The present short review deals with investigations of CNS-effects from acute and chronic exposure to some organic solvents and solvent mixtures, as measured by human performance. Some of the methodological problems in experimental and epidemiological investigations of effects from solvent exposure are discussed. Problem areas where further research is needed are indicated, and some methodological suggestions for future studies are presented.
words: Acute Performance effects
Key
exposure;
Chronic
exposure;
Organic
solvents;
INTRODUCTION The determination of limits for occupational and environmental exposure to neurotoxic substances is a major challenge to toxicologists, and many methodological and ethical problems are encountered in the process of gathering data relevant for setting of limits. The present paper discusses some of these problems, illustrating them with examples from research concerning the effects of exposure to organic solvents. However, this short paper should be regarded as an abstract. For more comprehensive reviews the reader is recommended those by Anshelm Olson [1], Gamberale [2], Grasso et al. [3], Iregren [4] or Spencer and Schaumburg [5]. First a few words on the use of the terms acute and chronic. In toxicology these 2 concepts are well defined as long as we are dealing with exposure. Regarding effects, however, there seems to be great confusion as to how to use these expressions. The present paper will therefore use the terms acute and chronic exclusively in connection with exposure, while effects will be discussed in terms of the time course of their development and their possible reversibility. 0300-483X/88/$03.50
© Elsevier ScientificPublishers Ireland Ltd. Printed and Published in Ireland
349
EFFECTS OF A C U T E E X P O S U R E
Narcotic effects on the central nervous system (CNS) from acute exposure to high concentrations of organic solvents are well known from clinical experience, and these effects have been described in detail (e.g. Browning, Ref. 6).
Experimental studies Systematic studies of the effects of acute solvent exposure on, e.g. human performance have been performed during the last 2 decades, and at least 50 experimental studies evaluating effects of some 10 of the more commonly used solvents have been reported. A basic hypothesis has been that exposure levels which cause reversible effects upon short-term exposure may produce long lasting or irreversible effects on the nervous system after chronic exposure in the working environment. The present occupational exposure limits for many solvents are based on CNS-effects demonstrated in these investigations. A list of the most extensively investigated solvents and major results obtained in these studies is presented in Table I. As can be seen from Table I, effects on performance following acute exposure have been documented for many solvents. For several of them a dose-response relationship has been obtained between performance decrement and the concentration of solvent in blood, inspiratory air and the total uptake of solvent in the organism [24,25]. However, the representativeness and validity of the effects on behavioral performance observed in laboratory experiments have been questioned. Important issues concern the number and selection of the subjects taking part in the studies. Most of the data on CNS-effects of experimental solvent exposure derive from studies of small numbers of healthy, young men, and the representativeness of results from such groups for the estimation of the risk for effects of acute exposure in the working population has been questioned. However, 2 recent studies by Baelum et al. [26] and Iregren [16] have experimentally investigated the effects of acute toluene exposure on groups of occupationally-exposed workers. The results from these studies did not indicate any differences in effects on performance from toluene exposure between occupationally-exposed workers and groups of unexposed volunteers. Other important issues concern the representativeness of exposure conditions which have been simulated experimentally. The validity of experimental exposure is a problem with regard to at least 3 important aspects: the variability in exposure levels, the simultaneous exposure to other neurotoxicants and the physical work load imposed during exposure. How the variability of exposure affects the results is not known, although at least one study addressing this issue has been reported [25]. The effects of simultaneous exposure to combinations of solvents on human subjects are largely unknown, in spite of the fact that several attempts at studying interactions have been made. For a review see Iregren
350
5
5,80 0.250,350, 450,550 0,100,200, 0,50,110 0,300,1000 090,290
4 x 30 min 1-3 h 4 x 30 min 7 h/day for 5 days 4h 4h 4h 4h 4 X 30 min 70 min 8h 2h 6 h/day for 5 days 70 min 4h
14 6 12 16 30 16 12 26 12 15
15 9
Styrene Tetracbloroethylene Toluene Toluene Toluene Toluen?? Trichloroethane Trichloroethylene Trichloroethylene Trichloroethylene Xylene Xylene Xylene
200
0,100,300,
0,80
0,80
100
0,200,400, 600,800 050,100, 200,300 0,50,150, 256,350 100
2-4
11
h
0,300,500, 800 100,200
3 and 4 h
12, 18
Methylene chloride Methylene chloride Methylene chloride Styrene
Winneke 1974 ]71 DiVicenzo et al. 1972 [S] Gamberale et al. 1975 [9] Oltramare et al. 1974 [lo] Gamberale et al. 1974 [ll] Stewart et al. 1970 [12] Dick et al. 1984 [13] Anshelm Olson et al. 1985 (141 Iregren et al. 1986 [15] Iregren 1986 [16] Gamberale et al. 1973 [17] Gamberale et al. 1976 [18] Stewart et al. 1974 [19] Vernon et al. 1970 [20] Savolainen et al. 1980 [21] Gamberale et al. 1978 [22] Savolainen et al. 1981 [23]
Exposure levels investigated (ppml
Duration of exposure
No. of subjects
Solvent
Author
90
1000
200
350
100
350
50
300
Lowest concentration with manifest effects (ppml
200
300
300
110
80 250
80
80
100
250
800
200
Highest concentration with no manifest effects (ppml
EXPERIMENTAL LABORATORY INVESTIGATIONS OF SOLVENT-INDUCED EFFECTS ON BEHAVIORAL PERFORMANCE
TABLE I
[4]. In animal studies potentiating interactions have been demonstrated for some combinations of solvents, e.g. methyl ethyl ketone (MEK) and n-hexane or methyl n-butyl ketone, but this kind of effect has not been shown in human subjects. The dose of solvent at a given atmospheric concentration varies with the physical work load, since the uptake of solvent in the organism is dependent upon factors such as pulmonary ventilation and blood circulation [27]. In the few studies where physical exercise has been introduced during exposure, effects on the CNS have been found at lower atmospheric concentrations [21,22]. Field studies It is not known to what extent the aforementioned methodological problems may affect the validity of the experimental results, but these issues make it especially valuable to follow up the laboratory studies with direct measurements of effects a t work sites. A number of quasiexperimental studies of performance effects from acute exposures have been reported [28--39]. The general design used in these studies is to measure performance in the morning before exposure and in the afternoon after the workshift, and in a majority of the studies a control group has been included. With a properly designed study of this type it is possible to evaluate separately the effects of exposure, time of day and learning. Effects of styrene exposure [31--35,38,39], solvent mixtures [28-30,36] and toluene [37] have been investigated directly at the work sites. In all of these studies, except 2 investigations of effects from styrene exposure [33,38], solvents were found to affect some aspect of performance negatively. In a field study of effects from styrene exposure by Mutti and his coworkers [39] some intriguing correlations between performance deficits and exposure measures were found. Performance on a reaction time task and the Digit Symbol test was negatively related to duration of exposure, measured as the number of years employed at exposed work. Intensity of exposure, measured as the level of styrene metabolites in urine, was found to correlate negatively to performance on the Block Design test and on a reaction time task. Furthermore, an interaction between the effects of duration of exposure and the effects of intensity of exposure was found in this investigation. Thus, the workers with longer employment at exposed work and high intensity of exposure clearly performed less well than others. This finding could be interpreted as an indication that chronic exposure may modify the response to acute exposure. Results somewhat similar to the ones presented by Mutti and his coworkers were reported by Gamberale and his colleagues [34]. In this study of workers exposed to styrene, a correlation was found between duration of exposure and performance decrement with time-on-task in a test of simple reaction time. Thus, results from several field studies have clearly demonstrated effects of acute exposures at the work sites, and furthermore correlations between
352
various exposure measures and performance have been found in several studies. Evidently the quasi-experimental approach with measurements of performance at the work sites has proved to be a feasible design for the early detection of CNS-effects from acute solvent exposures. This approach thus seems well suited for the monitoring of neurotoxic effects from occupational exposures. EFFECTS OF CHRONIC EXPOSURE
Effects of chronic or long-term occupational exposure to low atmospheric concentrations of solvents have been studied in a large number of retrospective investigations of different types, which range from statistically well designed cohort-studies to the accumulation of data from clinical patients.
Epidemiological studies The results of 2 case-referent studies indicate a doubled risk for premature retirement on psychiatric grounds for workers occupationally exposed to solvents [40,41]. A cohort study of painters also showed an increased risk among solvent-exposed workers to receive the diagnosis 'presenile dementia' [42]. For a review of the epidemiological studies of solvent effects see Hernberg [43]. Apart from the aforementioned register investigations many studies of a cross-sectional type, i.e. studies comparing the performance of different groups of exposed and non-exposed workers, have been reported [44--56]. Two of these studies are based at least partially on data from clinical patients [48,53], but in the others attempts have been made to select the study groups in statistically more appropriate ways. Effects of single solvents, i.e. carbon disulphide [48,56], methylene-chloride [44], styrene [50,54] and toluene [45,51] were investigated in several of these studies. No effects were found in 1 of the studies on carbon disulphide [56] and the study on methylene-chloride [44], but in all of the other studies at least some aspect of performance was found to be negatively affected by the solvent exposure. Several of the cross-sectional studies have been performed on groups of workers exposed to mixtures of solvents [45--47,49,52,53,55]. The exposed groups were painters in a naval dockyard [45], spray painters [46,49], house painters [47,55] and workers assembling and testing jet engines for aircraft [52]. The exposed workers performed less well than the reference groups in all of these studies. The duration of the measured effect is, however, uncertain, since in the above mentioned studies the workers were exposure-free only a day or two before testing, and the issue of the reversibility of the effects is largely unsolved. However, in a longitudinal study at a Swedish steel works the performance of a group of workers exposed mainly to methyl ethyl ketone (MEK) was monitored for 3 years [29]. The results showed improvements in
353
performance in connection with substantial reductions of exposure levels over the years. Another study [38] presented data indicating improved performance in connection with cessation of exposure to styrene. The long-term effects of chronic occupational exposure to solvents are recognized as a cause of premature retirement and are classed as occupational disease in Denmark, Finland, Norway and Sweden. A recent meeting organized by the World Health Organization (WHO) produced a consensus document providing guidelines for the clinical evaluation of this kind of effect [57]. These guidelines are similar to the procedures employed in Finland and Sweden, which have been used for several years for the diagnosis of solvent-caused insults to the CNS.
Clinical investigations Some investigations following up patients diagnosed as injured by solvent exposure also provide information on the reversibility of solvent effects [58,59]. However, although in some of the patients the symptoms tend to ameliorate after removal from exposure, the symptoms of others seem to increase in severity. Thus, the general impression gained from these studies indicates the great uncertainty of the prognosis. These data, as well as the aforementioned results from the studies in connection with reduction or cessation of exposure, indicate that the toxic effects on CNS from chronic occupational exposure to solvents are at least partially reversible. PERFORMANCETESTS It is clear that neurotoxic effects from exposure to organic solvents have been found in a large number of investigations using various performance measures in different study designs. However, there is no conclusive evidence that the effects of long-term or chronic occupational exposure are different from the effects studied after acute exposures in the laboratory, or that the effects of various solvents or solvent combinations on the CNS differ. The apparent differential deficits demonstrated in some investigations may simply be effects of differing metrical properties in the tests applied, since a general performance deficit may manifest itself more readily in the most reliable test. Some of the aforementioned problems are due to the fact that the performance tests used to study effects from solvent exposure emanate from a wide variety of applications of psychological methods, such as neuropsychology or differential and experimental psychology. This fact has severely limited the possibility of making direct comparisons of the results from different investigations. However, recent methodological developments in the field of behavioral toxicology may help to improve inter-study comparability of results. By the application of computer techniques to the measurement of performance, wellstandardized and highly reliable tests have been developed in Stockholm by
354
Iregren and colleagues [60]. This battery includes several tests that have been used for a long time in studies of, e.g. effects from solvent exposure, and the validity and reliability of most of these tests is well-documented. A similar computerized test battery, the Neurobehavioral Evaluation System (NES), was developed in Boston by Letz and his coworkers [61].Efforts are currently being made to establish a few core tests from these batteries, which should be administered in a highly standardized manner in different studies. The new tests in these computerized test batteries are far better suited than traditional tests for application in studies using repeated measurements designs, and thereby they may help to answer important questions regarding C N S effects from chronic exposure to organic solvents. CONCLUSIONS
Although the measurement of performance has proved to be a useful tool in the evaluation of early effects from exposure to organic solvents, several important issues remain to be solved. Essential questions regarding the CNS-effects from chronic solvent exposure, concerning for example critical exposure levels, the time course of the development of the effects and the possible reversibility of these effects, may possibly be answered by performing longitudinal studies monitoring large numbers of exposed workers for extended periods of time. Carefully planned and executed investigations of this kind, applying the recently developed tests, may eventually supply useful information regarding these important issues. This information, together with a better understanding of the basic biochemical effects of solvent exposure, can hopefully increase our possibility of preventing the toxic effects of solvent exposure in the working population. REFERENCES 1 2 3 4 5 6 7
8 9
B. Anshelm Olson, Early detection of organic solvent toxicity: The role of human performance assessment. Arbete och H~ilsa 21 (1985) 1. F. Gamberale, Use of behavioral performance tests in the assessment of solvent toxicity. Scand. J. Work, Environ. Health, Suppl. 1, 11 (1985) 65. P. Grasso, M. Sharratt, D.M. Davies and D. Irvine, Neurophysiological and psychological disorders and occupational exposure to organic solvents. Food Chem. Toxicol., 22 (1984) 819. A. Iregren, Effects of industrial solvent interactions. Studies of behavioral effects in man. Arbete och H~lsa 11 (1986) 1. P.S. Spencer and H.H. Schaumburg, Organic solvent neurotoxicity. Facts and research needs. Scand. J. Work, Environ. Health, Suppl. 1, 11 (1985) 53. E. Browning, Toxicity and Metabolism of Organic Solvents, Elsevier Publishing Co., Amsterdam, 1965. G. Winneke, Behavioral effects of methylene chloride and carbon monoxide as assessed by sensory and psychomotor performance, in C. Xintaras, B.L. Johnson and I. deGroot (Eds.), Behavioral Toxicology, US Government Printing Office, Washington DC, 1974, p. 130. G.D. DiVincenzo, F.J. Yanno and B.S. Astill, Human and canine exposure to methylene chloride vapor. Am. Ind. Hyg. Assoc. J., 33 (1972) 125. F. Gamberale, G. Anwall and M. Hultengren, Exposure to methylene chloride: II. Psychological functions. Scand. J. Work, Environ. Health, 2 (1975) 95.
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M. Oltramare, E. Desbaumes, C. Imhoff and W. Michiels, Toxicologie du styrene monomere. Recherches expdrimentales et clinique chez l'homme. Editions Mddicine et Hygidne, Geneve, 1974. 11 F. Gamberale and M. Hultenbren, Exposure to styrene If. Psychophysiological functions. Work, Environ., Health, II (1974) 86. 12 R.D. Stewart, E.D. Baretta, H.C. ])odd and T.R. Torkelson, Experimental human exposure to tetrachloroethylene. Arch. Environ. Health, 20 (1970) 224. 13 R.B. Dick, J.V. Setzer, R. Wait, M.B. Hayden, B.J. Taylor, B. Tolos and V. Putz-Andersen, Effects of acute exposure to toluene and methyl ethyl ketone on psychomotor performance. Int. Arch. Occup. Environ. Health, 54 (1984) 91. 14 B. Anshelm Olson, F. Gamherale and A. Iregren, Coexposure to toluene and p-xylene in man: Central nervous functions. Br. J. Ind. Med., 42 (1985) 117. 15 A. Iregren, T. ~kerstedt, B. Anshelm Olson and F. Gamberale, Experimental exposure to toluene in combination with ethanol intake. Psychophysiological functions. Scand. J. Work, Environ. Health, 12 (1986) 128. 16 A. Iregren, Subjective and objective signs of organic solvent toxicity among occupationally exposed workers. An experimental evaluation. Scand. J. Work, Environ. Health, 12 (1986) 469. 17 F. Gamberale and M. Hultengren, Methylchloroform exposure: II Psychophysiological functions. Work, Environ., Health, 10 (1973) 82. 18 F. Gamberale, G. Annwa]l and B. Anshelm Olson, Exposure to trichloroethylene: III Psychological functions. Scand. J. Work, Environ. Health, 4 (1976) 220. 19 R.D. Stewart, C.L. Hake, A.I. LeBrun, J.H. Kalbfleish, P.E. Newton, J.E. Peterson, H. Cohen, R. Strube and K.A. Bush, Effects Of trichloroethylene on behavioral performance capabilities, in C. Xintaras, B.L. Johnson and I. deGroot (Eds.), Behavioral Toxicology: Early Detection of Occupational Hazards, (DHEW publication no (NIOSH) 74), US Department of Health, Education and Welfare, Washington, DC, 1974, p. 96. 20 R.J. Vernon and R.K. Ferguson, Effects of trichloroethylene on visual-motor performance. Arch. Environ. Health, 18 (1969) 894. 21 K. Savolainen, V. Riihimiiki, A,M. Sepp~il~inen and M. Linnoi]a, Effects of short-term mxylene exposure and physical exercise on the central nervous system. Int. Arch. Occup. Environ. Health, 45 (1980) 105. 22 F. Gamberale, G. Anwall and M. Hultengren, Exposure to xylene and ethyl-benzene: Ill. Effects on central nervous functions. Scand. J. Work, Environ. Health, 4 (1978) 204. 23 K. Savolainen, V. Riihim~iki, A. Laine and J. Kekoni, Short-term exposure of human subjects to m-xylene and 1,1,l-trichloroethane. Int. Arch. Occup. Environ. Health, 49 (1981) 89. 24 I. ~strand and F. Gamberale, Effects on humans of solvents in the inspiratory air: A method for estimation of uptake. Environ. Res., 15 (1978) 1. 25 K. Savolainen, V. Riihim~iki and M. Linnoila, Effects of short-term xylene exposure on psychophysielogical functions in man. Int. Arch. Occup. Environ. Health, 44 (1979) 261. 26 J. Baelum, L. Andersen, G.R. Lundquist, L. M41have, O.F. Pedersen, M. Vaeth and D.P. Wyon, Response of solvent exposed printers and unexposed controls to six-hour toluene exposure. Scand. J. Work, Environ. Health, II (1985) 271. 27 I. ~strand, Uptake of solvents in the blood and tissues of man. A review. Scand. J. Work, Environ. Health, 1 (1975) 199. 28 B. Anshelm Olson, Effects of organic solvents on behavioral performance of workers in the paint industry. Neurobehav. Toxicol. Teratol., 4 (1982) 703. 29 B. Anshelm Olson, F. Gamberale and B. Gr~nqvist, Reaction time changes among steel workers exposed to solvent vapors. A longitudinal study. Int. Arch. Occup. Environ. Health, 48 (1981) 211. 30 S. Binaschi, G. Gazzaniga and E. Crovato, Behavioral toxicology in the evaluation of the effects of solvent mixtures, in M. Horvath (Ed.), Adverse Effects of Environmental Chemicals and Psychotropic Drugs, Vol. 2, Elsevier Scientific Publishing Co., Amsterdam, 1976, p. 91.
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31
32 33 34
35 36
37
38 39
40 41
42
43
44 45 46
47 48 49 50
51
N. Cherry, H.A. Waldron, C.G. Wells, R.T. Wilkinson, H.K. Wilson and S. Jones, An investigation of acute behavioural effects of styrene on factory workers. Br. J. Ind. Med. 37 (1980) 234. N. Cherry, B. Rodgers, H. Venables, H.A. Waldron and C.G. Wells, Acute bebaviour effects of styrene exposure: a further analysis. Br. J. Ind. Med., 38 (1981) 346. C. Edling and K. Ekberg, No acute effects of exposure to styrene: a safe level of exposure? Br. J. Ind. Med., 42 (1985) 301. F. Gamberale, H.0. Lisper and B. Anshelm 01son, The effect of styrene vapor on the reaction time of workers in the plastic boat industry, in M. Horvath (Ed.), Adverse Effects of Environmental Chemicals and Psychotropic Drugs, Vol. 2, Elsevier Scientific Publishing Co, Amsterdam, 1976, p. 135. P. G~tell, P. Axelson and B. Lindel~f, Field studies on human styrene exposure. Work, Environ., Health, 9 (1972) 76. P. Gregersen and B. Stigsby, Reaction time of industrial workers exposed to organic solvents: Relationship to degree of exposure and psychological performance. Am. J. Ind. Med., 2 (1981) 313. H. Kempe, A. Meister and A. Seeber, Psychological studies of the acute effects of exposure to toluene (in German). Zeitschrift f'dr die gesamte Hygiene und ihre Grenzgebiete, 26 (1980) 313. A. Kjellberg, E. Wigaeus, J. Engstr~m, I. ~strand and E. Ljungquist, Long-term effects of styrene exposure in a polyester plant (in Swedish). Arbete och H~ilsa 18 (1979) 1. M. Mutti, A. Mazzucchi, P. Rustichelli, G. Frigeri, G. Arfini and I. Franchini, Exposureeffect and exposure-response relationships between occupational exposure to styrene and neuropsycbological functions. Am. J. Ind. Med., 5 (1984) 275. O. Axelson, M. Hane and C. Hogstedt, A case-referent study on neuropsychiatric disorders among workers exposed to solvents. Scand. J. Work, Environ., Health, 2 (1976) 14. J. 01sen and S. Sabr4, A case-reference study of neuropsychiatric disorders among workers exposed to solvents in the Danish wood and furniture industry. Scand. J. Soc. Med., (Suppl. 16) (1980) 44. S. Mikkelsen, A cohort study of disability pension and death among painters with special regard to disabling preseni]e dementia as an occupational disease. Scand. J. Soc. Med. (Suppl. 16) (1980) 34. S. Hernberg, Neurotoxic effects of long-term exposure to organic hydrocarbon solvents. Epidemiologic aspects, in B. Holmstedt, R. Lauwerys,, M. Mercier and M. Roberfroid (Eds.), Mechanisms of Toxicity and Hazard Evaluation. Elsevier, Amsterdam, 1980, p. 307. N. Cherry, H. Venables, H.A. Waldron and C.G. Wells, Some observations on workers exposed to methylene chloride. Br. J. Ind. Med., 38 (1981) 351. N. Cherry, H. Venables and H.A. Waldron, British studies on the neuropsycbological effects of solvent exposure. Scand. J. Work, Environ., Health, 10 (Suppl 1) (1984) 1O. S.A. Elofsson, F. Gamberale, T. Hindmarsh, A. Iregren, A. Isaksson, I. Johnsson, B. Knave, E. Lydahl, P. Mindus, H.E. Persson, B. Philipson, M. Steby, G. Struwe, E. S~derman, A. Wennberg and L. Widen, Exposure to organic solvents. A cross-sectional epidemiologic investigation on occupationally exposed ear and industrial spray painters with special reference to the nervous system. Seand. J. Work, Environ., Health, 6 (1980) 239. M. Hane, 0. Axelson, J. Blume, C. Hogstedt, L. Sundell and B. Ydreborg, Psychological function changes among house painters. Scand. J. Work, Environ. Health, 3 (1977) 91. H. H~inninen, Psychological picture of manifest and latent carbon disulphide poisoning. Br. J. Ind. Med., 28 (1971) 374. H. H~nninen, L. Eskelinen, K. Husman and M. Nurminen, Behavioral effects of long-term exposure to a mixture of organic solvents. Scand. J. Work, Environ. Health, 2 (1976) 240. H. H~rk~nen, K. Lindstr6m, A.M. Sepp~il~iinen, S. Asp and S. Hernberg, Exposure-response relationship between styrene exposure and central nervous functions. Scand. J. Work, Environ. Health, 4 (1978) 53. A. Iregren, Effects on psychological test performance of workers exposed to a single solvent (toluene) -- A comparison with effects of exposure to a mixture of organic solvents. Neurobehav. Toxicol. Teratol., 4 (1982) 695. 357
52
53 54 55
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57 58 59 60
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B. Knave, B. Anshelm Olson, S. Elofsson, F. Gamberale, A. Isaksson, P. Mindus, H.E. Persson, G. Struwe, A. Wennberg and P. Westerholm, Long-term exposure to jet fuel. A cross-sectional epidemiologic investigation on occupationally exposed workers with special reference to the nervous system. Scand. J. Work, Environ. Health, 4 (1978) 19. K. LindstrSm, Psychological performances of workers exposed to various solvents. Work, Environ., Health, 10 (1973) 151. K. LindstrSm, H. H~irkSnen and S. Hernberg, Disturbances in psychological functions of workers occupationally exposed to styrene. Scand. J. Work, Environ. Health, 2 (1976) 129. K. LindstrSm and G. WiekstrSm, Psychological function changes among maintenance house painters exposed to low levels of organic solvent mixtures. Acta Psychiatr. Scand., (Suppl. 303) 67 (1983) 81. V. Putz-Andersen, B. Albright, S. Lee, B. Johnson, D. Chrislip, B. Taylor, S. Brightwell, N. Dickerson, M. Culver, D. Zentmeyer and P. Smith, A behavioral examination of workers exposed to carbon disulphide. Neurotoxicology, 41 (1983) 67. WHO, Organic solvents and the nervous system. Environmental Health, Vol. 5, WHO Regional Office for Europe, Copenhagen 1985, pp. 1-273. P. Bruhn, P. Arlien-S}borg, C. Gyldensted and E.L. Christensen, Prognosis in toxic encephalopaty. Acta Neurol. Scand., 64 (1981) 387. K. LindstrSm, M. Antti-Poika, S. Tola and A. Hyyti~iinen, Psychological prognosis of diagnosed chronic organic solvent intoxication. Neurobehav. Toxicol. Teratol., 4 (1982) 581. A. Iregren, F. Gamberale, A. Kjellberg, A microcomputer based behavioral testing system, in Neurobehavioral methods in occupational and environmental health. WHO, Copenhagen, 1985, p. 75. R. Letz and E.L. Baker, Computer-administered neurobehavioral testing in occupational health. Semin. Occup. Med., 1 (1986) 197.
E F F E C T S ON H U M A N P E R F O R M A N C E F R O M ACUTE AND CHRONIC E X P O S U R E TO O R G A N I C SOLVENTS: A SHORT R E V I E W
ANDERS IREGREN Research Unit of Psychophysiology, National Institute of Occupational Health, S-171 84 Solna (Sweden)
SUMMARY The present short review deals with investigations of CNS-effects from acute and chronic exposure to some organic solvents and solvent mixtures, as measured by human performance. Some of the methodological problems in experimental and epidemiological investigations of effects from solvent exposure are discussed. Problem areas where further research is needed are indicated, and some methodological suggestions for future studies are presented.
words: Acute Performance effects
Key
exposure;
Chronic
exposure;
Organic
solvents;
INTRODUCTION The determination of limits for occupational and environmental exposure to neurotoxic substances is a major challenge to toxicologists, and many methodological and ethical problems are encountered in the process of gathering data relevant for setting of limits. The present paper discusses some of these problems, illustrating them with examples from research concerning the effects of exposure to organic solvents. However, this short paper should be regarded as an abstract. For more comprehensive reviews the reader is recommended those by Anshelm Olson [1], Gamberale [2], Grasso et al. [3], Iregren [4] or Spencer and Schaumburg [5]. First a few words on the use of the terms acute and chronic. In toxicology these 2 concepts are well defined as long as we are dealing with exposure. Regarding effects, however, there seems to be great confusion as to how to use these expressions. The present paper will therefore use the terms acute and chronic exclusively in connection with exposure, while effects will be discussed in terms of the time course of their development and their possible reversibility. 0300-483X/88/$03.50
© Elsevier ScientificPublishers Ireland Ltd. Printed and Published in Ireland
349
EFFECTS OF A C U T E E X P O S U R E
Narcotic effects on the central nervous system (CNS) from acute exposure to high concentrations of organic solvents are well known from clinical experience, and these effects have been described in detail (e.g. Browning, Ref. 6).
Experimental studies Systematic studies of the effects of acute solvent exposure on, e.g. human performance have been performed during the last 2 decades, and at least 50 experimental studies evaluating effects of some 10 of the more commonly used solvents have been reported. A basic hypothesis has been that exposure levels which cause reversible effects upon short-term exposure may produce long lasting or irreversible effects on the nervous system after chronic exposure in the working environment. The present occupational exposure limits for many solvents are based on CNS-effects demonstrated in these investigations. A list of the most extensively investigated solvents and major results obtained in these studies is presented in Table I. As can be seen from Table I, effects on performance following acute exposure have been documented for many solvents. For several of them a dose-response relationship has been obtained between performance decrement and the concentration of solvent in blood, inspiratory air and the total uptake of solvent in the organism [24,25]. However, the representativeness and validity of the effects on behavioral performance observed in laboratory experiments have been questioned. Important issues concern the number and selection of the subjects taking part in the studies. Most of the data on CNS-effects of experimental solvent exposure derive from studies of small numbers of healthy, young men, and the representativeness of results from such groups for the estimation of the risk for effects of acute exposure in the working population has been questioned. However, 2 recent studies by Baelum et al. [26] and Iregren [16] have experimentally investigated the effects of acute toluene exposure on groups of occupationally-exposed workers. The results from these studies did not indicate any differences in effects on performance from toluene exposure between occupationally-exposed workers and groups of unexposed volunteers. Other important issues concern the representativeness of exposure conditions which have been simulated experimentally. The validity of experimental exposure is a problem with regard to at least 3 important aspects: the variability in exposure levels, the simultaneous exposure to other neurotoxicants and the physical work load imposed during exposure. How the variability of exposure affects the results is not known, although at least one study addressing this issue has been reported [25]. The effects of simultaneous exposure to combinations of solvents on human subjects are largely unknown, in spite of the fact that several attempts at studying interactions have been made. For a review see Iregren
350
5
5,80 0.250,350, 450,550 0,100,200, 0,50,110 0,300,1000 090,290
4 x 30 min 1-3 h 4 x 30 min 7 h/day for 5 days 4h 4h 4h 4h 4 X 30 min 70 min 8h 2h 6 h/day for 5 days 70 min 4h
14 6 12 16 30 16 12 26 12 15
15 9
Styrene Tetracbloroethylene Toluene Toluene Toluene Toluen?? Trichloroethane Trichloroethylene Trichloroethylene Trichloroethylene Xylene Xylene Xylene
200
0,100,300,
0,80
0,80
100
0,200,400, 600,800 050,100, 200,300 0,50,150, 256,350 100
2-4
11
h
0,300,500, 800 100,200
3 and 4 h
12, 18
Methylene chloride Methylene chloride Methylene chloride Styrene
Winneke 1974 ]71 DiVicenzo et al. 1972 [S] Gamberale et al. 1975 [9] Oltramare et al. 1974 [lo] Gamberale et al. 1974 [ll] Stewart et al. 1970 [12] Dick et al. 1984 [13] Anshelm Olson et al. 1985 (141 Iregren et al. 1986 [15] Iregren 1986 [16] Gamberale et al. 1973 [17] Gamberale et al. 1976 [18] Stewart et al. 1974 [19] Vernon et al. 1970 [20] Savolainen et al. 1980 [21] Gamberale et al. 1978 [22] Savolainen et al. 1981 [23]
Exposure levels investigated (ppml
Duration of exposure
No. of subjects
Solvent
Author
90
1000
200
350
100
350
50
300
Lowest concentration with manifest effects (ppml
200
300
300
110
80 250
80
80
100
250
800
200
Highest concentration with no manifest effects (ppml
EXPERIMENTAL LABORATORY INVESTIGATIONS OF SOLVENT-INDUCED EFFECTS ON BEHAVIORAL PERFORMANCE
TABLE I
[4]. In animal studies potentiating interactions have been demonstrated for some combinations of solvents, e.g. methyl ethyl ketone (MEK) and n-hexane or methyl n-butyl ketone, but this kind of effect has not been shown in human subjects. The dose of solvent at a given atmospheric concentration varies with the physical work load, since the uptake of solvent in the organism is dependent upon factors such as pulmonary ventilation and blood circulation [27]. In the few studies where physical exercise has been introduced during exposure, effects on the CNS have been found at lower atmospheric concentrations [21,22]. Field studies It is not known to what extent the aforementioned methodological problems may affect the validity of the experimental results, but these issues make it especially valuable to follow up the laboratory studies with direct measurements of effects a t work sites. A number of quasiexperimental studies of performance effects from acute exposures have been reported [28--39]. The general design used in these studies is to measure performance in the morning before exposure and in the afternoon after the workshift, and in a majority of the studies a control group has been included. With a properly designed study of this type it is possible to evaluate separately the effects of exposure, time of day and learning. Effects of styrene exposure [31--35,38,39], solvent mixtures [28-30,36] and toluene [37] have been investigated directly at the work sites. In all of these studies, except 2 investigations of effects from styrene exposure [33,38], solvents were found to affect some aspect of performance negatively. In a field study of effects from styrene exposure by Mutti and his coworkers [39] some intriguing correlations between performance deficits and exposure measures were found. Performance on a reaction time task and the Digit Symbol test was negatively related to duration of exposure, measured as the number of years employed at exposed work. Intensity of exposure, measured as the level of styrene metabolites in urine, was found to correlate negatively to performance on the Block Design test and on a reaction time task. Furthermore, an interaction between the effects of duration of exposure and the effects of intensity of exposure was found in this investigation. Thus, the workers with longer employment at exposed work and high intensity of exposure clearly performed less well than others. This finding could be interpreted as an indication that chronic exposure may modify the response to acute exposure. Results somewhat similar to the ones presented by Mutti and his coworkers were reported by Gamberale and his colleagues [34]. In this study of workers exposed to styrene, a correlation was found between duration of exposure and performance decrement with time-on-task in a test of simple reaction time. Thus, results from several field studies have clearly demonstrated effects of acute exposures at the work sites, and furthermore correlations between
352
various exposure measures and performance have been found in several studies. Evidently the quasi-experimental approach with measurements of performance at the work sites has proved to be a feasible design for the early detection of CNS-effects from acute solvent exposures. This approach thus seems well suited for the monitoring of neurotoxic effects from occupational exposures. EFFECTS OF CHRONIC EXPOSURE
Effects of chronic or long-term occupational exposure to low atmospheric concentrations of solvents have been studied in a large number of retrospective investigations of different types, which range from statistically well designed cohort-studies to the accumulation of data from clinical patients.
Epidemiological studies The results of 2 case-referent studies indicate a doubled risk for premature retirement on psychiatric grounds for workers occupationally exposed to solvents [40,41]. A cohort study of painters also showed an increased risk among solvent-exposed workers to receive the diagnosis 'presenile dementia' [42]. For a review of the epidemiological studies of solvent effects see Hernberg [43]. Apart from the aforementioned register investigations many studies of a cross-sectional type, i.e. studies comparing the performance of different groups of exposed and non-exposed workers, have been reported [44--56]. Two of these studies are based at least partially on data from clinical patients [48,53], but in the others attempts have been made to select the study groups in statistically more appropriate ways. Effects of single solvents, i.e. carbon disulphide [48,56], methylene-chloride [44], styrene [50,54] and toluene [45,51] were investigated in several of these studies. No effects were found in 1 of the studies on carbon disulphide [56] and the study on methylene-chloride [44], but in all of the other studies at least some aspect of performance was found to be negatively affected by the solvent exposure. Several of the cross-sectional studies have been performed on groups of workers exposed to mixtures of solvents [45--47,49,52,53,55]. The exposed groups were painters in a naval dockyard [45], spray painters [46,49], house painters [47,55] and workers assembling and testing jet engines for aircraft [52]. The exposed workers performed less well than the reference groups in all of these studies. The duration of the measured effect is, however, uncertain, since in the above mentioned studies the workers were exposure-free only a day or two before testing, and the issue of the reversibility of the effects is largely unsolved. However, in a longitudinal study at a Swedish steel works the performance of a group of workers exposed mainly to methyl ethyl ketone (MEK) was monitored for 3 years [29]. The results showed improvements in
353
performance in connection with substantial reductions of exposure levels over the years. Another study [38] presented data indicating improved performance in connection with cessation of exposure to styrene. The long-term effects of chronic occupational exposure to solvents are recognized as a cause of premature retirement and are classed as occupational disease in Denmark, Finland, Norway and Sweden. A recent meeting organized by the World Health Organization (WHO) produced a consensus document providing guidelines for the clinical evaluation of this kind of effect [57]. These guidelines are similar to the procedures employed in Finland and Sweden, which have been used for several years for the diagnosis of solvent-caused insults to the CNS.
Clinical investigations Some investigations following up patients diagnosed as injured by solvent exposure also provide information on the reversibility of solvent effects [58,59]. However, although in some of the patients the symptoms tend to ameliorate after removal from exposure, the symptoms of others seem to increase in severity. Thus, the general impression gained from these studies indicates the great uncertainty of the prognosis. These data, as well as the aforementioned results from the studies in connection with reduction or cessation of exposure, indicate that the toxic effects on CNS from chronic occupational exposure to solvents are at least partially reversible. PERFORMANCETESTS It is clear that neurotoxic effects from exposure to organic solvents have been found in a large number of investigations using various performance measures in different study designs. However, there is no conclusive evidence that the effects of long-term or chronic occupational exposure are different from the effects studied after acute exposures in the laboratory, or that the effects of various solvents or solvent combinations on the CNS differ. The apparent differential deficits demonstrated in some investigations may simply be effects of differing metrical properties in the tests applied, since a general performance deficit may manifest itself more readily in the most reliable test. Some of the aforementioned problems are due to the fact that the performance tests used to study effects from solvent exposure emanate from a wide variety of applications of psychological methods, such as neuropsychology or differential and experimental psychology. This fact has severely limited the possibility of making direct comparisons of the results from different investigations. However, recent methodological developments in the field of behavioral toxicology may help to improve inter-study comparability of results. By the application of computer techniques to the measurement of performance, wellstandardized and highly reliable tests have been developed in Stockholm by
354
Iregren and colleagues [60]. This battery includes several tests that have been used for a long time in studies of, e.g. effects from solvent exposure, and the validity and reliability of most of these tests is well-documented. A similar computerized test battery, the Neurobehavioral Evaluation System (NES), was developed in Boston by Letz and his coworkers [61].Efforts are currently being made to establish a few core tests from these batteries, which should be administered in a highly standardized manner in different studies. The new tests in these computerized test batteries are far better suited than traditional tests for application in studies using repeated measurements designs, and thereby they may help to answer important questions regarding C N S effects from chronic exposure to organic solvents. CONCLUSIONS
Although the measurement of performance has proved to be a useful tool in the evaluation of early effects from exposure to organic solvents, several important issues remain to be solved. Essential questions regarding the CNS-effects from chronic solvent exposure, concerning for example critical exposure levels, the time course of the development of the effects and the possible reversibility of these effects, may possibly be answered by performing longitudinal studies monitoring large numbers of exposed workers for extended periods of time. Carefully planned and executed investigations of this kind, applying the recently developed tests, may eventually supply useful information regarding these important issues. This information, together with a better understanding of the basic biochemical effects of solvent exposure, can hopefully increase our possibility of preventing the toxic effects of solvent exposure in the working population. REFERENCES 1 2 3 4 5 6 7
8 9
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