International Archives of
Int Arch Occup Environ Hlth 40, 231-239 (1977)
kcuplalional
atlnl Eivirlumlental Ilealth © Springer-Verlag 1977
Relationship of Symptoms to Occupational Styrene Exposure and to the Findings of Electroencephalographic and Psychological Examinations Hannu Hark 6nen Department of Occupational Medicine, Institute of Occupational Health, Haartmaninkatu 1, SF-00290 Helsinki 29, Finland
Summary Ninety-eight male laminating workers occupationally exposed to styrene were clinically examined, and their symptoms were clarified with the aid of a questionnaire The mandelic acid concentration in urine was used as the measure of current exposure The median mandelic acid concentration (mean of five determinations) of the exposed group was 808 mg/l (Q 1 439, Q 3 1390). The symptoms of the exposed group were compared with those of unexposed men (n= 98) and also correlated to the mandelic acid concentration Symptoms of fatigue, difficulties in concentration and symptoms of irritation occurred statistiscally significantly more often in the exposed group than in the unexposed one (p < 0 01) During the workday irritation and ,,prenarcotic" symptoms, e g , nausea, dizziness and a drunken feeling, were reported significantly more often (p < 0 001) in the exposed group When the relationship between symptoms, and also symptom scores, and the mandelic acid concentration was examined, no statistically significant correlation was found Also a comparison of symptoms of the most and least exposed groups revealed no statistically significant difference. Earlier abnormal electroencephalographic (EEG) findings and abnormal psychological functions (lowered psychomotor accuracy and speed) had been found to statistically significantly correlate with urinary mandelic acid concentration In the present investigation the symptoms and symptom scores of the groups with abnormal EEGs or psychological functions were compared to the group with corresponding normal findings, and no statistically significant difference was found The clinical examination did not reveal any neurological deficits In an attempt to determine whether mandelic acid causes uroepithelial atypias, a urinary cytologic examination was made; none of the 35 specimens showed any suspicious cellular changes The results of the symptom survey indicate that the presence of symptoms can not be used as a predictor of exposure or as a predictor of abnormal findings in psychological and EEG examinations They might also indicate that the symptoms and the objective findings describe different aspects of the effects of styrene exposure.
H Iirk 6nen
232
Key words: Styrene nation Symptoms
Mandelic acid
EEG examination
Psychological exami-
Introduction Although unsaturated polyester resin, for which styrene is a crosslinking agent and solvent, has been used for about 30 years, knowledge of the effects of occupational exposure to styrene is still scarce Using exposure chamber studies as a basis, Carpenter et al l4 l stated that exposure to 800 ppm of styrene causes immediate eye and throat irritation, increased nasal mucous secretion, a pronounced and persistent metallic taste, listlessness, and drowsiness After the termination of the exposure they found slight muscular weakness and unsteadiness accompanied by inertia and depression. Wilson l 19l described workers occupationally exposed to styrene as having symptoms of irritation, a feeling of lassitude, and fatigue One study even describes an illness called ,,styrene sickness' l 16l; the symptoms include nausea, with accompanying vomiting, loss of appetite, and general weakness Case reports have mainly described neurasthenic symptoms in subjects occupationally exposed to styrene l3, 12l. Earlier reports have not given details of the methods applied in the surveys. Therefore a comparison of their results is not possible The dose-response relationship between occupational exposure to styrene and symptoms of illness have not as yet been published in detail. A team of research workers at the Institute of Occupational Health in Helsinki has conducted a project in order to evaluate the symptoms and other subclinical effects of long-term occupational exposure to styrene with the aid of a questionnaire, psychological testing, and neurophysiological examinations The psychological and neurophysiological studies have been reported elsewhere l 13, 17 l The objective of this part of the study was to define the subjective symptoms of workers occupationally exposed to styrene in comparison with other workers not so exposed; furthermore the relationship between the subjective symptoms and the psychological and neurophysiological findings was investigated.
Material and Methods Exposed Group The exposed group comprised 98 male laminating workers from 24 plants manufacturing polyester plastic products in southern Finland Their median age was 28 years (Q 1 24, Q3 34) Workers with a history of diabetes, epilepsy or unconsciousness lasting for more than 30 min were excluded before the examinations.
Comparison Group For this subproject, a special comparison group was chosen from male postal exployees and electricity workers who had participated in a health screening examination and who had no known occupational exposure to physical or chemical agents Their median age was 28 years (Q 1 23, Q 3 34) They were selected so that their ages agreed with those of the exposed workers in 5year age classes Workers with a history of neurological disease, diabetes, or unconsciousness lasting more than 30 min were excluded This comparison group was not examind psychologically or neurophysiologically because of practical limitations.
Relationship of Symptoms to Occupational Styrene Exposure and to the Findings
233
Exposure The duration of exposure to styrene varied from O5 to 14 years (median 5 1 years; Q 1 2 6, Q 3 6.8) Mandelic acid determinations from urine samples taken after an 8-h workday were used as the measure of current exposure intensity l 6, 14 l The urine samples were collected from every subject once a week on consecutive workdays for five weeks prior to the chlinical examination. The mean of the five determinations was used for the estimation of the intensity of individual exposure This mean varied from 7 to 4715 mg/l (median 808 mg/I; Q 1 439, Q 3 1390) The sampling scheme and the methods for determining the mandelic acid concentration have been described in detail elsewhere l 131. Symptom Survey The questionnaire used in the symptom survey was divided into two parts, i e , questions concerning general symptoms and questions concerning acute symptoms during the workshift Those dealing with general symptoms were formulated so that they covered areas in which earlier studies concerning effects of solvent exposure, especially those on occupational styrene exposure, had revealed positive findings, i e , fatigue l 161, irritation of the mucous membranes and the skin l 18l, concentration difficulties (81 and symptoms of peripheral neuropathy Acute symptoms were probed with questions about irritation of the mucous membrances and skin and questions concerning the ,,prenarcotic state" l 15l In addition inquiries were made about possible changes in the general symptoms during weekends and vacations A three-step rating scale (never, sometimes, often) was used in the questionnaire The questions were constructed in a language that was simple and unambiguous in order to facilitate answering Before the final form was prepared, a pilot survey was submitted to workers participating in periodical health examinations The questions of the symptom survey are presented in Table 1 and Table 2 The subjects filled out the questionnaire themselves, and the interviewer only checked their answers. StatisticalMethods The seff-reported symptoms of the exposed group were compared to those of the comparison group The chi-square test was used for the calculation of the statistical significance of the difference between the symptom frequencies In addition the answers of the exposed group were scored from 1 to 3 and the scores were correlated to the exposure The scores of each exposed subject were also summed, and the correlations of the sum to the mean mandelic acid concentration (mg/1), to the duration of the exposure (years), and to their product were calculated, with the Pearson correlation analysis. The occurrence of those symptoms with a statistically significant difference in the group comparison was compared between the subjects with the highest mandelic acid value (of more than 1762 mg/1, i e , approximately more than a 8-h TWA of 75 ppm styrene exposure) and the lowest mandelic acid value (less than 674 mg/l, i e , approximately less than a 8-h TWA of 25 ppm styrene exposure) l71 The relationship between often occurring symptoms and the mean mandelic acid concentration was also examined Two groups were formed for each symptom, and the mean mandelic acid concentration of the subjects reporting a symptom ,,often" was compared to the mean of the group reporting the corresponding symptom ,,never" or ,,sometimes" The relationship between findings in the psychological and neurophysiological examinations and the reported symptoms were also studied. ClinicalExaminations Every exposed subject was clinically examined There was a physical examination with the determination of gross neurological status, laboratory tests (including hemoglobin concentration, leucocytes, alanine aminotransferase (S-ALAT), albumin and glucose in the urine), and psychological and neurophysiological examinations The last two have been described in other reports l 13, 171.
H Hrkbnen
234
Table 1 General symptoms of workers occupationally exposed to styrene compared with those of the unexposed group Symptom
Never Sometimes Often x 2 Significance expo unex expo unex o unexsed posed sed e poseda df 2 level/ p . ~ p~sed oposed ~ S~~~e W
I
I
I
I
1 Symptom of fatigue Do you feel excess tiredness after the workday?
9
49
48
41
40
8
49 47
< 0 001
Do you get up tired in the morning?
19
46
54
43
25
9
19 99
< 0 001
Do you feel tired and listless?
17
44
57
46
24
7
22 44
< 0 001
26 38
61 66
64 56
23 10
8 4
10 93 7 66
< 0 01 < 0 05
45
42
47
16
6
5 12
n s.
67
43
25
48
6
86 08
< 0 001
73 71
36 33
22 24
10 10
3 2
10 68 9 07
< 0 01 < 0 05
56
77
40
20
2
1
10 32
< 0 01
55
70
38
27
5
1
6 33
< 0 05
96
98
0
O
O
O
48
69
43
27
7
0
58
57
32
32
8
8
49 27 57
58 39 71
41 37 36
26 40 24
8 34 5
4 19 2
7 78 6 54 5 21
< 0 05 < 0 05 n s.
50
56
37
38
10
3
4 12
n s.
56 53
62 62
32 42
32 36
9 3
2 0
4 75 4 17
n s. n s.
2 Concentration difficulties Do you forget things easily? 14 Do you become irritated? 22 Do your thoughts stray when you try to concentrate? 40 3 Irritation symptoms Are you bothered by itching? 7 Do your eyes become red or inflamed? 52 Do you have a runny nose? 54 4 Headache and dizziness Do you have spells of dizziness? Do you have spells of headache? Do you have chronic dizziness? 5 Digestive disturbances Do you have a loss of appetite? Do you have abdominal swelling after a meal? 6 Vegetative symptoms Are you bothered by your heart pounding? Do you sweat easily? Do your hands tremble ? 7 Sleep disturbances Do you have difficulty falling asleep? Do you have difficulty staying asleep ? Do you have nightmares?
nnB s.
14 41
< 0 001 n.s.
235
Relationship of Symptoms to Occupational Styrene Exposure and to the Findings Table 1 (continued) 8 Symptoms of peripheral neuropathy Do your legs feel numb or tingle?
49
52
35
34
14
11
0 46
n s.
n.s = not significant, p > 0 05. Table 2 Symptoms during the workday of the workers exposed to styrene compared with those of the unexposed Symptom
Irritation symptoms Are your eyes red or inflamed? Do you blink a lot or do your eyes water? Do you have spells of sneezing? Is your nose stopped up? Are you bothered by itching? Does your nose run? Prenarcotic symptoms Do you feel nauseated? Do you have spells of dizziness? Do you have a drunken feeling? Do you hear tingling in your ears? Are you short of breath? Do you have a headache?
Never expo unex sed posed
Sometimes expo unex sed posed
Often expo unex sed posed
x2
I
Significance level p l
e
Sgii
an
41
67
44
24
12
5
15 02
< 0 001
25
72
47
24
25
0
55 22
< 0 001
22 18 8 47
51 26 61 67
63 46 42 37
40 61 32 27
12 34 47 12
5 10 4 3
38
64
55
32
4
1
14 51
< 0 001
54
79
36
16
6
1
15 96
< 0 001
32
76
48
19
16
1
43 71
< 0 001
58 66 35
74 81 51
32 29 58
20 13 42
8 3 5
4 3 4
6 04 7 62 6 54
< 0 05 < 0 05 n s.
19 16 78 10
53 64 32 47
< < <
0 05 In an attempt to determine the relationship between mandelic acid and uroepithelial atypias, a urinary cytologic examination of 43 of the subjects was made in connection with the clinical studies For the urinary cytologic examination only one morning urinary specimen was collected. The specimen consisted of 100 ml of midstream urine, which was immediately fixed in the same amount of 96% ethyl alcohol and taken to the laboratory The millipore filtration technique (8 jm poresize filters) and the Papanicolaou staining technique were used The findings were graded according to the classification of Papanicolaou. The subjects that participated in the cytologic examination were also given a chest X-ray examination and lung function tests The median age of this subgroup was 31 years (Q 27, Q3 36) and the median duration of their past exposure was 6 0 years (Q 4 1, Q, 8 8) The median mandelic acid concentration of this group was 472 mg/1 (Q 138, Q3 859).
ve
236
H Hirk 6nen
Results Group Comparison of Symptoms Table 1 shows the general symptoms of the exposed group in comparison with the symptoms of the unexposed group In this comparison the exposed group was characterized by symptoms of fatigue, concentration difficulties, and irritation symptoms. For instance 40 out of 98 exposed persons often felt excess tiredness after the workday, while in the comparison group such tiredness occurred in only 8 cases Also the feeling of exhaustion was present often in 25 of the 98 exposed persons, while only 7 unesposed persons felt exhaustion often Furthermore symptoms of irritation and fatigue occurred more often in the exposed group During the workday irritation symptoms and "prenarcotic symptoms", e g , nausea, dizziness, a drunken feeling, and tingling in the ears, were especially present (Table 2) Subjective symptoms, such as loss of appetite, tiredness, and the inability to concentrate, seemed to subside during the weekend and during vacation periods. Symptoms which fulfill the Medical Research Council's criteria l 5l for chronic bronchitis were more common in the exposed than in the unexposed group Chronic broncitis was diagnosed in this study by the production of phlegm on most days during at least two consecutive years In the exposed group 27 of 98 persons ( 28 %) had at least simple chronic bronchitis, while in the comparison group there were only 13 (about 12 %) such subjects (x2 ( 1) = 5 13 p < 0 05) The groups did not differ in smoking habits. Relationship between Symptoms and Exposure No single symptom showed a statistically significant correlation to any measure of exposure Neither did the sympton score, calculated for each exposed individual, correlate with exposure The same result was obtained when only the symptoms occurring frequently were compared to the exposure In addition an intragroup comparison of symptoms between the most and least exposed subjects showed no statistically significant difference. When the exposed group was divided into two subgroups, i e , those who stated that a sympton occurred "often" and those who reported that the same symptom occurred never or sometimes, no statistical differences were found between any symptom and the mean mandelic acid concentrations of the two groups. Comparison between Symptoms and Findings The occurrence of symptoms, which could be related to the central nervous system, e.g , headache and dizziness, and their total scores were compared between those who had an abnormal finding in the electroencephalographic (EEG) examination l17 l and those who had a normal EEG In this comparison no statistically significant difference was found The same negative result was obtained when the symptoms of concentration difficulties and fatigue of the groups with abnormal findings for visuomotor accuracy and speed l13l were compared to symptoms of the group classified as being normal in this respect.
Relationship of Symptoms to Occupational Styrene Exposure and to the Findings
237
ClinicalExamination The clinical examination revealed no gross manifest neurological defects Two subjects had skin lesions, caused by glass fiber dust, in the distal parts of the legs The diagnosis was verified in a dermatological consultation None of the 43 subjects X-rayed showed signs of pneumoconiosis Also the results of the lung function tests (forced expiratory capacity in 1 s, forced vital capacity) were within normal limits In the urinary cytologic examination 35 sufficient specimens were obtained from 43 subject All the findings were coded as Papanicolaou class I The laboratory tests showed an S-ALAT value that was higher than normal (more than 40 U/1) in 6 cases out of 98 The pathological values were scattered randomly with regard to the intensity and duration of exposure. Discussion The main subjective sumptoms characterizing the styrene exposure group were fatigue, difficulties to concentrate, and irritation During the workday irritation symptoms and symptoms which Oltramare et al l15 l termed "prenarcotic", including dizziness, feeling of drunkenness and nausea, were particularly present These symptoms point to a central nervous effect of styrene It has been suggested that symptoms of irritation are caused by the vinyl group of styrene, which confer irritating properties to an organic molecule l1l Also the fiberglass dust can irritate the skin and may cause dermatitis. Using exposure chamber studies, Stewart et al l18 l have described the occurrence of nasal irritation during exposure to 216 ppm of styrene and nose and eye irritation, nausea and headache at a level of 375 ppm. Oltramare et al l15 lreported that the symptoms increase as the concentration of the exposure increases, and this phenomenon indicates a dose-response relationship. However, in the present study no dose-response relationship between the symptoms and exposure was observed On the other hand, the exposure level during laminating work varies greatly during the workday l 10 l The peak exposure level in laminating work can be as high as 200-500 ppm even if the average exposure for the workday is below 100 ppm Presumably the symptoms are intensive during high exposure periods. Mandelic acid as an exposure test measures the average exposure of the workday, however, hence it is not surprising that the mandelic acid concentration is a poor predictor of symptoms. It may also be supposed that workers with more subjective symptoms move to jobs in which the exposure is lower or to tasks with no exposure This hypothesis is supported by the fact that those workers with long exposure periods had lower mandelic acid values l17 l In addition a tolerance to styrene may play a role in the development of symptoms l 9 l. In laminating work the workers are also exposed to acetone, which is used for the cleaning of tools The TWA acetone exposure has varied from 28 to 101 ppm; its share of the total exposure to solvents has been some 5-25 % in laminating work l10 l Since acetone is not considered to be toxic at such concentrations, its TLV being 1000 ppm l2 l, the styrene exposure is evidently the most important solvent exposure. The presence of the symptoms did not statistically significantly correlate with exposure even though some findings in the psychological and EEG examinations did On the other hand the symptoms did not correlate with these findings either, and thus the
238
H Hrkbnen
occurrence of subjective symptoms does not seem to have any predictive value for the presence of psychological and EEG-abnormalities However, the subjects studied were presumably healthy laminating workers who had not sought medical aid because of suspected occupational disease. The clinical examination revealed no neurological deficits Also the urinary cytologic examination showed no atypical uroepithelial cells However, the toxicity of mandelic acid is lower than that of styrene itself l20 l Also the examined group was small Thus the result is only suggestive. The factors influencing the results of symptom surveys by questionnaire have been reviewed by Kirscht l11 l The response is influenced, e g , by cognitive factors such as awareness of symptoms, definition of problems, memory for past events, and specificity of questions, and also by motivational factors such as willingness of the respondent to report information and the perceived consequence of reporting The rating scale used for the questionnaire in the present study seems to have been too gross; also the questions concerning the change in symptoms after the cessation of exposure appear to have been too difficult to rate. The lack of a relationship between the symptoms and the measures of exposure and the findings in psychological and neurophysiological examinations indicates that a general symptom survey, such as the one used in the present study, does not help to identify these effects However, it may be that the symptoms and the other findings obtained describe different aspects of the effect of styrene exposure. References 1 Alarie, Y : Irritating properties of airborne materials to the upper respiratory tract Arch environm hlth 13, 433-439 (1966) 2 American conference of governmental industrial hygienists: Documentation of the threshold limit values for substances in workroom air, with supplements for those substances added or changed since 1971 (3rd ed ) Cincinnati, Ohio 1976 3 Axelson, O , Frobarj, G , Wedefelt, U : Kan styren exposition orsaka cerebrolisionella tillstand? Lkartidningen 71, 137-138 (1974) 4 Carpenter, C P , Shaffer, C B , Well, C S , Smyth, H F : Studies of the inhalation of 1:3-butadiene; with a comparison of its narcotic effect with benzol, toluol, and styrene, and a note on the elimination of styrene by the human J industr Hyg 26, 69-78 (1944) 5 Definition and classification of chronic broncitis for clinical and epidemiological purposes A report to the Medical Research Council by their committee on the aetiology of chronic bronchitis Lancet 1, 775-779 (1965) 6 Engstr 6m, K , Rantanen, J : A new gas chromatographic method for determination of mandelic acid in urine Int Arch Arbeitsmed 33, 163-167 (1974) 7 Engstrom, K , Hark 6nen, H , Kalliokoski, P , Rantanen, J : Urinary mandelic acid concentration after occupational exposure to styrene and its use as a biological exposure test Scand j. work environ health 2, 21-26 ( 1976) 8 Gamberale, F , Lisper, H O , Anshelm-Olson, B : Styrengas effekt pa reaktionsfdrmaga hos arbetare i plastbatindustri Arbete och Halsa 8, 1975 Arbetarskyddsverket, Stockholm 9 Gdtell, P , Axelsson, O , Lindeldf, B : Field studies on human styrene exposure Work-environm -hlth 9, 76-83 (1972) 10 Kalliokoski, P : Lujitemuoviteollisuus ongelmallinen ty6ymparistb (The reinforced plastic industry A problem work environment) Ty 6terveyslaitoksen tutkimuksia 112 Helsinki: Institute of Occupational Health 1976 11 Kirscht, J P : Social and psychological problems of surveys on health and illness Soc Sci. Med 5,519-526 (1971)
Relationship of Symptoms to Occupational Styrene Exposure and to the Findings
239
12 Klimkovd-Deutschova, E : Neurologische Befunde in der Plastikindustrie bei Styrol-Arbeitern. Int Arch Gewerbepath Gewerbehyg 19, 35-50 (1962) 13 Lindstr 6m, K , Hark 6nen, H , Hernberg, S : Disturbances in psychological functions of workers occupationally exposed to styrene Scand J Work Environw Hlth 2, 129-139 (1976) 14 Ohtsuji, H , Ikeda, M : A rapid colometric method for the determination of phenylglyoxylic and mandelic acids Its application to the urinalysis of workers exposed to styrene vapour. Brit J industr Med 27, 150-154 (1970) 15 Oltramare, M , Desbaumes, E , Imhoff, C , Michiels, W : Toxicologie du Styrene Monomere. Geneve: Editions M6dicine et Hygiene 1974 16 Rogers, J C : Industrial hygiene problems in the field of plastics Arch industr Hlth 12, 470471 (1955) 17 Seppalainen, A M , Hark6 nen, H : Neurophysiological findings among workers occupationally exposed to styrene Scand J Work Environm Hlth 2, 140-146 (1976) 18 Stewart, R D , Dodd, H C , Baretta, E D , Schaffer, A W : Human exposure to styrene vapour. Arch environm Hlth 16, 656-662 (1968) 19 Wilson, R H : Health hazards encountered in the manufacture of synthetic rubber J Amer. med Assoc 124, 701-703 (1944) 20 Vrba, J , Madlo, Z : Some new aspects of the metabolism of styrene In: 15th international congress of occupational health, Vienna 19-24 Sept 1966, Vol l I-1, pp 461-464 Wien: Verlag der Wiener Medizinischen Akademie 1966 Received February 16, 1977 /Accepted August 12, 1977
Int Arch Occup Environ Hlth 40, 231-239 (1977)
kcuplalional
atlnl Eivirlumlental Ilealth © Springer-Verlag 1977
Relationship of Symptoms to Occupational Styrene Exposure and to the Findings of Electroencephalographic and Psychological Examinations Hannu Hark 6nen Department of Occupational Medicine, Institute of Occupational Health, Haartmaninkatu 1, SF-00290 Helsinki 29, Finland
Summary Ninety-eight male laminating workers occupationally exposed to styrene were clinically examined, and their symptoms were clarified with the aid of a questionnaire The mandelic acid concentration in urine was used as the measure of current exposure The median mandelic acid concentration (mean of five determinations) of the exposed group was 808 mg/l (Q 1 439, Q 3 1390). The symptoms of the exposed group were compared with those of unexposed men (n= 98) and also correlated to the mandelic acid concentration Symptoms of fatigue, difficulties in concentration and symptoms of irritation occurred statistiscally significantly more often in the exposed group than in the unexposed one (p < 0 01) During the workday irritation and ,,prenarcotic" symptoms, e g , nausea, dizziness and a drunken feeling, were reported significantly more often (p < 0 001) in the exposed group When the relationship between symptoms, and also symptom scores, and the mandelic acid concentration was examined, no statistically significant correlation was found Also a comparison of symptoms of the most and least exposed groups revealed no statistically significant difference. Earlier abnormal electroencephalographic (EEG) findings and abnormal psychological functions (lowered psychomotor accuracy and speed) had been found to statistically significantly correlate with urinary mandelic acid concentration In the present investigation the symptoms and symptom scores of the groups with abnormal EEGs or psychological functions were compared to the group with corresponding normal findings, and no statistically significant difference was found The clinical examination did not reveal any neurological deficits In an attempt to determine whether mandelic acid causes uroepithelial atypias, a urinary cytologic examination was made; none of the 35 specimens showed any suspicious cellular changes The results of the symptom survey indicate that the presence of symptoms can not be used as a predictor of exposure or as a predictor of abnormal findings in psychological and EEG examinations They might also indicate that the symptoms and the objective findings describe different aspects of the effects of styrene exposure.
H Iirk 6nen
232
Key words: Styrene nation Symptoms
Mandelic acid
EEG examination
Psychological exami-
Introduction Although unsaturated polyester resin, for which styrene is a crosslinking agent and solvent, has been used for about 30 years, knowledge of the effects of occupational exposure to styrene is still scarce Using exposure chamber studies as a basis, Carpenter et al l4 l stated that exposure to 800 ppm of styrene causes immediate eye and throat irritation, increased nasal mucous secretion, a pronounced and persistent metallic taste, listlessness, and drowsiness After the termination of the exposure they found slight muscular weakness and unsteadiness accompanied by inertia and depression. Wilson l 19l described workers occupationally exposed to styrene as having symptoms of irritation, a feeling of lassitude, and fatigue One study even describes an illness called ,,styrene sickness' l 16l; the symptoms include nausea, with accompanying vomiting, loss of appetite, and general weakness Case reports have mainly described neurasthenic symptoms in subjects occupationally exposed to styrene l3, 12l. Earlier reports have not given details of the methods applied in the surveys. Therefore a comparison of their results is not possible The dose-response relationship between occupational exposure to styrene and symptoms of illness have not as yet been published in detail. A team of research workers at the Institute of Occupational Health in Helsinki has conducted a project in order to evaluate the symptoms and other subclinical effects of long-term occupational exposure to styrene with the aid of a questionnaire, psychological testing, and neurophysiological examinations The psychological and neurophysiological studies have been reported elsewhere l 13, 17 l The objective of this part of the study was to define the subjective symptoms of workers occupationally exposed to styrene in comparison with other workers not so exposed; furthermore the relationship between the subjective symptoms and the psychological and neurophysiological findings was investigated.
Material and Methods Exposed Group The exposed group comprised 98 male laminating workers from 24 plants manufacturing polyester plastic products in southern Finland Their median age was 28 years (Q 1 24, Q3 34) Workers with a history of diabetes, epilepsy or unconsciousness lasting for more than 30 min were excluded before the examinations.
Comparison Group For this subproject, a special comparison group was chosen from male postal exployees and electricity workers who had participated in a health screening examination and who had no known occupational exposure to physical or chemical agents Their median age was 28 years (Q 1 23, Q 3 34) They were selected so that their ages agreed with those of the exposed workers in 5year age classes Workers with a history of neurological disease, diabetes, or unconsciousness lasting more than 30 min were excluded This comparison group was not examind psychologically or neurophysiologically because of practical limitations.
Relationship of Symptoms to Occupational Styrene Exposure and to the Findings
233
Exposure The duration of exposure to styrene varied from O5 to 14 years (median 5 1 years; Q 1 2 6, Q 3 6.8) Mandelic acid determinations from urine samples taken after an 8-h workday were used as the measure of current exposure intensity l 6, 14 l The urine samples were collected from every subject once a week on consecutive workdays for five weeks prior to the chlinical examination. The mean of the five determinations was used for the estimation of the intensity of individual exposure This mean varied from 7 to 4715 mg/l (median 808 mg/I; Q 1 439, Q 3 1390) The sampling scheme and the methods for determining the mandelic acid concentration have been described in detail elsewhere l 131. Symptom Survey The questionnaire used in the symptom survey was divided into two parts, i e , questions concerning general symptoms and questions concerning acute symptoms during the workshift Those dealing with general symptoms were formulated so that they covered areas in which earlier studies concerning effects of solvent exposure, especially those on occupational styrene exposure, had revealed positive findings, i e , fatigue l 161, irritation of the mucous membranes and the skin l 18l, concentration difficulties (81 and symptoms of peripheral neuropathy Acute symptoms were probed with questions about irritation of the mucous membrances and skin and questions concerning the ,,prenarcotic state" l 15l In addition inquiries were made about possible changes in the general symptoms during weekends and vacations A three-step rating scale (never, sometimes, often) was used in the questionnaire The questions were constructed in a language that was simple and unambiguous in order to facilitate answering Before the final form was prepared, a pilot survey was submitted to workers participating in periodical health examinations The questions of the symptom survey are presented in Table 1 and Table 2 The subjects filled out the questionnaire themselves, and the interviewer only checked their answers. StatisticalMethods The seff-reported symptoms of the exposed group were compared to those of the comparison group The chi-square test was used for the calculation of the statistical significance of the difference between the symptom frequencies In addition the answers of the exposed group were scored from 1 to 3 and the scores were correlated to the exposure The scores of each exposed subject were also summed, and the correlations of the sum to the mean mandelic acid concentration (mg/1), to the duration of the exposure (years), and to their product were calculated, with the Pearson correlation analysis. The occurrence of those symptoms with a statistically significant difference in the group comparison was compared between the subjects with the highest mandelic acid value (of more than 1762 mg/1, i e , approximately more than a 8-h TWA of 75 ppm styrene exposure) and the lowest mandelic acid value (less than 674 mg/l, i e , approximately less than a 8-h TWA of 25 ppm styrene exposure) l71 The relationship between often occurring symptoms and the mean mandelic acid concentration was also examined Two groups were formed for each symptom, and the mean mandelic acid concentration of the subjects reporting a symptom ,,often" was compared to the mean of the group reporting the corresponding symptom ,,never" or ,,sometimes" The relationship between findings in the psychological and neurophysiological examinations and the reported symptoms were also studied. ClinicalExaminations Every exposed subject was clinically examined There was a physical examination with the determination of gross neurological status, laboratory tests (including hemoglobin concentration, leucocytes, alanine aminotransferase (S-ALAT), albumin and glucose in the urine), and psychological and neurophysiological examinations The last two have been described in other reports l 13, 171.
H Hrkbnen
234
Table 1 General symptoms of workers occupationally exposed to styrene compared with those of the unexposed group Symptom
Never Sometimes Often x 2 Significance expo unex expo unex o unexsed posed sed e poseda df 2 level/ p . ~ p~sed oposed ~ S~~~e W
I
I
I
I
1 Symptom of fatigue Do you feel excess tiredness after the workday?
9
49
48
41
40
8
49 47
< 0 001
Do you get up tired in the morning?
19
46
54
43
25
9
19 99
< 0 001
Do you feel tired and listless?
17
44
57
46
24
7
22 44
< 0 001
26 38
61 66
64 56
23 10
8 4
10 93 7 66
< 0 01 < 0 05
45
42
47
16
6
5 12
n s.
67
43
25
48
6
86 08
< 0 001
73 71
36 33
22 24
10 10
3 2
10 68 9 07
< 0 01 < 0 05
56
77
40
20
2
1
10 32
< 0 01
55
70
38
27
5
1
6 33
< 0 05
96
98
0
O
O
O
48
69
43
27
7
0
58
57
32
32
8
8
49 27 57
58 39 71
41 37 36
26 40 24
8 34 5
4 19 2
7 78 6 54 5 21
< 0 05 < 0 05 n s.
50
56
37
38
10
3
4 12
n s.
56 53
62 62
32 42
32 36
9 3
2 0
4 75 4 17
n s. n s.
2 Concentration difficulties Do you forget things easily? 14 Do you become irritated? 22 Do your thoughts stray when you try to concentrate? 40 3 Irritation symptoms Are you bothered by itching? 7 Do your eyes become red or inflamed? 52 Do you have a runny nose? 54 4 Headache and dizziness Do you have spells of dizziness? Do you have spells of headache? Do you have chronic dizziness? 5 Digestive disturbances Do you have a loss of appetite? Do you have abdominal swelling after a meal? 6 Vegetative symptoms Are you bothered by your heart pounding? Do you sweat easily? Do your hands tremble ? 7 Sleep disturbances Do you have difficulty falling asleep? Do you have difficulty staying asleep ? Do you have nightmares?
nnB s.
14 41
< 0 001 n.s.
235
Relationship of Symptoms to Occupational Styrene Exposure and to the Findings Table 1 (continued) 8 Symptoms of peripheral neuropathy Do your legs feel numb or tingle?
49
52
35
34
14
11
0 46
n s.
n.s = not significant, p > 0 05. Table 2 Symptoms during the workday of the workers exposed to styrene compared with those of the unexposed Symptom
Irritation symptoms Are your eyes red or inflamed? Do you blink a lot or do your eyes water? Do you have spells of sneezing? Is your nose stopped up? Are you bothered by itching? Does your nose run? Prenarcotic symptoms Do you feel nauseated? Do you have spells of dizziness? Do you have a drunken feeling? Do you hear tingling in your ears? Are you short of breath? Do you have a headache?
Never expo unex sed posed
Sometimes expo unex sed posed
Often expo unex sed posed
x2
I
Significance level p l
e
Sgii
an
41
67
44
24
12
5
15 02
< 0 001
25
72
47
24
25
0
55 22
< 0 001
22 18 8 47
51 26 61 67
63 46 42 37
40 61 32 27
12 34 47 12
5 10 4 3
38
64
55
32
4
1
14 51
< 0 001
54
79
36
16
6
1
15 96
< 0 001
32
76
48
19
16
1
43 71
< 0 001
58 66 35
74 81 51
32 29 58
20 13 42
8 3 5
4 3 4
6 04 7 62 6 54
< 0 05 < 0 05 n s.
19 16 78 10
53 64 32 47
< < <
0 05 In an attempt to determine the relationship between mandelic acid and uroepithelial atypias, a urinary cytologic examination of 43 of the subjects was made in connection with the clinical studies For the urinary cytologic examination only one morning urinary specimen was collected. The specimen consisted of 100 ml of midstream urine, which was immediately fixed in the same amount of 96% ethyl alcohol and taken to the laboratory The millipore filtration technique (8 jm poresize filters) and the Papanicolaou staining technique were used The findings were graded according to the classification of Papanicolaou. The subjects that participated in the cytologic examination were also given a chest X-ray examination and lung function tests The median age of this subgroup was 31 years (Q 27, Q3 36) and the median duration of their past exposure was 6 0 years (Q 4 1, Q, 8 8) The median mandelic acid concentration of this group was 472 mg/1 (Q 138, Q3 859).
ve
236
H Hirk 6nen
Results Group Comparison of Symptoms Table 1 shows the general symptoms of the exposed group in comparison with the symptoms of the unexposed group In this comparison the exposed group was characterized by symptoms of fatigue, concentration difficulties, and irritation symptoms. For instance 40 out of 98 exposed persons often felt excess tiredness after the workday, while in the comparison group such tiredness occurred in only 8 cases Also the feeling of exhaustion was present often in 25 of the 98 exposed persons, while only 7 unesposed persons felt exhaustion often Furthermore symptoms of irritation and fatigue occurred more often in the exposed group During the workday irritation symptoms and "prenarcotic symptoms", e g , nausea, dizziness, a drunken feeling, and tingling in the ears, were especially present (Table 2) Subjective symptoms, such as loss of appetite, tiredness, and the inability to concentrate, seemed to subside during the weekend and during vacation periods. Symptoms which fulfill the Medical Research Council's criteria l 5l for chronic bronchitis were more common in the exposed than in the unexposed group Chronic broncitis was diagnosed in this study by the production of phlegm on most days during at least two consecutive years In the exposed group 27 of 98 persons ( 28 %) had at least simple chronic bronchitis, while in the comparison group there were only 13 (about 12 %) such subjects (x2 ( 1) = 5 13 p < 0 05) The groups did not differ in smoking habits. Relationship between Symptoms and Exposure No single symptom showed a statistically significant correlation to any measure of exposure Neither did the sympton score, calculated for each exposed individual, correlate with exposure The same result was obtained when only the symptoms occurring frequently were compared to the exposure In addition an intragroup comparison of symptoms between the most and least exposed subjects showed no statistically significant difference. When the exposed group was divided into two subgroups, i e , those who stated that a sympton occurred "often" and those who reported that the same symptom occurred never or sometimes, no statistical differences were found between any symptom and the mean mandelic acid concentrations of the two groups. Comparison between Symptoms and Findings The occurrence of symptoms, which could be related to the central nervous system, e.g , headache and dizziness, and their total scores were compared between those who had an abnormal finding in the electroencephalographic (EEG) examination l17 l and those who had a normal EEG In this comparison no statistically significant difference was found The same negative result was obtained when the symptoms of concentration difficulties and fatigue of the groups with abnormal findings for visuomotor accuracy and speed l13l were compared to symptoms of the group classified as being normal in this respect.
Relationship of Symptoms to Occupational Styrene Exposure and to the Findings
237
ClinicalExamination The clinical examination revealed no gross manifest neurological defects Two subjects had skin lesions, caused by glass fiber dust, in the distal parts of the legs The diagnosis was verified in a dermatological consultation None of the 43 subjects X-rayed showed signs of pneumoconiosis Also the results of the lung function tests (forced expiratory capacity in 1 s, forced vital capacity) were within normal limits In the urinary cytologic examination 35 sufficient specimens were obtained from 43 subject All the findings were coded as Papanicolaou class I The laboratory tests showed an S-ALAT value that was higher than normal (more than 40 U/1) in 6 cases out of 98 The pathological values were scattered randomly with regard to the intensity and duration of exposure. Discussion The main subjective sumptoms characterizing the styrene exposure group were fatigue, difficulties to concentrate, and irritation During the workday irritation symptoms and symptoms which Oltramare et al l15 l termed "prenarcotic", including dizziness, feeling of drunkenness and nausea, were particularly present These symptoms point to a central nervous effect of styrene It has been suggested that symptoms of irritation are caused by the vinyl group of styrene, which confer irritating properties to an organic molecule l1l Also the fiberglass dust can irritate the skin and may cause dermatitis. Using exposure chamber studies, Stewart et al l18 l have described the occurrence of nasal irritation during exposure to 216 ppm of styrene and nose and eye irritation, nausea and headache at a level of 375 ppm. Oltramare et al l15 lreported that the symptoms increase as the concentration of the exposure increases, and this phenomenon indicates a dose-response relationship. However, in the present study no dose-response relationship between the symptoms and exposure was observed On the other hand, the exposure level during laminating work varies greatly during the workday l 10 l The peak exposure level in laminating work can be as high as 200-500 ppm even if the average exposure for the workday is below 100 ppm Presumably the symptoms are intensive during high exposure periods. Mandelic acid as an exposure test measures the average exposure of the workday, however, hence it is not surprising that the mandelic acid concentration is a poor predictor of symptoms. It may also be supposed that workers with more subjective symptoms move to jobs in which the exposure is lower or to tasks with no exposure This hypothesis is supported by the fact that those workers with long exposure periods had lower mandelic acid values l17 l In addition a tolerance to styrene may play a role in the development of symptoms l 9 l. In laminating work the workers are also exposed to acetone, which is used for the cleaning of tools The TWA acetone exposure has varied from 28 to 101 ppm; its share of the total exposure to solvents has been some 5-25 % in laminating work l10 l Since acetone is not considered to be toxic at such concentrations, its TLV being 1000 ppm l2 l, the styrene exposure is evidently the most important solvent exposure. The presence of the symptoms did not statistically significantly correlate with exposure even though some findings in the psychological and EEG examinations did On the other hand the symptoms did not correlate with these findings either, and thus the
238
H Hrkbnen
occurrence of subjective symptoms does not seem to have any predictive value for the presence of psychological and EEG-abnormalities However, the subjects studied were presumably healthy laminating workers who had not sought medical aid because of suspected occupational disease. The clinical examination revealed no neurological deficits Also the urinary cytologic examination showed no atypical uroepithelial cells However, the toxicity of mandelic acid is lower than that of styrene itself l20 l Also the examined group was small Thus the result is only suggestive. The factors influencing the results of symptom surveys by questionnaire have been reviewed by Kirscht l11 l The response is influenced, e g , by cognitive factors such as awareness of symptoms, definition of problems, memory for past events, and specificity of questions, and also by motivational factors such as willingness of the respondent to report information and the perceived consequence of reporting The rating scale used for the questionnaire in the present study seems to have been too gross; also the questions concerning the change in symptoms after the cessation of exposure appear to have been too difficult to rate. The lack of a relationship between the symptoms and the measures of exposure and the findings in psychological and neurophysiological examinations indicates that a general symptom survey, such as the one used in the present study, does not help to identify these effects However, it may be that the symptoms and the other findings obtained describe different aspects of the effect of styrene exposure. References 1 Alarie, Y : Irritating properties of airborne materials to the upper respiratory tract Arch environm hlth 13, 433-439 (1966) 2 American conference of governmental industrial hygienists: Documentation of the threshold limit values for substances in workroom air, with supplements for those substances added or changed since 1971 (3rd ed ) Cincinnati, Ohio 1976 3 Axelson, O , Frobarj, G , Wedefelt, U : Kan styren exposition orsaka cerebrolisionella tillstand? Lkartidningen 71, 137-138 (1974) 4 Carpenter, C P , Shaffer, C B , Well, C S , Smyth, H F : Studies of the inhalation of 1:3-butadiene; with a comparison of its narcotic effect with benzol, toluol, and styrene, and a note on the elimination of styrene by the human J industr Hyg 26, 69-78 (1944) 5 Definition and classification of chronic broncitis for clinical and epidemiological purposes A report to the Medical Research Council by their committee on the aetiology of chronic bronchitis Lancet 1, 775-779 (1965) 6 Engstr 6m, K , Rantanen, J : A new gas chromatographic method for determination of mandelic acid in urine Int Arch Arbeitsmed 33, 163-167 (1974) 7 Engstrom, K , Hark 6nen, H , Kalliokoski, P , Rantanen, J : Urinary mandelic acid concentration after occupational exposure to styrene and its use as a biological exposure test Scand j. work environ health 2, 21-26 ( 1976) 8 Gamberale, F , Lisper, H O , Anshelm-Olson, B : Styrengas effekt pa reaktionsfdrmaga hos arbetare i plastbatindustri Arbete och Halsa 8, 1975 Arbetarskyddsverket, Stockholm 9 Gdtell, P , Axelsson, O , Lindeldf, B : Field studies on human styrene exposure Work-environm -hlth 9, 76-83 (1972) 10 Kalliokoski, P : Lujitemuoviteollisuus ongelmallinen ty6ymparistb (The reinforced plastic industry A problem work environment) Ty 6terveyslaitoksen tutkimuksia 112 Helsinki: Institute of Occupational Health 1976 11 Kirscht, J P : Social and psychological problems of surveys on health and illness Soc Sci. Med 5,519-526 (1971)
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12 Klimkovd-Deutschova, E : Neurologische Befunde in der Plastikindustrie bei Styrol-Arbeitern. Int Arch Gewerbepath Gewerbehyg 19, 35-50 (1962) 13 Lindstr 6m, K , Hark 6nen, H , Hernberg, S : Disturbances in psychological functions of workers occupationally exposed to styrene Scand J Work Environw Hlth 2, 129-139 (1976) 14 Ohtsuji, H , Ikeda, M : A rapid colometric method for the determination of phenylglyoxylic and mandelic acids Its application to the urinalysis of workers exposed to styrene vapour. Brit J industr Med 27, 150-154 (1970) 15 Oltramare, M , Desbaumes, E , Imhoff, C , Michiels, W : Toxicologie du Styrene Monomere. Geneve: Editions M6dicine et Hygiene 1974 16 Rogers, J C : Industrial hygiene problems in the field of plastics Arch industr Hlth 12, 470471 (1955) 17 Seppalainen, A M , Hark6 nen, H : Neurophysiological findings among workers occupationally exposed to styrene Scand J Work Environm Hlth 2, 140-146 (1976) 18 Stewart, R D , Dodd, H C , Baretta, E D , Schaffer, A W : Human exposure to styrene vapour. Arch environm Hlth 16, 656-662 (1968) 19 Wilson, R H : Health hazards encountered in the manufacture of synthetic rubber J Amer. med Assoc 124, 701-703 (1944) 20 Vrba, J , Madlo, Z : Some new aspects of the metabolism of styrene In: 15th international congress of occupational health, Vienna 19-24 Sept 1966, Vol l I-1, pp 461-464 Wien: Verlag der Wiener Medizinischen Akademie 1966 Received February 16, 1977 /Accepted August 12, 1977
