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Occupational and Environmental Medicine 1994;51:47-49 47 Exposure of workers to a mixture of toluene and xylenes. II Effects Zhen Chen, Shi-Jie Liu, Shi-Xiong Cai, Yi-Min Yao, Hong Yin, Hirohiko Ukai, Yoko Uchida, Haruo Nakatsuka, Takao Watanabe, Masayuki Ikeda Institute of Occupational Medicine, Chinese Academy of Preventive Medicine, Beijing, China Z Chen S-X Cai Beijing Medical University School of Public Health, Beijing, China S-J Liu H Yin Institute for Prevention and Treatment of Occupational Diseases, Bureau of Chemical Industry, Beijing City, Beijing, China Y M Kao Department of Public Health, Kyoto University Faculty of Medicine, Kyoto 60601, Japan H Ukai Y Uchida M Ikeda Kyoto Industrial Health Association, Kyoto 604, Japan H Ukai Department of Environmental Sciences, Tohoku University School of Medicine, Sendai 980, Japan H Nakatsuka Miyagi University of Education, Sendai 980, Japan T Watanabe Requests for reprints to: Professor M Ikeda, Department of Public Health, Kyoto University Faculty of Medicine, Kyoto 606-01, Japan. Accepted for publication 19 April 1993 Abstract The health effects of exposure to a mixture of toluene and xylene isomers was studied on the fourth or fifth days of a working week in factories in China. The study population comprised 233 subjects (122 men and 111 women), who were exposed to the time weighted geometric mean (maximum) concentrations of toluene (3 (203) ppm) and xylenes (4 (103) ppm). For comparison, 241 nonexposed controls (116 men and 125 women) were recruited from the same regions. The prevalence of some subjective symptoms significantly increased in the exposed population, and the symptom profiles were similar to those found after exposure to toluene or xylenes alone. Haematology and serum biochemistry did not show notable changes. It seems reasonable to conclude that the effects of the toxicities of toluene and xylenes in combination are additive. (Occup Environ Med 1994;51:47-49) Toluene (methylbenzene) and xylenes (three isomers of dimethylbenzene) are often present in combination in organic solvent preparations.'-3 Many reports from various countries have been published on exposure of workers,4"-l or of the general population.213 Whereas the toxicity of toluene has been extensively studied, reports on the health effects of xylenes alone are few; publications of the effects of toluene-xylene combinations on factory workers are rare, despite their wide use. More than 200 workers exposed to toluene and xylenes in combination were examined in our study and compared with a similar number of non-exposed controls in a search for possible effects on the central nervous system, as well as haematological and serum biochemical effects. The lack of metabolic interaction between the solvents is reported separately. 4 Materials and methods SELECTION OF WORKERS AND DESIGN OF HEALTH EXAMINATION The study was carried out in China on the fourth or fifth day of a working week.'4 The criteria of selection were that (1) the workers participated in the whole examination (personal diffusive sampling,'5-17 analysis of urine for monitoring of exposure, a questionnaire, haematology, and serum biochemistry for examination of effects on health), and (2) exposure was almost exclusively to toluene and xylenes (>90%), but not toluene alone (no more than 90% toluene"8), xylenes alone (not more than 70% xylenes"9), or gasoline. It was not possible beforehand to identify the workers who met the criteria. Accordingly, almost 1000 exposed workers were examined, of whom 233 subjects (122 men and 111 women) satisfied the two selection criteria. Some of them were exposed also to a few ppm ethylbenzene, but none was exposed to benzene.14 Non-exposed controls of 116 men and 125 women were recruited from the clerical sections of the same factory or factories in the same regions. Table 1 shows that there was no significant age difference between the sexes or between exposed and non-exposed populations. (p > 0-05 for both). Most exposures were low'4 with less than 10 ppm (geometric mean) for the sum of all exposures, although some workers were exposed to toluene and xylenes in excess of the current occupational exposure limit of 100 ppm of each.2>22 Health examination both for the exposed and for the non-exposed persons consisted of (1) interview by a doctor or a public health nurse for medical history and completion of questionnaires, (2) blood sampling for haematology and serum biochemistry for liver and kidney functions, (3) collection of urine for clinical urinary analysis by diagnostic kits, and (4) clinical examination (for details, see Ukai et al 18). Urine samples for metabolite analyses were collected at the end of the shift and on another separate occasion.2' The questionnaire has 12 questions on the symptoms during work and 57 questions (two additional questions for women on menstruation) for the past three months (when not at work).24 25 The prevalence of the subjective symptoms was calculated after Ukai et al 18 as: the number of affirmative answers by the group/(the number of the people in the group) x (number of questions) x 100 (%). Table 1 Mean (y) age ofexposed and control workers Workers Men (SD, n) Women (SD, n) Exposed Controls 30 9 (8-0, 122) 33-8 (9-2, 116) 31-9 (7-2, 111) 31-8 (7-1, 125) Men and women (SD, n) 31 4 (7-6, 233) 32-8 (8-3, 241) STATISTICAL ANALYSIS Significant differences in prevalences were tested for with the x 2 test, in means with a t test (one tailed) and in distribution with the Mann-Whitney U test. 48 Chen, Liu, Cai, Yao, Yin, Ukai, Uchida, Nakatsuka, Watanabe, Ikeda Table 2 Prevalence ofsubjective symptoms Subjective symptoms Duringwork Sex Men Women Total No of questions 12 12 Controls 71 (116):5-1 44 (125):2-9 115 (241):4-0 Exposed to toluene and xylenes Total 1-20ppm 274 (122):18-7** 336 (111):25-2** 610 (233):21-8** 226 (91):20-7 285 (90):26-4 511 (181):23-5 In past three months Men 57 Women 59 Total 404 (116):5-9 540 (125):7-3 944 (241):6-6 884 (122):12-3** 1218 (111):18-6** 2102 (233):15-3** 769 (91):14-3 1056 (90):19 9 1825 (181):17-1 *p < 0-01 Values in v controls. the table are number of affirmative answers (number of subjects):percentage prevalence. >21 ppm 48 (31):12-9 51 (21):20-2 99 (52):15-9 115 (31):6-3 162 (21):13-1 277 (52):9 0 Table 3 Frequency distribution ofsubjective symptoms Subjective symptoms During work Controls Exposed Sex I II III VI I II III IV Men 85 Women 104 Total 189 22 9 17 4 39 13 0 0 0 23 74 19 6 18 52 26 15 41 126 45 21 Inpastthree months Men 20 91 5 Women 16 97 12 Total 36 188 17 0 0 0 13 83 18 8 6 55 36 14 18 138 54 22 p < 0 01 by x2 test in all cases. Values in the table are number of persons; categories I, fl, III, and IV were 0, 1-3, 4-6, and 7 or more symptoms during work, and 0, 1-10, 11-20 and 21 or more symptoms in past 3 months. Table 4 Symptoms with significant difference (p < 0 01) in percentage prevalence (%) for men and women combined Code No Symptom Control (C) Exposed (E) EIC During work: 1 Eye irritation 2 Dimmed vision 3 Nasal irritation 5 Sorethroat 6 Unusual taste 7 Face flashing 8 Dizziness 9 Floating sensation 11 Heavy feeling in the head 12 Headache 6-2 28-6 4-6 3-1 22-2 7-2 8-3 28-2 3-4 5 2 40-2 7-7 0 4 14-2 35-5 2-1 8-6 4-1 2-8 14-1 5-0 7 9 55-1 70 2-4 14-1 5-9 6-9 32-9 4-8 In the past 3 months: 4 Nausea 6 Difficulty in sleeping 7 Nightmare 13 Forgetfulness 14 Inability to concentrate 18 Fainting after sudden standing up 19 Palpitation 24 Poor appetite 26 Dry mouth 51 Roughskin 8-6 18-2 13-8 16-8 3-4 27-5 11-0 3-8 7.9 2-4 26-5 38-5 28-2 42-7 18-0 50-9 26-9 16-7 39.7 21-4 3-1 2-1 2-0 2-5 5-3 1-9 2-4 4-4 50 8-9 Code for each symptom is as in Yin et al.25 Results PREVALENCE OF SUBJECTIVE SYMPTOMS Table 2 shows that the prevalence of symp- toms during work was significantly (p < 0 01) higher in the exposed than in the control group regardless of sex. This was also true for the prevalence of the symptoms in the past three months. As the response to two questions related to menstruation did not differ between exposed and control groups, the two sexes were combined after the exclusion of these questions. When both exposed and non-exposed sub- jects were classified by the number of symptoms per person, the frequency distribution was significantly (p < 0 01) different for both symptoms during work and in the past three months (table 3). Table 4 gives prevalences for each symp- tom with a significant increase (p < 0.01) in the exposed population. Most of the symptoms during work related depressive effects on the central nervous system (such as codes 9 and 11) or local irritation (codes 1, 3, and 5), whereas those in the past three month period were less specific. The exposed to con- trol ratio (E/I) ranged from 35-5 to 3A4 for the work period and 8-9 to 19 for the past three months and was significantly higher (p < 0-05 by U test) in the work period than in the past three months. For the detection of possible dose depen- dency, exposed workers were classified into two subgroups by exposure intensities of 1 to 20 ppm and 21 ppm or more. Comparison of prevalences indicated no dose dependent increase either during work or in the past three months (table 2). Table S Comparison of haematology and serum biochemistry values Men Women Item (TJnit) Exposed Controls Exposed Controls No of subjects 116 Haematology: Haemoglobin (g/100 ml) 14-8 (1-1) Leucocytes ( x 103/mm3) 6-70 (1-76) Serum biochemistry: Total protein (g/100 ml) 7-35 (0-51) Total bilirubin (mg/I00 ml) 0 57 (0 29)* y-GTP (U/1) 8-8 (1-60)* ASAT(IU/1) 22-5-(1-38) ALAT (IU/1) 23-9 (1-77) ALP (IU/1) 260 (1-39) LAP (IU/1) 48-9 (1-21) Creatinine (mg/100 ml) 0-90 (0-12)* 122 14-8 (1-3) 6-46 (1-65) 7-34 (0 40) 0-67 (0 47) 10-2 (1-69) 21-5 (1-41) 22-1 (1-94) 254 (1-34) 47-1 (1-15) 0-87 (0-11) 125 111 12-7 (1-5) 12-5 (1-1) 6-31 (1-63) 6-34 (1-73) 7-54 (0-53) 7-48 (0 46) 0-51 (0.26)* 0 57 (0 29) 5 9 (1-70) 6-4 (1-75) 18-8 (1-38) 18-7 (1-38) 15-4 (1-84) 14-7 1-83) 202 (1-37) 206 (1-35) 42-1 (1-17) 41-2 (1-17) 0-71 (0-12)** 066 (0-09) *p<0-05, **p <0-01. Values for haemoglobin, leucocytes, total protein, total bilirubin and creatinine are arithmetic mean (ASD), whereas those for y-GTP, ASAT, ALAT, ALP, and LAP are geometric mean (GSD) with assumptions of normal and log normal distributions, respectively. HAEMATOLOGY AND SERUM BIOCHEMISTRY Table 5 shows the results of haematology and serum biochemistry tests. Because haemoglobin concentrations are known to be different in the two sexes the findings were treated separately for men and for women. Differences between exposed and control groups were not significant for most of the items, and none of the statistically significant differences were clinically relevant. Discussion The health examination of 233 Chinese solvent workers occupationally exposed to a mixture of toluene and three xylene isomers at low concentrations and 241 controls showed that the prevalences of some subjec- Exposure ofworkers to a mixture of toluene and xylenes. II Effects 49 tive symptoms were significantly increased in the study population. The symptom profiles were similar to those found after occupational exposure to toluene"' or xylenes,19 and focused on depression of the central nervous system and local irritation. In agreement with other observations,2627 haematology and serum biochemistry did not show noteworthy changes: this was also the case for workers exposed to toluenet8 or xylenes.19 The toxicity profiles are essentially the same for toluene, xylenes, and the mixture of the two, the central nervous system being the primary target. This suggests that it is justified when evaluating the toxicity of mixtures of toluene and xylenes at such low levels of occupational exposure, to add the effects.20 The current occupational exposure limits for toluene and three xylene isomers are set at 100 ppm2022 indicating that their potencies are essentially equal in their ability to depress the central nervous system. 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