Document MJ2g2m7zdvN8X0mZ25JYGEe4M

Int Arch Occup Environ Health (1992) 63; 461-468 Oo<*u|a(ional* EnviitHiniental Health ffi Springer-Verlag 1992 Occupational dimethylformamide exposure 3. Health effects of dimethylformamide after occupational exposure at low concentrations Shi-Xiong Cai1, Mei-Yuan Huang1, Li-Qiang Xi1, Yan-Lin Li2, Jiang-Bin Qu3, Toshio Kawai4, Tomojiro Yasugi4 6, Kazunori Mizunuma4 6, Takao Watanabe5, and Masayuki Ikeda6 'Institute of Occupational Medicine, Chinese Academy of Preventive Medicine, Beijing, China 2Medical Department, Yantai Synthetic Leather General Factory. Yantai, China department of Public Health, Shandong Medical University. Jinan. China 4Osaka Occupational Health Service Center, Japan Industrial Health and Safety Association. Osaka 550. Japan 5Miyagi University of Education, Sendai 980, Japan `Department of Public Health, Kyoto University Faculty of Medicine, Kyoto 606-01, Japan Received August 5 / Accepted November 20,1991 Summary. A factory survey was conducted in a plant where N, A-dimethylformamide (DMF) was in use dur ing the production of polyurethan plastics and related materials. In all, 318 DMF-exposed workers (195 men and 123 women) and 143 non-exposed controls (67 men and 76 women) were examined for time-weighted aver age exposure (to DMF and other solvents by diffusive sampling), hematology, serum biochemistry, subjective symptoms, and clinical signs. Most of the exposed work ers were exposed only to DMF, whereas others were ex posed to a combination of DMF and toluene. DMF ex posure in the former group was up to 7.0 ppm (geometric mean on a workshop basis), whereas it was up to 2.1 ppm in combination with 4.2 ppm toluene. Both hematology and serum biochemistry, results (including aspartate and alanine aminotransferases, y-glutamyl transpeptidase and amylase) were essentially comparable among the 3 groups. There was, however, a dose-dependent increase in sub jective symptoms, especially during work, and in diges tive system-related symptoms such as nausea and ab dominal pain in the past 3-month period. The prevalence rate of alcohol intolerance complaints among male (assumedly) social drinkers was also elevated in relation to DMF dose. Key words: Alcohol intolerance - Dimethylformamide Hematology - Liver function - Serum biochemistry Subjective symptoms Introduction TV,jV-Dimethylformamide (DMF) is an organic solvent, popular especially in synthetic leather production. A re view of the literature concerning its toxicity reveals that Offprint requests to; M. Ikeda this solvent is predominantly toxic to the liver, especially at high doses (Massmann 1956) and even by inhalation (Tanaka 1971; Craig et al. 1984), and also to the kid neys although to a lesser extent (Massmann 1956). DMF is only weakly teratogenic, if at all (Hansen and Meyer 1990; Fritz and Giese 1990). although it may be embryotoxic (Stula and Krauss 1977; Hansen and Meyer 1990). The potency of DMF to induce testicular cancer has been suspected (Ducatman et al. 1986; Levin et al. 1987; Ducatman 1989) but not confirmed in occupational epidemiology studies (Chen et al. 1988; Walrath et al. 1989). From a mutagenicity viewpoint. DMF was nega tive in Ames' test (Antoine et al. 1983) but reported to be positive in a chromosomal aberration study with pe ripheral lymphocytes from DMF-exposed workers (Ber ger et al. 1985). A metabolism study has suggested that humans are more susceptible to DMF hepatotoxicity than experi mental animals (Mrdz et al. 1989). Thus, clinical case re ports on DMF poisoning are also available. Liver damage was confirmed by elevated serum aspartate and alanine aminotransferase (ASAT, ALAT) levels (e.g., Klavis 1970; Weiss 1971; Potter 1973), serum alkaline phos phatase (ALP) level (Guirguis 1981), as well as histopathology (Tolot et al. 196S: Redlich et al. 1990), and such liver damage may be reflected in the reduced al cohol tolerance among heavy drinkers (Tolot et al. 1958). The involvement of the pancreas after DMF exposure was also suspected (Chary 1974). In addition, DMF may sensitize skin after occupational exposure (Camarsa 1987). In contrast, essentially no cardiotoxicity was de tected (Taccola et al. 1981; Cirla et al. 1984). In occupational medicine, increased serum ALAT and ASAT levels were observed in a mass outbreak of hepatitis among coating workers exposed to DMF (Red lich et al. 1988, 1990; Fleming et al. 1990). In addition, elevation in y-glutamyl transpeptidase (y-GTP) levels was detected among DMF-exposed polyurethan produc- UCC - 110721 462 tion workers in whom ASAT and ALAT levels remained normal (Cirla et al. 1984). As for subjective symptoms, abdominal pain, dyspepsia, nausea, constipation, diar rhea, headache, and a feeling of intoxication had been described by various authors (Reinl and Urban 1965; Paoletti and lannaccone 1982; Cirla et al. 1984). Accordingly, attention was focussed in the present study on a large population of DMF-exposed workers to examine (1) the significance of serum enzyme levels as markers of the health effects of DMF, (2) the possible elevation in subjective symptom prevalence, and (3) the dose-response relationship of the observed health effects among the DMF-exposed working population. Materials and methods Workers participating in the study. A factory survey was conducted in China, in the second half of a working week. In all, 318 DMFexposed workers (195 men and 123 women) and 143 controls (67 men and 76 women) were studied. The exposed workers were en gaged in the production of polyurethan plastics, in their applica tion, e.g.. to produce artificial leather or shoe soles, or in plant maintenance and quality assurance of the products. Most of them were exposed only ot DMF, whereas others were exposed to a combination of DMF and toluene (for details, see Table 1), Nonexposed controls served in the sections supplying water/steam, N2, or H2. There was no difference in ages among the exposed and nonexposed workers (Table 1). It should be added that blood samples were not available from a man exposed to DMF only (i.e., in labo ratory B) and from a woman in the non-exposed control group. Diffusive sampling of vapors in breathing zone air. Time-weighted average DMF vapor concentration was measured with syringetype samplers utilizing water as absorbent (Uchida et al. 1990: Kawai et al. 1991). A previous study has shown that the samplers, originally developed for monitoring hydrophilic solvents such as acetone and methanol, absorb DMF in a linear manner according to both exposure duration (up to 8 h, which was the maximum time studied) and exposure concentrations (59 ppm being the highest concentration tested), and the response to short-time peak DMF exposure was satisfactory (Yasugi et al. 1992). Toluene concentra tions were monitored by means of carbon cloth-equipped diffusive samplers (Hirayama and Ikeda 1979; Kasahara and Ikeda 1987). Values are cited from Kawai et al. (1992). Analysis of blood for hematology and serum biochemistry. Hema tology [leukocyte (WBC) counts, erythrocyte (RBC) counts, he moglobin concentration, and platelet counts] was examined with an automated 8-parameter hematology analyzer (model E-3000. Toa Medical Electronics, Tokyo, Japan), whereas serum biochem istry [total protein concentration (TP), albumin concentration. ASAT (or GOT: EC 2.6.1.1), ALAT (or GPT: EC 2.6.1.2), yGTP (EC 23.2.2), ALP (EC 3.1.3.1), leucine aminopeptidase (LAP: EC 3.4.11.1), lactate dehydrogenase (LDH: EC 1.1.1.27). total bilirubin, amylase (EC 3.2.1.1), blood urea nitrogen (BUN), and creatinine] was studied with a clinical chemistry analyzer (model CL-20. Shimadzu, Kyoto, Japan). The normal ranges and the upper or lower limit or borderline values (beyond which values are considered to be abnormal) for each study item as well as for ASAT-ALAT pairs and ALP-LAP pairs were calculated as previously discussed (Cai et al. 1991), That is. the log-normal distribution was assumed for enzymic pa rameters. taking the clinically established normal range as a (GSD)\ whereas a normal distribution was employed for nonenzvmic ones, taking the normal range as 4 x ASD. Thus, the lower and upper limits of the borderline range (i.e., the line between the borderline and abnormal values) were set at GM/(GSD)-' and GM(GSD)3, re spectively for the former, and at AM-4ASD and AM+4ASD, re spectively, for the latter (except for WBC counts). These values agree well with the evaluation in clinical practice. In the case of WBC counts, 3000 cells/mm3 was selected as the lower borderline limit based on clinical experience. When ASAT and ALAT or ALP and LAP were evaluated in pairs, the case was classified as normal when both enzyme activities (ASAT and ALAT. for exam ple) stayed within their normal ranges, and as abnormal when one of the two parameters was in the borderline or abnormal range and the other was in the abnormal range. Other cases were classified as borderline. Subjective symptom survey. The prevalence of subjective symp toms was studied utilizing questionnaires previously established Table 1. Number of workers, their ages by workshop, and the intensity of exposure to IV, JV-dimethylformamide (DMF) and toluene Group/workshop DMF exposure only 1. Leather production 2. Polyurethan production 3. Shoe-sole production 4. Laboratory A 5, Laboratory B Number Total Men Age in years [mean (range)] Women Total Men Women Exposure3 DMFb TolueneL 43 26 17 65 51 14 17 8 9 23 5 18 59 24 35 28.0(18-44) 30.6(16-51) 23.5 (16-39) 31.2(20-52) 32.4(19-56) 29.2(19-44) 29.4(16-51) 22.4(16-39) 24.4 (20-30) 31.9(19-56) 26.1 (18-40) 34.8(21-49) 24.6(19-35) 33.1 (23-52) 32.7 (20-53) 7.0:9.I 2.3:3.9 0.6:0.7 0.3:0.4 o fs j - - - Total 207 114 93 30.0(16-56) 29.2(16-56) 31.1(18-53) 1.8:4.5 - DMFand toluene exposure 6. Leather printing 52 30 22 7. Resin production 59 51 8 27.2 (17-49) 27.3 (17-49) 27.0(17-43) 27.1 (20-46) 25.7 (20-46) 35.6 (27-43) 2.1:2.5 0.3:0.6 2.1:4.2 0.6:1.4 Total Non-exposed controls 111 81 30 143 67 76 27.1 (17-49) 26.3 (17-49) 29.3 (17-43) 29.6(17-54) 28.4 (18-54) 30.6(17-54) 1.2:1.9 - 1.6:3.6 - * Based on personal sampling results (8-h time-weighted average) and expressed in terms of geometric:arithmetic mean (GM: AM: both in ppm) b 6-45 determinations per workshop c 1-14 determinations per workshop ucc 110722 (Inoue 1983; Yin et al. 1987; Cai et al. 1991). The questionnaires consisted of 12 questions on the symptoms during work and 57 (for men) or 59 (for women, including 2 on menstrual disturbances) questions concerning the past 3-month period. The prevalence of each subjective symptom among the group is defined as follows; Prevalence (%) Number of affirmative answers x 100 Number of responders In the cases of overall evaluation of the prevalence of total symp toms (Table 4), the prevalence was calculated as; Prevalence (%) = Number of affirmative answers______ Number of responders x Number of questions Statistical analysis. The /' test was employed for comparison of prevalence among groups. Results Intensity of exposure to DMF and toluene The analysis of vapors in breathing zone air showed that workers in 5 out of the 7 workshops studied were ex posed almost exclusively to DMF and that their expo sure to other solvents was negligible, whereas those in the remaining 2 workshops were exposed to toluene in addition to DMF, with toluene concentrations up to twice as high as that of DMF when expressed in terms of ppm (Table 1). Accordingly, the exposed workers were classified into 2 groups, i.e., those exposed only to DMF (DMF-exposed) and those with combined exposure to 463 DMF and toluene in the other (DMF4-toluene-exposed); the observation in the latter group was evaluated sepa rately from those in the former group in the following analysis. Among the DMF-exposed, DMF exposure was up to 7-9 ppm in workshop 1, about 3 ppm in workshop 2, and less than lppm in workshops 3-5. In the com bined exposure group, the DMF exposure in workshop 6 was comparable with that in workshop 2, and that in workshop 7 was essentially the same as that in work shops 3-5 (Table 1). Serum biochemistry and hematology The findings in serum biochemistry and hematology ex amination of each of the exposed workers were classified into normal, borderline, and abnormal cases, and the prevalence was compared with that in non-exposed con trols. The observation in serum biochemistry did not show any significant deviation of the exposed groups from controls (Table 2). The prevalence of borderline or ab normal cases among the DMF-exposed or the DMF+ toluene-exposed was not different from that in the con trols, when liver function indicators such as albumin. ASAT-ALAT, y-GTP, ALP-LAP, and LDH were ex amined, although the prevalence of borderline/abnormal total bilirubin levels was somewhat higher in the com bined exposure group (but not in the DMF group) (Ta ble 2). No changes were observed in the level of serum amylase, an indicator of an effect on the pancreas. Table 2. Prevalence of borderline and abnormal cases in serum biochemistry Group/workshop (no. of workers) Albumin ASAT- y-GTP ALP- LDH Total Amylase BUN Creati ALAT3 LAP3 bilirubin nine Bo.b/Ab.b Bo./Ab. Bo./Ab. Bo./Ab. Bo./Ab. Bo./Ab. Bo./Ab. Bo./Ab. Bo./Ab. DMF exposure only 1. Leather production 2. Polyurethan production 3. Shoe-sole production 4. Laboratory A 5. Laboratory B (43) (65) (17) (23) (58)c 1/0 0/0 0/2 0/0 3/0 0/1 0/0 1/0 3/0 0/1 0/0 6/0 4/0 2/0 1/0 1/0 0/0 0/0 0/0 5/0 5/0 0/1 0/0 5/0 0/1 1/0 0/0 0/0 3/0 2/0 0/0 0/0 1/0 0/0 0/0 0/0 1/0 3/0 0/0 4/0 1/0 2/0 0/0 1/0 4/0 Total (206)' 4/2 7/2 1/0 11/0 5/1 3/1 0/0 12/0 17/0 DMF and toluene exposure 6. Leather printing (52) 0/0 1/0 0/0 2/0 4/0 2/3 0/0 2/0 3/0 7. Resin production (59) 0/0 1/1 0/0 2/0 3/0 1/0 0/1 4/0 1/0 Total Non-exposed controls (HI) (142)d 0/0 2/0 2/1 0/0 3/2 1/0 ASAT-ALAT, aspartate and alanine aminotransferases; y-GTP, y-glutamyl transpeptidase; ALP-LAP, alkaline phosphatase and leucine aminopeptidase; LDH, lactate dehydrogenase; BUN, blood urea nitrogen ** and * show that the distribution is significantly different (** for P<0.05 and * for Pc0.10) from that in the controls. Otherwise, there is no significant difference (P>0.10) in the distribution of the normal, borderline, and abnormal cases between.the DMF-ex posed group and the controls, or between the DMF+toluene-ex posed group and the controls 4/0 7/0 3/3** 0/1 6/0 4/0* 3/0 5/0 1/0 0/0 6/0 13/1 3 For combined evaluation of ASAT and ALAT, and ALP and LAP. see Materials and methods b Number of borderline (Bo.) and abnormal (Ab.) cases. The re maining subjects showed normal findings. For definition of nor mal, borderline, and abnormal cases, see Materials and methods c One blood sample was not available from a man d One blood sample was not available from a woman ucc 110723 464 Table 3. Increased prevalence of DMF-exposed workers and DMF + toluene-exposed workers with subjective symptoms Number of symp toms DMF-exposed (207 subjects) DMF+ tolueneexposed (111 subjects) Controls (143 subjects) Part 1 Part 2 0 1-2 3-4 5-6 2:7 0 1-5 6-10 11-15 S16 83 (40%)** 104 (50%) 15 (7%) 4 (2%) 1(<1%) 30 (14%)** 136 (66%) 34 (16%) 5 (2%) 2 (1%) 46(41%)** 57 (51%) 7 (6%) 1 d%) 0 (0%) 24(22%)** 61 (55%) 22 (20%) 3 (3%) 1 d%) 118(83%) 24(17%) 1 (1%) 0 (0%) 0 (0%) 48 (34%) 85(59%) 9 (6%) 0 (0%) 1 (1%) Values are numbers of subjects (men and women combined) with a given number of subjective symptoms. Asterisks (**) show that the distribution is significantly (P< 0.01) different from the con trols Table 4. Increased prevalence of subjective symptoms among DMF-exposed and DMF+toluene-exposed workers Questions DMF-exposed (207 subjects) DMF+tolueneexposed (111 subjects) Controls (143 subjects) Part 1 Part 2 218:8.8%** 718:6.0%** 106:8.0%** 379:5.9%** 34:2.0% 287:3.5% Values are number of affirmative answers: the prevalence. The prevalence is defined as follows: _____ Number of affirmative answers Prevalence (%) = x 100 Number ofresponders x number of questions Men and women were combined. The number of questions was 12 for both men and women in part 1, and 57 for men and 59 for women in part 2. Asterisks indicate the difference in the prevalence is statistically significant (** for PcO.Ol) The prevalence of borderline/abnormal cases in 2 kid ney function indicators (BUN and creatinine) were also comparable in the two exposed groups with that in the controls. The prevalence of borderline elevation in cre atinine level appeared to be even lower in the combined exposure group as compared with that in the controls (Table 2). There were no significant changes in the pre valence of abnormal or borderline cases in WBC counts, RBC counts, platelet counts, or hemoglobin concentra tion either in the DMF-exposed or in the DMF+tolueneexposed groups as compared with that in the controls (data not shown). Increase in subjective symptom prevalence in association with exposure The comparison of prevalence of subjects with various numbers of subjective symptoms showed that the preva lence both in part 1 and part 2 symptoms were signifi Table 5. Prevalence of part 1 symptoms among 3 groups of work ers Symptom Prevalence (%)a Con- DMFtrol exposed D+Texposed^ 1. Irritation in eyes 2. Dimmed vision 3. Nasal irritation 4. Unusual smell 5. Sore throat 6. Unusual taste 7. Face flashing 8. Dizziness 9. Floating sensation 10. Drunken feeling 11. Heavy feeling in the head 12. Headache 0.0 4.8**' 1.4 1,4 11.1**" 0.0 1.4 4.2 21.7**' 1.4 15.9**' 0.0 1.4 4.2 18.8**' 3.5 7.7 0.0 0.5 0.7 4.3*' 7.0 11.6 * 00 2.1~' 1.8 9.1--' 2.7* 21.6"" 10.8"' 1.8 18.9"' 3.6 0.0 0.0 15,3*' Values are prevalence in percent for men and women combined. Asterisks indicate that the prevalence is significantly different from that of controls (**, P<0.01, * 0.05). A dagger indicates that the difference in the prevalence is significant at least in one sex, when men and women are evaluated separately {' for P < 0.05 at least in one sex. including the P < 0.01 case) a For definition of the prevalence, see Materials and methods b Workers exposed to a combination of DMF and toluene cantly (PcO.Ol) higher both in the DMF-exposed and in DMF+toluene-exposed groups than in the non-exposed controls, when both men and women were combined (Table 3). The results were reproducible in part 1 symp toms even when men and women were evaluated sepa rately (PcO.Ol), whereas the difference in part 2 symp toms was significant (P<0.05) in men and barely so (P<0.10) in women (data not shown). Accordingly, the total number of symptoms per per son was also significantly (PcO.Ol) higher in DMF-ex posed and in DMF+toluene-exposed subjects than in the controls both in part 1 and part 2 symptoms (Table 4). The rate of the increase appeared to be higher in part 1 symptoms than in part 2 symptoms; the rate was 3 or more for the former, but less than 2 for the latter. It is also interesting to note that the prevalence was very close among those exposed to DMF only and those ex posed to a combination of DMF and toluene, although the former group included those exposed to DMF at 79ppm, which was not the case in the latter. Efforts were extended to identify the individual symp toms with significant increases. The analysis of Part 1 symptoms showed (Table 5) that the prevalence in the exposed group was significantly (P< 0.01) higher for the symptoms related to local irritation effects such as irrita tion in the eyes, nose, and throat both in the DMF-exposure and in the combined-exposure group. In contrast, the changes in the prevalence in association with the ex posure were less remarkable for CNS-depressing effects, that is, the difference from the control group was either insignificant (e.g., P>0.05 for floating sensation and drunken feeling) or less significant (e.g., 0.05 > F>0.01 for heavy feeling in head and headache). None of the 12 ucc 110724 Table 6. Part 2 symptoms with significant difference in prevalence Symptom Prevalence (%)a Con- DMF- D+Ttrol exposed exposed11 4. Nausea 5, Vomiting 7. Nightmare 20. Tightness in the chest 21. Breath shortage 25. Abdominal pain 26. Dry mouth 30. Body weight loss 50. Proneness to stumble during walk 51. Rough skin 52. Unusual feeling in throat 53. Frequent cough 4.2 0.7 4.2 9.8 4.9 2.8 2.8 0.7 0.0 0.0 0.0 3.5 26.1**' 4.8* 8.2' 26.6**' 18.4**7 9,2*' li.i*** 1.4 0.5* 3.4* 1.4 10.6*7 25.2**' 5.4*' 12.6*' 25.2**7 11.7* 9.0* 9.9*' 5.4*' 0.9 0.0 3.6*' 6.3 Notes are as under Table 5 symptoms was more prevalent in the controls than in the 2 exposed groups, regardless of sex. Part 2 symptoms with significant increases in preva lence were rather few (Table 6). When the symptoms with a significant (P < 0.05) increase in prevalence among men and women combined were identified in the DMFexposed group, it counted 12 (Table 6) among 57 symp toms (no significant changes being observed in the pre valence of 2 menstruation-related symptoms), in contrast to 7 out of 12 symptoms in part 1 (Table 5). Many of those with a significant (P<0.05) increase among the DMF-exposed were related to the digestive system (e.g., dry mouth, nausea, vomiting, and abdominal pain). The symptoms with significant increases among the DMF+toluene-exposed subjects were very similar to those among the DMF-exposed. The prevalences in part 1 symptoms were significantly (P<0.01) higher in the DMF-exposed than in the DMF+toluene-exposed group, whereas the difference in the prevalence was of border line significance (0.05 < P<0.10) in the case of part 2 symptoms. Difficulty in speech was the only part 2 symptom that appeared to be more prevalent in the controls (3.5%) than in the DMF-exposed (1.4%) or in the DMF+tolueneexposed (0.9%) group. The difference was, however, statistically insignificant (P> 0.10) in both cases. Symptoms with a dose-dependent increase in prevalence In order to identify the symptoms with an increasing trend in prevalence as a function of increasing DMF ex posure levels, the DMF-exposed workers were classified by intensity of DMF exposure into 3 subgroups, i.e., those in workshop 1 (with mean DMF exposure of 79ppm; see Table 1), workshop 2 (3ppm), and the com bination of workshops 3-5 (less than 1 ppm). Similarly, DMF+toluene-exposed workers were divided into 2 subgroups, i.e., those in workshop 6 (2-3ppm) and in workshop 7 (less than lppm). Comparison among the subgroups together with the control group showed that 2. Dlnrned vision 30 20 10 _ Q i i___ l...i_ 465 l 30 r 20 1. Irritation In eyes 10 r 0 --i----- L_L_l C3EO 30 -O 20 2>UJ 10 Q_ 0 6. Unusual taste iiii 8. Dizziness 30 " 20 7 rJJ10 -------------- i0 ___ L-... r P 24 6 3. Nasal irritation 30 20 10 111 1 11. Heavy feeling In the head 30 I" 20 -- 10 0 q/--- 1* -~T~T 1-------L. 0 24 DMF EXPOSURE (ppm) Fig-1- Dose-response relationship of some subjective symptoms during work among DMF-exposed workers. The prevalence of the subjects with the symptoms are shown some of the part 1 symptoms, e.g., dimmed vision and unusual taste, increased in a dose-related manner. Dosedependency may also be noted, although less clearly, for dizziness, eye irritation, nasal irritation, and heavy feel ing in the head. The changes in prevalence as a function of exposure intensity are depicted in Fig. 1. Dose-dependency was generally less remarkable among part 2 symptoms. Of particular interest is the fact that 2 digestive system-related symptoms (vomiting and abdominal pain) tended to increase in groups with heavier DMF exposure. In addition, dry mouth and nausea showed a dose-dependent increase among the 2 low-ex posed groups, although no further increase was observed in the group with the highest exposure. In contrast, the dose-related changes in the preva lence of subjective symptoms are essentially not detect able among DMF+toluene-exposed workers, for both part 1 and part 2 symptoms. The difficulty in detecting dose-dependency may be related to the absence of the highly exposed groups. Attention was paid to whether or not DMF exposure was associated with a reduced tolerance to alcohol. Wo men among the study population had no habit of drink ing. Among the men, 48, 42, and 40 subjects in the DMF-exposed, DMF+toluene-exposed and unexposed control groups, respectively, reported their drinking habits (presumably as social drinkers). The personal ex posure data were available in some of them. Accord ingly, these male workers were classified into subgroups either by workshop or by individual DMF-exposure in tensity, and the prevalence of the subjective complaint of reduced alcohol tolerance was compared (Table 7). UCC - 110725 466 Table 7. Reduced alcohol tolerance as a function of DMF exposure intensity Reduced alcohol tolerance All subjects Yes No DMF exposure grade 0I 10 (25%) 30 (75%) 2 (18%) 9 (82%) 11 9 (41%) 13 (59%) III 11 (73%)** 4 (27%) IV SumJ 32 56 Total 40(100%) 11(100%) 22(100%) 15(100%) 88 Selected subjects' Yes No 10 (25%) 30 (75%) 1 (14%) 6 (86%) 5 (71%)* 2 (29%) 4 (80%)* 1 (20%) 6 (86%)** 1 (14%) 26 40 Total 40(100%) 7(100%) 7(100%) 5(100%) 7(100%) 66 Values are number of subjects, with percentage in parentheses. Asterisks show that the distribution is significantly different from the non-exposed controls (** for P< 0.01 and * for P<0.05) a Sum of the numbers of subjects b All subjects with social drinking habits were studied. Exposure grades were classified by workshop: 0, I. II, III indicate no expo sure, less than lppm (workshops 3, 5), about 3 ppm (workshop 2). and about 7-9ppm (workshop 1). respectively (for details, see Table 1) c Only those whose personal exposure data were available were selected. Exposure grades 0.1. II, III, and IV indicate no exposure. 0.1-1.9ppm. 2-4,9ppm, 5-9.9ppm, and > lOppm. respectively There was a dose-dependent increase (P < 0.01) in the prevalence when the workers were divided by workshop. The changes were also significant (P<0.01) when per sonal exposure data were taken into account. It should be added that there was no difference in age among the subgroups. Discussion The present study has shown that the prevalence of some subjective symptoms, especially those related to the di gestive system, was increased (Tables 3-6), even though there was essentially no change in liver function indi cators or in kidney damage indicators (Table 2). Amylase levels also remained normal (Table 2), which is not in agreement with the report by Chary (1974). For the ab sence of changes in serum enzyme levels, at least two factors should be taken into account. One is that the DMF levels observed in the workshops were rather low in general, and GM values never exceeded the current occupational exposure limit of lOppm (e.g., Japan As sociation of Industrial Health 1990) in any of the work shops studied (Table 1). In addition, all the workers had been serving for several years. Thus, liver function may have turned to be normal even if it had been transitorily abnormal at the very beginning of the service, as noticed by Redlich et al. (1988). Experience shows that drug abuse is extremely rare among the population studied. The prevalence of hepatitis B virus (HBV) infection is about 60% -70% in general in China (Seiji et al. 1991), but the very low proportion of those with elevated serum ASAT and ALAT activities both in the exposed groups and the controls suggests that the confounding effect of HBV infection in the diagnosis is minimal. Regarding the dose-response relationship in health effects of DMF, only a limited number of reports de scribe the intensity of exposure of workers to DMF. 26. Dry mouth 4. Nausea 5. Vomiting 30 20 10 0 25. ADdaminal pain DMF EXPOSURE (ppm) Fig. 2. Dose-response relationship of 4 digestive system-related subjective symptoms in the past 3-month period among DMF-exposed workers. Notes are as under Fig. 1 Lauwerys et al. (1980) did not find DMF-induced signif icant changes in ASAT, ALAT, y-GTP, ALP. or or nithine carbamyl transferase levels in the sera of 22 workers exposed to DMF (up to 15ppm) in an acrylic fiber factory. In contrast, Cirla et al. (1984) observed that both subjective symptom prevalence and serum yGTP (but not ASAT or ALAT) levels were elevated among 100 polyurethan leather production workers as compared with 100 matched controls; the DMF expo sure was 7ppm (mean) with a range of 3-20 ppm. Paoletti and Iannaccone (1982) observed an increased pre valence of subjective symptoms (e.g., dyspepsia, diar rhea, and alcohol intolerance) among synthetic leather production workers exposed to DMF up to 68 ppm. The present observation of the increase in prevalence of sub jective symptoms (Tables 3-5) in the absence of appar ucc 110726 5 467 t ent effects on liver and kidney functions (Table 2) among the workers exposed to DMF at 9 ppm or below (Table 1) are in general agreement with the findings cited above. It may be worthwhile to note that symptoms related to the digestive system, especially vomiting and abdominal pain in the past 3-month period, showed a dose-dependent increase (Fig. 2). This contrasts with the observa tion that CNS effects and local irritation effects are more commonly complained about during work and may de serve attention because they might suggest subtle subclinical effects on the liver. In this regard, of particular interest is the observation that the complaint of reduced alcohol tolerance among drinkers increased in a manner dependent on DMF dose (Table 7). The observation is in line with the opinion of Lauwerys et al. (1980) that re duced alcohol tolerance is one of the earliest manifesta tions of excessive exposure to DMF. No conclusive evaluation is currently possible on the combined effect of DMF with toluene. Occupational health experience shows that, when coexposed, toluene will suppress the oxidative metabolism of DMF (Kawai et al. 1992). 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