Document Gg5g3axYKoeXZxBeovV6Goyv

iberland should itnder- iged by Aogical on with ionitoring 'cwrp Hyg Ivents, no ,iiroring of Iew York: ronitoring workers Biological JnlpOUnd3. -iability in miml and 16:447-60. lygienists. rillices for I vironmenl fsplurzkonTit. Wrin- e receptor: < 1985;29: :s of man. 1interrela)perties of .)luene and JlIlld tiyg British Journal of Industrial Medicine I989;46:559-565 Excretion of 1,2,4-benzenetriol in the urine of workers exposed to benzene o I N O U E , ~ `K S E I J I , ~ H N A K A T S U K A , ~T W A T A N A B E , ~S-N Y I N , ~G - L L I , ~ S-X CAI,' C JIN,' M IKPDA' From the Department of Environmental Health,` Tohoku University School of Medicine, and Center of Occupulionul Medicine,` Tohoku Rosai Hospital, Sendai 980 Jupan, and Institute of Occupational Medicine.] Chinese Acarlerny of Preventive Medicine. Beijing. Chino ABSTRACT Urine samples were collected from 152 workers (64 men, 88 women) who had been exposed to benzene, 53 workers (men only) exposed to a mixture of benzene a n d toluene, and 213 non-exposed controls (1 13 men, 100 women). T h e samples were analysed for I ,2,4-benzenetriol (a minor metabolite of benzene) by high performance liquid chromatography. The time weighted average solvent exposure of each worker was monitored by diffusive sampling technique. T h e urinary concentration of 1,2,4-benzentriol related linearly t o the intensity of exposure t o benzene both in men and women a m o n g workers exposed to benzene, a n d was suppressed by toluene co-exposure a m o n g male workers exposed t o a mixture of benzene and toluene. A cross sectional balance study in men at the end of the shift of a workday showed that only 0.47% of benzene absorbed will be excreted into urine as I ,2,4-benzenetriol, in close agreement with previous results in rabbits fed benzene. T h e concentration of I ,2,4-benzenetriol in urine was more closely related t o the concentration of quinol than that of catechol. T h e fact that phenol and quinol, but not catechol, are precursors of 1,2,4benzenetriol in urine was further confirmed by the intraperitoneal injection of the three phenolic compounds to rats followed by urine analysis for I ,2,4-benzenetriol. 1,2,4-Benzenetriol (1,2,4-trihydroxybenzene, or Material and methods hydroxyquinol) was identified as a minor urinary metabolite after administration of benzene to rabbits WORKERS STUDIED, URINE COLLECTION, A N D by mouth,' and catechol has been assumed to be a E X POSU R E MEASUREMENT precursor of this compound.' Although Creenlce et af The Factory survey was conducted in China in 1987. proposed a high performance liquid chromatographic Urine samples were collected from 152 workers (HPLC) method of determination,2no application has exposed to benzene (64 men, 88 women exposed up to been attempted in occupational health, probably 210 ppm benzene) and 53 workers (men only) exposed because the method rcquircs a nitrogcn atmosphcrc in to a mixture of benzene (up to 116 ppm) and toluene analysis. (up to 114 ppm). together with 213 non-exposed A HPLC method under aerobic conditions was controls (113 men, 100 women) (table 1) at around developed in this IilborilIory i t d s~icccssf\~liliypplicd 1500 in the sccond half of a working week, when to measure 1,7,4-benzcnctriol in ~ l i curinc of workcrs conccntrations of bcnzcnc and tolucnc mctabolitcs arc exposed to benzene. In addition, an experiment with expected to reach the maximum in the urine of workers rats showed that 1,2,4-benzenetriol is formed from exposed to solvents throughout a week.' The samples phenol through quinol (and not catechol) in vivo. The from exposed workers were previously analysed for details are given in this report. Other reports on phenolic metabolites and t, t-muconic acid.''6 The benzene metabolism in man have been published else- time weighted average exposures to solvent vapours where.'.' (table I ) were measured by diffusion sampling tech- nique,"' and are cited from a previous publication.' Part ol' tliir \ w r l \viis prcicirtcd ;II t l ~ c( r h l ;iiiiirI;tl tiwtiiiy oi' ~ I I C Japan Association of Indurtrial tlealtli, K a n a ~ a ~ Jaa.piii, 11-14 April 19x8. ANIMAL EXPERIMENTS Acccpled 25 July 1988 Female Wistar rats, weighing 150-165 g, were pur- I *Arithmetic mean (unit: ppm) f arithmetic standard deviation (unit; ppm): maximum (unit: ppm), and (geometric mean (unit: ppm] (geometric standard deviation)). chased from Funabashi Farm (Funabashi, Japan). The animal room was lit from 0800 till 2000 and then kept dark till 0800 next morning. In the experiment the rats (9-10 animals per group) were individually housed in metabolic cages and given 50 mg/kg phenol, quinol or catechol in saline intraperitoneally-that is, one third to a quarter the LD,"-at 0930. Urine excreted thereafter was collected separately from faeces for three four hour periods and then one I2 hour period till 0930 next morning. At each sampling, the urine was combined with the wash of the funnel in the bottom of the cage to a volume of 10ml in cases of four hour collections or 30 ml when collection was made for a 12 hour period. latter. The reason for the improved reproducibility is unknown. Typical chromatograms of authentic and endogenous 1,2,4-benzenetriol are shown in fig I, in Authentic I, 2,4 - benzenelriol ANALYSIS OF URINE FOR BENZENE METABOLITES The methods for determination of catechol and quin01,' and t, t-muconic acid6 have been described previously. To determine I,2,4-benzenetriol, an aliquot (0.5 ml) of the urine sample (diluted when necessary) was taken in a screw capped glass tube, acidified by the addition of 0.05 ml of 35% hydrochloric acid, and then successively mixed with 0.5 ml of 2% pyrogallol in methanol and 0.1 ml of 35% hydrochloric acid. The tube was sealed and heated at 100" C for 60 minutes for hydrolysis. The hydrolyzate was kept in the dark overnight and then spun at 3000 rpm in a clinical centrifuge. A portion (20-40 pl per injection) of the supernate was introduced into a high performance liquid chromatograph (HPLC; Hitachi Model 635) equipped with a Spherisorb ODS 5 pm column (4 mm in inner diameter and 250 mm in length). A mobile phase (a mixture of methanol/water/ acetic acid at the ratio of 20/971/9 by volume) was allowed to flow at a rate of 1.1 ml/min and the eluate was monitored at a wavelength of 290 nm. Under the conditions established, a nitrogen atmosphere' is not necessary, whereas keeping the hydrolyzate overnight in the dark apparently improves the reproducibility of the measurement. In a preliminary experiment a urine sample from a worker exposed to benzene containing about 30 mg endogenous 1,2,4-benzenetriol/ml was divided into 20 portions, of which IO were analysed immediately after hydrolysis and the remaining IO after standing overnight in the dark. The coefficient of variation was 7.0% in the former and 2.3% in the IOmin Endogenous 1,2,4- benzenelriol Pyrogallol I ZOA r1 0 10min 20m Fig I HPPC determination of I,2,4-benzenetriol in urinr. HPLC chromatogrom oJauthentic I .2,4-benzenetrioldissolved in water (top) and that of urinefiom a worker expd to benzene (bottom). i Jin, Ikeda Benzenetriol in urine of workers 56 I which the peak for 1,2,4-benzenetriol appeared at Table 3 Correlation between benzene in breath zone and about 3.4 min after the injection with no interference 1.2.4-benzenetriol in urine with other urine components whereas the pyrogallol peak came at about 4.1 min. Measurrinent Under the conditions of determination described group No of subjects* A t st rt .9(3.670)) (unit; ppm) itcibility is lentic and in fig I , in above, the space in the chromatogram related linearly to the added amount of 1,2,4-benzenetriol, and the coefficient of variation was 7.4%, 3.3%, and 4.1%, respectively, when urine samples containing about 5.6, 20.0, and 50.0 mg endogenous 1,2,4-benzenetriol/l were analysed 10 times each. The recovery was 93.9% and 99.5%, respectively, when I ,2,4-benzenetriol-free urine was spiked with authentic 1,2,4-benzenetriol at 50 and 100 mg/l. The detection limit for 1,2,4- benzenetrio1 was 0.5 mg/l urine when a spacelnoise +Observed value (mg/l): Men women 365 Men$ 177 (Men)il (166) Womenllll 188 Women** I72 0.I82 0.I95 (0.010) 0.180 0,209 Value corrected for creatinine (mgjg): Men + women 365 0 . 2I2 Men (Men)ll it)177 0.21I ( (0.008) Womenllll 0,213 Women** I72 0.262 0.018 0,052 (-0.006) -0,119 -0,386 0- I38 0-265 -- 0.002) 0.003 - 0.60I 0.762 0.807 (0.498) 0.744 0.672 0.747 0.826 (0.522) 0.724 0.678 ratio of 2 was taken. The results were presented as observed (in terms of mg/l), or after correction for creatinine concentration (unit; mg/g creatinine)," or for a specific gravity of urine of 1.016 (unit; mg/l)." The specific gravity was +Value corrected for specific grivity (rng/l): Men women 365 0.I48 Men (Men)ll ):1( I77 0.170 (OQO7) Women111 0.146 Women** I72 0.182 0.259 - 0.270 0.00009) 0,088 -0.299 0.790 0.800 (0.500) 0.784 0.749 measured by refractometry and creatinine by colorimetry." STATISTICAL ANALYSIS Regression analysis and Student's t-test (either paired or unpaired) were used when necessary. Results Including non-exposed subjects. +tSlope (A) and the intercept on the Y axis (6)in the equation as Y = A X B. where Y is the urinary concentration of 1.2.4benzcnctriol (unit; lis tlcscrikd iii tlic tuhlc) iuid X is tlic brcutli m n c concentration ol'hnzrnc (ppm). If for correlation coefficient (r) is <0.01 for all groups. Exposedup to 92 ppm. BllEx osed also to toluene (up io I14 ppm) in addition io benzene. 111, nposed up to 2 IO pm **Women exposed topess ihan 100 ppm. more intensively exposed, whereas the concentration INCREASE IN URINARY 1.2,4-BENZENETRIOL AS A was below the detection limit of 0.5 mg/l in the case of LINEAR FUNCTION OF BENZENE EXPOSURE workers exposed to benzene at low concentrations, I When the urine samples from workers (64 men, 88 ppm, for example. Further analysis of 213 urine women) in five benzene workshops were analysed for I ZOmin 1,2,4-benzenetrioland the results were classified in the increasing order of the benzene concentrations in breath zone air (table 2), the 1,2,4-benzenetriol con- centrations were higher in the urine of those who were samples from the non-exposed control subjects showed that I ,2,4-benzenetriol concentrations were essentially zero (below the detection limit) in all samples analysed. The results from workers exposed to benzene and 20 ;nin 01 in urine. ,triol diswker exposed Table 2 Urinary concentrations of 1,2,4-benzenetrioIin workers exposed to benzene at various workshops Value correctedfor No of Workshop workers Benzene in brearh zone uir ( p p ~ r i ) Observed value (wll) Creatinine Imgll) Men: A B C D E Women: A B C D E 3* 24 2. 20 IS I* 19 2' 37 29 1, 1. 1 11.1 (2.40) 7, 76 32.6 (1.42) 60.2 (1.28) I 18.1 (2.79) 5, 37 42.4 (2.49) 76.4 (1.58) ND, ND. ND 1.68 (2.012) ND, 2.9 6.66 (1.781) 11.62 (2.075) ND 2.68 (3.074) ND. 2.9 6.12 (3.078) 9-60 (2.748) ND. ND, ND 1.89 (2.460) ND. 5.5 9.22 (1.457) 13.1 I (1.667) ND 3.02 (3.365) ND. 4.8 7.55 (2.908) 12.85 (2,445) The resultsare shown in terms of geometric mean (geometric standard deviation) unless otherwise specified. `Individual values arc shown. N D = Below the detection limit of 0.5 mg/l. Specijc graviry lmglIl ND, ND. ND 1.76 (2.419) ND, 4.7 7.46 (1.546) 10.37 (1,649) ND 2.46 (2418) ND, 3.3 5.71 (2.785) 9.62 (2.274) 562 Inoue, Seiji, Nakatsuka, Watanabe, Yin. Li, Cui,Jin. Ikeda Corrected for specific gravity (1 0161 ( m g l l ) - ul 0 0 00 1 I, 2 , L - Benzenetrio1 in urine Corrected for creatinine (rng creatinine) ul 0 000 - VI 0 -N 0 N 0 0 ul nW 0 3 N$ 2 -. 3 e . - -ryt -0 -0 TJ 2s 0 hl yl 0 0 nw uol 3 Nn2 s -. 0 9 E. - Iu-l so -0 ,3 0 0 N ul 0 Fig 2 Relation between benzene in breath zone air and 1,2,4-benzentriolin urine. Points indicate individual values. Lines and curves are calculated regression line (line in centre). 95% confidence ranges of sample means (curves close to regressiorr line). and 95% confidence ranges ofthe individual sanzples (outmost lines). Ber; Tal am. var -var -1,2. AS3 AS < C ;-S PC( con ana rela lral creP zeni for the the (tab 0.7 den: 0.01 zerc' "0 I werc won for difk EFFl CON As s ben7 the benz only the r coefl mix1 benz in th grou Accc grou regre tolue Tab11 coeff coeffi cases 'ai. Jin. Ikeda Benzenetriol in uririe of workers Table 4 Correlation coeficients obtained in regression unulyses between i.2.4-benzenerriol in urine as a dependent -Imglll variable and benzene and toluene as two independent vwiables 0 0 1 PCC MCC Brnzenr loluene 3: n 3+ 5' j! 3 -# 1, x 0 2 1 As observed As corrected for: Creatinine consciitrdon Specific gravity ( I ,016) 0,663 0.673 0.656 0.652 0.660 0,642 -0.256 -0,282 -0.273 All the correlationcoefficients in the table are statistically significant (p 0.01). MCC = Multiple correlation coefficient. PCC = Partial correlation coefficient. fon~rolswere combined and subjected to regression analysis (fig 2). From fig 2, it was evident that a linear relation exists between the 1,2,4-benzenetriol concen- lration in urine (either as observed or corrected for creatinine concentration or specific gravity) and benm e concentration in breath zone air; the 95% range lor a group mean was generally narrow even though the range for individual values was much wider than the group mean range. The correlation coefficient ([able3) for men and women combined was between 0.7 and 0.8 (depending on the correction for urine density, yet all being statistically significant with p < 0.01)and the intercept on the vertical axis was next to zero. When men and women were treated separately, no pronounced sex difference was observed. As men were less intensively exposed (< 100 ppm) than women, women exposed below 100 ppm were selected for more precise comparison between the sexes; the difference was essentially negligible (table 3). 1 IYFBCT OF COEXPOSED T O L U E N E O N U R I N A R Y CONCENTRATION OF 1,2,4-BENZENETRIOL As some men were exposed to toluene in addition to benzene (the mixture group in table I), the relation of the urinary 1,2,4-benzenetriol concentrations with IC benzene in breath zone air in the mixture group (men n 3 only) was compared with the corresponding relation in the men exposed to benzene (table 3). The correlation coefficients were lower in the men exposed to the mixture (around 0.5) than in men exposed only to benzene ()0.8), but there was pronounced reduction in Ihe slope; the slope was about 0.2 in the benzene group whereas it was SO.01 in the mixture group. Accordingly, men in the benzene, mixture, and control groups were combined and subjected to multiple 'es. Linesand , :ressiori line), rcgression analysis to detect the effects of exposure to toluene separately from that of exposure to benzene. Table 4 summarises the multiple correlation coefficients (MCC) and the partial correlation coefficients(PCC) for benzene and toluene in the three cases of correction for urine density. The validity of 563 ' the analysis was confirmed by the fact that MCC was statistically significant (p < 0.01). As expected from the simple regression analysis (table 3, fig 2), the PCC for benzene was positive (>O) and significant (p < 0.01). The PCC for toluene in all three cases,was significantly (p < 0.01) negative( <O)even though the absolute values were small (-0.2 to -0.3),suggesting that the urinary excretion of 1,2,4-benzenetriol due to exposure to benzene will be reduced by the coexposure to toluene in man. QUINOL AS A PRECURSOR OF 1,2,4- BENZENETRIOL From their chemical structures, it is possible to speculate that either quinol (1, 4-benzenediol), catechol (1,2,-benzenediol), or both are precursors of 1,2,Cbenzenetriol in vivo. When the correlation coefficient between 1,2,4-benzenetriol and quinol was compared with the coefficient between 1,2,4-benzenetriol and catechol among the workers exposed to benzene, the former value (0.905 for men, 0.722 for women, and 0.750 for men and women combined) tended to be larger than the latter (0.713, 0.666, and 0.686 respectively), although the difference was statistically insignificant (0.10 < p c 0.15 by paired t test). The observation was in favour of the hypothesis that quinol rather than catechol is a precursor of 1,2,4benzenetriol in man. This possibility was further examined by an animal experiment in which rats were injected intraperitoneally with 50 mg/kg of either phenol, catechol, or quinol, and urinary excretion of 1,2,4-benzenetriol together with catechol, quinol, and t, t-muconic acid was followed up for 24 hours. The results are summarised in table 5. 1,2,4-Benzenetriol was found in the urine of rats given quinol, and to a lesser extent, of those given phenol, but no measurable amount was detected after injection with catechol, indicating that 1,2,4-benzenetriol is formed from phenol via quinol in vivo and that catechol will not be a precursor in 1,2,4benzenetriol formation in rats. No t, t-muconic acid was detected in the urine of rats given any of the three phenolic compounds (table 5). It is reasonable that a large amount ofcatechol or quinol was excreted in the urine of rats given catechol or quinol. The increase in excretion of quinol after injection of phenol agrees with the general belief that quinol is formed through phenol in benzene metabolism." Discussion The animal experiment in the present study clearly showed that quinol is a precursor of 1,2,4-benzenetriol in rats. The observation in the urine from workers exposed to benezene that 1,2,4-benzenetriol concentrations are more closely related to the quinol concen- 564 h u e , Seiii, Nakarsuka, Watanabe, Yin, Li,Cui,Jin, I,+& Table 5 Excretion ojcatechol, qtcinol, I ,2,4-benzenetriol,and t.t-muconic acid in the urine ojrats given phenol, catechol, or quinol intraperitoneally I Metabolite analysed l,2,4-Benzenetriol 1.1-Muconic acid Catechol Quinol Chemical given Control (n = IO) Phenol (n = 9) Catechol (n = IO) Quinol (n = 9) Control (n = IO) Phcnol (n = 9) Catechol (n = IO) Quinol (n = 9) Control (n = IO) Phenol (n = 9) Catechol (n = IO) Quinol (n = 9) Control (n = IO) Phenol (n = 9) Cntcchal (n J IO) Quinol (n = 9) Period ( h ) 0-4 ND 0.157 f 0.028. ND 0.531 f 0.141* ND ND ND ND 0.024 f 0.005 0,045 f 0409' 2.943 f 0,619. 0.049 f 0012' *0.013f 0.004 0,383 0.074. 0.041 f 0.019' F4H.l f WSSS* 4-8 ND 0.018 f 0.010' ND 0,082 f 0.069' ND ND NL) ND *0.042 f 0.009 0,049 0.015 0-851 f 0,305. 0.049 f 0.011 0.028 f 0408 0.156 f 0,072' 0.027 f 09090 0.6U.5f 0.391 8-12 ND ND ND 0.017 f 0.010' ND ND ND ND 0.039 f 0406 0,059 f 0.025 0.363 f 0,143' 0.053 f 0,013, 0.024 f 0.003 0.044 f 0.020 0,031 f 0,013 0. I OY f 0.029 12-24 ND ND ND ND ND ND N I) ND 0.030 f 04334 0.036f 0.005' 0,030i 0.008 0.033 f 0.004 0.023 f 0.003 0.028 f 0.005 0.029 0.043 f f 0o.m02s9* ND ND NL) ND 0781 I441 16.986 0.998 0.540 2-660 0839 17.m Rats were given 50 mg/kg of the chemical intraperitoneally at 0930,and urine from each rat was collected for three successive four hour periods one I2 hour period for an entire day till 0930 next morning. Values in the table are mean f SD of the metabolite in the urine (in mg/kg/h or n case of the total). N D means below the detection limit which is <0901 mg/kg/h or 0.02 mg/kg/24 h for the four metabolites analysed. 'Indicates a statistically significant difference from the corresponding control (p < 0.01 by unpaired test). t A total of the amount excreted in the 24 hour period. trations than to the catechol concentrations agrees with the finding in the animal experiment and suggests that 1,2,4-benzenetriol is probably formed via phenol through quinol in workers exposed to benzene. Assuming, as in previous studies,'J6 that the absorption rate of benzene through the lungs is 50% and that the respiration rate is 15 I/min, a worker exposed to benzene at I00 ppm will absorb 2392.5 pg/min. With an additional assumption that the rate of excretion of urine is 1 ml/min,3'6the amount of benzene excreted in urine in the form of 1,2,4-benzenetriol after one day's exposure to benzene a t 100 ppm (table 3) will be 0.182 x lOO(mg/l) x 1 x 10-3(l/min)= 18.2pg/min or 11.27 pg/min as benzene (= 18.2 jig/min x 78.1 I / 126.1I), where 78.1 I and 126.11 are the molecular weight of benzene and 1,2,4-benzenetriol, respectively. In other words, about 0 4 7 % ( = 11.27/2392.5) of benzene absorbed will be excreted into the urine as 1,2,4-benzenetriol at the end of a shift of a workday. Results of similar calculations for phenol, catechol, quinol, and t, t-muconic acid are summarised, with the present result, in table 6 and compared with the observation after oral administration of benzene to rabbits.' There is pronounced similarity between the results from an animal feeding study' and urine analysis after occupational exposure.' The observation that phenol and less quinol were excreted in rabbits as compared with man will be understandable when the fact that a large amount of benzene (04-0.5 g/kg) was given by gavage at one time to rabbits is taken into account; the pathway from phenol to quinol may be temporarily saturated by massive formation phenol, leading to relatively less formation of quint and therefore I ,2,4-benzenetriol. From the view point of biological monitoring ( exposure to benzene by means of urine analysis, 42: benzenetriol has an advantage in that the level is zei in non-exposed subjects and there is no "backgroun level"; monitoring low level exposure by pheno catechol, quinol, and t, t-muconic acid is complicate by the presence of the target chemical in the urinec non-exposed s~bjects.''~The complexity of the prc HPLC treatment necessary for the analysis of 1,2,4 benzenetriol contrasts with the simple procedure fori t-muconic acid determination: but the greatest dir Table 6 Comparison of benzene metabolism in man and rabbir Urinary metabolite Man' RaMit Phenol Catechol Quinol I ,2,4-8enzenetriol t.t-Muconic acid *The estimate for the end shift urine from a worker e x p o d b benzene at 100 ppm as a time weighted average. t f h e observation in the urine of a rabbit after oral administrationd 0 . 4 4 5 g/kg of benzene. Values are cited from Williams.' $Value nted from lnoue et of.' Values cited from lnoue et a/.' IIThe r a n t study. lnValue cited from Inoue et 01.' I keda ,no1 - ralt 699 f 0 1 516 f 0 3 3 D 3 781 f 0 041 f 0 986 f 2 998 f 0 540 f 0 660f0 I839 f 0 -299 f 2 ods follo or mglh ton of luinol ng of 1,2,4s zero round thenol, icated ine of e pre1,2,4;for 1, jt dis- Benzenetriol in wine of workers advantage of the method is the suppressive effect of toluene, since the coexistence of this solvent is likely in various workplaces.'6i' This is the problem common to monitoring exposure to benzene by urine analysis for metabolites (with the possible exception of catechol'), and must be taken into account. In this connection, it should be noted that both benzene and toluene can be analysed simultaneously either by grab sampling or by diffusive samplingnYas long as gaschromatography is used. We thank the Health Bureau of Hefei City and Dr S-L Fu, Ms R-G Zhang, Mr W-G Wu, Ms G-F Cui, M r LH Zai, Ms J -F Wan, Dr X-Z Wang, and Ms L-S Hong (Heifei, China) for support and cooperation during the field study. We also thank Professor T Suzuki (Tohoku Rosai Hospital, Sendai 980, Japan) for his interest in and support of this study. Requests for reprints to: Professor M Ikeda. Refereoces I Williams RT. Dzro.rirarion merhonunu. London; Chapman and Hall. 1959;I SS-31. 2 Grccnlcc \VF. Chim JP, Riiicn DE. .A n o \ d m c t h d ior thc separation and quaatitation of benzcnc mctabolitcs using higbpressure liquid chromatography. Analb'r Chem 1981;112: 367-70. 3 lnoue 0, Sciji K. Kawhara hf. er a/. Quantitative relation of urinary phenol Icvcls to breathzone benzene conccntrdtions: a factory suncy. Br J InJ .\led 1986;43:692-7. 4 lnouc 0, Seiji K , Watanabe K, et a/. Mutual metabolic suppres- 565 sion between benzene and toluene in man. Int Arch Occup Environ Healrh 1988;60:15-20, 5 lnoue 0, Seiji K. Kasahara M , et a/. Determination of catechol and quinol in the urine of workers exposed to benzene. Er J Ind Med 1988;45:487-92. 6 lnouc 0.Seiji K, Nakatsuka H, et 01. Urinary 1. t-muconic acid as an indicator of exposure of workers to benzene. Br J Ind Afed 1989;46:122-1. 7 lkeda M. Hara 1. Evaluation of theexposure to organic solvents by means of urinalysis for metaboliles. Sangyo lguku 1980;22:3-17. 8 Hirayama T.Ikcda M.Applicabilily of activated carbon felt in the dosimetry of solvent vapor mixture. Am /nd Hyg Assoc J l979;4O:1091-6. 9 lkeda M, Kumai M. Aksoy M. Application of carbon felt dosimetry in field studies distant from analytical laboratory. lndusrrial Hralrh 1984;22:53-8. 10 Kasahdra M. lkeda M. Sponlaneous desorption of organic solvents from carbon cloth. lndusrrial Health 1987;25:73-81, I I National lnslilute for OccupationalSafely and Health. Registry of roxir rfecrs of chemical subsrunrrs. 1983-84 cummularive supplrmenr ro the 1981-82 edition. Cincinnati: NIOSH. 1985. (DHHS (NIOSH) pub1 N o 86-103.) I2 Jackson S. Creatinine in urincas an index of urinary excretion rate. Hralrh Phjs 1966;12:843-50. 13 Rainsford SG,Lloyd Davies TA. Urinary excretion of phenol by men exposed to vapour of benzene: a screening test. Br J I d M r d 1y65:22:214. I4 l k d a hf. Ohtsuji H. Hippuric acid. phenol vnJ triihloroarrtic a d ktcli in thc urinc O K Jdpxncsc suhjn.ts. u-ith no known c r p w m to organic wl\cnu. Br J I d . V d I YbY:26:1624. 15 Sn)dcr CA. Bcnzroc. In: Salder R. 4.Erh$ BroMningi ro.ririr.v MdmcrJwivn ~finOlJtrtJso1wnu.2nd d.VoI 1. HISMJP has.Arnstcddnl: Elsc\icr. IW::.;-27. lo lnouc T.TdcUihi 1'.Hiandgd S. <I d.A ndtionuidc r u n q on organicwl\cnt componcnrs in banow whcnt products. Part I. Homogeneous products such as thinners. degreasers and reagents. InJurrrial H d r h 1983;21:17%33. 17 Kumai hl. Koizumi A, Saito K. et a/. A nationwide survey on organic sohent componcnts in various solvcnt products. Part 2. Heierogenous products such as paints. inks and adhesives. InJusrrial Healrh 1983;21:185-97. Id -Rabbifi 13 5% 2 2% 48% -0 3% I 3% , oscd Lo 4$ 1 ation ' I 1 I "E