mutual metabolic suppression between benzene and toluene in man

Int Arch Occup Environ Health ( 1988) 60:15-20International Archives of

Oe Ce Upaonlal-dEnvironmentalHealth© Springer-Verlag 1988

Mutual metabolic suppression between benzene and toluene in man

Osamu Inoue l' 2, Kazunori Seiji l ' 2, Takao Watanabe 2 , Miyuki Kasahara 2 , Haruo Nakatsuka 2 , Songnian Yin 3 ,Guilan Li 3 , Shixiong Cai 3 , Chui Jin 3, and Masayuki Ikeda 2

'Center of Occupational Medicine, Tohoku Rosai Hospital, Sendai 980, Japan2Department of Environmental Health, Tohoku University School of Medicine, Sendai 980, Japan3 Institute of Occupational Medicine, Chinese Academy of Preventive Medicine, Beijing, China

Summary The exposure intensity during a shift andthe metabolite levels in the shift-end urine were ex-amined in male workers exposed to either benzene( 65 subjects; the benzene group), toluene ( 35 sub-jects; the toluene group), or a mixture of both ( 55subjects; the mixture group) In addition, 35 non-exposed male workers (the control group) were simi-larly examined for urinary metabolites to definebackground levels A linear relationship was estab-lished between the intensity of solvent exposure andthe corresponding urinary metabolite levels (i e.phenol, catechol and quinol from benzene, and hip-puric acid and o-cresol from toluene) in each casewhen one of the three exposed groups was combinedwith the control group for calculation Comparison ofregression lines in combination with regression analy-sis disclosed that urinary levels of phenol and quinol(but not catechol) were lower in the mixture groupthan in the benzene group when the intensities of ex-posure to benzene were comparable, indicating thatthe biotransformation of benzene to phenolic com-pounds (excluding catechol) in man is suppressed byco-exposure to toluene Conversely, metabolism oftoluene to hippuric acid was suppressed by benzeneco-exposure Conversion of toluene to o-cresol wasalso reduced by benzene, but to a lesser extent Thesignificance of the present findings on the mutualsuppression of metabolism between benzene andtoluene is discussed in relation to solvent toxicologyand biological monitoring of exposure to the solvents.

Key words: Benzene Biological monitoring Sup-pression in metabolism Toluene Urinary meta-bolites

Offprint requests to: M Ikeda at the above address

Introduction

Benzene and toluene (methylbenzene) are twoaromatic compounds often detected in combinationin automobile and solvent gasoline (e g Ikeda et al.1984 b; Ikeda and Kasahara 1986), and less frequentlyin solvent products (Inoue et al 1983 ; Kumai et al.1983) In experimental animals it was previouslyfound that the oxidative biotransformation of bothbenzene and toluene is suppressed mutually when thetwo are given together (Ikeda et al 1972), that tol-uene suppresses benzene metabolism more potentlythan the reverse (Ikeda et al 1972), and that theleukopenic action of benzene is also reduced whentoluene is co-administered (Ikeda and Hirayama1979).

The present study was initiated to confirm mutualmetabolic suppression of benzene and toluene in manby means of analyses for metabolites in urine fromworkers exposed to benzene, toluene or a mixture ofthe two The results are described in this report.

Materials and methods

Examinees The factory survey was conducted in the latter halfof the week (Ikeda and Hara 1980) Since previous studies inhumans have shown, that there is a sex difference in toluenemetabolism (Inoue et al 1986 b), only male workers wereselected The examinees (male Chinese workers, 190 in total)consisted of four groups: those exposed to benzene (the ben-zene group), to toluene (the toluene group), to a mixture ofbenzene and toluene (the mixture group) and to none (the con-trol group) The numbers of the subjects in the groups, theirjobs and the exposure intensities are summarized in Table 1.

Exposure analysis To determine time-weighted average(TWA) vapor concentration in the breath zone, each solventworker was equipped with a diffusive sampler (Hirayama and

O Inoue et al : Metabolic suppression of benzene and toluene in man

Table 1 The number of examinees, their jobs and exposure intensities by group

Exposure Na Jobs Exposureb

Benzene Toluene

Benzene 65 Majority in shoe-making, 31 9 ± 24 8: 92and some in printing l 20 4 ( 3 086)l

Toluene 35 Shoe-making, printing, or 44 7 + 21 3: 86audio-equipment producing l 38 2 ( 1 920)l

Mixture 55 Spray painting in 17 9 ± 29 3:116 20 5 ± 25 8:114automobile body plants l 6 2 ( 4 187)l l 11 9 ( 3 670)l

Control 35 Leather cutting andsewing, clerical, etc.

Workers examined were all male.a No of examineesb Arithmetic mean (unit; ppm) arithmetic standard deviation (unit; ppm): maximum (unit; ppm), and lgeometric mean (unit;ppm) (geometric standard deviation)l

Ikeda 1979 ; Ikeda et al 1984 a) on the lapel from the beginningof the shift (at around 8:00 h) of the day till the time of urinecollection (at around 15:00 to 16:00 h) The solvents adsorbedon the carbon cloth were analyzed with a FID-gaschromato-graph (GC) as previously described (Hirayama and Ikeda1979).

Urinalysis Each worker was asked to pass urine at 13:00 to14:00 h, and then urine discharged at 15:00 to 16:00 h was sam-pled The samples were analyzed for phenol (by GC; Inoue etal 1986 a), catechol lby high performance liquid chromato-graphy (HPLC); Inoue et al 1987 l, quinol (by HPLC; Inoue etal 1987), hippuric acid (by HPLC; Hasegawa et al 1983), o-cresol (by GC; Hasegawa et al 1983), creatinine (by col-orimetry; Ikeda and Ohtsuji 1969) and specific gravity (refrac-tometry) The concentrations of the urinary metabolites wereexpressed as observed, or after correction for creatinine con-centration (Jackson 1966) or specific gravity of urine of 1 016(Rainsford and Lloyd Davies 1965).

Statistical analysis When the exposure excretion correlationwas calculated, the control group was employed to define thenon-exposed level (i e the metabolite level without exposure)for the benzene, toluene and mixture groups In practice, thecorrelation was calculated utilizing the combination of the con-trol group with one of the other three (i e , benzene, tolueneand mixture) groups For example, the benzene exposure -phenol excretion relationship was analyzed with the combina-tion of the benzene group and the control group The regres-sion analysis was conducted by the use of a package programsupplied by Nippon Electric Co (Tokyo, Japan) for the ACOS1000 in the Computer Center, Tohoku University.

Results

Comparison between the single and mixture exposuregroups

The metabolite levels were assumed to distribute log-normally (Heath 1967) Thus, the levels of the fivemetabolites (i e phenol, catechol, quinol, hippuricacid and o-cresol) in the urine of the 35 non-exposedworkers are summarized in terms of geometric mean(geometric standard deviation) in Table 2 The geo-

Table 2 Metabolite concentrations in urine samples from 35non-exposed male workers

Urinary Observed Value corrected formetabolite value Creatinine Spec grav a

(mg/I)' (mg/g)b (mg/g)b

Phenol 6 9 ( 2 691) 9 5 ( 1 740) 8 5 ( 1 755)Catechol 9 4 ( 2 075) 12 7 ( 1 708) 11 2 ( 1 621)Quinol 4 8 ( 3 029) 5 9 ( 2 767) 5 3 ( 2 625)Hippuric acid 72 5 ( 3 424) 95 9 ( 2 929) 83 4 ( 2 814)o-Cresol 66 0 ( 4 803) 80 2 ( 4 262) 68 8 ( 4 587)

Values in the table are geometric means (geometric standarddeviations) calculated with an assumption of log-normal dis-tribution (Heath 1967).a A specific gravity of urine of 1 016b The unit in the case of o-cresol is gtg/l for the observed valueand the value corrected for a specific gravity, and lig/gcreatinine for the value corrected for creatinine concentration

metric mean levels of the three benzene metabolites(i.e phenol, catechol and quinol) were about 10 mg/gcreatinine when corrected for the creatinine concen-tration) or less; among them catechol appeared to bemost abundant, followed by phenol and then quinol.Of the two toluene metabolites, the level of hippuricacid (slightly less than 100 mg/l or mg/g) was severaltimes higher than the levels of above-cited threephenolic compounds, while that of o-cresol was in theorder of tg/l or gg/g and was much less than theothers The latter two metabolites, especially o-cre-sol, showed much wider variations in concentrationsthan the former three (phenol, catechol and quinol)as the differences in geometric standard deviationsindicate.

The relationship between the intensity of expo-sure to benzene and the level of phenol, catechol andquinol in urine was examined in the benzene groupand the mixture group Similarly, an examination

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Table 3 Comparison of correlations between single solvent exposure and mixture exposure

Solvent Group Correlation between exposurea and urinary metabolitebMetabolite As observed As corrected for

Creatinine A specific gravity

Benzene Benzene Ph = 4 11 B + 4 3 ( 0 789) Ph = 4 10 B + 15 6 ( 0 858) Ph = 3 35 B + 13 3 ( 0 840)

Phenol Mixture Ph = 1 66 B + 14 1 ( 0 721) Ph = 1 81 B + 14 7 ( 0 760) Ph = 1 41 B + 13 1 ( 0 760)

Benzene Benzene Ca = 0 45 B + 9 8 ( 0 663) Ca = 0 41 B + 13 7 ( 0 745) Ca = 0 33 B + 11 9 ( 0 674)

Catechol Mixture Ca = 0 30 B + 11 3 ( 0 592) Ca = 0 35 B + 13 1 ( 0 619) Ca = 0 25 B + 11 5 ( 0 614)

Benzene Benzene Qu = 3 79 B + 12 3 ( 0 782) Qu = 4 05 B + 24 3 ( 0 794) Qu = 3 25 B + 21 8 ( 0 779)

Quinol Mixture Qu = 1 51 B + 8 4 ( 0 619) Qu = 1 46 B + 11 0 ( 0 696) Qu = 1 19 B + 9 4 ( 0 670)

Toluene Toluene Ha = 10 47 T + 140 9 ( 0 751) Ha = 10 77 T + 159 8 ( 0 827) Ha = 9 98 T + 145 0 ( 0 801)

Hippuric acid Mixture Ha = 7 31 T + 119 2 ( 0 644) Ha = 8 46 T + 129 3 ( 0 700) Ha = 6 16 T + 120 0 ( 0 646)

Toluene Toluene o C = 8 19 T + 146 6 ( 0 647) o C = 8 14 T + 161 6 ( 0 714) o C = 7 37 T + 144 4 ( 0 720)

o-Cresol Mixture o C = 5 30 T + 179 4 ( 0 464) o C = 6 35 T + 187 1 ( 0 608) o C = 4 53 T + 174 5 ( 0 505)

The figures in the table indicate the calculated regression lines followed by the correlation coefficients in parentheses All the coef-ficients were statistically significant (P < 0 01).a B and T stand for benzene (unit; ppm) and toluene (unit; ppm), respectivelyb Ph, Ca, Qu, Ha and o C stand for phenol, catechol, quinol, hippuric acid and o-cresol, respectively The unit for the former fourmetabolites is mg/l for the observed value, mg/g creatinine for the creatinine-corrected value and mg/liter for the specific gravity-corrected value, and that for o-cresol is gg/l for the observed value, gtg/g creatinine for the creatinine-corrected value and jig/l forthe specific gravity-corrected valueCA specific gravity of urine of 1 016

was carried out on the relation of toluene in airagainst urinary hippuric acid and o-cresol The re-sults are presented in terms of the calculated regres-sion line between exposure concentrations and uri-nary metabolite concentrations, the correlation coef-ficient and the statistical significance (Table 3) Uri-nary metabolite levels are expressed as observed, orcorrected for creatinine concentration or for a specif-ic gravity of urine of 1 016 When the regression linesfor phenol excretion were compared between thebenzene group and the mixture group, it was evidentthat the slope of the regression line in the mixturegroup was only less than half of that in the benzenegroup, independent of the correction for urine densi-ty Very similarly, the slope of the regression line forquinol excretion in the mixture group was less than ahalf of that in the benzene group The findings sug-gest that, when the workers are exposed to toluene inaddition to benzene (for actual concentrations of thetwo solvents, see Table 1), the urinary levels ofphenol and quinol will be much lower than the levelsin the urine of those exposed only to benzene at simi-lar concentrations In contrast, when the regressionlines for catechol excretion were compared, the slopefor the mixture group was about 80 % or even moreof that for the benzene group.

Analogous comparison of the regression lines be-tween the toluene group and the mixture group dis-closed that the slopes for the mixture group were

smaller than, yet larger than the half of, the slopesfor the toluene group, both in the cases of hippuricacid excretion and o-cresol excretion (Table 3) Asan example, the regression lines accompanied by the95 % confidence ranges in case metabolite levels arecorrected for a specific gravity of urine of 1 016 aredepicted in Fig 1, to compare the case of the singlesolvent exposure with that of the mixture exposure.It is evident that there is essentially no overlapping inthe 95 % confidence ranges between the benzenegroup and the mixture group in the Fig 1 A (benzeneversus phenol) and Fig 1 C (benzene versus quinol),while overlapping is remarkable in Fig 1 B (benzeneversus catechol) The cases shown in Fig 1 D (to-luene versus hippuric acid) and Fig 1 E (toluene ver-sus o-cresol) are between the two extremes with lessoverlapping in the former and more in the latter.

Regression analysis for quantitative evaluation ofmutual suppression of metabolism

Regression analysis was conducted with 190 subjectsin total taking each metabolite as a dependent vari-able and the exposure concentrations of benzene andtoluene as independent variables The results of thecalculation are summarized in terms of multiple cor-relation coefficients (MCC), and partial correlationcoefficients (PCC) of benzene and toluene in Table4 It is evident that MCC was statistically significant

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( B )

i loo(

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° I 50 ta

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(E )

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Fig 1 Comparison of the regres-sion lines between the singlesolvent exposure group and themixture exposure group Thecalculated regression line of thesingle exposure group (i e eitherthe benzene or the toluene group)is compared with that of themixture group The shaded area isthe 95 % confidence range of eachregression line; shades withhorizontal lines are for themixture group and those withvertical lines are for the benzeneor toluene groups, and thus, theareas with crosses indicate theoverlapping between two 95 %confidence ranges

50 100

TOLUENE IN AIR (ppm)

0 50 100

BENZENE IN AIR (ppm)

Table 4 Correlation coefficients obtained in regression analyses

Metabolite Metabolite as observed Metabolite as corrected for

MC Ca PC Cb Creatinine A specific gravity

Benzene Toluene MCC PCC MCC PCC

Benzene Toluene Benzene Toluene

Phenol 0 740 ** 0 732 ** -0 133 0 804 ** 0 793 ** -0 163 * 0 788 ** 0 776 ** -0 170 *Catechol 0 629 ** 0 621 ** 0 072 0 711 ** 0 704 ** 0 073 0 666 ** 0 658 ** 0 076Quinol 0 726 ** 0 709 ** -0 185 * 0 745 ** 0 717 ** -0 229 ** 0 733 ** 0 705 ** -0 231 *Hippuric acid 0 649 ** -0 090 0 646 ** 0 777 ** -0 094 0 775 ** 0 725 ** -0 135 0 717 **o-Cresol 0 583 ** -0 067 0 581 ** 0 667 ** -0 032 0 667 ** 0 646 ** -0 078 0 643 **

Asterisks indicate statistical significance (** for P < 0 01, * for P < 0 05)a MCC: multiple correlation coefficientb PCC: partial correlation coefficientCA specific gravity of urine of 1 016

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in all of the 15 cases (i e 5 metabolites in 3 cases ofeither with or without correction for the density ofurine), indicating the validity of the analysis As ex-pected the urinary levels of the three benzene meta-bolites (i e phenol, catechol and quinol) were signif-icantly (P< 0 01) and positively (i e with a coeffi-cient larger than 0) related to the intensity of the ex-posure to benzene Similarly, the relationship of hip-puric acid and o-cresol levels with toluene exposurewas significant (P < 0 01) and positive Of particularinterest is the observation that the phenol and quinollevels relate negatively (i e with a coefficient smallerthan 0) to the co-exposed toluene, although the sta-tistical significance varies depending on the correc-tion for the urine density, and that the relation of hip-puric acid and o-cresol levels with benzene co-expo-sure is also negative even though statistically insig-nificant Thus, it is possible to deduce that the uri-nary levels of the two benzene metabolites, phenoland quinol, will be reduced by co-exposure to tol-uene, and that the levels of the two toluene metabo-lites, hippuric acid and o-cresol, in urine may also belowered (even if to a lesser extent) by the benzeneco-exposure, when benzene and toluene are co-ex-posed together.

Discussion

The present study on factory workers clearly demon-strated that the formation of phenol and quinol (butnot catechol) from benzene in man is suppressedwhen the worker is also exposed to toluene, and thatconversely formation of hippuric acid and o-cresolfrom toluene are reduced by co-exposure to benzene.As the suppressed formation of phenol from benzene(Ikeda et al 1972) is known to be associated with thealleviation of benzene-induced leukopenia in rats(Ikeda and Hirayama 1979), it may be most plausiblethat benzene is less potent in reducing peripheralleukocyte counts in benzene-exposed workers whenthe workers in question are co-exposed to toluene.Such would be the case of those exposed to the va-pors of automobile or industrial gasoline, in both ofwhich benzene and toluene are detected in combina-tion (Ikeda et al 1984 b; Ikeda and Kasahara 1986).It is known that, in rats, toluene suppresses benzenemetabolism more potently on an equimolar basisthan benzene affects toluene metabolism Namely,when benzene toluene mixtures were given intra-peritoneally to rats, toluene at a dose four times thatof benzene markedly suppressed the conversion ofbenzene to phenol, whereas four times as much ben-zene as toluene caused only retardation and no re-duction in the formation of hippuric acid from tol-

uene (Ikeda et al 1972) In accordance with this ob-servation in experimental animals, effects of co-ex-posed toluene in suppressing benzene metabolism isalso more evident in man than that of benzene on tol-uene metabolism (Tables 3, 4) In addition, previousexperiments in animals have shown that the metabo-lism of benzene to phenol under co-exposure to tol-uene is more markedly suppressed when the ratio oftoluene over benzene is higher (Ikeda and Hirayama1979) Experience generally indicates that commer-cial solvent products as well as gasoline contain moretoluene than benzene, if the latter is also present(Inoue et al 1983 ; Kumai et al 1983 ; Ikeda et al.1984 b; Ikeda and Kasahara 1986) Thus, it is furtherpossible that in industrial environments, metabolismof benzene will be more extensively suppressed bymassive toluene than a small quantity of benzene willaffect toluene metabolism, even though benzene ismore volatile than toluene.

Exposure monitoring of workers by means ofurinalyses for metabolites (Rainsford and LloydDavies 1965 ; Pagnotto and Lieberman 1967 ; Ikedaand Ohtsuji 1969 ; Sherwood 1972 ; Angerer 1979,1985 ; Pfaffli et al 1979 ; Woiwode and Drysch 1981 ;Apostoli et al 1982 ; Hasegawa et al 1983 ; Inoue etal 1986 a,b) has been a focus of attention for a longperiod of time From the findings in the presentstudy, however, it is deducible that caution will beneeded in evaluating when workers are exposed tobenzene and toluene in combination, because thebiotransformation of the two chemicals will be mutu-ally suppressed and the exposure may be underesti-mated From a practical viewpoint, it would be betterto monitor benzene exposure by means of catecholrather than phenol in urine, when workers are ex-posed not only to benzene but to toluene, as the for-mation of catechol from benzene is modified muchless, if any, by co-exposure to toluene (Table 3).

Opinion is unanimous regarding the formation ofphenol and quinol in that benzene is converted tophenol via benzene oxide and that further oxidationof phenol gives rise to quinol (e g Dean 1978 ;Greenlee et al 1981 ; Irons et al 1981) The pathwayof catechol formation is, however, still debatable.For example, Billings ( 1985) investigated the mecha-nism to form catechols with seven aromatic com-pounds including benzene and concluded that themore general route of catechol formation may be viadihydrodiols rather than via phenols In contrast,Sawahara and Neal ( 1983) incubated 14 C-phenol withrat liver microsomes in the presence of a NADPH-generating system, and observed the formation ofcatechol in addition to the formation of quinol, al-though the transformation was biased to quinol witha catechol: quinol ratio of 1: 20 The present observa-

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0 Inoue et al : Metabolic suppression of benzene and toluene in man

tion (Table 3) that the formation of catechol is less af-fected by toluene co-exposure than that of phenoland quinol appears to support the former mecha-nism, because the suppression of phenol formationshould result in the suppression of both catechol andquinol formation in case phenol is a common precur-sor of both catechol and quinol Further studies are,however, apparently needed before reaching anysolid conclusion.

Acknowledgements The authors are grateful to the HealthBureau of Hefei City, China, and Dr S -L Fu, Dr R -G.Zhang, Mr W -G Wu, Ms G -F Cui, Mr L -H Zai, Ms J -F.Wan, and L -S Hong for their supportive cooperation in thefield investigation in Hefei, China.

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Angerer J ( 1985) Occupational chronic exposure to organicsolvents XII O-cresol excretion after toluene exposure.Int Arch Occup Environ Health 56:323-328

Apostoli P, Brugnone F, Perbellini L, Cocheo V, BellomoML, Silvestri R ( 1982) Biomonitoring of occupational tol-uene exposure Int Arch Occup Environ Health 50:153-168

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Ikeda M, Hirayama T ( 1979) Alleviation of benzene leuko-penia in rats simultaneously exposed to toluene Arh HigRada Toksikol (Suppl) 30:477-481

Ikeda M, Kasahara M ( 1986) n-Hexane and benzene contentsin gasoline for industrial purpose Ind Health 24:63-66

Ikeda M, Kumai M, Aksoy M ( 1984 a) Application of carbonfelt dosimetry to field studies distant from analytical labo-ratory Ind Health 22:53-58

Ikeda M, Kumai M, Watanabe T, Fujita H ( 1984 b) Aromaticand other contents in automobile gasoline in Japan IndHealth 22:235-241

Ikeda M, Ohtsuji H ( 1969) Significance of urinary hippuricacid determination as an index of toluene exposure Br JInd Med 26:244-246

Ikeda M, Ohtsuji H, Imamura T ( 1972) In vivo suppression ofbenzene and styrene oxidation by co-administered toluenein the rats and effects of phenobarbital Xenobiotica 2:101-106

Inoue O, Seiji K, Kasahara M, Nakatsuka H, Watanabe T,Yin S-N, Li G-L, Jin C, Cai S-X, Wang X-Z, Ikeda M( 1986 a) Quantitative relation of urinary phenol level tobreathzone benzene concentration: A field survey Br JInd Med 43:692-697

Inoue O, Seiji K, Kasahara M, Nakatsuka H, Watanabe T,Yin S-N, Li G-L, Jin C, Cai S-X, Wang X-Z, Ikeda M( 1987) Determination of catechol and quinol in the urine ofworkers exposed to benzene Br J Ind Med (in press)

Inoue O, Seiji K, Watanabe T, Yin S-N, Li G-L, Cai S-X, JinC, Ikeda M ( 1986 b) Possible ethnic difference in toluenemetabolism: a comparative study among Chinese, Turkishand Japanese solvent workers Toxicol Lett 34:167-174

Inoue T, Takeuchi Y, Hisanaga N, Ono Y, Iwata M, OgataM, Saito K, Sakurai H, Hara I, Matsushita T, Ikeda M( 1983) A nationwide survey on organic solvent products:Part I Homogeneous products such as thinners, degreas-ers and reagents Ind Health 21: 175-183

Irons RD, Neptun DA, Pfeifer RW ( 1981) Inhibition of lym-phocyte transformation and microtubule assembly by qui-none metabolites of benzene, evidence for a commonmechanism J Reticuloendothel Soc 30:359-372

Jackson S ( 1966) Creatinine in urine as an index of urinaryexcretion rate Health Phys 12:843-850

Kumai M, Koizumi A, Saito K, Sakurai H, Inoue T, TakeuchiY, Hara I, Ogata M, Matsushita T, Ikeda M ( 1983) Anationwide survey on organic solvent products: Part II.Heterogeneous products such as paints, inks and adhe-sives Ind Health 21:185-197

Pagnotto LD, Lieberman LM ( 1967) Urinary hippuric acidexcretion as an index of toluene exposure Am Ind HygAss J 28:129-134

Pfaffli P, Savolainen H, Kalliomaki P-L ( 1979) Urinary o-cre-sol in toluene exposure Scand J Work Environ Health 5:286-289

Rainsford SG, Lloyd Davies TA ( 1965) Urinary excretion ofphenol by men exposed to vapor of benzene: A screeningtest Br J Ind Med 22:21-26

Sawahara T, Neal RA ( 1981) Biotransformation of phenol tohydraquinone and catechol by rat liver microsomes MolecPharmacol 23:453-460

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Received January 8 / Accepted July 17, 1987

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mutual metabolic suppression between benzene and toluene in man

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