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Effects of smoking and drinking on excretionof hippuric acid among toluene-exposed workers

Osamu Inouel , Kazunori Seiji l , Takao Watanabe 2, Haruo Nakatsuka 3, Chui Jin 4 , Shi-Jie Liu 5, and Masayuki Ikeda 6

1Tohoku Rosai Hospital, Sendai 980, Japan2Miyagi University of Education, Sendai 980, Japan3Department of Environmental Sciences, Tohoku University School of Medicine, Sendai 980, Japan4 Institute of Occupational Medicine, Chinese Academy of Preventive Medicine, Beijing, China5Beijing Medical University School of Public Health, Beijing, China6Department of Public Health, Kyoto University Faculty of Medicine, Kyoto 606, Japan

Received May 7 / Accepted October 18, 1992

Summary In order to investigate possible effects ofsmoking and drinking on the metabolism of toluence inoccupational settings, 206 toluene-exposed men (meanage: 31 4 years) in shoemaking, painting, or surface-coat-ing workshops together with 246 nonexposed controlmen ( 36 8 years) were studied for the time-weighted av-erage intensities of exposure to toluene, hippuric acidconcentration in shift-end urine samples, and the two so-cial habits of smoking and drinking The mean daily con-sumptions of cigarettes and ethanol were about 20 piecesand 10 g among smokers and drinkers, respectively Thegeometric mean toluene concentration among the exposedsubjects was about 20 ppm, with a maximum of 521 ppm.Regression analysis after classification of the subjects bysmoking and drinking clearly demonstrated that the twosocial habits, when combined, markedly reduce the hip-puric acid level in the urine of workers exposed to toluene.There was a significant association between smoking anddrinking habits, which hindered separate evaluation ofthe effects of the two habits on toluene metabolism.Comparison of the present results with the findings re-ported in the literature, however, suggested that the ob-served effects may be attributable to smoking rather thanto drinking habits.

Key words: Biological monitoring Drinking Hippuricacid Smoking Toluene Urinalysis

Introduction

Applications of toluene in industries are quite varied.Toluene is in fact the leading solvent in many industrialsolvent preparations (Inoue et al 1983 ; Kumai et al 1983 ;Ikeda et al 1984 a; Kasahara et al 1987 ; Seedorff andOlsen 1990) Reflecting this wide application, hippuric

Correspondence to: M Ikeda

acid, a urinary toluene metabolite in man, has been re-peatedly evaluated as a biological indicator of occupa-tional exposure to toluene (for a review, see Lauwerys1983) Experiences are accumulating to suggest that thetwo popular social habits of smoking and drinking arepossible confounders in establishing a quantitative re-lationship between intensity of exposure to toluene andconcentration of hippuric acid in urine in humans (Riihi-maki et al 1982 ; Waldron et al 1983 ; Wilson et al 1983 ;D O ssing et al 1983, 1984 ; Wall 6 N et al 1984 ; Wall 6 n1986 ; Baelum et al 1987 ; Hjelm et al 1988 ; Nise 1992).Trials have been conducted in the present study to exam-ine whether this is really the case among toluene-exposedworking populations The results will be presented inthis article.

Materials and methods

Study population The survey was conducted in shoemaking, paint-ing, or surface-coating workshops in China, in the second halves ofworking weeks when urinary metabolite concentration was expect-ed to reach a maximum (Ikeda and Hara 1980 ; Konietzko et al.1980) Three criteria were applied in selecting the workers (allmen) for the present analysis: ( 1) determination of time-weightedaverage solvent exposure concentration and collection of shift-endurine had to have been performed, ( 2) toluene had to account for90 % or more of the solvents to which the workers were exposedwhen evaluated on a parts per million (ppm) basis, and ( 3) infor-mation had to be available on smoking and drinking habits Over-all, 206 exposed subjects met the requirements Control subjects( 246 men) were recruited from factories of the same regions Themean age (+ SD) was 31 4 ± 6 6 and 36 8 + 9 3 years for the formerand latter groups, respectively Smoking and drinking habits wereconfirmed in a medical interview Only cigarettes were smoked,and the intensity of smoking was expressed as the number of ciga-rettes consumed daily In the case of drinking, only daily drinkerswere taken into consideration The intensity of drinking was evalu-ated as the amount of ethanol taken a day, making the assumptionthat the ethanol concentrations in beer, brewage (e g , wine), anddistilled liquor (e g , spirits) are 4 5, 15 0, and 55 0 %, respectively(Institute of Health 1982) It should be added that the amounts of

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Determination of intensity of exposure to toluene, and hippuric acidconcentration in urine The time-weighted average intensity of ex-posure to toluene was measured by means of diffusive sampling(with carbon cloth as an adsorbent) followed by carbon disulfideextraction and FID gas chromatography (Hirayama and Ikeda1979 ; Ikeda et al 1984 b) A urine sample was collected at the shiftend, and hippuric acid, creatinine, and specific gravity were deter-mined by high-performance liquid chromatography, spectrometry,and refractometry, respectively, as previously described (Hase-gawa et al 1983) The results were expressed as observed (i e ,without correction), or after correction for creatinine concentra-tion (Jackson 1966) or a specific gravity of urine of 1 016 (Rains-ford and Lloyd Davies 1965) Both toluene exposure data andurinalysis data are cited from a previous publication (Liu et al.1992).

Statistical analysis Regression analysis was conducted to calculatethe regression lines Multiple regression analysis was employed toevaluate separately the effects of more than two factors (Inoue etal 1988) The difference in the slopes of the regression lines wereexamined by the F test When necessary, the chi-square test wasalso employed to examine biased distribution.

Results

Consumption of cigarettes and alcohol

Both exposed and nonexposed subjects ( 452 subjects intotal) were classified by their smoking and drinking habits.A preliminary analysis showed that both numbers of cig-arettes and amounts of alcohol distribute log-normallyrather than normally, as shown by rather large coefficientsof variation when normal distribution was assumed (Table1) Accordingly, the two consumptions were expressedin terms of both geometric mean (GM) and geometricstandard deviation (GSD) together with arithmetic mean(AM) and arithmetic standard deviation (ASD) Exami-nation by the chi-square test showed that smoking anddrinking habits distributed unevenly: smokers were morefrequently drinkers than nonsmokers, and drinkers weremore prone to be smokers than nondrinkers (P < 0 01).

When quantitatively evaluated, drinkers smoked sig-nificantly (P < 0 01) more cigarettes per day than non-drinkers, and smokers tended to drink more alcoholthan nonsmokers although the difference was not statis-tically significant (P > O 10 ; Table 1) A significant cor-relation (P< 0 01) between the number of cigarettesconsumed daily and the amount of ethanol taken daily isdepicted in Fig 1 When the exposed subjects were clas-sified by smoking and drinking habits, the average inten-sities of exposure to toluene were generally low, i e ,around 20 ppm as GM except for the nonsmoking butdrinking group ( 42 ppm), although GS Ds were ratherlarge (i e , 4-5 ; Table 1).

Comparison of regression linesby smoking and drinking habits

The entire study population (i e , both exposed and non-exposed combined) was classified by smoking and drink-ing habits, and the correlation between intensity of ex-

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Fig 1 Correlation between smoking and drinking habits Circlesindicate individual values; the open and solid ones are for exposedand nonexposed workers, respectively Some circles on the twoaxes are not shown to avoid congestion The line in the center is acalculated regression line, y = 0 093 x + 7 289, where x is the amountof ethanol (g/day) and y is the number of cigarettes consumeddaily The correlation coefficient is 0 303 (P< 0 01) The curveson both sides of the regression line show the 95 % confidence rangeof the mean, and the outmost curves are the 95 % range for indi-vidual values

posure to toluene and resulting excretion of hippuric acidin urine was examined Hippuric acid concentrationswere expressed as observed (i e , without any correction)and after correction for urine density in terms of creati-nine concentration or a specific gravity of urine of 1 016.The results of analyses are summarized as parameters ofthe regression lines (i e , the slope and the intercept on

the vertical axis) and correlation coefficients togetherwith the significance of the coefficients in Table 2.

When the population was divided by smoking habits(i.e , smokers vs nonsmokers), the slopes for the smok-ers were significantly (P < 0 05) smaller than those fornonsmokers regardless of correction for urine density.Classification by drinking habits (i e , drinkers vs non-drinkers) also showed that the slopes for drinkers weresignificantly (P < 0 01) smaller than those for nonsmok-ers in the three cases studied (upper half in Table 2).

Moreover, the population was divided into four groupstaking both smoking and drinking habits simultaneouslyinto consideration (lower half in Table 2) The slopes forthe nonsmoking-drinking group or the smoking-nondrink-ing group differed from that for the nonsmoking-non-drinking group only when no correction for urine densitywas made for hippuric acid concentration, but no signifi-cant difference was detected when correction was made.In contrast, the difference in the slopes was significant(P < 0 01) in each of the three cases when comparisonwas made between the nonsmoking-nondrinking groupand the smoking-drinking group (bottom line in Table 2).

Comparison by multiple linear regression analysis

A correlation matrix was established to examine possibleassociations among the four variables of smoking, drink-ing, age, and toluene The results are summarized inTable 3 It is clear from the table that the two variablesof smoking and drinking are significantly (P < 0 01) as-sociated with each other, as discussed above, whereas noother significant association could be detected.

Although smoking and drinking are not independentof each other, multiple and partial correlation coeffi-cients were tentatively calculated taking hippuric acidconcentrations (as observed or corrected for creatinineor specific gravity) as a dependent variable, and smok-ing, drinking, age, and toluene as independent variables.The multiple correlation coefficients and the partial cor-relation coefficients for hippuric acid were essentially

Table 2 Correlation between toluene exposure and urinary excretion of hippuric acid by smoking and drinking habitsa

Classification Group(n) Observed values Values corrected for

by a 1 r Creatinine Sp gr ( 1 016)

a 3 r a P r

Smoking Nonsmokers ( 148) 8 3 157 0 843 7 5 164 0 787 6 9 147 0 869Smokers ( 304) 5 5 ** 234 0 587 6 0 * 184 0 651 4 8 ** 189 0 650

Drinking Nondrinkers ( 293) 8 8 188 0 745 8 7 163 0 742 6 8 174 0 766Drinkers ( 159) 5 1 ** 194 * 0 687 5 1 ** 180 * 0 727 4 8 ** 145 ** 0 750

Smoking and NS-ND ( 121) 10 2 142 0 834 8 5 167 0 741 6 9 155 0 821drinking NS-D ( 27) 7 1 ** 142 0 895 7 0 99 0 864 6 9 98 0 910

S-ND ( 172) 7 9 * 225 0 681 8 8 159 0 740 6 7 189 0 732S-D ( 132) 3 6 ** 218 0 515 3 8 ** 184 0 607 3 3 ** 168 0 604

* P < 0 05 ; ** P < 0 01 ; all correlation coefficients are statisticallysignificant (P < 0 01)Ns, Nonsmokers; ND, nondrinkers; D, drinkers; S, smokers

a a and are parameters of calculated regression lines of y =ax + 3, where x is the toluene concentration in air (in ppm) and yis that of hippuric acid in urine (mg/l for observed values or valuescorrected for a specific gravity, and mg/g creatinine for values cor-rected for creatinine concentration)

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Table 3 Correlation matrix

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Smoking 0 303 ** 0 061 0 079Drinking 0 041 0 029Age 0 171

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Table 4 Correlation coefficients by regression analyses

Correlation Observed Values corrected forcoefficient values Creatinine Sp gr ( 1 016)

Multiple 0 699 0 736 0 771Partial toluene 0 689 0 732 0 755

the same (Table 4), suggesting that intensity of exposureto toluene is the strongest and almost exclusive determi-nant of hippuric acid concentrations among the variablestested.

Discussion

The present study has clearly demonstrated that the twosocial habits of smoking and drinking, when combined,markedly reduce hippuric acid levels in the urine of work-ers occupationally exposed to toluene (Table 2, Fig 2).The intensity of exposure to toluene was such that theGM was about 20 ppm with a maximum of above 500ppm, and the average number of cigarettes and mean al-cohol consumption among smokers and drinkers were

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about 10 cigarettes and about 20 g alcohol daily, respec-tively (Table 1) It was not possible, however, to sepa-rate the effect of smoking from that of drinking becausethe two habits were found to be associated with eachother (Table 2, Fig 1).

A literature survey disclosed that there are six andfive reports on the effects of drinking (Table 5) and smok-ing (Table 6), respectively, on toluene metabolism Theeffect of ethanol on toluene appears to be biphasic Whenethanol was ingested in combination with toluene expo-sure by inhalation, there was always an inhibitory effecton toluene metabolism as evidenced by the observationthat the toluene level in blood was higher and clearancefrom blood was slower than when no ethanol was taken(Waldron et al 1983 ; D O ssing et al 1984 ; Walldn et al.1984) This was reproduced by a rat liver experiment inwhich ethanol was found to be a competitive inhibitor oftoluene metabolism (Wal 16 N et al 1985) Studies of theeffects of ethanol intake on the metabolism of aromaticsolvents other than toluene are very few, limited tom-xylene (Riihimaki et al 1982) and styrene (Wilson etal 1983), and have dealt with the acute effect of ethanol(Table 5) The findings are generally in line with thoseobserved with toluene.

In contrast to the suppressive effect of ethanol afteracute administration, ethanol is known to induce solventmetabolism after repeated dosing to experimental ani-mals (e g , Sato et al 1980) Concerning toluene in par-ticular, Wang and Nakajima ( 1992) administered 2 g etha-nol daily for 3 weeks to 8-week-old male rats and thenexposed the animals to up to 4000 ppm toluene for 6 h.The toluene level in blood was significantly lower in theethanol-treated rats than in the nontreated controls, es-pecially when toluene exposure was at high concentra-

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Fig 2 A-C Comparison between the nonsmoking-nondrinking group and the smoking-drinking group in respect of the exposure-excretionrelationship The lines and curves are the calculated regression lines (lines in the center) and 95 % confidence ranges for sample means

429

Table 5 Effects of drinking on solvent metabolism; a literature reviewa

Exposure Effects Reference

Toluene, 80 ppm + Et OH, 1 g/kg Elevated toluene level in blood Waldron et al ( 1983)Toluene, 78 ppm + Et OH, 0 69 g/kg Elevated toluene level in blood and Wall 6 N et al ( 1984)

reduced toluene clearanceOccup toluene exp ( 50-200 ppm) Lower toluene level in blood among Waldron et al ( 1983)

+ drinking habits (up to several days/wk) regular drinkersToluene, 100 ppm + Et OH ( 0 1 % in blood) Reduced excretion of hippuric acid in urine D O ssing et al ( 1984)Occup toluene exp ( 26 ppm as median) Reduced excretion of hippuric acid in urine Nise ( 1992)

+ drinking habits (> 57 g/day in some)Toluene + Et OH in rat liver perfusion Competitive inhibition Wall 6 N et al ( 1985)m-Xylene, 280 ppm + Et OH, 0 8 g/kg Suppression of xylene metabolism Riihimaki et al ( 1982)Styrene, 52 ppm + Et OH, 1 g/kg Suppression of mandelic acid in blood Wilson et al ( 1983)Ethanol, 2 82 g/day to rats for 3 wk Increase in solvent metabolism Sato and Nakajima ( 1984)Et OH 2 g/day to rats for 3 wk and Changes in metabolism dependent Wang and Nakajima ( 1992)

then toluene, up to 4 000 ppm for 6 h on toluene concentration

Et OH, Ethanola Studies were on humans (either volunteers or workers) unless otherwiese specified

Table 6 Effects of smoking on hippuric acid excretion after toluene exposure; a literature review

Exposure Effets Reference

Toluene, 100 ppm + smoking habit No change in hippuric acid excretion D O ssing et al ( 1983)Toluene, 100 ppm + smoking habit Small reduction in hippuric acid excretion Baelum et al ( 1987)Toluene, 80 ppm + smoking habit Enhanced toluene clearance in blood Wall 6 N ( 1986)Toluene, 78 ppm + smoking habit Slight enhancement of toluene clearance in blood Hjelm et al ( 1988)Occup toluene exp ( 26 ppm as median) + smoking habits No change in hippuric acid excretion Nise ( 1992)

tions (e g , > 250 ppm); this finding was accompanied byincreased excretion of hippuric acid as well as o and p-cresols in urine.

It was reported by Waldron et al ( 1983) that the to-luene level in blood is lower among regular drinkers(amount of ethanol unknown) than among nondrinkers.Nevertheless, it is possible to argue about the occupa-tional health implications of the metabolism-inducing ef-fects of ethanol In a simulation study utilizing a phar-macokinetic model after Sato et al ( 1991 a), Sato et al.( 1991 b) calculated that ethanol intake (e g , 20 mmol/kgor some 50-60 g ethanol per person) on the previousevening will cause only small changes in the pharmaco-kinetics of trichloroethylene after exposure at 50 ppm,even though the change may be appreciable when theexposure is at 500 ppm The explanation offered for theessential absence of the effects of ethanol after low leveltrichloroethylene exposure is that the factor which limitsthe metabolism in the liver under such conditions is theflow of blood to the liver (i e , supply of the substrate)and not the enzyme activity.

The same group (Kaneko and Sato 1992) further ex-tended their simulation study to the case of m-xylene (atoluene homologue) and predicted that the urinary ex-cretion of m-methylhippuric acid (a major metabolite ofm-xylene in man) will be comparable between drinkersand nondrinkers after 8 h m-xylene exposure at 50 ppmbecause there is no change in the blood flow to the liver,wheras more m-methylhippuric acid will be excreted inthe urine of drinkers than in that of nondrinkers when

m-xylene exposure is as high as 1000 ppm owing toethanol-associated induction of liver enzymes.

It should be added that the amount of ethanol con-sumed by the present study participants ( 10 g/day perperson) is only one-fifth or even less of the ethanol doseassumed in the simulation (e g , 50-60 g/day per per-son) In addition, observation in the factories indicatedthat workers have no custom of drinking alcoholic bever-ages at lunch or dinner time on weekdays In contrast,some of the subjects in the study by Nise ( 1992) consum-ed more than 400 g ethanol/week or almost 60 g/day sothat a measurable amount of ethanol was detected in thepreshift blood samples, suggesting that the suppressedexcretion of hippuric acid in urine observed among drin-kers (Nise 1992) is very probably a direct competitive ef-fect of ethanol on toluene metabolism Thus, with refer-ence to the present study it is quite unlikely that the ob-served suppression of hippuric acid excretion is associat-ed with the drinking habits of the workers.

Studies on the effect of smoking on toluene metabo-lism in humans (Table 6) by nature concern long-termexposure to cigarette smoke The implications of thefindings in four reports (Wallen 1986 ; Baelum et al 1987 ;Hjelm et al 1988 ; Nise 1992) appear complicated, owingat least in part to a lack of information on the intensityof smoking; 1-25 and 10-40 cigarettes were consumedby the subjects of the studies by Baelum et al ( 1987) andHjelm et al ( 1988), respectively, but no quantitativedata are given by other authors Wallen ( 1986) and Hjelmet al ( 1988) observed that clearance of toluene from the

430

blood is enhanced in smokers as compared with nonsmok-ers This, however, was not associated with any signifi-cant change in hippuric acid excretion (D O ssing et al.1983 ; Hjelm et al 1988 ; Nise 1992) Moreover, it wasfound in the study of Wallin ( 1986) that smokers used totake more ethanol than nonsmokers, making it difficultto evaluate the effect of smoking separately from that ofdrinking.

In the study of Baelum et al ( 1987), excretion of hip-puric acid after experimental exposure to toluene at 100ppm tended to be lower among smokers (with a dailyconsumption of 1-25 cigarettes) than among nonsmok-ers, even though the difference was not statistically sig-nificant (P > O 10) The present results are apparently inline with the observation of Baelum et al ( 1987), thoughthe differences were more marked in our study It maybe further possible to speculate on the combined effectsof smoking and drinking, because suppression is moreevident when the two habits are present in combination(Table 2) No theoretical explanation for such combinedeffects is, however, currently available.

Acknowledgements Thanks are due to Prof T Suzuki and Prof.K Yoshinaga, the former and the present Director of Tohoku Ro-sai Hospital, Sendai, Japan, respectively, for their interest in andsupport for this work This work was supported in part by a Grants-in-Aid for International Research Program for 1988 and 1989 (No.63044017) from the Ministry of Education, Science and Culture ofthe Government of Japan.

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