Occupational chronic exposure to organic solvents XVI. Ambient and biological monitoring of workers exposed to toluene

Object Ambient air and biological monitoring of an occupational toluene exposure was carried out on a group of 33 workers. Method The biological monitoring of the workers was based on determination of the concentration of toluene in blood and on quantification of the urinary metabolites o-cresol and hippuric acid. All blood and urine samples were collected post-shift. Results The average toluene concentration in the workplace air was 65?ppm, ranging from 13 to 151?ppm. An average concentration of toluene in blood of 911?μg/l was found, corresponding to an average urinary concentration of 2.9?mg/l (2.3?mg/g creatinine) o-cresol and 2.4?g/l (1.9?g/g creatinine) hippuric acid. Both urinary metabolites can be correlated with the concentration of toluene in ambient air and blood, respectively. Conclusions The results of our study indicate that the determination of the urinary o-cresol excretion represents a diagnostically specific and sensitive parameter for the estimation of an individual toluene uptake. In contrast, monitoring of the concentration of hippuric acid in urine cannot be recommended for assessment of individual exposure. To set up a biological tolerance value (BAT) for o-cresol, a urinary concentration of 3?mg/l o-cresol should be in accordance with the current MAK value of 50?ppm toluene.     

Chronic occupational exposure to toluene

Summary Chronic occupational exposure to toluene was studied in a factory preparing tarpaulins. Seventy-eight workers were studied; 46 were exposed to various concentrations of toluene in air (20–200 ppm), 32 were unexposed workers in the same factory. In many cases the exposure had lasted for 10–20 years. The urinary hippuric acid excretion at the end of work shift showed good correlations to toluene concentrations in air, and it seems to be a good measure of exposure. The hippuric acid in urine samples collected overnight showed that elimination of toluene still occurs several hours after exposure. Most of the biological parameters measured showed no correlation to toluene exposure. The blood leukocyte count did show slight positive correlations to toluene exposure, but even this parameter stayed inside the range of normal values. The occurrence of chronic diseases, drug using habits, and drinking and smoking habits did not show any correlations to toluene exposure.This study has been supported by the grant of Y. Jahnsson Foundation in Finland     

Effects of smoking and drinking habits on urinary o-cresol excretion after occupational exposure to toluene vapor among chinese workers

The relationship between the time-weighted average intensity of exposure to toluene and o-cresol concentration in shift-end urine was investigated in nearly 500 factory workers of both sexes in China, together with a similar number of nonexposed control subjects. Toluene concentration (25 ppm as geometric mean and 550 ppm as the maximum) was monitored by diffusive sampling using carbon cloth as adsorbent followed by gas chromatographic (GC) analysis. o-Cresol (up to 7 mg/1) was measured by GC after acid hydrolysis of samples. Urinary o-cresol levels correlated significantly (r = 0.69–0.77; p < 0.01) with toluene exposure in men, women and the two sexes in combination, regardless of correction for urine density. When compared with hippuric acid, however, o-cresol was less sensitive as an indicator of exposure to toluene and is not a suitable biological marker for detecting low level toluene exposure. Since urinary o-cresol level was significantly reduced by smoking, drinking, and the two habits combined, it cannot be considered reliable as an indicator of exposure to toluene. © 1994 Wiley-Liss, Inc.     

Biomonitoring of occupational toluene exposure

Summary Toluene exposure was studied in 20 workers employed in painting and hand-finishing in an art furniture factory. Toluene was determined in the environmental air of places of work and in the alveolar air and blood of the workers. Hippuric acid and cresols were also tested in the workers' urine. Blood and urine tests were carried out before the work shift on Monday and Friday morning and at the end of the work shift on Friday afternoon. The other tests were performed on Friday afternoon only. Alveolar toluene concentrations, which were significantly correlated with environmental toluene concentrations (r= 0.6230; P < 0.01), corresponded to 19.4% of the toluene concentration in the atmosphere. Blood toluene was also found in painters on Monday morning and was significantly correlated with the other parameters. On Friday afternoon it was three times higher than the environmental toluene concentration. Urinary o-Cresol was highly correlated with toluene in the atmosphere, in blood and with hippuric acid in urine. On the basis of the slope of the regression line the ratio between urinary o-Cresol and blood toluene concentration was 0.99. At the end of the work shift urinary hippuric acid concentration was highly correlated with o-Cresoluria and with toluene in blood and in the atmosphere.     

Toluene in blood as a marker of choice for low-level exposure to toluene

The validity of two new biological exposure markers of toluene in blood (TOL-B) and toluene in urine (TOL-U) was examined in comparison with that of the traditional marker of hippuric acid in urine (HA-U) in 294 male workers exposed to toluene in workroom air (TOL-A), mostly at low levels. The exposure was such that the geometric mean for toluene was 2.3 ppm with a maximum of 132 ppm; the workers were also exposed to other solvents such as hexane, ethyl acetate, styrene, and methanol, but at lower levels. The chance of cutaneous absorption was remote. Higher correlation with TOL-A and better sensitivity in separating the exposed workers from the nonexposed subjects were taken as selection criteria. When workers exposed to TOL-A at lower concentrations (< 50 ppm, < 10 ppm, < 2 ppm, etc.) were selected and correlation with TOL-A was examined, TOL-B showed the largest correlation coefficient which was significant even at TOL-A of < 1 ppm, whereas correlation of HA-U was no longer significant when TOL-A was < 10 ppm. TOL-U was between the two extremes. The sensitivities of TOL-B and TOL-U were comparable; HA-U showed the lowest sensitivity. Thus, it was concluded that TOL-B is the indicator of choice for detecting toluene exposure at low levels.     

Occupational toluene exposure induces cytochrome P450 2E1 mRNA expression in peripheral lymphocytes

Print workers are exposed to organic solvents, of which the systemic toxicant toluene is a main component. Toluene induces expression of cytochrome P450 2E1 (CYP2E1), an enzyme involved in its own metabolism and that of other protoxicants, including some procarcinogens. Therefore, we investigated the association between toluene exposure and the CYP2E1 response, as assessed by mRNA content in peripheral lymphocytes or the 6-hydroxychlorzoxazone (6OH-CHZ)/chlorzoxazone (CHZ) quotient (known as CHZ metabolic ratio) in plasma, and the role of genotype (5 -flanking region RsaI/PstI polymorphic sites) in 97 male print workers. The geometric mean (GM) of toluene concentration in the air was 52.80 ppm (10-760 ppm); 54% of the study participants were exposed to toluene concentrations that exceeded the maximum permissible exposure level (MPEL). The GM of urinary hippuric acid at the end of a work shift (0.041 g/g creatinine) was elevated relative to that before the shift (0.027 g/g creatinine; p < 0.05). The GM of the CHZ metabolic ratio was 0.33 (0-9.3), with 40% of the subjects having ratios below the GM. However, the average CYP2E1 mRNA level in peripheral lymphocytes was 1.07 (0.30-3.08), and CYP2E1 mRNA levels within subjects correlated with the toluene exposure ratio (environmental toluene concentration:urinary hippuric acid concentration) (p = 0.014). Genotype did not alter the association between the toluene exposure ratio and mRNA content. In summary, with further validation, CYP2E1 mRNA content in peripheral lymphocytes could be a sensitive and noninvasive biomarker for the continuous monitoring of toluene effects in exposed persons.     

Effect of ethanol,cimetidine and propranolol on toluene metabolism in man

Summary In a climatic exposure chamber four healthy volunteers were exposed to 100ppm toluene, 100ppm toluene + ethanol, 100ppm toluene + cimetidine, and 100ppm toluene + propranolol for 7h each at random over four consecutive days. A control experiment and 3.5 h of exposure to 200 ppm toluene were also performed. Ethanol inhibited toluene metabolism by 0.5 as expressed by the urinary excretion of two of the metabolites of toluene, namely o-cresol and hippuric acid. In agreement with this, the mean alveolar concentration of toluene was greater by 1.7 during ethanol exposure; 45 min after discontinuation of exposure the increase was by 3.3. Neither cimetidine nor propranolol changed toluene metabolism significantly. The results indicate that ethanol may prolong the time interval in which toluene is retained in the human body in persons simultaneously exposed to ethanol and toluene. When using o-cresol or hippuric acid in biological monitoring of persons occupationally exposed to toluene, the consumption of ethanol should be considered.Supported by grants from the Working Environment Fund, Denmark     

Occupational chronic exposure to organic solvents XII. O-cresol excretion after toluene exposure

Summary Thirty-five printing workers were investigated according to their external and internal exposure to toluene. The concentration of toluene in the air of the working place was determined using stationary air sampling and gas chromatography. To determine the levels of toluene in blood as well as the concentrations of o-cresol, hippuric acid, and phenol in urine, biological specimens were collected at the end of exposure. The parameters were determined by gas chromatography and gas chromatography/mass spectrometry. According to our results, o-cresol concentrations higher than 5.3 mg per litre of post-shift urine might indicate an external exposure higher than the present MAK-value of 200 ppm.     

Method for simultaneous determination of six metabolites of toluene, xylene and ethylbenzene, and its application to exposure monitoring of workers in a printing factory with gravure machines

For the biological monitoring of exposure to solvent composed of toluene, xylene, and ethylbenzene used in a printing factory with gravure machines, we developed a HPLC method for the simultaneous determination of urinary metabolites of this solvent, i.e. hippuric acid, o-, m-, and p-methylhippuric acid, mandelic acid and phenylglyoxylic acid. Except for phenylglyoxylic acid, urinary concentrations of the metabolites determined by the present method correlated well with the air concentrations of the respective solvent components. Hence the present method is useful in monitoring solvent exposure. In 91 workers of the printing factory and 53 control subjects, we also determined the concentrations of some phenolic metabolites and confirmed that o-cresol is a useful indicator for monitoring toluene exposure.     

Experimental human exposure to toluene

Summary The relationship between the individual toluene uptake and the urinary hippuric acid excretion was studied under experimental conditions. Six healthy male subjects were exposed to various concentrations in inspired air (50, 100, 125, 150, and 200 ppm) at rest or under different levels of physical effort.The hippuric acid excretion near the end of the exposure appeared under all circumstances directly proportional to the time-weighted uptake rate of toluene. The correlation between respiratory uptake rate and the rate of metabolite excretion near the end of the exposure period proved not to be systematically influenced by personal factors such as body weight, amount of body fat, urine flow rate and urinary pH. The relatively pronounced differences in background excretion of hippuric acid and, perhaps, distribution phenomena of toluene between different tissues under heavy workload conditions, can partly explain the greater variability in metabolite excretions as compared to the individual uptake rates.The correlation between the individual uptake rate of toluene and the hippuric acid excretion proved substantially better when using the end exposure excretion rate as exposure parameter as compared with the end exposure hippuric acid concentration, even after correcting the latter for urine density.Reasonable biological limit values complying to an acceptable time-weighted toluene dose were found to be 3000–3500 mg/l and 2.0–2.5 mg/min, resp. for average hippuric acid concentrations and excretion rates in spot samples during the second half of a complete work shift.     

Urinary hippuric acid and orthocresol excretion in man during experimental exposure to toluene.

It is not known whether urinary excretion of hippuric acid (HA) or orthocresol (O-Cr) is to be preferred for the biological monitoring of workers with occupational exposure to toluene. To study this, 42 printing trade workers with more than 10 years' exposure to a mixture of organic solvents including toluene (0-20 ppm) and 43 control subjects matched by age, smoking habits, and living accommodation were investigated. Each matched pair was randomised to an experimental exposure of either 100 ppm or 0 ppm toluene for 6.5 hours under controlled conditions in an exposure chamber. Urinary excretion of HA and O-Cr was determined by high pressure liquid chromatography from samples obtained before exposure, during the first three hours, and during the last 3.5 hours of exposure. No difference in HA and O-Cr excretion was found between printing trade workers and controls. The median O-Cr excretion increased 29 times during exposure, whereas the HA excretion increased only five times. Thus only 3% of the O-Cr excretion originated from other sources than toluene whereas the corresponding value for HA was 19%. Standardisation of the concentrations of HA and O-Cr in relation to urinary creatinine reduced the relative variation by 29% and 56% respectively. This was not reduced further by expressing the excretions as average excretion rates based on total volume of urine collected. Background urinary O-Cr excretion was three to four times higher among smokers than non-smokers, probably due to the content of O-Cr in cigarettes. The O-Cr excretion in unexposed smokers was, however, 10 times lower that that of the non-smokers during the end of the experimental exposure to 100 ppm toluene.     

Occupational exposure to solvent mixtures: effects on health and metabolism.

Exposure monitoring by personal diffusive samplers, biological monitoring of toluene exposure by urinary hippuric acid determination, haematology, serum biochemistry for liver function, and a subjective symptom survey by questionnaire were conducted on 303 male solvent workers. They were exposed to a mixture of solvents including toluene (geometric mean 18 ppm), methyl ethyl ketone (MEK; 16 ppm), isopropyl alcohol (IPA; 7 ppm), and ethyl acetate (9 ppm). The intensity was mostly below unity using the additiveness formula based on current Japanese occupational exposure limits, but more than eight times unity at the maximum. The results were compared with the findings in 135 non-exposed male workers of similar ages. Haematology and liver function tests did not show any exposure related abnormality, and subjective symptoms were mostly related to central nervous system depression and local irritation. Further analysis suggested that the irritation effects were not related to exposure to MEK. Analysis of the relation between toluene exposure and hippuric acid excretion in urine showed that there was no metabolic interaction between MEK and toluene, or between IPA and toluene. Overall, therefore, it is concluded that there was no sign or symptom detected to suggest anything other than toluene toxicity, that there was no evidence to indicate any modification of toluene toxicity or metabolism due to coexposure, and that the additiveness assumption is reasonable for risk assessment for the combination of solvents under these exposure conditions.     

Three fatal cases of thinner-sniffing,and experimental exposure to toluene in human and animals

Summary Three fatal cases of organic solvent abuse revealed high levels of toluene in blood and alveolar air and a high level of hippuric acid, metabolite of toluene, in urine. The lethal concentration of toluene was estimated to be 2,000 ppm.Furthermore, 10 male and female volunteer students were exposed to 107 ±12 ppm toluene for 4 hours. Hippuric acid in urine increased with the exposure time and reached maximum 2 hours after initiation of toluene exposure and remained at the same level thereafter. Following cessation of exposure to toluene, hippuric acid in urine showed a rapid decrease and recovered almost to the normal level 4 hours after cessation of exposure.Urinary excretion of hippuric acid in 7 rabbits exposed to 350 ppm for 100 minutes or to 4,500 ppm toluene for 10 minutes, reached its maximum 1.5–2 hours after initiation of exposure and decreased rapidly after cessation of exposure to toluene to recover to the normal level 4 hours later.Read before the 43rd Annual Meeting of Japanese Association of Industrial Health at Tokushima on April 2, 1970, and the 18th Annual Meeting of North Kanto Medical Association at Maebashi on November 14, 1971.     

Comparative evaluation of blood and urine analysis as a tool for biological monitoring of n-hexane and toluene

Blood and urine samples were collected from 57 male Japanese solvent workers [exposed to n-hexane (Hex-A), ethyl acetate, and toluene (Tol-A) at 1.5, 2.3, and 2.3 ppm as GM-TWA, respectively] and also from 20 male nonexposed workers at the end of a 8-h shift, and analyzed for n-hexane (Hex-B) and toluene (Tol-B) in blood, and n-hexane (Hex-U), toluene (Tol-U), 2,5-hexanedione [both with (HD-U/cHYD) and without hydrolysis (HD-U/sHYD)] and hippuric acid (HA-U) in urine. Regression analysis showed that both Hex-B and Tol-B correlated significantly with corresponding exposure to the solvents. Solvents in urine (Hex-U and Tol-U) also correlated with solvents in air but with smaller correlation coefficients than the solvents in blood. Both HD-U/cHYD and HD-U/sHYD showed significant correlation with Hex-A, but HA-U failed to do so with Tol-A. Based on the correlation among biological exposure indicators and solvent concentration in air, sensitivity as an exposure indicator was compared between the solvent in blood and the metabolite in urine in terms of the lowest solvent concentration at which the exposed can be separated (with statistical significance) from the nonexposed (the lowest separation concentration; LSC). The LSC was 3.9 ppm for Hex-B, 1 to 2 ppm for HD-U/sHYD and 10 to 30 ppm for HD-U/cHYD, suggesting that HD-U/sHYD is superior even to Hex-B in detecting low n-hexane exposure; this high sensitivity of HD-U/sHYD is due to the absence of HD-U/sHYD in the urine from the nonexposed. In contrast, Tol-B (with LSC of 2.4 ppm) was more sensitive than HA-U; no LSC for HA-U could be obtained because of lack of correlation with Tol-A at low toluene exposure.     

甲苯的慢性危害和尿中的马尿酸作为职业性接触的生物学监测指标探讨

本文对１４０名接触以甲苯为主的有机溶剂的包漆工（平均接触工龄８．３９年）进行了横断面调查，发现头昏、头痛、失眠、乏力、腹隐痛等症状的出现率，神衰综合征和慢性咽炎的患病率明显高放对照组（Ｐ＜０．０５或Ｐ＜０．０１）。常规肝功能和血清碱性磷酸酶（Ｓ－ＡＫＰ）无明显改变（Ｐ＞０．０５）。包漆工班末尿马尿酸平均浓度显著高於班前和对照组班末的平均浓度（分别Ｐ＜０．０５，Ｐ＜０．０１）。男、女包漆工班末尿马尿酸平均浓度均高于班前（分别Ｐ＜０．０５，Ｐ＜０．０１）。空气中苯系物的浓度均在最高允许浓度范围内。结果提示，长期接触低浓度的以甲苯为主的有机溶剂，对中枢神经系统有不利影响。尿中马尿酸水平可作为反映工人接触低浓度甲苯的有用的、生物学监测指标。     

Comparative evaluation of biomarkers of occupational exposure to toluene

Objectives This study was initiated to make comparative evaluation of five proposed urinary markers of occupational exposure to toluene, i.e., benzyl alcohol, benzylmercapturic acid, o-cresol, hippuric acid and un-metabolized toluene. Methods In practice, six plants in Japan were surveyed, and 122 Japanese workers (mostly printers; all men) together with 12 occupationally nonexposed control subjects (to be called controls; all men) agreed to participate in the study. Surveys were conducted in the second half of working weeks. Time-weighted average exposure (about 8 h) to toluene and other solvents were monitored by diffusive sampling. End-of-shift urine samples were collected and analyzed for the five markers by the methods previously described; simultaneous determination of o-cresol was possible by the method originally developed for benzyl alcohol analysis. Results The toluene concentration in the six plants was such that the grand geometric mean (GM) for the 122 cases was 10.4 ppm with the maximum of 121 ppm. Other solvents coexposed included ethyl acetate (26 ppm as GM), methyl ethyl ketone (26 ppm), butyl acetate (1 ppm) and xylenes (1 ppm). By simple regression analysis, hippuric acid correlated most closely with toluene in air (r = 0.85 for non-corrected observed values) followed by un-metabolized toluene (r = 0.83) and o-cresol (r = 0.81). In a plant where toluene in air was low (i.e., 2 ppm as GM), however, un-metabolized toluene and benzylmercapturic acid in urine showed better correlation with air-borne toluene (r = 0.79 and 0.61, respectively) than hippuric acid (r = 0.12) or o-cresol (r = 0.17). Benzyl alcohol tended to increase only when toluene exposure was intense. Correction for creatinine concentration or specific gravity of urine did not improve the correlation in any case. Multiple regression analysis showed that solvents other than toluene did not affect the levels of o-cresol, hippuric acid or un-metabolized toluene. Levels of benzylmercapturic acid and un-metabolized toluene were below the limits of detection [limit of detections (LODs); 0.2 and 2 μg/l, respectively] in the urine from the control subjects. Conclusions In over-all evaluation, hippuric acid, followed by un-metabolized toluene and o-cresol, is the marker of choice for occupational toluene exposure. When toluene exposure level is low (e.g., 2 ppm), un-metabolized toluene and benzylmercapturic acid in urine may be better indicators. Detection of un-metabolized toluene or benzylmercapturic acid in urine at the levels in excess of the LODs may be taken as a positive evidence of toluene exposure, because their levels in urine from the controls are below the LODs. The value of benzyl alcohol as an exposure marker should be limited.     

Effect of various exposure scenarios on the biological monitoring of organic solvents in alveolar air

Summary The present study was undertaken to investigate the influence of different exposure scenarios on the elimination of toluene and m-xylene in alveolar air and other biological fluids in human volunteers. The study was also aimed at establishing the effectiveness of physiologically based toxicokinetic models in predicting the value of biological monitoring data after exposure to toluene and m-xylene. Two adult male and two adult female white volunteers were exposed by inhalation, in a dynamic, controlled-environment exposure chamber, to various concentrations of toluene (21–66 ppm) or mxylene (25–50 ppm) in order to establish the influence of exposure concentration, duration of exposure, variation of concentration within day, and work load on respective biological exposure indices. The concentrations of unchanged solvents in end-exhaled air and in blood as well as the urinary excretion of hippuric acid and m-methylhippuric acid were determined. The results show that doubling the exposure concentration for both solvents led to a proportional increase in the concentrations of unchanged solvents in alveolar air and blood at the end of a 7-h exposure period. Cumulative urinary excretion of the respective metabolites exhibited a nearly proportional increase. Adjustment of exposure concentration to account for a prolongation of the duration of exposure resulted in essentially identical cumulative urinary excretion of the metabolites. Induced within-day variations in the exposure concentration led to corresponding but not proportional changes in alveolar concentration for both solvents, depending on whether or not sampling preceded or followed peak exposure to solvent. At the end of repeated 10-min periods of physical exercise at 50 W, alveolar air concentrations of both solvents were increased by 40%. Experimental data collected during the present study were adequately simulated by physiologically based toxicokinetic modeling. These results suggest that alveolar air solvent concentration is a reliable index of exposure to both toluene and m-xylene under various experimental exposure scenarios. For clinical situations likely to be encountered in the workplace, physiologically based toxicokinetic modeling appears to be a useful tool both for developing strategies of biological monitoring of exposure to volatile organic solvents and for predicting alveolar air concentrations under a given set of exposure conditions.     

Experimental study on the pulmonary absorption and excretion of toluene

Summary Three exposure levels of toluene were inhaled by dogs for 1h. Toluene concentrations in expired air, arterial blood and venous blood were repeatedly measured. Absorptions of toluene within one hour of exposure were 25, 56 and 74 mg/kg at 700, 1500 and 2000 ppm respectively (absorption ratio = 27%). The cumulative excretion one hour after exposure was 63% of the absorped material at all three exposure levels. Multiple regression analyses were performed to interconnect the independent variables.     

Delayed and Competitively Inhibited Excretion of Urinary Hippuric Acid in Field Workers Coexposed to Toluene,Ethyl Benzene,and Xylene

The purpose of this study was to investigate whether the metabolic suppression of hippuric acid (HA) occurs in field workers coexposed to toluene, xylene and ethyl benzene. Eleven male spray painters were recruited into this study and monitored for 2 weeks using a repeated-measures study design. The sampling was conducted for 3 consecutive working days each week. Toluene, ethyl benzene, and xylene in the air were collected using 3M 3500 organic vapor monitors. Urine samples were collected before and after work shift, and urinary HA, methyl hippuric acid, mandelic acid, and phenylgloxylic acid concentrations were determined. In the first week, toluene concentrations were 2.66 ± 0.95 (mean ± SE) ppm, whereas ethyl benzene and xylene concentrations were 27.84 ± 3.61 and 72.63 ± 13.37 ppm, respectively, for all subjects. Pre–work shift HA concentrations were 230.23 ± 37.31 mg/g creatinine, whereas pre–work shift HA concentrations were 137.81 ± 14.15 mg/g creatinine. Mean urinary HA concentration was significantly greater in the pre–work shift samples than in the pre–work shift samples (p = 0.043). In the second week, toluene concentrations were much lower (0.28 ppm), whereas ethyl benzene and xylene were 47.12 ± 8.98 and 23.88 ± 4.09 ppm, respectively, for all subjects. Pre–work shift HA concentrations were 351.98 ± 116.23 mg/g creatinine, whereas pre–work shift HA concentrations were 951.82 ± 116.23 mg/g creatinine. Mean urinary HA concentration was significantly greater in the pre–work shift samples than in the pre–work shift samples (p <0.01); a significant correlation (r = 0.565; p = 0.002) was found between pre–work shift urinary HA levels and ethyl benzene exposure. This study showed that urinary HA peak was delayed to next morning for workers coexposed to toluene, ethyl benzene, and xylene; xylene and ethyl benzene probably played competitive inhibitors for metabolism of toluene. The study also presumed that urinary HA became the major metabolite of ethyl benzene at the end of work shift, when the exposure concentrations of ethyl benzene were 2.0 times those of xylene.     

Biological monitoring of controlled toluene exposure

Objectives: Widespread exposure to toluene occurs in the printing, painting, automotive, shoemaking, and speaker-manufacturing industries. The relationship between air concentrations and the absorbed dose is confounded by dermal exposure, personal protective devices, movement throughout the workplace, and interindividual differences in toluene uptake and elimination. Methods: To determine the best biological indicator of exposure we examined the blood and alveolar breath concentrations of toluene as well as the urinary excretion rates of hippuric acid and of o-, m-, and p-cresols from 33 controlled human inhalation exposures to 50 ppm for 2 h. Results: Among the metabolites, o-cresol was least influenced by background contributions, whereas the p-cresol and hippuric acid rates were obscured by endogenous and dietary sources. Toluene levels in alveolar breath proved to be the most accurate and noninvasive indicator of the absorbed dose. A physiologic model described blood and breath data using four measured anthropometric parameters and the fit values of extrahepatic metabolism and adipose-tissue blood flow. Conclusions: After breathing rate and extrahepatic metabolism had been set to conservative (protective) values (the 97.5th and 2.5th percentiles, respectively) the model predicted that pre-final-shift breath levels of ≤10 μmol/m³ and post-final-shift levels of ≤150 μmol/m³ corresponded to average workplace exposure levels of ≤50 ppm toluene. Alternately, we used the distributions and covariances of the measured and fit model parameters to yield conservative pre-final-shift levels of ≤7.3 μmol/m³ and post-final-shift breath levels of ≤120 μmol/m³ that were reflective of workplace exposure levels of ≤50 ppm toluene. Received: 30 December 1997 / Accepted: 12 June 1998