BENZENE

CAS number: 71-43-2 Synonyms: Benzol; Phenyl hydride Molecular formula: C6H6 RECOMMENDED BEI®
Determinant
S-Phenylmercapturic acid in urine t,t-Muconic acid in urine

Sampling Time
End of shift End of shift

BEI
25 µg/g creatinine 500 µg/g creatinine

Notation
B B

Basis for the Biological Exposure Index
The BEI for both determinants is based on the ® TLV –TWA of 0.5 ppm, which itself is derived from the extensive review with 217 references made by (1) the Chemical Substances TLV Committee. The TLV, which also includes a 2.5 ppm short-term exposure limit (TLV–STEL) and a Skin notation, was established from epidemiological studies of past occupational exposure that, in the absence of reliable biological monitoring data, was based on air sampling results. It should be recognized that there are considerable uncertainties in the extrapolation of estimates of high exposures in the past to levels of risk that can be considered acceptable today. Acute toxic effects of narcosis have been recognized for many years; chronic effects, such as blood dyscrasias, have been identified since the 1930s. A (2) definitive review made by Alice Hamilton in 1931 makes specific reference to the risk of lymphatic and myeloid leukemia and provides a 125-item bibliography. In contrast, the 1993 U.S. Agency for Toxic Substances and Disease Registry toxicological pro(3) file lists more than 800 references. While animal studies have been helpful in establishing mechanisms, the key information was derived from reevaluation of exposure data and medical records of workers, particularly those employed in the manufacture of Pliofilm® during a period stretching from the (4–6) (7,8) 1940s to the 1960s and elsewhere. Other (9) (10) studies, principally in Italy, Turkey, and Chi(11,12) na, have confirmed acute myelogenous leukemia as the most common malignant disease associated with chronic benzene exposure. Animal studies and occupational epidemiological studies have been extensively reviewed in the TLV Documentation for (1) Benzene, and reference should be made to that text for a detailed discussion and interpretation of risk. A review of retrospective exposure assessment (13) published in 1996, which summarized four studies of benzene exposure in petroleum marketing and distribution, emphasized the uncertainties of extra2001 © ACGIH

polation of past studies. A meta-analysis of 250,000 (14) petroleum workers indicated that they were not at an increased risk of multiple myeloma as a result of exposure to benzene or other petroleum products.

Uses and Properties
Benzene is a colorless, highly flammable, nonpolar liquid with an odor that is characteristic of aromatic hydrocarbons. Benzene can be supplied as industrial grade, nitration grade, or refined. Benzene has a molecular weight of 78.11 and specific gravity of 0.8765 at 20°C. It has a melting point of 5.5°C, a boiling point of 80.1°C, and a vapor pressure of 95.2 torr at 25°C. Conversion factors at 25°C and 760 3 3 torr: 1 ppm = 3.19 mg/m ; 1 mg/m = 0.31 ppm. Solubility in water is poor (e.g., 1.8 mg/mL at 25°C), but it is miscible in all proportions with ethanol, (3) chloroform, diethyl ether, acetone, and fat and oils. At body temperature, the partition coefficients are (15) reported to be 7.8 for blood–gas, 425 for fat– (15) (16) gas, and 334 for adipose tissue–air.

Absorption
Under most workplace exposure conditions, benzene is absorbed by inhalation. Dermal absorption from gaseous benzene probably contributes rather little to total absorption, but absorption from (17) liquid benzene can be significant. Gastrointestinal absorption is practically unknown in occupational exposure. The limited solubility in water and preferential partition in the lipid phase leads to the bioac(18) cumulation of benzene in fat and fatty tissues.

Pulmonary
Inhaled benzene is readily absorbed. The pulmonary retention stays at approximately 50% for several hours at exposures between 2 and 100 (19–22) ppm. Assuming a respiratory rate of 16 breaths per minute and a tidal volume of 0.5 liter, approximately 7.5 µL benzene can be expected to be
Benzene BEI – 1

Chemical structures in brackets are postulated intermediates. 2 – Benzene BEI ACGIH © 2001 . The major pathways of benzene metabolism.FIGURE 1.

) Benzene is oxidized primarily in the liver by the cytochrome P450-dependent monooxygenase to benzene oxide.36) reported as 8% to 39%.5% benzene would absorb 4 to 8 mg. Laitinen (26) et al. Under conditions where contact time was short. Elimination Metabolism is the main elimination pathway. Based on studies of benzene absorption through the (24) skin of hairless mice. and Yardley-Jones et al. Hydroquinone and catechol are further metabolized to 1. Larger doses that persisted on the skin for up to 3 hours resulted in 10 to 100 times greater (17) absorption. conjugation with glutathione. though the first may be better represented by two phases of about 20 minutes and 2 hours. and the reaction product of benzene with guanine.35) detected in the urine.737. the latter of which dehydrogenates to catechol. hydroquinone. and urinary elimination of benzene as the S-phenylmercapturic acid (S-PMA) are considered detoxication pathways. 0. The amount of benzene absorbed and eliminated over 10 or more work hours appears to depend directly on the energy (36) expenditure of the subject.3. triphasic elimination has been reported with rate constants of 3. This compares to the estimated retention of 14 mg after 8-hour exposure at 1 ppm of (25) benzene in air.0158 for men and 3. Susten et al. which is a precursor to phenylmercapturic acid.4-trihydroxybenzene.absorbed each hour through the lungs of a person (21) inhaling air containing 10 ppm benzene. Although several cytochrome P-450 isozymes may catalyze this reaction. mercapturic acids. at low levels of exposure. Metabolic Pathways and Biochemical Interactions The metabolic pathway of benzene in humans is shown in Figure 1. The proportion of absorbed benzene excreted via exhalation was (20. half-times of about 1.4-benezentriol. for reviews of the toxicity and metabolism of benzene. The elimination of benzene following typical levels of occupational exposure follows first order kinetics with several consecutive half-times corresponding to the disposition of benzene in different body compartments.t-MA. and the flux of benzene from air saturated 2 with benzene at 31°C to average 1. The long-term retention and elimination of benzene is influenced by both the concentration and duration of exposure. formation of water-soluble phenyl glucuronide and sulfate conjugates. N-7-phenylguanine. Benzene was mainly excreted in the urine as metabolites. 4. (See Snyder et (39) (40) al.t-MA via the corresponding aldehyde inter-mediate. less than 0. 1. and catechol. Benzene is primarily metabolized to phenol.2. Approximately one-third of retained benzene was excreted rapidly in urine as conjugated phenol and (28–31) dihydroxy-phenols. estimated that a worker dermally exposed 150 times per day to a rubber solvent containing 0.t-MA). notably as the conjugates of phenol with glucuronic and sulfuric acids. Elimination may also be influenced by energy expenditure after work and by circadian rhythms. which suggests effective absorption.6% as t. and 25 hours have (36) also been reported. 1. Benzene metabolism to phenol. The metabolism is very complex and has not been fully elucidated. the ethanol-inducible isozyme IIE1 seems to be mainly (39) responsible. The majority of these metabolites are excreted in urine as glucuronide and sulfate conjugates of phenol are the primary urinary metabolites of benzene.5% (33) each of catechol and 1.4-benzoquinone and 1. as the unchanged form. The remainder was further degraded to become incorporated in tissue or (32) exhaled as carbon dioxide (CO2). Others include conjugates of catechols and quinol.4 × 10 cm/hour.28. Dermal Franz concluded from in vivo and in vitro tests on human and other skin that contact time was a major factor controlling percutaneous absorption of benzene.2% as phenol.0429 for (37) women. (23) sure for 4 hours.66. and 0.2 to 0. The presence of other hydrocarbons at concentrations about the TLV did not appear to influence the uptake (36) or metabolism of benzene at about 10 ppm. For a single subject exposed for 1 or 8 hours. respectively. t. Workers occupationally exposed at 100 ppm benzene excreted in urine the following proportions of their absorbed does: 13. Initial oxidation of benzene occurs via two concurrent pathways involving either direct hydroxylation or formation of an epoxide (benzene oxide).22. 1.7 mg/cm /hour. reported that the skin was the main route of absorption of benzene among garage workers exposed to liquid gasoline.t-muconic acid (t.01 µL/cm ).2% of the applied dose was 2 absorbed (approximately 0. Benzene is also metabolized to the ring-opened oxidation product t. Animal experiments confirmed that gastrointes(27) tinal absorption was essentially complete. Following experimental expo2001 © ACGIH . and 0. Small amounts of unmetabolized benzene have also been (34. due to its volatility. and 0. Enzymatic hydrolysis of benzene oxide yields phenol and benzene glycol.9% as quinol. Benzene oxide also forms an addition product with glutathione.09. Benzene BEI – 3 Gastrointestinal Gastrointestinal uptake of benzene has led to acute intoxications. and in exhaled air. Fiserova-Bergerova reported skin 2 penetration rates of 0.0 µL/cm /hour. Elimination studies have recently been (38) reviewed.02. Blank and McAuliffe determined penetration of benzene in a gasoline solution through –3 human abdominal skin in vitro to be 1.

2. Summary The evaluation of occupational exposure to benzene with biomarkers is based on 1) the determination of the unchanged parent compound in blood. At present. This may be compared with a calculated absorption of about 50 mg/ day for a worker exposed at a TWA concentration of 10 ppm or 2500 µg/day if exposed at 0. was adopted in 1997. but greater sensitivity is required for analysis. Sampling of benzene or metabolites in urine offers the advantage of lower dependence on time but introduces additional variability due to fluctuations in urinary excretion rate. S-PMA in urine requires a more sophisticated technique than t.5 ppm. The TLV is based on the prevention of excess risk of cancer (leukemia) in humans associated with occupational benzene exposure. 3 Median indoor benzene concentrations were 7 µg/m in 200 homes without a resident smoker and 10 3 µg/m in 300 homes in which one or more smokers (43) resided. and this may affect the relationship between biological levels and degree of exposure close to the TLV range. a specific BEI for benzene in urine could not be determined due to insufficient data.6 3 3 mg/m ) and a TLV–STEL of 2. S-PHENYLMERCAPTURIC ACID IN URINE In this Documentation. and the methods require validating. Possible Nonoccupational Exposure Exposure to vehicle emissions and smoking are the two major sources of benzene exposure in the general population. At the TLV–TWA of 0. with a Skin notation and an A1. the units in analytical ACGIH © 2001 .The TLV Documentation for benzene provides a summary of benzene biotransformation and the (1) implication for human health risk assessment. and previous shifts. Consequently. urinary S-PMA and t. (18) and from the exhausts of automobile engines. 4 – Benzene BEI The determination of benzene in blood provides a sensitive and specific method but is markedly affected by current or recent exposure. Benzene in exhaled air reflects the concentration of benzene in blood. The recommended TLV considers all routes of occupational exposure to benzene and is derived from relative risk calculations of excess risk of human leukemia associated with chronic occupational exposure to benzene. but sensitive methods of sampling and analysis have yet to be standardized.1 to 140 µg/g. Smokers show higher levels than nonsmokers. The long-term average daily intake of benzene by the general nonsmoking population in the United States has been estimated to be between 63 and 73 µg/day (maximum 149–222 µg/day) using three in(44) dependent methods. BEIs are recommended for measurement of SPMA and of t. TLV–TWA The TLV–TWA for benzene of 0. Confirmed Human Carcinogen. marking pens. Due to the initial short half-life of benzene in blood. Increased concentrations of benzene in postshift urine samples appear to be a sensitive indicator of benzene exposure in the intended TLV range. an additional exposure of about 600 to 800 µg/day can be calculated. The emissions result from evaporation from gasoline which commonly contains 1% to 5% benzene. This method has the advantage of offering a noninvasive method. it seems that hemoglobin and albumin adducts are not applicable for routine biological monitoring because of the sophisticated methods involved and their limited sensitivity. notation. Paints. The measurements are principally indicators of exposure during the last shift but may also be influenced by longer-term retention of benzene in the body. rubber products. The determination of phenol. Sidestream smoke (345–529 µg/cigarette) contained more benzene than the mainstream smoke (6–68 (41) µg/cigarette).t-MA can be recommended as sensitive indicators of workplace exposure.5 ppm (8 mg/m ).S.t-MA in urine collected at the end of daily exposure. Benzene is ubiquitous in the environment. and exhaled air and 2) the determination of various benzene metabolites in urine. quinol.5 ppm. About 400 of 5000 materials and products tested by U. For the average smoker (20 cigarettes/day). However. the quantitative interpretation of the measurement is ambiguous at present. Both determinants are present in very low concentrations in urine samples collected from occupationally unexposed persons.t-MA and S-PMA in urine appear to present an alternative approach for biological monitoring of benzene exposure in a very low range. and 1.5 ppm (1.4-benzene-triol is not specific and sensitive enough for the low-exposure range. catechol. and tapes were identified as products that emit benzene and may contribute to indoor air benzene concentrations. and presents the same problem of interpretation in end-of-shift sampling. the amount according to country. Benzene and other aromatic hydrocarbons are (40) formed during the pyrolysis of tobacco.t-MA. Recent methods developed using high-performance liquid chromatography (HPLC) and gas chromatography–mass spectrometry (GC-MS) for the determination of t. Samples taken before the following shift can provide a good measure of exposure during that. urine. National Aeronautics and Space Administration are understood to emit benzene vapors in (42) amounts ranging from 0. adhesives. samples taken at the end of shift reflect only the most recent exposure.

Exposure The following factors can affect the biological levels: dermal exposure. The latter is used to reduce the effect of the variability of urinary flow rate. Since S-PMA is not likely to be present in the workplace.29 µg/g creatinine in 38 nonsmokers and 3.57 µg/g creatinine in 14 smokers. a mean of 9. appears to be highly sophisticated and has not been validated in other laboratories. the selection of the method is critical.4 ± 5. Determination using GC-MS is preferred because it is the more sensitive and specific of the two methods. ® ACGIH recommends GC-MS methods.1 µg/L. The detection limit is dependent on matrix effects. S-PMA concentrations in smoking and nonsmoking control persons were mostly below the detection limit of 1 to 5 µg/L urine. a tentative second phase of elimination was seen with half-time of 45 hours (SD = 4 hours). The use of this internal standard (49) allowed a detection limit of 1 µg/L. special precautions are not necessary to avoid contamination of the sample. and the detection limit should be about 1 µg/L urine.05% and 0. and (48) experience of the operator. Stability studies of SPMA in urine have shown that concentrations did not (48) change for at least one month if stored at 4°C.11%). a deuterium labeled S(pentadeuterophenyl)-mercapturic acid internal standard was used.methods for urine samples are always expressed in µg/L. and in this document. For purposes of conversion.. S-PMA was excreted in a single phase. SPMA excretion in urine of exposed and nonexposed persons has been assessed using liquid chromato(45.29% (average 0.8%. and the highest SPMA concentrations were detected in samples at the end of the shift. Kinetics The proportion of benzene taken up by the lungs excreted in urine as S-PMA was estimated to be between 0. some SPMA (16%–30%) may still be excreted in samples (48) collected at the beginning of the next shift. The percentage was calculated from S-PMA concentrations in samples collected at the beginning and the (48. With the improved (49) GC-MS method. which may have led to a slower absorption of benzene into the body than through respiratory exposure. conditions of the ion selection detector.9 µg/g creatinine for nonexposed smokers.46) (47–50) graphic and GC-MS methods.5 hours]. the mean S-PMA level was 1. (49) Boogaard and van Sittert suspected that the formation of S-PMA may be influenced by coexposure to other aromatic hydrocarbons. Factors Affecting Interpretation of Measurements Analytical Procedure and Sampling Because the outcome of the chemical analysis depends on the analytical procedure. the recovery of S-PMA is 90%. sophisticated methodology is necessary.99 2001 © ACGIH Justification Relationships between external benzene exposure and renal S-PMA excretion have been evaluBenzene BEI – 5 .1 and 50. interindividual differences in toxicokinetics (see Kinetics). Analytical Methods For adequate sensitivity of S-PMA determination in urine. the highest S-PMA concentrations were measured at the beginning of the next shift. In most workers. According to the study of van Sittert et (48) al. The average urinary half-time of elimination was nine hours [standard deviation (SD) = 4.5% and 3. but in some workers.9% was found by (47) Stommel et al.. GC-MS is required for adequate sensitivity. A higher conversion of about 0.5% at a spiked concentration of 13. Biological Levels Without Occupational Exposure With the HPLC technique. Sampling and Storage The urine specimen should be collected at the end of shift in polyethylene bottles and acidified to pH 2 with hydrochloric acid. For S-PMA determination. The detection limits are 1 to 5 µg/L urine using S-benzylmercapturic acid as an internal standard. It has a detection limit of 1 µg/L urine. The detection limit is 0. In some workers. From the half-time exposure to benzene.49) end of a shift during several consecutive days.5 ± 1.5 µg/L. and the coefficient of variation is 3. 1 µg/L is assumed to be equal to 1 µg/g creatinine. respectively.46) reported. and smoking. The coefficient of variation of replicate analyses was 2. ± 0. The HPLC method.2 µg/g creatinine for nonexposed nonsmokers was (35. Reports on samples from occupational exposure are quoted in units of µg/g creatinine. In a recent study from the same working group. the creatinine concentration is taken to be 1 g/L.61 ± 0. This difference may be due to interindividual differences in toxicokinetics or the exposure of skin to benzene in the second group of workers. described by Maestri et (46) al. and 1. In some workers. The GC-MS method recommended by the Working Group for Analysis of Hazardous Substances in Biological Materials of the German Commission of (50) Health Hazards at the Workplace utilizes S-pfluorophenylmercapturic acid as an internal standard. The elimination kinetics indicate that the timing of sample collection is critical for quantitative evaluation of exposure. a biphasic excretion was found. S-PMA was present at detectable concentrations in the urine of all smokers and in 20 of the 38 nonsmokers.

t-MUCONIC ACID IN URINE Analytical Methods Specific and sensitive HPLC methods have been developed for determining t. which employs a preloading column in the HPLC.t-MA down (60) to 25 µg/L from nonsmokers and smokers. although these are likely to only reach the level recommended for the BEI for very heavy smokers.t-MA were only suitable in the past for measuring exposures to benzene in air greater than 1 ppm. (51) Popp et al. Ghittori et al. a more reliable and sensitive method was used.5 ppm. The latter are more tedious as derivatization to trimethylsilyl esters is necessary. The more recent technique used (57) by Ghittori et al. collected at end of shift. including the determination of t. An 8-hour exposure at 1 ppm benzene corresponds to 46 µg S-PMA/g creatinine [95% confidence interval (CI) = 41–50 µg/g creatinine]. Exposure at an 8-hour TWA of 1 ppm benzene leads to a calculated average concentration of 47 µg S-PMA/g creatinine in samples from the end of shift. A similar study was performed by the same (49) working group. Other publications that describe analytical methods for t. but inhalation of tobacco smoke will introduce elevated background values. The most (56) sensitive method was probably that of Lee et al. where methods (53) have been compared by these workers and by (54) Ong et al. as a determinant of occupational benzene exposure. strong anion exchange (SAX) clean-up is essential. reported in a study on automobile mechanics that the best correlation to benzene in air was found with S-PMA concentration in urine at the end of shift with a correlation coefficient of: r = 0. This study confirmed the suitability of S-PMA to detect benzene exposures as low as 0.t-MA in urine. From the calculated regression at an 8-hour TWA of 3250 6 – Benzene BEI ìg/m (1 ppm) benzene. From the extrapolation to the TLV–TWA of 0. the TLV–TWA of 0.ated in field studies.5 ppm would correspond to a S-PMA excretion of (49) 25 µg/g creatinine.81 [S-PMA-urine mg/g creatinine = 4.98 benzene-air (mg/m3)]. For a group of 145 workers exposed to benzene (35) in a chemicals plant. where a similar value was found. reported a sensitivity corresponding to an 8-hour TWA of 0. (48) Van Sittert et al. The test is specific. Recent techniques are (52) based on the work of Ducos et al.tMA and S-PMA in urine. A less-labor intensive method using capillary electrophoresis has recently been reported for discriminating urinary t. refineries.t-MA in urine and are preferred to gas chromatographic–mass spectrometric (GC-MS) methods. Therefore.47–49.51) specimens.8% and a recovery of about 90%. To ensure consistent results. Controlled laboratory and simulation studies are not available. a TLV–TWA of 0.5 ppm. For the comparison of the method. Due to its superior specificity and its longer elimination half-life. Analytical techniques for t. An airborne benzene exposure at the TLV–TWA of 0. and Inoue et al. 12 studies at eight locations in four countries were performed from 1992 to 1994 on workers who were potentially exposed to benzene during manufacturing and maintenance operations in natural gas production installations. and a within-assay coefficient of variation of < 7%.5 ppm corresponds to a S-PMA excretion of 25 µg/g creatinine. who reported that concentrations as low as 25 µg/L could be detected. clearly demonstrates the enhanced sensitivity of the new techniques. The value of 25 µg/g (36 µmol/mol) creatinine is recommended as a BEI. on workers who were potentially exposed to benzene during manufacturing and maintenance operations in chemical plants and refineries and in natural gas installations began in 1989. Strong correlations were found between t. The studies. is reported to have a detection limit of 3 µg/L with an interassay coefficient of variation of 3. The paper by Bartczak et (58) al. (55) Lauwerys et al. 3 Current Database Available Sufficient data from four field studies are available to support a BEI.. Therefore. ACGIH © 2001 . The value of 47 µg/g creatinine for S-PMA agrees well with the findings from the previous studies... validated S-PMA as a biomarker in 12 separate studies.tMA and S-PMA concentrations in samples from the end of shift and between either of these variables and airborne benzene concentrations. Significant correlations were observed for the relationship between benzene in air and S-PMA in postshift urine (35. TWA exposure of 0.3 ppm could be determined reliably. For the determination of SPMA in urine. t. and the urine samples should be alkalized to pH 7–10. found a significant correlation between benzene in air and SPMA (µg/g creatinine) in postshift urine. S-PMA was considered by the authors to be a more reliable and sensitive biomarker than t. The authors estimated that with the sensitivity of their method.t-MA include those by Boogard and van (49) (59) Sittert. the average S-PMA concentration in urine samples was 45 µg/g creatinine (90% CI = 20–95 µg/g creatinine).5 ppm should correspond to S-PMA excretion of 22 µg/g creatinine. and ultraviolet (UV) measurement at 259 nm. Recommendation ACGIH recommends monitoring S-PMA in urine.10 + 10. there would be a S-PMA level in urine of about 25 µg/g creatinine. and chemical plants.3 ppm.

The longer halflife for phenol (about 24 hours) demonstrated by Sher(36) wood and others may be masked by the natural background of t. In 2001 © ACGIH .06–0.13 mg/L t.067 mg/g creatinine. and 95th percentiles of 0.t-MA in groups of male.t-MA was stable in urine samples stored at room temperature for up to one week without preservation. and as 0. The elimination kinetics indicate that the timing of sample collection is particularly critical for quantitative evaluation of exposure. 3.53) (56) own studies and those by Lee demonstrate that the percentage of inhaled benzene that is retained (assumed to be 50%) which is eliminated as t.8. A detailed study of benzene-related compounds in the urine of cigarette smokers has been reported by (63) Ong et al. Benzene BEI – 7 Kinetics The biological formation of muconic acid from benzene was first demonstrated by Jaffe in 1909. Thierfelder and Klenk determined that 3.t-MA and the effect of smoking.06 mg/g creati(59) nine for nonsmokers. Lee et al. The ability to convert benzene into t. Sorbitol. only the most recently reported methods should be used.t-MA in 32 smokers and 0.t-MA determinant for benzene.3%) of an occupationally inhaled dose was excreted as t.29). smoking. reported similar values of 0. and 4. They show that some elevation of urinary t. and 5% to 25% in smokers.4% respectively.9% (range 1. In 1924.03–0. Geometric mean values have been reported by Lau(55) werys et al.7% of benzene injected as an intraperitoneal dose in rabbits was eliminated in urine as muconic acid.5% and 1. Rupport et al.t-MA (range.t-MA in 64% of the men and women (57) tested. Exposure The following factors can affect biological levels of t.19 mg/g creatinine (0. 0. 1953. The significant absorption of benzene from inhalation of tobacco smoke limits the sensitiveity of monitoring for occupational exposure. corresponding values were 0. as 0.33) and 0. (61) pregnancy.t-MA may be genetically determined and varies (66) (67) significantly. which is present in some foods.77) and 0. Ghittori et al. Inoue et al. (49) Biological Levels Without Occupational Exposure The principal source of t.08 to 0. showed that mean levels of t.t-MA. they reported an increase in t. Factors Affecting Interpretation of Measurements Analytical Procedure and Sampling Because the outcome of the chemical analysis depends on the analytical procedure.25 mg/L (0. For 35 smokers. samples should be taken at a mid-shift break. (59) Inoue et al.13 mg/g creatinine t.13 mg/g creatinine for smokers not exposed to benzene. Gobba et al.t-MA in urine of nonoccupationally exposed persons is benzene in tobacco smoke.88 mg/24h from a dietary supplement of 500 mg sorbic (61) acid.0%. t.5% value of 1.t-MA is not likely to be present in the workplace. the selection of the method is critical. compared concentrations of muconic acid in urine with those of benzene in urine (as a surrogate of benzene exposure) among bus drivers.01–0. (62) Melikian et al. female. Although t. but the sensitivity of the method they used did not permit detection of t. deduced that a typical dietary intake of 6 to 30 mg/day of sorbic acid accounts for 10% to 50% of background t.Sampling and Storage Boogard and van Sittart report that samples acidified to pH 2 with 6 M hydrochloric acid are stable at least up to a month if stored at room temperature or 4°C. 1.t-MA is 2. low concentration samples kept at room temperature without a preservative lost (56) 10% to 30% t.0 (SD = 2.9%–7. 0.43).3) hours. with mean values for muconic acid of 108 and 916 µg/g creatinine.30 mg/g creatinine. who provide a useful general background to the t. If expo-sure is known to occur early in the shift. 4.56 and 0.t-MA was still evident 16 hours after exposure. special precautions are not necessary to avoid contamination of the sample.t-MA: dermal exposure.tMA is considered to have a half-life comparable to that of phenol ( 5. These percentages are reasonably consistent with (49) the report of Boogard and van Sittert that. (65) as do Ong et al. The former conclude that their (52. Ruppert et al. interindividual differences in toxicokinetics (see Kinetics). In eight nonsmokers.6. (56) For 23 nonsmokers.t-MA determination. and absorption of sorbitol. From this. Since t. respectively. on average. Urine samples must be alkalized at the start of the analytical procedure to ensure reproducible recoveries greater than 95% from all ion-exchange columns.065 mg/g creatinine in 82 nonsmokers.207 and 0.4 mg/L in unexposed persons.61) may also elevate background values of t.t-MA in nonsmokers.5 times those of nonsmoking (62) counterparts.14 mg/g creatinine (range.t-MA with an (49) apparent half-life of 5. and pregnant smokers were 3. These data are quoted by (64) Ducos and Gaudin. (52. reported a 97. For t. Further studies on levels from smokers are reported under Field Studies in the “Justification” section below. Parke and Williams recovered 1% to 1.t-MA excretion from 0. reported a mean value of 0.8% of an oral dose in rabbits.03–0. Samples should be collected within one hour of the end of a shift.7 hours).t-MA after two weeks. reported a median background concentration of 0. and concluded that they could be grouped as poor muconic metabolizers and efficient metabolizers. suggest that the level of elimination may be suppressed by the concomitant absorption of toluene.

989 benzene in air (ppm) + 4.18 (r = 0.t-muconic acid above the limit of detection. C Based on 151 workers who excreted t.860) Women: t. Database of Field Studies of t.02 (r = 0.68–70) specimens.81) Benzene (mg/m3) = 2.58C) log MA (µg/g cr) = 0.5 ppm in air (µg/g creat. reported the application 8 – Benzene BEI of HPLC to urine samples from 64 men and 88 women occupationally exposed to benzene and from 213 nonexposed controls.041 MA (mg/g cr) = 0. cr = creatinine.123 (r = 0860) MA (mg/g cr) = 0.814) From these.41 for S-PMA.304 (r = 0. (59) In 1989.t-MA (mg/g cr) = 0.8502 benzene (ppm) + 0.4815 log benzene (mg/m ) + 2.900 (r = 0. Field data generally indicate a greater variation in urinary t. The principal data are shown in Table 1.429 log benzene (ppm) – 0. Values for women are heavily influenced by exposures > 100 ppm.396 (r = 0. Hotz showed a correlation coefficient of 0.69 log benzene (ppb) + 0.) 4900 2700 5900 (610 µg/L) 430 800 1000 430 370 450 770 760 390 208 1996 1995 1996 1997 1998 A B 57 65 69 68 70 Male & Female: 171 64 Male: 131 Male: 410 31 MA = t. in a study of 410 workers exposed to (68) benzene.58) log MA (mg/g cr) = 0. Includes non-exposed subjects.t-MA (mg/g cr) = 1.123 (r = 0. In most of these. Justification Field Studies Relationships between external benzene exposure and renal t. Inoue et al.t-MA in post-shift urine (35.5 ppm: log MA (mg/g cr) = 0. Significant correlations were observed for the relationship between benzene in air and t. and of 0.49. # of Workers 59 All: 365B Male: 177B Female: 188B 1992 1993 1994 1995 1995 53 56 55 49 35 23 19 Male: 38 58 Male & Female: 145 RegressionA MA (mg/g cr) = 0.t-muconic acid.88) log MA (mg/g cr) = 0.429 (r = 0.989 benzene (ppm) + 4.614) log MA (mg/g cr) = 1.59.05 log benzene (ppm) + 0.223 benzene (ppm) + 2.56) For all air concentrations measured (up to 20 ppm): log MA (mg/g cr) = 0.t-MA concentrations than in S-PMA.55–57.t-MA for the 151 urine samples above the limit of detection. The latter were mostly below the detection limit of the analytical method.53.86 log benzene (ppm) + 0.939 benzene (ppm) + 5.t-MA excretion have been evaluated in numerous field studies.814) log MA (mg/L) = 0.53) (r = 0.939 benzene in air (ppm) + 5. However.891 log benzene (ppm) + 0.20 (r = 0.959) For air concentrations in limited range 0.01 to 0.549 log benzene (ppm) – 0.396 (r = 0.506 log benzene (ppm) – 0. comparison was also made with elimination of S-PMA.51.t-MA (mg/g cr) = 0.429 (r = 0.223 benzene in air (ppm) + 2.213 (r = 0.09 (r = 0.827) Men: t.t-Muconic Acid as a Benzene Exposure Determinant Sex and Number Ref.58 between air concentration and urinary elimination of t.8270) MA (mg/g cr) = 1. Controlled laboratory and simulation studies are not available. The following correlations were reported for exposed and nonexposed persons: Men + Women: t.2208 (r = 0.38 MA (mg/g cr) – 0.46) 3 Date 1989 Index for 0. the following urinary concentrations ACGIH © 2001 . Correction of results from exposed workers for creatinine concentration or specific gravity of urine made little difference to the correlation coefficients.TABLE 1.89) log MA (µg/g cr) = 0.65.15 (r = 0.

t-MA concentration before and after shift and benzene exposure.8 mg/g creatinine after an 8-hour TWA benzene exposure at 0.38 t.1 ppm. and 0. The regression equation for the highly significant correlation obtained for 58 workers exposed for about 8 hours was: Benzene in air (mg/m3) = 2.506 log benzene in air (ppm) – 0. The mean concentration was 0.of t.t-MA (mg/g creatinine) = 0.37 mg/g creatinine.t-MA is suitable for routine biological monitoring. The authors found it essential to alkalize urine samples to ensure reproducible recoveries from all ion-exchange columns > 95%.5 ppm benzene in air. the statistical analysis was on exposure concentrations 3 up to 80 mg/m (25 ppm).61 mg/L.56) Over the full range of air concentrations measured (< 20 ppm). The authors concluded that t.058 mg/g creati(49) nine in 14 smokers.304 (r = 0.5 ppm.9 mg/g creatinine for men+women. measured t. geometric mean values for t. The data presented did not permit estimation of t. These calculated values may not be valid at concentrations around 0.06 mg/g creatinine and 0.0 mg/g creatinine.t-MA (mg/g creatinine) = 0.062 mg/g creatinine for nonsmokers.8 ppm). Urinary t.t-MA is a reliable indicator of benzene exposure even as low as 0.5 ppm (8-hour TWA). the linear regression was found to be: log t.t-MA and that at a TLV–TWA of 0.900 (r = 0.5 ppm (8-hour TWA) is 0.01 to 0.28 mg/g creatinine at the end of the shift.t-MA in 188 workers with measured exposure to benzene vapor. (49) Boogaard and van Sittert. as the exposure concentrations measured were generally much higher (up to 200 ppm). the linear regression was found to be: log t.7 mg/g creatinine for men alone.19 mg/g creatinine in 35 smokers and 0.5 ppm the concentration in urine is 0. These may be compared with the reported background arithmetic mean values among those not occupationally exposed to benzene of 0.tMA (µg/g creatinine) in postshift urine of a group of 145 workers in a chemicals plant.t-MA concentration following exposure at 0. The authors also warn that the ability to convert t.23 mg/g creatinine for 20 smokers and of 0.t-MA concentrations in non-exposed persons were determined to be 0.037 mg/g creatinine among the unexposed controls in 38 nonsmokers. reported a statistically significant correlation between air concentrations of benzene and t. reported that sampling results from 23 workers demonstrated a linear correlation between benzene exposure and urinary concentration of t. A significant difference between men and women was reported.5 ppm is 1.tMA was 1.15 (r = 0. (56) Lee et al. reported a significant correlation between benzene exposure in air and t.429 log benzene in air (ppm) – 0. they reported no improvement of correlation coefficients after correction for creatinine concentration.5 ppm benzene in air (8-hour TWA).02 (r = 0.58) At the 8-hour TLV–TWA of 0. The authors reported significant correlation between benzene exposure and concentration of t.t-MA. The authors conclude that t. Ducos et al. summarized 12 studies of urinary t.t-MA in urine of 0.t-MA elimination in 26 car mechanics exposed to benzene up to a maximum of 4 ppm. (55) Lauwerys et al. The post2001 © ACGIH shift concentrations were twice those in preshift samples. respectively.t-MA (mg/g creatinine) = 0. (53) In 1992. the mean urinary excretion of t. which suggests a value of about 0. From linear correlation of the difference between t. After logarithmic transformation. are deduced: 4. (35) In 1995.01 to 0. Only 16% of air samples were below 1 ppm (53) benzene.43 and 0. respectively.t-MA concentration in urine corresponding to the TLV–TWA of 0.t-MA in urine were 0. 2.t-MA concentration after exposure to a benzene concentration of 0. the urinary t.213 (r = 0. No separate regression was given for exposures in a limited range about the TLV.130 mg/g creatinine. and 5.43 mg/g creatinine. at least on a group basis.8 mg/g creatinine.16) after logarithmic transformation. At the mean value for benzene concentration in air of 2.9 mg/g creatinine for women alone. they determined the following relationship: t.t-MA (mg/g creatinine) – 0. The (64) 1995 review by this group includes an analysis of results obtained by other workers. In 21 nonsmokers and 14 smokers not occupationally exposed to benzene.54).t-MA has been reported to vary (66) significantly and that this may complicate assessBenzene BEI – 9 .86 log benzene in air (ppm) + 0.t-MA corresponding to a benzene exposure at 0.959) From this.t-MA (mg/g creatinine) = 0.63 ppm.5 ppm (8-hour TWA) can be calculated as 0. Ghittori et al. Unlike subsequent publications. determined urinary t. corresponding to 0.614) From this. the t.5 ppm.5 ppm (geometric mean = 0. and 52 control workers with no exposure.81) The urinary concentration of t.6 3 mg/m (0.14 mg/g creatinine in 23 nonsmokers. the regression was: log t.8502 benzene in air (ppm) + 0. the regressions predicted values for t.5 ppm.t-MA in 19 refinery workers exposed to benzene in the range 0. For exposure concentrations in the limited range 0.t-MA in postshift urine (r = 0.t-MA in postshift urine of 38 male subjects employed in garages and coke ovens. geometric standard deviation = 4. (51) Popp et al.

and the method was found reliable even around the cut-off airborne exposure level of 0. Summary/Current Database Available Sufficient data from 11 field studies are available to support a BEI.77 mg/g creatinine.45 mg/g creatinine in urine appears to correspond to over 50 cigarettes per day. This paper also reported background values in non-exposed persons. varies significantly between (66) individuals. which is considerably (70) less than reported in other studies.t-MA metabolism. the urinary t. The following linear regres-sion of logarithmic values was determined: log t.t-MA as a determinant for benzene exposure have been reported.69 log benzene in air (ppb) + 0. The value of 500 µg/g creatinine is recommended as a BEI.09 (r = 0. further reported a 95% upper limit of 0. restricting monitoring to workers with benzene exposures greater than 0. collected at end of shift.t-MA (µg/g creatinine) = 0. may also elevate (62) background values. and may depend on the efficiency of (67) t.45 mg/g creatinine. a value of 208 µ/g t.563 mg/g creatinine for smokers and 0.53) for those exposed to less than 0. This is in close accord with the earlier assessment.20 (r = 0. while concomitant exposure (59) to toluene may depress t. The test is specific. An extension of this study to 171 workers was (57) published in 1996.614) The t.25 ppm: r = 0. but the application of their conclusions is restricted to nonsmoking workers.55 From the regression.76 mg/g creatinine. urine. The following linear correlation was reported: log t.5 ppm.t-MA is genetically deter-mined.05 log benzene in air (ppm) + 0. (65.t-MA (µg/g) = 2. (70) Javelaud et al. The first paper covered studies of nine car mechanics and 13 pump attendants at filling kiosks who were generally exposed below 1 ppm.g.5 ppm (8 hour TWA) is calculated to be 0. Fifty smokers not occupationally exposed to benzene showed a geometric mean of 0. The following linear regression was determined after logarithmic transformation of all results: log t. from which they concluded that t.t-MA (mg/g creatinine) = 1. Sorbitol. blood. but inhalation of tobacco smoke will raise background values. whose exposure was generally above 1 ppm and occasion-ally peaked at 100 ppm. These authors also applied likelyhood ratios to test the probability of exposure given a specific test result. as a determinant of benzene exposure. rather than Biological Tolerance Values (BAT) values. while 50 nonsmokers showed 0.25 ppm (8-hour TWA). The EKA values.6 mg/g.549 log benzene in air (ppm) – 0.1 ppm.t-MA (mg/g creatinine) = 0.2208 + 0.5 ppm benzene in air was deduced. Other Reference Values The German Commission for the Investigation of Health Hazards of Chemical Compounds in the (71) Work Area treats benzene as a carcinogen and provides EKA values (exposure equivalents for carcinogenic substances). 10 – Benzene BEI with a range of 0. for various degrees of inhalation exposure. and 42 nonsmoking workers in the shoe industry. appear in Table 2.69) Ong et al.25 ppm.t-MA was not specific for monitoring benzene exposures below (63) 0. the urinary t. 95% of whom were exposed to benzene below 0. (69) The later paper reports samples from 131 nonsmokers chosen from a larger group who were randomly selected from petroleum refinery workers. Nonsmokers exposed at 0. reported a study of benzeneexposed car mechanics and road tanker drivers.t-MA concentration following exposure to a benzene concentration of 0.5 ppm averaged 0.296 mg/g creatinine for nonsmokers.t-MA for 0. The authors suggested that this could be explained by the differences in jobs or in the air sampling devices. The ability to convert benzene into t.ment of benzene exposure. Laboratory and Simulation Studies Neither human laboratory studies nor simulation studies specific to t.25 ppm: r = 0. Very few false positive results were found.t-MA in workers exposed to benzene. undertook the most detailed studies of urinary t.39 mg/g creatinine. Ghittori et al.. and alveolar air) for the assessment of exposure to ACGIH © 2001 (54) (72) . compared S-PMA and t.89) From this. Other Indicators of Exposure Ong et al. (68) Hotz et al.t-MA concentration following exposure to a benzene concentration of 0. which is present in some foods.067 mg/g (57) creatinine.t-MA concentrations. and for the 31 drivers reported the regression log t. as well as the corresponding airborne level.18 (r = 0. and Schaller reviewed the variety of monitoring indicators (e.t-MA in urine.4815 log atmospheric benzene (mg/m3) From this.2 to 0.t-MA concentration in urine corresponding to the TLV–TWA of 0.5 ppm (8hour TWA) is calculated to be 0.5 ppm is 0. Recommendation ACGIH recommends monitoring of t.t-MA acid in urine in 410 male workers.207 mg/g creatinine.14 for those exposed to more than 0. A value of 0.

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