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 g/g creatinine 500 g/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 (TLVSTEL) 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 (46) (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 20C. It has a melting point of 5.5C, a boiling point of 80.1C, and a vapor pressure of 95.2 torr at 25C. Conversion factors at 25C 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 25C), 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 bloodgas, 425 for fat (15) (16) gas, and 334 for adipose tissueair.

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 (1922) ppm. Assuming a respiratory rate of 16 breaths per minute and a tidal volume of 0.5 liter, approximately 7.5 L benzene can be expected to be
Benzene BEI 1

FIGURE 1. The major pathways of benzene metabolism. Chemical structures in brackets are postulated intermediates.

2 Benzene BEI

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absorbed each hour through the lungs of a person (21) inhaling air containing 10 ppm benzene.

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. Under conditions where contact time was short, less than 0.2% of the applied dose was 2 absorbed (approximately 0.01 L/cm ), due to its volatility. Larger doses that persisted on the skin for up to 3 hours resulted in 10 to 100 times greater (17) absorption. Blank and McAuliffe determined penetration of benzene in a gasoline solution through 3 human abdominal skin in vitro to be 1.4 10 cm/hour, and the flux of benzene from air saturated 2 with benzene at 31C to average 1.0 L/cm /hour. Based on studies of benzene absorption through the (24) skin of hairless mice, Susten et al. estimated that a worker dermally exposed 150 times per day to a rubber solvent containing 0.5% benzene would absorb 4 to 8 mg. This compares to the estimated retention of 14 mg after 8-hour exposure at 1 ppm of (25) benzene in air. Fiserova-Bergerova reported skin 2 penetration rates of 0.2 to 0.7 mg/cm /hour. Laitinen (26) et al. reported that the skin was the main route of absorption of benzene among garage workers exposed to liquid gasoline.
(23)

sure for 4 hours, triphasic elimination has been reported with rate constants of 3.66, 0.737, and 0.0158 for men and 3.02, 1.09, and 0.0429 for (37) women. For a single subject exposed for 1 or 8 hours, half-times of about 1, 4, and 25 hours have (36) also been reported, though the first may be better represented by two phases of about 20 minutes and 2 hours. Elimination studies have recently been (38) reviewed. The long-term retention and elimination of benzene is influenced by both the concentration and duration of exposure. 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. Elimination may also be influenced by energy expenditure after work and by circadian rhythms.

Metabolic Pathways and Biochemical Interactions

The metabolic pathway of benzene in humans is shown in Figure 1. The metabolism is very complex and has not been fully elucidated. (See Snyder et (39) (40) al. and Yardley-Jones et al. for reviews of the toxicity and metabolism of benzene.) Benzene is oxidized primarily in the liver by the cytochrome P450-dependent monooxygenase to benzene oxide. Although several cytochrome P-450 isozymes may catalyze this reaction, at low levels of exposure, the ethanol-inducible isozyme IIE1 seems to be mainly (39) responsible. Benzene is primarily metabolized to phenol, hydroquinone, and catechol. Hydroquinone and catechol are further metabolized to 1,4-benzoquinone and 1,2,4-trihydroxybenzene, respectively. Benzene is also metabolized to the ring-opened oxidation product t,t-MA via the corresponding aldehyde inter-mediate. Initial oxidation of benzene occurs via two concurrent pathways involving either direct hydroxylation or formation of an epoxide (benzene oxide). Enzymatic hydrolysis of benzene oxide yields phenol and benzene glycol, the latter of which dehydrogenates to catechol. Benzene oxide also forms an addition product with glutathione, which is a precursor to phenylmercapturic acid. The majority of these metabolites are excreted in urine as glucuronide and sulfate conjugates of phenol are the primary urinary metabolites of benzene. Others include conjugates of catechols and quinol, mercapturic acids, t,t-MA, and the reaction product of benzene with guanine, N-7-phenylguanine. Benzene metabolism to phenol, formation of water-soluble phenyl glucuronide and sulfate conjugates, conjugation with glutathione, and urinary elimination of benzene as the S-phenylmercapturic acid (S-PMA) are considered detoxication pathways. 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.
Benzene BEI 3

Gastrointestinal
Gastrointestinal uptake of benzene has led to acute intoxications, which suggests effective absorption. Animal experiments confirmed that gastrointes(27) tinal absorption was essentially complete.

Elimination
Metabolism is the main elimination pathway. Approximately one-third of retained benzene was excreted rapidly in urine as conjugated phenol and (2831) dihydroxy-phenols. The remainder was further degraded to become incorporated in tissue or (32) exhaled as carbon dioxide (CO2). Benzene was mainly excreted in the urine as metabolites, notably as the conjugates of phenol with glucuronic and sulfuric acids, and in exhaled air, as the unchanged form. Workers occupationally exposed at 100 ppm benzene excreted in urine the following proportions of their absorbed does: 13.2% as phenol; 1.9% as quinol; 1.6% as t,t-muconic acid (t,t-MA); and 0.5% (33) each of catechol and 1,3,4-benezentriol. Small amounts of unmetabolized benzene have also been (34,35) detected in the urine. The proportion of absorbed benzene excreted via exhalation was (20,22,28,36) reported as 8% to 39%. 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. Following experimental expo2001 ACGIH

The TLV Documentation for benzene provides a summary of benzene biotransformation and the (1) implication for human health risk assessment.

Possible Nonoccupational Exposure

Exposure to vehicle emissions and smoking are the two major sources of benzene exposure in the general population. The emissions result from evaporation from gasoline which commonly contains 1% to 5% benzene, the amount according to country, (18) and from the exhausts of automobile engines. Benzene and other aromatic hydrocarbons are (40) formed during the pyrolysis of tobacco. Sidestream smoke (345529 g/cigarette) contained more benzene than the mainstream smoke (668 (41) g/cigarette). About 400 of 5000 materials and products tested by U.S. National Aeronautics and Space Administration are understood to emit benzene vapors in (42) amounts ranging from 0.1 to 140 g/g. Paints, adhesives, marking pens, rubber products, and tapes were identified as products that emit benzene and may contribute to indoor air benzene concentrations. Benzene is ubiquitous in the environment. 3 Median indoor benzene concentrations were 7 g/m in 200 homes without a resident smoker and 10 3 g/m in 300 homes in which one or more smokers (43) resided. 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 g/day (maximum 149222 g/day) using three in(44) dependent methods. For the average smoker (20 cigarettes/day), an additional exposure of about 600 to 800 g/day can be calculated. 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 g/day if exposed at 0.5 ppm.

TLVTWA
The TLVTWA for benzene of 0.5 ppm (1.6 3 3 mg/m ) and a TLVSTEL of 2.5 ppm (8 mg/m ), with a Skin notation and an A1, Confirmed Human Carcinogen, notation, was adopted in 1997. The TLV is based on the prevention of excess risk of cancer (leukemia) in humans associated with occupational benzene exposure. 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.

Summary
The evaluation of occupational exposure to benzene with biomarkers is based on 1) the determination of the unchanged parent compound in blood, urine, and exhaled air and 2) the determination of various benzene metabolites in urine.
4 Benzene BEI

The determination of benzene in blood provides a sensitive and specific method but is markedly affected by current or recent exposure. Due to the initial short half-life of benzene in blood, samples taken at the end of shift reflect only the most recent exposure. Samples taken before the following shift can provide a good measure of exposure during that, and previous shifts, but greater sensitivity is required for analysis. Benzene in exhaled air reflects the concentration of benzene in blood, and presents the same problem of interpretation in end-of-shift sampling. This method has the advantage of offering a noninvasive method, but sensitive methods of sampling and analysis have yet to be standardized. 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. Increased concentrations of benzene in postshift urine samples appear to be a sensitive indicator of benzene exposure in the intended TLV range. However, the quantitative interpretation of the measurement is ambiguous at present, and the methods require validating. Consequently, a specific BEI for benzene in urine could not be determined due to insufficient data. The determination of phenol, catechol, quinol, and 1,2,4-benzene-triol is not specific and sensitive enough for the low-exposure range. At present, it seems that hemoglobin and albumin adducts are not applicable for routine biological monitoring because of the sophisticated methods involved and their limited sensitivity. Recent methods developed using high-performance liquid chromatography (HPLC) and gas chromatographymass spectrometry (GC-MS) for the determination of t,t-MA and S-PMA in urine appear to present an alternative approach for biological monitoring of benzene exposure in a very low range. S-PMA in urine requires a more sophisticated technique than t,t-MA. At the TLVTWA of 0.5 ppm, urinary S-PMA and t,t-MA can be recommended as sensitive indicators of workplace exposure. Both determinants are present in very low concentrations in urine samples collected from occupationally unexposed persons. Smokers show higher levels than nonsmokers, and this may affect the relationship between biological levels and degree of exposure close to the TLV range. BEIs are recommended for measurement of SPMA and of t,t-MA in urine collected at the end of daily exposure. 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.

S-PHENYLMERCAPTURIC ACID IN URINE

In this Documentation, the units in analytical
ACGIH 2001

methods for urine samples are always expressed in g/L. Reports on samples from occupational exposure are quoted in units of g/g creatinine. The latter is used to reduce the effect of the variability of urinary flow rate, and in this document, the creatinine concentration is taken to be 1 g/L. For purposes of conversion, 1 g/L is assumed to be equal to 1 g/g creatinine.

0.29 g/g creatinine in 38 nonsmokers and 3.61 0.57 g/g creatinine in 14 smokers. S-PMA was present at detectable concentrations in the urine of all smokers and in 20 of the 38 nonsmokers.

Kinetics
The proportion of benzene taken up by the lungs excreted in urine as S-PMA was estimated to be between 0.05% and 0.29% (average 0.11%). The percentage was calculated from S-PMA concentrations in samples collected at the beginning and the (48,49) end of a shift during several consecutive days. A higher conversion of about 0.9% was found by (47) Stommel et al. In most workers, S-PMA was excreted in a single phase, but in some workers, a biphasic excretion was found, and the highest SPMA concentrations were detected in samples at the end of the shift. In some workers, the highest S-PMA concentrations were measured at the beginning of the next shift. This difference may be due to interindividual differences in toxicokinetics or the exposure of skin to benzene in the second group of workers, which may have led to a slower absorption of benzene into the body than through respiratory exposure. The average urinary half-time of elimination was nine hours [standard deviation (SD) = 4.5 hours]. In some workers, a tentative second phase of elimination was seen with half-time of 45 hours (SD = 4 hours). From the half-time exposure to benzene, some SPMA (16%30%) may still be excreted in samples (48) collected at the beginning of the next shift.

Analytical Methods
For adequate sensitivity of S-PMA determination in urine, sophisticated methodology is necessary. SPMA excretion in urine of exposed and nonexposed persons has been assessed using liquid chromato(45,46) (4750) graphic and GC-MS methods. The HPLC method, described by Maestri et (46) al., appears to be highly sophisticated and has not been validated in other laboratories. The detection limit is 0.5 g/L, the recovery of S-PMA is 90%, and the coefficient of variation is 3.8%. Determination using GC-MS is preferred because it is the more sensitive and specific of the two methods. The detection limits are 1 to 5 g/L urine using S-benzylmercapturic acid as an internal standard. The detection limit is dependent on matrix effects, conditions of the ion selection detector, and (48) experience of the operator. In a recent study from the same working group, a deuterium labeled S(pentadeuterophenyl)-mercapturic acid internal standard was used. The use of this internal standard (49) allowed a detection limit of 1 g/L. The coefficient of variation of replicate analyses was 2.5% and 3.5% at a spiked concentration of 13.1 and 50.1 g/L, respectively. 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. It has a detection limit of 1 g/L urine. ACGIH recommends GC-MS methods.

Factors Affecting Interpretation of Measurements Analytical Procedure and Sampling

Because the outcome of the chemical analysis depends on the analytical procedure, the selection of the method is critical. For S-PMA determination, GC-MS is required for adequate sensitivity, and the detection limit should be about 1 g/L urine. The elimination kinetics indicate that the timing of sample collection is critical for quantitative evaluation of exposure. Since S-PMA is not likely to be present in the workplace, special precautions are not necessary to avoid contamination of the sample.

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. Stability studies of SPMA in urine have shown that concentrations did not (48) change for at least one month if stored at 4C.

Exposure
The following factors can affect the biological levels: dermal exposure, interindividual differences in toxicokinetics (see Kinetics), and smoking. (49) Boogaard and van Sittert suspected that the formation of S-PMA may be influenced by coexposure to other aromatic hydrocarbons.

Biological Levels Without Occupational Exposure

With the HPLC technique, a mean of 9.4 5.9 g/g creatinine for nonexposed smokers, and 1.5 1.2 g/g creatinine for nonexposed nonsmokers was (35,46) reported. According to the study of van Sittert et (48) al., S-PMA concentrations in smoking and nonsmoking control persons were mostly below the detection limit of 1 to 5 g/L urine. With the improved (49) GC-MS method, the mean S-PMA level was 1.99
2001 ACGIH

Justification
Relationships between external benzene exposure and renal S-PMA excretion have been evaluBenzene BEI 5

ated in field studies. Controlled laboratory and simulation studies are not available. Significant correlations were observed for the relationship between benzene in air and S-PMA in postshift urine (35,4749,51) specimens. (48) Van Sittert et al. validated S-PMA as a biomarker in 12 separate studies. The studies, 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. An 8-hour exposure at 1 ppm benzene corresponds to 46 g S-PMA/g creatinine [95% confidence interval (CI) = 4150 g/g creatinine]. The authors estimated that with the sensitivity of their method, TWA exposure of 0.3 ppm could be determined reliably. An airborne benzene exposure at the TLVTWA of 0.5 ppm corresponds to a S-PMA excretion of 25 g/g creatinine. A similar study was performed by the same (49) working group, including the determination of t,tMA and S-PMA in urine. For the determination of SPMA in urine, a more reliable and sensitive method was used. For the comparison of the method, 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, refineries, and chemical plants. Strong correlations were found between t,tMA and S-PMA concentrations in samples from the end of shift and between either of these variables and airborne benzene concentrations. Exposure at an 8-hour TWA of 1 ppm benzene leads to a calculated average concentration of 47 g S-PMA/g creatinine in samples from the end of shift. The value of 47 g/g creatinine for S-PMA agrees well with the findings from the previous studies, where a similar value was found. Therefore, the TLVTWA of 0.5 ppm would correspond to a S-PMA excretion of (49) 25 g/g creatinine. This study confirmed the suitability of S-PMA to detect benzene exposures as low as 0.3 ppm. Due to its superior specificity and its longer elimination half-life, S-PMA was considered by the authors to be a more reliable and sensitive biomarker than t,t-MA in urine. (51) Popp et al. 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 = 0.81 [S-PMA-urine mg/g creatinine = 4.10 + 10.98 benzene-air (mg/m3)]. Therefore, a TLVTWA of 0.5 ppm should correspond to S-PMA excretion of 22 g/g creatinine. For a group of 145 workers exposed to benzene (35) in a chemicals plant, Ghittori et al. found a significant correlation between benzene in air and SPMA (g/g creatinine) in postshift urine. From the calculated regression at an 8-hour TWA of 3250
6 Benzene BEI

g/m (1 ppm) benzene, the average S-PMA concentration in urine samples was 45 g/g creatinine (90% CI = 2095 g/g creatinine). From the extrapolation to the TLVTWA of 0.5 ppm, there would be a S-PMA level in urine of about 25 g/g creatinine.

Current Database Available

Sufficient data from four field studies are available to support a BEI.

Recommendation
ACGIH recommends monitoring S-PMA in urine, collected at end of shift, as a determinant of occupational benzene exposure. The value of 25 g/g (36 mol/mol) creatinine is recommended as a BEI. The test is specific, but inhalation of tobacco smoke will introduce elevated background values, although these are likely to only reach the level recommended for the BEI for very heavy smokers.

t,t-MUCONIC ACID IN URINE

Analytical Methods
Specific and sensitive HPLC methods have been developed for determining t,t-MA in urine and are preferred to gas chromatographicmass spectrometric (GC-MS) methods. The latter are more tedious as derivatization to trimethylsilyl esters is necessary. Analytical techniques for t,t-MA were only suitable in the past for measuring exposures to benzene in air greater than 1 ppm. Recent techniques are (52) based on the work of Ducos et al., where methods (53) have been compared by these workers and by (54) Ong et al. (55) Lauwerys et al. reported a sensitivity corresponding to an 8-hour TWA of 0.5 ppm. The most (56) sensitive method was probably that of Lee et al., who reported that concentrations as low as 25 g/L could be detected, and a within-assay coefficient of variation of < 7%. The more recent technique used (57) by Ghittori et al., which employs a preloading column in the HPLC, and ultraviolet (UV) measurement at 259 nm, is reported to have a detection limit of 3 g/L with an interassay coefficient of variation of 3.8% and a recovery of about 90%. To ensure consistent results, strong anion exchange (SAX) clean-up is essential, and the urine samples should be alkalized to pH 710. The paper by Bartczak et (58) al. clearly demonstrates the enhanced sensitivity of the new techniques. Other publications that describe analytical methods for t,t-MA include those by Boogard and van (49) (59) Sittert, and Inoue et al. A less-labor intensive method using capillary electrophoresis has recently been reported for discriminating urinary t,t-MA down (60) to 25 g/L from nonsmokers and smokers.
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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 4C. Although t,t-MA was stable in urine samples stored at room temperature for up to one week without preservation, low concentration samples kept at room temperature without a preservative lost (56) 10% to 30% t,t-MA after two weeks.
(49)

Biological Levels Without Occupational Exposure

The principal source of t,t-MA in urine of nonoccupationally exposed persons is benzene in tobacco smoke. Sorbitol, which is present in some foods, (52,61) may also elevate background values of t,t-MA. (56) For 23 nonsmokers, Lee et al. reported a mean value of 0.13 mg/L t,t-MA (range, 0.030.33) and 0.14 mg/g creatinine (range, 0.010.29). For 35 smokers, corresponding values were 0.25 mg/L (0.030.77) and 0.19 mg/g creatinine (0.060.43). Geometric mean values have been reported by Lau(55) werys et al. as 0.13 mg/g creatinine for smokers not exposed to benzene, and as 0.06 mg/g creati(59) nine for nonsmokers. Inoue et al. reported a 97.5% value of 1.4 mg/L in unexposed persons, but the sensitivity of the method they used did not permit detection of t,t-MA in 64% of the men and women (57) tested. Ghittori et al. reported similar values of 0.207 and 0.067 mg/g creatinine, and 95th percentiles of 0.56 and 0.30 mg/g creatinine. (62) Melikian et al. showed that mean levels of t,t-MA in groups of male, female, and pregnant smokers were 3.6, 4.8, and 4.5 times those of nonsmoking (62) counterparts. Ruppert et al. reported a median background concentration of 0.13 mg/g creatinine t,t-MA in 32 smokers and 0.065 mg/g creatinine in 82 nonsmokers. In eight nonsmokers, they reported an increase in t,t-MA excretion from 0.08 to 0.88 mg/24h from a dietary supplement of 500 mg sorbic (61) acid. From this, Rupport et al. deduced that a typical dietary intake of 6 to 30 mg/day of sorbic acid accounts for 10% to 50% of background t,t-MA in nonsmokers, and 5% to 25% in smokers. Further studies on levels from smokers are reported under Field Studies in the Justification section below. The significant absorption of benzene from inhalation of tobacco smoke limits the sensitiveity of monitoring for occupational exposure. A detailed study of benzene-related compounds in the urine of cigarette smokers has been reported by (63) Ong et al.

1953, Parke and Williams recovered 1% to 1.8% of an oral dose in rabbits. These data are quoted by (64) Ducos and Gaudin, who provide a useful general background to the t,t-MA determinant for benzene, (65) as do Ong et al. The former conclude that their (52,53) (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,t-MA is 2.0%, 1.5% and 1.4% respectively. t,tMA is considered to have a half-life comparable to that of phenol ( 5.7 hours). The longer halflife for phenol (about 24 hours) demonstrated by Sher(36) wood and others may be masked by the natural background of t,t-MA and the effect of smoking. These percentages are reasonably consistent with (49) the report of Boogard and van Sittert that, on average, 3.9% (range 1.9%7.3%) of an occupationally inhaled dose was excreted as t,t-MA with an (49) apparent half-life of 5.0 (SD = 2.3) hours. They show that some elevation of urinary t,t-MA was still evident 16 hours after exposure.

Factors Affecting Interpretation of Measurements Analytical Procedure and Sampling

Because the outcome of the chemical analysis depends on the analytical procedure, the selection of the method is critical. For t,t-MA determination, only the most recently reported methods should be used. Urine samples must be alkalized at the start of the analytical procedure to ensure reproducible recoveries greater than 95% from all ion-exchange columns. The elimination kinetics indicate that the timing of sample collection is particularly critical for quantitative evaluation of exposure. Samples should be collected within one hour of the end of a shift. If expo-sure is known to occur early in the shift, samples should be taken at a mid-shift break. Since t,t-MA is not likely to be present in the workplace, special precautions are not necessary to avoid contamination of the sample.

Exposure
The following factors can affect biological levels of t,t-MA: dermal exposure, interindividual differences in toxicokinetics (see Kinetics), smoking, (61) pregnancy, and absorption of sorbitol. (59) Inoue et al. suggest that the level of elimination may be suppressed by the concomitant absorption of toluene. The ability to convert benzene into t,t-MA may be genetically determined and varies (66) (67) significantly. Gobba et al. compared concentrations of muconic acid in urine with those of benzene in urine (as a surrogate of benzene exposure) among bus drivers, and concluded that they could be grouped as poor muconic metabolizers and efficient metabolizers, with mean values for muconic acid of 108 and 916 g/g creatinine, respectively.
Benzene BEI 7

Kinetics
The biological formation of muconic acid from benzene was first demonstrated by Jaffe in 1909. In 1924, Thierfelder and Klenk determined that 3.7% of benzene injected as an intraperitoneal dose in rabbits was eliminated in urine as muconic acid. In
2001 ACGIH

TABLE 1. Database of Field Studies of t,t-Muconic Acid as a Benzene Exposure Determinant Sex and Number Ref. # 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) = 0.989 benzene (ppm) + 4.429 (r = 0.8270) MA (mg/g cr) = 1.223 benzene (ppm) + 2.123 (r = 0860) MA (mg/g cr) = 0.939 benzene (ppm) + 5.396 (r = 0.814) log MA (mg/L) = 0.891 log benzene (ppm) + 0.041 MA (mg/g cr) = 0.8502 benzene (ppm) + 0.02 (r = 0.88) log MA (mg/g cr) = 0.86 log benzene (ppm) + 0.15 (r = 0.81) Benzene (mg/m3) = 2.38 MA (mg/g cr) 0.900 (r = 0.959) For air concentrations in limited range 0.01 to 0.5 ppm: log MA (mg/g cr) = 0.506 log benzene (ppm) 0.213 (r = 0.56) For all air concentrations measured (up to 20 ppm): log MA (mg/g cr) = 0.429 log benzene (ppm) 0.304 (r = 0.58) log MA (mg/g cr) = 0.549 log benzene (ppm) 0.18 (r = 0.614) log MA (mg/g cr) = 1.05 log benzene (ppm) + 0.20 (r = 0.89) log MA (g/g cr) = 0.69 log benzene (ppb) + 0.09 (r = 0.53) (r = 0.58C) log MA (g/g cr) = 0.4815 log benzene (mg/m ) + 2.2208 (r = 0.46)
3

Date 1989

Index for 0.5 ppm in air (g/g creat.) 4900 2700 5900 (610 g/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,t-muconic acid; cr = creatinine. Includes non-exposed subjects. Values for women are heavily influenced by exposures > 100 ppm. C Based on 151 workers who excreted t,t-muconic acid above the limit of detection.

Field data generally indicate a greater variation in urinary t,t-MA concentrations than in S-PMA. However, in a study of 410 workers exposed to (68) benzene, Hotz showed a correlation coefficient of 0.58 between air concentration and urinary elimination of t,t-MA for the 151 urine samples above the limit of detection, and of 0.41 for S-PMA.

Justification Field Studies

Relationships between external benzene exposure and renal t,t-MA excretion have been evaluated in numerous field studies. The principal data are shown in Table 1. In most of these, comparison was also made with elimination of S-PMA. Significant correlations were observed for the relationship between benzene in air and t,t-MA in post-shift urine (35,49,51,53,5557,59,65,6870) specimens. Controlled laboratory and simulation studies are not available. (59) In 1989, Inoue et al. 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. The latter were mostly below the detection limit of the analytical method. Correction of results from exposed workers for creatinine concentration or specific gravity of urine made little difference to the correlation coefficients. The following correlations were reported for exposed and nonexposed persons: Men + Women: t,t-MA (mg/g cr) = 0.989 benzene in air (ppm) + 4.429 (r = 0.827) Men: t,t-MA (mg/g cr) = 1.223 benzene in air (ppm) + 2.123 (r = 0.860) Women: t,t-MA (mg/g cr) = 0.939 benzene in air (ppm) + 5.396 (r = 0.814) From these, the following urinary concentrations
ACGIH 2001

of t,t-MA, corresponding to 0.5 ppm benzene in air (8-hour TWA), are deduced: 4.9 mg/g creatinine for men+women; 2.7 mg/g creatinine for men alone; and 5.9 mg/g creatinine for women alone. These calculated values may not be valid at concentrations around 0.5 ppm, as the exposure concentrations measured were generally much higher (up to 200 ppm). A significant difference between men and women was reported. (53) In 1992, Ducos et al. reported that sampling results from 23 workers demonstrated a linear correlation between benzene exposure and urinary concentration of t,t-MA and that at a TLVTWA of 0.5 ppm the concentration in urine is 0.61 mg/L. Only 16% of air samples were below 1 ppm (53) benzene. Unlike subsequent publications, they reported no improvement of correlation coefficients after correction for creatinine concentration. The (64) 1995 review by this group includes an analysis of results obtained by other workers. (56) Lee et al. determined urinary t,t-MA in 19 refinery workers exposed to benzene in the range 0.01 to 0.63 ppm. From linear correlation of the difference between t,t-MA concentration before and after shift and benzene exposure, they determined the following relationship: t,t-MA (mg/g creatinine) = 0.8502 benzene in air (ppm) + 0.02 (r = 0.614) From this, the urinary t,t-MA concentration following exposure at 0.5 ppm (8-hour TWA) can be calculated as 0.43 mg/g creatinine. Urinary t,t-MA concentrations in non-exposed persons were determined to be 0.19 mg/g creatinine in 35 smokers and 0.14 mg/g creatinine in 23 nonsmokers. (55) Lauwerys et al. reported a statistically significant correlation between air concentrations of benzene and t,t-MA in postshift urine of 38 male subjects employed in garages and coke ovens. After logarithmic transformation, the linear regression was found to be: log t,t-MA (mg/g creatinine) = 0.86 log benzene in air (ppm) + 0.15 (r = 0.81) The urinary concentration of t,t-MA corresponding to a benzene exposure at 0.5 ppm (8-hour TWA) is 0.8 mg/g creatinine. In 21 nonsmokers and 14 smokers not occupationally exposed to benzene, geometric mean values for t,t-MA in urine were 0.06 mg/g creatinine and 0.130 mg/g creatinine, respectively. The authors concluded that t,t-MA is a reliable indicator of benzene exposure even as low as 0.5 ppm. (51) Popp et al. measured t,t-MA elimination in 26 car mechanics exposed to benzene up to a maximum of 4 ppm. The authors reported significant correlation between benzene exposure and concentration of t,t-MA in postshift urine (r = 0.54). The post2001 ACGIH

shift concentrations were twice those in preshift samples. The data presented did not permit estimation of t,t-MA concentration after exposure to a benzene concentration of 0.5 ppm (8-hour TWA). At the mean value for benzene concentration in air of 2.6 3 mg/m (0.8 ppm), the mean urinary excretion of t,tMA was 1.28 mg/g creatinine at the end of the shift, which suggests a value of about 0.8 mg/g creatinine after an 8-hour TWA benzene exposure at 0.5 ppm. The authors conclude that t,t-MA is suitable for routine biological monitoring, at least on a group basis. (49) Boogaard and van Sittert. summarized 12 studies of urinary t,t-MA in 188 workers with measured exposure to benzene vapor, and 52 control workers with no exposure. The regression equation for the highly significant correlation obtained for 58 workers exposed for about 8 hours was: Benzene in air (mg/m3) = 2.38 t,t-MA (mg/g creatinine) 0.900 (r = 0.959) From this, the t,t-MA concentration in urine corresponding to the TLVTWA of 0.5 ppm is 1.0 mg/g creatinine. No separate regression was given for exposures in a limited range about the TLV; the statistical analysis was on exposure concentrations 3 up to 80 mg/m (25 ppm). The mean concentration was 0.037 mg/g creatinine among the unexposed controls in 38 nonsmokers, and 0.058 mg/g creati(49) nine in 14 smokers. The authors found it essential to alkalize urine samples to ensure reproducible recoveries from all ion-exchange columns > 95%. (35) In 1995, Ghittori et al. reported a significant correlation between benzene exposure in air and t,tMA (g/g creatinine) in postshift urine of a group of 145 workers in a chemicals plant. For exposure concentrations in the limited range 0.01 to 0.5 ppm (geometric mean = 0.1 ppm, geometric standard deviation = 4.16) after logarithmic transformation, the linear regression was found to be: log t,t-MA (mg/g creatinine) = 0.506 log benzene in air (ppm) 0.213 (r = 0.56) Over the full range of air concentrations measured (< 20 ppm), the regression was: log t,t-MA (mg/g creatinine) = 0.429 log benzene in air (ppm) 0.304 (r = 0.58) At the 8-hour TLVTWA of 0.5 ppm benzene in air, the regressions predicted values for t,t-MA in urine of 0.43 and 0.37 mg/g creatinine, respectively. These may be compared with the reported background arithmetic mean values among those not occupationally exposed to benzene of 0.23 mg/g creatinine for 20 smokers and of 0.062 mg/g creatinine for nonsmokers. The authors also warn that the ability to convert t,t-MA has been reported to vary (66) significantly and that this may complicate assessBenzene BEI 9

ment of benzene exposure. An extension of this study to 171 workers was (57) published in 1996. The following linear correlation was reported: log t,t-MA (mg/g creatinine) = 0.549 log benzene in air (ppm) 0.18 (r = 0.614) The t,t-MA concentration in urine corresponding to the TLVTWA of 0.5 ppm is 0.45 mg/g creatinine. This is in close accord with the earlier assessment. Fifty smokers not occupationally exposed to benzene showed a geometric mean of 0.207 mg/g creatinine, while 50 nonsmokers showed 0.067 mg/g (57) creatinine. Ghittori et al. further reported a 95% upper limit of 0.563 mg/g creatinine for smokers and 0.296 mg/g creatinine for nonsmokers. A value of 0.45 mg/g creatinine in urine appears to correspond to over 50 cigarettes per day. (65,69) Ong et al. undertook the most detailed studies of urinary t,t-MA in workers exposed to benzene, from which they concluded that t,t-MA was not specific for monitoring benzene exposures below (63) 0.25 ppm. The first paper covered studies of nine car mechanics and 13 pump attendants at filling kiosks who were generally exposed below 1 ppm, and 42 nonsmoking workers in the shoe industry, whose exposure was generally above 1 ppm and occasion-ally peaked at 100 ppm. The following linear regres-sion of logarithmic values was determined: log t,t-MA (mg/g creatinine) = 1.05 log benzene in air (ppm) + 0.20 (r = 0.89) From this, the urinary t,t-MA concentration following exposure to a benzene concentration of 0.5 ppm (8hour TWA) is calculated to be 0.77 mg/g creatinine. (69) The later paper reports samples from 131 nonsmokers chosen from a larger group who were randomly selected from petroleum refinery workers. The following linear regression was determined after logarithmic transformation of all results: log t,t-MA (g/g creatinine) = 0.69 log benzene in air (ppb) + 0.09 (r = 0.53) for those exposed to less than 0.25 ppm: r = 0.14 for those exposed to more than 0.25 ppm: r = 0.55 From the regression, the urinary t,t-MA concentration following exposure to a benzene concentration of 0.5 ppm (8 hour TWA) is calculated to be 0.76 mg/g creatinine. This paper also reported background values in non-exposed persons, but the application of their conclusions is restricted to nonsmoking workers. (68) Hotz et al. compared S-PMA and t,t-MA acid in urine in 410 male workers, 95% of whom were exposed to benzene below 0.5 ppm. Nonsmokers exposed at 0.5 ppm averaged 0.39 mg/g creatinine,
10 Benzene BEI

with a range of 0.2 to 0.6 mg/g. Very few false positive results were found, and the method was found reliable even around the cut-off airborne exposure level of 0.1 ppm. These authors also applied likelyhood ratios to test the probability of exposure given a specific test result. (70) Javelaud et al. reported a study of benzeneexposed car mechanics and road tanker drivers, and for the 31 drivers reported the regression log t,t-MA (g/g) = 2.2208 + 0.4815 log atmospheric benzene (mg/m3) From this, a value of 208 /g t,t-MA for 0.5 ppm benzene in air was deduced, which is considerably (70) less than reported in other studies. The authors suggested that this could be explained by the differences in jobs or in the air sampling devices.

Laboratory and Simulation Studies

Neither human laboratory studies nor simulation studies specific to t,t-MA as a determinant for benzene exposure have been reported.

Summary/Current Database Available

Sufficient data from 11 field studies are available to support a BEI.

Recommendation
ACGIH recommends monitoring of t,t-MA in urine, collected at end of shift, as a determinant of benzene exposure. The value of 500 g/g creatinine is recommended as a BEI. The test is specific, but inhalation of tobacco smoke will raise background values, restricting monitoring to workers with benzene exposures greater than 0.25 ppm (8-hour TWA). Sorbitol, which is present in some foods, may also elevate (62) background values, while concomitant exposure (59) to toluene may depress t,t-MA concentrations. The ability to convert benzene into t,t-MA is genetically deter-mined, varies significantly between (66) individuals, and may depend on the efficiency of (67) t,t-MA metabolism.

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), rather than Biological Tolerance Values (BAT) values, for various degrees of inhalation exposure. The EKA values, as well as the corresponding airborne level, appear in Table 2.

Other Indicators of Exposure

Ong et al. and Schaller reviewed the variety of monitoring indicators (e.g., blood, urine, and alveolar air) for the assessment of exposure to
ACGIH 2001
(54) (72)

TABLE 2. German EKA Values for Benzene (71) Sampling Time: End of Exposure or End of Shift Whole Urine Blood Benzene S-PMA t,t-MA (g/L) (mg/g cr)* (mg/L) 0.9 0.010 2.4 0.025 1.6 4.4 0.040 5.0 0.045 2 14 0.090 3 38 0.180 5 0.270 7

Airborne Concentration of Benzene in ppm3 0.3 0.6 0.9 1.0 2.0 4.0 6.0
*cr = creatinine

benzene. Table 3 provides an overview of other indicators currently available for biological monitoring of benzene exposure. The advantages and disadvantages are listed for each parameter taking into particular consideration specificity, sensitivity and practicability. (34) Ghittori et al. demonstrated that the determination of benzene in urine can provide a sensitive and specific indicator for the biological monitoring of occupationally exposed workers. Ong (65,69) et al. reported that unmetabolized benzene in urine provided good correlation with ambient benzene, but data were insufficient to confirm it as a useful biomarker of exposure, and serious technical drawbacks limit its use. At present, the experience with the benzene in urine parameter is quite limited, and the method requires validating. This determinant has been applied, together with a simple but sensitive method of determining benzene in exhaled (73) breath, by Nordlinder et al. to determine occupational exposure to gasoline. (65) Ong et al. also reported from two field studies that urinary hydroquinone shows a good correlation with benzene concentrations in the breathing zone, even at concentrations below 1 ppm. This finding was based on one study and requires validation. In a (69) subsequent review, they reported that a study of hydroquinone excretion showed good correlation with exposure but could not detect airborne exposure below 0.25 ppm. Excretion of 1,2,4-benzenetriol in the urine of workers exposed to benzene was investigated by (33) Inoue et al., using an HPLC method that required more complex preliminary treatment than t,t-MA. The detection limit was 0.5 mg/L, which corresponded to an 8-hour TWA benzene exposure of about 2 ppm. Excretion was suppressed by concomitant exposure to toluene.

References
1. American Conference of Governmental Industrial Hygienists: Benzene. In: Documentation of Threshold Limit Values and Biological Exposure Indices, 7th ed. 2001 ACGIH

ACGIH, Cincinnati, OH (2001). 2. Hamilton, A.; General Review: Benzene (Benzol) Poisoning. Arch. Path. Lab. Med. 11:434454, 601 632 (1931). 3. U.S. Agency for Toxic Substances and Disease Registry: Toxicological Profile for Benzene (Update). TP-92/03. DHHS, PHS, ATSDR, Atlanta, GA (1993). 4. Kipen, H.M.; Cody, R.P.; Crump, K.S.; et al: Hematologic Effects of Benzene: A Thirty-Five Year Longitudinal Study of Rubber Workers. Toxicol. Ind. Health 4:411430 (1988). 5. Hornung, R.W.; Ward, E.; Morris, J.A.; Rinsky, R.A.: Letters to the Editor. Toxicol. Ind. Health 5:11531155 (1989). 6. Kipen, H.M.; Cody, R.P.; Goldstein, B.D.: Letters to the Editor. Toxicol. Ind. Health 5:11561158 (1989). 7. Infante, P.F.; Rinsky, R.A.; Wagoner, J.K.; Young, R.J.: Leukaemia in Benzene Workers. Lancet 2:7678 (1977). 8. Rinsky, R.A.; Smith, A.B.; Hornung, R.; et al.: Benzene and Leukemia. An Epidemiologic Risk Assessment. N. Engl. J. Med. 316(17):10441050 (1987). 9. Vigliani, E.C.: Leukemia Associated with Benzene Exposure. Ann. N.Y. Acad. Sci. 271:143151 (1976). 10. Aksoy, M.: Benzene as a Leukemogenic and Carcinogenic Agent. Am. J. Ind. Med. 8:920 (1985) 11. Yin, S.N.; Li, G.L.; Tain, F.D.; et al: A Retrospective Cohort Study of Leukemia and Other Cancers in Benzene Workers. Environ. Health Perspect. 82:207 213 (1989). 12. Yin, S.A.: A Cohort Study of Cancer Among BenzeneExposed Workers in China: Overall Results. Presented at the International Conference on the Toxicity, Carcinogenicity and Epidemiology of Benzene. Environmental Health Sciences Institute, Piscataway, NJ (June 1720, 1995). 13. Rushton, L.; Thar, W.E.: Retrospective Exposure Assessment for Benzene: Issues, Methods and Recommendations from an International Workshop on Petroleum Marketing and Distribution Worker Studies. Occup. Hyg. 3:295305 (1996). 14. Wong, O.; Raabe, G.K.: Multiple Myeloma and Benzene Exposure in a Multinational Cohort of More than 250,000 Petroleum Workers. Regul. Toxicol. Pharmacol. 26:188199 (1997). 15. Fiserova-Bergerova, V.: Gases and Their Solubility: A Review of Fundamentals. In: Modeling of Inhalation Exposure to Vapors: Uptake, Distribution, and Elimination, Vol.1, pp. 16, 21. V. Fiserova-Bergerova, Ed. CRC Press, Boca Raton, FL (1983). 16. Pierce, C.H.; Dills, R.L.; Silvey, G.W.; Kalman, D.A.: Partition Coefficients between Human Blood or Adipose Tissue and Air for Aromatic Solvents. Scand. J. Work Environ. Health 22:112118 (1996). 17. Blank, I.H.; McAuliffe, D.J.: Penetration of Benzene Through Human Skin. J. Invest. Dermatol. 85:522526 (1985). 18. International Programme on Chemical Safety: Benzene. Environmental Health Criteria 150. World Health Organization, Geneva (1993). 19. Srbova, J.; Teisinger, J.; Skramovsky, S.: Absorption and Elimination of Inhaled Benzene in Man. Arch. Ind. Hyg. Occup. Med. 2:18 (1950). 20. Nomiyama, K.; Nomiyama, H.: Respiratory Retention Uptake and Excretion of Organic Solvents in Man. Ing. Arch. Arbeitsmed. 32:7283 (1974). 21. Rusch, G.M.; Leong, B.K.; Laskin, S.: Benzene Benzene BEI 11

TABLE 3. Indicators, Other than S-Phenylmercapturic and t,t-Muconic Acids, That Have Been Used or Tested for Assessment of Benzene Exposure at the Workplace and in the Environment Minimum 8-Hour Exposure Detected Determinant Advantages Disadvantages Method (ppm) Measurement of Benzene in Biological Samples Benzene in exhaled air Benzene in blood Benzene in urine Specific, sensitive, simple Limited practicability, not widely used, influenced by a number of parameters Invasive, influenced by sampling time Limited experience GC-MS <1

Specific, sensitive Specific, sensitive, noninvasive; correlates well with exposure technique

GC-FID headspace technique GC-FID headspace

<1 <1

Measurement of Benzene Metabolites in Urine Phenol Catechol and quinol 1,2,4-Benzene-triol N-Acetyl-cysteine and thiophenol N-7-Phenyl-guanine Hydroquinone Specific to damage route, low background level Sensitive Well-established methods Insensitive, nonspecific Limited experience, insensitive Limited experience and sensitivity Influenced by tobacco smoking, limited experience, sophisticated methodology Insensitive, rat data only Very limited experience Other Indicators Hemoglobin & albumin adducts, and N-phenylvaline adducts Chromosome aberrations in lymphocytes Specific to damage route Insensitive, sophisticated methodology, limited practicability and experience GC-MS HPLC, GC GC-HPLC HPLC HPLC 5 10 10

Specific to damage route Sensitive, correlates with external exposure

GC-MS HPLC

5 0.25

Nonspecific, insensitive

GC = gas chromatography; FID = flame ionization detector; HPLC = high-pressure liquid chromatography; MS = mass spectrometry Metabolism. J. Toxicol. Environ. Health 2:2336 (1977). 22. Pekari, K.; Vainiotalo, S.; Heikila, P.; et al.: Biological Monitoring of Occupational Exposure to Low Levels of Benzene. Scand. J. Work Environ. Health 18:317322 (1992). 23. Franz, T.J.: Percutaneous Absorption of Benzene. In: Applied Toxicology of Petroleum Hydrocarbons, Advances in Modern Environmental Toxicology, Vol. V1. H.N. MacFarland, C.E. Holdsworth, J.A. MacGregor, et al., Eds. Princeton Scientific Publishers, Princeton NJ (1984). 24. Susten, A.S.; Dames, B.L.; Burg, J.R.; Niemeier, R.W.: Percutaneous Penetration of Benzene in Hairless Mice: An Estimate of Dermal Absorption During TireBuilding Operations. Am. J. Ind. Med. 7:323335 (1985) 25. Fiserova-Bergerova, V.: Relevance of Occupational Skin Exposure. Ann. Occup. Hyg. 37:673685 (1993). 26. Laitinen, J.; Kangas, J.; Pekari, K.; Liesivuori, J.: Short Time Exposure to Benzene and Gasoline at Garages. Chemosphere 28:197205 (1994). 27. Sabourin, P.J.; Chen, B.T.; Lucier, G.; et al.: Effect of 14 Dose on the Absorption and Excretion of [ C]Benzene Administered Orally or by Inhalation in Rats and Mice. Toxicol. Appl. Pharmacol. 87:325336 (1987). 28. Teisinger, J.; Fiserova-Bergerova, V.; Kudrna, J.: The Metabolism of Benzene in Man. Pracovni Lekarstvi 4:175188 (in Czech) (1952). 29. Teisinger, J.; Fiserova-Bergerova, V.: Valeur

12 Benzene BEI

ACGIH 2001

Historical BEIs
Date 1985 Action Proposed Determinant Total phenol in urine Benzene in exhaled air: mixed-exhaled end-exhaled Total phenol in urine Benzene in exhaled air: mixed-exhaled end-exhaled S-Phenylmercapturic acid in urine S-Phenylmercapturic acid in urine t,t Muconic acid in urine S-Phenylmercapturic acid in urine t,t-Muconic acid in urine Sampling Time End of shift Prior to next shift End of shift Prior to next shift End of shift End of shift End of shift End of shift End of shift BEI 50 mg/L 0.08 ppm 0 12 ppm 50 mg/L 0.08 ppm 0.12 ppm 25 g/g creatinine 25 g/g creatinine 500 g/g creatinine 25 g/g creatinine 500 g/g creatinine B B B B B, Ns Cf Cf Notation G

1987

Adopted

1996 1997 1999 2000

Proposed Adopted Proposed Adopted

Compare de le Dtermination des Sulfates et du Phnol Contenus dans l'Urine pour l'Evaluation de la Concentration du Benzne dans l'Air. Arch. Mal. Profes. 16:221232 (1965). 30. Hunter, C.G.; Blair, D.: Benzene: Pharmacokinetic Studies in Man. Ann. Occup. Hyg. 15:193199 (1972). 31. Sherwood, R.J.: Benzene: The Interpretation of Monitoring Results. Ann. Occup. Hyg. 15:409421 (1972). 32. Parke, D.V.; Williams, R.T.: The Metabolism of 14 Benzene Containing C-Benzene. Biochem. J. 54:231238 (1953). 33. Inoue, O.; Seiji, K.; Nakatsuka, H.; et al.: Excretion of 1,2,4-Benzenetriol in the Urine of Workers Exposed to Benzene. Br. J. Ind. Med. 46:559565 (1989). 34. Ghittori, S.; Florentino, M.L.; Maestri, L.; et al.: Urinary Excretion of Unmetabolized Benzene as an Indicator of Benzene Exposure. J. Toxicol. Environ. Health 38:233243 (1993). 35. Ghittori, S.; Maestri, L.; Florentino, M.L.; Imbriani, M.: Evaluation of Occupational Exposure to Benzene by Urine Analysis. Int. Arch. Occup. Environ. Health 67:195200 (1995). 36. Sherwood, R.J.: Pharmacokinetics of Benzene in a Human after Exposure at About the Permissible Limit. In: Living in a Chemical World. C. Maltoni and I.J. Schikoff, Eds. Ann. N.Y. Acad. Sci. 534:635647 (1988). 37. Nomiyama, K.; Nomiyama, H.: Respiratory Elimination of Organic Solvents in Man. Int. Arch. Arbeitsmed. 32:8591 (1974). 38. Aitio, A.: Benzene. In: Guidelines on Biological Monitoring of Chemical Exposure at the Workplace, Vol. 2. Biological Monitoring of Solvent Exposures. WHO, Geneva (in press). 39. Snyder, R.; Witz, G.; Goldstein, B.D.: The Toxicology of Benzene. Environ. Health Perspect. 100:293306 (1993). 40. Yardley-Jones, A.; Anderson, D.; Parke, D.V.: The Toxicity of Benzene and Its Metabolism and Molecular Pathology in Human Risk Assessment. Br. J. Ind. Med. 48:437444 (1991). 41. Hoffmann, D.; Brunnemann, K.D.; Hoffmann, I.: Significance of Benzene in Tobacco Carcinogenesis. Adv. Med. Environ. Toxicol. 16:99 (1989). 42. National Aeronautics and Space Administration: Spacecraft Maximum Allowable Concentrations. 2001 ACGIH

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14 Benzene BEI

ACGIH 2001