(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

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derived metabolites in target organs. Benzene is known to be metabolized in the lung (Snyder and Hedli, 1996 Sheets and Carlson, 2004; Powley and Carlson, 1999, 2000, 2001) and rabbit bone marrow (Andrews et al., 1977). It is probable that benzene itself is not metabolized in human marrow, which lacks the P450 enzyme CYP2E1 (Genter and Recio, 1994). A current map of the pathways for benzene metabolism is shown in Fig. 1 (from Ross, 2000). This map is simplified to focus on metabolites that are thought to be important for toxicity and does not include the conjugation pathways and their products that are excreted or, perhaps, are further metabolized in target organs. Metabolites that have been proposed as being responsible for benzene toxicity include: 1) benzene oxide (epoxide), 2) mucondialdehyde, 3) quinones (e.g., benzoquinone, p-benzoquinone 4,4’-diphenoquinone), and 4) polyphenols (e.g., benzene dihydrodiol, catechol, trihydroxybenzene). Benzene oxide is a highly reactive intermediate and would be expected to form adducts with proteins in the vicinity of its synthesis and with DNA, and it is difficult to explain why toxicity would be higher in bone marrow than in liver. Also, stable DNA adducts in rodents are not detected consistently by the 32 P postlabeling technique after acute benzene exposure or after long-term administration (Reddy et al., 1990, 1994), although protein adducts are observed (McDonald et al., 1994) even in untreated animals. Small amounts of mucondialdehyde are probably produced in vivo from benzene (Kline et al., 1993), and it is a reactive intermediate, but there is no evidence that it is involved in benzeneinduced toxicity or carcinogenicity. Polyphenols are produced in large amounts via benzene metabolism and are released into the blood either as the phenols themselves (phenol, benzene dihydrodiol, catechol trihydroxybenzene, and catechol) or in conjugated form (e.g., as sulfate or glucuronide) where they can subsequently reach target organs (Ross, 2000). Reactive phenolic benzene metabolites such as hydroquinone and trihydroxybenzene produce DNA damage in human myeloid cells in vitro similar to that seen in mouse bone marrow by benzene (Kolachana et al., 1993). Phenol itself is probably not solely responsible for the toxic effects of benzene, because the administration of phenol alone does not reproduce the myelotoxicity caused by benzene (Tunek et al., 1981). However, concomitant administration of both phenol and hydroquinone does reproduce the toxicity (Eastmond et al., 1987; EPA-NCEA, 1998). It is plausible that the target-organ and target-cell toxic effects induced by benzene in vivo result from polyphenols, based on known effects of the polyphenols and the known enzymology (Ross et al., 2000). p-Benzoquinone might be a key reactive intermediate in the formation of acute myeloid leukemia, because only the myeloid cell line has the enzymatic capacity (e.g., myeloperoxidase) to convert hydroquinone to p-benzoquinone (Ross et al., 1996). Also, p-benzoquinone is a known clastogen (Smith et al., 1989). Hydroquinone can enhance the number of myeloid progenitor cells, which could then increase the conversion of hydroquinone to p-benzoquinone, thereby raising the cellular concentration (Irons and Stillman, 1996). Because the formation of stable DNA adducts has not been detected in vivo for the highly reactive p-benzoquinone, a potential mechanism for leukemogenic effects might be through protein binding, such as to histone protein, which in turn, might produce chromosomal damage. This type of mechanism might be considered a secondary toxic effect for which a threshold could exist. The main conclusions regarding metabolism from the EPA IRIS benzene assessment are: 1. It is generally agreed that chronic toxicity of benzene in animals and humans results from the formation of reactive metabolites. Benzene VCCEP Submission March 2006 93
2. Evidence indicates that myelotoxicity and genotoxicity occur from a combination of phenol with hydroquinone, muconaldehyde, or catechol. 3. The pathways of oxidative benzene metabolism are understood, and the first metabolic step is catalyzed by CYP2E1 (see Figure 6.1 – adapted from Ross, 2000). 4. The major metabolites in animals and humans are phenol, hydroquinone, and catechol. Benzene VCCEP Submission March 2006 94
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Voluntary Children’s Chemical Eva
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6.1.2 Types of Adverse Health Effec
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Glossary of Terms μg Microgram AA
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STEL Short-Term Exposure Limit TEAM
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enzene induced pancytopenias can pr
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A fertility study in female rats ex
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estimate is very conservative both
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2.0 BASIS FOR INCLUSION OF BENZENE
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2.5 Air Monitoring Data Several of
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Table 3.1: Proposed Benzene AEGL Va
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4.0 Regulatory Overview This sectio
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passenger vehicles operated at cold
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Benzene has been designated a hazar
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products had ceased” [46 Fed. Reg
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5.0 CHEMICAL OVERVIEW This section
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Table 5.3: Environmental Fate and T
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general, the production rate is abo
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gasoline. Aromatic hydrocarbons, su
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The EPA Office of Air Quality Plann
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Benzene VCCEP Submission March 2006
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Table 5.11: Benzene Releases for Al
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6.1.2.2 Chronic Toxicity Toxicity a
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6.1.2.2e Other Hematopoietic Malign
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that transient, high peak exposures
Page 49 and 50: absorption compared to inhalation,
Page 51 and 52: increased risk of disease. It shoul
Page 53 and 54: The National Cancer Institute (NCI)
Page 55 and 56: exposure. This was also supported b
Page 57 and 58: follow-up of this same cohort, Wong
Page 59 and 60: development of MDS)and/or AML. It i
Page 61 and 62: quantification of benzene air conce
Page 63 and 64: 4.0, 95% CI = 1.8-9.3) but not ALL
Page 65 and 66: 6.2 Benzene Toxicology—Animal Haz
Page 67 and 68: eakage and loss was comparable whet
Page 69 and 70: Benzene VCCEP Submission March 2006
Page 71 and 72: Table 6.2: In Vivo Genotoxicity of
Page 73 and 74: Table 6.2 Continued: In Vivo Genoto
Page 75 and 76: 6.2.2.3 Transplacental Genotoxicity
Page 77 and 78: induce solid tumors in animals in t
Page 79 and 80: mice in the 300-ppm group had bilat
Page 81 and 82: decreases in maternal weight gain,
Page 87 and 88: increased resorptions. The effects
Page 89 and 90: proposed that transplacental effect
Page 91 and 92: glycerol lysis time, and incidence
Page 93 and 94: 6.2.5.2 Chronic Toxicity Repeat-dos
Page 95 and 96: LOAELs for carcinogenic effects in
Page 97 and 98: the measurements of doses are suspe
Page 99: intracellular pathogen, Listeria mo
Page 103 and 104: 7.0 Exposure Assessments This secti
Page 105 and 106: throughout childhood, see Table 7.1
Page 107 and 108: 7.2 Sources of Benzene Exposure Chi
Page 109 and 110: Table 7.3: Outdoor Ambient Air Benz
Page 111 and 112: Table 7.5: County-Wide 24-hour Ambi
Page 113 and 114: Age-specific benzene intakes are pr
Page 115 and 116: Table 7.9: Total ADDs for Exposure
Page 117 and 118: Table 7.10 (cont.) Study Location a
Page 119 and 120: Table 7.11: Summary of Benzene Meas
Page 121 and 122: factor change attributable to benze
Page 123 and 124: where: ADD = average daily dose (mg
Page 125 and 126: Table 7.16: Total ADDS from In-Home
Page 127 and 128: Table 7.18: Summary of Age-Specific
Page 129 and 130: Table 7.20: Summary Statistics for
Page 135 and 136: In-Vehicle Exposures In-vehicle exp
Page 137 and 138: Table 7.30: Average of Mean In-Vehi
Page 139 and 140: e similar to those in other U.S. st
Page 141 and 142: vehicle); the total amount of time
Page 143 and 144: use of small non-road engine equipm
Page 145 and 146: Children may be exposed to benzene
Page 147 and 148: Table 7.36: Typical School Year Wee
Page 149 and 150: An addition of less than 1 µg/m 3
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In the mid-1990s, the American Petr
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Table 7.44: Dermal Benzene Absorpti
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Table 7.47: Product Names and Manuf
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Table 7.49: Summary of Age-Specific
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For children and non-smoking adults
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Benzene Exposure (mg/kg-day) Figure
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ackground pathways of exposure, inc
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8.1.3 EPA Default Risk Assessment N
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8.2.1 Potential for Increased Sensi
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These findings illustrate examples
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information associated with benzene
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species are more sensitive than oth
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8.2.3.1 Point of Departure for Non-
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Cancer risks were calculated using
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NONCANCER HAZARD QUOTIENT 1.00 0.09
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Table 8.1. Derivation of noncancer
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Table 8.3. Points of departure for
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Table 8.4. (cont.) Noncancer Hazard
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Table 8.5. Noncancer hazard quotien
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Table 8.6. Cancer risk estimates as
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Table 8.7. Indoor air comparison (i
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Table 8.9. Noncancer margins of saf
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Table 8.10. Noncancer margins of sa
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Table 8.11. Indoor air comparison (
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Table 8.13. (cont.) Notes: Cancer M
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the continental U.S. for each leuke
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in significant reductions in benzen
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Aksoy M (1977) Leukemia in workers
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Austin, C.C., Wang, D., Ecobichon,
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Buckley, J.D., Ribison, L.L., Swoti
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CONCAWE. 1996. Scientific basis for
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Ding, X-J, Li, Y., Ding, Y. el al.
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Forni, A. 1994. Comparison of chrom
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Goldwater LJ (1941) Disturbances in
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Hsieh, G.C., Parker, R.D., and Shar
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Jo, W.K. and Park, K.H. 1998. Expos
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Lange, A., Smolik, R., Zatonski, W.
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Lynge E, Andersen A, Nilsson R, Bar
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Meadows, A., Obringer, A. M. O., Ba
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Nedelcheva V, Gut I, Soucek P, Tich
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Picciani, D. 1979. Cytogenetic stud
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Ross D, Siegel D, Gibson NW, Pachec
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Sathiakumar, N., Delzell, E., Cole,
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Smith, M. T., Zhang, L. P., Wang, Y
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Thomas, K.W., Pellizzari, E.D., Cla
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United States Environmental Protect
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URS. 2002. Air Quality Trend in the
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Weisel, C.P. 2002. Assessing exposu
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Xing, S.G., Shi, X., Wu, Z.L., Chen
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(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

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