(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

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petroleum fractions dissolved in benzene to facilitate dermal administration. At present, there is no acceptable animal model for the human leukemogenic effects. Recently, French and Saulnier (2000) reported that leukemia can be produced in the TgAC mouse after dermal administration of benzene. However, it is not known whether experiments with this mouse will ultimately yield a satisfactory model. In animal studies, responses to benzene administration are variable and may depend on a variety of factors, including species, strain, exposure duration, and whether exposure is intermittent or continuous. Serious toxicological effects are primarily confined to hematological parameters and involve all aspects of the hematopoietic system, from depression of stem cells up to pancytopenia and histopathological alterations in the marrow. Effects have been observed after acute, sub-acute, subchronic, and chronic exposure via different routes of administration. However, AML, which is of primary concern in humans, is not produced reliably in standard laboratory test species, and occasional reports of cancer in experimental animals (usually the mouse) are of questionable value in cancer risk assessments. The subchronic toxicity of benzene has been studied primarily in the mouse and rat. Depending on the level of dosing, the effects are hematotoxicity, reduction in body-weight gain, and death. Effects on body weight and mortality may be secondary to hematotoxicity. Thus, hematotoxicity is the parameter for quantifying toxic effects of benzene and for estimating risk from exposure. The hematotoxicity in the rodent appears to compare well with benzene-induced hematologic changes in cases of human exposure. Results of benzene-induced mortality and hematotoxicity in key rodent studies conducted by inhalation and oral routes of exposure are summarized below. Information was obtained mainly from several major reviews of benzene toxicity (ATSDR, 1997; U.S. EPA, 1998a, 2003a). Inhalation (see Table 6.4) Mortality: In the rat, exposure of males and females to 200 ppm, 4–7 hours/day, 4– 5 days/week, caused significant mortality (Maltoni et al., 1983, 1985). In the mouse, deaths occurred in males and females at 300–302ppm, 6 hours/day, 5 days/week, for 16–26 week (Cronkite et al., 1985; Cronkite et al., 1989; Farris et al., 1993; Green et al., 1981a,b). Hematological Effects: Mouse and rat studies were identified that evaluated effects on peripheral blood and/or hematopoiesis (IRIS, 1998). Only one of the rat studies was performed over a dose range, and the results are considered here as being representative of effects in the rat. Male and female rats (10 M, 10 F/group) were exposed to benzene at concentrations of 0, 1.0, 100, and 300 ppm, 6 hours/day, 5 days/week for up to 90 days, with serial sacrifice after 7, 14, 28, 56, and 91 days of exposure. Results showed significant decreases in WBC counts in males (day 14), and females (days 14–19) and slightly decreased femoral cellularity at 300 ppm. Of the mouse studies, only one was performed over a dose range in both males and females. Results are consistent with other single-sex and single-dose studies and are considered to be representative of effects in the mouse in standard-protocol toxicity studies. In this assay, groups of 30 male and 30 female mice were exposed at 0, 1.0, 3.0, 30, and 300 ppm, 6 hours/day, 5 days/week for up to 91 days, with serial sacrifices after 7, 14, 28, 56, and 91 days of exposure (Ward et al., 1985). Hematological effects were not observed at 1, 10, or 30 ppm. However, at 300 ppm, mice showed reduced hematocrit, total hemoglobin concentration, RBC count, WBC count, platelet count, myeloid/erythroid ratios, and percent of lymphocytes. Red blood cells had increased mean corpuscular volume, mean cell hemoglobin, Benzene VCCEP Submission March 2006 83
glycerol lysis time, and incidence and severity of red cell morphological changes. Values for red blood cells, mean corpuscular hemoglobin and glycerol lysis were significant in males and females; other effects were significant only in males. Other mouse studies contribute to understanding the hematopoietic effects of benzene. Mice were exposed to benzene for 10 weeks (Green et al., 1981a,b), and samples of peripheral blood, bone marrow, and spleen were examined. Mice exposed to 300 ppm had decreased numbers of lymphocytes and RBC in peripheral blood, decreased granulocyte/macrophage progenitor cells in bone marrow, decreased spleen weight and number of lymphocytes, decreased multipotential stem cells and committed granulocyte/macrophage progenitor cells in the spleen, and increased atypical cell morphology in peripheral blood, bone marrow, and spleen. A second study by Green et al. was performed at 10 ppm for 10 weeks, and spleen weight, nucleated cells/spleen, and nucleated RBC/spleen were significantly increased. A study by Farris et al. (1997) demonstrated the progression of effects from inhaled benzene on hematological parameters after exposing male mice to 0, 1, 5, 10, 100, and 200 ppm benzene, 6 hours/day, 5 days/week for 1, 2, 4, or 8 weeks. A subset of mice from the 4-week exposure were allowed a recovery period of up to 25 days. There were no significant effects until exposure level reached 100 ppm. At 100 ppm and above, there was a reduction in bone marrow cells. Highly proliferative potential primitive progenitor cells were decreased at all time points at 200 ppm and at 2, 4, and 8 weeks at 100 ppm. The number returned to control level during recovery in all but the 200-ppm group. Replication of these cells increased to compensate for toxicity during exposure. The number of granulocyte-macrophage colonyforming units was reduced at 2, 4, and 8 weeks at 100 and 200 ppm. Granulocytic marrow cells were decreased by 100 ppm at week 4 and by 200 ppm at all time points. Blood leukocytes were lowered at week 2 onward at 100 and 200 ppm. Platelets were reduced at 2 weeks at 100 ppm and at all time points at 200 ppm. Snyder et al. (1988) examined the influence of two modifications in dosing regimens on hematotoxicity in two strains of mice. In one procedure, intermittent exposures (1 week benzene at 300 ppm) were followed by 2 weeks of non-exposure for life; in the second procedure, exposure was to 1200 ppm, 6 hours/day, 5 days/week for 10 weeks. The intermittent exposures produced earlier mortality than was seen in the 10-week study. Both exposures caused severe lymphocytopenia and moderate anemia. Tumor incidences were increased in both procedures, but neither strain had leukemia or lymphoma. With intermittent exposures, there is a rise in the population of cells that are actively dividing, and a larger target cell population. This increased population might increase the risk of myelodysplastic syndrome and myelocytic leukemia in human populations (Irons and Stillman, 1996) Benzene VCCEP Submission March 2006 84
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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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Page 41 and 42: Table 5.11: Benzene Releases for Al
Page 43 and 44: 6.1.2.2 Chronic Toxicity Toxicity a
Page 45 and 46: 6.1.2.2e Other Hematopoietic Malign
Page 47 and 48: 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 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: proposed that transplacental effect
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 and 100: intracellular pathogen, Listeria mo
Page 101 and 102: 2. Evidence indicates that myelotox
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
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vehicle); the total amount of time
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use of small non-road engine equipm
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Children may be exposed to benzene
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Table 7.36: Typical School Year Wee
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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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