Noreen N. Khan-Mayberry, Ph.D.
Habitability and Environmental Factors Division
Johnson Space Center
National Aeronautics and Space Administration
Spacecraft maximum allowable concentrations (SMACs) for benzene were initially published in Volume 2 of Spacecraft Maximum Allowable Concentrations for 1-h, 24-h, 7-d, 30-d, and 180-d exposure durations (James and Kaplan 1996). As NASA will be conducting longer exploration missions, longer-duration SMACs are required. This document establishes a benzene SMAC for 1,000-d extended duration exposure. It also demonstrates that a review of published research since the original publication supports the original SMACs for 1-h, 24-h, 7-d, 30-d, and 180-d exposures.
Benzene is a clear liquid with a sweet odor (see Hazardous Substance Data Bank (HSDB 2005). This aromatic hydrocarbon is used as a solvent; however, this use has decreased in many countries because of concerns about carcinogenicity. Benzene occurs naturally but is primarily produced from petroleum products. It is a constituent of gasoline, in which it is used to enhance octane rating and as an antiknock agent (Krewski et al. 2000). Uses for benzene are numerous including acting as the intermediate in the manufacture of several chemicals, such as ethylbenzene, cumene, cyclohexane, and nitrobenzene. Benzene is a precursor in the manufacture of urethanes, chlorobenzene, and maleic anhydride (HSDB 2005).
Benzene can enter the environment during any of the stages involved in its production, storage, use, and transport (Krewski et al. 2000). Vehicular emissions constitute the main source of benzene in the environment. Benzene has been detected in approximately 10% of recent air samples in the space-shuttle cabin and in Spacelab at concentrations of 0.01 to 0.1 milligrams per cubic meter (mg/m3) (James and Kaplan 1996).
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4 Benzene Noreen N. Khan-Mayberry, Ph.D. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas Spacecraft maximum allowable concentrations (SMACs) for benzene were initially published in Volume 2 of Spacecraft Maximum Allowable Con- centrations for 1-h, 24-h, 7-d, 30-d, and 180-d exposure durations (James and Kaplan 1996). As NASA will be conducting longer exploration missions, longer-duration SMACs are required. This document establishes a benzene SMAC for 1,000-d extended duration exposure. It also demonstrates that a re- view of published research since the original publication supports the original SMACs for 1-h, 24-h, 7-d, 30-d, and 180-d exposures. OCCURRENCE AND USE Benzene is a clear liquid with a sweet odor (see Hazardous Substance Data Bank (HSDB 2005). This aromatic hydrocarbon is used as a solvent; however, this use has decreased in many countries because of concerns about carcino- genicity. Benzene occurs naturally but is primarily produced from petroleum products. It is a constituent of gasoline, in which it is used to enhance octane rating and as an antiknock agent (Krewski et al. 2000). Uses for benzene are numerous including acting as the intermediate in the manufacture of several chemicals, such as ethylbenzene, cumene, cyclohexane, and nitrobenzene. Ben- zene is a precursor in the manufacture of urethanes, chlorobenzene, and maleic anhydride (HSDB 2005). Benzene can enter the environment during any of the stages involved in its production, storage, use, and transport (Krewski et al. 2000). Vehicular emis- sions constitute the main source of benzene in the environment. Benzene has been detected in approximately 10% of recent air samples in the space-shuttle cabin and in Spacelab at concentrations of 0.01 to 0.1 milligrams per cubic me- ter (mg/m3) (James and Kaplan 1996). 62
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63 Benzene In September 2006, overheating of the oxygen generator in the Russian segment of the International Space Station resulted in high concentrations of several aromatic compounds. Samples taken several hours after the incident showed a concentration of benzene in the U.S. segment of 0.5 mg/m3. TOXIC MECHANISM OF ACTION Acute benzene toxicity causes gastrointestinal problems and neurotoxicity (HSDB 2005). Chronic benzene toxicity can lead to hematotoxicity. In the body, benzene is metabolized by a hepatic enzyme (CYP2E1) to benzene oxide, which spontaneously forms phenol. Phenol is further metabolized to hydroquinone by the same hepatic enzyme. Hydroquinone and related hydroxy metabolites are converted to benzoquinones by myeloperoxidase in the bone marrow. Benzo- quinones are hematotoxic, genotoxic compounds that can be transformed to less toxic hydroxyl metabolites by NAD(P)H: quinone oxidoreductase 1 (Rothman et al. 1997). SUMMARY OF ORIGINAL APPROACH James and Kaplan (1996), along with the National Research Council (NRC) Subcommittee on Toxicology, analyzed the acute and chronic toxicity of benzene by assessing available research. They set SMACs based on four catego- ries of benzene toxic effects; nervous system effects, hematologic effects, im- munologic effects, and risk of leukemia. The lowest values were selected as the final SMACs, all of which were set to protect the immune system, with the ex- ception of the 180-d SMAC, which was also set to be protective against leuke- mia. Their analysis of toxic effects followed the guidelines provided to NASA by the NRC Committee on Toxicology, with a few notable exceptions (NRC 1992). Deviations from defaults require an explanation. Some key deviations from past practices include the following: (1) using a species factor of 3 instead of 10 for effects caused by metabolites of benzene, (2) applying a spaceflight factor to an immunotoxicant because of the immune-modulating effects of spaceflight, (3) applying a radiation uncertainty factor because of benzene’s leukemogenic properties and the relatively high radiation exposure of astronauts, and (4) deviating their analysis from the NRC-recommended linearized multi- stage model because of uncertainty about the human epidemiology database and variations in low-dose extrapolation methods used by investigators (James and Kaplan 1996). Explanations are provided for specific acceptable concentrations (ACs) below. 1- and 24-h SMACs, 1996 The 1- and 24-h SMACs were set at 10 and 3 parts per million (ppm), re-
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64 SMACs for Selected Airborne Contaminants spectively. These short-term values are meant to be protective against a decrease in the number of peripheral lymphocytes. The Dempster et al. (1984) study was used to calculate this value; it found that five 6-h exposures to benzene at 100 ppm induced a 30% reduction in circulating lymphocytes in mice. No significant change was noted after a single 6-h exposure; therefore, the no-observed- adverse-effect level (NOAEL) was determined to be 100 ppm for 6 h. The short- term ACs were calculated as follows: 1-h AC = 100 ppm (NOAEL) × 1/3(species factor) × 1/3(spaceflight factor) = 11 ppm 24-h AC = 100 ppm (NOAEL) × 1/3(species factor) × 1/3(spaceflight factor) × 6/24(time extrapolation) = 3 ppm James and Kaplan (1996) noted that because immunologic effects, which are similar or greater in mice than in humans, were presumably induced by ben- zene’s toxic metabolites such as phenol, catechol, and hydroquinone, as opposed to benzene itself, the species factor should be 3. A spaceflight factor of 3 was deemed appropriate because of numerous reports on spaceflight effects on im- mune function in rats and to a lesser extent in astronauts (Taylor 1993). 7-, 30-, and 180-d SMACs, 1996 The 7- and 30-d ACs were set based on the data of Rosenthal and Snyder (1985), which showed that 12, 6-h exposures (72 h total) of mice to benzene at 10 ppm did not increase their susceptibility to infection by Listeria monocyto- genes. The ACs were calculated as follows: 7-d AC = 10 ppm (NOAEL) × 1/3 (species factor) × 1/3 (spaceflight factor) × 72/168 (time extrapolation) = 0.5 ppm 30-d AC = 10 ppm (NOAEL) × 1/3 (species factor) × 1/3 (spaceflight factor) × 72/720 (time extrapolation) = 0.1 ppm These values were the lowest of the immunotoxicity ACs calculated by James and Kaplan (1996) and were also the lowest for any toxic effect known to be caused by benzene (see Table 4-1). No long-term exposure data were avail- able on the immunotoxicologic effects of benzene exposure. Haber’s rule was used to extrapolate a 180-d AC of 0.07 ppm from the 30-d AC of 0.4 ppm (cal- culated from Green et al. 1981a, as cited by James and Kaplan 1996), which was set to be protective against leukemia. The 30-d AC used a spaceflight factor of 3 to be protective against radiation effects. 180-d AC = 0.4 ppm × 30/180 (time extrapolation) = 0.07 ppm
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TABLE 4-1 Benzene End Points and Acceptable Concentrations, 1996 Uncertainty Factor Acceptable Concentration, ppm Space- End Point Exposure Data Genus and Reference Time Species flight 1 h 24 h 7d 30 d 180 d Nervous system toxicity, NOAEL at 300 ppm, Mus (Dempster et al. 1 10 1 30 30 30 30 30 loss of hind-limb grip 1984) 10 × 6 h strength Hematotoxicity Anemia NOAEL at 300 ppm, Mus (Dempster et al. 1 3 3 33 16 —a — — 1984) 2×6h Hemotoxic effects NOAEL at 10 ppm, Mus (Green et al. 1 or 3 3 — — 1.1 0.5 — 1981b) HR 50 × 6h NOAEL at 10 ppm, Mus (Toft et al. 1982) HR 3 3 — — — — 0.3 8 wk continuous Immunotoxicity Decrease in peripheral NOAEL at 100 ppm, Mus (Dempster et al. 1 or 3 3 11 3 — — — lymphocytes 6h 1984) HR Resistance to bacterial NOAEL at 10 ppm, Mus (Rosenthal and 1 or 3 3 — — 0.5 0.1 — infection and reduced Snyder 1986) HR 12 × 6 h splenic lymphocyte count Decrease in peripheral NOAEL at 9.6 ppm, Mus (Green et al. 1 or 3 3 — — 1.1 0.4 0.07 lymphocytes 1981b) HR 50 × 6 h Leukemia Lowest of 0.01% risk Varieties — — 3 rad — 12 1.7 0.4 0.07 estimates at 0.2 ppm, 180 d continuous SMAC 10 3 0.5 0.1 0.07 a Extrapolation to these exposure durations produces unacceptable uncertainty in the values. Abbreviation: HR, Haber’s rule; rad, radiation. Source: James and Kaplan 1996. 65
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66 SMACs for Selected Airborne Contaminants NEW DATA SINCE 1996 Short-Term AC Data Acute exposure to benzene results in central nervous system (CNS) de- pression such as dizziness, ataxia, and confusion. These effects are believed to be caused by benzene and not its metabolites, because the onset of CNS effects at extremely high doses is too rapid for metabolism to have occurred. Fatality due to acute benzene exposure has been attributed to asphyxiation, respiratory arrest, CNS depression, or cardiac dysrhythmia. Pathologic results in fatal cases have noted respiratory tract inflammation, lung hemorrhage, kidney congestion, and cerebral edema (ATSDR 1992). There were no new data supporting a change in short-term (1 or 24 h) benzene ACs. Long-Term AC Data A review of the long-term exposure data since the original SMAC publica- tion primarily focused on identifying biomarkers of benzene exposure in urine. No data were identified that would support changing the 7-, 30-, or 180-d ben- zene ACs. There are extensive case study data on long-term occupational (5 years) exposure to benzene. Yin et al. (1987) investigated workers in 28 prov- inces of China between 1979 and 1981. This group of industrial workers (paint- ing, paint production, shoe manufacturing, organic synthesis, insulation varnish, printing, rubber and petroleum refineries) was exposed to benzene or benzene mixtures. Yin et al. (1987) concluded that the prevalence of aplastic anemia in these individuals was 5.8 times the rate in the general population. The same group of investigators claimed that chronic occupational exposure to low levels (<1 ppm) of benzene caused increased risk of hematotoxicity (Lan et al. 2004, Vermeulen et al. 2004). This group previously reported (Qu et al. 2002) red blood cell, white blood cell (WBC), and neutrophil changes in the lowest ben- zene exposure group (at or below 0.25 ppm). In the studies of Qu et al. (2002), Vermeulen et al. (2004), and Lan et al. (2004), 250 exposed workers from the shoe industry along with 140 age- and sex-matched controls from the clothing industry near Tianjin, China, were com- pared for exposure and toxic effects from benzene. The workforce used had at least 5 years of exposure, with little or no shoe-making task rotation. The work- ers were classified on the basis of their tasks and exposure to glue containing benzene and toluene (dominant exposures) along with exposures to 18 other hydrocarbons. Expected benzene exposure concentrations were distinguished on the basis of the work task. Individual benzene and toluene exposure was moni- tored repeatedly with organic vapor monitors, which were attached to the worker’s lapel for the full shift (total of 2,783 measurements); home (personal) exposure measurements were taken on up to three different occasions (a total of 595 measurements).
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67 Benzene The Vermeulen et al. (2004) study focused on determining the broad range of benzene exposures in the two shoe manufacturing facilities. Although the work exposures were to several compounds, the authors did a good job of esti- mating the predicted benzene exposure by calculating the personal exposures from the benzene monitors by a gas chromatography flame ionization detector and showing a high correlation between the logged air levels of benzene and the monitors analyzed in China and at a commercial laboratory in the United States. The workers wore personal benzene monitors for 16 months. The same group provided postshift urine samples for the Lan et al. (2004) study. These samples were collected from each subject at the end of the 16- month monitoring study (Vermeulen et al. 2004). Subjects in the Lan et al. (2004) research study were categorized into four groups by mean level of ben- zene during the month before phlebotomy (controls, <1 ppm, 1 to <10 ppm, and ≥10 ppm). More than 100 of the exposed workers had exposures below 1 ppm. In the <1 ppm, 1 to <10 ppm, and ≥10 ppm exposure groups, WBC counts de- creased. The authors contend that these data show evidence of hematotoxic effects at <1 ppm, but the WBC, granulocyte, lymphocyte, CD4 and CD8 T-cell, B-cell, NK-cell, monocyte, and platelet counts for the <1-ppm and 1 to <10-ppm groups are still in a range that would be considered normal. NASA contends that the 1-ppm threshold appears to be at worst a marginal lowest-observed- adverse-effect level (LOAEL) for hematotoxicity (Lan et al. 2004). The amount of hemoglobin (grams/deciliter) remained unchanged in these two exposure groups as well. This observation is bolstered by Lamm and Grunwald (2006), who pub- lished a response to the Lan et. al (2004) study in which they agreed with hema- totoxicity data at >10 ppm, but their data do not show consistent evidence of hematotoxicity at lower concentrations. Lamm and Grunwald (2006) specifi- cally stated that the Lan et al. (2004) study showed a monotonically increasing effect only for platelets and B cells but not for the measured cell lines that might be expected to lead to myeloid leukemic lines; WBC counts and granulocyte counts that showed a reduction in cell number at <1 ppm did not show a further reduction among workers with exposures up to 10 ppm. Lamm and Grunwald (2006) presented a figure adapted from data Lan et al. (2004) supplied to them. The data were requested because Lamm and Grunwald (2006) noted that the Lan et al. (2004) article did not separate progenitor cell colony data below 10 ppm and could not demonstrate an effect below 1 ppm. Lamm and Grunwald stated that their figure shows a monotonically increasing trend only for granulocyte- macrophage colony formation, which appears at >1 ppm in the absence of erythropoietin and at <1 ppm in the presence of erythropoietin, and that neither reduction is statistically significant until the >10-ppm exposure group is consid- ered, concluding that the Lan et al. (2004) data do not support hematotoxicity at concentrations below 10 ppm. In response to Lamm and Grunwald (2006), Lan et al. (2006) remarked that a spline regression analysis of benzene exposure and WBC counts, which used the total study population from Lan et al. (2004), demonstrates an inverse
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68 SMACs for Selected Airborne Contaminants relationship with a slope that was significantly less than zero for every point between 0.2 and 15 ppm and finds no apparent threshold within this occupa- tional range. Lan et al. (2006) showed a figure of this spline analysis, which displays solely the regression line and confidence limits without the actual data points. The figure presented by Lan et al. (2006) does not provide enough data to identify potential thresholds or breakpoints in the relationship. Also in response to the assertions of Lamm and Grunwald (2006), Kim et al. (2006) published metabolite production data (also from the Qu, Lan, and Vermeulen China study) in which 13 groups of 30 workers were distinguished by their benzene exposures (median concentrations about 1.2 ppm). Kim et al. (2006) found that the urine concentration of each measured metabolite (phenol, E,E-muconic acid, hydroquinone, and catechol as well as the minor metabolite S-phenylmercapturic acid) was elevated at or above air concentrations of 0.2 ppm for E,E-muconic acid and S-phenylmercapturic acid, 0.5 ppm for phenol and hydroquinone, and 2 ppm for catechol. They concluded that at benzene con- centrations less than 1 ppm, metabolism favors production of the toxic metabo- lites hydroquinone and E,E-muconic acid. A study by Shen et al. (2006) reported an association between total counts of WBCs, granulocytes, lymphocytes, B cells, and platelets (hematotoxicity) and the cohort’s benzene exposure that occurred in the preceding month (mean about 5 ppm). These investigators performed a follow-up study on the cohort used by Lan et al. (2004). Their study population included the same 250 workers who were exposed to benzene in two shoe manufacturing factories and 140 unex- posed controls from comparable populations who worked in three Chinese cloth- ing manufacturing factories. The exposed group had a mean benzene air concen- tration of 5 ppm in the month before phlebotomy. Total WBC counts were lower in the exposed group than in the unexposed controls. An association was re- ported between total counts of WBCs, granulocytes, lymphocytes, B cells, and platelets (hematotoxicity) and the cohort’s benzene exposure that occurred in the preceding month. Four single nucleotide polymorphisms were associated with decreased WBCs in the benzene-exposed workers. The NRC Committee on Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants (NRC 2008) recently selected the point of departure from the Shen et al. (2006) study for derivation of the 90-d continuous exposure guidance level—specifically, 0.2 ppm. The mean value of about 5 ppm reported by Shen et al. (2006) was used as a LOAEL for hematologic effects relevant for submariners. The original 180-d SMAC was set based on the following logic (James and Kaplan 1996). A survey of nine estimates of the leukemogenic potency of benzene in humans was summarized in a single table with calculations for 6 months of continuous exposure (180 d). The predictions ranged from 0.2 to 2.2 ppm for the various risk estimate methods. The lowest estimate was based on the work of Infante and White (1985) from an epidemiologic study of benzene- exposed workers. We selected this lowest value as our point of departure. We noted that radiation exposure in space is typically elevated, so we placed a factor
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69 Benzene of 3 on this to compensate for the likelihood that the radiation and benzene are known leukemogens. Thus, the 180-d SMAC was determined to be 0.2/3 = 0.07 ppm. PROPOSED 1,000-d AC NASA will base the 1,000-d AC calculations on the Shen et al. (2006) study of WBC reductions and polymorphisms in the same occupational group studied by Lan et al (2004). Shen et al. (2006) showed a LOAEL of 5 ppm for hematologic effects. Therefore, NASA will calculate the 1,000-d AC using 5 ppm as a LOAEL, with the following adjustment factors: 10 for LOAEL to NOAEL, 3 for variability among humans as reported by Shen et al. (2006), and 3 for spaceflight risk for anemia. These adjustments result in a 1,000-d AC of 0.06 ppm. 1,000-d AC = 5 ppm (LOAEL) × 1/10 (LOAEL to NOAEL) × 1/3 (interindividual variability) × 1/3 (spaceflight anemia) = 0.06 ppm NASA will base the 1,000-d SMAC on an extrapolation of the 180-d SMAC set to protect against the risk of leukemia. The 180-d AC will be time adjusted to 1,000 d, resulting in an AC of 0.013 ppm. 1,000-d SMAC = 0.07 ppm (180-d SMAC) × 180d/1,000 d (time adjustment) = 0.013 ppm (0.04 mg/m3) CONCLUSIONS The NASA AC is conservative compared with the benzene exposure rec- ommendations set by other organizations (see Table 4-2). We are confident, after a review of the literature since our original AC publication, that NASA’s SMACs are fully protective of astronaut crews during missions of short- and long-term duration. TABLE 4-2 Exposure Limits Set by Other Organizations Recommended Exposure Level, ppma Reference Organization, Standard OSHA NIOSH 2005 PEL, 8-h TWA 1 ATSDR ATSDR 1992 PEL, STEL 5 Action level TWA 0.5 (Continued)
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70 SMACs for Selected Airborne Contaminants TABLE 4-2 Continued Recommended Exposure Level, ppma Reference Organization, Standard ACGIH ATSDR 1992 TWA, 8 h 0.5 STEL, 15-min ceiling 2.5 NIOSH NIOSH 2005 10-h TWA (advisory) 0.1 STEL, 15-min ceiling 1 IDLH 500 NRC NRC 2008 EEGL, 1 h 40 EEGL, 24 h 3 CEGL, 90 d 0.2 NASA SMAC, 1 h 10 James and Kaplan 1996 SMAC, 24 h 3 SMAC, 7 d 0.5 SMAC, 30 d 0.1 SMAC, 180 d 0.07 SMAC, 1,000 d (proposed) 0.013 a Conversion factors at 25°C, 1 atm: 1 ppm = 3.26 mg/m3; 1 mg/m3 = 0.31 ppm. Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; ATSDR, Agency for Toxic Substances and Disease Registry; CEGL, continuous expo- sure guidance level; EEGL, emergency exposure guidance level; IDLH, immediately dangerous to life and health; NASA, National Aeronautics and Space Administration; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible expo- sure limit; STEL, short-term exposure limit; TWA, time-weighted average; SMAC, Spacecraft Maximum Allowable Concentration. REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry). 1992. Benzene Toxicity Standards and Regulations. Case Studies in Environmental Medicine (CSEM). Course: SS3039. U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry [online]. Available: http://www.atsdr. cdc.gov/HEC/CSEM/benzene/standards_regulations.html [accessed April 11, 2008]. Dempster, A.M., H.L. Evans, and C.A. Snyder. 1984. The temporal relationship between behavioral and hematological effects of inhaled benzene. Toxicol. Appl. Pharma- col. 76(1):195-203 (as cited in James and Kaplan 1996). Green, J.D., C.A. Snyder, J. LoBue, B.D. Goldstein, and R.E. Albert. 1981a. Acute and chronic dose/response effects of inhaled benzene on multipotential hematopoietic stem (CFU-S) and granulocyte/macrophage progenitor (GM-CFU-C) cells in CD-1 mice. Toxicol. Appl. Pharmacol. 58(3):492-503 (as cited in James and Kaplan 1996). Green, J.D., C.A. Snyder, J. LoBue, B.D. Goldstein, and R.E. Albert. 1981b. Acute and chronic dose/response effect of benzene inhalation on the peripheral blood, bone
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72 SMACs for Selected Airborne Contaminants Rothman, N., M.T. Smith, R.B. Hayes, R.D. Traver, B. Hoener, S. Camplemen, G.L. Li, M. Dosemeci, M. Linet, L. Zhang, L. Xi, S. Wacholder, W. Lu, K.B. Meyer, N. Titenko-Holland, J.T. Stewart, S. Yin, and D. Ross. 1997. Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C→T mutation and rapid fractional excretion of chlorzoxazone. Cancer Res. 57(14):2839-2842. Shen, M., Q. Lan, L. Zhang, S. Chanock, G. Li, R. Vermeulen, S.M. Rappaport, W. Guo, R.B. Hayes, M. Linet, S. Yin, M. Yeager, R. Welch, M.S. Forrest, N. Rothman, and M.T. Smith. 2006. Polymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity. Car- cinogenesis 27(10):2083-2089. Taylor, G.R. 1993. Immune changes during short-duration missions. J. Leukoc. Biol. 54(3):202-208 (as cited in James and Kaplan 1996). Toft, K., T. Olofsson, A. Tunek, and M. Berlin. 1982. Toxic effects on mouse marrow caused by inhalation of benzene. Arch. Toxicol. 51:295-302 (as cited in James and Kaplan 1996). Vermeulen, R., G. Li, Q. Lan, M. Dosemeci, S.M. Rappaport, X. Bohong, M.T. Smith, L. Zhang, R.B. Hayes, M. Linet, R. Mu, L. Wang, J. Xu, S. Yin, and N. Rothman. 2004. Detailed exposure assessment for a molecular epidemiology study of ben- zene in two shoe factories in China. Ann. Occup. Hyg. 48(2):105-116. Yin, S.N., Q. Li, Y. Liu, F. Tian, C. Du, and C. Jin. 1987. Occupational exposure to ben- zene in China. Br. J. Ind. Med. 44(3):192-195.