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--> B2 Benzene John T. James, Ph.D., and Harold L. Kaplan, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch Houston, Texas Physical and Chemical Properties Benzene is a clear, colorless, highly flammable liquid with an odor characteristic of aromatic hydrocarbons (Sandmeyer, 1981; ATSDR, 1989). The odor threshold is 4-5 ppm (ATSDR, 1989). Synonym: Benzol Chemical structure: Formula: C6H6 CAS number: 71-43-2 Molecular weight: 78.11 Boiling point: 80.1 °C Melting point: 5.5°C Specific gravity: 0.88 (20°C) Vapor pressure: 95 torr (25°C) Solubility: Slightly soluble in water, very soluble in organic solvents Conversion factors at 25°C, 1 atm: 1 ppm = 3.26 mg/m3 1 mg/m3 = 0.31 ppm
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--> Occurrence and Use Benzene is a natural constituent of crude oil, coal tar, and other fossil fuels (Sandmeyer, 1981). Most of the millions of gallons of benzene that are used in the United States each year are produced by petroleum refining. A major use of benzene is as a component in gasoline, particularly in unleaded fuels, because of its antiknock properties (ATSDR, 1989). Its content in gasoline is estimated to range from 1% to 2% in the United States and up to 5% in European countries. Large quantities are also used to synthesize chemicals for the manufacture of various plastics, resins, elastomers, dyes, and pesticides (Marcus, 1987). Minimal amounts are now used as a solvent in paints, cements, adhesives, and paint removers. Sources of atmospheric contamination include fugitive emissions from gasoline handling, thermal degradation of plastics, solid waste gasification, and tobacco smoke (Sandmeyer, 1981; Marcus, 1987). Benzene has been detected in approximately 10% of recent air samples in the space-shuttle cabin and in Spacelab at concentrations of 0.01-0.1 mg/m3 (James et al., 1994). Benzene has not been used as a payload or system chemical aboard the space shuttle; hence, the low concentrations observed are due to materials out-gassing. Benzene has been found as a pyrolysis product of electronic components identical to ones that failed in data-display units aboard STS-35 (J. Boyd, NASA, unpublished data). Pharmacokinetics and Metabolism Absorption In humans, benzene vapor is rapidly absorbed by the lungs in amounts equivalent to about 50% of the doses inhaled over several hours of exposure to concentrations of 50-100 ppm (Nomiyama and Nomiyama, 1974a,b; Sato and Nakajima, 1979; R. Snyder et al., 1981; IARC, 1982). In men and women exposed to 52-62 ppm for 4 h, respiratory uptake was 47%, with little difference between the sexes (Nomiyama and Nomiyama, 1974a,b; IARC, 1982). Absorption was greatest during the first 5 min of exposure and reached a constant level
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--> between 15 min (Srbova et al., 1950) and 3 h (Nomiyama and Nomiyama, 1974a,b; IARC, 1982). Respiratory retention (the difference between respiratory uptake and excretion) was estimated as 30% of the inhaled dose (Nomiyama and Nomiyama, 1974a,b; IARC, 1982). Benzene can also be absorbed through the skin, but the rate of absorption is lower than that for inhalation exposure (ATSDR, 1989). It has been calculated that an adult working in ambient air containing benzene at 10 ppm would absorb 7.5 µL/h from inhalation versus 1.5 µL/h from whole-body dermal absorption (Blank and McAuliffe, 1985). Absorption of benzene vapor by animals also is rapid, but retention of absorbed benzene might be affected by exposure concentration. In rats and mice, the percentage of inhaled vapor that was retained decreased from 33% to 15% during a 6-h exposure and from 50% to 10%, respectively, as the concentration was increased from approximately 10 ppm to 1000 ppm (Sabourin et al., 1987). Distribution Once benzene is absorbed into the blood, it is rapidly distributed to tissues; the relative uptake is dependent on the perfusion rate of tissues (ATSDR, 1989). Because of its high lipophilicity, benzene tends to accumulate in fatty tissues. In experimental human exposures, lower blood concentrations and slower elimination in females than in males were attributed primarily to relatively higher fat content of females (Sato et al., 1975). Tissue levels of benzene in accidental- or intentional-exposure victims are variable but generally indicate higher concentrations in brain, fat, and liver (Winek et al., 1967; Winek and Collom, 1971). About 60% of the absorbed benzene was found in bone marrow, adipose tissue, and liver of humans exposed to unspecified concentrations (Duvoir et al., 1946). Distribution of benzene in animals also is rapid; the relative uptake and accumulation in tissues appear to be dependent on perfusion rate and lipid content (Schrenk et al., 1941; Ghantous and Danielsson, 1986). Following a 10-min inhalation exposure of mice, benzene was present in well-perfused tissues, such as liver and kidney, and in lipid-rich tissues, such as brain and fat (Ghantous and Danielsson, 1986). In rats exposed to 500 ppm, steady-state concentrations were highest in
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--> fat, bone marrow, and blood (15:5.5:1 ratio) and lower in kidney, lung, liver, brain, and spleen (Rickett et al., 1979). Female rats and male rats with large body fat content stored benzene longer and eliminated it more slowly than lean animals (Sato et al., 1974). Excretion Following inhalation, benzene is eliminated from the body by humans and animals in unchanged form in the exhaled air and in metabolized form in the urine (ATSDR, 1989). Estimates of the fraction of absorbed benzene excreted in the expired air of humans range from 12% to 50% (Srbova et al., 1950; Teisinger et al., 1952; Nomiyama and Nomiyama, 1974a,b; IARC, 1982). The respiratory elimination is described as triphasic-an initial fast component having a half-life of 0.9 h and two slower components having half-lives of 3 and 15 h, respectively (Nomiyama and Nomiyama, 1974a,b; IARC, 1982). No differences in respiratory elimination were observed between men and women (Nomiyama and Nomiyama, 1974a,b; IARC, 1982). In rats exposed to 500 ppm for 6 h, a biphasic pattern of respiratory elimination of benzene was observed, with half-lives of 0.7 and 13.1 h (Rickert et al., 1979). Respiratory elimination might be increased as a result of saturation of metabolic pathways by high doses of benzene. At lower concentrations (10-130 ppm), less than 6% of inhaled 14C-benzene was exhaled by rats and mice, whereas at concentrations of 260 and 870 ppm (rats) and 990 ppm (mice), exhaled radioactivity increased from 11% to 48% (Sabourin et al., 1987). Metabolism The metabolism of benzene is complex and not completely elucidated. It is well established that most of the absorbed benzene is metabolized through a variety of major and minor pathways in humans and animals and excreted as metabolites in the urine (Snyder, 1987). The major site of metabolism is the liver, although mixed-function oxidases that catalyze the oxidation of benzene also occur in bone marrow, the target organ of benzene toxicity (Snyder, 1987). Benzene is
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--> metabolized mostly by oxidation to the major metabolites—phenol, catechol, and hydroquinone, which are excreted in the urine as sulfate and glucuronide conjugates (Snyder, 1987). Many minor metabolites also are formed, of which phenylmercapturic acid and trans, trans-muconic acid are the most important. In the initial metabolic step, benzene is thought to be oxidized by hepatic microsomal mixed-function oxidase to a reactive intermediate, benzene oxide (Erexson et al., 1985; Yardley-Jones et al., 1991). Most of the benzene oxide rearranges spontaneously to phenol. Phenol is mostly conjugated and excreted as sulfate ester and glucuronide, but some can be further oxidized to catechol and hydroquinone (Erexson et al., 1985; ATSDR, 1989). The latter compound spontaneously oxidizes to form 1,4-benzoquinone. The remaining benzene oxide can be conjugated with glutathione to produce phenylmercapturic acid, which is excreted in the urine, or it can be converted to benzene glycol (ATSDR, 1989; Erexson et al., 1985). The latter compound can undergo dehydrogenation to form catechol or further oxidation and ring breakage to produce trans, trans-muconic acid. Most of the catechol is conjugated and excreted, but a small amount is oxidized to the trihydroxybenzene 1,2,4-benzenetriol. In humans, the major urinary metabolite of benzene is phenol (Teisinger et al., 1952). Most of the phenol is excreted as sulfate ester (Teisinger et al., 1952), but significant amounts of glucuronide can be formed, especially after exposure to high concentrations of benzene (Sherwood, 1972). In an inhalation study with human subjects, 28.8% of the absorbed benzene was excreted in the urine as phenol, 2.9% as catechol, and 1.1 % as hydroquinone (Teisinger et al., 1952). Urinary excretion was highest within the first 24 h following exposure and was essentially complete within 48 h. In workers exposed for 7 h to benzene at 1-76 ppm, the correlation between exposure concentration and urinary phenol excretion was 0.891 (Inoue et al., 1986). A urinary phenol concentration of 75 mg/L indicates an 8-h (time-weighted average) exposure at 10 ppm (NIOSH, 1974) and a concentration of 100 mg/L indicates an 8-h exposure at 25 ppm (Sandmeyer, 1981). The ACGIH biological exposure index (BEI) for benzene exposure is a urinary concentration of phenol at 50 mg/g of creatinine at the end of a work shift, but ACGIH notes that phenol is usually present in unexposed individuals and also might result from ex-
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--> posure to other chemicals (ACGIH, 1991). Recently, S-phenylmercapturic acid in urine (Stommel et al., 1989) and benzene hemoglobin adducts in blood (Sun et al, 1990) were evaluated as possible biomarkers of benzene exposure. In a study in which radiolabeled benzene was administered to rabbits by oral intubation, 43 % of the radioactivity was recovered as exhaled, unmetabolized benzene and 1.5% was recovered as carbon dioxide (Parke and Williams, 1953). Urinary metabolites (representing 35% of the dose) were mainly in the form of phenolic sulfates and glucuronides and included phenol (23%), hydroquinone (4.8%), catechol (2.2%), trans, trans-muconic acid (1.3%), phenylmercapturic acid (0.5%), and 1,2,4-trihydroxybenzene (0.3%). This same general profile was also found in rats (Cornish and Ryan, 1965), mice (Longacre et al., 1981), and cats and dogs (Oehme, 1969). Benzene metabolism appears to be qualitatively similar but quantitatively different among species. Mice metabolized the largest fraction of benzene (67%) to hydroquinone conjugates and muconic acid metabolites, followed by monkeys (31%), rats (17%), and chimpanzees (14%) (Sabourin et al., 1992). Urinary metabolite data from workers exposed for about 7 h to benzene at 50 ppm suggest that the metabolism of benzene to hydroquinone compounds in humans is quantitatively comparable to that in mice, whereas the metabolism to muconic acid is comparable to that in rats and one-third of that in mice (Henderson et al., 1992). Metabolic pathways leading to putative toxic metabolites, such as hydroquinone and muconic acid metabolites, have been designated ''toxification pathways'' in contrast to "detoxification pathways," which lead to the less toxic metabolites, such as phenyl conjugates and phenylmercapturic acid products (Henderson et al., 1992). In mice, rats, and monkeys, the toxification pathways appear to be low-capacity, high-affinity pathways that become saturated at relatively low concentrations, resulting in proportionately less formation of hydroquinone and muconic acid at higher concentrations (Henderson et al., 1992). Stimulation or inhibition of hepatic mixed-function oxidase activity by benzene, other chemicals, or dietary factors might alter the rate of metabolism of benzene. Exposure of mice to benzene enhanced the in vitro metabolism of benzene by hepatic microsomes from these animals, but exposure to phenolic metabolites did not (Dean, 1978; Gonasun et
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--> al., 1973). In contrast, repeated inhalation exposure of mice and rats to benzene at 600 ppm for 6 h/d, 5 d/w, for 3 w had minimal effects on urinary metabolite profiles (Sabourin et al., 1990). Ethanol ingestion as well as food deprivation and carbohydrate restriction enhanced the metabolism of benzene in rats (Sato and Nakajima, 1985). Three physiologically based pharmacokinetic (PBPK) models were recently proposed to describe the pharmacokinetics and metabolism of benzene in animals (Medinsky et al., 1989; Woodruff et al., 1989; Travis et al., 1990). The models are herein arbitrarily referred to by the name of the first author as the Medinsky model (Medinsky et al., 1989), the Travis model (Travis et al., 1990), and the Woodruff model (Woodruff et al., 1989). The Medinsky model was adjusted to data obtained experimentally with mice and rats (Medinsky et al., 1989), the Travis model with data on mice, rats, and humans (Travis et al., 1990), and the Woodruff model with data on rats (Woodruff et al., 1989). The models have similar structures but differ in the parameter values used for the same species. In a comparison and evaluation of the models, the investigators concluded that PBPK models are useful for investigating the mechanism of toxicity of benzene but not for risk assessment of cancer (Bois et al., 1991). Toxicity Summary Acute and Short-Term Toxicity Neurotoxicity In humans, acute inhalation of benzene produces CNS effects, including euphoria, giddiness, nausea and drowsiness at lower concentrations, and ataxia, narcosis, delirium, convulsions, unconsciousness, and even death at high concentrations (Sandmeyer, 1981). Recovery is usually rapid, but, in some cases, symptoms have persisted for weeks. The symptoms, and their severity, vary with concentration and duration of exposure. It is estimated (without supporting data) that exposure at 25 ppm for 8 h has no effects; 50-150 ppm for 5 h produces headache, lassitude, and weakness, symptoms that are exaggerated at 500 ppm; 3000 ppm for 0.5-1.0 h can be tolerated; 7500 ppm for 30 min is
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--> dangerous to life; and 19,000-20,000 ppm can be fatal in 5-10 min (Gerarde, 1962; Von Oettingen, 1940). The rapid development of CNS effects, including death in some cases, suggests that benzene, not a metabolite, is responsible for the acute toxicity and that the cause of sudden death is asphyxiation, respiratory arrest, CNS depression, or cardiac arrhythmia (Sandmeyer, 1981). Acute inhalation exposure to benzene also causes CNS effects in animals. In mice, exposure at 2200 ppm produced narcosis, and at 4600 ppm and 11,800 ppm produced narcosis in 51 min and 8 min, respectively (Von Oettingen, 1940). At 11,800 ppm, deaths occurred in 38295 min, and at 24,000 ppm, deaths occurred in 50 min. About 4000 ppm was the narcotic concentration threshold for laboratory animals, and more than 10,000 ppm was fatal after several hours of exposure (Leong, 1977). At 35,000-45,000 ppm, anesthesia occurred in about 4 min, with excitation and tremors after 5 min, loss of pupillary reflexes after 6.5 min, involuntary blinking after 15 min, and death after 22-71 min (Carpenter, et al., 1944). Lethality data of rats confirm the low potential for benzene to cause death via inhalation. A 4-h exposure at 16,000 ppm resulted in the deaths of four of six rats (Smyth et al., 1962). An LC50 value of 13,700 ppm was determined for a 4-h exposure of rats (Drew and Fouts, 1974). Respiratory paralysis followed by ventricular fibrillation was observed in male rats exposed to lethal concentrations (Sandmeyer, 1981). A limited number of animal studies measured electroencephalographic and behavioral changes to investigate the CNS effects of benzene. In cats, exposure to benzene at a concentration of 12,000 ppm for 10 min caused restlessness, rapid respiration, and head nodding, accompanied by hypersynchronous amygdaloid EEG activity (Contreras et al., 1979). Ataxia and postural collapse occurred when concentrations were increased to 52,000 ppm. With repeated daily 10-min exposures, a 3-Hz spike-wave activity in the gyrus cinguli developed and generalized tonic-clonic seizures developed after a sensitization period. Behavioral disturbances, characterized by increased milk-licking, were evident in C57BL mice after the first week of exposure to 100 or 300 ppm (Dempster et al., 1984). Less sensitive parameters, home-cage food intake and hind-limb grip strength, were reduced at 1000 and 3000 ppm, but not at 100 or 300 ppm, even when exposure durations were adjusted to yield a minimum Ct (concentration x time) product of 3000 ppm.
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--> Cardiac Sensitization Acute inhalation of high concentrations of benzene by cats and monkeys induced ventricular dysrhythmias, which were abolished by removal of the adrenals and the stellate ganglia, and were restored by injections of epinephrine (Nahum and Hoff, 1934). The effects were attributed to the sensitization of the myocardium to epinephrine by benzene. In Wistar rats, previous inhalation of benzene at 3000 and 7000 ppm, but not at 1500 ppm, for 15 min increased the number of ectopic ventricular beats induced by coronary ligation or intravenous administration of aconitine (Magos et al., 1990). With an increased dose of aconitine, ventricular fibrillation developed rapidly at 7000 ppm, and progressed to asystole and death after 16 min. Hematotoxicity and Immunotoxicity Although benzene-induced hematotoxicity and immunotoxicity are generally associated with prolonged exposure, abnormal hematological parameters have been observed in some workers exposed to low concentrations for short periods (ATSDR, 1989). These observations are consistent with the results of animal studies showing hematological changes after short-term, and even acute, exposures. After an 8-h inhalation exposure of mice to 4680 ppm, a significant depletion of bone-marrow colony-forming cells was evident in an in vitro cell culture (Uyeki et al., 1977). In mice, continuous exposure at 100 ppm for 2 d produced leukocytopenia (Gill et al., 1980) and a 1-w exposure (6 h/d, 5 d/w) at 300 ppm decreased peripheral blood erythrocyte and lymphocyte counts (Snyder et al., 1978). Continuous exposure of NMRI mice at a concentration of 21 ppm for 4-10 d significantly decreased cellularity (number of nucleated cells) and colony-forming granulopoietic stem cells (CFU-C) in tibia bone marrow (Toft et al., 1982). Intermittent exposure (8 h/d, 5 d/w) for 2 w at 21 ppm reduced the number of CFU-C cells. In female Wistar rats exposed 8 h/d for 7 d, peripheral leukocyte counts were depressed significantly after exposures at 50-300 ppm but not at 20 ppm (Li et al., 1986). Leukocyte alkaline phosphatase (LAP) concentrations were significantly increased at 300 ppm, marginally increased at 100 ppm, and not affected at 20 or 50 ppm.
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--> Short-term exposures of animals at low concentrations might produce hematological changes that can affect immune-associated processes. In male C57BL mice exposed at 10 ppm for 6 h/d for 6 d, femoral lipopolysaccharide (LPS)-induced B-lymphocyte-colony-forming ability was significantly depressed, but total numbers of B lymphocytes were not (Rozen et al., 1984). At 30 ppm, splenic phytohemagglutinin (PHA)-induced blastogenesis was significantly depressed, but there was no concomitant significant depression in numbers of T lymphocytes. After six exposures at 300 ppm, mitogen-induced proliferation of bone marrow and splenic B and T lymphocytes was depressed, and numbers of T lymphocytes in thymus and spleen were reduced (Rozen and Snyder, 1985). Genotoxicity Benzene is not mutagenic in most in vitro test systems, including both Salmonella typhimurium (five strains) and Saccharomyces cerevisiae with and without metabolic activation, Drosophila melanogaster, mouse lymphoma cells, various human, mouse, and Chinese hamster cells, and others (ATSDR, 1989; Marcus, 1987). In vitro studies of chromosomal aberrations and other genotoxic effects of benzene yielded positive, negative, or mixed results, depending on the end point and test system. Positive results were obtained in studies of DNA binding in rabbit bone marrow and rat liver mitoblasts; negative results were obtained in studies of DNA breaks in rat hepatocytes, Chinese hamster V79 cells, and mouse L5178Y cells; and mixed results were obtained in studies of chromosomal aberrations and sister chromatid exchange (SCE) in human lymphocytes (ATSDR, 1989). Benzene did not increase SCE frequency in human lymphocytes stimulated by phytohemagglutinin (Morimoto and Wolff, 1980) or in human lymphocytes incubated without rat liver S-9 (Morimoto, 1983). Delaying addition of benzene, however, to 24 h after mitogen stimulation produced significant concentration-related increases in SCE frequency, decreases in mitotic indices, and inhibition of cell-cycle kinetics without S-9 (Erexson et al., 1985). In contrast to in vitro results, benzene-induced cytogenetic effects,
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--> including chromosomal and chromatid aberrations, SCE, and micronuclei, were consistently found in in vivo animal studies (ATSDR, 1989). Acute inhalation studies have shown cytogenetic effects in animals, even at low exposure concentrations. Exposure of mice at 10 ppm for 6 h induced SCE in peripheral blood lymphocytes and bone marrow as well as micronuclei in bone-marrow polychromatic erythrocytes (Erexson et al., 1985). Exposure of DBA/2 mice at 3100 ppm for 4 h significantly increased SCE frequency in bone-marrow cells in both sexes and inhibited marrow cellular proliferation in males only, but did not affect the frequency of chromosomal aberrations (Tice et al., 1980). Subchronic and Chronic Toxicity Prolonged inhalation of benzene by humans can result in CNS, hematotoxic, myelotoxic, immunotoxic, genotoxic, or carcinogenic effects. These effects are well established for chronic exposure, but less is known about some of these effects as a result of subchronic exposure. Limited information exists on the potential of benzene to cause adverse effects on reproductive function and pre-and postnatal development in humans. Neurotoxicity Involvement of the CNS might be an important effect of chronic inhalation exposure of humans and animals to benzene, but it can be masked by other more-visible effects (Sandmeyer, 1981). Workers exposed even to low concentrations (e.g., 50 ppm) reported symptoms of headaches, dizziness, fatigue, anorexia, dyspnea, and visual disturbances (Sandmeyer, 1981). Some workers also exhibited signs of CNS lesions, such as abnormal caloric labyrinth irritability and impairment of hearing. Although there are reports of polyneuritis associated with exposure to benzene, other chemicals were also involved (Sandmeyer, 1981). Exposure of rats for 5.5 mo to 20 ppm resulted in a delay in conditioned reflex response time; however, the effect was not seen at 4 ppm (Novikov, 1956).
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--> Guberan, E., and P. Kocher. 1971. Pronostic lointain de l'intoxication benzolique chronique: Controle d'une population 10 ans apres l'exposition. Schweiz Med. Worchenscher 101:1789-1790. Harigaya, K., M.E. Miller, E.P. Cronkite, and R.T. Drew. 1981. The detection of in vivo hematotoxicity of benzene by in vitro liquid bone marrow cultures. Toxicol. Appl. Pharmacol. 60:346-353. Hirokawa, T., and K. Nomiyama. 1962. Studies on the poisoning by benzene and its homologues: Oxidation rate of benzene in the rat liver homogenate. Med. J. Shinshu Univ. 7:29-39. Henderson, R.F., P.J. Sabourin, M.A. Medinsky, L.S. Birnbaum, and G.L. Lucier. 1992. Benzene dosimetry in experimental animals: Relevance for risk assessment. Pp. 93-105 in Relevance of Animal Studies to the Evaluation of Human Cancer Risk. New York: Wiley-Liss. Huff, J.E., W. Eastin, J. Roycroft, S.L. Eustis, and J.K. Haseman. 1988. Carcinogenesis studies of benzene, methyl benzene, and dimethyl benzenes. Ann. N.Y. Acad. Sci. 534:427-440. IARC. 1982. International Agency for Research on Cancer. Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Some industrial chemicals and dyestuffs. IARC Monogr. Eval. Carcinog. Risk Chem. Man. 29:93-148. Ikeda, M., and H. Ohtsuji. 1971. Phenobarbital-induced protection against toxicity of toluene and benzene in the rat. Toxicol. Appl. Pharmacol. 20:30-43. Infante, P.F. 1978. Leukemia among workers exposed to benzene. Tox. Rep. Biol. Med. 37:153-161. Infante, P.F. 1992. Benzene and leukemia: The 0.1 ppm ACGIH proposed threshold limit value for benzene. Appl. Occup. Environ. Hyg. 7:253-262. Infante, P.F., and M.C. White. 1985. Projections of leukemia risk associated with occupational exposure to benzene. Am. J. Ind. Med. 7:403-413. Infante, P.F., R.A. Rinsky, J.K. Waggoner, and R.J. Young. 1977. Leukemia in benzene workers. Lancet. ii: 76-78. Inoue, O.K., K. Seiji, and M. Kasahira. 1986. Quantitative relation of urinary phenol levels to breath zone benzene concentrations: A factory survey. Br. J. Ind. Med. 43:692-697. Irons, R.D., and D.A. Neptun. 1980. Effects of the principal hy-
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--> droxy-metabolites of benzene on microtubule polymerization. Arch. Toxicol. 45:297-305. Irons, R.D., D. Wierda, and R.W. Pfeifer. 1982. The immunotoxicity of benzene and its metabolites. Pp. 37-50 in Carcinogenicity and Toxicity of Benzene, M.A. Mehlman, ed. Princeton, N.J.: Princeton Scientific. James, J.T., T.F. Limero, H.J. Leano, J.F. Boyd, and P.A. Covington. 1994. Volatile organic contaminants found in the habitable environment of the space shuttle: STS-26 to STS-55. Aviat. Space Environ. Med. 65:851-857. Kalf, G.F., T. Rushmore, and R. Snyder. 1982. Benzene inhibits RNA synthesis in mitochondria from liver and bone marrow. Chem. Biol. Interact. 42:353-370. Kalf, G.F., G.B. Post, and R. Snyder. 1987. Solvent toxicology: Recent advances in the toxicology of benzene, the glycol ethers, and carbon tetrachloride. Annu. Rev. Pharmacol. Toxicol. 27:399-427. Keller, K.A., and C.A. Snyder. 1986. Mice exposed in utero to low concentrations of benzene exhibit enduring changes in their colony forming hematopoietic cells. Toxicology 42:171-181. Kline, S., J. Forbes-Robertson, V. Lee-Grotz, B.D. Goldstein, and G. Witz. 1993. Identification of 6-hydroxy-trans, trans-2,4-hexadienoic acid, a novel ring-opened urinary metabolite of benzene. Environ. Health Perspect. 101:310-312. Lange, A., R. Smolik, W. Zatonski, and J. Szymanska. 1973. Serum immunoglobulin levels in workers exposed to benzene, toluene and xylene. Int. Arch. Arbeitsmed. 31:37-44. Leong, B.K. 1977. Experimental benzene intoxication. J. Toxicol. Environ. Health Suppl. 2:45-61. Lesnyak, A.T., G. Sonnenfeld, M.P. Rykova, D.O. Meshkov, A. Mastro, and I. Konstantinova. 1993. Immune changes in test animals during space flight. J. Leuk. Biol. 54:214-226. Li, G.L., N. Yin, and T. Watanabe. 1986. Benzene-specific increase in leukocyte alkaline phosphatase activity in rats exposed to vapors of various organic solvents. J. Toxicol. Environ. Health. 19:581-589. Longacre, S., J. Kocsis, and R. Snyder. 1981. Influence of strain differences in mice on the metabolism and toxicity of benzene. Toxicol. Appl. Pharmacol. 60:398-409. Luke, C.A., R.R. Tice, and R.T. Drew. 1988a. The effect of expo-
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--> sure regimen and duration on benzene-induced bone marrow damage in mice. II. Strain comparisons involving B6C3F1, C57B1/6 and DBA/2 male mice. Mutat. Res. 203:273-295. Luke, C.A., R.R. Tice, and R.T. Drew. 1988b. The effect of exposure regimen and duration on benzene-induced bone marrow damage in mice. I. Sex comparison in DBA/2 mice. Mutat. Res. 203:251-271. Lutz, W.K., and C.H. Schlatter. 1977. Mechanism of the carcinogenic action of benzene: Irreversible binding to rat liver DNA. Chem. Biol. Interact. 18:241-245. Marcus, W.L. 1987. Chemical of current interest-Benzene. Toxicol. Ind. Health 3:205-266. Magos, G.A., M. Lorenzana-Jimenez, and H. Vidrio. 1990. Toluene and benzene inhalation influences on ventricular arrhythmias in the rat. Neurotoxicol. Teratol. 12:119-124. Maltoni, C., A. Ciliberti, G. Cotti, B. Conti, and F. Belpoggi. 1989. Benzene, an experimental multipotential carcinogen: Results of the long-term bioassays performed at the Bologna Institute of Oncology. Environ. Health Perspect. 82:109-124. Medinsky, M.A., P.J. Sabourin, G. Lucier, L.S. Birnbaum, and R.F. Henderson. 1989. A physiological model for simulation of benzene metabolism by rats and mice. Toxicol. Appl. Pharmacol. 99:193-206. Michon, S. 1965. Disturbances of menstruation in women working in an atmosphere polluted with aromatic hydrocarbons. Pol. Tig. Lek. 20:1648-1649. Morimoto, K. 1983. Induction of sister chromatid exchanges and cell cycle division delays in human lymphocytes by microsomal activation of benzene. Cancer Res. 43:1330-1334. Morimoto, K., and S. Wolff. 1980. Increase of sister chromatid exchanges and cell cycle perturbations of cell division kinetics in human lymphocytes by benzene metabolites. Cancer Res. 40:1189-1193. Mukhametova, I.M., and M.A. Vozovaya. 1972. Reproductive power and the incidence of gynecological disorders in female workers exposed to the combined effect of benzene and chlorinated hydrocarbons. Gig. Tr. Prof. Zabol. 16:6-9.
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--> Murray, F.J., J.A. John, L.W. Rampy, R.A. Kuna, and B.A. Schwetz. 1979. Embryotoxicity of inhaled benzene in mice and rabbits. Am. Ind. Hyg. Assoc. J. 40:993-998. Nahum, L.H., and H.E. Hoff. 1934. The mechanism of sudden death in experimental acute benzol poisoning. J. Pharmacol. Exp. Ther. 50:336-345. NIOSH. 1974. Criteria for a Recommended Standard . . . Occupational Exposure to Benzene. National Institute for Occupational Safe ty and Health, Department of Health, Education and Welfare. NIOSH-74-137. National Institute for Occupational Safety and Health, Cincinnati, Ohio. NIOSH. 1977. Revised Recommendation for an Occupational Exposure Standard for Benzene. National Institute for Occupational Safety and Health, Cincinnati, Ohio. Nomiyama, K., and H. Nomiyama. 1974a. Respiratory retention, uptake and excretion of organic solvents in man. Benzene, toluene, n-hexane, trichloroethylene, acetone, ethyl acetate and ethyl alcohol. Int. Arch. Arbeitsmed. 32:75-83. Nomiyama, K., and H. Nomiyama. 1974b. Respiratory elimination of organic solvents in man. Benzene, toluene, n-hexane, trichloroethylene, acetone, ethyl acetate and ethyl alcohol. Int. Arch. Arbeitsmed. 32:85-91. Novikov, Y.V. 1956. Effects of small benzene concentrations on higher nervous activity of animals in chronic experiments. Gig. Sanit. 21:20. NRC. 1986. Emergency and Continuous Exposure Guidance Levels for Selected Airborne Contaminants. Benzene and Ethylene Oxide, Vol. 6. Washington, D.C.: National Academy Press. NRC. 1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Washington, D.C.: National Academy Press. Oehme, F. 1969. Ph.D. thesis. Comparative Study of the Biotransformation and Excretion of Phenol. Columbia: University of Missouri. 207 pp. Ott, M.G., J.C. Townsend, W.A. Fishbeck, and R.A. Langner. 1978. Mortality among workers occupationally exposed to benzene. Arch. Environ. Health 33:3-10.
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