Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 45
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 2 Benzene Noreen N. Khan-Mayberry, Ph.D. and John T. James, Ph.D., DABT Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Benzene is a colorless liquid aromatic hydrocarbon. It is readily soluble in water and has a smell similar to aromatic hydrocarbons. Its odor threshold is 4 to 5 parts per million (ppm) (ATDSR 1989). Its physical and chemical properties are shown in Table 2-1. TABLE 2-1 Physical and Chemical Properties of Benzene Synonym Benzol, benzole 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 mm Hg (25°C) Solubility Slightly soluble in water, very soluble in organic solvents Conversion 1 ppm = 3.19 mg/m3; 1 mg/m3 = 0.31 ppm
OCR for page 46
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 OCCURRENCE AND USE Benzene is a clear liquid with a sweet odor, according to the Hazardous Substance Data Bank (HSDB 2005). This aromatic hydrocarbon is used as a solvent; however, its use has declined in many countries because of concerns about carcinogenicity. Benzene occurs naturally but is primarily produced from petroleum products. It is a constituent of gasoline, where it is used to enhance octane rating and as an antiknock agent (Krewski et al. 2000). Uses for benzene are numerous including as an 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 milligram per cubic meter (mg/m3) (James and Kaplan 1996). In September 2006, an overheating of the oxygen generator in the Russian segment of the International Space Station resulted in elevated concentrations of several aromatic compounds. Samples taken several hours after the incident showed a concentration of benzene in air of 0.5 mg/m3 in the U.S. segment. Benzene is typically not detected in spacecraft water samples. Consumption of benzene in the public water supply is highly unlikely; however, accidental ingestion of water from contaminated streams occurs from leaking gasoline storage tanks, landfills, and other sources (HSDB 2005). PHARMACOKINETICS AND METABOLISM Absorption Acute ingestion of benzene causes gastrointestinal and neurologic toxicity (HSDB). In humans, the lungs rapidly absorb benzene vapor in amounts equivalent to about 50% or less of the doses inhaled over several hours of exposure to concentrations of 50 to 100 ppm (Nomiyama and Nomiyama 1974a,b; Sato and Nakajima 1979; R. Snyder et al. 1981; IARC 1982; James and Kaplan 1996). In men and women exposed to 52 to 62 ppm for 4 h, respiratory uptake was 47% of the original dose, 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 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
OCR for page 47
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 that an adult working in ambient air containing benzene at 10 ppm would absorb 7.5 microliters (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 increased from approximately 10 to 1,000 ppm (Sabourin et al. 1987). Distribution Once benzene is absorbed into the blood, it is rapidly distributed to tissues; the relative uptake depends 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 the relatively higher fat content of females (Sato et al., 1975). Tissue levels of benzene in victims of accidental or intentional exposures vary but generally indicate higher concentrations in brain, fat, and liver (Winek et al. 1967; Winek and Collom 1971). In humans exposed to unspecified concentrations, about 60% of the absorbed benzene was found in bone marrow, adipose tissue, and liver (Duvoir et al. 1946). Distribution of benzene in animals also is rapid; the relative uptake and accumulation in tissues appear to depend on perfusion rate and lipid content (Schrenk et al. 1941, Ghantous and Danielsson 1986). After 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 fat, bone marrow, and blood (15:5.5:1 ratio) and lower in kidney, lung, liver, brain, and spleen (Rickert et al. 1979). Female rats and male rats with a high content of body fat stored benzene longer and eliminated it more slowly than lean animals (Sato et al. 1974). Excretion After inhalation, humans and animals eliminate benzene from the body in unchanged form in exhaled air and in metabolized form in 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 has a half-life of 0.9 h and two slower components have half-lives of 3 and 15 h, respectively (Nomiyama and Nomiyama 1974a,b; IARC 1982). No differences in respiratory elimination
OCR for page 48
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 were observed in men and women (Nomiyama and Nomiyama 1974a,b; IARC 1982). In rats exposed to 500 ppm of benzene in air 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), rats and mice exhaled less than 6% of inhaled [14C]benzene, 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 has not been 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 is excreted as metabolites in the urine (Snyder 1987). Nebert et al. (2002) described the process of benzene metabolism (see Figure 2-1). 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). Benzene oxide and oxepin are formed by cytochrome P450 2E1 (CYP2E1). Most of the benzene oxide rearranges spontaneously to phenol, which may be further metabolized by CYP2E1 to di- and trihydroxybenzenes (Nebert et al. 2002). The latter compound spontaneously oxidizes to form 1,4-benzoquinone. 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 formation of p-benzoquinone and o-benzoquinone from hydroquinone and catechol can be catalyzed by myeloperoxidase (MPO) as well as through spontaneous oxidation. MPO in the bone marrow is considered vital to benzene’s tissue-selective toxicity. MPO can convert the intermediates to highly reactive and toxic free radical semiquinones and quinones. 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 (Erexson et al. 1985, ATSDR 1989), which 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. NAD(P)H:quinone oxidoreductase catalyzes the reverse reductive reaction of benzoquinones to hydroquinone and catechol, resulting in detoxification. This reaction is seen as a protective process, whereby the tissue burden of reactive toxin is decreased, giving the conjugative enzymes an additional opportunity to
OCR for page 49
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 FIGURE 2-1 Metabolic fate of benzene. Source: Nebert et al. 2002. Reprinted with permission; copyright 2002, Genetics in Medicine. detoxify the phenol-containing intermediates. Glutathione S-transferase also plays a role in detoxification via conversion of the oxide to nontoxic S-phenylmercapturic acid. In contrast, benzene oxepin may be converted through alcohol and aldehyde dehydrogenases to the toxic metabolite trans,trans-muconaldehyde (Nebert et al. 2002). Many minor metabolites are formed in benzene metabolism, of which phenylmercapturic acid and trans,trans-muconic acid are the most important (see Figure 2-2). 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 humans, 28.8% of the absorbed benzene was excreted in urine as phenol, 2.9% as catechol, and 1.1% as hydroquinone (Teisinger et al., 1952). Urinary excretion was highest in the first 24 h after exposure and was essentially complete within 48 h.
OCR for page 50
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 FIGURE 2-2 Urinary metabolites of benzene. Source: Snyder and Hedli 1996. Reprinted with permission; copyright 1996, Environmental Health Perspectives. In workers exposed for 7 h to benzene at concentrations of 1 to 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 American Conference of Governmental Industrial Hygienists (ACGIH) biological exposure index (BEI) for benzene exposure is a urinary concentration of phenol at 50 mg per g of creatinine at the end of a work shift, but ACGIH noted that phenol is usually present in unexposed individuals and also might result from exposure to other chemicals (ACGIH 1991). 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%). The same general
OCR for page 51
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 profile was 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 is one-third 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 (MFO) 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 (Gonasun et al. 1973, Dean 1978). In contrast, repeated inhalation exposure of mice and rats to benzene at 600 ppm for 6 h/d, 5 d/wk, for 3 wk 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 models were proposed to describe the pharmacokinetics and metabolism of benzene in animals (Medinsky et al. 1989, Woodruff et al. 1989, Travis et al. 1990). Here, we arbitrarily refer to the models by the name of the first author—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 physiologically based pharmacokinetic (PBPK) models are useful for investigating the mechanism of toxicity of benzene but not for risk assessment of cancer (Bois et al. 1991).
OCR for page 52
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 TOXICITY SUMMARY Acute and Short-Term Toxicity Acute benzene exposure results in central nervous system (CNS) depression such as dizziness, ataxia, and confusion. These effects are believed to be caused by benzene rather than by 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, and cardiac dysrhythmia. Pathologic results in fatal cases have noted respiratory tract inflammation, lung hemorrhages, kidney congestion, and cerebral edema (ATSDR 1992). 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. Gerarde (1962) and von Oettingen (1940) estimated (without supporting data) that exposure at 25 ppm for 8 h has no effects; 50 to 150 ppm for 5 h produces headache, lassitude, and weakness, symptoms that are exaggerated at 500 ppm; 3,000 ppm for 0.5 to 1.0 h can be tolerated; 7,500 ppm for 30 min is dangerous to life; and 19,000 to 20,000 ppm can be fatal in 5 to10 min (Von Oettingen 1940, Gerarde 1962). 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 2,200 ppm produced narcosis, and at 4,600 ppm and 11,800 ppm it produced narcosis in 51 min and 8 min, respectively (Von Oettingen 1940). At 11,800 ppm, deaths occurred in 38 to 95 min; at 24,000 ppm, deaths occurred in 50 min. About 4,000 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 to 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 to 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). A median lethal concentration of 13,700 ppm was determined for a 4-h exposure of rats (Drew and Fouts 1974). Respiratory paraly-
OCR for page 53
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 sis 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 12,000 ppm for 10 min caused restlessness, rapid respiration, and head nodding, accompanied by hypersynchronous amygdaloid electroencephalogram activity (Contreras et al. 1979). Ataxia and postural collapse occurred when concentrations increased to 52,000 ppm. With repeated daily 10-min exposures, a 3-Hz spike-wave activity in the gyrus cinguli of the brain 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 benzene at 100 or 300 ppm (Dempster et al. 1984). Less sensitive parameters, home-cage food intake and hind-limb grip strength, were reduced at 1,000 and 3,000 ppm, but not at 100 or 300 ppm, even when exposure durations were adjusted to yield a minimum Ct (concentration × time) product of 3,000 ppm. 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 sensitization of the myocardium to epinephrine by benzene. In Wistar rats, inhalation of benzene at 3,000 and 7,000 ppm, but not at 1,500 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 7,000 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 hematologic 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 hematologic changes after short-term, and even acute, exposures. After an 8-h inhalation exposure of mice to 4,680 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-wk exposure (6 h/d, 5 d/wk) at 300 ppm decreased peripheral blood erythrocyte and lymphocyte counts (Snyder et al. 1978). Continuous exposure of NMRI mice at a concentration of
OCR for page 54
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 21 ppm for 4 to 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/wk) for 2 wk at 21 ppm also 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 to 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. Short-term exposures of animals at low concentrations might produce hematologic 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 standard tests in most in vitro test systems, including 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 (Marcus 1987, ATSDR 1989). 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 the 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, 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
OCR for page 55
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 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 3,100 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 the effects as a result of subchronic exposure. Limited information also 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 headaches, dizziness, fatigue, anorexia, dyspnea, and visual disturbances (Sandmeyer 1981). Some workers also exhibited signs of CNS lesions, such as abnormal inner ear 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 months to 20 ppm resulted in a delay in conditioned reflex response time; however, the effect was not seen at 4 ppm (Novikov 1956). Hematotoxicity and Myelotoxicity The effects of benzene on the hematopoietic system have been known for many years. Prolonged exposure causes hypoplasia and depressed function of bone marrow, resulting in leukopenia, anemia, or thrombocytopenia (Sandmeyer 1981, ATSDR 1989). With continued exposure, bone marrow aplasia results in pancytopenia and aplastic anemia; bone marrow aplasia might progress and develop into myelogenous leukemia or other types of leukemia. These are not distinct diseases but rather are a continuum of changes reflecting the severity of damage to the bone marrow. The cytopenias, which can occur as a group or in various combinations, can manifest themselves as specific adverse health effects (ATSDR 1989). For example, thrombocytopenia induces capillary fragility, petechiae, and hemor-
OCR for page 75
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 tinue (Snyder et al. 1993). Discovery of new potentially toxic metabolites, such as 6-hydroxy-trans,trans-2,4-hexadienoic acid, will further elucidate benzene’s mechanism of toxicity (Kline et al. 1993). Refinement of toxicokinetic models will lead to better definition of research aims and will facilitate comparative toxicity study (Woodruff and Bois 1993). Taken together, such scientific investigations will result in an improved definition of time and concentration dynamics, particularly in the areas of continuous versus intermittent exposure and low-concentration extrapolation. Experiments designed to assess the interaction of chemical toxicity and spaceflight-induced changes would be valuable in evaluating the accuracy of such selections. For example, rodent experiments involving concomitant exposure to benzene and spaceflight (or a model of spaceflight) could be designed to show whether spaceflight modulates benzene’s hematotoxicity or immunotoxicity. Findings in such experiments would improve the risk assessment and circumvent the need to make arbitrary choices in uncertainty factors. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1991. 1991-1992 Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Aksoy, M. 1978. Benzene and leukaemia. Lancet 1(8061):441. Aksoy, M. 1980. Different types of malignancies due to occupational exposure to benzene: A review of recent observations in Turkey. Environ. Res. 23(1):181-190. Aksoy, M., and S. Erdem. 1978. Followup study on the mortality and the development of leukemia in 44 pancytopenic patients with chronic benzene exposure. Blood 52(2):285-292. Aksoy, M., K. Dincol, T. Akgun, S. Erdem, and G. Dincol. 1971. Haematological effects of chronic benzene poisoning in 217 workers. Br. J. Ind. Med. 28(3):296-302. Aksoy, M., K. Dincol, S. Erdem, T. Akgun, and G. Dincol. 1972. Details of blood changes in 32 patients with pancytopenia associated with long-term exposure to benzene. Br. J. Ind. Med. 29(1):56-64. Aksoy, M., S. Erdem, and G. Dincol. 1974. Leukemia in shoe-workers exposed chronically to benzene. Blood 44(6):837-841. Aksoy, M., S. Erdem, G. Erdogan, and G. Dincol. 1976. Combination of genetic factors and chronic exposure to benzene in the aetology of leukemia. Hum. Hered. 26(2):149-153. ATSDR (Agency for Toxic Substances and Disease Registry). 1989. Toxicological Profile for Benzene. ATSDR/TP-88/03. U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, Atlanta, GA. 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].
OCR for page 76
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Au, W.W., V.M.S. Ramanujam, J.B. Ward Jr., and M.S. Legator. 1991. Chromosome aberrations in lymphocytes of mice after sub-acute low-level inhalation exposure to benzene. Mutat. Res. 260(2):219-224. Austin, H., E. Delzell, and P. Cole. 1988. Benzene and leukemia. A review of the literature and a risk assessment. Am. J. Epidemiol. 127(3):419-439. Baarson, K.A., C.A. Snyder, and R.E. Albert. 1984. Repeated exposures of C57B1 mice to 10 ppm inhaled benzene markedly depressed erythropoietic colony formation. Toxicol. Lett. 20(3):337-342. Blank, I.H., and D.J. McAuliffe. 1985. Penetration of benzene through human skin. J. Invest. Dermatol. 85(6):522-526. Bois, F.Y., T.J. Woodruff, and R.C. Spear. 1991. Comparison of three physiologically based pharmacokinetic models of benzene disposition. Toxicol. Appl. Pharmacol. 110(1):79-88. Bond, G.G., E.A. McLaren, C.L. Baldwin, and R.R. Cook. 1986. An update of mortality among chemical workers exposed to benzene. Br. J. Ind. Med. 43(1):685-691. Brett, S.M., J.V. Rodricks, and V.M. Chinchilli. 1989. Review and update of leukemia risk potentially associated with occupational exposure to benzene. Environ. Health Perspect. 82:267-281. Carpenter, C., C. Shaffer, C. Weil, and H. Smyth. 1944. Studies on the inhalation of 1:3-butadiene; with comparison of its narcotic effect with benzol, toluol, and styrene, and a note on the elimination of styrene by the human. J. Ind. Hyg. Toxicol. 26(3):69-78. Chang, I.W. 1972. Study on the threshold limit value of benzene and early diagnosis of benzene poisoning. J. Cathol. Med. Coll. 23:429-434. Choy, W.N., J.T. MacGregor, M.D. Shelby, and R.R. Maronpot. 1985. Induction of micronuclei by benzene in B6C3F1 mice: Retrospective analysis of peripheral blood smears from the NTP carcinogenesis bioassay. Mutat. Res. 143(1-2):55-59. Clare, M.G., A. Yardley-Jones, A.C. MacLean, and B.J. Dean. 1984. Chromosome analysis from peripheral blood lymphocytes of workers after an acute exposure to benzene. Br. J. Ind. Med. 41(2): 249-253. Contreras, C.M., T. Gonzalez-Estrada, D. Zarabozo, and A. Fernandez-Guardiola. 1979. Petit mal and grand mal seizures produced by toluene or benzene intoxication in the cat. Electroencephalogr. Clin. Neurophysiol. 46(3):290-301. Cornish, H.H., and R.C. Ryan. 1965. Metabolism of benzene in non-fasted, fasted, and aryl-hydroxylase inhibited rats. Toxicol. Appl. Pharmacol. 7(6):767-771. Cronkite, E.P., J.E. Bullis, T. Inoue, and R.T. Drew. 1984. Benzene inhalation produces leukemia in mice. Toxicol. Appl. Pharmacol. 75(2):358-361. Cronkite, E.P., R.T. Drew, T. Inoue, and J.E. Bullis. 1985. Benzene hematotoxicity and leukemogenesis. Am. J. Ind. Med. 7(5-6):447-456. Cronkite, E.P., R.T. Drew, T. Inoue, Y. Hirabayashi, and J.E. Bullis. 1989. Hematotoxicity and carcinogenicity of inhaled benzene. Environ. Health Perspect. 82:97-108. Crump, K.C., and B.C. Allen. 1984. Quantitative Estimates of the Risk of Leukemia from Occupational Exposure to Benzene. Prepared for the Occupational Safety and Health Administration, Washington, DC. Dean, B.J. 1978. Genetic toxicology of benzene, toluene, xylenes and phenols. Mutat. Res. 47(2):75-97. Dean, B.J. 1985. Recent findings on the genetic toxicology of benzene, toluene, xylenes and phenols. Mutat. Res. 154(3):153-181. Deichmann, W.B., W.E. MacDonald, and E. Bernal. 1963. The hemopoietic tissue toxicity of benzene vapors. Toxicol. Appl. Pharmacol. 5:210-224.
OCR for page 77
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Dempster, A.M., H.L. Evans, and C.A. Snyder. 1984. The temporal relationship between behavioral and hematological effects of inhaled benzene. Toxicol. Appl. Pharmacol. 76(1):195-203. Dowty, B.J., J.L. Laseter, and J. Storer. 1976. The transplacental migration and accumulation in blood of volatile organic constituents. Pediatr. Res. 10(7):696-701. Drew, R.T., and J.R. Fouts. 1974. The lack of effects of pretreatment with phenobarbital and chlorpromazine on the acute toxicity of benzene in rats. Toxicol. Appl. Pharmacol. 27(1):183-193. Driscoll, K.E., and C.A. Snyder. 1984. The effects of ethanol ingestion and repeated benzene exposures on benzene pharmacokinetics. Toxicol. Appl. Pharmacol. 73(3):525-532. Duvoir, M.R., A. Fabre, and L. Derobert. 1946. The significance of benzene in the bone marrow in the course of benzene blood diseases. Arch. Mal. Prof. 7:77-79. EPA (U.S. Environmental Protection Agency). 1989. Health Effects Assessment for Benzene. EPA/600/8-89/086. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Office of Research and Development,U.S. Environmental Protection Agency, Cincinnati, OH. August 1989. EPA (U.S. Environmental Protection Agency). 2003. Benzene (CASRN 71-43-2). Integrated Risk Information System, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/NCEA/iris/subst/0276.htm [accessed Apr. 24, 2008]. Erexson, G.L., J.L. Wilmer, and A.D. Kligerman. 1985. Sister chromatid exchange induction in human lymphocytes exposed to benzene and its metabolites in vitro. Cancer Res. 45(6):2471-2477. Forni, A., E. Pacifico, and A. Limonta. 1971a. Chromosome studies in workers exposed to benzene or toluene or both. Arch. Environ. Health 22:373-378. Forni, A.M., A. Cappellini, E. Pacifico, and E.C. Vigliani. 1971b. Chromosome changes and their evolution in subjects with past exposure to benzene. Arch. Environ. Health 23(5):385-391. Funes-Cravioto, F., C. Zapata-Gayon, B. Kolmodin-Hedman, B. Lambert, J. Lindsten, E. Norberg, M. Nordenskjöld, R. Olin, and A. Swensson. 1977. Chromosome aberrations and sister chromatid exchange in workers in chemical laboratories and a rotoprinting factory and in children of women laboratory workers. Lancet 2(8033):322-325. Gerarde, H.W. 1962. The aromatic hydrocarbons. Pp. 1219-1240 in Patty's Industrial Hygiene and Toxicology, Vol. 2. Toxicology, 2nd Rev. Ed., D.W. Fassett and D.D. Irish, eds. New York: Interscience. Ghantous, H., and B.R. Danielsson. 1986. Placental transfer and distribution of toluene, xylene and benzene, and their metabolites during gestation in mice. Biol. Res. Pregnancy Perinatol. 7(3):98-105. Gill, D.P., and A.E. Ahmed. 1981. Covalent binding to [14C]benzene to cellular organelles and bone marrow nucleic acids. Biochem. Pharmacol. 30(10):1127-1132. Gill, D.P., V.K. Jenkins, R.R. Kempen, and S. Ellis. 1980. The importance of pluripotential stem cells in benzene toxicity. Toxicology 16(2):163-171. Gofmekler, V.A. 1968. Effect on embryonic development of benzene and formaldehyde in inhalation experiments [in Russian]. Gyg. Sanit. 33(1-3):327-332. Goldstein, B.D. 1977. Benzene toxicity: A critical evaluation: Hematotoxicity in humans. J. Toxicol. Environ. Health 2(Suppl.):69-105.
OCR for page 78
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Goldstein, B.D., C.A. Snyder, S. Laskin, I. Bromberg, R.E. Albert, and N. Nelson. 1982. Myelogenous leukemia in rodents inhaling benzene. Toxicol. Lett. 13(3-4):169-173. Goldwater, L.J. 1941. Disturbances in the blood following exposure to benzol. J. Lab. Clin. Med. 26:957-973. Gonasun, L., C. Witmer, J.J. Kocsis, and R. Snyder. 1973. Benzene metabolism in mouse liver microsomes. Toxicol. Appl. Pharmacol. 26(3):398-406. Green, J.D., B.K. Leong, and S. Laskin. 1978. Inhaled benzene fetotoxicity in rats. Toxicol. Appl. Pharmacol. 46(1):9-18. 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. 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 marrow, and spleen cells of CD-1 male mice. Toxicol. Appl. Pharmacol. 59(2):204-214. Greenlee, W.F., E.A. Gross, and R.D. Irons. 1981. Relationship between benzene toxicity and the disposition of 14C-labelled benzene metabolites in the rat. Chem. Biol. Interact. 33(2-3):285-299. Guberan, E., and P. Kocher. 1971. Long-term prognosis of chronic benzene poisoning checking of a population ten years after exposure [in French}. Schweiz Med. Worchensch. 101(49):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(2):346-353. 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, R. D’Amato, T.J. Slaga, W.H. Farland, and C. Henry, eds. Progress in Clinical and Biological Research Vol. 374. New York: Wiley-Liss. 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. HSDB (Hazardous Substance Data Bank). 2005. Benzene (CASRN: 71-43-2). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/search [accessed Apr. 24, 2008]. 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 (International Agency for Research on Cancer). 1982. Benzene. Pp. 93-148 in Some Industrial Chemicals and Dyestuffs. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Vol. 29. World Health Organization, International Agency for Research on Cancer [online]. Available: http://monographs.iarc.fr/ENG/Monographs/vol29/volume29.pdf [accessed Apr. 24, 2008]. Ikeda, M., and H. Ohtsuji. 1971. Phenobarbital-induced protection against toxicity of toluene and benzene in the rat. Toxicol. Appl. Pharmacol. 20(1):30-43.
OCR for page 79
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Infante, P.F. 1978. Leukemia among workers exposed to benzene. Tex. 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(4):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 2(8028):76-78. Inoue, O.K., K. Seiji, M. Kasahira, H. Nakatsuka, T. Watanabe, S.G. Yin, G.L. Li, C. Jin, S.X. Cai, X.Z. Wang, and M. Ikeda. 1986. Quantitative relation of urinary phenol levels to breath zone benzene concentrations: A factory survey. Br. J. Ind. Med. 43(10):692-697. Irons, R.D., and D.A. Neptun. 1980. Effects of the principal hydroxy-metabolites of benzene on microtubule polymerization. Arch. Toxicol. 45(4):297-305. Irons, R.D., D. Wierda, and R.W. Pfeifer. 1983. The immunotoxicity of benzene and its metabolites. Pp. 37-50 in Carcinogenicity and Toxicity of Benzene, M.A. Mehlman, ed. Advances in Modern Environmental Toxicology Vol. 4. Princeton, N.J.: Princeton Scientific Publishers. James, J.T., and H.L. Kaplan. 1996. Benzene. Pp. 39-103 in Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol. 2. Washington, DC: National Academy Press. Kalf, G.F., T. Rushmore, and R. Snyder. 1982. Benzene inhibits RNA synthesis in mitochondria from liver and bone marrow. Chem. Biol. Interact. 42(3):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(2-3):171-181. Kim, S., R. Vermeulen, S. Waidyanatha, B.A. Johnson, Q. Lan, N. Rothman, M.T. Smith, L. Zhang, G. Li, M. Shen, S. Yin, and S.M. Rappaport. 2006. Using urinary biomarkers to elucidate dose-related patterns of human benzene metabolism. Carcinogenesis 27(4):772-781. 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. Krewski, D., R. Snyder, P. Beatty, G. Granville, B. Meek, and B. Sonawane. 2000. Assessing the health risks of benzene: A report on the benzene state-of-the-science workshop. J. Toxicol. Environ. Health A 61(5-6):307-338. Lamm, S.H., and H.W. Grunwald. 2006. Benzene exposure and hematotoxicity. Science 312(5776): 998-999. Lan, Q., L. Zhang, G. Li, R. Vermeulen, R.S. Weinberg, M. Dosemeci, S.M. Rappaport, M. Shen, B.P. Alter, Y. Wu, W. Kopp, S. Waidyanatha, C. Rabkin, W. Guo, S. Chanock, R.B. Hayes, M. Linet, S. Kim, S. Yin, N. Rothman, and M.T. Smith. 2004. Hematotoxicity in workers exposed to low levels of benzene. Science 306(5702):1774-1776. 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(1):37-44.
OCR for page 80
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Leong, B.K. 1977. Experimental benzene intoxication. J. Toxicol. Environ. Health Suppl. 2:45-61. Li, G.L., S.N. Yin, T. Watanabe, H. Nakatsuka, M. Kasahara, H. Abe, and M Ikeda. 1986. Benzene-specific increase in leukocyte alkaline phosphatase activity in rats exposed to vapors of various organic solvents. J. Toxicol. Environ. Health 19(4):581-589. Longacre, S.L., J.J. Kocsis, and R. Snyder. 1981. Influence of strain differences in mice on the metabolism and toxicity of benzene. Toxicol. Appl. Pharmacol. 60(3):398-409. Luke, C.A., R.R. Tice, and R.T. Drew. 1988a. The effect of exposure 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(4):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(4):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(2):241-245. Marcus, W.L. 1987. Chemical of current interest-benzene. Toxicol. Ind. Health 3(1):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(2):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(2):193-206. Michon, S. 1965. Disturbances of menstruation in women working in an atmosphere polluted with aromatic hydrocarbons [in Polish]. Pol. Tig. Lek. 20:1648-1649. Morimoto, K. 1983. Induction of sister chromatid exchanges and cell division delays in human lymphocytes by microsomal activation of benzene. Cancer Res. 43(3):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(4):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 [in Russian]. Gig. Tr. Prof. Zabol. 16(11):6-9. 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(11):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(3):336-345. Nebert, D.W., A.L. Roe, S.E. Vandale, E. Bingham, and G.G. Oakley. 2002. NAD(P)H: Guinine oxidoreductase (NQO1) polymorphism, exposure to benzene, and predisposition to disease: A HuGE review. Genet. Med. 4(2):62-70. NIOSH (National Institute for Occupational Safety and Health). 1974. Criteria for a Recommended Standard: Occupational Exposure to Benzene. HEW (NIOSH) 74-137.
OCR for page 81
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 U.S. Department of Health, Education and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, Cin-d cinnati, OH [online]. Available: http://www.cdc.gov/niosh/74-137.html [accessed Apr. 25, 2008]. NIOSH (National Institute for Occupational Safety and Health). 1976. Revised Recommendation for an Occupational Exposure Standard for Benzene. National Institute for Occupational Safety and Health, Cincinnati, OH. August 1976 [online]. Available: http://www.cdc.gov/niosh/pdfs/76-benz.pdf [accessed Apr. 25, 2008]. Nomiyama, K., and H. Nomiyama. 1974a. Respiratory retention, uptake and excretion of organic solvents in man. Int. Arch. Arbeitsmed. 32(1):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(1):85-91. Novikov, Y.V. 1956. Effects of small benzene concentrations on higher nervous activity of animals in constant experiments [in Russian]. Gig. Sanit. 21(2):20-25. NRC (National Research Council). 2000. Guidelines for Developing Spacecraft Water Exposure Guidelines for Space Station Contaminants. Washington, DC: National Academy Press. NRC (National Research Council), 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants, Vol. 2. Washington, DC: The National Academies Press. NTP (National Toxicology Program). 1986. Toxicology and Carcinogenesis Studies of Benzene (CAS No. 71-43-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report No. 289. NIH 86-2545. U.S. Department of Health and Human Services, Public Health Service, National Institute of Health, National Toxicology Program, Research Triangle Park, NC. Oehme, F.W. 1969. Comparative Study of the Biotransformation and Excretion of Phenol. Ph.D. Thesis, University of Missouri, Columbia. 207 pp. Ott, M.G., J.C. Townsend, W.A. Fishbeck, and R.A. Langner. 1978. Mortality among individuals occupationally exposed to benzene. Arch. Environ. Health 33(1):3-10. Parke, D.V., and R.T. Williams. 1953. Studies in detoxication. 49. The metabolism of benzene containing [14C]benzene. Biochem. J. 54(2):231-238. Pfeifer, R.W., and R.D. Irons. 1981. Inhibition of lecithin-stimulated lymphocyte agglutination and mitogenesis by hydroquinone: Reactivity with intracellular sulfhydryl groups. Exp. Mol. Pathol. 35(2):189-198. Picciano, D. 1979. Cytogenetic study of workers exposed to benzene. Environ. Res. 19(1):33-38. Pushkina, N.N., V.A. Gofmekler, and G.N. Klevtsova. 1968. Changes in ascorbic and nucleic acid concentration under the influence of benzene and formaldehyde [in Russian]. Bull. Exp. Biol. Med. 66(8):51-53. Qu, Q., R. Shore, G. Li, X. Jin, L.C. Chen, B. Cohen, A.A. Melikian, D. Eastmond, S.M. Rappapport, S. Yin, H. Li, S. Waidyanatha, Y. Li, R. Mu, X. Zhang, and K. Li. 2002. Hematological changes among Chinese workers with a broad range of benzene exposures. Am. J. Ind. Med. 42(4):275-285. Rickert, D.E., T.S. Baker, J.S. Bus, and C.S. Barrow, and R.D. Irons. 1979. Benzene disposition in the rat after exposure by inhalation. Toxicol. Appl. Pharmacol. 49(3):417-423. Rinsky, R.A., R.J. Young, and A.B. Smith. 1981. Leukemia in benzene workers. Am. J. Ind. Med. 2(3):217-245.
OCR for page 82
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Rinsky, R.A., A.B. Smith, R. Hornung, T.G. Filloon, R.J. Young, A.H. Okun, and P.J. Landrigan. 1985. Benzene and Leukemia: An Epidemiological Risk Assessment. U. S. Department of Health and Human Services, National Institute for Occupational Safety and Health, Cincinnati, OH. August 9, 1985. Rinsky, R.A., A.B. Smith, R. Hornung, T.G. Filloon, R.J. Young, A.H. Okun, and P.J. Landrigan. 1987. Benzene and leukemia: An epidemiological risk assessment. N. Engl. J. Med. 316(17):1044-1050. Rosenthal, G.J., and C.A. Snyder. 1985. Modulation of the immune response to Listeria monocytogenes by benzene inhalation. Toxicol. Appl. Pharmacol. 80(3):502-510. Rosenthal, G.J., and C.A. Snyder. 1986. Altered T-cell responses in C57BL/6J mice following sub-chronic benzene inhalation. Toxicologist 6(1):68 [Abstact No. 270]. Rozen, M.G., and C.A. Snyder. 1985. Protracted exposure of C57BL/6 mice to 300 ppm benzene depresses B- and T-lymphocyte numbers and mitogen responses. Evidence for thymic and bone marrow proliferation in response to the exposures. Toxicology 37(1-2):13-26. Rozen, M.G., C.A. Snyder, and R.E. Albert. 1984. Depressions in B- and T-lymphocyte mitogen-induced blastogenesis in mice exposed to low concentrations of benzene. Toxicol. Lett. 20(3):343-349. Sabourin, P.J., B.T. Chen, G. Lucier, L.S. Birnbaum, E. Fisher, and R.F. Henderson. 1987. Effect of dose on the absorption and excretion of [14C]benzene administered orally or by inhalation in rats and mice. Toxicol. Appl. Pharmacol. 87(2):325-336. Sabourin, P.J., J.D. Sun, J.T. MacGregor, C.M. Wehr, L.S. Birnbaum, G. Lucier, and R.F. Henderson. 1990. Effect of repeated benzene inhalation exposures on benzene metabolism, binding to hemoglobin, and induction of micronuclei. Toxicol. Appl. Pharmacol. 103(3):452-462. Sabourin, P.J., B.A. Muggenburg, R.C. Couch, D. Lefler, G. Lucier, L.S. Birnbaum, and R.F. Henderson. 1992. Metabolism of [14C]-benzene by cynomolgus monkeys and chimpanzees. Toxicol. Appl. Pharmacol. 114(2):277-284. Sammett, D., E.W. Lee, J.J. Kocsis, and R. Snyder. 1979. Partial hepatectomy reduces both metabolism and toxicity of benzene. J. Toxicol. Environ. Health 5(5):785-792. Sarto, F.S., I. Cominato, A.M. Pinton, P.G. Brovedani, E. Merler, M. Peruzzi, V. Bianchi, and A.G. Levis. 1984. A cytogenetic study on workers exposed to low concentrations of benzene. Carcinogenesis 5(6):827-832. Sandmeyer, E.E. 1981. Aromatic hydrocarbons. Pp. 3253-3431 in Patty's Industrial Hygiene and Toxicology, Vol. 2B. Toxicology, 3rd Rev. Ed., G.D. Clayton and F.E. Clayton, eds. New York: John Wiley and Sons. Sato, A., and T. Nakajima. 1979. Partition coefficients of some aromatic hydrocarbons and ketones in water, blood, and oil. Br. J. Ind. Med. 36(3):231-234. Sato, A., and T. Nakajima. 1985. Enhanced metabolism of volatile hydrocarbons in rat liver following food deprivation, restricted carbohydrate intake, and administration of ethanol, phenobarbital, polychlorinated biphenyl, and 3-methylcholanthrene: A comparative study. Xenobiotica 15(1):67-75. Sato, A., Y. Fujiwara, and T. Nakajima. 1974. Solubility of benzene, toluene, and m-xylene in various body fluids and tissues of rabbits. Sangyo Igaku 16(1):30-31. Sato, A., T. Nakajima, Y. Fujiwara, and N. Murayama. 1975. Kinetic studies on sex difference in susceptibility to chronic benzene intoxication-with special reference to body fat content. Br. J. Ind. Med. 32(4):321-328.
OCR for page 83
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Schrenk, H.H., W.P. Yant, S.J. Pearce, F.A. Patty, and R.R. Sayers. 1941. Absorption, distribution and elimination of benzene by body tissues and fluids of dogs exposed to benzene vapor. J. Ind. Hyg. Toxicol. 23(1):20-34. Seidel, H.J., E. Barthel, and D. Zinser. 1989a. The hematopoietic stem cell compartments in mice during and after long-term inhalation of three doses of benzene. Exp. Hematol. 17(3):300-303. Seidel, H.J., G. Beyvers, M. Pape, and E. Barthel. 1989b. The influence of benzene on the erythroid cell system in mice. Exp. Hematol. 17(7):760-764. Seidel, H.J., R. Bader, L. Weber, and E. Barthel. 1990. The influence of ethanol on the stem cell toxicity of benzene in mice. Toxicol. Appl. Pharmacol. 105(1):13-18. 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. Carcinogenesis 27(10):2083-2089. Sherwood, R.J. 1972. Benzene: The interpretation of monitoring results. Ann. Occup. Hyg. 15(2):409-421. Smyth, H.F., C.P. Carpenter, C.S. Weil, U.C. Pozzani, and J.A. Striegel. 1962. Range-finding toxicity data: List VI. Am. Ind. Hyg. Assoc. J. 23:95-107. Snyder, C.A. 1987. Benzene. Pp. 3-37 in Ethel Browning's Toxicity and Metabolism of Industrial Solvents. Vol. 1: Hydrocarbons, 2nd Ed. R. Snyder, ed. New York: Elsevier. Snyder, C.A, B.D. Goldstein, A.R. Sellakumar, S.R. Wolman, I. Bromberg, M.N. Erlichman, and S. Laskin. 1978. Hematotoxicity of inhaled benzene to Sprague-Dawley rats and AKR mice at 300 ppm. J. Toxicol. Environ. Health 4(4):605-618. Snyder, C.A., B.D. Goldstein, A.R. Sellakumar, I. Bromberg, S. Laskin, and R.E. Albert. 1980. The inhalation toxicology of benzene: Incidence of hematopoietic neoplasms and hematotoxicity in AKR/J and C57BL/6J mice. Toxicol. Appl. Pharmacol. 54(2):323-331. Snyder, C.A., J.D. Green, J. LoBue, B.D. Goldstein, C.D. Valle, and R.E. Albert. 1981. Protracted benzene exposure causes a proliferation of myeloblasts and/or promyelocytes in CD-1 mice. Bull. Environ. Contam. Toxicol. 27(1):17-22. Snyder, C.A., B.D. Goldstein, A.R. Sellakumar, and R.E. Albert. 1984. Evidence for hematotoxicity and tumorigenesis in rats exposed to 100 ppm benzene. Am. J. Ind. Med. 5(6):429-434. Snyder, R., and C.C. Hedli. 1996. An overview of benzene metabolism. Environ Health Perspect. 104 (Suppl. 6):1165-1171. Snyder, R., E.W. Lee, J.J. Kocsis, and C.M. Witmer. 1977. Bone marrow depressant and leukemogenic actions of benzene. Life Sci. 21(12):1709-1722. Snyder, R., S.L. Longacre, C.M. Witmer, J.J. Kocsis, L.S. Andrews, and E.W. Lee. 1981. Biochemical toxicology of benzene. Pp. 123-153 in Reviews in Biochemical Toxicology 3, E. Hodgson, J.R. Bend, and R.M. Philpot, eds. Amsterdam: Elsevier. Snyder, R., T. Chepiga, C.S. Yang, H. Thomas, K. Platt, and F. Oesch. 1993. Benzene metabolism by reconstituted cytochromes P450 2B1 and 2E1 and its modulation by cytochrome b5, microsomal epoxide hydrolase, and glutathione transferases: Evidence for an important role of microsomal epoxide hydrolase in the formation of hydroquinone. Toxicol. Appl. Pharmacol. 122(2):172-181. Srbova, J., J. Teisinger, and S. Skramovsky. 1950. Absorption and elimination of inhaled benzene in man. Arch. Ind. Hyg. Occup. Med. 2(1):1-8.
OCR for page 84
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Stommel, P., G. Muller, W. Stucker, C. Verkoyen, S. Schobel, and K. Norpoth. 1989. Determination of S-phenylmercapturic acid in the urine: An improvement in the biological monitoring of benzene exposure. Carcinogenesis 10(2):279-282. Stoner, R.D., R.T. Drew, and D.M. Bernstein. 1981. Benzene inhalation effect upon tetanus antitoxin: Responses and leukemogenesis in mice. Pp. 445-461 in Coal Conversion and the Environment: Chemical , Biomedical and Ecological Considerations, D.D. Mahlum, R.H. Gray, and W.D. Felix, eds. Technical Information Center, U.S. Department of Energy, Oak Ridge, TN. Su, J.D., M.A. Medinsky, L.S. Birnbaum, G. Lucier, and R.F. Henderson. 1990. Benzene hemoglobin adducts in mice and rats: Characterization of formation and physiological modeling. Fundam. Appl. Toxicol. 15(3):468-475. Teisinger, J., V. Bergerova-Fiserova, and J. Kudrna. 1952. The metabolism of benzene in man. Prac. Lek. 4(3):175-188. Tice, R.R., D.L. Costa, and R.T. Drew. 1980. Cytogenetic effects of inhaled benzene in murine bone marrow: Induction of sister chromatid exchanges, chromosomal aberrations and cellular proliferation inhibition in DBA/2 mice. Proc. Natl. Acad. Sci. USA 77(4):2148-2152. Toft, K., T. Olofsson, A. Tunek, and M. Berlin. 1982. Toxic effects on mouse bone marrow caused by inhalation of benzene. Arch. Toxicol. 51(4):295-302. Tough, I.M., and W.M. Brown. 1965. Chromosome aberrations and exposure to ambient benzene. Lancet 1(7387):684. Travis, C.C., J.L. Quillen, and A.D. Arms. 1990. Pharmacokinetics of benzene. Toxicol. Appl. Pharmacol. 102(3):400-420. Ungvary, G., and E. Tatrai. 1985. On the embryotoxic effects of benzene and its alkyl derivatives in mice, rats and rabbits. Arch. Toxicol. Suppl. 8:425-430. Uyeki, E.M., A.E. Ashkar, D.W. Shoeman, and T.U. Bisel. 1977. Acute toxicity of benzene inhalation to hemopoietic precursor cells. Toxicol. Appl. Pharmacol. 40(1):49-57. Valle-Paul, C., and C.A. Snyder. 1986. Effect of benzene exposure on bone marrow precursor cells of splenectomized mice. Toxicologist 6(1):285 [Abstract No. 1145]. Van Raalte, H.G., and P. Grasso. 1982. Hematological, myelotoxic, clastogenic, carcinogenic, and leukemogenic effects of benzene. Regul. Toxicol. Pharmacol. 2(2):153-176. Vara, P., and O. Kinnunen. 1946. Benzene toxicity as a gynecologic problem. Acta Obstet. Gynecol. Scand. 26:433-452. 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 benzene in two shoe factories in China. Ann. Occup. Hyg. 48(2):105-116. Vigliani, E.C. 1976. Leukemia associated with benzene exposure. Ann. N.Y. Acad. Sci. 271:143-151. Vigliani, E.C., and A. Forni. 1976. Benzene and leukemia. Environ. Res. 11(1):122-127. Von Oettingen, W.F. 1940. Toxicity and Potential Dangers of Aliphatic and Aromatic Hydrocarbons: A Critical Review of the Literature. Public Health Bulletin No. 255, U.S. Public Health Service, Washington, DC. Ward, C.O., R.A. Kuna, N.K. Snyder, R.D. Alsaker, W.B. Coate, and P.H. Craig. 1985. Subchronic inhalation toxicity of benzene in rats and mice. Am. J. Ind. Med. 7(5-6):457-473.
OCR for page 85
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Ward, J.B., Jr., M.M. Ammenheuser, V.M. Ramanujam, D.L. Morris, E.B. Whorton, Jr., and M.S. Legator. 1992. The mutagenic effects of low level sub-acute inhalation exposure to benzene in CD-1 mice. Mutat. Res. 268(1):49-57. Watanabe, T., A. Endo, Y. Kato, S. Shima, T. Watanabe, and M. Ikeda. 1980. Cytogenetics and cytokinetics of cultured lymphocytes from benzene-exposed workers. Int. Arch. Occup. Environ. Health 46(1):31-41. White, M.C., P.F. Infante, and B. Walker. 1980. Occupational exposure to benzene: A review of the carcinogenic and related health effects following the United States Supreme Court decision. Am. J. Ind. Med. 1(2):233-243. White, M.C., P.F. Infante, and K.A. Chu. 1982. A quantitative estimate of leukemia mortality associated with occupational exposure to benzene. Risk Anal. 2(3):195-204. Wierda, D., and R. Irons. 1982. Hydroquinone and catechol reduce the frequency of progenitor B lymphocytes in mouse spleen and bone marrow. Immunopharmacology 4(1):41-54. Wilson, R.H. 1942. Benzene poisoning in industry. J. Lab. Clin. Med. 27:1517-1521. Winek, C.L., and W.D. Collom. 1971. Benzene and toluene fatalities. J. Occup. Med. 13(5):259-261. Winek, C.L., W.D. Collom, and C.H. Wecht. 1967. Fatal benzene exposure by glue sniffing. Lancet 1(7491):683. Wolf, M.A., V.K. Rowe, D.D. McCollister, R.L. Hollingsworth, and F. Oyen. 1956. Toxicological studies of certain alkylated benzenes and benzene: Experiments on laboratory animals. AMA Arch. Ind. Health 14(4):387-398. Woodruff, T.J., and F.Y. Bois. 1993. Optimization issues in physiological toxicokinetic modeling: A case study with benzene. Toxicol. Lett. 69(2):181-196. Woodruff, T., F.Y. Bois, J. Parker, D. Auslander, S. Selvin, M. Smith, and R. Spear. 1989. Design and analysis of a model of benzene toxicokinetics in mammals. Pp. 254-255 in Proceedings of the 11th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Part 1, Y. Kim, and F.A. Spelman, eds. Seattle: IEEE. Yardley-Jones, A., D. Anderson, and D.V. Parke. 1991. The toxicity of benzene and its metabolism and molecular pathology in human risk assessment. Br. J. Ind. Med. 48(7):437-444.