Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Volume 2 (1996) / Chapter Skim
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B2 Benzene
B2 Benzene
Pages 39-104
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From page 39... ...
95 torr (25 °C) Slightly soluble in water, very soluble in organic solvents 1 ppm = 3.26 mg/m3 1 mg/m3 = 0.31 ppm 39
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From page 40... ...
~ mg/m3 (lames et al., 19941. 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.
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From page 41... ...
Following a 10-min inhalation exposure of mice, benzene was present in well-perfused tissues, such as liver and kidney, and in lipidrich 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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From page 42... ...
No differences in respiratory elimination were observed between men and women (Nomiyama and Nomiyama, 1974a,b; lARC, 19821. 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.
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From page 43... ...
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)
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From page 44... ...
(Sabourin et al., 19921. 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.
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From page 45... ...
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, 19811. Recovery is usually rapid, but, in some cases, symptoms have persisted for weeks.
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From page 46... ...
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.
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From page 47... ...
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.
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From page 48... ...
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 L517SY cells; and mixed results were obtained in studies of chromosomal aberrations and sister chromatic exchange (SCE)
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From page 49... ...
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., 19851. 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., 19801.
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From page 50... ...
A high prevalence and wide range of hematological responses to benzene are evident in the numerous epidemiological studies and case reports of occupationally exposed workers. Of 332 rotogravure workers exposed to benzene at 11-1060 ppm for 6-60 mo, 23 had severe cytopenia (23 of 23, leukopenia; 15 of 23, erythropenia; 18 of 23, thrombocytopenia)
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From page 51... ...
A threshold of about 10 pun for cytopenia was suggested on the basis of observations of minimal hematotoxicity in workers exposed at 20 ppm (Chang, 1972~. There is evidence that benzene-induced pancytopenia or aplastic anemia is associated with the later development of leukemia (ATSDR, 1989~.
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From page 52... ...
Bone-marrow cellularity and pluripotential stem cells were significantly reduced in C57BE mice exposed for 2 w at 100 ppm, but not at 10 or 25 ppm (Cronkite et al., 19851. At 300 ppm, 2 w were required for recovery of stem-cell numbers after 2- or 4-w exposures, and 25 w were required for recovery to 92% of control values after a 16-w exposure.
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From page 53... ...
On the other hand, ethanol ingestion generally increases benzene-induced hematotoxicity, possibly by increasing the rate of formation of toxic metabolites (Driscoll and Snyder, 19841. Also supporting a causative role of benzene metabolites in bone-marrow suppression and hematotoxicity are studies showing the accumulation of metabolites in bone marrow.
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From page 54... ...
With advances in immunology, alterations in serum immunogiobulin and complement levels were detected in occupationally exposed workers (Marcus, 19871. In 35 painters exposed to benzene, along with toluene and xylene, at concentrations of 3.4-48 ppm, serum TgG and IgA levels were significantly decreased compared with controls, and TgM levels were increased (Lange et al., 19731.
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From page 55... ...
was unaffected at 50, 200, or 400 ppm. The secondary antibody response In a study of cell-mediated immunity, host resistance to Wisteria monocytogenes was measured in mice exposed to benzene for either 5 d prior to infection (pre-exposure regimen)
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From page 56... ...
. Even at low concentrations, chromosomal aberrations were increased; for example, increases were found in 52 workers exposed at < 10 ppm (estimated time-weighted-average exposure 2.1 ppm)
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From page 57... ...
effects of benzene inhalation (Vigliani, 1976; Tnfante et al., 1977; Ott et al., 1978; Rinsky et al., 1981;Maltonietal., 19891. The first epidemiological study of benzene, published in 1974, reported a leukemia incidence during 19671973 of 13/100,000 among 2S,500 Turkish shoe workers exposed to benzene at concentrations of 150-650 ppm for 4 mo to 15 y (Aksoy et al., 1974~.
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From page 58... ...
of 1.0 ppm for benzene, relying on the Crump and Allen linear risk assessment, which was based on combined data from three high-quality epidemiological studies (Brett et al., 1989~. The assessment projects a risk of 10 excess leukemia deaths per 1000 workers as a result of a 45-y occupational exposure to benzene at 1 ppm.
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From page 59... ...
The investigators suggested a causative role for benzene because spontaneous myelogenous leukemia had not been observed in these strains. However, the results might be of questionable significance because of the small numbers of animals and marginally increased incidences (Maltoni et al., 19891.
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From page 60... ...
At an exposure of 200 ppm, 4-7 in/d, 5 d/w, for 19 w, followed by an exposure at 300 ppm, 7 in/d, 5 d/w, for 85 w, with exposure started in embryonal life, the incidence of malignant tumors increased from 17.3% in male and female controls to 43.6%, Zymbal gland carcinomas increased from 0.7% to 10.0%, and hepatomas increased from 0.3% to 6.4%. Tn females, mammary gland tumors increased from 5.4% in controls to 13.~%.
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From page 61... ...
One of the favored mechanisms involves the covalent binding of benzene metabolites to cellular macromolecules. Covalent binding to DNA was observed in the livers of rats exposed to benzene vapor (Lutz and SchIatter, 1977~.
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From page 62... ...
In CD-1 mice exposed at 1, 10, 30, or 300 ppm, 6 in/d, 5 d/w, for 13 w, exposure at 300 ppm resulted in histopathological changes to the testes and ovaries (Ward et al., 1985~. Changes to the testes included atrophy and degeneration, decreases in spermatozoa, and moderate increases in abnormal sperm forms.
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From page 63... ...
resulted in growth retardation and increased skeletal variants in fetuses, but no malformations. in rats, concentrations of 50-2200 ppm caused decreased fetal weight, but numbers of skeletal variants increased significantly at 125 ppm and higher (Green et al., 19781.
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From page 64... ...
The administration of ethanol increased the depression of hematopoietic progenitor cells, CFU-E, BFU-E, and CFU-C, induced by exposure to benzene at 300 or 900 ppm in BDF1 mice (Seide!
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From page 69... ...
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From page 71... ...
71 to , ^ ^ ~To .
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From page 72... ...
24 h 7 d 30 d 180 d 3 0.5 0.1 0.07 10 1.5 0.3 0.2 RATIONALE FOR ACCEPTABLE CONCENTRATIONS Because a large database exists on benzene's toxicity to animals and humans, multiple toxic effects must be considered in setting safe exposure concentrations. The immediate effects of benzene exposure are thought to be due to benzene itself, whereas the delayed effects are caused by toxic metabolites reaching target cells, particularly in the bone marrow.
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From page 73... ...
for studying the effects induced by benzene metabolites. Analyses of urinary metabolites indicated that both humans and mice have a higher propensity to metabolize benzene to its toxic metabolites, muconic acid and hydroquinone, than do rats, monkeys, or chimpanzees.
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From page 74... ...
concentrations of benzene apparently caused menstrual disorders in 12 of 30 female workers exhibiting other signs of benzene toxicity (Vera and Kinnunen, 1946~; however, other studies in humans have not confirmed this finding (Barlow and Sullivan, 1982~. Animal studies have shown ovarian and testicular changes in mice after subchronic exposure at 300 ppm, but nonreproductive effects (e.g., hematological)
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From page 75... ...
= 300 ppm x 1/3 x 1/3 x 12/24 = 16 ppm.
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From page 76... ...
= 100 ppm x 1/3 x 1/3 x 6/24 = 3 ppm. Since the immunological effects, which are similar (or greater)
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From page 77... ...
= 9.6 ppm x 1/3 x 1/3 x 300/720 = 0.4 ppm. No long-term exposure data are available on the immunological effects of benzene exposure; however, Haber's rule can be used to extrapolate a value of 0.07 ppm for continuous exposures of 180 d.
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From page 78... ...
The only point of agreement among investigators seems to be that cumulative benzene exposures above 300 ppm-y induce a significant increase in the occurrence of leukemia in workers. This observation is based on the results of a thorough epidemiological study of 1165 workers exposed at two industrial sites in Ohio (Infante et al., 19774.
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From page 79... ...
= ~ ppm x 70/0.5 x 0.0001/0.024 = 0.6 ppm. This value is not the upper confidence limit of a 0.01 % risk; it is the most likely value estimated from the cited studies.
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From page 80... ...
= 0.002 ppm x 10/0.5 x 0.0001/0.00001 = 0.4 ppm. This is not an upper limit, and it applies, in principle, to all benzeneinduced cancers.
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From page 81... ...
Using both positive and negative epidemiological data and a linear model, Swaen and Meijers (1989) estimated five to six excess deaths from nonlymphatic leukemia per 1000 deaths in workers exposed at 300 ppm-y of benzene (10 ppm x 30 y work exposure, or 6.6 y continuous
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From page 82... ...
Variations in control matching with Rinsky's exposure assumptions gave predicted increases in leukemia death rates in the range of 4.2-6.4/1000 after 45 ppm-y of exposure (equivalent to 10 y continuous exposure at 1 ppm) , whereas the exposure assumptions of C rump and Allen (1984)
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From page 83... ...
was statistically insignificant in predicting leukemia risks at low concentrations. Furthermore, in the parts-per-billion range, the largest degree of uncertainty is due to
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From page 84... ...
Therefore, the AC to protect against excess leukemia for a continuous exposure of IS0 ~ is 0.07 ppm. Using linear extrapolation to shorter times, the ACs for 30, 7, and 1 Swede found tobe0.4ppm, 1.7ppm, and 12 ppm, respectively.
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From page 86... ...
important deviations from past practices were the following: (~) A species extrapolation factor of 3 was used rather than 10 for effects caused by metabolites of benzene.
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From page 88... ...
The acceptable concentration for protection from neurotoxicity induced by short-term benzene exposures was based on rodent data. That was because the reported effects in humans appeared to be based on impressions from industrial experience rather than on specific human data.
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From page 89... ...
1974. Leukemia in shoe-workers exposed chronically to benzene.
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From page 90... ...
1986. An update of mortality among chemical workers exposed to benzene.
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From page 91... ...
1984. The temporal relationship between behavioral and hematological effects of inhaled benzene.
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From page 92... ...
1971a. Chromosome studies in workers exposed to benzene or toluene or both.
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1981b. Acute and chronic dose/response effect of benzene inhalation on the peripheral blood, bone marrow, and spleen celIs of CD-1 male mice.
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From page 94... ...
1978. Leukemia among workers exposed to benzene.
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1986. Mice exposed in utero to low concentrations of benzene exhibit enduring changes in their colony forming hematopoietic celIs.
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From page 96... ...
1972. Reproductive power and the incidence of gynecological disorders in female workers exposed to the combined effect of benzene and chIorinated hydrocarbons.
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From page 97... ...
1986. Emergency and Continuous Exposure Guidance Levels for Selected Airborne Contaminants.
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From page 98... ...
1979. Cytogenetic study of workers exposed to benzene.
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From page 99... ...
1984. A cytogenetic study on workers exposed to low concentrations of benzene.
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From page 100... ...
1981. Protracted benzene exposure causes a proliferation of myeloblasts and/or promyelocytes in CD-1 mice.
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From page 101... ...
1980. Cytogenetic effects of inhaled benzene in murine bone marrow: Induction of sister chromatid exchanges, chromosomal aberrations and cellular proliferation
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From page 102... ...
1986. Effect of benzene exposure on bone marrow precursor cells of splenectomized mice.
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From page 103... ...
1980. Occupational exposure to benzene: A review of the carcinogenic and related health effects following the United States Supreme Court decision.
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