Multi-step metabolic activation of benzene. Effect of superoxide dismutase on covalent binding to microsomal macromolecules, and identification of glutathione conjugates using high pressure liquid chromatography and field desorption mass spectrometry

Tunek, Anders; Platt, Karl L.; Przybylski, Michael; Oesch, Franz

doi:10.1016/0009-2797(80)90040-x

Cited by 117 publications

(33 citation statements)

References 28 publications

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“…Because human lymphocytes have mixed-function oxidases and can metabolize many phenolic compounds (208,209) and because benzene can be metabolized to these phenolic derivatives in bone marrow in situ, Tunek et al (210) benzene-associated leukemia were exposed to other chemicals, although exposure to benzene was common to all. The possibility exists, albeit equivocally, that other chemicals in addition to benzene may have been involved in the development of the leukemia, and this possibility could help explain the failure to reproduce benzeneassociated leukemia is the present NTP studies or in other such studies in experimental animals (212); nonetheless, benzene caused lymphomas in both sexes of mice in the NTP study.…”

Section: Genetic Toxicologymentioning

confidence: 99%

Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.

Huff

Haseman

DeMarini

et al. 1989

Environ Health Perspect

113

107

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Toxicology and carcinogenesis studies of benzene (CAS No. 71-43-2; greater than 99.7% pure) were conducted in groups of 60 F344/N rats and 60 B6C3FW mice of each sex for each of three exposure doses and vehicle controls. These composite studies on benzene were designed and conducted because of large production volume and widespread human exposure, because of the epidemiologic association with leukemia, and because previ. ous experiments were considered inadequate or inconclusive for determining carcinogenicity in laboratory animals. Using the results from 17-week studies, doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten animals in each of the 16 groups were killed at 12 months, and necropsies were performed. Hematologic profiles were performed at 3-month intervals.For the 2-year studies, mean body weights of the top dose groups of male rats and of both sexes of mice were lower than those of the controls. Survivals of the top dose group of rats and mice of each sex were reduced; however, at week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the dosed animals that died before week 103 had neoplasia. Compound-related nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found both for rats and mice. Further, the oral cavity was affected in rats, and the lung, liver, Harderian gland, preputial gland, ovary, and mammary gland were affected in mice. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of benzene in male F344/N rats, female F344/N rats, male B6C3FW mice, and female B6C3FM mice. In male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. In female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity. In male mice, benzene caused increased incidences of Zymbal gland squamous cell carcinomas, malignant lymphomas, alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined), Harderian gland adenomas, and squamous cell carcinomas of the preputial gland. In female mice, benzene caused increased incidences of malignant lymphomas, ovarian granulosa cell tumors, ovarian benign mixed tumors, carcinomas and careinosarcomas of the mammary gland, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and Zymbal gland squamous cell carcin...

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Section: Genetic Toxicologymentioning

confidence: 99%

Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.

Huff

Haseman

DeMarini

et al. 1989

Environ Health Perspect

113

107

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“…BQ binds covalently to the 2-amino position of deoxyguanosine in vitro (Jowa et al 1990), and is known to react with both nucleophilic amino acids and peptides such as glutathione (Lunte et al 1983). One of the most reactive groups of the amino acids is the cysteinyl sulfhydryl group, and sulfhydryl conjugates of BQ to both cysteine and glutathione have been synthesized, detected and conclusively identified in microsomal incubations of benzene and phenol (Tunek et al 1980). Thus, it is logical to assume that BQ will bind to hemoglobin, which has a free sulfhydryl group.…”

Section: Discussionmentioning

confidence: 97%

S-Phenylcysteine formation in hemoglobin as a biological exposure index to benzene

et al. 1992

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Benzene is metabolized to intermediates that bind to hemoglobin, forming adducts. These hemoglobin adducts may be usable as biomarkers of exposure. In this paper, we describe the development of a gas chromatography/mass spectroscopy assay for quantitating the binding of the benzene metabolite, benzene oxide, to cysteine groups in hemoglobin. We used this assay to study the hemoglobin adduct, S-phenylcysteine (SPC), in the blood of rats and mice exposed to benzene either by inhalation or by gavage. We were able to detect SPC in the hemoglobin of exposed rats and mice, to show the linearity of the exposure dose-response relationship, and to establish the sensitivity limits of this assay. For the same exposure regime, rats showed considerably higher levels of SPC than did mice. As yet, we have not been able to detect SPC in the globin of humans occupationally exposed to benzene. We attempted to determine whether the SPC found in hemoglobin originated from the metabolism of benzene within or outside of the red blood cell. We hypothesized that the greatest red blood cell metabolism would be associated with peripheral reticulocytes, which retain high metabolic capacity. After exposing rats to benzene, we isolated the red blood cells and used discontinuous Percoll gradients to fractionate them into age groups. No differences in SPC levels were found among any of the fractions, suggesting that the SPC found in globin originates from the metabolism of benzene to benzene oxide in a location external to the red blood cell. To our knowledge, this is the first demonstration of the nonenzymatic binding of the benzene metabolite, benzene oxide, to protein.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…This step leads to catechol formation (111). Benzene oxide can also rearrange nonenzymatically to phenol, which is metabolized to hydroquinone (112). There is also evidence that the major hydroxylated metabolites of benzene can be formed by direct hydroxylation involving free radical insertion (113).…”

Section: Metabolismmentioning

confidence: 99%

Benzene toxicity and risk assessment, 1972-1992: implications for future regulation.

Paustenbach¹,

Bass²,

Price³

1993

Environ Health Perspect

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Acute and chronic exposure to benzene vapors poses a number of health hazards to humans. To evaluate the probability that a specific degree of exposure will produce an adverse effect, risk assessment methods must be used. This paper reviews much of the published information and evaluates the various risk assessments for benzene that have been conducted over the past 20 years. There is sufficient evidence that chronic exposure to relatively high concentrations of benzene can produce an increased incidence of acute myelogenous leukemia (AML). Some studies have indicated that benzene may cause other leukemias, but due to the inconsistency of results, the evidence is not conclusive. To predict the leukemogenic risk for humans exposed to much lower doses of benzene than those observed in most epidemiology studies, a model must be used. Although several models could yield plausible results, to date most risk assessments have used the linear-quadratic or conditional logistic models. These appear to be the most appropriate ones for providing the cancer risk for airborne concentrations of 1 ppb to 10 ppm, the range most often observed in the community and workplace. Of the seven major epidemiology studies that have been conducted, there is a consensus that the Pliofilm cohort (rubber workers) is the best one for estimating the cancer potency because it is the only one with good exposure and incidence of disease data. The current EPA, OSHA, and ACGIH cancer potency estimates for benzene are based largely on this cohort. A retrospective exposure assessment and an analysis of the incidence of disease in these workers were completed in 1991. All of these issues are discussed and the implications evaluated in this paper. The range of benzene exposures to which Americans are commonly exposed and the current regulatory criteria are also presented.

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Multi-step metabolic activation of benzene. Effect of superoxide dismutase on covalent binding to microsomal macromolecules, and identification of glutathione conjugates using high pressure liquid chromatography and field desorption mass spectrometry

Cited by 117 publications

References 28 publications

Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.

Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.

S-Phenylcysteine formation in hemoglobin as a biological exposure index to benzene

Benzene toxicity and risk assessment, 1972-1992: implications for future regulation.

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