Benzene myeloclastogenicity: A function of its metabolism

Gad-El-Karim, M.; Ramanujam, V. M. Sadagopa; Ahmed, A. E.; Legator, Marvin S.

doi:10.1002/ajim.4700070511

Cited by 34 publications

(10 citation statements)

References 50 publications

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“…In addition, Tice (82,84). In addition, hydroquinone also induced micronuclei in mice in vivo (92,98,202,203). As expected for a clastogen, hydroquinone was not mutagenic in Salmonella (38,202,204).…”

Section: Genetic Toxicologymentioning

confidence: 90%

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: 90%

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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“…Glucuronidation and sulfation pathways have been omitted for clarity. al., 1979), while pretreatment of mice with inducers of metabolism such as 3-methylcholanthrene and b -naphthoflavone increased both benzene metabolism and benzene toxicity (Gad-el-Karim et al, 1985. The primary step of benzene oxidation is catalyzed primarily by cytochrome P-4502E1 (CYP2E1), and inhibition of this pathway has been shown to reduce benzene-induced genotoxicity in mice, as measured using the comet assay (Tuo et al, 1996).…”

Section: Figurementioning

confidence: 99%

“…Phenol does not reproduce the myelotoxicity of benzene: This issue was perhaps the major problem associated with the phenolic mechanism. Phenol is metabolized to hydroquinone and other polyphenolics, so its inability to reproduce the myelotoxicity of benzene (Tunek et al, 1981;Gad-el-Karim et al, 1985) was puzzling. Recent data suggested an explanation for this problem related to zonation of liver enzymes (Medinsky et al, 1995;Hedli et al, 1997).…”

Section: Rossmentioning

confidence: 99%

The Role of Metabolism and Specific Metabolites in Benzene-Induced Toxicity: Evidence and Issues

Ross¹

2000

Journal of Toxicology and Environmental Health, Part A

162

111

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“…Many studies indicate that benzene must be metabolized to produce its major toxic effects (31,89,(165)(166)(167)(168). However, the mechanism for benzene toxicity remains unclear.…”

Section: Mechanisms Of Actionmentioning

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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Benzene myeloclastogenicity: A function of its metabolism

Cited by 34 publications

References 50 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.

The Role of Metabolism and Specific Metabolites in Benzene-Induced Toxicity: Evidence and Issues

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

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