Influence of strain differences in mice on the metabolism and toxicity of benzene*1, *2

Longacre, Stephen L.; Kocsis, James J.; Snyder, Robert

doi:10.1016/0041-008x(81)90324-0

Cited by 64 publications

(21 citation statements)

References 19 publications

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“…Our studies of the covalent interaction of benzene metabolites with cellular macromolecules suggested that this phenomenon might play an important role in the expression of toxicity. Sammett et al (5) showed that in rats partial hepatectomy correlated with both protection against benzene toxicity and reduced levels of covalent binding of benzene metabolites in bone marrow; Longacre et al (27) showed that the levels of covalently bound metabolites measured in the hematopoietic tissues were higher in mouse strains that were more sensitive to benzene toxicity than in those that were less sensitive. Rushmore et al (28) extensively investigated covalent binding in an isolated mitochondrial system; they showed that the benzene metabolites are capable of covalent binding to DNA and inhibiting protein and RNA synthesis.…”

Section: Microsomal Metabolismmentioning

confidence: 99%

An Overview of Benzene Metabolism

Snyder¹,

Hedli²

1996

Environ Health Perspect

105

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Benzene toxicity involves both bone marrow depression and leukemogenesis caused by damage to multiple classes of hematopoietic cells and a variety of hematopoietic cell functions. Study of the relationship between the metabolism and toxicity of benzene indicates that several metabolites of benzene play significant roles in generating benzene toxicity. Benzene is metabolized, primarily in the liver, to a variety of hydroxylated and ring-opened products that are transported to the bone marrow where subsequent secondary metabolism occurs. Two potential mechanisms by which benzene metabolites may damage cellular macromolecules to induce toxicity include the covalent binding of reactive metabolites of benzene and the capacity of benzene metabolites to induce oxidative damage. Although the relative contributions of each of these mechanisms to toxicity remains unestablished, it is clear that different mechanisms contribute to the toxicities associated with different metabolites. As a corollary, it is unlikely that benzene toxicity can be described as the result of the interaction of a single metabolite with a single biological target. Continued investigation of the metabolism of benzene and its metabolites will allow us to determine the specific combination of metabolites as well as the biological target(s) involved in toxicity and will ultimately lead to our understanding of the relationship between the production of benzene metabolites and bone marrow toxicity.

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Section: Microsomal Metabolismmentioning

confidence: 99%

An Overview of Benzene Metabolism

Snyder¹,

Hedli²

1996

Environ Health Perspect

105

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“…Other studies on the urinary metabolites in mice (Longacre et al 1981), have indicated that 81% is represented by phenol, 15% by catechol, and 4% by hydroquinone. Trace amounts of trans-tr~.ns muconic acid and of 1 ,2,4-trihydroxybenzene have also been 8.81 Fig.…”

Section: Kinetics and Metabolismmentioning

confidence: 99%

Possible implications from results of animal studies in human risk estimations for benzene: nonlinear dose-response relationship due to saturation of metabolism

Grilli

Lutz

Parodi

1987

J Cancer Res Clin Oncol

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Summary. To date, all risk assessment studies on benzene have been based almost exclusively on epiderniological data. Wehave attempted a more integrated and quantitative evaluation of carcinogenic risk for hurnans, trying to utilize, in addition to the epidemiological data, all data available, specifically data on metabolism, genotoxicity, and carcinogenicity in small rodents. An integrated evaluation of the globality of the available data seems to suggest a progressive saturation of metabolic capacity both for man and rodents between 10 and 100 ppm. The most susceptible target cells seem tobe different in humans (predominant induction of myelogenous leukemia) and small rodents (induction of a wide variety of tumors). Nevertheless, both epidemiological and experimental carcinogenicity data tend to indicate a flattening ofthe response for the highest dosages, again suggesting a general Saturation of mechanisms of metabolic activation, extended to different target tissues. From a quantitative point of view, the data suggest a carcinogenic potency at 10 ppm two to three times higher than that computable by a linear extrapolation from data in the 100 ppm range. These observations are in accord with the recent proposal of the European Economic Community of reducing benzene time-weighted average occupationallevels from 10 to 5 ppm.

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“…Of importance are those pathways giving rise to mono-and polyhydroxylated metabolites (e.g., phenol, hydroquinone, catechol, 1,2,4-benzenetriol), ring-opened metabolites (e.g., muconaldehyde, muconic acid) and biphenolic metabolites (e.g., 4,4'-biphenol) (9)(10)(11)(12)(13)(14)(15). The metabolism of benzene has been extensively studied in the liver and bone marrow (4,(19)(20)(21), but little effort has been than 99%. Benzene was obtained from American Burdick and Jackson (Muskegon, MI) (99.7% pure by GC analysis).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Metabolism of Benzene in Zymbal Gland and Other Key Target Tissues after Oral Administration in Rats

Low¹,

Meeks²,

Norris³

et al. 1989

Environmental Health Perspectives

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Solid tumors have been reported in the Zymbal gland, oral and nasal cavities, and mammary gland of Sprague-Dawley rats following chronic oral administration of benzene. The cause for the specificity of such lesions remains unclear, but it is possible that tissue-specific metabolism or pharmacokinetics of benzene is responsible. Metabolism and pharmacokinetic studies were carried out in our laboratory with '4C-benzene at oral doses of 0.15 to 500 mg/kg to ascertain tissue retention, metabolite profile, and elimination kinetics in target and nontarget organs and in blood. Findings from thoses studies indicate the following: a) the Zymbal gland is not a sink or a site of accumulation for benzene or its metabolites even after a single high dose (500 mg/kg) or after repeated oral administration; b) the metabolite profile is quantitatively different in target tissues (e.g., Zymbal gland, nasal cavity), nontarget tissues and blood; and c) pharmacokinetic studies show that the elimination of radioactivity from the Zymbal gland is biphasic.

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Influence of strain differences in mice on the metabolism and toxicity of benzene1, 2

Cited by 64 publications

References 19 publications

An Overview of Benzene Metabolism

An Overview of Benzene Metabolism

Possible implications from results of animal studies in human risk estimations for benzene: nonlinear dose-response relationship due to saturation of metabolism

Pharmacokinetics and Metabolism of Benzene in Zymbal Gland and Other Key Target Tissues after Oral Administration in Rats

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