Effects of toluene on the metabolism, disposition and hemopoietic toxicity of [3H]benzene

Andrews, Larry S.; Lee, Eun Woo; Witmer, Charlotte; Kocsis, James J.; Snyder, Robert

doi:10.1016/0006-2952(77)90180-0

Cited by 185 publications

(54 citation statements)

References 15 publications

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“…Thus, inhibition of benzene metabolism by toluene, a competitive inhibitor, results in a decrease in benzene metabolism and a reduction in benzene toxicity (4). Decreasing the hepatic metabolism of benzene by partial hepatectomy also reduced benzene toxicity, suggesting that hepatic metabolism plays an important role in toxicity (5). In addition to hepatic metabolism, it appears that secondary metabolism of benzene metabolites in bone marrow contributes to toxicity (6)(7)(8)(9)(10)(11).…”

Section: Benzene Metabolism and Toxicitymentioning

confidence: 99%

“…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%

See 1 more Smart Citation

An Overview of Benzene Metabolism

Snyder¹,

Hedli²

1996

Environ Health Perspect

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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: Benzene Metabolism and Toxicitymentioning

confidence: 99%

Section: Microsomal Metabolismmentioning

confidence: 99%

An Overview of Benzene Metabolism

Snyder¹,

Hedli²

1996

Environ Health Perspect

Self Cite

105

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“…In humans, following benzene exposure at relatively low concentrations (amount of absorbed benzene ......,4-10 mglkg) (Teisinger et al 1952;Nomiyama and Nomiyama 1974a, b), about (Andrews et al 1977). 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.…”

Section: Kinetics and Metabolismmentioning

confidence: 99%

“…The results of Andrews et al (1977) Total amount ol Benzene lnhaled by an exposed rat urine were measured over a 24-h period. The micromole equivalents of benzene found as metabolites in the urine were similar (60.1 and 72.6), irrespective of doubling the dose.…”

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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“…Previous research has shown that benzene itself is probably not the actual toxicant, but is converted by hepatic metabolism to a metabolite(s) that travels to the bone marrow and exerts its toxic effects (1,2). There is, however, also the potential for benzene to be directly activated within the bone marrow itself (3).…”

Section: Introductionmentioning

confidence: 99%