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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzene is a potent hematotoxin and has been shown to cause leukemia in man. Chronic toxicity studies indicate that B6C3F1 mice are more susceptible than F334/N rats to benzene toxicity. The purpose of the studies presented in this paper was to determine if there were metabolic differences between F344/N rats and B6C3F1 mice which might be responsible for this increased susceptibility. Metabolites of benzene in blood, liver, lung, and bone marrow were measured during and following a 6-hr 50 ppm exposure to benzene vapor. Hydroquinone glucuronide, hydroquinone, and muconic acid, which reflect pathways leading to potential toxic metabolites of benzene, were present in much greater concentrations in the mouse than in rat tissues. Phenylsulfate, a detoxified metabolite, and an unknown water-soluble metabolite were present in approximately equal concentrations in these two species. These results indicate that the proportion of benzene metabolized via pathways leading to the formation of potentially toxic metabolites as opposed to detoxification pathways was much higher in B6C3F1 mice than in F344 rats, which may explain the higher susceptibility of mice to benzene-induced hematotoxicity and carcinogenicity.
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PMID:Differences in the metabolism and disposition of inhaled [3H]benzene by F344/N rats and B6C3F1 mice. 337 10

Benzene is one of the world's major commodity chemicals. It is derived from petroleum and coal and is used both as a solvent and as a starting material in chemical syntheses. The numerous industrial uses of benzene over the last century need not be recounted here, but the most recent addition to the list of uses of benzene is as a component in a mixture of aromatic compounds added to gasoline for the purpose of replacing lead compounds as anti-knock ingredients. The best known and longest recognized toxic effect of benzene is the depression of bone marrow function seen in occupationally exposed individuals. These people have been found to display anemia, leucopenia, and/or thrombocytopenia. When pancytopenia, i.e., the simultaneous depression of all three cell types, occurs and is accompanied by bone marrow necrosis, the syndrome is called aplastic anemia. In addition to observing this decrease in humans and relating it to benzene exposure, it has been possible to establish animal models which mimic the human disease. The result has been considerable scientific investigation into the mechanism of benzene toxicity. Although the association between benzene exposure and aplastic anemia has been recognized and accepted throughout most of this century, it is only recently that leukemia, particularly of the acute myelogenous type, has been related to benzene. The acceptance of benzene as an etiological agent in aplastic anemia in large measure derives from our ability to reproduce the disease in most animals treated with sufficiently high doses of benzene over the necessary time period. Unfortunately, despite extensive efforts in several laboratories, it has not been possible to establish a reproducible, reliable model for the study of benzene-induced leukemia. The recent demonstration that several animals exposed to benzene either by inhalation or in the drinking water during studies by Drs. B. Goldstein and C. Maltoni suggests that such a model may be forthcoming. Nevertheless, at this time it is not clear whether bone marrow damage of the type that leads to aplastic anemia is required for the development of leukemia. Most studies of benzene toxicity have involved dosing animals with benzene either by inhalation or by injection, using high doses to ensure a toxic response. Very few studies have concentrated on the oral route of administration and none have concentrated on administering benzene by mouth at the low doses occasionally detected in drinking water.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Chemical of current interest--benzene. 359 Feb 6

In 1982, White et al published an assessment of quantitative leukemia risk associated with lifetime occupational exposure to benzene. At about the same time, IARC (1982) published estimates of quantitative cancer risk associated with industrial chemicals. Benzene was one of the two chemicals selected by IARC for its risk estimation. This paper presents a summary of these assessments along with new study results demonstrating adverse effects on bone marrow and peripheral blood cells as a result of low-level benzene exposure. Mathematical extrapolations based on epidemiologic studies are consistent with a finding of significant risk of dying from leukemia under the current occupational permissible exposure limit of 10 ppm. Although a significant reduction of risk could be expected to be achieved by reducing exposure to 1 ppm, a significant risk may still remain. The uncertainty of the dose-response projections rests on the underlying estimates of relative risk of death from leukemia, the estimates of benzene exposure (dose), and the appropriateness of the mathematical model. Recent findings in experimental animals demonstrate chromosomal damage to bone marrow cells, significant depression of the bone marrow, and disturbances of immune system function as a result of less than 1 week of exposure to the current permissible benzene exposure limit of 10 ppm. This was the lowest dose tested. These experimental findings provide further evidence of a potentially significant risk of bone marrow proliferative cancer (leukemia) as a result of low-dose benzene exposure.
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PMID:Projections of leukemia risk associated with occupational exposure to benzene. 389 May 30

Benzene has the sad privilege of being the only industrial chemical inducing leukemia in susceptible individuals chronically exposed to its vapors. Hence, benzene has been included in the list of human carcinogens. Acute myeloblastic leukemia and erythroleukemia are typical examples of benzene leukemia. Most cases show some features in common: 1) development after many years of exposure and, in some cases many months after leaving the toxic atmosphere; 2) leucopenia or moderate degree of leucocytosis; and 3) splenohepatomegaly discrete or absent. Finding of an antecedent of pancytopenia reinforces the suspicion of benzene as the causative agent. There is still no agreement about the role played by benzene in chronic types of leukemia. In assessing diagnosis of benzene leukemia much importance has been attached by French authors and by myself to the demonstration of benzene in blood or in bone marrow aspirates or biopsies. Treatment of benzene hemopathy based on the oral administration of "anti-benzene compounds" such as methyl-donors and thiol-aminoacids is proposed here based on personal research in rabbits, in leukemic patients treated by benzene in the past and on myself as a volunteer. In pre-leukemic states, lowering the benzene burden of the bone marrow might prevent the further development of acute leukemia. Recently, I found out that: 1) benzene can be converted to phenol in the bone marrow independently of liver oxidizing enzymes; 2) benzene injected in the femoral artery of the rabbit can provoke histological changes at the isolated tibial marrow.
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PMID:An hypothesis for the induction of leukemia by benzene. 657 48

Benzene has been known to be a bone marrow poison for almost a century. However, it was not until the last decade that benzene's carcinogenic potential was demonstrated by epidemiologic studies. The proposed regulation by the Occupational Safety and Health Administration (OSHA) to lower exposure levels of benzene in the workplace, and the court challenges that followed, have made the evidence of benzene toxicity a frequent topic of discussion and analysis. Epidemiologic evidence of leukemia risk associated with benzene exposure is summarized, including a discussion of certain contentions raised during the OSHA hearing. Special attention is given to information on specific cell types of leukemia associated with benzene and to qualitative and quantitative assessments of health risks associated with low-level benzene exposure.
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PMID:Benzene: epidemiologic observations of leukemia by cell type and adverse health effects associated with low-level exposure. 665 40

Benzene is a major commodity chemical of great value to industry. It has long been recognized that overexposure to benzene could result in damage to the blood-forming organs of the body. More recently, it has become apparent that chronic high levels of exposure are associated with the development of leukemia. Animal experiments have also suggested that overexposure to benzene may result in certain reproductive risks.
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PMID:Benzene in the workplace. 745 81

Benzene is a carcinogen in rodents and a cause of bone marrow toxicity and leukemia in humans. p-Benzoquinone (p-BQ) is one of the stable metabolites of benzene, as well as of a number of drugs and other chemicals. 2'-Deoxycytidine (dC) and 2'-deoxyadenosine (dA) were allowed to react with p-BQ in aqueous solution at pH 7.4 and 4.5. The yields were considerably higher at pH 4.5 than at pH 7.4, as indicated by HPLC analysis. The desired products were isolated by column chromatography on silica gel or cellulose. Identification was done by FAB-MS, 1H NMR, and UV spectroscopy. The reaction of p-BQ with dC and dA at pH 4.5 produced the exocyclic compounds 3-hydroxy-1,N4-benzetheno-2'-deoxycytidine (p-BQ-dC), and 9-hydroxy-1,N6-benzetheno-2'-deoxyadenosine (p-BQ-dA), respectively, in a large scale and high yield. These adducts have been previously made in a microgram scale as the 3'-phosphate for 32P-postlabeling studies of their incidence in DNA. The p-BQ-dC and p-BQ-dA adducts have, in addition to the two hydroxyl groups of deoxyribose, one newly formed hydroxyl group at the C-3 or C-9 of the exocyclic base of each product respectively. Incorporation of these adducts into oligonucleotides as the phosphoramidite requires the protection of all three hydroxyl groups in these compounds. The exocyclic hydroxyl on the base has been successfully protected by acylation after protecting the 5'- and the 3'-hydroxyl groups of the sugar moiety with a 4,4'-dimethoxytrityl group and a cyanoethyl N,N-diisopropylphosphoramidite group, respectively. For the first time, to our knowledge, the fully protected phosphoramidites of p-BQ-dC and p-BQ-dA were prepared and incorporated site-specifically into a series of oligonucleotides. The coupling efficiency was very high (> 98%). However, deprotection of the DNA oligomers with ammonia produced only 50% of the desired oligomers containing the adduct. In contrast, when 10% of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in methanol at room temperature was used, only the desired oligomers were detected by HPLC. Thus, by deprotecting the oligomers with methoxide ions (DBU/methanol) and avoiding the use of ammonia, a high yield of modified DNA was obtained. After purification of these oligomers by HPLC, they were hydrolyzed enzymatically and analyzed by HPLC, which confirmed the base composition and the incorporation of the adducts. The mass spectroscopic analysis of the DNA oligomers was confirmed by electrospray MS. These oligomers are now under investigation for their biochemical properties.
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PMID:Large scale synthesis of p-benzoquinone-2'-deoxycytidine and p-benzoquinone-2'-deoxyadenosine adducts and their site-specific incorporation into DNA oligonucleotides. 749 36

Benzene is a human carcinogen; exposure to benzene can result in aplastic anemia and leukemia. Data from animal models are frequently used in the risk assessment for benzene. In rodent studies, mice have been shown to be more sensitive to benzene-induced hematotoxicity than rats. In this regard, we have observed that bone marrow stromal cells from mice were significantly more susceptible to the cytotoxicity induced by the benzene metabolites hydroquinone (HQ) and benzoquinone (BQ) than cells from rats. Since cellular glutathione (GSH) and quinone reductase (QR) are known to play critical roles in modulating HQ-induced cytotoxicity, we have measured the GSH content and the QR and glutathione S-transferase (GST) activity in stromal cells from both species. In rat cells, the GSH content and the QR specific activity were 2 and 28 times as much as those from mice, respectively. GSH and QR in both mouse and rat stromal cells were inducible by 1,2-dithiole-3-thione (D3T). D3T pretreatment of both mouse and rat stromal cells resulted in a marked protection against HQ-induced toxicity. Pretreatment of both mouse and rat stromal cells with GSH ethyl ester also provided a dramatic protection against HQ-induced toxicity. Conversely, dicoumarol, an inhibitor of QR, enhanced the HQ-induced toxicity in stromal cells from both mice and rats, indicating an important role for QR in modulating HQ-induced stromal toxicity in both species. Buthionine sulfoximine (BSO), which depleted GSH significantly in both species, potentiated the HQ-induced toxicity in mouse but not in rat stromal cells. Surprisingly, incubation of stromal cells with BSO resulted in a significant induction of QR, especially in rats. The failure of BSO to potentiate HQ-induced toxicity in rat stromal cells may be due to the concomitant induction of QR by BSO. Overall, this study demonstrates that the differences in stromal cellular GSH content and QR activity between mice and rats contribute to their respective susceptibility to HQ-induced cytotoxicity in vitro, and may be involved in the greater in vivo sensitivity of mice to benzene-induced hematotoxicity.
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PMID:Differences in xenobiotic detoxifying activities between bone marrow stromal cells from mice and rats: implications for benzene-induced hematotoxicity. 756 17

Occupational exposure to benzene is known to cause leukemia, but the mechanism remains unclear. Unlike most other carcinogens, benzene and its metabolites are weakly or nonmutagenic in most simple gene mutation assays. Benzene and its metabolites do, however, produce chromosomal damage in a variety of systems. Here, we have used the glycophorin A (GPA) gene loss mutation assay to evaluate the nature of DNA damage produced by benzene in 24 workers heavily exposed to benzene and 23 matched control individuals in Shanghai, China. The GPA assay identifies stem cell or precursor erythroid cell mutations expressed in peripheral erythrocytes of MN-heterozygous subjects, distinguishing the NN and N phi mutant variants. A significant increase in the NN GPA variant cell frequency (Vf) was found in benzene-exposed workers as compared with unexposed control individuals (mean +/- SEM, 13.9 +/- 1.7 per million cells vs. 7.4 +/- 1.1 per million cells in control individuals; P = 0.0002). In contrast, no significant difference existed between the two groups for the N phi Vf (9.1 +/- 0.9 vs. 8.8 +/- 1.8 per million cells; P = 0.21). Further, lifetime cumulative occupational exposure to benzene was associated with the NN Vf (P = 0.005) but not with the N phi Vf (P = 0.31), suggesting that NN mutations occur in longer-lived bone marrow stem cells. NN variants result from loss of the GPA M allele and duplication of the N allele, presumably through recombination mechanisms, whereas NO variants arise from gene inactivation, presumably due to point mutations and deletions. Thus, these results suggest that benzene produces gene-duplicating mutations but does not produce gene-inactivating mutations at the GPA locus in bone marrow cells of humans exposed to high benzene levels. This finding is consistent with data on the genetic toxicology of benzene and its metabolites and adds further weight to the hypothesis that chromosome damage and mitotic recombination are important in benzene-induced leukemia.
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PMID:Benzene induces gene-duplicating but not gene-inactivating mutations at the glycophorin A locus in exposed humans. 773 33

Benzene exposure causes leukemia and lymphomas. Recent epidemiological findings have also shown an association between cigarette smoking and an increased risk of leukemia. However, further evidence is required to document the biological plausibility of this association. In evaluating this link, it is important to note that cigarette smoke contains benzene and various pyrolytic compounds, among other carcinogens. This study aims to determine the uptake of benzene by measuring 3 benzene-related compounds in cigarette smokers and non-smokers. Urinary concentrations of catechol (CAT), hydroquinone (HQ), and trans,trans-muconic acid (tt-MA) were measured by high-performance liquid chromatography (HPLC) with fluorimetric and UV detection, respectively. The results showed that these compounds were present in all urine samples. However, the concentrations were significantly higher in smokers than in non-smokers. The mean level of urinary tt-MA was 0.19 +/- 0.09 mg/g creatinine for 46 male smokers and the corresponding value for 40 non-smokers was 0.14 +/- 0.07 mg/g creatinine. The mean concentrations of HQ and CAT were 0.81 +/- 0.4 and 3.51 +/- 2.6 mg/g creatinine for smokers, and 0.45 +/- 0.4 and 1.94 +/- 1.2 mg/g creatinine for non-smokers, respectively. These results suggest that cigarette smoking is associated with a significant additional exposure to benzene and its related compounds. Furthermore, significant correlations were observed between the concentrations of cotinine, the metabolite of nicotine, and the above compounds. These findings suggest that the exposure originated from cigarette smoking.
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PMID:Elevated levels of benzene-related compounds in the urine of cigarette smokers. 792 15


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