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

Benzene, a common industrial chemical and a component of gasoline, is radiomimetic and exposure may lead progressively to aplastic anaemia, leukaemia, and multiple myeloma. Although benzene has been shown to cause many types of genetic damage, it has consistently been classified as a non-mutagen in the Ames test, possibly because of the inadequacy of the S9 microsomal activation system. The metabolism of benzene is complex, yielding glucuronide and sulphate conjugates of phenol, quinol, and catechol, L-phenylmercapturic acid, and muconaldehyde and trans, trans-muconic acid by ring scission. Quinol is oxidised to p-benzoquinone, which binds to vital cellular components or undergoes redox cycling to generate oxygen radicals; muconaldehyde, like p-benzoquinone, is toxic through depletion of intracellular glutathione. Exposure to benzene may also induce the microsomal mixed function oxidase, cytochrome P450 IIE1, which is probably responsible for the oxygenation of benzene, but also has a propensity to generate oxygen radicals. The radiomimetic nature of benzene and its ability to induce different sites of neoplasia indicate that formation of oxygen radicals is a major cause of benzene toxicity, which involves multiple mechanisms including synergism between arylating and glutathione-depleting reactive metabolites and oxygen radicals. The occupational exposure limit in the United Kingdom (MEL) and the United States (PEL) was 10 ppm based on the association of benzene exposure with aplastic anaemia, but recently was lowered to 5 ppm and 1 ppm respectively, reflecting a concern for the risk of neoplasia. The American Conference of Governmental Industrial Hygienists (ACGIH) has even more recently recommended that, as benzene is considered an A1 carcinogen, the threshold limit value (TLV) should be decreased to 0.1 ppm. Only one study in man, based on nine cases of benzene associated fatal neoplasia, has been considered suitable for risk assessment. Recent re-evaluation of these data indicated that past assessments may have overestimated the risk, and different authors have considered that lifetime exposure to benzene at 1 ppm would result in an excess of leukaemia deaths of 9.5 to 1.0 per 1000. Although in this study, deaths at low levels of benzene exposure were associated with multiple myeloma and a long latency period, instead of leukaemia, which might justify further lowering of the exposure limit, the risk assessment model has been found to be non-significant for response at low levels of exposure. The paucity of data for man, the complexity of the metabolic activation of benzene, the interactive and synergistic mechanisms of benzene toxicity and carcinogenicity, the different disease endpoints (aplastic anaemia, leukaemia, and multiple myeloma), and different individual susceptibilities, all indicate that in such a complex scenario, regulators should proceed with caution before making further changes to the exposure limit for this chemical.
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PMID:The toxicity of benzene and its metabolism and molecular pathology in human risk assessment. 185 46

Benzene is one of the best studied of the known human carcinogens. It causes leukemia in humans and a variety of solid tumors in rats and mice. Decades of research on benzene metabolism, pharmacokinetics, cytotoxicity, genotoxicity, and carcinogenicity in vivo and in vitro are starting to converge on a small set of overlapping hypotheses about the most probable biological mechanisms of benzene toxicity and carcinogenicity. Although there is still room for surprises, it seems likely that the ultimate answer to the mystery of how benzene exerts its multiple effects will consist of elaborations and extensions of one or more of the current hypotheses. This paper reviews benzene health effects and biology, showing how various aspects of metabolism and cytotoxicity fit together with genotoxic and nongenotoxic effects to help explain how benzene may cause cancer. Its goals are: (i) to introduce the qualitative biological background needed for detailed quantitative dose-response modeling of benzene cancer risks; and (ii) to survey a rapidly evolving area of research that shows promise of producing fundamental insights into the mechanisms of toxicity and carcinogenesis for several chemicals--benzene and perhaps phenols, catechols, and other hydroxylated ring hydrocarbons--in the decade ahead.
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PMID:Biological basis of chemical carcinogenesis: insights from benzene. 194 51

Benzene is an established human leukemogen. Workers occupationally exposed to benzene exhibit increased frequencies of both structural and numerical chromosomal aberrations in their peripheral blood lymphocytes. The metabolite(s) responsible for these chromosomal aberrations has not yet been identified. Using a modified micronucleus assay, we have examined the ability of the metabolites of benzene to induce chromosomal damage in human lymphocytes. An antikinetochore antibody was used to distinguish micronuclei that have a high probability of containing a whole chromosome (kinetochore positive) from those containing acentric fragments (kinetochore negative). In vitro treatments with the benzene metabolites hydroquinone, 1,4-benzoquinone, phenol, and catechol resulted in significant increases in micronuclei formation. Phenol, catechol, and 1,4-benzoquinone treatments resulted in moderate (2- to 5-fold) increases in micronuclei, whereas hydroquinone treatments resulted in a larger (11-fold) increase in micronuclei. Significant dose-related increases in kinetochore-positive micronucleated cells were not observed following 1,4-benzoquinone treatment but were observed following treatment with phenol, catechol, and hydroquinone. The higher efficacy of hydroquinone in inducing both total micronuclei and kinetochore-positive micronucleated cells when compared with catechol, phenol, and 1,4-benzoquinone suggests that hydroquinone is a major contributor to the clastogenicity and aneuploidy observed in the lymphocytes of benzene-exposed workers. Other metabolites may also contribute, however, to the genotoxic effects of benzene. Since consistent chromosomal aberrations are often observed in human leukemias, the ability of the phenolic metabolites of benzene to induce chromosomal damage in human cells also implicates them in benzene-induced leukemia.
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PMID:Characterization of micronuclei induced in human lymphocytes by benzene metabolites. 229 79

The hematotoxicity of benzene exposure has been well known for a century. Benzene causes leukocytopenia, thrombocytopenia, pancytopenia, etc. The clinical and hematologic picture of aplastic anemia resulting from benzene exposure is not different from classical aplastic anemia; in some cases, mild bilirubinemia, changes in osmotic fragility, increase in lactic dehydrogenase and fecal urobilinogen, and occasionally some neurological abnormalities are found. Electromicroscopic findings in some cases of aplastic anemia with benzene exposure were similar to those observed by light microscopy. Benzene hepatitis-aplastic anemia syndrome was observed in a technician with benzene exposure. Ten months after occurrence of hepatitis B, a severe aplastic anemia developed. The first epidemiologic study proving the leukemogenicity of benzene was performed between 1967 and 1973 to 1974 among shoe workers in Istanbul. The incidence of leukemia was 13.59 per 100,000, which is a significant increase over that of leukemia in the general population. Following the prohibition and discontinuation of the use of benzene in Istanbul, there was a striking decrease in the number of leukemic shoe workers in Istanbul. In 23.7% of our series, consisting of 59 leukemic patients with benzene exposure, there was a preceding pancytopenic period. Furthermore, a familial connection was found in 10.2% of them. The 89.8% of our series showed the findings of acute leukemia. The possible factors that may determine the types of leukemia in benzene toxicity are discussed. The possible role of benzene exposure is presented in the development of malignant lymphoma, multiple myeloma, and lung cancer.
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PMID:Hematotoxicity and carcinogenicity of benzene. 267 98

Benzene exposure can cause leukemia, aplastic anemia, and possibly lymphoma. In 1978, on the basis of strong but incomplete data then available on the risk of benzene-induced leukemia, the U.S. Occupational Safety and Health Administration (OSHA) reduced the permissible occupational exposure standard for benzene from 10 ppm to 1 ppm. Shortly thereafter, the Fifth Circuit Court of Appeals stayed this ruling, and in 1980, the Supreme Court overturned the regulation, citing insufficient evidence of benefit. Thus, from 1978 until the standard was again lowered to 1 ppm in 1987, American workers were exposed to benzene at levels in excess of 1 ppm. An estimated 9600 were exposed to levels between 1 and 10 ppm, and an additional 370 were exposed at levels above 10 ppm. To assess the risk resulting from this delay in regulation, we have conducted an epidemiologic risk analysis. We merged data on numbers of persons (238,000) exposed to benzene in seven occupational categories with dose-response data from three epidemiologic studies. The range of risk in these studies indicates that 44 to 152 excess leukemia deaths will ultimately result from exposure to benzene at 10 ppm over a working lifetime (45 years) and that lower or briefer exposures will result in proportionately fewer deaths. On this basis, we calculated that between 30 and 490 excess leukemia deaths will ultimately result from occupational exposures to benzene greater than 1 ppm that occurred between 1978 and 1987. Deaths from aplastic anemia and lymphoma will likely add to this toll. These data confirm the risk of regulatory delay. They suggest that the courts, in reviewing public health regulations, must beware of facile cost-benefit arguments and be willing to accept strong evidence of health risk even when such evidence is incomplete.
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PMID:Quantitative assessment of lives lost due to delay in the regulation of occupational exposure to benzene. 279 39

CBA/Ca male mice have been exposed to benzene in air at 10, 25, 100, 300, 400, and 3000 ppm for variable intervals 6 hr/day, 5 days/week for up to 16 weeks. Two weeks of inhaling 10 ppm produced no hematologic effects; 25 ppm induced a significant lymphopenia. Inhalation of 100, 300, and 400 ppm produced dose-dependent decreases in blood lymphocytes, bone marrow cellularity, marrow content of spleen colony-forming units (CFU-S) and an increased fraction of CFU-S in DNA synthesis. Exposure of mice to 300 ppm for 2, 4, 8, and 16 weeks produced severe lymphopenia and decrease in marrow CFU-S. Recovery was rapid and complete after 2 and 4 weeks of exposure. After 8 and 16 weeks of exposure, recovery of lymphocytes was complete within 8 weeks. It took 16 weeks for the CFU-S to recover to that of the age-matched controls after 8 weeks of exposure and 25 weeks to recover to age-matched after 16 weeks of exposure. Inhalation of 3000 ppm for 8 days was less damaging than inhalation of 300 ppm for 80 days (same integral amount of benzene inhaled). The inhalation of 3000 ppm has not increased the incidence of leukemia or shortened its latency for development. Inhalation of 300 ppm 6 hr/day for 16 weeks significantly increases the incidence of myelogenous neoplasms in male CBA/Ca mice. Inhalation of 100 ppm for same interval does not influence incidence of myelogenous neoplasms but does increase incidence of solid neoplasms particularly in female CBA/Ca mice. Benzene is a potent carcinogen in CBA/Ca mice.
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PMID:Hematotoxicity and carcinogenicity of inhaled benzene. 279 54

Benzene is a well documented carcinogen for the hematic and lymphopoietic system, and experimental research confirms its carcinogenicity for tumors of other sites. This report presents the results of a historical cohort study in a shoe manufacturing plant in Florence where cases of aplastic anemia and leukemia were reported in the 1960s. A total of 1008 men and 1005 women were considered eligible members of the cohort. For total mortality, comparing the rates of the cohort with the national rates, the standardized mortality ratio (SMR) was 79 for the women and 95 for the men. For the men excesses of risk for aplastic anemia [SMR 1566; 95% confidence interval (95% CI) 547-3264] and leukemia (SMR 400, 95% CI 146-870) were observed. The increased risk occurred among workers first employed during the period in which benzene was used, but the expected number of cases in the subsequent period was too small to evaluate whether any reduction in risk had occurred. No increasing pattern with duration of employment was discernible.
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PMID:Aplastic anemia, leukemia and other cancer mortality in a cohort of shoe workers exposed to benzene. 279 16

Benzene. The evidence for carcinogenicity of benzene in humans was evaluated by the IARC in 1982 as follows: "It is established that human exposure to commercial benzene or benzene-containing mixtures can cause damage to the haematopoietic system, including pancytopenia. The relationship between benzene exposure and the development of acute myelogenous leukaemia has been established in epidemiological studies. "Reports linking exposure to benzene with other malignancies were considered to be inadequate for evaluation. "There is sufficient evidence that benzene is carcinogenic to man." This evaluation now warrants some elaboration and updating. While the epidemiological evidence concerning benzene carcinogenicity is strongest for acute myelocytic leukaemia, there is some limited evidence of increased risks of chronic myeloid and chronic lymphocytic leukaemia. In addition, recent studies have suggested an increased risk of multiple myeloma, while others indicate a dose-related increase for total lymphatic and haematopoietic neoplasms. Corroborative evidence for such a generalized effect comes from experimental studies showing that exposure to benzene depresses all lympho-haematopoietic cell lines. While only limited evidence of benzene carcinogenicity in experimental animals exists, the recent findings of the National Toxicology Program (NTP, 1984) in the U.S.A. and Maltoni et al. (1985) strongly indicate that benzene is an experimental carcinogen. Toluene and xylene. While no direct human evidence is available, there is recent evidence of carcinogenicity of toluene and xylene at high concentrations in experimental animals. It should also be noted that any future epidemiological observations of cancer risks associated with toluene or xylene would have to take account of the suspected effects of benzene impurities.
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PMID:Carcinogenicity of benzene, toluene and xylene: epidemiological and experimental evidence. 305 47

Benzene is widely recognized as a leukemogen, and the Occupational Safety and Health Administration is currently attempting to limit exposure to it more strictly. The proposed new regulation is a limit of an eight-hour time-weighted average of 1 ppm in place of the current limit of 10 ppm. The fundamental rationale for the change is a perception that the current standard is associated with an inordinate excess of leukemia. The epidemiologic literature on benzene and leukemia supports the inference that benzene causes acute myelocytic leukemia. However, the available data are too sparse, or suffer other limitations, to substantiate the idea that this causal association applies at low levels (i.e., 1-10 ppm) of benzene. Nonetheless, under the assumption that causation does apply at such low levels, a number of authors, including ourselves, have performed risk assessments using similar data but different methodologies. The assessments that we consider acceptable suggest that, among 1,000 men exposed to benzene at 10 ppm for a working lifetime of 30 years, there would occur about 50 excess deaths due to leukemia in addition to the baseline expectation of seven deaths. However, this estimate is speculative and whether or not enough confidence can be placed in it to justify a lower occupational benzene standard remains a decision for policy makers.
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PMID:Benzene and leukemia. A review of the literature and a risk assessment. 263 57

Benzene is a heavily used industrial chemical, a petroleum byproduct, an additive in unleaded gas, and a ubiquitous environmental pollutant. Benzene is also a genotoxin, hematotoxin, and carcinogen. Chronic exposure causes aplastic anemia in humans and animals and is associated with increased incidence of leukemia in humans and lymphomas and certain solid tumors in rodents. Bioactivation of benzene is required for toxicity. In the liver, the major site of benzene metabolism, benzene is converted by a cytochrome P-450-mediated pathway to phenol, the major metabolite, and the secondary metabolites, hydroquinone and catechol. The target organ of benzene toxicity, the hematopoietically active bone marrow, metabolizes benzene to a very limited extent. Phenol is metabolized in the marrow cells by a peroxidase-mediated pathway to hydroquinone and catechol, and ultimately to quinones, the putative toxic metabolites. Benzene and its metabolites appear to be nonmutagenic, but they cause myeloclastogenic effects such as micronuclei, chromosome aberrations, and sister chromatid exchange. It is unknown whether these genomic changes, or the ability of the quinone metabolites to form adducts with DNA, are involved in benzene carcinogenicity. Benzene, through its active metabolites, appears to exert its hematological effects on the bone marrow stromal microenvironment by preventing stromal cells from supporting hemopoiesis of the various progenitor cells. Recent advances in our understanding of the mechanisms by which benzene exerts its genotoxic, hematotoxic, and carcinogenic effects are detailed in this review.
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PMID:Recent advances in the metabolism and toxicity of benzene. 331 42


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