Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzene is an important industrial chemical and environmental contaminant that causes leukemia. To obtain mechanistic insight into benzene's mechanism of action, we examined the impact of benzene on the human serum proteome in a study of exposed healthy shoe-factory workers and unexposed controls. Two sequential studies were performed, each using sera from 10 workers exposed to benzene (overall mean benzene air level >30 ppm) and 10 controls. Serum samples were subjected to anion-exchange fractionation and bound to three types of ProteinChip arrays (Ciphergen Biosystems, Fremont, CA) [hydrophobic (H50), metal affinity (IMAC3-Cu), and cation exchange (WCX2)]. Protein-expression patterns were detected by surface-enhanced laser desorption/ionization (SELDI)-TOF MS. Three proteins (4.1, 7.7, and 9.3 kDa) were consistently down-regulated in exposed compared with control subjects in both studies. All proteins were highly inversely correlated with individual estimates of benzene exposure (r > 0.75). The 7.7- and 9.3-kDa proteins were subsequently identified as platelet factor (PF)4 and connective tissue activating peptide (CTAP)-III. Initial proteomic results for PF4 and CTAP-III were subsequently confirmed in a single experiment using a ProteinChip-array-based immunoassay(Ciphergen Biosystems). The altered expression of the platelet-derived CXC-chemokines (40% and 63% for PF4 and CTAP-III, respectively) could not be explained by changes in absolute platelet counts. Thus, SELDI-TOF analysis of a limited number of exposed and unexposed subjects revealed that lowered expression of PF4 and CTAP-III proteins is a potential biomarker of benzene's early biologic effects and may play a role in the immunosuppressive effects of benzene.
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PMID:Decreased levels of CXC-chemokines in serum of benzene-exposed workers identified by array-based proteomics. 1628 41

Benzene is myelotoxic and leukemogenic in humans exposed at high doses (>1 ppm, more definitely above 10 ppm) for extended periods. However, leukemia risks at lower exposures are uncertain. Benzene occurs widely in the work environment and also indoor air, but mostly below 1 ppm, so assessing the leukemia risks at these low concentrations is important. Here, we describe a human physiologically-based pharmacokinetic (PBPK) model that quantifies tissue doses of benzene and its key metabolites, benzene oxide, phenol, and hydroquinone after inhalation and oral exposures. The model was integrated into a statistical framework that acknowledges sources of variation due to inherent intra- and interindividual variation, measurement error, and other data collection issues. A primary contribution of this work is the estimation of population distributions of key PBPK model parameters. We hypothesized that observed interindividual variability in the dosimetry of benzene and its metabolites resulted primarily from known or estimated variability in key metabolic parameters and that a statistical PBPK model that explicitly included variability in only those metabolic parameters would sufficiently describe the observed variability. We then identified parameter distributions for the PBPK model to characterize observed variability through the use of Markov chain Monte Carlo analysis applied to two data sets. The identified parameter distributions described most of the observed variability, but variability in physiological parameters such as organ weights may also be helpful to faithfully predict the observed human-population variability in benzene dosimetry.
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PMID:Physiologically-based pharmacokinetic modeling of benzene in humans: a Bayesian approach. 1694 86

A case-control study nested in the Health Watch cohort of petroleum industry workers, investigated whether the excess of lymphohematopoetic cancers, identified among male members of the Health Watch cohort, was associated with benzene exposure. Cases of non-Hodgkin's lymphoma (n = 31), multiple myeloma (n = 15), and leukemia (n = 33) were identified between 1981 and 1999. Cases were age-matched to five controls. Exposure was retrospectively estimated for each occupational history using an algorithm in a relational database. Benzene exposure measurements, supplied by Australian petroleum companies, were used to estimate exposure for specific tasks. The tasks carried out within the job, the products handled, and the technology used, were identified from interviews with contemporary colleagues. More than half of the subjects started work after 1965 and had an average exposure period of 20 years. Exposure was low, 85% of the cumulative exposure estimates were <10 ppm years. Matched analyses showed that non-Hodgkin's lymphoma and multiple myeloma were not associated with benzene exposure. Leukemia risk, however, was significantly increased for the subjects with greater than 16 ppm years cumulative exposure, odds ratio (OR) 51.9 (5.6-477) or with greater than 0.8 ppm intensity of highest exposed job. Cumulative exposures were similar to those found in comparable studies. The inclusion of occasional high exposures, for example, as a result of spillages, reduced the ORs, when the exposure was treated as either a continuous or a categorical variable. Our data demonstrate a strong association between leukemia and modest benzene exposure. The choice of cut-point and reference group has a marked effect on the ORs, but does not change the overall conclusions.
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PMID:The health watch case-control study of leukemia and benzene: the story so far. 1711 94

Benzene and benzene-containing products and solvents have long been associated with bone marrow toxicity. Both animal studies and human epidemiological studies have shown statistically significant increases of leukemia and other lymphohematopoietic cancers in workers exposed to benzene. The most common leukemia that has been associated with benzene exposure, also called benzene poisoning, is acute myelocytic leukemia (AML). A review of the epidemiological literature on workers exposed to benzene or benzene-containing solvents and products shows, without question, that this exposure is significantly related to other types of leukemia and lymphoma. In this article, we review the literature on the relationship between benzene exposure and chronic myelogenous leukemia (CML) and find that benzene and benzene-containing products are significantly related to morbidity and mortality from CML.
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PMID:Dangerous and cancer-causing properties of products and chemicals in the oil refining and petrochemical industries. Part XXX: Causal relationship between chronic myelogenous leukemia and benzene-containing solvents. 1711 96

Benzene is an organic solvent that has been used in industry for about 100 years throughout the world. Since 1973, a series of toxicological and molecular epidemiological studies on benzene were conducted by researchers at the Chinese Academy of Preventive Medicine (CAPM) (1973-1986) and subsequently by a collaboration between the CAPM and the National Cancer Institute (NCI) in the United States that began in 1986, which was joined by investigators from the University of California at Berkeley, the University of North Carolina at Chapel Hill, and New York University. The findings demonstrated that the risk of leukemia and lymphoma among benzene-exposed workers was significantly increased, with elevated risks for leukemia present not only at higher exposure but also among workers exposed to under 10 ppm. Therefore, the benzene permissible level was decreased to 1.8 ppm (6 mg/m(3)) and benzene-induced leukemia is treated as an occupational cancer in China. The benzene permissible level is 1.0 in the United States and in several other developed countries and it has been suggested to be decreased to 0.5 ppm (ACGIH). A number of potential biomarkers are related to benzene exposure and poisoning. Some of these are benzene oxide-protein adducts, chromosome aberration of lymphocytes, and GPA mutations in erythrocytes, a decrease in B cell and CD4(-)T cell counts in peripheral blood, and altered expression of CXCL16, ZNF331, JUN, and PF4 in lymphocytes. Variation in multiple benzene metabolizing genes may be associated with risk of benzene hematotoxicity, including CYP2E1, MPO, NQO1, and GSTT1.
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PMID:Progress of epidemiological and molecular epidemiological studies on benzene in China. 1711 57

Benzene is a known leukemogen. It has been hypothesized that benzene and natural estrogens initiate cancer by forming ortho-quinones (catechol quinones) that react with DNA in cells. These quinones form depurinating DNA adducts that generate the mutations leading to cancer. This study examined whether the treatment of normal human peripheral blood mononuclear cells with the ortho-quinones of benzene or estradiol would form DNA adducts and elicit an alteration in the proliferation of these cells. Both estradiol-3,4-quinone and benzene ortho-quinone formed depurinating DNA adducts and significantly increased the mitogen-induced proliferation of normal blood mononuclear cells. Immunophenotyping of the estradiol-3,4-quinone-treated blood cells indicated that monocyte/macrophage, natural killer and T-cells were particularly prone to hyperproliferation. Thus, DNA damage induced by the ortho-quinones of benzene and estradiol may promote the growth of human blood mononuclear cells, including those that appear in large numbers in leukemia and lymphoma.
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PMID:Ortho-quinones of benzene and estrogens induce hyperproliferation of human peripheral blood mononuclear cells. 1716 9

Epidemiological studies show that benzene exposure is associated with an increased incidence of leukemia and perhaps lymphoma. Chromosomal rearrangements are common in these hematopoietic diseases. Translocation t(14;18), the long-arm deletion of chromosome 6 [del(6q)], and trisomy 12 are frequently observed in lymphoma patients. Rearrangements of the MLL gene located on chromosome 11q23, such as t(4;11) and t(6;11), are common in therapy-related leukemias resulting from treatment with topoisomerase II inhibiting drugs. To examine numerical and structural changes in these chromosomes (2, 4, 6, 11, 12, 14, and 18), fluorescence in situ hybridization (FISH) was employed on metaphase spreads from workers exposed to benzene (n = 43) and matched controls (n = 44) from Shanghai, China. Aneuploidy (both monosomy and trisomy) of all seven chromosomes was increased by benzene exposure. Benzene also induced del(6q) in a dose-dependent manner (P(trend) = 0.0002). Interestingly, translocations between chromosomes 14 and 18, t(14;18), known to be associated with follicular non-Hodgkin lymphoma, were increased in the highly exposed workers (P < 0.001). On the other hand, translocations between chromosome 11 and other partner chromosomes that are found in therapy-induced leukemias were not increased. These data add weight to the notion that benzene can induce t(14;18) and del(6q) found in lymphoma, but do not support the idea that benzene induces t(4;11) or t(6;11). However, they do not rule out the possibility that other rearrangements of the MLL gene at chromosome 11q23 may be induced by benzene.
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PMID:Aberrations in chromosomes associated with lymphoma and therapy-related leukemia in benzene-exposed workers. 1758 86

In 1983, in the face of mounting evidence of excess leukemia among workers at Shell Oil's Wood River (IL) and Deer Park (TX) petroleum refineries, Shell initiated the Benzene Historical Exposure Study (BHES). Shell's prior research had implicated occupational exposure to benzene as the source of the excess leukemia. The BHES report submission, which ultimately found no link between exposure and the excess morbidity, coincided with OSHA's planned hearings over a new regulatory standard for benzene. Over the next two decades, Shell published several papers based on or expanding the BHES data, all of which concluded that the excess of leukemia was unrelated to benzene. A review of the raw data on which Shell and its consultants relied reveals that Shell manipulated and omitted data in order to reach conclusions that exculpated it from liability and helped delay stricter benzene regulation.
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PMID:Manipulated data in Shell's Benzene Historical Exposure Study. 1771 80

Benzene-induced cancer in humans was first reported in the late 1920s. Carcinogenesis findings in animals were not reported conclusively until 1979. Industry exploited this "discrepancy" to discredit the use of animal bioassays as surrogates for human exposure experience. The cardinal reason for the delay between first recognizing leukemia in humans and sought-after neoplasia in animals centers on poor design and conduct of experimental studies. The first evidence of carcinogenicity in animals manifested as malignant tumors of the zymbal glands (sebaceous glands in the ear canal) of rats, and industry attempted to discount this as being irrelevant to humans, as this organ is vestigial and not present per se in humans. Nonetheless, shortly thereafter benzene was shown to be carcinogenic to multiple organ sites in both sexes of multiple strains and multiple species of laboratory animals exposed via various routes. This paper presents a condensed history of the benzene bioassay story with mention of benzene-associated human cancers.
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PMID:Benzene-induced cancers: abridged history and occupational health impact. 1771 79

A large population of humans is exposed to benzene from various occupational and environmental sources. Benzene is an established human and animal carcinogen. Exposure to benzene has been associated with leukaemia in humans and several types of malignancies in animals. The exact mechanism of benzene-induced toxicity is poorly understood. It is believed that benzene exerts its adverse effects by metabolic activation to toxic metabolites. Certain benzene metabolites are genotoxic and mutagenic. This consolidated short-review is composed of human and animal studies to summarize the adverse effects of benzene with special reference to molecular mechanisms involved in benzene-induced toxicity.
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PMID:Benzene's toxicity: a consolidated short review of human and animal studies. 1798 39


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