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Benzene, formaldehyde (FA) and trichloroethylene (TCE) are ubiquitous chemicals in workplaces and the general environment. Benzene is an established myeloid leukemogen and probable lymphomagen. FA is classified as a myeloid leukemogen but has not been associated with non-Hodgkin lymphoma (NHL), whereas TCE has been associated with NHL but not myeloid leukemia. Epidemiologic associations between FA and myeloid leukemia, and between benzene, TCE and NHL are, however, still debated. Previously, we showed that these chemicals are associated with hematotoxicity in cross-sectional studies of factory workers in China, which included extensive personal monitoring and biological sample collection. Here, we compare and contrast patterns of hematotoxicity, monosomy 7 in myeloid progenitor cells (MPCs), and B-cell activation biomarkers across these studies to further evaluate possible mechanisms of action and consistency of effects with observed hematologic cancer risks. Workers exposed to benzene or FA, but not TCE, showed declines in cell types derived from MPCs, including granulocytes and platelets. Alterations in lymphoid cell types, including B cells and CD4+ T cells, and B-cell activation markers were apparent in workers exposed to benzene or TCE. Given that alterations in myeloid and lymphoid cell types are associated with hematological malignancies, our data provide biologic insight into the epidemiological evidence linking benzene and FA exposure with myeloid leukemia risk, and TCE and benzene exposure with NHL risk. [ABSTRACT FROM AUTHOR]

Benzene is a recognized hematotoxicant and carcinogen that produces genotoxic damage. DNA double-strand breaks (DSB) are one of the most severe DNA lesions caused directly and indirectly by benzene metabolites. DSB may lead to chromosome aberrations, apoptosis and hematopoietic progenitor cell suppression. We hypothesized that genetic polymorphisms in genes involved in DNA DSB repair may modify benzene-induced hematotoxicity. We analyzed one or more single nucleotide polymorphisms (SNPs) in each of seven candidate genes (WRN, TP53, NBS1, BRCA1, BRCA2, XRCC3 and XRCC4) in a study of 250 workers exposed to benzene and 140 controls in China. Four SNPs in WRN (Ex4 −16 G > A, Ex6 +9 C > T, Ex20 −88 G > T and Ex26 −12 T > G), one SNP in TP53 (Ex4 +119 C > G) and one SNP in BRCA2 (Ex11 +1487 A > G) were associated with a statistically significant decrease in total white blood cell (WBC) counts among exposed workers. The SNPs in WRN and TP53 remained significant after accounting for multiple comparisons. One or more SNPs in WRN had broad effects on WBC subtypes, with significantly decreased granulocyte, total lymphocyte, CD4+-T cell, CD8+-T cell and monocyte counts. Haplotypes of WRN were associated with decreased WBC counts among benzene-exposed subjects. Likewise, subjects with TP53 Ex4 +119 C > G variant had reduced granulocyte, CD4+-T cell and B cell counts. The effect of BRCA2 Ex11 +1487 A > G polymorphism was limited to granulocytes. These results suggest that genetic polymorphisms in WRN, TP53 and BRCA2 that maintain genomic stability impact benzene-induced hematotoxicity. [ABSTRACT FROM AUTHOR]

Although the toxicity of benzene has been linked to its metabolism, the dose-related production of metabolites is not well understood in humans, particularly at low levels of exposure. We investigated unmetabolized benzene in urine (UBz) and all major urinary metabolites [phenol (PH), E,E-muconic acid (MA), hydroquinone (HQ) and catechol (CA)] as well as the minor metabolite, S-phenylmercapturic acid (SPMA), in 250 benzene-exposed workers and 139 control workers in Tianjin, China. Median levels of benzene exposure were ∼1.2 p.p.m. for exposed workers (interquartile range: 0.53–3.34 p.p.m.) and 0.004 p.p.m. for control workers (interquartile range: 0.002–0.007 p.p.m.). (Exposures of control workers to benzene were predicted from levels of benzene in their urine.) Metabolite production was investigated among groups of 30 workers aggregated by their benzene exposures. We found that the urine concentration of each metabolite was consistently elevated when the group's median benzene exposure was at or above the following air concentrations: 0.2 p.p.m. for MA and SPMA, 0.5 p.p.m. for PH and HQ, and 2 p.p.m. for CA. Dose-related production of the four major metabolites and total metabolites (μmol/l/p.p.m. benzene) declined between 2.5 and 26-fold as group median benzene exposures increased between 0.027 and 15.4 p.p.m. Reductions in metabolite production were most pronounced for CA and PH <1 p.p.m., indicating that metabolism favored production of the toxic metabolites, HQ and MA, at low exposures. [ABSTRACT FROM AUTHOR]

Benzene is an established human hematotoxicant and leukemogen but its mechanism of action is unclear. To investigate the role of single-nucleotide polymorphisms (SNPs) on benzene-induced hematotoxicity, we analyzed 1395 SNPs in 411 genes using an Illumina GoldenGate assay in 250 benzene-exposed workers and 140 unexposed controls. Highly significant findings clustered in five genes (BLM, TP53, RAD51, WDR79 and WRN) that play a critical role in DNA repair and genomic maintenance, and these regions were then further investigated with tagSNPs. One or more SNPs in each gene were associated with highly significant 10–20% reductions (P values ranged from 0.0011 to 0.0002) in the white blood cell (WBC) count among benzene-exposed workers but not controls, with evidence for gene–environment interactions for SNPs in BLM, WRN and RAD51. Further, among workers exposed to benzene, the genotype-associated risk of having a WBC count <4000 cells/μl increased when using individuals with progressively higher WBC counts as the comparison group, with some odds ratios >8-fold. In vitro functional studies revealed that deletion of SGS1 in yeast, equivalent to lacking BLM and WRN function in humans, caused reduced cellular growth in the presence of the toxic benzene metabolite hydroquinone, and knockdown of WRN using specific short hairpin RNA increased susceptibility of human TK6 cells to hydroquinone toxicity. Our findings suggest that SNPs involved in DNA repair and genomic maintenance, with particular clustering in the homologous DNA recombination pathway, play an important role in benzene-induced hematotoxicity. [ABSTRACT FROM AUTHOR]