Benzene exposure-response and risk of lymphoid neoplasms in Chinese workers: A multicenter case-cohort study.

BACKGROUND: While international agreement supports a causal relationship of benzene exposure with acute myeloid leukemia, there is debate about benzene and lymphoid neoplasm risks. METHODS: In a case-cohort study with follow-up of 110 631 Chinese workers during 1972-1999, we evaluated benzene exposure-response for non-Hodgkin lymphoma (NHL), lymphoid leukemias (LL), acute lymphocytic leukemia (ALL), and total lymphoid neoplasms (LN). We estimated benzene exposures using state-of-the-art hierarchical modeling of occupational factors calibrated with historical routine measurements and evaluated cumulative exposure-response using Cox regression. RESULTS: NHL and other specified LN were increased in exposed vs unexposed workers. However, there was no evidence of exposure-response for NHL or other specified LN. Based on a linear exposure-response, relative risks at 100 parts per million-years (RR at 100 ppm-years) for cumulative benzene exposure using a 2-year lag (exposure at least 2 years before the time at risk) were 1.05 for NHL (95 percent confidence interval (CI) = 0.97, 1.27; 32 cases), 1.11 for LL (95% CI < 0, 1.66; 12 cases), 1.21 for ALL (95% CI < 0, 3.53; 10 cases), and 1.02 for total LN (95% CI < 0, 1.16; 49 cases). No statistically significant exposure-response trends were apparent for these LN for 2 to <10-year or ≥10-year lags. NHL risks were not significantly modified by sex, age, or year at first exposure, attained age, or time since exposure. CONCLUSION: Given the study strengths and limitations, we found little evidence of exposure-response for benzene and NHL, LL, ALL, or total LN, although NHL and other specified LN were increased in exposed vs unexposed individuals.

Benzene Exposure Response and Risk of Myeloid Neoplasms in Chinese Workers: A Multicenter Case-Cohort Study.

BACKGROUND: There is international consensus that benzene exposure is causally related to acute myeloid leukemia (AML), and more recent evidence of association with myelodysplastic syndromes (MDS). However, there are uncertainties about the exposure response, particularly risks by time since exposure and age at exposure. METHODS: In a case-cohort study in 110 631 Chinese workers followed up during 1972-1999 we evaluated combined MDS/AML (n = 44) and chronic myeloid leukemia (n = 18). We estimated benzene exposures using hierarchical modeling of occupational factors calibrated with historical routine measurements, and evaluated exposure response for cumulative exposure and average intensity using Cox regression; P values were two-sided. RESULTS: Increased MDS/AML risk with increasing cumulative exposure in our a priori defined time window (2 to <10 years) before the time at risk was suggested (Ptrend = 08). For first exposure (within the 2 to <10-year window) before age 30 years, the exposure response was stronger (P = .004) with rate ratios of 1.12 (95% confidence interval [CI] = 0.27 to 4.29), 5.58 (95% CI = 1.65 to 19.68), and 4.50 (95% CI = 1.22 to 16.68) for cumulative exposures of more than 0 to less than 40, 40 to less than 100, and at least 100 ppm-years, respectively, compared with no exposure. There was little evidence of exposure response after at least 10 years (Ptrend = .94), regardless of age at first exposure. Average intensity results were generally similar. The risk for chronic myeloid leukemia was increased in exposed vs unexposed workers, but appeared to increase and then decrease with increasing exposure. CONCLUSION: For myeloid neoplasms, the strongest effects were apparent for MDS/AML arising within 10 years of benzene exposure and for first exposure in the 2 to less than 10-year window before age 30 years.

Adductomic signatures of benzene exposure provide insights into cancer induction.

Although benzene has long been recognized as a cause of human leukemia, the mechanism by which this simple molecule causes cancer has been problematic. A complicating factor is benzene metabolism, which produces many reactive intermediates, some specific to benzene and others derived from redox processes. Using archived serum from 20 nonsmoking Chinese workers, 10 with and 10 without occupational exposure to benzene (exposed: 3.2-88.9 ppm, controls: 0.002-0.020 ppm), we employed an adductomic pipeline to characterize protein modifications at Cys34 of human serum albumin, a nucleophilic hotspot in extracellular fluids. Of the 47 measured human serum albumin modifications, 39 were present at higher concentrations in benzene-exposed workers than in controls and many of the exposed-control differences were statistically significant. Correlation analysis identified three prominent clusters of adducts, namely putative modifications by benzene oxide and a benzene diolepoxide that grouped with other measures of benzene exposure, adducts of reactive oxygen and carbonyl species, and Cys34 disulfides of small thiols that are formed following oxidation of Cys34. Benzene diolepoxides are potent mutagens and carcinogens that have received little attention as potential causes of human leukemia. Reactive oxygen and carbonyl species-generated by redox processes involving polyphenolic benzene metabolites and by Cyp2E1 regulation following benzene exposure-can modify DNA and proteins in ways that contribute to cancer. The fact that these diverse human serum albumin modifications differed between benzene-exposed and control workers suggests that benzene can increase leukemia risks via multiple pathways involving a constellation of reactive molecules.

Retrospective benzene exposure assessment for a multi-center case-cohort study of benzene-exposed workers in China.

Quality of exposure assessment has been shown to be related to the ability to detect risk of lymphohematopoietic disorders in epidemiological investigations of benzene, especially at low levels of exposure. We set out to build a statistical model for reconstructing exposure levels for 2898 subjects from 501 factories that were part of a nested case-cohort study within the NCI-CAPM cohort of more than 110,000 workers. We used a hierarchical model to allow for clustering of measurements by factory, workshop, job, and date. To calibrate the model we used historical routine monitoring data. Measurements below the limit of detection were accommodated by constructing a censored data likelihood. Potential non-linear and industry-specific time-trends and predictor effects were incorporated using regression splines and random effects. A partial validation of predicted exposures in 2004/2005 was performed through comparison with full-shift measurements from an exposure survey in facilities that were still open. Median cumulative exposure to benzene at age 50 for subjects that ever held an exposed job (n=1175) was 509 mg/m(3) years. Direct comparison of model estimates with measured full-shift personal exposure in the 2004/2005 survey showed moderate correlation and a potential downward bias at low (<1 mg/m(3)) exposure estimates. The modeling framework enabled us to deal with the data complexities generally found in studies using historical exposure data in a comprehensive way and we therefore expect to be able to investigate effects at relatively low exposure levels.

A retrospective cohort study of cause-specific mortality and incidence of hematopoietic malignancies in Chinese benzene-exposed workers.

Benzene exposure has been causally linked with acute myeloid leukemia (AML), but inconsistently associated with other hematopoietic, lymphoproliferative and related disorders (HLD) or solid tumors in humans. Many neoplasms have been described in experimental animals exposed to benzene. We used Poisson regression to estimate adjusted relative risks (RR) and the likelihood ratio statistic to derive confidence intervals for cause-specific mortality and HLD incidence in 73,789 benzene-exposed compared with 34,504 unexposed workers in a retrospective cohort study in 12 cities in China. Follow-up and outcome assessment was based on factory, medical and other records. Benzene-exposed workers experienced increased risks for all-cause mortality (RR = 1.1, 95% CI = 1.1, 1.2) due to excesses of all neoplasms (RR = 1.3, 95% CI = 1.2, 1.4), respiratory diseases (RR = 1.7, 95% CI = 1.2, 2.3) and diseases of blood forming organs (RR = ∞, 95% CI = 3.4, ∞). Lung cancer mortality was significantly elevated (RR = 1.5, 95% CI = 1.2, 1.9) with similar RRs for males and females, based on three-fold more cases than in our previous follow-up. Significantly elevated incidence of all myeloid disorders reflected excesses of myelodysplastic syndrome/acute myeloid leukemia (RR = 2.7, 95% CI = 1.2, 6.6) and chronic myeloid leukemia (RR = 2.5, 95% CI = 0.8, 11), and increases of all lymphoid disorders included excesses of non-Hodgkin lymphoma (RR = 3.9, 95%CI = 1.5, 13) and all lymphoid leukemia (RR = 5.4, 95%CI = 1.0, 99). The 28-year follow-up of Chinese benzene-exposed workers demonstrated increased risks of a broad range of myeloid and lymphoid neoplasms, lung cancer, and respiratory diseases and suggested possible associations with other malignant and non-malignant disorders.

[Association of the glycophorin A gene mutation in peripheral erythrocytes and chronic benzene poisoning].

OBJECTIVE: To explore the association of the glycophorin A(GPA) gene mutation in peripheral erythrocytes and chronic benzene poisoning. METHODS: Sixty-three patients with chronic benzene poisonings and 45 benzene-exposed workers who were engaged in the same job title were investigated. Fluorescence immunolabeling technique and flow cytometry were used to detect GPA mutation frequency in peripheral read blood cell. RESULTS: A significant decrease in WBC count and neutrophil count was found in patients with chronic benzene poisoning compared with control individuals (P<0.01). The WBC count and neutrophil count both decreased along with the GPA-NN frequency, and the trends were significant(P<0.05).Both WBC counts and neutrophil counts decreased as the frequency, and trends were significant(P<0.05). GPA-NN frequency increased along with the accumulative exposure score, and the trend was significant (P = 0.0026). There was no significant trend between the GPA-Nphi frequency and the accumulative exposure score (P = 0.2037). CONCLUSION: A decrease in WBC count and neutrophil count is found in patients with chronic benzene poisoning, which can arise from genetic damage in bone marrow stem cells, namely gene-duplicating mutations (NN) at the GPA locus in bone marrow cells of MN-heterozygous subjects, GPA-NN mutagens contributed to the pathogenesis of chronic benzene poisoning.

[Study on repair capacity of DNA damage associated with chronic benzene poisoning].

OBJECTIVE: To explore the repair capacity of DNA damage associated with chronic benzene poisonings. METHODS: 63 workers suffered from chronic benzene poisonings and 45 workers exposed to benzene, who were engaged in the same job title, were investigated. Comet assay and cytokinesis-block micronucleus (CBMN) detection were used to evaluate gamma-radiation-induced DNA and chromosomal damage and repair capacity in peripheral blood lymphocyte. RESULTS: The comet tail length difference of the benzene poisoning group (4.64 +/- 1.57 microm) was significantly higher than that of the control group (3.77 +/- 1.30 microm) (P = 0.0029). There was no significant difference of the 3AB index between the poisoning group and the control group. The relative risk of benzene poisoning in the subject with comet tail length difference > 3.81 was significantly higher than that in the subject with comet tail length difference < or = 3.81 microm (OR = 2.490, 95% CI:1.068 - 5.806, P = 0.0346). The relative risk increased along with the comet tail length difference, and the trend was significant (P = 0.0024). There was no significant difference between the relative risk of benzene poisoning in the subject with 3AB index < 0.20 and that in the subject with 3AB index > or = 0.20. CONCLUSION: DNA repair capacity on DNA-strand level might tightly associate with chronic benzene poisoning. The DNA repair capacity on DNA-strand level would be worse, and the benzene poisoning risk could be higher. There was no clear relation between the DNA repair capacity on chromosome level and the benzene poisoning risk.