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Benzene is an established human leukemogen that increases the level of chromosome aberrations in lymphocytes of exposed workers. Numerical aberrations (aneusomy) can be observed by fluorescence in situ hybridization (FISH) in both interphase and metaphase cells. Whereas interphase FISH allows nondividing cells to be analyzed, one advantage of metaphase FISH is that it can also detect structural changes. The present study compares the abilities of metaphase and interphase FISH to detect aneusomy of chromosomes 7 and 8 in healthy benzene-exposed human subjects. Metaphase and interphase cells from the peripheral blood of 43 workers exposed to benzene (median = 31 ppm, 8-hr TWA) and 44 frequency-matched controls were analyzed by FISH. Normal diploid cells contained two hybridization signals, whereas those that were potentially monosomic contained one, trisomic 3 and tetrasomic 4. The frequency of cells with one hybridization signal for chromosome 7 in metaphase spreads rose from 2.72 +/- 0.19 (%, mean +/- SE) in controls to 3.79 +/- 0.63 in workers exposed to 31 or fewer ppm benzene and 5.9 +/- 0.85 in those exposed to more than 31 ppm (P(trend) < 0.0001). No similar dose-dependent increase in the frequency of cells with one hybridization signal was observed by interphase FISH, probably because of probe overlap artifact. Although significant dose-dependent increases in the frequency of cells with three hybridization signals for chromosome 7 were detected by both methods in the higher-exposed group, a larger, more significant difference was detected by metaphase FISH between controls and workers exposed to 31 or fewer ppm. Similar data were obtained for chromosome 8. Interphase and metaphase FISH were moderately correlated for three hybridization signals but not for one hybridization signal in chromosome 7 or 8. In general, metaphase FISH was more sensitive in detecting both monosomy and trisomy in the lymphocytes of exposed workers., (Copyright 1999 Wiley-Liss, Inc.)

Objectives: Animal inhalation studies and theoretical models suggest that the pattern of formation of benzene metabolites changes as exposure to benzene increases. To determine if this occurs in humans, benzene metabolites in urine samples collected as part of a cross sectional study of occupationally exposed workers in Shanghai, China were measured., Methods: With organic vapour monitoring badges, 38 subjects were monitored during their full workshift for inhalation exposure to benzene. The benzene urinary metabolites phenol, catechol, hydroquinone, and muconic acid were measured with an isotope dilution gas chromatography mass spectroscopy assay and strongly correlated with concentrations of benzene air. For the subgroup of workers (n = 27) with urinary phenol > 50 ng/g creatinine (above which phenol is considered to be a specific indicator of exposure to benzene), concentrations of each of the four metabolites were calculated as a ratio of the sum of the concentrations of all four metabolites (total metabolites) and were compared in workers exposed to > 25 ppm v < or = 25 ppm., Results: The median, 8 hour time weighted average exposure to benzene was 25 ppm. Relative to the lower exposed workers, the ratio of phenol and catechol to total metabolites increased by 6.0% (p = 0.04) and 22.2% (p = 0.007), respectively, in the more highly exposed workers. By contrast, the ratio of hydroquinone and muconic acid to total metabolites decreased by 18.8% (p = 0.04) and 26.7% (p = 0.006), respectively. Similar patterns were found when metabolite ratios were analysed as a function of internal benzene dose (defined as total urinary benzene metabolites), although catechol showed a more complex, quadratic relation with increasing dose., Conclusions: These results, which are consistent with previous animal studies, show that the relative production of benzene metabolites is a function of exposure level. If the toxic benzene metabolites are assumed to be derived from hydroquinone, ring opened products, or both, these results suggests that the risk for adverse health outcomes due to exposure to benzene may have a supralinear relation with external dose, and that linear extrapolation of the toxic effects of benzene in highly exposed workers to lower levels of exposure may underestimate risk.

A large cohort of 74,828 benzene-exposed and 35,805 nonexposed workers employed between 1972 and 1987 in 12 cities in China was followed to determine mortality from all causes. Benzene-exposed study subjects were employed in a variety of occupations including coating applications, and rubber, chemical, and shoe production. Mortality was slightly increased among workers with greater cumulative exposure to benzene (ptrend < 0.05), but this excess was largely due to cancer deaths (ptrend < 0.01). Deaths due to lymphatic and hematopoietic malignancies (ptrend = 0.01) and lung cancer (ptrend = 0.01) increased with increasing cumulative exposure to benzene. Investigations continue to relate benzene exposure to specific lymphatic and hematopoietic malignancies and other causes of death.

Benzene is a recognized hematotoxin and leukemogen, but its mechanisms of action in humans are still uncertain. To provide insight into these processes, we carried out a cross-sectional study of 44 healthy workers currently exposed to benzene (median 8-hr time-weighted average; 31 ppm), and unexposed controls in Shanghai, China. Here we provide an overview of the study results on peripheral blood cells levels and somatic cell mutation frequency measured by the glycophorin A (GPA) gene loss assay and report on peripheral cytokine levels. All peripheral blood cells levels (i.e., total white blood cells, absolute lymphocyte count, platelets, red blood cells, and hemoglobin) were decreased among exposed workers compared to controls, with the exception of the red blood cell mean corpuscular volume, which was higher among exposed subjects. In contrast, peripheral cytokine levels (interleukin-3, interleukin-6, erythropoietin, granulocyte colony-stimulating factor, tissue necrosis factor-alpha) in a subset of the most highly exposed workers (n = 11) were similar to values in controls (n = 11), suggesting that benzene does not affect these growth factor levels in peripheral blood. The GPA assay measures stem cell or precursor erythroid cell mutations expressed in peripheral red blood cells of MN heterozygous subjects, identifying NN variants, which result from loss of the GPA M allele and duplication of the N allele, and N phi variants, which arise from gene inactivation. The NN (but not N phi) GPA variant cell frequency was elevated in the exposed workers compared with controls (mean +/- SD, 13.9 +/- 8.4 mutants per million cells versus 7.4 +/- 5.2 per million cells, (respectively; p = 0.0002), suggesting that benzene produces gene-duplicating but not gene-inactivating mutations at the GPA locus in bone marrow cells of exposed humans. These findings, combined with ongoing analyses of benzene macromolecular adducts and chromosomal aberrations, will provide an opportunity to comprehensively evaluate a wide range of early biologic effects associated with benzene exposure in humans.

We present a validation study of a quantitative retrospective exposure assessment method used in a follow-up study of workers exposed to benzene. Assessment of exposure to benzene was carried out in 672 factories in 12 cities in China. Historical exposure data were collected for 3179 unique job titles. The basic unit for exposure assessment was a factory/work unit/job title combination over seven periods between 1949 and 1987. A total of 18,435 exposure estimates was developed, using all available historical information, including 8477 monitoring data. Overall, 38% of the estimates were based on benzene monitoring data. The highest time-weighted average exposures were observed for the rubber industry (30.7 ppm) and for rubber glue applicators (52.6 ppm). Because of its recognized link with benzene exposure, the association between a clinical diagnosis of benzene poisoning and benzene exposure was evaluated to validate the assessment method that we used in the cohort study. Our confidence in the assessment method is supported by the observation of a strong positive trend between benzene poisoning and various measures, especially recent intensity of exposure to benzene.

Benzene is a well-established hematotoxin. However, reports of its effects on specific blood cells have been somewhat inconsistent and the relative toxicity of benzene metabolites on peripheral blood cells in humans has not been evaluated. We compared hematologic outcomes in a cross-sectional study of 44 workers heavily exposed to benzene (median: 31 parts permillion [ppm] as an 8-hr time-weighted average [TWA] and 44 age and gender-matched unexposed controls from Shanghai, China. All hematologic parameters (total white blood cells [WBC], absolute lymphocyte count, platelets, red blood cells, and hematocrit) were decreased among exposed workers compared to controls, with the exception of the red blood cell mean corpuscular volume (MCV), which was higher among exposed subjects. In a subgroup of workers who were not exposed to more than 31 ppm benzene on any of 5 sampling days (n = 11, median 8 hr TWA = 7.6 ppm, range = 1-20 ppm), only the absolute lymphocyte count was significantly different between exposed workers (mean [sd]1.6 [0.4] x 10(3) mu L) and controls (1.9 [0.4] x l0(3) uL, p = 0.03). Among exposed subjects, a dose response relationship with various measures of current benzene exposure (i.e., personal air monitoring, benzene metabolites in urine) was present only for the total WBC count, the absolute lymphocyte count, and the MCV. Correlations between benzene metabolites and hematologic parameters were generally similar, although hydroquinone was somewhat more strongly associated with a decrease in the absolute lymphocyte count, and catechol was more strongly associated with an increase in MCV. Morphologic review of peripheral blood slides demonstrated an excess of red blood cell abnormalities (i.e., stomatocytes and target cells) only in the most heavily exposed workers, with no differences in granulocyte, lymphocyte, or platelet morphology noted. Although benzene can affect all the major peripheral blood elements, our results support the use of the absolute lymphocyte count as the most sensitive indicator of benzene-induced hematotoxicity.

A large cohort study of 74,828 benzene-exposed and 35,805 unexposed workers employed between 1972 and 1987 in 12 cities in China were followed to determine mortality from all causes and the incidence of lymphohematopoietic malignancies and other hematologic disorders. Benzene-exposed study subjects were employed in a variety of occupations, including painting, printing, and the manufacture of footwear, paint, and other chemicals. All-cause mortality was similar in the benzene-exposed and unexposed comparison group. Statistically significant excess deaths were noted among benzene-exposed subjects for leukemia (RR = 2.3, 95% CP 1.1-5.0), malignant lymphoma (RR = 4.5, 95% CI: 1.3-28.4), and nonneoplastic diseases of the blood (RR = 95% CP 2.5-infinity), and a marginally significant excess was noted for lung cancer (RR = 1.4, 95% CI: 1.0-2.0). Risk was significantly elevated for the incidence of all lymphohematopoietic malignancies (RR = 2.6, 95% CI: 1.5-5.0), malignant lymphoma (RR = 3.5, 95% CI: 1.2-14.9), and leukemia (RR = 2.6, 95% CI.. 1.3-5.7). Among the leukemia subtypes, only acute myelogenous leukemia (AML) incidence was significantly elevated (RR = 3.1, 95% CI: 1.2-10.7), although nonsignificant excesses were also noted for chronic myelogenous leukemia (CML) (RR = 2.6, 95% CI: 0.7-16.9) and lymphocytic leukemias (RR = 2.8, 95% CI.. 0.5-54.5). Significant excesses were found for aplastic anemia (RR = infinity, 95% CI: 2.2-co) and myelodysplastic syndrome (RR = infinity, 95% CI: 1.7-infinity). Employment in benzene-associated occupations in China is associated with a wide spectrum of myelogenous and lymphocytic malignant diseases and related disorders. Investigations continue to assess the nature of these associations.

Benzene is recognized internationally as a leukemogen, but the available data to clarify dose-response relationships and examine risks of malignancies other than leukemia are sparse. A collaborative study was therefore carried out to expand on a previous retrospective cohort mortality study of Chinese benzene-exposed workers. Methods and resources used in the 16-year follow-up of 74,828 benzene-exposed and 35,805 unexposed workers employed for any length of time during 1972-1987 in 712 factories in 12 cities in China are described. Details are provided of the study organization, assessment of benzene exposures since 1949, characterization of factories and workers by exposure status, city, and sex, identification and confirmation of cancers and other deaths, and quality control procedures. The distinguishing features of the study are discussed in relation to earlier cohort studies, and study limitations as well as strengths are presented.

This report describes a retrospective exposure assessment method used in a follow-up mortality study of workers exposed to benzene. The approach quantified historical exposure to benzene in a multi-industry, multicenter cohort, involving 672 factories in 12 cities in China. Historical exposure data were collected to obtain exposure information related to 1,427 work units (departments) and 3,179 unique job titles from benzene-producing or -using factories in which written records and other data sources were evaluated. The basic unit for exposure assessment was a factory/work unit/job title combination which was considered separately during each of seven calendar-year time periods between 1949 and 1987 for a total of 18,435 exposure assignments. Historical information collected to estimate exposure included benzene monitoring data; lists of raw materials and factory products, and the percentage of benzene in each; the total amount and dates of use of benzene or benzene-containing materials; use of engineering controls and personal protective equipment; and other available exposure information. Overall, 38% (ranging from 3% for the earliest periods to 67% for the last period) of the estimates were based primarily on benzene monitoring data. In the absence of job-specific benzene monitoring data for a given calendar period, measurement results or exposure estimates for similar jobs and/or other calendar periods were used in conjunction with other exposure information to derive estimates. Estimated exposure levels are presented by industries and occupations. The highest average exposures during 1949-1987 were observed for the rubber and plastic industry (30.7 ppm), and for rubber glue applicators (52.6 ppm).

Gender differences in risk for leukemia and other selected and combined disease categories were examined by major occupational category for 74,828 benzene-exposed workers compared to 35,805 unexposed workers from 12 cities in China. No significant differences in the relative risks for total mortality and cancer mortality were found between female and male benzene-exposed workers, although risks tended to be somewhat higher among male than among female employees. Both female and male workers in several occupational categories had notably increased risks for all hematopoietic and lymphoproliferative (HLP) malignant and nonmalignant disorders combined and for total leukemia. Variation in risk for HLP disorders by occupational category was observed in both genders, with highest risks for male and female chemical manufacturing workers, female nonproduction employees, and male printers. However, the numbers of leukemia and other HLP malignancies in each category were small. The findings suggest that both female and male benzene-exposed workers in several occupational categories experience excess leukemia and other HLP disorders with relatively minor gender differences. Although this population is one of the largest cohorts of benzene-exposed workers studied to date, evaluation of the observed variation in risk for HLP neoplasms among the occupational groups for workers of each gender is limited by the small numbers of these relatively rare malignancies.