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Background Quantitative evaluations of benzene-associated risk for cancer have relied primarily on findings from a cohort study of highly exposed U.S. rubber workers. An epidemiologic investigation in China (NCI/CAPM study) extended quantitative evaluations of cancer risk to a broader range of benzene exposures, particularly at lower levels. Methods We review the evidence implicating benzene in the etiology of hematopoietic disorders, clarify methodologic aspects of the NCI/CAPM study, and examine the study in the context of the broader literature on health effects associated with occupational benzene exposure. Results Quantitative relationships for cancer risk from China and the U.S. show a relatively smooth increase in risk for acute myeloid leukemia and related conditions over a broad dose range of benzene exposure (below 200 ppm-years mostly from the China study and above 200 ppm-years mostly from the U.S. study). Conclusions Risks of acute myeloid leukemia and other malignant and nonmalignant hematopoietic disorders associated with benzene exposure in China are consistent with other information about benzene exposure, hematotoxicity, and cancer risk, extending evidence for hematopoietic cancer risks to levels substantially lower than had previously been established. Am. J. Ind. Med. 40:117–126, 2001. Published 2001 Wiley-Liss, Inc.

Background Several studies have shown that Catholic nuns have a different mortality experience than women of similar age in the general population. We had a unique opportunity to evaluate mortality patterns of nuns identified in an occupational study of nearly 145,000 radiologic technologists (73% female). Methods A total of 1,103 women were classified as nuns based on their titles of ‘‘Sister’’ or ‘‘SR’’. Their mortality experience was compared to other female radiologic technologists and to U.S. white females. Results Five hundred eighty-three nuns (53%) were deceased as of January 1, 1995. Compared to other technologists, nuns were at significantly increased risk of dying from all causes (Standardized mortality ratio (SMR)a 1.1; 95% Confidence interval (CI)a 1.0‐1.2, stomach cancer (SMRa 2.7; 95% CIa 1.2‐5.4), diabetes (SMRa 2.2; 95% CIa 1.0‐4.1), ischemic heart disease (SMRa 1.2; 95% CIa 1.1‐1.4), all digestive diseases (SMRa 2.0; 95% CIa 1.3‐3.0), and gastric and duodenal ulcers (SMRa 8.3; 95% CIa 2.3‐21.3). In contrast, we observed a significant deficit in lung cancer (SMRa 0.5; 95% CIa 0.2‐0.9), no deaths from cervical cancer, and a breast cancer risk 10% lower than expected (SMRa 0.9; 95% CIa 0.6‐1.3). When compared to U.S. females, nuns experienced significantly reduced mortality from all causes (SMRa 0.8; 95% CIa 0.7‐0.9), cervical cancer (SMRa 0.0; 95% CIa 0.0‐0.7), all endocrine, metabolic and nutritional diseases (SMRa 0.5; 95% CIa 0.3‐0.9), all circulatory diseases (SMRa 0.7; 95% CIa 0.7‐0.8) including ischemic heart disease and cerebrovascular disease, and all respiratory diseases (SMRa 0.5; 95% CIa 0.3‐0.8), and a nearly significant deficit of diabetes (SMRa 0.6; 95% CIa 0.3‐1.0). In contrast, nuns had an almost 3-fold greater risk of tuberculosis (SMRa 2.9; 95% CIa 1.4‐5.3) and a 20% excess of breast cancer (SMRa 1.2; 95% CIa 0.8‐1.7). The breast cancer excess was concentrated among nuns first certified before 1940 (SMRa 2.0; CIa 1.3‐ 3.0), when radiation doses were possibly the highest, but the risk did not increase with increasing length of certification. Conclusions Compared with the general population, the mortality experience of nuns was favorable and reflected the ‘‘healthy worker effect’’ commonly seen in occupational studies. Patterns observed for breast and cervical cancer possibly indicate differences in reproductive and sexual activities associated with belonging to a religious order. The possibility of a radiation-related excess for breast cancer among nuns certified before 1940 cannot be completely discounted, although there was no dose-response relationship

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.

Using the Cancer Environment Registry of Sweden, which links the 1960 census information on employment with cancer incidence data from 1961-1979, we conducted a systematic, population-based assessment of esophageal cancer incidence by industry and occupation for men in Sweden. A general reduction in esophageal cancer incidence was found among agricultural and professional workers, whereas excess incidence was found among business, sales, and some craftsmen and production jobs. Elevated incidence was associated with several specific industries, including the food (SIR = 1.3, p < 0.05), beverage and tobacco (SIR = 1.8, p < 0.05) industries, vulcanizing shops within the rubber industry (SIR = 4.7, p < 0.01), and certain automotive building industries. Incidence also was increased among brewery workers (SIR = 4.2, p < 0.01) and butchers (SIR = 2.1, p < 0.01), and among individuals with certain service jobs, particularly waiters in the hotel and restaurant industry (SIR = 3.1, p < 0.01). Some of the occupational associations may be explained by lifestyle factors such as alcohol drinking and smoking, whereas others are specific and tend to support those of earlier investigations. This study adds to the evidence of a small but possibly important role of occupation in esophageal cancer etiology.

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).

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.

A linked-registry was used to examine systematically, on a national basis, the leukemia incidence in Swedish men by industry and occupation. New associations were observed for chronic lymphocytic leukemia among cloth and pattern cutters and for chronic myelocytic leukemia among brewery workers and motor mechanics. A number of additional findings were consistent with previous observations in other countries. Although etiologic inferences are limited when using linked-registry data, this hypothesis-generating study may provide new clues to the occupational determinants of specific forms of leukemia.