Benzene exposure and hematopoietic mortality: A long-term epidemiologic risk assessment.

BACKGROUND: Previous studies of a cohort of rubber hydrochloride workers indicated an association between benzene exposure and excess mortality from leukemia and multiple myeloma. To determine whether risks remain elevated with increasing time since plant shutdown, we extended follow-up from 1981 through 1996. MATERIALS AND METHODS: We evaluated risk using standardized mortality ratios (SMR) and generalized Cox proportional hazards regression models. RESULTS: Five new leukemia cases were observed in benzene-exposed white males, but the summary SMR for this group declined from 3.37 (95% CI = 1.54-6.41) to 2.56 (95% CI = 1.43-4.22). In regression models, cumulative exposure was significantly associated with elevated relative risks for leukemia mortality. Four new multiple myeloma deaths occurred, three of which were in workers judged to be unexposed. CONCLUSIONS: These findings reaffirm the leukemogenic effects of benzene exposure and suggest that excess risk diminishes with time.

Effect of follow-up time on risk estimates: a longitudinal examination of the relative risks of leukemia and multiple myeloma in a rubber hydrochloride cohort.

BACKGROUND: Choice of follow-up time for an occupational cohort can influence risk estimates. We examined the effects of follow-up time on relative risk estimates for leukemia and multiple myeloma in a cohort of 1,845 rubber hydrochloride workers. MATERIALS AND METHODS: We generated standardized mortality ratios (SMRs) for yearly follow-ups, beginning each study in 1940 and increasing study end dates from 1950 through 1996. We used Cox proportional hazards modeling to explore the effects of follow-up time on the exposure-response relationship. RESULTS: The SMR for leukemia rose to 13.55 in 1961 and fell nearly monotonically to 2.47 by 1996. Cox modeling suggested interaction between cumulative exposure and time since exposure. A longer time to peak risk was seen for multiple myeloma. CONCLUSIONS: Because summary risk estimates change with follow-up time, exposure limits set using these estimates may not adequately protect workers. Consideration of appropriate follow-up time and use of more complex temporal models are critical to the risk assessment process.

Mortality study of workers employed in 1,3-butadiene production units identified from a large chemical workers cohort.

The IARC has given the designations of "sufficient evidence" of carcinogenicity of 1,3-butadiene in experimental animals and "limited evidence" of carcinogenicity in humans. To investigate the carcinogenic effect in humans, a cohort mortality study was conducted among 364 men who were assigned to any of three 1,3-butadiene production units located within several chemical plants in the Kanawha Valley of West Virginia, including 277 men employed in a U.S. Rubber Reserve Plant which operated during World War II. The butadiene production units included in this study were selected from an index developed by the Union Carbide Corporation which listed for each chemical production unit within their South Charleston and Institute plants all products, by-products and reactants. Departments included in the study were those where butadiene was a primary product and neither benzene nor ethylene oxide was present. A total of 185 deaths were observed; the standardized mortality ratio (SMR) for all causes of death was 91, reflecting lower mortality among the study population than the U.S. population. The study found a significantly elevated standardized mortality ratio (SMR) for lymphosarcoma and reticulosarcoma based on four observed cases (SMR = 577; 95% confidence interval (CI) = 157-1480), which persisted in an analysis using county referent rates. An excess of lymphosarcoma and reticulosarcoma among all workers and among workers with routine exposure to 1,3-butadiene was also observed in the only other cohort of 1,3-butadiene production workers previously studied. A statistically non-significant excess of stomach cancer was observed in the overall cohort (five cases; SMR = 243; CI = 79-568) that was most pronounced among workers employed in the Rubber Reserve plant for 2 or more years (five cases; SMR = 657; CI = 213-1530). We conclude that the results of this study add to the weight of evidence suggesting that butadiene is carcinogenic in humans.

Risk of low red or white blood cell count related to estimated benzene exposure in a rubberworker cohort (1940-1975)

This study evaluated the relationship between benzene exposure and low white blood cell (WBC) and red blood cell (RBC) counts. Hematologic screening data collected over a 35 year period at a rubber hydrochloride manufacturing plant were analyzed; an increased risk of leukemia had been demonstrated previously among workers at the plant [Infante et al. (1977).' Lancet 2:76-78; Rinsky et al. (1981): Am J Ind Med 2:217-45 (1987): NEJM 316:1044-1050/. Hematologic screening data were available for 657 of 1,037 (63.3%) individuals employed at the plant from 1939 through 1976. There was a total of 21. 710 blood test records (range per individual 1-354). The study utilized a case-control design and estimated benzene exposures using the job exposure matrix developed by Rinsky et al. (1987): NEJM 316:1044-1050]. The effects of benzene exposure in the 30, 90, and 180 days before the blood test date, as well as cumulative exposure up until the blood test date, were examined using conditional logistic regression. For WBCs there was a strong exposure response and all of the exposure metrics selected showed a significant relationship with low blood count. For RBCs there was a weak positive exposure-response, which was significant (p = 0.03) for one of the dose metrics. The finding of an exposure-response relationship in the range of exposures represented in this study, where the maximum daily benzene exposure estimate was 34 ppm, is consistent with findings of several animal studies demonstrating a decrease in peripheral lymphocyte counts at benzene exposures as low as 10 ppm, and a stronger effect of benzene exposure on lymphocytes (as reflected in total WBC count) than on red cells. There was no evidence for a threshold for the hematologic effects of benzene exposure, suggesting that even exposure to relatively low levels of benzene (e.g., <5 ppm) may result in hematologic suppression.

Mortality study of workers in 1,3-butadiene production units identified from a chemical workers cohort.

The International Agency for Research on Cancer has given the designations of "sufficient evidence" of carcinogenicity of 1,3-butadiene in experimental animals and "limited evidence" of carcinogenicity in humans. To investigate the carcinogenic effect in humans, we conducted a cohort mortality study among 364 men who were assigned to any of three 1,3-butadiene production units located within several chemical plants in the Kanawha Valley of West Virginia, including 277 men employed in a U.S. Rubber Reserve Plant which operated during World War II. The butadiene production units included in this study were selected from an index developed by the Union Carbide Corporation, which listed for each chemical production unit within their South Charleston, West Virginia and Institute, West Virginia, plants all products, by-products, and reactants. Departments included in the study were those where butadiene was a primary product and neither benzene nor ethylene oxide was present. A total of 185 deaths were observed; the standardized mortality ratio (SMR) for all causes of death was 91, reflecting lower mortality among the study population than the U.S. population. The study found a significantly elevated standardized mortality ratio (SMR) for lymphosarcoma and reticulosarcoma based on four observed cases (SMR = 577; 95% CI = 157-1480), which persisted in an analysis using county referent rates. An excess of lymphosarcoma and reticulosarcoma among all workers and among workers with routine exposure to 1,3-butadiene was also observed in the only other cohort of 1,3-butadiene production workers previously studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzene exposure assessment in rubber hydrochloride workers: a critical evaluation of previous estimates.

Many risk assessments for leukemia associated with benzene exposure have been based on the mortality experience of the rubber hydrochloride worker cohort. Although there have been several different historical exposure assessments proposed for this cohort, Paustenbach et al. [1992, J Tox Environ Health], recently published a new historical characterization of benzene exposures based on data previously developed by Rinsky et al. [1981, Am J Ind Med] and further modified by Crump and Allen [1984: OSHA]. Adjustments by Paustenbach et al. in the Rinsky et al. data result in retrospective benzene exposure estimates far greater than those previously reported, by an order of magnitude in many cases. Judgments made on the significance of dermal contact and interpretation of historical measurement data led Paustenbach et al. to arrive at exposure estimates for this cohort that are in conflict with what is known about the adverse effects of benzene exposure. More reasonable estimates for dermal absorption are included in this report that do not substantially affect total estimates of benzene exposure for the cohort. The exposure estimates originally presented in the Rinsky et al. article appear in concordance with data not previously reported in any analyses.

Mortality in a cohort of antimony smelter workers.

Animal studies show that antimony may cause lung cancer and heart and lung disease in rodents. In exposed humans, ECG abnormalities and heart and lung disease have been reported. This mortality study of 1,014 men employed between 1937 and 1971 in a Texas antimony smelter consisted primarily of workers of Spanish ancestry (n = 928, 91.5%). Hispanics are known to smoke at much lower rates than non-Hispanics, and their lung cancer and heart disease mortality is generally low. When ethnic-specific Texas lung cancer death rates were used for comparison, mortality from lung cancer among antimony workers was elevated (SMR) 1.39, 90% CI 1.01-1.88), and we observed a significant positive trend in mortality with increasing duration of employment. When ischemic heart disease death rates from three different Spanish-surnamed populations were used for comparison, the rate ratios for mortality from ischemic heart disease were 0.91 (90% CI 0.84-1.09), 1.22 (90% CI 0.78-1.89), and 1.49 (90% CI 0.84-2.63). Pneumoconiosis/ other lung disease death rates for Spanish-surnamed men were unavailable and so calculation of rate ratios used white males as a comparison population (SMR 1.22; 90% CI 0.80-1.80). These data suggest some increased mortality from lung cancer and perhaps nonmalignant respiratory heart disease in workers exposed to antimony. However, conclusions are limited by possible confounders and the difficulty of identifying appropriate referent groups.

Benzene and leukemia: an epidemiologic risk assessment.

To assess quantitatively the association between benzene and leukemia, we evaluated the rate of mortality experienced by a cohort occupationally exposed to benzene. Using data from historical air sampling surveys, we estimated the daily benzene exposure for each member of the cohort. The expected number of leukemia deaths was calculated and compared to the actual number of leukemia deaths that occurred. The overall standardized mortality ratio (SMR) for leukemia was 337. Person-years at risk within the cohort were stratified by increasing levels of cumulative benzene exposure. The resulting SMRs increased from 109 to 322 to 1186 and to 6637 with respective increases in cumulative benzene exposure from less than 40 ppm-years to 40-199, 200-399, and greater than 400. The shape of the exposure-response relation was examined with a case-control analysis. Another analysis was performed to take into account an induction period for leukemia. All of the analyses demonstrated that a strongly positive exposure-response relationship exists between benzene and leukemia. Previous attempts to quantify this cohort's risk of developing leukemia were based on surrogates of exposure, such as duration of employment. Using actual air sampling data to estimate individual exposures represents a marked improvement over these previous attempts and emphasizes the importance of conducting industrial hygiene surveys and maintaining historical exposure records.

Study of mortality among chemical workers in the Kanawha Valley of West Virginia.

To assess the mortality experience of a cohort of chemical workers in the Kanawha Valley of West Virginia, 29,139 males who worked at any one of three facilities over a 39-year period were followed-up for vital status. The facilities include two chemical manufacturing plants and a research and development center. From this cohort, 5,785 men were found to have died as of the study end, December 31, 1978. This was less than the 6,148.5 men expected to have died, based upon the United States white male population (standardized mortality ratio (SMR) = 94, 95% confidence interval (CI) = 92-96). Eighty-six specific causes of death were examined. Statistically significant increased deaths were observed for two causes; cancers of the liver (not specified as primary or secondary) (SMR = 174; CI = 102-280) and lympho- and reticulosarcoma (SMR = 140; CI = 104-187). When all biliary and liver cancer was examined by duration and time since initial employment, the SMR for those who worked at least 25 years and whose deaths occurred 30 years or more after first employment was 301 (95% confidence limit = 168-497). The identification and follow-up of this complete cohort provides the basis for future study of subcohorts with specific chemical and process exposures and case control studies of specific causes of death.

Case-control study of lung cancer in civilian employees at the Portsmouth Naval Shipyard, Kittery, Maine.

Case-control analysis of deaths due to lung cancer (International Classification of Diseases, Eighth Revision, code 162) among persons who worked at the Portsmouth Naval Shipyard, Kittery, Maine, between 1952 and 1977 found elevated odds ratios for exposures to ionizing radiation, asbestos, and welding byproducts. The radiation-related excess was statistically significant in persons with cumulative lifetime exposures of 1.0-4.999 rem. When asbestos and welding histories were combined into a single risk factor, odds ratios for the combined exposure were significantly elevated for two of three duration-of-exposure categories examined. Further analysis of data on radiation exposure, controlling for exposures to asbestos and welding, found reductions in initial estimates of radiation risk at all levels of radiation exposure. This reduction suggests that radiation workers were more heavily exposed to asbestos and/or welding fumes than were other workers and that those exposures confounded the observed association between radiation and lung cancer. Analysis of mortality by time since first exposure to radiation revealed no pattern of progressive increase as latency increased. By contrast, odds ratios for asbestos/welding increased with latency. Data on cigarette smoking and socioeconomic status were not available. The results of this study do not preclude a possible association between radiation exposure at the Portsmouth Naval Shipyard and excess mortality from lung cancer. However, they provide no evidence in support of such a relation.

Benzene and leukemia. An epidemiologic risk assessment.

To assess quantitatively the association between benzene exposure and leukemia, we examined the mortality rate of a cohort with occupational exposure to benzene. Cumulative exposure for each cohort member was estimated from historical air-sampling data and, when no sampling data existed, from interpolation on the basis of existing data. The overall standardized mortality ratio (a measure of relative risk multiplied by 100) for leukemia was 337 (95 percent confidence interval, 154 to 641), and that for multiple myeloma was 409 (95 percent confidence interval, 110 to 1047). With stratification according to levels of cumulative exposure, the standardized mortality ratios for leukemia increased from 109 to 322, 1186, and 6637 with increases in cumulative benzene exposure from less than 40 parts per million-years (ppm-years), to 40 to 199, 200 to 399, and 400 or more, respectively. A cumulative benzene exposure of 400 ppm-years is equivalent to a mean annual exposure of 10 ppm over a 40-year working lifetime; 10 ppm is the currently enforceable standard in the United States for occupational exposure to benzene. To examine the shape of the exposure-response relation, we performed a conditional logistic-regression analysis, in which 10 controls were matched to each cohort member with leukemia. From this model, it can be calculated that protection from benzene-induced leukemia would increase exponentially with any reduction in the permissible exposure limit.

A case-control study of leukemia at a naval nuclear shipyard.

A matched case-control study was conducted of 53 leukemia deaths and of 212 controls within a previously studied cohort of 24,545 on-shore workers employed between January 1, 1952 and August 15, 1977 at the Portsmouth (New Hampshire) Naval Shipyard. The study sought to ascertain a priori whether there was an association between leukemia deaths and occupational exposure to either ionizing radiation or organic solvents. To obtain information on individual exposures, radiation dose histories and detailed work histories by job and shop were evaluated for each subject. No statistically significant associations were found either between ionizing radiation or presumed solvent exposure and myelogenous or lymphatic leukemia. However, when specific job categories and shops were examined without benefit of a priori hypotheses, two occupations, electrician and welder, were found to be associated with leukemia. For electricians, the Mantel-Haenszel odds ratio (ORMH) was significantly elevated for all leukemias (ORMH = 3.00, 95% confidence interval (CI) = 1.29-6.98), particularly for lymphatic leukemia (ORMH = 6.00, 95% CI = 1.47-24.45). For welders, the odds ratio was not significantly elevated for all leukemias (ORMH = 2.25, 95% CI = 0.92-5.53), but was significantly elevated for myeloid leukemia (ORMH = 3.83, 95% CI = 1.28-11.46). These findings persisted when potential confounders were adjusted by means of a conditional logistic regression model.

An investigation of bias in a study of nuclear shipyard workers.

The authors examined discrepant findings between a 1978 proportional mortality study and a 1981 cohort study of workers at the Portsmouth, New Hampshire, Naval Shipyard to determine whether the healthy worker effect, selection bias, or measurement bias could explain why only the proportional mortality study found excess cancer deaths among nuclear workers. Lower mortality from noncancer causes in nuclear workers (the healthy worker effect) partly accounted for the observed elevated cancer proportional mortality. More important, however, was measurement bias which occurred in the proportional mortality study when nuclear workers who had not died of cancer were misclassified as not being nuclear workers based on information from their next of kin, thereby creating a spurious association. Although the proportional mortality study was based on a small sample of all deaths occurring in the cohort, selection bias did not contribute materially to the discrepant results for total cancer deaths. With regard to leukemia, misclassification of occupation in the proportional mortality study and disagreement about cause of death accounted for some of the reported excess deaths.

The application of epidemiology to the prevention of occupational cancer.

Epidemiology attempts to establish a quantitative causality which is essential in preventive medicine strategies for occupational cancer. By studying carefully exposure effect relationships and populations at risk, subtle causes of occupational cancer can be identified. The nature of epidemiological reasoning and the criticism of this methodology are outlined. Using combined epidemiological and industrial hygiene data, a quantitative risk assessment of a lifetime exposure of workers to benzene and its association with leukemia is presented. In a population of 1,000 workers exposed for a working lifetime to 100 ppm benzene vapor, 140 excess deaths from leukemia would occur. At a lifetime exposure of 10 ppm, it is calculated that 14 excess leukemia deaths would occur. Because the current legal standard is 10 ppms for occupational exposure, this epidemiological risk assessment indicates that an unexpectedly large number of excess leukemia deaths will result in a population of workers exposed to 10 ppm.

More on direct estimates of low-level radiation risks.

In an epidemiologic study of mortality at the Portsmouth Naval Shipyard (PNS), the National Institute for Occupational Safety and Health (NIOSH) found no evidence of excess deaths due to leukemia or other cancers among workers exposed to low levels of ionizing radiation [1]. In a subsequent analysis, Bross and Driscoll [2] identified excess lung cancer mortality in PNS workers with lifetime radiation dose of 1 rem or greater and with more than 15 years' latency since first radiation exposure. Although that observation may be important and is currently being examined through case-control analyses, it must be recognized that Bross and Driscoll extracted their observation from matrices of over 4,000 data cells apparently by recombination of innumerable possible permutations of dosage and latency intervals. For that reason, their finding can be regarded as no more than a suggestion for further study. It certainly does not represent a proper scientific conclusion. Bross and Driscoll's analysis illustrates the hazard of performing multiple statistical comparisons on complex data sets in the absence of a priori hypotheses.