Mortality Among Hardmetal Production Workers: German Historical Cohort Study.

OBJECTIVE: The aim of this study was to investigate a cohort in German hardmetal industry, especially relationship between exposures to cobalt, with and without tungsten, and risks of total and cause-specific mortality. METHODS: The cohort comprises blue-collar workers at three German plants who were employed in hardmetal processing. Individual cumulative exposures and long-term average concentrations were estimated for cobalt, nickel, tungsten, respirable, and inhalable dust. Standardized mortality ratios (SMRs) were calculated for external comparisons. Time-dependent multivariable Cox models were performed for internal analyses. RESULTS: Elevated SMRs were found for all-cause, heart diseases, and nonmalignant respiratory diseases mortality, but not for lung cancer. Internal analyses did not show increased risks for any endpoints, and no exposure-response relationship was indicated. CONCLUSIONS: This study does not provide evidence for elevated lung cancer risks. Methodologic limitations, incomplete ascertainment of death causes in particular, impede conclusions about exposure effects.

Mortality Among Hardmetal Production Workers: US Cohort and Nested Case-Control Studies.

OBJECTIVES: To evaluate total and cause-specific mortality among hardmetal production workers with emphasis on lung cancer. METHODS: Subjects were 7304 workers ever employed in one of eight US plants from 1952 to 2008. Vital status through 2012 was determined for 97% of subjects and cause of death for 98.3% of 1087 deaths. We computed standardized mortality ratios (SMRs) and evaluated exposure-response via relative risk regression analysis. RESULTS: We observed overall deficits in deaths for total mortality, all cancers, and lung cancer and found no evidence of any exposure-response relationships for lung cancer. CONCLUSIONS: We found no evidence that exposure to tungsten, cobalt, or nickel, at levels experienced by the workers examined, increases lung cancer mortality risks. We also found no evidence that work in the US hardmetal industry increases mortality risks from any other causes of death.

Mortality Among Hardmetal Production Workers: Pooled Analysis of Cohort Data From an International Investigation.

OBJECTIVES: Based on a pooled analysis of data from an international study, evaluate total and cause-specific mortality among hardmetal production workers with emphasis on lung cancer. METHODS: Study members were 32,354 workers from three companies and 17 manufacturing sites in five countries. We computed standardized mortality ratios and evaluated exposure-response via relative risk regression analysis. RESULTS: Among long-term workers, we observed overall deficits or slight excesses in deaths for total mortality, all cancers, and lung cancer and found no evidence of any exposure-response relationships for lung cancer. CONCLUSIONS: We found no evidence that duration, average intensity, or cumulative exposure to tungsten, cobalt, or nickel, at levels experienced by the workers examined, increases lung cancer mortality risks. We also found no evidence that work in these facilities increased mortality risks from any other causes of death.

Mortality Among Hardmetal Production Workers: UK Cohort and Nested Case-Control Studies.

OBJECTIVE: The aim of this study was to characterize the mortality at two hardmetal production factories in the United Kingdom as part of an international study. METHODS: Standardized mortality ratios (SMRs) were calculated on the basis of mortality rates for England and Wales, and local rates. A nested case-control study of lung cancer was undertaken. RESULTS: The cohort comprised 1538 workers, with tracing complete for 94.4%. All-cause mortality was statistically significantly low for all cancers and nonmalignant respiratory disease, and for lung cancer was nonsignificantly low. The SMR for lung cancer for maintenance workers was elevated, based on only six deaths. The odds ratio for lung cancer per year of exposure to hardmetal was 0.93 (0.76 to 1.13). CONCLUSIONS: In this small study, there is no evidence to support that working in the UK hardmetal manufacturing industry increased mortality from any cause including lung cancer.

Mortality Among Hardmetal Production Workers: Occupational Exposures.

OBJECTIVE: To generate quantitative exposure estimates for use in retrospective occupational cohort mortality studies of the hardmetal industry. METHODS: Job-exposure matrices (JEMs) were constructed for cobalt, tungsten, and nickel over the time period 1952 to 2014. The JEMs consisted of job class categories, based on job titles and processes performed, and exposure estimates calculated from available company industrial hygiene measurements. RESULTS: Exposure intervals of one-half order magnitude were established for all three agents. Eight job classes had significantly decreasing time trends for cobalt exposure; no significant time trends were detected for tungsten or nickel exposures. CONCLUSIONS: The levels of exposures determined for this study were similar to or lower than those previously reported for the hardmetal industry during the 1952 to 2014 study period.

Characterization of size-specific particulate matter emission rates for a simulated medical laser procedure--a pilot study.

Prior investigation on medical laser interaction with tissue has suggested device operational parameter settings influence laser generated air contaminant emission, but this has not been systematically explored. A laboratory-based simulated medical laser procedure was designed and pilot tested to determine the effect of laser operational parameters on the size-specific mass emission rate of laser generated particulate matter. Porcine tissue was lased in an emission chamber using two medical laser systems (CO2, λ = 10,600 nm; Ho:YAG, λ = 2100 nm) in a fractional factorial study design by varying three operational parameters (beam diameter, pulse repetition frequency, and power) between two levels (high and low) and the resultant plume was measured using two real-time size-selective particle counters. Particle count concentrations were converted to mass emission rates before an analysis of variance was used to determine the influence of operational parameter settings on size-specific mass emission rate. Particle shape and diameter were described for a limited number of samples by collecting particles on polycarbonate filters, and photographed using a scanning electron microscope (SEM) to examine method of particle formation. An increase in power and decrease in beam diameter led to an increase in mass emission for the Ho:YAG laser at all size ranges. For the CO2 laser, emission rates were dependent on particle size and were not statistically significant for particle ranges between 5 and 10 µm. When any parameter level was increased, emission rate of the smallest particle size range also increased. Beam diameter was the most influential variable for both lasers, and the operational parameters tested explained the most variability at the smallest particle size range. Particle shape was variable and some particles observed by SEM were likely created from mechanical methods. This study provides a foundation for future investigations to better estimate size-specific mass emission rates and particle characteristics for additional laser operational parameters in order to estimate occupational exposure, and to inform control strategies.

Long-term health experience of jet engine manufacturing workers: VII: occupational exposures.

OBJECTIVE: To reconstruct agent-specific occupational exposures for a cohort of jet engine manufacturing workers for use in an epidemiological mortality study. METHODS: Potential chemical and physical exposures at eight jet engine manufacturing and overhaul/repair plants were evaluated for the period 1952 to 2001. Eleven agents were selected for detailed examination, and a job-exposure matrix was constructed. RESULTS: Quantitative exposure estimates were generated for metalworking fluids, nickel, cobalt, chromium, solvents, and incomplete combustion aerosol from metalworking fluids. Qualitative exposure estimates were assigned for ionizing radiation, electromagnetic fields, polychlorinated biphenyls, and lead-cadmium. All exposures showed decreasing trends over the study period. CONCLUSIONS: The quantitative exposure levels generated in this study were lower than early contemporaneous professional practice recommendations and were similar to or lower than published data from other industries.

Long-term health experience of jet engine manufacturing workers: VI: incidence of malignant central nervous system neoplasms in relation to estimated workplace exposures.

OBJECTIVE: To determine whether glioblastoma (GB) incidence rates among jet engine manufacturing workers were associated with specific chemical or physical exposures. METHODS: Subjects were 210,784 workers employed from 1952 to 2001. We conducted a cohort incidence study and two nested case-control studies with focus on the North Haven facility where we previously observed a not statistically significant overall elevation in GB rates. We estimated individual-level exposure metrics for 11 agents. RESULTS: In the total cohort, none of the agent metrics considered was associated with increased GB risk. The GB incidence rates in North Haven were also not related to workplace exposures, including the "blue haze" exposure unique to North Haven. CONCLUSIONS: If not due to chance alone, GB rates in North Haven may reflect external occupational factors, nonoccupational factors, or workplace factors unique to North Haven unmeasured in the current evaluation.

Long-term health experience of jet engine manufacturing workers: VIII. glioblastoma incidence in relation to workplace experiences with parts and processes.

OBJECTIVE: To determine whether glioblastoma (GB) incidence rates among jet engine manufacturing workers were associated with workplace experiences with specific parts produced and processes performed. METHODS: Subjects were 210,784 workers employed between 1952 and 2001. We conducted nested case-control and cohort incidence studies with focus on 277 GB cases. We estimated time experienced with 16 part families, 4 process categories, and 32 concurrent part-process combinations with 20 or more GB cases. RESULTS: In both the cohort and case-control studies, none of the part families, process categories, or both considered was associated with increased GB risk. CONCLUSIONS: If not due to chance alone, the not statistically significantly elevated GB rates in the North Haven plant may reflect external occupational factors or nonoccupational factors unmeasured in the current evaluation.

Long-term health experience of jet engine manufacturing workers: IX. further investigation of general mortality patterns in relation to workplace exposures.

OBJECTIVE: To evaluate mortality rates among a cohort of jet engine manufacturing workers. METHODS: Subjects were 222,123 workers employed from 1952 to 2001. Vital status was determined through 2004 for 99% of subjects and cause of death for 95% of 68,317 deaths. We computed standardized mortality ratios and modeled internal cohort rates. RESULTS: Mortality excesses reported initially no longer met the criteria for further investigation. We found two chronic obstructive pulmonary disease-related mortality excesses that met the criteria in two of eight study plants. CONCLUSIONS: At the total cohort level, chronic obstructive pulmonary disease-related categories were not related to any factors or occupational exposures considered. A full evaluation of these excesses was limited by lack of data on smoking history. Occupational exposures received outside of work or uncontrolled positive confounding by smoking cannot be ruled out as reasons for these excesses.

A novel method for reducing the number of agents to be studied in an occupational epidemiologic study.

A novel screening tool method to select chemicals for exposure reconstruction was developed and validated using data generated for a hypothetical work force consisting of 10 job classes (ranging from 10,000 to 55,000 person-years). To achieve the required efficiency in the reconstruction of exposures, this method treats each product (defined as a part or process) as an "exposure." Exposure to 10 products was assigned to each job class at random using a computer program. The expected rate of a given disease was assumed to be constant throughout the job classes (tested at five levels), and the observed numbers of cases in the job classes were generated based on neutral deviations from background with error rates of ± 1% to 16%. One job class was assigned to be the "excess-class" and the number of cases in that class was increased by a factor of Q, which was set at levels that ranged from 1.25 to 5. All of the experimental conditions were replicated 10,000 times in a Monte Carlo scheme for scenarios in which each job class had been designated as the excess-class. Following each run, significant excesses (if any) were determined using a modified version of Daniel's method, and the percentages of false positive and false negative identifications were tabulated. We found that the sensitivity of the method is largely dependent on the relative risk (Q) associated with the exposure. Specifically, the results indicate that as the relative risk increases, the percentage of false negative identifications of the excesses is reduced to nearly 0% and the percentage of false positive identifications is approximately 13%. When applied to real data, should an association be detected between any product and a health outcome, this preliminary analysis will yield a reduced "product" set that can then be investigated in detail and the agents involved considered further for quantitative reconstruction. The proposed method is highly efficient and has the potential to benefit future complex exposure reconstruction studies, particularly when there is no predetermined exposure associated with an observed increase in a cause-specific health end point.

Long-term health experience of jet engine manufacturing workers: V. Issues with the analysis of non-malignant central nervous system neoplasms.

OBJECTIVE: We attempted to examine non-malignant central nervous system (CNS) neoplasms incidence rates for workers at 8 jet engine manufacturing facilities in Connecticut. The objective of this manuscript is to describe difficulties encountered regarding these analyses to aid future studies. METHODS: We traced the cohort for incident cases of CNS neoplasms in states where 95% of deaths in the total cohort occurred. We used external and internal analyses in an attempt to obtain the true risk of non-malignant CNS in the cohort. Because these analyses were limited by data constraints, we conducted sensitivity analyses, including using state driver's license data to adjust person-year stop dates to help minimize underascertainment and more accurately determine cohort risk estimates. RESULTS: We identified 3 unanticipated challenges: case identification, determination of population-based cancer incidence rates, and handling of case underascertainment. These factors precluded an accurate assessment of non-malignant CNS neoplasm incidence risks in this occupational epidemiology study. CONCLUSIONS: The relatively recent (2004) mandate of capturing non-malignant CNS tumor data at the state level means that, in time, it may be possible to conduct external analyses of these data. Meanwhile, similar occupational epidemiology studies may be limited to descriptive analysis of the non-malignant CNS case characteristics.

Long-term health experience of jet engine manufacturing workers: IV. A comparison of central nervous system cancer ascertainment using mortality and incidence data.

PURPOSE: To compare ascertainment of central nervous system (CNS) neoplasms with the use of mortality and incidence data as part of an occupational epidemiology study. METHODS: Deaths were identified by matching the cohort of 223,894 jet engine manufacturing employees to the U.S. Social Security Administration death files and the National Death Index. Incident cancer cases were identified by matching the cohort to 19 state cancer registries. RESULTS: We identified 718 cases overall: 59% by the use of both mortality and cancer incidence tracing; 24% by the use of only mortality tracing, and 17% by the use of only cancer incidence tracing. Compared with state cancer registries, death certificates missed 38% of the malignant, more than six times the benign and nearly 1.5 times the unspecified CNS cases. The positive predictive value of death certificates, with cancer registry as gold standard, was 6% for unspecified, 35% for benign, and 86% for malignant histologies. CONCLUSIONS: Death certificates seriously underascertained benign and unspecified CNS tumors; analyses determined with mortality data would not accurately capture the true extent of disease among the cohort. Most state cancer registries have only collected nonmalignant CNS tumor information since 2004, which currently limits the usefulness of state cancer registries as a source of nonmalignant CNS tumor identification. Underascertainment of CNS deaths could seriously affect interpretation of results, more so if examining nonmalignant CNS.

Long-term health experience of jet engine manufacturing workers: III. Incidence of malignant central nervous system neoplasms.

OBJECTIVE: To explore a perceived unusual occurrence of glioblastoma at one jet engine manufacturing facility located in North Haven (NH), Connecticut (CT). METHODS: Subjects were 212,513 workers ever employed in 1 of 8 manufacturing facilities from 1952 to 2001 and at risk from 1976 to 2004. We identified 722 cases of CNS neoplasms mainly by tracing through 19 state cancer registries. We computed standardized incidence ratios (SIRs) based on CT state and national rates and modeled internal relative risks (RRs). RESULTS: We found overall deficits in cases for glioblastoma (275 cases, SIR = 0.77, CI = 0.68-0.87) and most other histology categories examined. NH workers had a not statistically significant overall 8% excess in glioblastoma (43 cases, SIR = 1.08, CI = 0.78-1.46). Salaried NH workers had a statistically significant twofold risk of glioblastoma compared with hourly workers (17 cases, RR = 2.04, CI = 1.15-3.57). Other subgroups of NH workers revealed elevated but not statistically significant glioblastoma risks but little evidence of an association with duration of employment or time since first employment. CONCLUSIONS: Incidence rates for glioblastoma and other malignant CNS neoplasm histologies were not elevated in the total cohort. The glioblastoma excesses observed among NH workers may reflect external occupational factors, non-occupational factors or workplace factors unique to NH unmeasured in the current study.

Pharmaceutical production workers and the risks of mortality from respiratory system cancer and lymphatic and hematopoietic tissue cancers.

OBJECTIVES: To evaluate further elevated mortality risks from respiratory system cancer (RSC) and lymphatic and hematopoietic tissue cancers (LHTC) in a cohort of 1466 male workers employed full-time in pharmaceutical production. METHODS: We computed standardized mortality ratios, and in nested case-control studies of RSC and LHTC, evaluated mortality risks by plant exposures with adjustment for potential confounding factors. RESULTS: Subjects with potential plant exposure had no elevated RSC risk and a statistically significant LHTC excess. The case-control study found many RSC risks reduced with adjustment for smoking, and LHTC risks increased with increasing levels of average exposure to dimethyl-formamide. CONCLUSIONS: RSC mortality risks decreased, and we found limited evidence that positive confounding by smoking may explain some remaining excess risks. For LHTC, increased mortality risks and exposure-response patterns in the case-control study may indicate a possible workplace association.

Mortality patterns among workers exposed to arsenic, cadmium, and other substances in a copper smelter.

OBJECTIVE: To evaluate the long-term mortality experience of workers exposed to arsenic, cadmium, and other substances at a copper mine and smelter in Copperhill, Tennessee studied earlier as part of an industry-wide study. METHODS: Subjects were 2,422 male workers employed three or more years in the smelter or mill between 1/1/46 until the plant strike and scale-down of operations in April 1996. Vital status was determined through 2000 for 99.4% of subjects and cause of death for 91.3% of 878 deaths. Historical exposures were estimated for lead, SO(2), arsenic, cadmium, dust, and cobalt. We computed standardized mortality ratios (SMRs) based on U.S. and local county rates and modeled internal relative risks (RRs). RESULTS: We observed overall deficits in deaths based on national and local county comparisons from all causes, all cancers and most of the cause of death categories examined. We found limited evidence of increasing mortality risks from cerebrovascular disease with increasing duration and cumulative arsenic exposure, but no evidence of an exposure-response relationship for cadmium exposure and bronchitis. CONCLUSIONS: Our limited evidence of an association between inhaled arsenic exposure and CVD is an exploratory finding not observed in other epidemiology studies of more highly exposed occupational populations. Possible alternative explanations include chance alone and uncontrolled confounding or effect modification by co-exposures or other factors correlated with arsenic exposure and unique to the Copperhill facility.

Methodological issues in a retrospective cancer incidence study.

The authors traced incidence of central nervous system cancer in a large occupational cohort of jet engine manufacturing workers from 1976 to 2004 in the 24 US states that comprised 95% of the cohort deaths. The cohort of approximately 224,000 employees was matched with cancer registry data; all central nervous system cancer matches were requested with their diagnostic data. This paper highlights the obstacles encountered while conducting this retrospective cancer incidence study. The authors spent approximately 700 hours completing applications and obtaining the cohort matches. Approximately 70% of the cases were identified in the state in which the facility of interest is located. In addition to the large amount of time involved, identified issues include complicated approval processes, high costs, temporal differences among the registries, and registry agency difficulty in performing the matching. Several states do not allow individual-level data to be used for research purposes. Researchers can gain important cancer incidence information by matching retrospective cohorts to multiple state cancer registries. However, they should carefully weigh the time and costs required and plan accordingly. Despite some serious obstacles, many of which are potentially resolvable, cancer incidence studies of retrospective cohorts using multiple cancer registries are feasible.

Long-term health experience of jet engine manufacturing workers: II. Total and cause-specific mortality excluding central nervous system neoplasms.

OBJECTIVE: As part of an exploratory investigation of an unusual occurrence of glioblastoma at one jet engine manufacturing facility located in North Haven, Connecticut (CT), we examined total and cause-specific (excluding central nervous system neoplasms) mortality rates at eight of the company's CT facilities. METHODS: Subjects were 223,894 workers ever employed in one or more of the manufacturing facilities from 1952 to 2001. Vital status was determined through 2004 for 99% of subjects and cause of death for 95% of 68,701 deaths. We computed standardized mortality ratios (SMRs) based on US and CT state rates and modeled internal cohort rates. RESULTS: We observed overall deficits in deaths based on national and state comparisons from all causes, all cancers and most of the cause of death categories examined. State comparisons revealed statistically significant excesses in deaths greater than 25% for kidney cancer (68 deaths, SMR = 1.30, CI = 1.01-1.65) and "other non-malignant respiratory disease" (291 deaths, SMR = 1.27, CI = 1.13-1.42) among subjects employed only at North Haven, and for bronchitis (713 deaths, SMR = 1.28, CI = 1.18-1.37) among all hourly workers. These excesses occurred mainly among short-term workers and hourly workers. CONCLUSIONS: We found no evidence of elevated mortality risks for all causes combined, all cancers combined and most of the causes of death categories examined. The pattern of findings for kidney cancer, bronchitis and other non-malignant respiratory disease, based on currently available data, suggests these excesses may be due to non-occupational risk factors or to external occupational factors. We will investigate these excesses further when detailed work history and exposure data from the companion exposure assessment project become available.

Long-term health experience of jet engine manufacturing workers: I. Mortality from central nervous system neoplasms.

OBJECTIVE: In response to an unusual occurrence of glioblastoma at one jet engine manufacturing facility located in North Haven (NH), Connecticut (CT), we examined mortality rates from central nervous system (CNS) neoplasms at NH and seven other company facilities. METHODS: Subjects were 223,894 workers ever employed in one or more of the company's eight CT manufacturing facilities from 1952 to 2001. Vital status was determined through 2004 for 99% of subjects and cause of death for 95% of 68,701 deaths. We computed standardized mortality ratios (SMRs) based on US and CT state rates and modeled internal relative risks (RRs). RESULTS: State comparisons revealed overall deficits in deaths from all CNS neoplasms (606 deaths, SMR = 0.84, confidence interval [CI] = 0.78 to 0.91), including all malignant (462 deaths, SMR = 0.87, CI = 0.79 to 0.95), all benign (23 deaths, SMR = 0.65, CI = 0.41 to 0.98), and all unspecified (121 deaths, SMR = 0.79, CI = 0.65 to 0.94). Not statistically significant excesses in deaths from all malignant brain neoplasms were found among subjects who worked only at NH (49 deaths, SMR = 1.11, CI = 0.82 to 1.47) or partly at NH (24 deaths, SMR = 1.04, CI = 0.67 to 1.55) compared with deficits in non-NH plant groups. In the combined NH plant groups, we found not statistically significant higher risks of malignant brain neoplasms for salaried workers, older hires and the most recent time period, but no association with duration of employment or time since first employment. CONCLUSIONS: Total cohort mortality rates for malignant, benign or unspecified CNS neoplasms were not elevated relative to the US and CT general populations. The malignant brain neoplasm excesses in certain subgroups of workers from NH may reflect external occupational factors, nonoccupational factors or workplace factors unique to NH that were not measured in the current study. We will explore reasons for the NH excesses and examine specific types of brain neoplasms (eg, glioblastoma) in our companion cancer incidence, case-control and exposure assessment studies.