Nurtan A. Esmen

An updated meta-analysis of formaldehyde exposure and upper respiratory tract cancers

In this study, we summarize 47 epidemiologic studies related to formaldehyde exposure and use meta-analytic techniques to assess findings for cancers of the lung, nose/nasal sinuses, and nasopharynx. Our analyses indicate that workers with formaldehyde exposure have essentially null findings for lung cancer and a slight deficit of sinonasal cancer. Nasopharyngeal cancer rates were elevated moderately in a minority of studies. Most studies, however, did not find any nasopharyngeal cancers, and many failed to report their findings. After correcting for underreporting, we found a meta relative risk of 1.0 for cohort studies. Case-control studies had a meta relative risk of 1.3. Our review of the exposure literature indicated that the nasopharyngeal cancer case-control studies represented much lower and less certain exposures than the cohort studies. We conclude that the available studies do not support a causal relation between formaldehyde exposure and nasopharyngeal cancer. This conclusion conflicts with conclusions from two previous meta-analyses, primarily because of our consideration of unreported data.

A Review and Meta-Analysis of Formaldehyde Exposure and Pancreatic Cancer

BACKGROUND Most reviews on the carcinogenicity of formaldehyde have focused on cancers of the respiratory tract. Two recent studies have suggested that exposure to formaldehyde may increase the risk for pancreatic cancer. METHODS We examine 14 epidemiology studies of workers exposed to formaldehyde where pancreatic cancer rates were reported and use meta-analytic techniques to summarize the findings. We also rank formaldehyde exposures for the industries in these studies. RESULTS We found a small increase of pancreatic cancer risk in the studies overall (meta Relative Risk [mRR] 1.1, 95%CI 1.0-1.3); however, this increased risk was limited to embalmers (mRR 1.3, 95%CI 1.0-1.6) and pathologists and anatomists (mRR 1.3, 95%CI 1.0-1.7). There was no increased risk among industrial workers (mRR 0.9, 95%CI 0.8-1.1) who on average had the highest formaldehyde exposures. CONCLUSIONS A small increased risk of pancreatic cancer from formaldehyde exposure cannot be ruled out from the studies examined. However, the null findings among industrial workers and the lack of biological plausibility would argue against formaldehyde as a cause. The increased risk of pancreatic cancer among embalmers, pathologists, and anatomists may be due to a diagnostic bias or to occupational exposures other than formaldehyde in these professions.

Pharyngeal cancer mortality among chemical plant workers exposed to formaldehyde

Objectives: To assess the possible relationship between formaldehyde exposure and mortality risk from pharyngeal cancer (PC), in particular nasopharyngeal cancer (NPC). Methods: Subjects were 7328 workers employed at a plastics-producing plant (1941-1984). Vital status for 98% of the cohort and cause of death for 95% of 2872 deaths were determined. Reconstructed exposures to formaldehyde, particulates and pigment were used to compute several exposure measures. Standardized mortality ratios (SMRs) were computed for several demographic, work history and formaldehyde exposure variables. In a nested case-control study, seven cases of NPC and 15 cases of other PC were matched on race, sex, age and year of birth to four controls from the cohort. Among interviewed subjects, lifetime smoking history was determined using respondents or proxies for all but one control subject. Results: Statistically significant 2.23-fold and fivefold excesses for PC and NPC, respectively, were observed. Fivefold range NPC excesses were observed for both short (B / 1 year) and long-term workers and were concentrated among workers hired during 1947-1956. Only three NPC cases were exposed to formaldehyde for longer than one year, and each had low average intensity of formaldehyde exposure (0.03-0.60 ppm). Only a few exposure measures revealed some evidence of an association with all PC or NPC. For all PC combined, adjustment for smoking and year-of-hire in the case-control study generally corroborated findings from the cohort study. Conclusions: Overall, the pattern of findings suggests that the large, persistent nasopharyngeal and other PC excesses observed among the Wallingford workforce are not associated with formaldehyde exposure, and may reflect the influence of nonoccupational risk factors or occupational risk factors associated with employment outside the Wallingford plant.

Mortality among chemical workers in a factory where formaldehyde was used.

OBJECTIVES: An independent and updated historical cohort mortality study was conducted among chemical plant workers to investigate further an association between exposures to formaldehyde and particulates and cancers of the nasopharynx and lung reported in an earlier National Cancer Institute study of the same plant. METHODS: Subjects were 7359 workers who were first employed between 1941 and 1984 in a factory in Wallingford, Connecticut where formaldehyde was used. Vital status was determined on 31 December 1984 for 96% of the cohort and death certificates were obtained for 93% of 1531 known deaths. Exposures of individual workers were estimated quantitatively for formaldehyde, product particulates, and non-product particulates, and qualitatively for pigment. Statistical analyses focused on 6039 white men in 1945-84. Cohort data that could not have been included in the National Cancer Institute study were also analysed separately. RESULTS: Mortality among long term workers (employed > or = 1 y) was generally similar to or more favourable than that of the general population, and there was little evidence of a relation between either rates of lung cancer or standardised mortality ratios (SMRs) and several measures of exposure to formaldehyde, particulates, and pigment. For several causes including lung cancer, death rates among short term workers (employed < 1 y) were significantly increased. Short term workers did not seem to differ from long term workers for the exposures considered. Among all white men, a significant SMR of 550 (local comparison) for nasopharyngeal cancer (NPC) was based on the same four index cases identified in the earlier study of this plant. Only one case of nasopharyngeal cancer had any appreciable exposure to formaldehyde. No new cases of nasopharyngeal cancers were found among the cohort data that could not have been included in the National Cancer Institute study--that is, extended observation time and additional study members. CONCLUSIONS: Among workers employed for at least one year, this study provides little evidence that the risk of lung cancer is associated with exposure to formaldehyde alone or in combination with particulates or pigment. The significant increases in both the rates and SMRs for lung cancer seem to be primarily a phenomenon of short term workers, but the possibility remains that unmeasured occupational or non-occupational factors may have played a part.

BIOAVAILABILITY OF BERYLLIUM OXIDE PARTICLES: AN IN VITRO STUDY IN THE MURINE J774A.1 MACROPHAGE CELL LINE MODEL

Beryllium metal and its oxide and alloys are materials of industrial significance with recognized adverse effects on worker health. Currently, the degree of risk associated with exposure to these materials in the workplace is assessed through measurement of beryllium aerosol mass concentration. Compliance with the current mass-based occupational exposure limit has proven ineffective at eliminating the occurrence of chronic beryllium disease (CBD). The rationale for this research was to examine the mechanism of beryllium bioavailability, which may be pertinent to risk. The authors tested the hypothesis in vitro that dissolution of particles engulfed by macrophages is greater than dissolution in cellular medium alone. Physicochemical changes were evaluated in vitro for well-characterized high-purity beryllium oxide (BeO) particles in cell-free media alone and engulfed by and retained within murine J774A.1 monocyte-macrophage cells. The BeO particles were from a commercially available powder and consisted of diffuse clusters (aerodynamic diameter range 1.5 to 2.5 μm) of 200-nm diameter primary particles. Following incubation for 124 to 144 hours, particles were recovered and recharacterized. Recovered particles were similar in morphology, chemical composition, and size relative to the original material, confirming the relatively insoluble nature of the BeO particles. Measurable levels of dissolved beryllium, representing 0.3% to 4.8% of the estimated total beryllium mass added, were measured in the recovered intracellular fluid. Dissolved beryllium was not detected in the extracellular media. The BeO chemical dissolution rate constant in the J774A.1 cells was 2.1 ± 1.7 × 10−8 g/(cm2 ⋅ day). In contrast, the BeO chemical dissolution rate constant in cell-free media was < 8.1 × 10−9 g/(cm2 ⋅ day). In vivo, beryllium dissolved by macrophages may be released in the pulmonary alveolar environment, in the lymphatic system after transport of beryllium by macrophages, or in the alveolar interstitium after migration and dissolution of beryllium particles in tissue. These findings demonstrate a mechanism of bioavailability for beryllium, are consistent with previously observed results in canine alveolar macrophages, and provide insights into additional research needs to understand and prevent beryllium sensitization and CBD.

Urinary Concentrations of Toxic Substances: An Assessment of Alternative Approaches to Adjusting for Specific Gravity

Alternative approaches of adjusting urinary concentration of cadmium for differences in specific gravity of biological samples were assessed. The main analysis used 2922 cadmium-in-urine samples collected in the period 1968–1989 from workers at a UK nickel-cadmium battery facility. Geometric means of cadmium-in-urine, adjusted and unadjusted for specific gravity, were obtained for 21 different values of specific gravity ranging from 1.010 to 1.030. There was a highly significant positive trend (P < 0.001) of unadjusted cadmium-in-urine with specific gravity. Conventional adjustment for specific gravity led to a highly significant negative trend (P < 0.001) of adjusted cadmium-in-urine with specific gravity, SG. An approach proposed by Vij and Howell, involving the introduction of a z coefficient, led to satisfactory adjustment. Conventional adjustment of specific gravity leads to overcompensation of the confounding effects of specific gravity. An alternative method is available and should probably be adopted when interpreting urine biological samples for all chemical substances.

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.

A Case-Control Study of Lung Cancer Mortality in Four Rural Arizona Smelter Towns

To investigate factors related to lung cancer mortality in four Arizona copper-smelter towns, the authors identified 142 lung cancer cases and 2 matched controls per case from decedent residents during 1979-1990. The authors obtained detailed information on lifetime residential, occupational, and smoking histories via structured telephone interviews with knowledgeable informants. The authors linked estimated historical environmental exposures to smelter emissions (based on atmospheric diffusion modeling of measured sulfur dioxide concentrations) with residential histories to derive individual profiles of residential exposure. The results of this study provided little evidence of a positive association between lung cancer and residential exposure to smelter emissions. Conditional logistic regression analysis revealed a statistically significant positive association between lung cancer and reported employment in copper mines and/or smelters, although specific factors associated with the apparently increased risk among these workers could not be identified in this community-based study.

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.

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.