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Objectives: To evaluate the extent to which lung cancer mortality risk estimates in relation to acrylonitrile (AN) exposure may have been confounded by smoking in the presence of misclassified smoking data., Methods: Subjects were 992 white men employed for three or more months between 1960 and 1996 at a chemical plant in Lima, Ohio. We used Monte Carlo-based sensitivity analysis to address possible confounding by smoking., Results: In Monte Carlo simulations that accounted for the relationship between smoking and AN exposure, mean relative risks for lung cancer mortality in relation to AN exposure decreased and we observed somewhat less evidence of an exposure-response relationship., Conclusions: Our simulations suggest that the relationship between AN exposure and lung cancer mortality was positively confounded by smoking in the original Lima cohort study.

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.

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.

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.

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.

Objective: To determine whether IARC's 2001 decision to downgrade the classification of insulation glass wool from Group 2B to Group 3 remains valid in light of epidemiological evidence reported after 2001., Methods: We performed a systematic review of epidemiological evidence regarding respiratory cancer risks in relation to man-made vitreous fiber (MMVF) exposure before and after the 2001 IARC re-evaluation with focus on glass wool exposure and respiratory system cancer., Results: Since 2001, three new community-based, case-control studies, two detailed analyses of existing cohort studies and two reviews/meta-analyses were published. These studies revealed no consistent evidence of an increased respiratory system cancer risk in relation to glass wool exposure., Conclusions: From our evaluation of the epidemiological evidence published since 2001, we conclude that IARC's 2001 decision to downgrade insulation glass wool from Group 2B to Group 3 remains valid., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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., (Copyright 2010 S. Karger AG, Basel.)

Objective: To investigate further the possibility that the large nasopharyngeal cancer (NPC) mortality excess among a cohort of formaldehyde-exposed workers may be related to occupational factors external to the study plant., Methods: Subjects were 7345 workers employed at a plastics-producing plant (1941-1984) in Wallingford, Connecticut evaluated independently as part of a National Cancer Institute cohort study. Vital status for 98% of the cohort and cause of death for 95% of 2872 deaths were determined through 2003. Reconstructed worker exposures to formaldehyde were used to compute unlagged and lagged exposure measures. We computed standardized mortality ratios (SMRs) based on US and local county rates. In a nested case-control study we evaluated mortality risks from NPC and from all other pharyngeal cancers combined (AOPC) in relation to formaldehyde exposure while accounting for potential confounding or effect modification by smoking or external (non-Wallingford) employment. Job applications, Connecticut commercial city directories and a previous survey were used to assign subjects to three external job groups., Results: We observed no new deaths from NPC and one additional AOPC death (pharynx unspecified) yielding, respectively, SMRs of 4.43 (7 deaths, 95% CI=1.78-9.13) and 1.71 (16 deaths, 95% CI=1.01-2.72). Five of seven NPC cases worked in silver smithing (including brass plating and other jobs related to silver or brass) or other metal work (including steel working and welding), and this type of work was relatively rare in the remaining study population (OR=14.41, 95% CI=1.08-82.1). For AOPC, we found a moderate increase in risk for other metal work (OR=1.40, 95% CI=.31-5.1). Interaction models suggested that NPC and AOPC risks were not elevated in subjects exposed only to formaldehyde., Conclusions: The results of our nested case-control study suggest that the large nasopharyngeal cancer mortality excess in the Wallingford cohort may not be due to formaldehyde exposure, but rather reflects the influence of external employment in the ferrous and non-ferrous metal industries of the local area that entailed possible exposures to several suspected risk factors for upper respiratory system cancer (e.g., sulfuric acid mists, mineral acid, metal dusts and heat). Our findings may also help to explain why the associations with formaldehyde and nasopharyngeal cancer reported in the 1994 update of the 10-plant NCI formaldehyde cohort study were unique to the Wallingford plant (Plant 1 in NCI study). Further updates of the NCI formaldehyde cohort study should include co-exposure data on silver smithing and other metal work for all study plants to help explain the unique findings for nasopharyngeal cancer in Plant 1 compared with the other nine plants.

An IARC (International Agency for Research on Cancer) working group categorized formaldehyde as a human carcinogen (Group 1) in 2004. A major component of the epidemiologic evidence evaluated by IARC to reach this decision was the analysis published by Hauptmann et al. [Hauptmann, M., Lubin, J. H., Stewart, P. A., Hayes, R. B., Blair, A. 2004. Mortality from solid cancers among workers in formaldehyde industries. Am. J. Epidemiol. 159, 1117-1130.] of the National Cancer Institute (NCI) historical cohort comprising industrial workers exposed to formaldehyde in 10 U.S. plants. The NCI authors emphasized the relationship found between highest formaldehyde peak exposure and death from nasopharyngeal cancer (NPC). We performed two additional types of re-analyses of the NCI cohort data with focus on peak exposure and NPC mortality. The analyses were aimed at (1) investigating whether the model specification chosen by Hauptmann et al. (2004) was appropriate (interaction assessment) and (2) exploring the degree of instability of the risk estimates for NPC in relation to highest peak exposure (sensitivity analysis). Hauptmann et al. (2004) failed to account for an important interaction structure between plant group and the exposure variable that prohibits a generalization of formaldehyde effects within the NCI cohort and, in particular, beyond the NCI cohort. In addition, our sensitivity analysis demonstrates considerable uncertainties in the risk estimates and points convincingly to instability problems particularly related to Plant 1. Even a simple sensitivity model taking only one additional death into account produced a variation of the risk estimates beyond the instability conveyed by standard confidence intervals. The results of our current reanalysis of the NCI study do not support NCI's suggestion of a causal association with formaldehyde exposure and nasopharyngeal cancer. The decision by the IARC working group to reclassify formaldehyde as a Group 1 substance was clearly premature considering: (1) the missing evidence of an NPC excess from the large British and NIOSH cohort studies; (2) the absence of an association with formaldehyde and NPC in the independent and expanded study of Plant 1; and (3) the mis-specified and non-robust internal analysis of the NCI cohort study brought to light in our current re-analysis. Thus, the 2004 IARC decision to reclassify formaldehyde as a Group 1 substance should be reconsidered.

Objective: The objective of this study was to update the mortality experience of a cohort of workers with and without potential exposure to acrylamide (AMD) at three U.S. plants (n = 8508) and one plant in The Netherlands (n = 344)., Methods: We computed standardized mortality ratios (SMRs) using national and local rates and modeled internal cohort rates to assess site-specific cancer risks by demographic and work history factors and several exposure indicators for AMD., Results: For the 1925-2002 study period, we observed both deficit and excess overall mortality risks among the U.S. cohort for cancer sites implicated in experimental animal studies: brain and other central nervous system (SMR = 0.67, confidence interval [CI] = 0.40-1.05), thyroid gland (SMR = 1.38, CI = 0.28-4.02), testis and other male genital organs (SMR = 0.64, CI = 0.08-2.30); and for sites selected in earlier exploratory analyses of this cohort: respiratory system cancer (RSC) (SMR = 1.17, CI = 1.06-1.27), esophagus (SMR = 1.20, CI = 0.86-1.63), rectum (SMR = 1.25, CI = 0.84-1.78), pancreas (SMR = 0.94, CI = 0.70-1.22), and kidney (SMR = 1.01, CI = 0.66-1.46). Except for RSC, attributed earlier to muriatic acid exposure, none of the mortality excesses was statistically significant. In the Dutch cohort, we observed deficits in deaths for all sites of a priori interest. An updated analysis of our previous exploratory findings for pancreatic cancer in the U.S. cohort revealed much less evidence of a possible exposure-response relationship with AMD., Conclusion: AMD exposure at the levels present in our study sites was not associated with elevated cancer mortality risks.

Objective: To determine whether the National Cancer Institute's (NCI) recent suggestion of a causal association between formaldehyde exposure and mortality from nasopharyngeal cancer (NPC) is robust with respect to alternative methods of data analysis and alternative categorizations of formaldehyde exposure., Methods: The original authors provided the cohort data. We computed U.S. and local county (regional) rate-based standardized mortality ratios (SMRs) and internal cohort rate-based relative risks (RR) by categories of four formaldehyde exposure metrics (highest peak, average intensity, cumulative, and duration of exposure), using both NCI categories and an alternative categorization based on tertiles of all NPC deaths among exposed subjects. We computed SMRs and RRs for each of 10 study plants and by plant group (Plant 1 (n = 4261) vs. Plants 2-10 (n = 21,358))., Results: Six of 10 NPC deaths observed in the NCI study occurred in only one plant (Plant 1) and the remaining four cases occurred individually in four of the other nine plants studied. A large, statistically significant, regional rate-based NPC SMR of 10.32 (95% CI = 3.79-22.47) among formaldehyde-exposed workers in Plant 1 contrasted sharply with a 35% deficit in NPC deaths (SMR = .65, 95% CI = .08-2.33) among exposed workers in Plants 2-10 combined. The statistically significant exposure-response relationship with formaldehyde and NPC reported in the NCI study for highest peak exposure was driven entirely by a large, statistically significant excess NPC risk in Plant 1 for the highest peak exposure category (4+ ppm). For the remaining nine plants, RRs for all non-baseline highest peak exposure categories were less than 1.0, and we observed no evidence of an exposure-response relationship. Most of the observed NPC excesses for the non-baseline categories of the other exposure metrics (average intensity, cumulative, and duration of formaldehyde exposure) were concentrated in Plant 1, and by contrast to the NCI findings, none of the corresponding exposure-response relationships was statistically significant., Conclusions: Overall, our reanalysis provided little evidence to support NCI's suggestion of a causal association between formaldehyde exposure and mortality from NPC. NCI's conclusion of a possible causal association was driven heavily by anomalous findings in one study plant (Plant 1). An independent and larger study of Plant 1 by the current authors concluded the NPC excess was not associated with formaldehyde exposure. Our findings cast considerable additional uncertainty regarding the validity of NCI's suggested causal association.

Purpose: To examine mortality among workers in a pharmaceutical production plant and to address community concerns about 1980 to 1990 increases in local county cancer mortality rates., Methods: Subjects were 1999 workers with some full-time employment during the period between 1970 and 1996. We identified deaths through the year 2000 and reconstructed exposures to nine chemical agents with available exposure measurements. Data analyses included standardized mortality ratios (SMRs) and time trends in local cancer mortality rates., Results: We observed deficits in deaths from all causes combined, all cancers combined, and most cause of death categories examined. Male workers with potential plant exposure had excesses in deaths from all lymphatic-hematopoietic tissue cancers (LHTC), in particular non-Hodgkin's lymphoma (NHL), and respiratory system cancers (RSC) that were larger among long-term workers, but the pattern of findings suggested the excesses were probably not related to occupational factors at the plant. The increase in local county cancer mortality rates was simply the upward cycle of a periodic trend that peaked in 1990 and returned to 1980 levels in 2000., Conclusions: With the possible exceptions of LHTC, in particular NHL, and RSC, this study provided no evidence of elevated total or cause-specific cohort mortality risks. It does not appear that plant factors played a role in the 1980 to 1990 increases in local county cancer mortality rates.

Purpose: In a cohort in which racial data are unknown for some persons, race-specific persons and person-years are imputed using a model-based iterative allocation algorithm (IAA)., Methods: An EM algorithm-based approach to address misclassification in a censored data regression setting can be adapted to estimate the probability that a person of unknown race is white. The corresponding race-specific person-years are obtained as a by-product of the estimation procedure. Variance estimates are computed using the bootstrap. The proposed approach is compared with the proportional allocation method (PAM)., Results: In an occupational cohort where racial data were missing for 41% of the workers, the age-time-race-specific person-years were estimated within a relative variation of approximately 20%, using the IAA. The deaths were less reliably estimated. The standardized mortality ratios (SMRs) for all-cause mortality estimated using the IAA and the PAM were more similar for the non-white workers than for a smaller subgroup of white workers., Conclusions: The IAA provides a method to reliably estimate race-specific person-year denominators in cohort studies with missing racial data. This method is applicable to other incompletely observed non-time-dependent categorical covariates. Internal cohort rates or SMRs can be computed and modeled, with bootstrap confidence intervals that account for the uncertainty in the determination of race.

An historical cohort study was conducted of workers at a pharmaceutical manufacturing plant. The cohort mortality experience of workers ever employed at the plant over the period from 1950 to 1999 was examined. The 1958 workers accumulated 44,294 person-years of experience at the plant, and a total of 384 deaths were identified. Our findings from external comparisons based on standardized mortality ratios (SMRs) in the cohort provide no evidence of excess mortality risk from all causes combined (SMR=0.75), all cancers combined (SMR=0.96), or from certain other individual causes of death. No patterns of excess mortality risk were apparent after stratifying on age and sex or job classification. The mortality experience of this cohort was generally more favorable than that of the general population.

We report the 1946-1992 mortality experience of 4008 females employed in any of 10 U.S. fiberglass manufacturing plants between 1945 and 1978 relative to external population rates. We also examine respiratory system cancer (RSC) mortality as a function of estimated exposure to respirable fibers (RFib), formaldehyde (FOR), silica, phenolics, urea, and other agents based on internal cohort comparisons. No statistically significantly elevated standardized mortality ratios were observed for all-cause mortality (930 deaths), any of the 25 nonmalignant causes considered, all malignant neoplasms (266 deaths), or any of the 27 malignant causes considered. Internal cohort comparisons revealed no significant positive associations between RSC mortality (53 cases) and exposure to RFib, FOR, or any of the other agents considered, although exposure levels were generally low. Some demographic subgroups appear to be at relatively increased risk of RSC.

Objective: To investigate further bladder cancer mortality excess based on four deaths observed among the internal comparison population of a previous historical cohort study of workers from a chemical plant in Lima, Ohio. The internal population mainly comprised workers from the Nitrogen Products (NP) Division., Methods: The original Lima cohort was expanded to include all workers (n = 1,841) employed between 1955 and 1996. A subcohort of workers employed mainly in the NP Division (NP Subcohort) was identified and used as the primary study population and as the source of cases and controls for a matched case-control study of bladder cancer. All death records were reviewed for any mention of bladder cancer; all available personnel, medical, and insurance files were reviewed to identify any current or former employees with an existing diagnosis of bladder cancer. A qualitative exposure assessment of all cases and controls was performed to evaluate an exploratory hypothesis that the bladder cancer excess may be associated with work histories involving both NP and urea, specifically, nitric acid and urea., Results: We identified 96 new deaths among the expanded Lima cohort and obtained cause of death for 90. One additional bladder cancer death and one living case were identified and these were members of the original Lima cohort. The bladder cancer standardized mortality ratio (SMR) for the NP Subcohort (SMR = 3.31, 95%CI = 0.90-8.47) fell between the SMRs observed for all workers in the original and expanded Lima cohort (SMR = 3.93, 95%CI = 1.07-10.06 and 3.10, 95%CI = 1.01-7.24, respectively), but was markedly less than the SMR observed for corresponding subcohort of AN-unexposed workers in the original Lima cohort (SMR = 7.01, 95%CI = 1.91-17.96). Sparse data and a high prevalence of exposure among controls precluded an informative statistical analysis of the possible association between work histories involving both nitric acid and urea and bladder cancer risk., Conclusions: This study confirms that bladder cancer mortality is elevated among persons who worked mainly in the NP Division of the Lima plant, but at a lower, less statistically significant level than indicated by the original cohort study. No occupational risk factors considered to be causally related to the bladder cancer excess could be identified by this intensive investigation; other possible reasons for the excess are suggested by the descriptive data., (Copyright 2002 Wiley-Liss, Inc.)

As part of our ongoing mortality surveillance program for the US man-made vitreous fiber industry, we surveyed a random sample of study members to estimate tobacco-smoking habits for the total cohort. Separate sampling frames were constructed for four study groups: male and female workers within the fiberglass and rock/slag wool subcohorts. The frames included all persons who had worked a year or more between 1945 and 1986 (with some exceptions), and who were alive as adults (18+ years) on January 1, 1980, the year the age distribution of the cohort most resembled the US comparison population. Subjects were randomly selected from the frames, and a structured telephone interview was administered to the subject or a proxy respondent between January 1995 and December 1997. Using survey data, we estimated the point prevalence of ever and current cigarette smoking on January 1, 1980, and made comparisons with other occupational groups and general populations. Overall response rates (interviews/targeted sample) were greater than 78% for each of the four study groups. From our estimates, we infer that male workers from both the fiberglass and rock/slag wool cohorts and female rock/slag wool workers had higher rates of ever smoking than the corresponding general populations of the United States and most of the states where the study plants were located. These findings suggest that at least part of the elevated externally standardized mortality ratios (US and regional rate-based) for respiratory system cancer noted among male subjects and the male-dominated total cohort in our previous cohort analyses were due to uncontrolled positive confounding by smoking.

Objective: To update the mortality experience of a cohort of 8508 workers with potential exposure to acrylamide at three plants in the United States from 1984-94., Methods: Analyses of standardised mortality ratios (SMR) with national and local rates and relative risk (RR) regression modelling were performed to assess site specific cancer risks by demographic and work history factors, and exposure indicators for acrylamide and muriatic acid., Results: For the 1925-94 study period, excess and deficit overall mortality risks were found for cancer sites of interest: brain and other central nervous system (CNS) (SMR 0.65, 95% confidence interval (95% CI) 0.36 to 1.09), thyroid gland (SMR 2.11, 95% CI 0.44 to 6.17), testis and other male genital organs (SMR 0.28, 95% CI 0.01 to 1.59), and cancer of the respiratory system (SMR 1.10, 95% CI 0.99 to 1.22); however, none was significant or associated with exposure to acrylamide. A previously reported excess mortality risk of cancer of the respiratory system at one plant remained increased among workers with potential exposure to muriatic acid (RR 1.50, 95% CI 0.86 to 2.59), but was only slightly increased among workers exposed or unexposed to acrylamide. In an exploratory exposure-response analysis of rectal, oesophageal, pancreatic, and kidney cancer, we found increased SMRs for some categories of exposure to acrylamide, but little evidence of an exposure-response relation. A significant 2.26-fold risk (95% CI 1.03 to 4.29) was found for pancreatic cancer among workers with cumulative exposure to acrylamide > 0.30 mg/m3.years; however, no consistent exposure-response relations were detected with the exposure measures considered when RR regression models were adjusted for time since first exposure to acrylamide., Conclusion: The contribution of 1115 additional deaths and nearly 60,000 person-years over the 11 year follow up period corroborate the original cohort study findings of little evidence for a causal relation between exposure to acrylamide and mortality from any cancer sites, including those of initial interest. This is the most definitive study of the human carcinogenic potential of exposure to acrylamide conducted to date.