Exposure-response models based on extended follow-up of a cohort mortality study in the automobile industry.

OBJECTIVE: This report describes the extended follow-up of a cohort of 46 399 automobile manufacturing workers with potential exposure to metalworking fluids (MWF). The outcomes of interest were cancers of the esophagus, stomach, colon, rectum, liver, pancreas, larynx, skin, prostate, and brain, as well as leukemia. Additional follow-up increased the power to detect modest elevations in mortality rates in association with specific types of MWF, including synthetic fluids not in widespread use until the 1970s. METHODS: Standardized mortality ratios (SMR) were computed for the most recent 10 years of follow-up, as well as for the entire study period. Adjusted relative risks (RR) were estimated in Poisson regression models with categorical variables for cumulative exposure to each type of MWF and in proportional hazards models with continuous exposure variables. RESULTS: Associations were found between straight MWF and esophageal, laryngeal and rectal cancer; soluble MWF and cancer of the esophagus, larynx, skin, and brain; synthetic MWF and cancer of the esophagus, liver, and prostate. The elevated RR values were modest in magnitude (1.5 to 2.0). SMR values were increased for stomach, liver, and pancreatic cancer and also for leukemia in the last 10 years of follow-up. The SMR values were also elevated for stomach and liver cancer among the persons recently hired. CONCLUSIONS: The results provide further evidence that exposure to metalworking fluids causes cancer among workers in automobile manufacturing. Although airborne exposures declined over the study period, this study suggests that modest risk of several digestive cancers, as well as prostatic cancer and leukemia, may persist at current levels of exposure to water-based metalworking fluids.

Personal fluoride and solvent exposures, and their determinants, in semiconductor manufacturing.

Personal air sampling for fluorides and solvents was done at 35 semiconductor fabrication facilities in the United States. Fluoride compounds were used in etching and cleaning operations, and solvents were used in photoresist and developing operations. All personal solvent and fluoride levels were less than 2 percent of current Occupational Safety and Health Administration (OSHA) standards. Statistical models of the exposure determinants for the target agents found production level, as indicated by number of semiconductor wafer cassettes loaded/unloaded from the target machines or baths, was predictive of fluoride, xylene and 1-methoxy-2-propyl acetate exposures. The percent of fresh air ventilation and the percent of xylene in the photoresist were also significant determinants in the statistical model predicting personal xylene exposure levels.

Mortality studies of metalworking fluid exposure in the automobile industry: VI. A case-control study of esophageal cancer.

BACKGROUND: Results are reported from a nested case-control study of 60 esophageal cancer deaths among 46,384 automobile manufacturing workers potentially exposed to metalworking fluids (MWF) in machining and grinding operations. METHODS: By using incidence-density sampling, controls were selected with a sampling ratio of 20:1 from among co-workers who remained at risk by the age of death of the case, matched on race, gender, plant, and year of birth. Conditional logistic regression was used to evaluate the risk associated with cumulative exposure (mg/m3-years) to each of three types of metalworking fluid (straight, soluble, and synthetic MWF), as well as with years of exposure to selected components of MWF, including nitrosamines, sulfur, biocides, and several metals. RESULTS: Esophageal cancer was found to be significantly associated with exposure to both soluble and synthetic MWF in grinding operations. The odds ratios (ORs) for grinding with soluble MWF were elevated at 2.5 or greater in all categories of cumulative exposure, although the exposure-response trend was statistically significant only when exposure was measured as duration. Those with 12 or more years exposure to soluble MWF in grinding operations experienced a 9.3-fold relative risk of esophageal cancer mortality (95% CI = 2.1-42.1). The OR for ever grinding with synthetic MWF was 4.1 (95% CI = 1.1-15.0). Elevated risk was also associated with two agents found in both synthetic and soluble fluids, nitrosamines, and biocides. For exposure to nitrosamines, the OR was 5.4 (95% CI = 1.5-19.9); for biocides the OR was 3.8 (95% CI = 0.8-18.9). However, because the same workers were exposed to grinding with synthetics, nitrosamines and biocides, it was not possible to separate the specific risks associated with these components.

Mortality studies of machining fluid exposure in the automobile industry. V: A case-control study of pancreatic cancer.

Results are presented from a case-control study of 97 cases of pancreatic cancer nested in a cohort of workers from three automobile manufacturing plants. Risk was examined for lifetime exposure to straight, soluble, and synthetic metalworking fluids, as used in specific machining or grinding operations, as well as for constituents of the fluids. Pancreatic cancer was associated with exposure to synthetic fluids in grinding operations, with an odds ratio of 3.0 (95% CI: 1.2-7.5) among those with more than 1.4 mg/m3-years of exposure. We were unable to examine synthetic exposure in the absence of grinding because there was virtually no exposure to synthetics in machining operations in this study population. Although a disproportionately high percent of the cases were black, no black workers had any exposure to synthetic fluids, and no other measured exposure was found to be related to risk. Thus, the previously documented excess risk of pancreatic cancer among blacks in this cohort remains unexplained.

Mortality studies of machining fluid exposure in the automobile industry. IV: A case-control study of lung cancer.

Machining fluids are diverse products that contain numerous additives and contaminants, including polycyclic aromatic hydrocarbons. Studies treating machining fluids as an aggregate exposure have found both positive and negative associations with lung cancer. In this nested case-control study of automotive workers (667 cases and 3,041 matched controls), individual estimates of exposure quantity and duration for specific classes of machining fluids were derived. An inverse dose-response relationship was found between synthetic machining fluids and lung cancer mortality, with an odds ratio of 0.6 (95% CI = 0.4, 0.8) for the highest level of lifetime exposure. The relationship was strongest for recent exposures. There was little evidence of an association with soluble or straight oil machining fluids. Risks were inconsistently elevated in workers exposed to aluminum. Results from this study provide strong evidence that exposure to machining fluids is not associated with an increased risk of lung cancer mortality in automotive workers.

Tiered exposure-assessment strategy in the Semiconductor Health Study.

The Semiconductor Health Study included 14 U.S. companies with 82 silicon-based wafer-fabrication rooms and a complex array of processes and chemicals. Its epidemiologic components were a historical examination of spontaneous abortion rates among 902 women, a prospective evaluation of reproductive outcomes in 483 women, and a cross-sectional review of male fertility and of respiratory, ergonomic, neurologic, or gastrointestinal problems among 3,175 men and women. Designing an exposure assessment strategy presented unique problems, and multiple agents had to be evaluated. A three-tiered approach to exposure assessment was developed to reflect increasing specificity of exposures. At the first tier, employees were divided into fabrication and nonfabrication groups. At the second tier, work groups with qualitatively different exposures were determined. At the third tier, intensity of exposures to specific chemical, physical, and ergonomic agents was evaluated. Evaluations were based on worker reports of tasks performed, moderated by fabrication-specific factors observed by study industrial hygienists during site visits.

Patterns of chemical use and exposure control in the Semiconductor Health Study.

Information on chemical use and exposure control between 1986 and 1990 was collected from 14 companies participating in the Semiconductor Health Study. Questionnaires and site visits provided data used to develop exposure categories for three epidemiological studies: prospective, historical, and cross-sectional. Patterns of use of target chemicals were compiled for 82 silicon-wafer fabrication rooms (fabs), including 47 from which subjects were selected for study. Chemical use was examined by operation, year, and epidemiological component. Target agents for epidemiological analyses were present in more than 50% of fabs. Use of these agents was fairly constant from 1986 to 1990, except for a moderate increase in use of propylene glycol monomethyl ether acetate, a solvent being substituted for ethylene-based glycol ethers (EGE) in photoresists. The distribution of personal protective equipment, engineering controls, and other factors potentially affecting employee exposure was also examined. Controls designed to manage processes or high acute toxicity were present in most fabs; their prevalence remained unchanged from 1986 through 1990. Controls designed to reduce exposures to chemicals with low acute toxicity were less widely distributed; their prevalence increased moderately from 1986 to 1990.

Algorithms for estimating personal exposures to chemical agents in the Semiconductor Health Study.

For exposure assessment in a series of epidemiologic studies of semiconductor industry workers, estimates of potential personal exposures to selected chemical agents were developed using a set of algorithms. A worker's total exposure to each agent was defined as the sum of task scores for each task using that agent. Task scores were calculated as the intensity and frequency score for each task, modified by a factor indicating degree of presence of the target agent and a process-specific emission factor representing degree of emission control present for that process. The algorithms used multiple sources of information to generate an exposure score for each worker-process-agent combination. Exposure scores were then placed into ordinal categories of exposure (0-3) for use in the epidemiologic analysis.

Hierarchical cluster analysis for exposure assessment of workers in the Semiconductor Health Study.

The fabrication of integrated circuits in the semiconductor industry involves worker exposures to multiple chemical and physical agents. The potential for a high degree of correlation among exposure variables was of concern in the Semiconductor Health Study. Hierarchical cluster analysis was used to identify groups or "clusters" of correlated variables. Several variations of hierarchical cluster analysis were performed on 14 chemical and physical agents, using exposure data on 882 subjects from the historical cohort of the epidemiological studies. Similarity between agent pairs was determined by calculating two metrics of dissimilarity, and hierarchical trees were constructed using three clustering methods. Among subjects exposed to ethylene-based glycol ethers (EGE), xylene, or n-butyl acetate (nBA), 83% were exposed to EGE and xylene, 86% to EGE and nBA, and 94% to xylene and nBA, suggesting that exposures to EGE, xylene, and nBA were highly correlated. A high correlation was also found for subjects exposed to boron and phosphorus (80%). The trees also revealed cluster groups containing agents associated with work-group exposure categories developed for the epidemiologic analyses.

Historical cohort investigation of spontaneous abortion in the Semiconductor Health Study: epidemiologic methods and analyses of risk in fabrication overall and in fabrication work groups.

The risk of spontaneous abortion (SAB) in the semiconductor industry was examined in a historical cohort study of pregnancies at 14 companies. We identified female employees who had worked for at least 6 months and whose ages ranged from 18 to 44 years during the 1986-1989 study period. Using company records, we included all fabrication-room (fab) employees and an approximately equal number of nonfabrication (nonfab) employees, for a total sample of 7,269. Telephone interviews with 6,088 women (84%) identified 904 eligible pregnancies and 113 SABs. Exposure classification was based on questionnaire and industrial hygiene assessments of tasks the women performed during the first trimester of pregnancy. Using logistic regression to control for age, smoking, ethnicity, education, income, year of pregnancy, and stress, we found a higher risk of SAB in fab employees than in nonfab employees (15.0% of fab pregnancies ended in SAB vs. 10.4% of nonfab pregnancies, adjusted relative risk [RR] = 1.43, 95% CI = 0.95-2.09). Analysis of fab work groups showed that the highest relative risk was in masking employees (17.5% SAB rate, adjusted RR = 1.78, 95% CI = 1.17-2.62 in comparison with nonfab employees). Within masking, the highest risk was found in etching-related process employees (22.2% SAB rate, adjusted RR = 2.08, 95% CI = 1.27-3.19 in comparison to nonfab employees.

Historical cohort study of spontaneous abortion among fabrication workers in the Semiconductor Health Study: agent-level analysis.

Risk of spontaneous abortion (SAB) was examined in relation to chemical and physical agents in a retrospective study of employees of 14 seminconductor manufacturers: After screening over 6,000 employees, 506 current and 385 former workers were eligible. If a woman had multiple eligible pregnancies, one was selected at random. Telephone interviews provided data on demographics and occupational and other exposures during the first trimester. Two groups of chemicals accounted for the 45% excess risk of SAB among fabrication-room (fab) workers: photoresist and developed solvents (PDS), including glycol ethers, and fluoride compounds used in etching. Women exposed to high levels of both these agents were at greater risk (RR = 3.21, 95% confidence interval [CI] = 1.29-5.96). In fab workers without these exposures, SAB rates were not elevated (adjusted relative risk [RR] = 0.98, 95% CI = 0.55-1.69). An association was seen with workplace stress, which was not limited to women exposed to PDS or fluoride, nor did stress explain the associations between these chemicals and SAB.

Estimation of historical exposures to machining fluids in the automotive industry.

A retrospective exposure assessment study in the automotive parts industry conducted in conjunction with a cancer mortality and respiratory morbidity study [Kennedy et al. (1989): Am J Ind Med 15:627-641; Eisen et al. (1992): Am J Ind Med 22:809-824; Tolbert et al. (1992): Scand J Work Environ Health 18:351-360] describes exposure to different types of machining fluids and selected components that may contribute to the conditions investigated. A dataset of 394 industrial hygiene measurements made between 1958 and 1987 was used to estimate past machining fluid levels using a linear statistical model. The effects of different plants, machining fluid types, machining operations, and time periods were examined in the model. Separate analyses examined the effects of different sampling and analysis methods and other measurement variables. Machining fluid levels prior to 1970 were generally two to five times higher than subsequent measurements. The arithmetic mean exposure of all measurements taken before 1970 was 5.42 mg/m3. Arithmetic means for different subgroups ranged from 0.59 to 20.28 mg/m3, depending upon plant, machining fluid, and operation. The arithmetic mean exposure after 1980 was 1.82 mg/m3 with subgroups ranging from 0.45 to 2.79 mg/m3. Changes in exposure levels generally corresponded with reported changes in plant environments such as installation of enclosures and local exhaust ventilation on machines.

Mortality studies of machining fluid exposure in the automobile industry. III: A case-control study of larynx cancer.

A case-control study of larynx cancer was conducted within a cohort of automobile workers exposed to metal working fluids, commonly referred to as machining fluids (MF). Results are based on 108 cases of larynx cancer and 5:1 matched controls. Risks associated with specific types of MF, as well as specific components of the fluids were evaluated. Based on a retrospective exposure assessment, lifetime exposures to straight and soluble fluids, grinding particulate, biocides, selected metals, sulfur, and chlorine were examined. Exposure to asbestos and acid mists at two of the three study sites was also characterized. Results suggest that straight mineral oils are associated with almost a two-fold excess in larynx cancer risk. There was also evidence of an association with elemental sulfur, commonly added to straight MF to improve the integrity of the materials under extreme pressure and heat. It is not clear whether sulfur is causally related to an excess relative risk of larynx cancer or whether the observed association is the result of unmeasured confounding by another contaminant or process feature. For example, the high stress operations that require MF enriched with sulfur are also more likely to produce polycyclic aromatic hydrocarbons (PAHs) during the process. Thus, the observed association with sulfur may be due to an association with PAH. The finding of excess risk of laryngeal cancer associated with MF is consistent with several previous reports in the literature. This is the first study, however, to distinguish straight mineral oils from other types of MF. Based on these findings, a general reduction in concentrations of straight mineral oil particulate in occupational environments would be prudent.

Size-selective pulmonary dose indices for metal-working fluid aerosols in machining and grinding operations in the automobile manufacturing industry.

The current metal-working fluid exposures at three locations that manufacture automotive parts were assessed in conjunction with epidemiological studies of the mortality and respiratory morbidity experiences of workers at these plants. A rationale is presented for selecting and characterizing epidemiologic exposure groups in this environment. More than 475 full-shift personal aerosol samples were taken using a two-stage personal cascade impactor with median size cut-offs of 9.8 microns and 3.5 microns, plus a backup filter. For a sample of 403 workers exposed to aerosols of machining or grinding fluids, the mean total exposure was 706 micrograms/m3 (standard error (SE) = 21 micrograms/m3). Among 72 assemblers unexposed to machining fluids, the mean total exposure was 187 +/- 10 (SE) micrograms/m3. An analysis of variance model identified factors significantly associated with exposure level and permitted estimates of exposure for workers in the unsampled machine type/metal-working fluid groups. Comparison of the results obtained from personal impactor samples with predictions from an aerosol-deposition model for the human respiratory tract showed high correlation. However, the amount collected on the impactor stage underestimates extrathoracic deposition and overestimates tracheobronchial and alveolar deposition, as calculated by the deposition model. When both the impactor concentration and the deposition-model concentration were used to estimate cumulative thoracic concentrations for the worklives of a subset of auto workers, there was no significant difference in the rank order of the subjects' cumulative concentration. However, the cumulative impactor concentration values were significantly higher than the cumulative deposition-model concentration values for the subjects.

A case-control study of cancer mortality at a transformer-assembly facility.

To address earlier reports of excess cancer mortality associated with employment at a large transformer manufacturing plant, each plant operation was rated for seven exposures: Pyranol (a mixture of polychlorinated biphenyls and trichlorobenzene), trichloroethylene, benzene, mixed solvents, asbestos, synthetic resins, and machining fluids. Site-specific cancer deaths among active or retired employees were cases; controls were selected from deaths (primarily cardiovascular deaths) presumed to be unassociated with any of the study exposures. Using job records, we then computed person-years of exposure for each subject. All subjects were white males. The only unequivocal association was that of resin systems with lung cancer (odds ratio = 2.2 at 16.6 years of exposure, P = 0.001, in a multiple logistic regression including asbestos, age, year of death, and year of hire). Certain other odds ratios appeared larger, but no other association was so robust and remained as distinct after considering the multiplicity of comparisons. Study power was very limited for most associations, and several biases may have affected our results. Nevertheless, further investigation of synthetic resin systems of the type used in the study plant appears warranted.

Mortality studies of machining-fluid exposure in the automobile industry. II. Risks associated with specific fluid types.

Excesses of digestive and respiratory cancers have been reported previously in association with exposure to machining fluids, agents in widespread use as coolants and lubricants in machining operations. Previous studies have had limited power to distinguish the effects of the different types of machining fluids in use. In a cohort of over 30,000 workers employed at two automotive plants in Michigan, mortality patterns were studied in relation to exposure to each of the three major fluid types--straight oils, soluble oils, and synthetic fluids. Standardized mortality ratios were estimated for subgroups of the cohort ever exposed to each of the three fluid types, and Poisson regression analyses were used to assess trends in risk with duration of exposure. The data suggest modest positive associations between exposure to straight oils and rectal, laryngeal, and prostatic cancer and a negative association between soluble and synthetic fluid exposure and lung cancer.

A new technique for collecting ambient diesel particles for bioassays.

This paper describes a new application of a viable aerosol sampler, the Liquid Electrostatic Aerosol Precipitator (LEAP), for the collection of diesel particles for bioassays of pulmonary toxicity and mutagenicity or carcinogenicity. Currently used methods (filtration, dry electrostatic precipitation) cause agglomeration of particles and increases in particle size up to twenty-fold, which may alter particle toxicity significantly. Collection of diesel particles with the LEAP preserved submicronic particle size. Differences in chemical composition of extracts of surface adsorbents as compared to particles collected on filters also were observed. This technique may be applicable for collection of other types of combustion products or oil mists that agglomerate when collected by filtration.

Some characteristics of amnesia induced by FLA-63 an inhibitor of dopamine beta hydroxylase.

The amnesic effects of FLA-63, a potent dopamine-beta-hydroxylase (DBH) inhibitor, were investigated in a food motivated spatial discrimination task. Groups of C57BL/6J mice were injected with either 5 mg/kg, 15 mg/kg, 25 mg/kg, 35 mg/kg or physiological saline 4 hr prior to training. Amnesia was observed 24 hr following training at all dose levels except 5 mg/kh. The performance deficit was specific to memory of the discrimination and not the result of state-dependency. Training conditions which produce an increase in habit strength prevented the amnestic effects of FLS-63. Spontaneous recovery of memory occurred 48 hr following drug administration. Recovery from amnesia was also induced by injections of a monoamine oxidase inhibitor, pargyline, administered 2 hr prior to the retention test. These data suggest that amnesia induced by norpinephrine (NE) depletion is the result of impairment of mechanisms necessary for memory retrieval.