Occupational Exposure to Metalworking Fluids and Incidence of Cancer in the United Autoworkers-General Motors Cohort: Assessing and Accounting for the Healthy Worker Survivor Effect

Metalworking fluids (MWF) are coolants and lubricants used in industrial machining and grinding operations and have been linked with several cancers. Components found in MWFs, including polycyclic aromatic hydrocarbons found in oil-based straight fluids and nitrosamines found in water-based synthetic fluids, have been linked with mammary gland as well as respiratory organ tumors in laboratory animals. Epidemiologic evidence for these cancers, however, is less conclusive. Despite the provocative toxicologic evidence, there are few epidemiologic studies on MWF exposure and breast cancer. Results for lung cancer have been null for oil-based MWF and appeared inversely related to synthetic fluids, possible due to presence of endotoxin. The United Autoworkers-General Motors (UAW-GM) study includes an occupational cohort of 46,316 hourly workers in automotive manufacturing and extensive MWF exposure data, with annual average exposure estimates available for workers’ full employment history, and over two decades of cancer incidence follow-up. To better understand the exposure-response relationship between MWF exposure and these cancer outcomes, this dissertation set out to improve upon prior studies by first evaluating the presence of a common source of bias in occupational epidemiology, the healthy worker survivor effect (HWSE) in the UAW-GM cohort, and second collecting additional data and using advanced methods to evaluate these relationships./nChapter 1 is the assessment of the presence of the HWSE in cancer studies of the UAW-GM cohort. The HWSE can affect the validity of occupational studies when data are analyzed incorrectly. HWSE depends on three underlying conditions: (1) leaving work predicts future exposure, (2) leaving work is associated with disease outcome, and (3) prior exposure increases probability of leaving work. If all these conditions are satisfied employment status is a time-varying confounder affected by prior exposure and standard methods will produce bias. I evaluated the presence of these conditions for select cancer outcomes, including lung cancer, in the UAW-GM cohort and found evidence for all three conditions. This suggested that standard methods may underestimate the exposure-response for lung cancer and therefore a g-method should be applied to control for employment status as a time-varying confounder affected by prior exposure. A secondary analysis examining breast cancer among female workers found insufficient evidence for condition (3), indicating that standard methods are appropriate for this outcome and will not produce bias due to HWSE./nIn Chapter 2, I evaluated the exposure-response relation between cumulative MWF exposure and breast cancer incidence among female workers in the UAW-GM cohort. Additional data was obtained by extending follow-up four more years for female cohort members using data linkage with the Michigan Cancer Registry and the National Death Index. We identified 221 total incident breast cancer cases among 4,503 female workers. Risks associated with exposure to the three types of MWFs, straight, soluble, and synthetic, were evaluated using Cox proportional hazards models for all breast cancer cases as well as for pre-menopausal cases defined by age at diagnosis. Results suggest an increasing exposure-response curve for straight fluids and breast cancer. While the number of the pre-menopausal cancers is small, results are modestly suggestive of an increased risk associated with higher synthetic fluid exposure, suggesting a different mechanism for the younger cases./nIn Chapter 3, I examined the relationship between lung cancer mortality and exposure to straight and synthetic MWF, as well as to the biocides that are added to water-based fluids to control microbial growth. Using the parametric g-formula, ratios were estimated comparing cumulative risk of lung cancer mortality under the hypothetical interventions always high exposure while at work and always unexposed. We also intervened on both synthetic MWF and biocides simultaneously to estimate independent effects. Results from this study suggest slightly elevated lung cancer mortality related to straight MWF exposure, albeit with wide confidence intervals. Our results do not support a negative association for synthetic fluids, as reported in earlier studies; instead, biocide in the fluid, a marker for the release of endotoxin, was associated with decreased lung cancer./nThe hypotheses addressed in this dissertation are of public health importance in light of the extremely high incidence of both breast and lung cancer in the US. These studies provide information on the relationships between MWF exposure, breast and lung cancer incidence, adding to the scientific literature that informs regulatory measures and protects workers from the risks of MWF exposure.

Advisor: Eisen, Ellen A