The United AutoWorkers–General Motors cohort included all workers at 3 General Motors plants in Michigan (Detroit, Ypsilanti, and Saginaw) with a hire date between 1938 and 1982 and an employment duration of at least 3 years (18). For our analysis, follow-up of 38,666 workers began 3 years after they were hired and continued regardless of employment status until the earliest of 3 possible end points: death, the end of 1994, or age 95 years. Outcomes studied included all-cause mortality (all International Classification of Disease, Ninth Revision codes) and deaths due to cardiovascular disease (codes 390–459), IHD (codes 410–414), acute myocardial infarction (AMI; code 410), and cerebrovascular disease (codes 430–438).

Exposures and intermittent time off work were determined by combining detailed employment records with a job-exposure matrix developed in an extensive exposure assessment (18, 19). Industrial hygienists measured exposures to 3 types of metalworking fluids (straight oils, soluble oils, and synthetic fluids) as PM in several size fractions. Here, PM with a diameter of 3.5 µm or less composed of straight metalworking fluids was analyzed as the exposure of interest, with the other 2 fluid types treated as potential confounders.

Tables 1 and 2 provide demographic characteristics for the mostly male, mostly white cohort. Approximately 8% of workers who died of cerebrovascular disease were women; only 4% of workers who died of AMI were women. Table 1.

Demographic and Employment Characteristics of the United AutoWorkers–General Motors Cohort, 1941–1994

Table 3 summarizes the exposure distribution. The average duration of exposure was slightly longer among cases. The distribution of exposure level (among exposed person-years) was mostly low, with a long tail to the right. Exposures exceeded the current recommended limit of 0.4 mg/m³ in a total of 14,949 person-years for 2,732 distinct workers. Table 3.

Distribution of Exposure to Oil-Based Metalworking Fluids Among Ever-Exposed Workers in the United AutoWorkers–General Motors Cohort (n = 38,666), 1941–1994^a

If straight metalworking fluids had been banned, workers who were ever exposed and who died of cardiovascular disease would have lived an average of 1.58 (95% confidence interval: 0.63, 2.52) years longer. On average, IHD deaths would have happened 2.77 (95% confidence interval: 1.56, 3.98) years later, and those who died of AMI would have lived 3.13 (95% confidence interval: 1.74, 4.53) years longer. Deaths from cerebrovascular disease among exposed workers would have occurred a mean of 3.19 (95% confidence interval: −0.14, 6.51) years later.

Figure 1 shows the estimates of the population effects on cardiovascular mortality under the different exposure limits. Although a ban is estimated to have a reasonably strong impact, the magnitude quickly decreases for exposure limits only slightly above 0. Figure 1.

Number of years of life that could have been saved among workers who died of cardiovascular disease by enforcing various occupational exposure limits for oil-based metalworking fluids, United AutoWorkers–General Motors cohort, 1941–1995.

We estimated that reducing the occupational exposure limit for straight metalworking fluids to 0.01 mg/m³ would have saved 2,000 life-years among autoworkers in this cohort who died of cardiovascular disease. Banning straight metalworking fluids would have saved an estimated 3,500 life-years among those who died of cardiovascular disease and 6,047 life-years overall. Thus, approximately 58% of the impact would be attributable to cardiovascular mortality, which only accounted for 44% of all deaths observed. The results suggest that the most life-years could have been saved per person for exposed workers who died of AMI or cerebrovascular disease. As a subcategory of IHD, AMI was the most specific cause of death studied, and the results for IHD and cardiovascular disease mortality were probably driven largely by the relationship of straight metalworking fluids with AMI.

However, the strongest etiological relationship was estimated for cerebrovascular disease mortality. To our knowledge, associations specifically between exposure to metalworking fluids and cerebrovascular disease have only been reported in 1 study. A higher odds ratio for stroke was reported for exposure to soluble metalworking fluids in an analysis restricted to decedents (23). That study presented little data on straight metalworking fluids.

In a systematic review of occupational studies in which the relationships between various kinds of PM and cardiovascular disease were examined, Fang et al. (24) found only 37 studies in a 20-year period. They did not find strong evidence of an effect of exposure on cerebrovascular outcomes, though they did find some for IHD. However, studies in the review considered exposures to several types of PM with different compositions and toxicities, some of which might not be relevant here.

More recently, in an exposure-response analysis of incident IHD among fabrication workers in the aluminum industry (a group similar to the autoworkers considered here), Costello et al. (25) found that persons exposed to higher levels of PM_2.5 had a higher risk of IHD over most of the exposure range. The relationship was approximately linear up to a concentration of almost 1.0 mg/m³, an order of magnitude higher than the limits considered here.

Metalworking fluids are known to irritate the skin and respiratory tract (26). Oil-based metalworking fluids increase the organic carbon and polycyclic aromatic hydrocarbon content of the respirable particle fraction by forming droplets, accumulating on the surfaces of solid particles, or transforming to secondary organic aerosols when heated. Metals that have contaminated the fluids or dissolved in them contribute to respirable particles. These properties have the potential to render PM in these occupational settings at least as toxicologically relevant for the development of cardiovascular disease as ambient PM (1). In particular, particles generated by the use of straight metalworking fluids are likely to contribute to all 3 major modes of action, namely: 1) inducing systemic inflammation and oxidative stress through organic polycyclic aromatic hydrocarbons and metal compounds, 2) activating the autonomic nervous system by irritating the respiratory tract, and 3) exhibiting direct effects by translocation of newly formed ultrafine particles or activated surfaces of particles. Evidence for the link between PM_2.5 at ambient levels and cardiovascular disease has further strengthened since 2010 (27, 28), supporting the need to protect workers from cardiovascular disease by lowering the exposure limit to 0.01 mg/m³.

Our methods contribute to the occupational literature in 2 important ways: We minimized healthy-worker survivor bias and also approached the research from a public health perspective. G-estimation provided better control for the healthy-worker survivor effect than is generally possible using traditional analytic methods in occupational studies in which follow-up continues after employment termination. By estimating the number of years of life that would have been saved by enforcing exposure limits, we obtained results with a concrete interpretation. Although banning straight metalworking fluids would have had the greatest effect on all of the cardiovascular mortality outcomes that we considered, a limit of 0.1 mg/m³ could still have saved over 1,000 life-years among those who died of IHD.

Under the assumptions of our analysis, the true number of life-years that would have been saved by enforcing an occupational exposure limit depends on 1) the incidence of the outcome in the study population during follow-up, 2) the distribution of exposure among the cases, and 3) the shape of the exposure-response curve. Thus, the analysis does not address a purely etiological question, but rather estimates the burden of disease that could have been avoided by enforcing a lower exposure limit in the cohort under study. For a given outcome, the estimates of this measure also allow us to compare the potential impacts of the different cutoffs.

Lowering the occupational exposure limit for straight metalworking fluids to any value from 0 mg/m³ to 0.02 mg/m³ would have affected the rate cerebrovascular mortality approximately equally, saving 800–900 years of life for the 501 workers who died of these causes. This seems to suggest a threshold; limits above 0.04 mg/m³ would have had little impact on this outcome. In contrast, although the estimated effects were higher for the other 3 (more prevalent) outcomes, increasing the limit from 0 showed rapidly decreasing impacts: The estimated effects for cardiovascular disease and IHD associated with a limit of 0.01 mg/m³ were half those for a total ban.

These estimates depend on several untestable assumptions. As in any observational study, we must assume that the variables that we measured were sufficient to control for confounding. Plausible unmeasured confounders include job transfer and the use of respirators or other protective equipment, both of which might be mechanisms by which a worker could reduce his or her exposure for health-related reasons. However, any residual confounding by these variables is likely to be toward the null. Furthermore, we lacked data on smoking, so there might be confounding by this important risk factor for cardiovascular disease. However, in a quantitative evaluation of the potential for bias due to uncontrolled confounding by alcohol and tobacco in occupational cohorts, Kriebel et al. (29) estimated that bias would be less than 20%.

Furthermore, we assume consistency, that is, that each person's counterfactual survival time under her or his observed exposure is equal to her or his observed survival time. This holds when the exposure is subject to well-defined interventions. For example, a workplace could comply with an occupational exposure limit in several ways: by improving ventilation, enforcing respirator use, or replacing straight metalworking fluids with other fluid types. We assume that the effects of such different interventions are equivalent if they correspond to the same limit.

A related assumption is that, for each cutoff, exposure being above or below that limit is the relevant exposure classification and that a worker's actual annual average daily exposure level within those categories is not relevant. By studying the potential effects of interventions based on several different cutoffs, we hope to have minimized any bias due to violations of this exposure classification assumption. However, a related technical point is briefly described in Web Appendix 1.

We also assumed correct model specification. Aside from unmeasured confounders, mentioned above, our exposure prediction model could be misspecified if the functional forms of our predictor variables were wrong or if interaction terms should have been included. More importantly, our structural model is based on 2 strong assumptions. First, it assumes there is no effect modification by covariate history. If effect modification (e.g., by (unmeasured) time-varying smoking status) is present, our results might be biased (12).

Second, any structural accelerated failure time model assumes that all individuals who experienced the outcome of interest would have done so under every possible exposure scenario; exposure merely affects the time at which the outcome occurs. This modeling assumption might be realistic for IHD because the underlying process of atherosclerosis is likely to be inflicted by multiple risk factors and accelerated by exposure to straight metalworking fluids. Nevertheless, if the magnitudes of the etiologic effects of metalworking fluids on different outcomes are substantially different, reducing exposure could mean that a worker who actually died of (for example) IHD would have instead died of some other cause, or vice versa. Cardiovascular disease is not a rare outcome, so assuming that those who died of it would have still died of it under other exposure scenarios is more plausible than it might be for a rare cancer. There were fewer cerebrovascular deaths, so those results may be more affected by this issue.

To avoid this problem, one could consider all-cause mortality, for which the modeling assumption is simply the incontrovertible fact that everyone would have died at some point and for which there are no competing risks. Our analysis of all-cause mortality yielded results that looked similar in shape to those for cardiovascular disease, but with greater impacts and confidence intervals that mostly excluded the null. Another way to avoid both this modeling assumption and the need for weights to adjust for competing risks would be to use the parametric g-formula instead of g-estimation (see Web Appendix 1) (13).

In most previous occupational studies, investigators aimed to address an etiologic question. We chose instead to work within a public health framework, attempting to estimate the potential effects of various interventions to limit exposures to metalworking fluid. G-estimation is an analytic method that permits us to answer such questions in an easily interpretable way while also avoiding healthy-worker survivor bias. These analyses suggest that there might be a threshold of 0.02 mg/m³ for exposure to straight metalworking fluids, above which the time to cerebrovascular death is decreased; to our knowledge, ours is the first study to report a relationship between straight fluids and this outcome, so further study is needed. Furthermore, restricting exposures to straight metalworking fluids as much as possible could have saved many years of life among the workers who died of other cardiovascular causes, especially IHD and AMI. Overall, our results indicate that the currently recommended limit of 0.4 mg/m³ does not provide adequate protection for workers.