Epidemiological studies likely need to consider PM_2.5 composition even if total outdoor PM_2.5 mass concentration is the exposure of interest

Background: Outdoor fine particulate air pollution, <2.5 µm (PM_2.5) mass concentrations can be constructed through many different combinations of chemical components that have varying levels of toxicity. This poses a challenge for studies interested in estimating the health effects of total outdoor PM_2.5 (i.e., how much PM_2.5 mass is present in the air regardless of composition) because we must consider possible confounders of the version of treatment-outcome relationships. Methods: We evaluated the extent of possible bias in mortality hazard ratios for total outdoor PM_2.5 by examining models with and without adjustment for sulfate and nitrate in PM_2.5 as examples of potential confounders of version of treatment-outcome relationships. Our study included approximately 3 million Canadians and Cox proportional hazard models were used to estimate hazard ratios for total outdoor PM_2.5 adjusting for sulfate and/or nitrate and other relevant covariates. Results: Hazard ratios for total outdoor PM_2.5 and nonaccidental, cardiovascular, and respiratory mortality were overestimated due to the confounding version of treatment-outcome relationships, and associations for lung cancer mortality were underestimated. Sulfate was most strongly associated with nonaccidental, cardiovascular, and respiratory mortality suggesting that regulations targeting this specific component of outdoor PM_2.5 may have greater health benefits than interventions targeting total PM_2.5. Conclusions: Studies interested in estimating the health impacts of total outdoor PM_2.5 (i.e., how much PM_2.5 mass is present in the air) need to consider potential confounders of the version of treatment-outcome relationships. Otherwise, health risk estimates for total PM_2.5 will reflect some unknown combination of how much PM_2.5 mass is present in the air and the kind of PM_2.5 mass that is present.