Abstract
Long-term mortality effects of particulate air pollution have been investigated in a causal analytic frame, while causal evidence for associations with gaseous air pollutants remains extensively lacking, especially for carbon monoxide (CO) and sulfur dioxide (SO(2)). In this study, we estimated the causal relationship of long-term exposure to nitrogen dioxide (NO(2)), CO, SO(2), and ozone (O(3)) with mortality. Utilizing the data from National Morbidity, Mortality, and Air Pollution Study, we applied a variant of difference-in-differences (DID) method with conditional Poisson regression and generalized weighted quantile sum regression (gWQS) to investigate the independent and joint effects. Independent exposures to NO(2), CO, and SO(2) were causally associated with increased risks of total, nonaccidental, and cardiovascular mortality, while no evident associations with O(3) were identified in the entire population. In gWQS analyses, an interquartile range-equivalent increase in mixture exposure was associated with a relative risk of 1.067 (95% confidence interval: 1.010-1.126) for total mortality, 1.067 (1.009-1.128) for nonaccidental mortality, and 1.125 (1.060-1.193) for cardiovascular mortality, where NO(2) was identified as the most significant contributor to the overall effect. This nationwide DID analysis provided causal evidence for independent and combined effects of NO(2), CO, SO(2), and O(3) on increased mortality risks among the US general population.