Abstract
The exposure-response associations of ambient heavy metals and persistent organic pollutants (POPs) with mortality in the general population remain unclear. This cohort study aimed to explore the long-term effect of exposure to four air pollutants, including lead (Pb), cadmium (Cd), mercury (Hg), and benzo(a)pyrene [B(a)P] on all-cause and cause-specific mortality. This study involved 497,056 participants from the UK Biobank cohort. We used the Cox proportional hazards model to calculate associations. Effects of joint exposure to heavy metals were estimated using quantile g-computation. Shape of the exposure-response association was examined by fitting penalty splines, in both the total population and subpopulations stratified by age, sex, smoking status, and genetic factors. Modifying effects of age, sex, smoking status, and genetic factors were also examined. Over a median follow-up of 13.7 years, we identified 39,530 (8.0%) deaths. Exposure to mixtures of Pb, Cd, and Hg was associated with 1.040-1.154 times increased risk of all-cause cancer, cardiovascular disease (CVD), stroke, and respiratory disease mortality. Of the specific causes of mortality, Pb and Cd were most strongly associated with respiratory diseases, including chronic obstructive pulmonary disease, followed by ischemic heart disease, CVD, and cancer. Hg and B(a)P seemed to exhibit lower toxicity compared with Pb and Cd. Exposure-response curves demonstrated monotonically increased risk for most mortality outcomes, though Hg was found to be nonlinearly associated with all-cause and stroke mortality. Age, smoking status, and genetic factors were found to modify the susceptibility to heavy metals. Our findings suggested that long-term exposure to heavy metals and B(a)P was monotonically associated with elevated risk of multiple mortality outcomes, indicating there may be no safe threshold for these chemicals. Substantial benefits to public health could be achieved through stringent environmental regulations and clean air initiatives.