Associations between a mixture of trace elements and bladder cancer occurrence: A study of possible reverse causation.

Background: The association between trace elements and bladder cancer risk is not well understood. Individuals are typically exposed to a mixture of multiple elements simultaneously, such as through water pollution or diet. While previous studies have explored associations between individual elements and bladder cancer, there has been limited work in exploring the overall or joint effect of these elements. Methods: We leveraged the New England Bladder Cancer Study, a population-based matched case-control study, to estimate associations between a mixture of 12 trace elements and bladder cancer. Toenail clipping samples were collected and analyzed for 12 trace elements from 979 cases and 1232 controls. Using quantile-based g-computation, we assessed associations between the overall elements mixture and bladder cancer risk. Results: After adjustment for matching factors (i.e., age, sex, and state) and other potential confounders (e.g., smoking habits and high-risk occupation), we estimated an inverse association between the overall mixture of trace elements and bladder cancer (odds ratio: 0.78, 95% confidence interval: 0.66, 0.93). Results were relatively unchanged after adjustment for smoking, high-risk occupation, and diet. We examined indirect evidence for reverse causation in explaining this inverse relationship for arsenic and found evidence that bladder cancer diagnosis may lead to changes in short-term behavior, which affects concentrations of arsenic and possibly other elements in toenail samples.