Environmental metal mixtures and overactive bladder: insights from population-based data

Dear Editor, Wang and colleagues analyzed data from the National Health and Nutrition Examination Survey (NHANES) spanning 2005–2018 to explore the association between urinary heavy metal exposure and the risk of overactive bladder (OAB) in U.S. adults[1]. Using inductively coupled plasma–mass spectrometry (ICP–MS) to quantify urinary metals with creatinine adjustment, the authors observed that higher levels of cadmium (Cd), lead (Pb), and uranium (Ur) were associated with increased odds of OAB. Importantly, mixture analyses applying weighted quantile sum (WQS) regression and quantile-based g-computation (qgcomp) suggested an overall adverse effect of combined metal exposure, with Cd emerging as the dominant contributor[1]. This study is timely and relevant, as OAB is highly prevalent and remains etiologically heterogeneous at the population level[2]. By moving beyond single-metal models, the authors adopt a mixture-based analytical framework that better reflects real-world environmental exposures. Such approaches are increasingly recommended in environmental health research to reduce bias arising from correlated pollutants and to improve interpretability of cumulative exposure effects[3]. The prominent role of Cd identified here is biologically plausible, given extensive evidence that cadmium exposure induces neurotoxicity and disrupts central and peripheral neural pathways involved in bladder storage and voiding control[4], potentially contributing to overactive bladder symptoms. Several considerations are important for contextual interpretation. First, the cross-sectional design precludes causal inference. Urinary metal concentrations primarily reflect recent exposure and renal handling, whereas OAB symptoms are chronic and fluctuating; reverse causation cannot be excluded. Second, although creatinine correction is standard, OAB-related voiding frequency and hydration behavior may affect urinary dilution, potentially introducing exposure misclassification. Sensitivity analyses using alternative adjustment methods, such as urine specific gravity, could strengthen robustness. Third, OAB ascertainment relied on questionnaire-based symptom definitions rather than clinically confirmed diagnoses. While appropriate for large epidemiologic studies, such definitions may introduce non-differential misclassification and attenuate true associations[2]. Finally, interpretation of mixture models warrants caution: WQS regression imposes a single-direction constraint, whereas qgcomp allows bidirectional effects; thus, apparent inverse contributions of certain metals should be considered hypothesis-generating rather than protective. Overall, this study provides an important epidemiologic signal linking urinary heavy metal mixtures – particularly Cd and Pb – to OAB symptom burden. Prospective studies with repeated exposure assessment, incorporation of mechanistic biomarkers (e.g., oxidative stress or neuroinflammation), and clinically adjudicated outcomes will be essential to clarify causality and inform preventive strategies. This commentary was prepared in line with the TITAN 2025 guideline to support transparent and responsible reporting[5].