Environmental metal exposure patterns and health-related quality of life in northeast Indian gallbladder cancer patients: A metallomic clustering study.

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Background: Northeast India is a global gallbladder cancer (GBC) hotspot, where environmental metal exposure is a suspected risk factor. However, the relationship between multi-metal exposure patterns and patient quality of life (QoL) remains unexamined. Methods: In a cross-sectional study of 86 histologically confirmed GBC patients from Assam, India, we quantified serum concentrations of eleven trace metals (Be, V, Cr, Co, Ni, As, Se, Sr, Cd, Hg, Pb) using ICP-MS. Principal component analysis (PCA) and K-means clustering were applied to log-transformed metal data to identify exposure patterns. HRQoL was assessed using the EORTC QLQ-C30 and QLQ-BIL21 questionnaires. Differences in metal levels and HRQoL scores across clusters were tested, with multivariable linear regression adjusting for key demographics. Results: We identified three distinct metallomic clusters: low (n=33), intermediate (n=34), and high (n=19) exposure. Ten metals differed significantly between clusters (FDR p<0.05). A paradoxical relationship with QoL was observed: the intermediate exposure cluster had significantly worse global health status (26.0 ± 10.2) compared to the low (31.3 ± 9.3) and high (31.6 ± 8.6) clusters. Multivariable analysis confirmed that intermediate cluster membership was independently associated with a clinically important 6.22-point reduction in global health (95% CI: -11.2 to -1.3; p=0.01). Conclusions: Distinct multi-metal exposure phenotypes exist among GBC patients. The finding that intermediate, not high, exposure was linked to the poorest QoL challenges conventional dose-response models and underscores the complex health impacts of environmental metal mixtures, necessitating integrated public health and clinical strategies.