Confounding Effects of Primary Hepatocellular Carcinoma on Urinary Arsenic as an Environmental Exposure Indicator in a Karst High-Background Population

Arsenic (As) concentrations in bodily fluids are widely used to assess external environmental exposure, governed jointly by external intake and internal metabolism. However, current research largely overlooks the confounding effects of primary hepatocellular carcinoma (PHC) on these biomarkers. To clarify the utility of bodily fluid As as an environmental exposure indicator, we first conducted an exposure association study across five villages in Guangxi, China. Total As levels in water, soil, and rice were measured to estimate multi-pathway external exposure doses, while blood and urine samples from long-term residents were synchronously collected and analyzed to elucidate the relationship between external exposure and internal As burden. Subsequently, a comparative study between a healthy population and PHC patients was conducted to evaluate the interference of PHC on fluid As distribution. Results indicated that rice consumption constituted the primary exposure pathway, contributing 66.32% to 95.25% of the total intake. In the healthy group, the geometric mean of urinary As (33.96 µg/L) was significantly higher than that of blood As (2.02 µg/L). Notably, in the PHC group, both urinary As (4.55 µg/L) and blood As (1.81 µg/L) were lower than those in the Normal group. Receiver Operating Characteristic (ROC) curve analysis confirmed that urinary As was highly confounded by PHC (Area Under the Curve [AUC] = 0.916). In conclusion, threshold evaluations based solely on environmental media fail to accurately reflect the true internal As burden. While urinary and blood As are generally effective indicators of human exposure, the onset of PHC induces an abnormal decline in urinary As. Consequently, relying on urinary As may lead to a critical underestimation of environmental As exposure risks in PHC populations.