Dermal exposure to heavy metals contaminated soil from e-waste sites: Linking bioaccessibility to cellular uptake, cytotoxicity, and transport mechanisms in skin cells.

Soil heavy metals (HMs) pollution stemming from e-waste dismantling poses a significant global threat to human health, with dermal contact being a critical yet underexplored exposure pathway. This study investigated the contamination characteristics of Cd, Pb, Ni, Cu, Zn, As, Cr, and Mn in soils from a typical e-waste dismantling area in Wenling, Zhejiang Province, China. Subsequently, we used in vitro assays to test dermal bioaccessibility of HMs, integrated this data into a probabilistic health risk assessment model to refine risk estimates, and further investigated the underlying cytotoxic mechanisms. Dermal bioaccessibility results revealed significant variability, with Cd (29.12 %) and Ni (24.51 %) exhibiting the highest bioaccessibility, whereas the highly abundant Pb presented a remarkably low bioaccessibility. A probabilistic health risk assessment incorporating both total and bioaccessibility revealed negligible non-carcinogenic risks for children and adults. The inclusion of bioaccessibility reduced non-carcinogenic risk by 93.3 % and lowered the overestimation of carcinogenic risks by approximately 87 %. However, notable carcinogenic risks remained, with Ni identified as the primary contributor. In vitro toxicological validation using human skin keratinocytes (HaCaT) demonstrated that soil extracts induced dose-dependent cytotoxicity, intracellular reactive oxygen species (ROS) generation, and apoptosis. Furthermore, we identified a significant dysregulation of key metal transporter genes, with CTR1 and GLUT2 being upregulated and DMT1 and ZIP14 downregulated, providing mechanistic insight into the altered cellular uptake of these metals. This study demonstrates that integrating bioaccessibility measurements, in vitro toxicity data, and probabilistic modeling is essential for accurately assessing the health risks of dermal exposure to HMs-contaminated soils. The proposed framework offers a more science-based approach for environmental management and risk mitigation.