Characterization of toxicological effects of complex nano‐sized metal particles using in vitro human cell and whole blood model systems.

Metal oxide fumes form at high temperatures, for instance, during welding or firing ammunition. Inhalation exposure to high levels of airborne metal oxide particles can cause metal fume fever, cardiovascular effects, and lung damage in humans, but the associated underlying pathological mechanisms are still not fully understood. Using human alveolar epithelial cells, vascular endothelial cells, and whole blood model systems, we aimed to elucidate the short‐term effects of well‐characterized metal particles emitted while firing pistol ammunition. Human lung epithelial cells exposed to gunshot smoke particles (0.1–50 μg/ml) produced reactive oxygen species (ROS) and pro‐inflammatory cytokines (interleukin 8 (IL‐8), granulocyte‐macrophage colony‐stimulating factor (GM‐CSF)) that activate and recruit immune cells. Particles comprising high copper (Cu) and zinc (Zn) content activated human endothelial cells via a non‐ROS‐mediated mechanism that triggered immune activation (IL‐8, GM‐CSF), leukocyte adhesion to the endothelium (soluble intercellular adhesion molecule 1 (sICAM‐1)), and secretion of regulators of the acute‐phase protein synthesis (interleukin 6 (IL‐6)). In human whole blood, metal oxides in gunshot smoke demonstrated intrinsic properties that activated platelets (release of soluble cluster of differentiation 40 ligand (sCD40L), platelet‐derived growth factor B‐chain homodimer(PDGF‐BB), and vascular endothelial growth factor A (VEGF‐A)) and blood coagulation and induced concomitant release of pro‐inflammatory cytokines from blood leukocytes that further orchestrate thrombogenesis. The model systems applied provide useful tools for health risk assessment of particle exposures, but more studies are needed to further elucidate the mechanisms of metal fume fever and to evaluate the potential risk of long‐term cardiovascular diseases. Inhalation exposure to metal fumes emitted during pistol firing can cause metal fume fever in humans. The mechanisms behind short‐term toxic responses to metal fumes were investigated in exposure systems using lung epithelium, vascular endothelium, and whole blood. Gunshot smoke particles elicited toxic responses and immune activation in lung epithelial cells, vascular endothelial cells, and white blood cells and activated thrombocytes that orchestrate thrombogenesis, creating a milieu that contributes to metal fume fever and potentially accelerates the development of cardiovascular diseases. [ABSTRACT FROM AUTHOR]