Role of surface charge and oxidative stress in cytotoxicity of organic monolayer-coated silicon nanoparticles towards macrophage NR8383 cells

Background - Surface charge and oxidative stress are often hypothesized to be important factors in cytotoxicity of nanoparticles. However, the role of these factors is not well understood. Hence, the aim of this study was to systematically investigate the role of surface charge, oxidative stress and possible involvement of mitochondria in the production of intracellular reactive oxygen species (ROS) upon exposure of rat macrophage NR8383 cells to silicon nanoparticles. For this aim highly monodisperse (size 1.6 ± 0.2 nm) and well-characterized Si core nanoparticles (Si NP) were used with a surface charge that depends on the specific covalently bound organic monolayers: positively charged Si NP-NH2, neutral Si NP-N3 and negatively charged Si NP-COOH. Results - Positively charged Si NP-NH2 proved to be more cytotoxic in terms of reducing mitochondrial metabolic activity and effects on phagocytosis than neutral Si NP-N3, while negatively charged Si NP-COOH showed very little or no cytotoxicity. Si NP-NH2 produced the highest level of intracellular ROS, followed by Si NP-N3 and Si NP-COOH; the latter did not induce any intracellular ROS production. A similar trend in ROS production was observed in incubations with an isolated mitochondrial fraction from rat liver tissue in the presence of Si NP. Finally, vitamin E and vitamin C induced protection against the cytotoxicity of the Si NP-NH2 and Si NP-N3, corroborating the role of oxidative stress in the mechanism underlying the cytotoxicity of these Si NP. Conclusion - Surface charge of Si-core nanoparticles plays an important role in determining their cytotoxicity. Production of intracellular ROS, with probable involvement of mitochondria, is an important mechanism for this cytotoxicit

Integrating in vitro data and physiologically based kinetic (PBK) modelling to assess the in vivo potential developmental toxicity of a series of phenols

Toxicity outcomes derived in vitro do not always reflect in vivo toxicity values, which was previously observed for a series of phenols tested in the embryonic stem cell test (EST). Translation of in vitro data to the in vivo situation is therefore an important, but still limiting step for the use of in vitro toxicity outcomes in the safety assessment of chemicals. The aim of the present study was to translate in vitro embryotoxicity data for a series of phenols to in vivo developmental toxic potency values for the rat by physiologically based kinetic (PBK) modelling-based reverse dosimetry. To this purpose, PBK models were developed for each of the phenols. The models were parameterised with in vitro-derived values defining metabolism and transport of the compounds across the intestinal and placental barrier and with in silico predictions and data from the literature. Using PBK-based reverse dosimetry, in vitro concentration–response curves from the EST were translated into in vivo dose–response curves from which points of departure (PoDs) were derived. The predicted PoDs differed less than 3.6-fold from PoDs derived from in vivo toxicity data for the phenols available in the literature. Moreover, the in vitro PBK-based reverse dosimetry approach could overcome the large disparity that was observed previously between the in vitro and the in vivo relative potency of the series of phenols. In conclusion, this study shows another proof-of-principle that the in vitro PBK approach is a promising strategy for non-animal-based safety assessment of chemicals