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Fig. 4 | Particle and Fibre Toxicology

Fig. 4

From: Predicting the in vivo pulmonary toxicity induced by acute exposure to poorly soluble nanomaterials by using advanced in vitro methods

Fig. 4

Dose intervals calculated for a 20% increase in inflammation markers in function of methodologies used. Comparisons of dose intervals were performed between the in vivo and in vitro methods used. The comparisons were performed using two dose metrics: the mass/alveolar surface (a) or the mass/macrophages (b). In vitro and in vivo experiments were performed using the same TiO2 (NM105, NM101, NM100) and CeO2 (NM212) NMs. In vitro, alveolar epithelial cells in co-culture with macrophages were exposed for 24 h at the air-liquid interface (ALI) to aerosols or in submerged conditions to suspensions of NMs. Different deposition kinetics were tested. At the ALI the NM deposition via aerosol was maintained for 3 h. The cells were then kept at the incubator for the remaining 21 h (3 h + 21 h). In submerged conditions, two deposition kinetics were used. In inserts, the deposition was maintained for 3 h. After 3 h, NM suspensions were replaced by fresh medium and the cells were then kept a the incubator for the remaining 21 h (3 h + 21 h) with the NMs deposited on their surface. In plates, classic exposure conditions were used and NM depositions were maintained for 24 h. In vivo, rats were exposed by intratracheal instillation with NM suspensions and the NMs were deposited almost instantly into the lungs. After 24 h of exposure, the biological activity was assessed, focusing more particularly on pro-inflammatory mediators. For each exposure method and for each NM, benchmark dose-response modeling was used to estimate the critical dose related to a 20% increase of pro-inflammatory mediator level and the lowest (BMDL) and the highest (BMDU) dose of the interval corresponding to confidence interval of 90%. A median dose intervals was then calculated by pooling the dose intervals of the four cytokine to have a general pro-inflammatory response

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