Comparative lung toxicity of engineered nanomaterials utilizing in vitro, ex vivo and in vivo approaches

Abstract

BackgroundAlthough engineered nanomaterials (ENM) are currently regulated either in the context of a new chemical, or as a new use of an existing chemical, hazard assessment is still to a large extent reliant on information from historical toxicity studies of the parent compound, and may not take into account special properties related to the small size and high surface area of ENM. While it is important to properly screen and predict the potential toxicity of ENM, there is also concern that current toxicity tests will require even heavier use of experimental animals, and reliable alternatives should be developed and validated. Here we assessed the comparative respiratory toxicity of ENM in three different methods which employed in vivo, in vitro and ex vivo toxicity testing approaches.MethodsToxicity of five ENM (SiO2 (10), CeO2 (23), CeO2 (88), TiO2 (10), and TiO2 (200); parentheses indicate average ENM diameter in nm) were tested in this study. CD-1 mice were exposed to the ENM by oropharyngeal aspiration at a dose of 100 μg. Mouse lung tissue slices and alveolar macrophages were also exposed to the ENM at concentrations of 22–132 and 3.1-100 μg/mL, respectively. Biomarkers of lung injury and inflammation were assessed at 4 and/or 24 hr post-exposure.ResultsSmall-sized ENM (SiO2 (10), CeO2 (23), but not TiO2 (10)) significantly elicited pro-inflammatory responses in mice (in vivo), suggesting that the observed toxicity in the lungs was dependent on size and chemical composition. Similarly, SiO2 (10) and/or CeO2 (23) were also more toxic in the lung tissue slices (ex vivo) and alveolar macrophages (in vitro) compared to other ENM. A similar pattern of inflammatory response (e.g., interleukin-6) was observed in both ex vivo and in vitro when a dose metric based on cell surface area (μg/cm2), but not culture medium volume (μg/mL) was employed.ConclusionExposure to ENM induced acute lung inflammatory effects in a size- and chemical composition-dependent manner. The cell culture and lung slice techniques provided similar profiles of effect and help bridge the gap in our understanding of in vivo, ex vivo, and in vitro toxicity outcomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-014-0047-3) contains supplementary material, which is available to authorized users.

Amine modification of nonporous silica nanoparticles reduces inflammatory response following intratracheal instillation in murine lungs

“…9,29,30,31 While in vitro experiments are commonly used to predict the toxicity of engineered silica NPs in vivo, there are limitations to the interpretation of the results because of the over-simplified environment of cell culture experiments versus animal models where there is a more complex, physiological environment. 32,33,34 Although the evaluation of the side effects of silica NPs have been investigated previously, there is a lack of data in the literature where both in vitro cytotoxicity and in vivo inflammatory response studies have been performed using the same batch of silica NPs and reported together in a single study.…”

Comparative chemistry and toxicity of diesel and biomass combustion emissions

“…Murine lung tissue slices had a similar pattern of responses to those observed in whole animals [32]. Recently, we also revealed that lung tissue slices were capable of predicting in vivo pro-inflammatory responses of engineered nanomaterials, depending on their size and chemistry [42]. Importantly, lung slices from specific mouse strains or transgenic mice will also provide the opportunity to identify or discriminate key factor(s) that induce pulmonary toxicity [39].…”

Cytotoxicity of vanadium oxide nanoparticles and titanium dioxide‐coated vanadium oxide nanoparticles to human lung cells

“…The in vitro cell studies could help us identify the toxicity of VO 2 and reveal the related mechanism. Although there is the uncertainty in extrapolating the in vitro results into in vivo, let alone human beings (Joris et al, ), some studies indicate that there was a positive relationship between in vitro and in vivo results (Han et al, ; Kim, Boykin, Stevens, Lavrich, & Ian Gilmour, ). For instance, Kim et al reported that the toxicities of five kinds of metal oxide nanomaterials to lungs from the cell tests were well accordant with those from the animal experiments (Kim, Boykin, Stevens, Lavrich, & Ian Gilmour, ).…”