Assessing the relevance of in vitro studies in nanotoxicology by examining correlations between in vitro and in vivo data

Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA.
Toxicology (Impact Factor: 3.62). 04/2012; 297(1-3):1-9. DOI: 10.1016/j.tox.2012.03.006
Source: PubMed


There is an urgent need for in vitro screening assays to evaluate nanoparticle (NP) toxicity. However, the relevance of in vitro assays is still disputable. We administered doses of TiO(2) NPs of different sizes to alveolar epithelial cells in vitro and the same NPs by intratracheal instillation in rats in vivo to examine the correlation between in vitro and in vivo responses. The correlations were based on toxicity rankings of NPs after adopting NP surface area as dose metric, and response per unit surface area as response metric. Sizes of the anatase TiO(2) NPs ranged from 3 to 100 nm. A cell-free assay for measuring reactive oxygen species (ROS) was used, and lactate dehydrogenase (LDH) release, and protein oxidation induction were the in vitro cellular assays using a rat lung Type I epithelial cell line (R3/1) following 24 h incubation. The in vivo endpoint was number of PMNs in bronchoalveolar lavage fluid (BALF) after exposure of rats to the NPs via intratracheal instillation. Slope analyses of the dose response curves shows that the in vivo and in vitro responses were well correlated. We conclude that using the approach of steepest slope analysis offers a superior method to correlate in vitro with in vivo results of NP toxicity and for ranking their toxic potency.

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    • "Increased apprehension over health concerns surrounds CNTs owing to increased biological persistence and non-degradability, similar to asbestos (Aschberger et al., 2010). On the contrary, the primary concern associated with metal NMs is their rapid dissolution into ions, which disrupts cellular functions (Khan et al., 2012; Maurer et al., 2014). Currently, even more complex novel materials are being produced which have incorporate nanocarbon and nanometals, further complicating bioexposure responses (Poulsen et al., 2015; Zhang and Wang, 2007). "
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    ABSTRACT: The exponential growth in the employment of nanomaterials (NMs) has given rise to the field of nanotoxicology; which evaluates the safety of engineered NMs. Initial nanotoxicological studies were limited by a lack of both available materials and accurate biodispersion characterization tools. However, the years that followed were marked by the development of enhanced synthesis techniques and characterization technologies; which are now standard practice for nanotoxicological evaluation. Paralleling advances in characterization, significant progress was made in correlating specific physical parameters, such as size, morphology, or coating, to resultant physiological responses. Although great strides have been made to advance the field, nanotoxicology is currently at a crossroads and faces a number of obstacles and technical limitations not associated with traditional toxicology. Some of the most pressing and influential challenges include establishing full characterization requirements, standardization of dosimetry, evaluating kinetic rates of ionic dissolution, improving in vitro to in vivo predictive efficiencies, and establishing safety exposure limits. This Review will discuss both the progress and future directions of nanotoxicology: highlighting key previous research successes and exploring challenges plaguing the field today. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.
    Toxicological Sciences 09/2015; 147(1):5-16. DOI:10.1093/toxsci/kfv106 · 3.85 Impact Factor
    • "To circumvent some of these drawbacks, in vitro cell-based assays have been gaining momentum in recent years in becoming a reliable alternative to in vivo testing for ENM toxicity and ranking their toxic potency (Han et al., 2012). Amongst others, in vitro approaches are particularly attractive because of the high costs and ethical issues associated with animal testing. "
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    ABSTRACT: Abstract In the past few years, promising efforts to utilize microfabrication-based technologies have laid the foundation for developing advanced, and importantly more physiologically-realistic, microfluidic methods for risk assessment of engineered nanomaterials (ENMs). In the present review, we discuss the wave of recent developments using microfluidic-based in vitro models and platforms for nanotoxicological assays, such as determination of cell viability, cellular dose, oxidative stress and nuclear damage. Here, we specifically highlight the tangible advantages of microfluidic devices in providing promising tools to tackle many of the current and ongoing challenges faced with traditional toxicology assays. Most importantly, microfluidic technology not only allows to recreate physiologically-relevant in vitro models for nanotoxicity examinations, but also provides platforms that deliver an attractive strategy towards improved control over applied ENM doses. In a final step, we present examples of state-of-the-art microfluidic platforms for in vitro assessment of potential adverse ENM effects.
    Nanotoxicology 07/2014; 9(3):1-15. DOI:10.3109/17435390.2014.940402 · 6.41 Impact Factor
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    • "Both in vitro and in vivo studies of nanoparticles toxicity are currently in progress [8,9,10,11,12,13]. In vitro studies have revealed several cytotoxic mechanisms, such as (1) reactive oxygen species (ROS) generation by cells that uptake titanium oxide particles [14,15] or silicon/silica particles [16,17]; and (2) the release of metallic material from Cd/Se quantum dots (QDs) after UV exposure [16] or silver particles [18]; and (3) structure-related toxicity caused by multi-walled carbon nanotubes [19]. "
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    ABSTRACT: Several in vivo studies suggest that nanoparticles (smaller than 100 nm) have the ability to reach the brain tissue. Moreover, some nanoparticles can penetrate into the brains of murine fetuses through the placenta by intravenous administration to pregnant mice. However, it is not clear whether the penetrated nanoparticles affect neurogenesis or brain function. To evaluate its effects on neural stem cells, we assayed a human neural stem cell (hNSCs) line exposed in vitro to three types of silica particles (30 nm, 70 nm, and <44 µm) and two types of titanium oxide particles (80 nm and < 44 µm). Our results show that hNSCs aggregated and exhibited abnormal morphology when exposed to the particles at concentrations = 0.1 mg/mL for 7 days. Moreover, all the particles affected the gene expression of Nestin (stem cell marker) and neurofilament heavy polypeptide (NF-H, neuron marker) at 0.1 mg/mL. In contrast, only 30-nm silica particles at 1.0 mg/mL significantly reduced mitochondrial activity. Notably, 30-nm silica particles exhibited acute membrane permeability at concentrations =62.5 µg/mL in 24 h. Although these concentrations are higher than the expected concentrations of nanoparticles in the brain from in vivo experiments in a short period, these thresholds may indicate the potential toxicity of accumulated particles for long-term usage or continuous exposure.
    International Journal of Molecular Sciences 07/2014; 15(7):11742-11759. DOI:10.3390/ijms150711742 · 2.86 Impact Factor
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