scholarly journals Novel Methods and Approaches for Safety Evaluation of Nanoparticle Formulations: A Focus Towards In Vitro Models and Adverse Outcome Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Mounika Gayathri Tirumala ◽  
Pratibha Anchi ◽  
Susmitha Raja ◽  
Mahesh Rachamalla ◽  
Chandraiah Godugu
Keyword(s):  
Risk Assessment ◽  
Adverse Outcome ◽  
Safety Concern ◽  
Single Cells ◽  
High Surface ◽  
Adverse Outcomes ◽  
Novel Methods ◽  
Adverse Outcome Pathways

Nanotoxicology is an emerging field employed in the assessment of unintentional hazardous effects produced by nanoparticles (NPs) impacting human health and the environment. The nanotoxicity affects the range between induction of cellular stress and cytotoxicity. The reasons so far reported for these toxicological effects are due to their variable sizes with high surface areas, shape, charge, and physicochemical properties, which upon interaction with the biological components may influence their functioning and result in adverse outcomes (AO). Thus, understanding the risk produced by these materials now is an important safety concern for the development of nanotechnology and nanomedicine. Since the time nanotoxicology has evolved, the methods employed have been majorly relied on in vitro cell-based evaluations, while these simple methods may not predict the complexity involved in preclinical and clinical conditions concerning pharmacokinetics, organ toxicity, and toxicities evidenced through multiple cellular levels. The safety profiles of nanoscale nanomaterials and nanoformulations in the delivery of drugs and therapeutic applications are of considerable concern. In addition, the safety assessment for new nanomedicine formulas lacks regulatory standards. Though the in vivo studies are greatly needed, the end parameters used for risk assessment are not predicting the possible toxic effects produced by various nanoformulations. On the other side, due to increased restrictions on animal usage and demand for the need for high-throughput assays, there is a need for developing and exploring novel methods to evaluate NPs safety concerns. The progress made in molecular biology and the availability of several modern techniques may offer novel and innovative methods to evaluate the toxicological behavior of different NPs by using single cells, cell population, and whole organisms. This review highlights the recent novel methods developed for the evaluation of the safety impacts of NPs and attempts to solve the problems that come with risk assessment. The relevance of investigating adverse outcome pathways (AOPs) in nanotoxicology has been stressed in particular.

Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment

2011 ◽  
pp. n/a-n/a ◽  
Author(s):  
Gerald T. Ankley ◽  
Richard S. Bennett ◽  
Russell J. Erickson ◽  
Dale J. Hoff ◽  
Michael W. Hornung ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Conceptual Framework ◽  
Adverse Outcome ◽  
Adverse Outcome Pathways

scholarly journals Osseointegrating and phase-oriented micro-arc-oxidized titanium dioxide bone implants

2021 ◽  
Vol 19 ◽  
pp. 228080002110068
Author(s):  
Hsien-Te Chen ◽  
Hsin-I Lin ◽  
Chi-Jen Chung ◽  
Chih-Hsin Tang ◽  
Ju-Liang He
Keyword(s):  
Titanium Dioxide ◽  
High Surface ◽  
Cell Activity ◽  
Active Surface ◽  
Rutile Phase ◽  
Hydroxyl Groups ◽  
Bone Implant ◽  
Implant System

Here, we present a bone implant system of phase-oriented titanium dioxide (TiO2) fabricated by the micro-arc oxidation method (MAO) on β-Ti to facilitate improved osseointegration. This (101) rutile-phase-dominant MAO TiO2 (R-TiO2) is biocompatible due to its high surface roughness, bone-mimetic structure, and preferential crystalline orientation. Furthermore, (101) R-TiO2 possesses active and abundant hydroxyl groups that play a significant role in enhancing hydroxyapatite formation and cell adhesion and promote cell activity leading to osseointegration. The implants had been elicited their favorable cellular behavior in vitro in the previous publications; in addition, they exhibit excellent shear strength and promote bone–implant contact, osteogenesis, and tissue formation in vivo. Hence, it can be concluded that this MAO R-TiO2 bone implant system provides a favorable active surface for efficient osseointegration and is suitable for clinical applications.

In Vitro Toxicology Methods in Risk Assessment

1996 ◽  
Vol 24 (3) ◽  
pp. 325-331
Author(s):  
Iain F. H. Purchase
Keyword(s):  
Risk Assessment ◽  
Hazard Assessment ◽  
Human Health Risk ◽  
In Vitro Test ◽  
In Vitro Methods ◽  
New Concepts ◽  
Vitro Test

The title of this paper is challenging, because the question of how in vitro methods and results contribute to human health risk assessment is rarely considered. The process of risk assessment usually begins with hazard assessment, which provides a description of the inherent toxicological properties of the chemical. The next step is to assess the relevance of this to humans, i.e. the human hazard assessment. Finally, information on exposure is examined, and risk can then be assessed. In vitro methods have a limited, but important, role to play in risk assessment. The results can be used for classification and labelling; these are methods of controlling exposure, analogous to risk assessment, but without considering exposure. The Ames Salmonella test is the only in vitro method which is incorporated into regulations and used widely. Data from this test can, at best, lead to classification of a chemical with regard to genotoxicity, but cannot be used for classification and labelling on their own. Several in vitro test systems which assess the topical irritancy and corrosivity of chemicals have been reasonably well validated, and the results from these tests can be used for classification. The future development of in vitro methods is likely to be slow, as it depends on the development of new concepts and ideas. The in vivo methods which currently have reasonably developed in vitro alternatives will be the easiest to replace. The remaining in vivo methods, which provide toxicological information from repeated chronic dosing, with varied endpoints and by mechanisms which are not understood, will be more difficult to replace.

Use of Toxicokinetics in Risk Assessment Based on In Vitro Data

1993 ◽  
Vol 21 (2) ◽  
pp. 173-180
Author(s):  
Gunnar Johanson
Keyword(s):  
Risk Assessment ◽  
Whole Body ◽  
External Exposure ◽  
Target Dose ◽  
Toxic Response ◽  
Route Of Exposure ◽  
Vitro Data ◽  
In Vitro Data

This presentation addresses some aspects of the methodology, advantages and problems associated with toxicokinetic modelling based on in vitro data. By using toxicokinetic models, particularly physiologically-based ones, it is possible, in principle, to describe whole body toxicokinetics, target doses and toxic effects from in vitro data. Modelling can be divided into three major steps: 1) to relate external exposure (applied dose) of xenobiotic to target dose; 2) to establish the relationship between target dose and effect (in vitro data, e.g. metabolism in microsomes, partitioning in tissue homogenates, and toxicity in cell cultures, are useful in both steps); and 3) to relate external exposure to toxic effect by combining the first two steps. Extrapolations from in vitro to in vivo, between animal and man, and between high and low doses, can easily be carried out by toxicokinetic simulations. In addition, several factors that may affect the toxic response by changing the target dose, such as route of exposure and physical activity, can be studied. New insights concerning the processes involved in toxicity often emerge during the design, refinement and validation of the model. The modelling approach is illustrated by two examples: 1) the carcinogenicity of 1,3-butadiene; and 2) the haematotoxicity of 2-butoxyethanol. Toxicokinetic modelling is an important tool in toxicological risk assessment based on in vitro data. Many factors, some of which can, and should be, studied in vitro, are involved in the expression of toxicity. Successful modelling depends on the identification and quantification of these factors.

scholarly journals A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Celinda M. Kofron ◽  
Tae Yun Kim ◽  
Fabiola Munarin ◽  
Arvin H. Soepriatna ◽  
Rajeev J. Kant ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Action Potentials ◽  
Induced Pluripotent Stem Cell ◽  
Human Action ◽  
Environmental Toxicants ◽  
Pharmaceutical Drugs ◽  
Industrial Chemicals ◽  
Endocrine Disrupting Chemical

AbstractCardiotoxicity of pharmaceutical drugs, industrial chemicals, and environmental toxicants can be severe, even life threatening, which necessitates a thorough evaluation of the human response to chemical compounds. Predicting risks for arrhythmia and sudden cardiac death accurately is critical for defining safety profiles. Currently available approaches have limitations including a focus on single select ion channels, the use of non-human species in vitro and in vivo, and limited direct physiological translation. We have advanced the robustness and reproducibility of in vitro platforms for assessing pro-arrhythmic cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes and human cardiac fibroblasts in 3-dimensional microtissues. Using automated algorithms and statistical analyses of eight comprehensive evaluation metrics of cardiac action potentials, we demonstrate that tissue-engineered human cardiac microtissues respond appropriately to physiological stimuli and effectively differentiate between high-risk and low-risk compounds exhibiting blockade of the hERG channel (E4031 and ranolazine, respectively). Further, we show that the environmental endocrine disrupting chemical bisphenol-A (BPA) causes acute and sensitive disruption of human action potentials in the nanomolar range. Thus, this novel human 3D in vitro pro-arrhythmic risk assessment platform addresses critical needs in cardiotoxicity testing for both environmental and pharmaceutical compounds and can be leveraged to establish safe human exposure levels.

scholarly journals Combined In Vitro and In Vivo Approaches to Propose a Putative Adverse Outcome Pathway for Acute Lung Inflammation Induced by Nanoparticles: A Study on Carbon Dots

Nanomaterials ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 180
Author(s):  
Maud Weiss ◽  
Jiahui Fan ◽  
Mickaël Claudel ◽  
Luc Lebeau ◽  
Françoise Pons ◽  
...  
Keyword(s):  
Carbon Dots ◽  
Lung Inflammation ◽  
Adverse Outcome ◽  
Cellular Responses ◽  
Target Cells ◽  
Inflammasome Activation ◽  
Adverse Outcome Pathway ◽  
Acute Lung Inflammation

With the growth of nanotechnologies, concerns raised regarding the potential adverse effects of nanoparticles (NPs), especially on the respiratory tract. Adverse outcome pathways (AOP) have become recently the subject of intensive studies in order to get a better understanding of the mechanisms of NP toxicity, and hence hopefully predict the health risks associated with NP exposure. Herein, we propose a putative AOP for the lung toxicity of NPs using emerging nanomaterials called carbon dots (CDs), and in vivo and in vitro experimental approaches. We first investigated the effect of a single administration of CDs on mouse airways. We showed that CDs induce an acute lung inflammation and identified airway macrophages as target cells of CDs. Then, we studied the cellular responses induced by CDs in an in vitro model of macrophages. We observed that CDs are internalized by these cells (molecular initial event) and induce a series of key events, including loss of lysosomal integrity and mitochondrial disruption (organelle responses), as well as oxidative stress, inflammasome activation, inflammatory cytokine upregulation and macrophage death (cellular responses). All these effects triggering lung inflammation as tissular response may lead to acute lung injury.

scholarly journals Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Luigi Margiotta-Casaluci ◽  
Stewart F. Owen ◽  
Belinda Huerta ◽  
Sara Rodríguez-Mozaz ◽  
Subramanian Kugathas ◽  
...  
Keyword(s):  
Predictive Power ◽  
Adverse Outcome ◽  
Plasma Concentrations ◽  
Internal Exposure ◽  
Adverse Outcome Pathway ◽  
Conceptual Tool ◽  
Fish Model ◽  
Species Specific

Abstract The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-specific uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.

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