A systematic process for identifying key events for advancing the development of nanomaterial relevant adverse outcome pathways

Halappanavar, Sabina; Ede, James D.; Shatkin, Jo Anne; Krug, Harald F.

doi:10.1016/j.impact.2019.100178

Cited by 37 publications

(45 citation statements)

References 16 publications

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“…Recently, an OECD WPMN-supported project 'Advancing Adverse Outcome Pathway Development for Nanomaterial Risk Assessment and Categorization' (OECD WPMN AOP project) developed, through a case study approach, a systematic methodology for identifying KEs from the existing nanotoxicology literature and demonstrated how incorporation of data on KEs can be potentially linked to AOs and lead to the development of full AOPs in the future [40]. The OECD WPMN AOP project was led by the Canadian delegation (Health Canada and Environment and Climate Change Canada) of the OECD WPMN, involved several international partners, and was supported by SmartNanoTox (Smart Tools for Gauging Nano Hazards), a European Union Horizon 2020 (H2020)-funded consortium.…”

Section: Oecd Working Party For Manufactured Nanomaterials (Wpmn) Promentioning

confidence: 99%

“…Nanotoxicology research has established that nanomaterial-induced toxicity involves an acute inflammatory component [41][42][43]. The OECD WPMN AOP project reviewed a database of 191 individual studies selected from a larger collection of 11,000 studies published between 2000 and 2013, which included in vivo and in vitro reports on~60 endpoints associated with inflammation for 45 different nanomaterials [40]. These individual studies were reviewed to identify KEs and the results showed that inflammation, oxidative stress and cytotoxicity events are overrepresented in the nanotoxicology literature, which are also frequently identified KEs in many of the AOPs for chemicals documented on AOPwiki (https://aopwiki.…”

Section: Oecd Working Party For Manufactured Nanomaterials (Wpmn) Promentioning

confidence: 99%

“…Moreover, it was noted that these three KEs represent nanomaterial-induced effects at the cellular level of biological organization and share a causal relationship; persistent inflammation, oxidative stress and cytotoxicity and the consolidated interplay between the three cellular level KEs results in 'tissue injury', a tissue level effect or a KE. Tissue injury occurs downstream of inflammation and can be considered as a tipping point in the process of an inflammation-associated disease as it precedes tissue dysfunction [40]. Tissue injury can also be considered an AO in itself.…”

Section: Oecd Working Party For Manufactured Nanomaterials (Wpmn) Promentioning

confidence: 99%

“…The most highly connected KE ('Increased, recruitment of pro-inflammatory cells') is related to inflammation, which represents a tissue level KE. The most central KE was 'Loss of alveolar membrane integrity', a tissue level KE reflecting tissue injury, which was identified as one of the critical events potentially preceding nanomaterial-induced tissue dysfunction and adverse outcome [40]. The acute cell injury, oxidative stress, and inflammation triggered immediately following exposure to nanomaterials act in a positive feedback loop mechanism propagating the initial inflammatory response, resulting in tissue injury.…”

Section: Network Of Aopsmentioning

confidence: 99%

“…Lastly, owing to their comprehensiveness and sensitivity in differentiating subtle toxicity response induced by two individual nanomaterials of different properties [40,42], high content toxicogenomic data can help define the structural properties of nanomaterials that are responsible for triggering an MIE and thus, an AO. For example, an approach that uses proteomic data to profile the protein corona of 84 gold nanoparticles as a basis for developing biological descriptors as input into quantitative structue activity relationship (Q) SAR modelling was recently described [156].…”

Section: Network Of Aopsmentioning

confidence: 99%

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Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale

et al. 2020

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Toxicity testing and regulation of advanced materials at the nanoscale, i.e. nanosafety, is challenged by the growing number of nanomaterials and their property variants requiring assessment for potential human health impacts. The existing animal-reliant toxicity testing tools are onerous in terms of time and resources and are less and less in line with the international effort to reduce animal experiments. Thus, there is a need for faster, cheaper, sensitive and effective animal alternatives that are supported by mechanistic evidence. More importantly, there is an urgency for developing alternative testing strategies that help justify the strategic prioritization of testing or targeting the most apparent adverse outcomes, selection of specific endpoints and assays and identifying nanomaterials of high concern. The Adverse Outcome Pathway (AOP) framework is a systematic process that uses the available mechanistic information concerning a toxicological response and describes causal or mechanistic linkages between a molecular initiating event, a series of intermediate key events and the adverse outcome. The AOP framework provides pragmatic insights to promote the development of alternative testing strategies. This review will detail a brief overview of the AOP framework and its application to nanotoxicology, tools for developing AOPs and the role of toxicogenomics, and summarize various AOPs of relevance to inhalation toxicity of nanomaterials that are currently under various stages of development. The review also presents a network of AOPs derived from connecting all AOPs, which shows that several adverse outcomes induced by nanomaterials originate from a molecular initiating event that describes the interaction of nanomaterials with lung cells and involve similar intermediate key events. Finally, using the example of an established AOP for lung fibrosis, the review will discuss various in vitro tests available for assessing lung fibrosis and how the information can be used to support a tiered testing strategy for lung fibrosis. The AOPs and AOP network enable deeper understanding of mechanisms involved in inhalation toxicity of nanomaterials and provide a strategy for the development of alternative test

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Section: Oecd Working Party For Manufactured Nanomaterials (Wpmn) Promentioning

confidence: 99%

Section: Oecd Working Party For Manufactured Nanomaterials (Wpmn) Promentioning

confidence: 99%

Section: Oecd Working Party For Manufactured Nanomaterials (Wpmn) Promentioning

confidence: 99%

Section: Network Of Aopsmentioning

confidence: 99%

Section: Network Of Aopsmentioning

confidence: 99%

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Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale

et al. 2020

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Opportunities and Challenges for Integrating New In Vitro Methodologies in Hazard Testing and Risk Assessment

Burden

Clift

Jenkins

et al. 2021

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Nanomaterials are defined as materials with at least one dimension of 100 nm or less. Their small size confers unique properties that may alter the toxicity profile when compared to larger forms of the same material, requiring additional considerations for safety assessment. There has been a rise in the development of nanomaterials for many applications, and although traditional approaches for toxicity testing may address some of the new toxicity concerns, many may not be directly applicable to nanomaterials and new tools or approaches may need to be developed. Since nanomaterials can exist in many different forms, each of which may cause different adverse biological effects, reliance on traditional in vivo models for safety assessment will simply not be feasible or sustainable, given the volume of materials that may need to be tested. It is essential to consider and develop new in vitro methods that can be applied for hazard identification and risk assessment. Many challenges are associated with using alternative approaches to ensure they are as robust and reliable as traditional in vivo approaches, but by overcoming these issues and adopting new testing strategies there are opportunities to improve safety assessments and reduce the reliance on animal‐based toxicity testing strategies.

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Non‐Animal Strategies for Toxicity Assessment of Nanoscale Materials: Role of Adverse Outcome Pathways in the Selection of Endpoints

Halappanavar

Nymark

Krug³

et al. 2021

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Faster, cheaper, sensitive, and mechanisms‐based animal alternatives are needed to address the safety assessment needs of the growing number of nanomaterials (NM) and their sophisticated property variants. Specifically, strategies that help identify and prioritize alternative schemes involving individual test models, toxicity endpoints, and assays for the assessment of adverse outcomes, as well as strategies that enable validation and refinement of these schemes for the regulatory acceptance are needed. In this review, two strategies 1) the current nanotoxicology literature review and 2) the adverse outcome pathways (AOPs) framework, a systematic process that allows the assembly of available mechanistic information concerning a toxicological response in a simple modular format, are presented. The review highlights 1) the most frequently assessed and reported ad hoc in vivo and in vitro toxicity measurements in the literature, 2) various AOPs of relevance to inhalation toxicity of NM that are presently under development, and 3) their applicability in identifying key events of toxicity for targeted in vitro assay development. Finally, using an existing AOP for lung fibrosis, the specific combinations of cell types, exposure and test systems, and assays that are experimentally supported and thus, can be used for assessing NM‐induced lung fibrosis, are proposed.

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A systematic process for identifying key events for advancing the development of nanomaterial relevant adverse outcome pathways

Cited by 37 publications

References 16 publications

Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale

Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale

Opportunities and Challenges for Integrating New In Vitro Methodologies in Hazard Testing and Risk Assessment

Non‐Animal Strategies for Toxicity Assessment of Nanoscale Materials: Role of Adverse Outcome Pathways in the Selection of Endpoints

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