New approach methodologies in human regulatory toxicology – Not if, but how and when!

Environment International, Journal Year: 2023, Volume and Issue: 178, P. 108082 - 108082

Published: July 4, 2023

The predominantly animal-centric approach of chemical safety assessment has increasingly come under pressure. Society is questioning overall performance, sustainability, continued relevance for human health risk and ethics this system, demanding a change paradigm. At the same time, scientific toolbox used continuously enriched by development "New Approach Methodologies" (NAMs). While term does not define age or state readiness innovation, it covers wide range methods, including quantitative structure-activity relationship (QSAR) predictions, high-throughput screening (HTS) bioassays, omics applications, cell cultures, organoids, microphysiological systems (MPS), machine learning models artificial intelligence (AI). In addition to promising faster more efficient toxicity testing, NAMs have potential fundamentally transform today's regulatory work allowing human-relevant decision-making in terms both hazard exposure assessment. Yet, several obstacles hamper broader application current Constraints addressing repeated-dose toxicity, with particular reference chronic hesitance from relevant stakeholders, are major challenges implementation context. Moreover, issues regarding predictivity, reproducibility quantification need be addressed legislative frameworks adapted NAMs. conceptual perspective presented here its focus on grounded main findings conclusions symposium workshop held Berlin November 2021. It intends provide further insights into how can gradually integrated aimed at protection health, until eventually paradigm replaced an animal-free "Next Generation Risk Assessment" (NGRA).

Language: Английский

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Establishment of a human cell-based in vitro battery to assess developmental neurotoxicity hazard of chemicals

Chemosphere, Journal Year: 2022, Volume and Issue: 311, P. 137035 - 137035

Published: Oct. 31, 2022

Developmental neurotoxicity (DNT) is a major safety concern for all chemicals of the human exposome. However, DNT data from animal studies are available only small percentage manufactured compounds. Test methods with higher throughput than current regulatory guideline methods, and improved relevance urgently needed. We therefore explored feasibility hazard assessment based on new approach (NAMs). An in vitro battery (IVB) was assembled ten individual NAMs that had been developed during past years to probe effects various fundamental neurodevelopmental processes. All assays used neural cells at different developmental stages. This allowed us assess disturbances of: (i) proliferation progenitor (NPC); (ii) migration crest cells, radial glia neurons oligodendrocytes; (iii) differentiation NPC into (iv) neurite outgrowth peripheral central neurons. In parallel, cytotoxicity measures were obtained. The concentration-dependent screening reliable biostatistical processing complex multi-dimensional set 120 test compounds, containing subsets pre-defined positive negative provided alerts (hit or borderline) 24 28 known toxicants (82% sensitivity), none 17 controls. Based results this screen project, strategies how IVB may be context risk scenarios employing integrated approaches testing (IATA).

Language: Английский

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Next-generation risk assessment of chemicals – Rolling out a human-centric testing strategy to drive 3R implementation: The RISK-HUNT3R project perspective

ALTEX, Journal Year: 2022, Volume and Issue: unknown

Published: Jan. 1, 2022

In many industrial sectors, there is a need for reliable ways to evaluate the safety of chemicals with methods anchored human biology and pathology. For this purpose, animal-free new approach (NAMs) have been developed implemented in various stages risk assessment. Now it time assemble individual NAMs into comprehensive next-generation assessment (NGRA) strategy. The European Horizon 2020 RISK-HUNT3R project (Risk integrating human-centric testing strategies promoting 3Rs) has designed promote combination computational toxicology, vitro systems biology. It anticipated that will lead faster more accurate procedures. NGRA strategy be address implementation NAM toolbox regulatory framework. Critical conceptual approaches include i) integration human-relevant data on biotransformation elimination, ii) translation high-content mode-of-action datasets predictions adverse outcomes, iii) development quantitative outcome pathways (qAOPs), iv) quantification uncertainties associated based strategies. Many steps used iteratively generate sufficient quality certainty NGRA. Scientists regulators work together case studies practical applicability combine information therefrom. Here we delineate how deployed establish an overall framework chemicals, pesticides, food additives, drugs.

Language: Английский

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Recent advances and current challenges of new approach methodologies in developmental and adult neurotoxicity testing

Archives of Toxicology, Journal Year: 2024, Volume and Issue: 98(5), P. 1271 - 1295

Published: March 13, 2024

Abstract Adult neurotoxicity (ANT) and developmental (DNT) assessments aim to understand the adverse effects underlying mechanisms of toxicants on human nervous system. In recent years, there has been an increasing focus so-called new approach methodologies (NAMs). The Organization for Economic Co-operation Development (OECD), together with European American regulatory agencies, promote use validated alternative test systems, but date, guidelines DNT ANT assessment rely primarily classical animal testing. Alternative methods include both non-animal approaches systems non-vertebrates (e.g., nematodes) or non-mammals fish). Therefore, this review summarizes advances NAMs focusing highlights potential current critical issues full implementation these in future. status vitro battery (DNT IVB) is also reviewed as a first step context. Critical such (i) need batteries method integration (from silico vivo alternatives, e.g., zebrafish, C. elegans ) requiring interdisciplinarity manage complexity, (ii) interlaboratory transferability, (iii) urgent validation are discussed.

Language: Английский

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Comprehensive mapping of the AOP-Wiki database: identifying biological and disease gaps

Frontiers in Toxicology, Journal Year: 2024, Volume and Issue: 6

Published: March 8, 2024

Introduction: The Adverse Outcome Pathway (AOP) concept facilitates rapid hazard assessment for human health risks. AOPs are constantly evolving, their number is growing, and they referenced in the AOP-Wiki database, which supported by OECD. Here, we present a study that aims at identifying well-defined biological areas, as well gaps within future research needs. It does not intend to provide systematic comprehensive summary of available literature on but summarizes maps knowledge diseases represented already developed (with OECD endorsed status or under validation). Methods: Knowledge from database were extracted prepared analysis using multi-step procedure. An automatic mapping existing information (i.e., genes/proteins diseases) was performed bioinformatics tools overrepresentation Gene Ontology DisGeNET), allowing both classification development AOP networks (AOPN). Results: related genitourinary system, neoplasms developmental anomalies most frequently investigated AOP-Wiki. evaluation three priority cases immunotoxicity non-genotoxic carcinogenesis, endocrine metabolic disruption, adult neurotoxicity) EU-funded PARC project (Partnership Risk Assessment Chemicals) presented. These used highlight under- over-represented adverse outcomes identify prioritize further research. Discussion: results contribute more understanding effects associated with molecular events AOPs, aid refining risk stressors mitigation strategies. Moreover, FAIRness data meets principles findability, accessibility, interoperability, reusability (FAIR)) appears be an important consideration development.

Language: Английский

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A vision for safer food contact materials: Public health concerns as drivers for improved testing

Environment International, Journal Year: 2023, Volume and Issue: 180, P. 108161 - 108161

Published: Sept. 26, 2023

Food contact materials (FCMs) and food articles are ubiquitous in today's globalized system. Chemicals migrate from FCMs into foodstuffs, so called chemicals (FCCs), but current regulatory requirements do not sufficiently protect public health hazardous FCCs because only individual substances used to make tested mostly for genotoxicity while endocrine disruption other hazard properties disregarded. Indeed, a known source of wide range chemicals, they likely contribute highly prevalent non-communicable diseases. can also include non-intentionally added (NIAS), which often unknown therefore subject risk assessment. To address these important shortcomings, we outline how the safety may be improved by (1) testing overall migrate, including (unknown) NIAS, finished articles, (2) expanding toxicological beyond multiple endpoints associated with diseases relevant human health. identify mechanistic testing, group chronic outcomes chemical exposure Six Clusters Disease (SCOD) propose that should their impacts on SCOD. Research focus developing robust, relevant, sensitive in-vitro assays based information linked SCOD, e.g., through Adverse Outcome Pathways (AOPs) or Key Characteristics Toxicants. Implementing this vision will improve prevention exposures, FCMs.

Language: Английский

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Revolutionizing developmental neurotoxicity testing – a journey from animal models to advanced in vitro systems

ALTEX, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Developmental neurotoxicity (DNT) testing has seen enormous progress over the last two decades. Preceding even publication of animal-based OECD test guideline for DNT in 2007, a series non-animal technology workshops and conferences (starting 2005) shaped community that delivered comprehensive battery vitro methods (IVB). Its data interpretation is covered by very recent guidance (No. 377). Here, we aim to overview field, focusing on evolution strategies, role emerging technologies, impact guidelines testing. In particular, this an example targeted development animal-free approach one most complex hazards chemicals human health. These developments started literally from blank slate, with no proposed alternative available. Over decades, cutting-edge science enabled design spares animals enables throughput challenging hazard. While it evident field needs regulation, massive economic decreased cognitive capacity caused chemical exposure should be prioritized more highly. Beyond this, claim fame scientific brought understanding brain, its development, how can perturbed. Plain language summaryDevelopmental predicts hazard brain development. Comprehensive advanced strategies using now replace approaches assess large numbers accurately efficiently than approach. Recent formalized DNT, marking pivotal achievement field. The shift towards reflects both commitment animal welfare growing recognition public health impacts associated impaired function exposures. innovations ultimately contribute safer management better protection health, especially during vulnerable stages

Language: Английский

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Scientific Validation of Human Neurosphere Assays for Developmental Neurotoxicity Evaluation

Frontiers in Toxicology, Journal Year: 2022, Volume and Issue: 4

Published: March 2, 2022

There is a call for paradigm shift in developmental neurotoxicity (DNT) evaluation, which demands the implementation of faster, more cost-efficient, and human-relevant test systems than current vivo guideline studies. Under umbrella Organisation Economic Co-operation Development (OECD), guidance document currently being prepared that instructs on regulatory use DNT vitro battery (DNT IVB) fit-for-purpose applications. One crucial issue OECD application methods validation, new approach (NAMs) requires novel approaches. Here, mechanistic information previously identified vivo, as well reported neurodevelopmental adversities response to disturbances cellular tissue level, are central importance. In this study, we scientifically validate Neurosphere Assay, based human primary neural progenitor cells (hNPCs) an integral part IVB. It assesses key events (KEs) like NPC proliferation (NPC1ab), radial glia cell migration (NPC2a), neuronal differentiation (NPC3), neurite outgrowth (NPC4), oligodendrocyte (NPC5), thyroid hormone-dependent maturation (NPC6). addition, extend our work from hNPCs induced pluripotent stem cell-derived NPCs (hiNPCs) (iNPC1ab) assays (iNPC2a). The validation process report endpoints studied with Assays 1) describing relevance respective brain development, 2) confirmation type-specific morphologies observed vitro, 3) expressions markers consistent those morphologies, 4) appropriate anticipated responses physiological pertinent signaling stimuli 5) alterations specific upon challenges confirmed compounds. With these strong underpinnings, posit Assay screening poised evaluation purposes.

Language: Английский

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Effects of all-trans and 9-cis retinoic acid on differentiating human neural stem cells in vitro

Toxicology, Journal Year: 2023, Volume and Issue: 487, P. 153461 - 153461

Published: Feb. 16, 2023

Cyanobacterial blooms are known sources of environmentally-occurring retinoid compounds, including all-trans and 9-cis retinoic acids (RAs). The developmental hazard for aquatic organisms has been described, while the implications human health assessment not yet sufficiently characterized. Here, we employ a neural stem cell model that can differentiate in vitro into mixed culture neurons glia. Cells were exposed to non-cytotoxic 8–1000 nM or RA 9–18 days (DIV13 DIV22, respectively). Impact on biomarkers was analyzed gene expression (RT-qPCR) protein level (western blot proteomics) at both time points; network patterning (immunofluorescence) DIV22. exposure significantly concentration-dependently increased acid receptors metabolizing enzyme CYP26A1, confirming chemical-specific response model. Expression thyroid hormone signaling-related genes remained mostly unchanged. Markers progenitors/stem cells (PAX6, SOX1, SOX2, NESTIN) decreased with increasing concentrations, though basal population remained. Neural markers (DCX, TUJ1, MAP2, NeuN, SYP) unchanged high concentrations (200–1000 nM). Conversely, (astro-)glial marker S100β Together, biomarker analysis indicates an RA-dependent promotion glial fates over differentiation, despite abundance during differentiation. Interestingly, induced substantial changes morphology: low resulted network-like differentiation pattern, RA) almost completely prevented such patterning. After functional confirmation function, morphological features could present proxy formation assessment, apical key event (neuro-)developmental Adverse Outcome Pathways. described application (developmental) neurotoxicity emerging environmentally-relevant retinoids contributes evidence-base use differentiating models risk assessment.

Language: Английский

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Zebrafish and nematodes as whole organism models to measure developmental neurotoxicity

Critical Reviews in Toxicology, Journal Year: 2024, Volume and Issue: 54(5), P. 330 - 343

Published: May 27, 2024

Despite the growing epidemiological evidence of an association between toxin exposure and developmental neurotoxicity (DNT), systematic testing DNT is not mandatory in international regulations for admission pharmaceuticals or industrial chemicals. However, to date around 200 compounds, ranging from pesticides, chemicals, have been tested current OECD test guidelines (TG-443 TG-426). There are calls development new approach methodologies (NAMs) DNT, which has resulted a battery using

Language: Английский

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