Neurotoxic Effects of Mixtures of Perfluoroalkyl Substances (PFAS) at Environmental and Human Blood Concentrations

Environmental Science & Technology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 11, 2024

Per- and polyfluoroalkyl substances (PFAS) may cause various deleterious health effects. Epidemiological studies have demonstrated associations between PFAS exposure adverse neurodevelopmental outcomes. The cytotoxicity, neurotoxicity, mitochondrial toxicity of up to 12 including perfluoroalkyl carboxylates, sulfonates, 6:2 fluorotelomer sulfonic acid (6:2 FTSA), hexafluoropropylene oxide-dimer (HPFO-DA) were tested at concentrations typically observed in the environment (e.g., wastewater, biosolids) human blood using high-throughput

Language: Английский

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Nuclear hormone receptors control fundamental processes of human fetal neurodevelopment: Basis for endocrine disruption assessment

Environment International, Journal Year: 2025, Volume and Issue: 198, P. 109400 - 109400

Published: March 21, 2025

Despite growing awareness of endocrine disrupting chemicals (EDCs), knowledge gaps remain regarding their effects on human brain development. EDC risk assessment focuses primarily EATS modalities (estrogens, androgens, thyroid hormones, and steroidogenesis), overlooking the broader range hormone receptors expressed in developing brain. This limits evaluation for potential to cause disruption-mediated developmental neurotoxicity (ED-DNT). The Neurosphere Assay, an vitro test method (DNT) evaluation, is integral component DNT testing battery, which has been used screen a broad domain environmental chemicals. Here, we define endocrine-related applicability Assay by assessing impact specificity 14 seven key neurodevelopmental processes (KNDPs), neural progenitor cell (NPC) proliferation, migration radial glia, neurons, oligodendrocytes, neurite outgrowth, differentiation neurons oligodendrocytes. Comparative analyses rat NPCs both sexes revealed species- sex-specific responses. Mechanistic insights were obtained through RNA sequencing agonist/antagonist co-exposures. Most receptor agonists modulated KNDPs at concentrations physiologically relevant concentrations. Phenotypic induced glucocorticoid (GR), liver X (LXR), peroxisome proliferator-activated beta/delta (PPARβδ), retinoic acid (RAR) retinoid (RXR) activation counteracted antagonists, confirming specificity. Transcriptomics highlighted crosstalk involvement conserved pathways (e.g. Notch Wnt). Species comparisons identified limited concordance receptor-regulated between NPCs. study presents novel findings cellular molecular actions fetal NPCs, highlights major species differences, illustrates Assay's relevance detecting MoAs, supporting its application human-based ED-DNT assessment.

Language: Английский

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Development of a Roadmap for Action on New Approach Methodologies in Risk Assessment

EFSA Supporting Publications, Journal Year: 2022, Volume and Issue: 19(6)

Published: June 1, 2022

While whole animal studies have their place in risk assessment of food and feed components, it is thought that more modern approaches such as human focused new approached methodologies (NAMs) would bring advantages including a greater focus to the species, on molecular mechanism kinetics possibility addressing susceptible populations. This report outlines thinking from authors culminates activity proposals seven distinct but interacting scientific areas i.e. development additional AOPs/AOP networks (AOPs), advanced cell culture models Organ chip (OoC), toxicokinetic with physiological based kinetic modelling (PBK), exposome, susceptibility, data integration concepts assessment. Furthermore, Forum proposed facilitate implementation The was compiled by project team, renowned experts various areas, recommendations were discussed EFSA further refined following consultation external via dedicated workshop. are convinced if taken up, there will be significant impact field, resulting increasing uptake utilisation these emerging technologies all stakeholders involved.

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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Implementing New Approach Methodologies (NAMs) in food safety assessments: Strategic objectives and actions taken by the European Food Safety Authority

Trends in Food Science & Technology, Journal Year: 2023, Volume and Issue: 133, P. 277 - 290

Published: Feb. 8, 2023

New Approach Methodologies (NAMs) comprise in silico and vitro methods applied as alternative to animal testing. Even though NAMs are already fully implemented research tools, their use regulatory risk assessments (RA) is limited currently. To promote the uptake/acceptance of NAMs, a paradigm shift assessment approaches, proper dialogue between assessors managers needed. Several reviews addressed for chemical RA generic terms, but without providing specific considerations on food/feed safety assessments. Therefore, this review, we give insights potential purposes EU. We summarise relevant projects activities coordinated by European Food Safety Authority (EFSA), which agency Union that contributes food feed chain. The review informs future developments human health RA, touches protein toxicity allergenicity, well environmental risks. Reducing testing filling some gaps via almost reality. Moreover, there growing body evidence confirming inclusion mechanistic information improves EFSA's address main challenge using intermediate effects observed non-animal models assessments, especially those linked adverse insufficiently covered or uncovered apical endpoints.

Language: Английский

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New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project

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

Published: April 26, 2024

In the European regulatory context, rodent in vivo studies are predominant source of neurotoxicity information. Although they form a cornerstone neurotoxicological assessments, costly and topic ethical debate. While public expects chemicals products to be safe for developing mature nervous systems, considerable numbers commerce have not, or only limited extent, been assessed their potential cause neurotoxicity. As such, there is societal push toward replacement animal models with vitro alternative methods. New approach methods (NAMs) can contribute knowledge base, increase chemical safety, modernize hazard risk assessment. Provided reach an acceptable level relevance reliability, NAMs may considered as replacements specific studies. The Partnership Assessment Risks from Chemicals (PARC) addresses challenges development implementation collaboration agencies, Project 5.2.1e (Neurotoxicity) aims develop evaluate developmental (DNT) adult (ANT) understand applicability domain detection endocrine disruption epigenetic perturbation. To speed up assay time reduce costs, we identify early indicators later-onset effects. Ultimately, will assemble second-generation first-generation test batteries, both which aim provide assessors industry stakeholders robust, speedy, lower-cost, informative next-generation assessment tools.

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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Statement on the toxicological properties and maximum residue levels of acetamiprid and its metabolites

EFSA Journal, Journal Year: 2024, Volume and Issue: 22(5)

Published: May 1, 2024

Abstract Acetamiprid is a pesticide active substance with insecticidal action whose approval was renewed by Commission Implementing Regulation (EU) 2018/113. In January 2022, the EFSA PPR Panel published statement following request from European to advise on human health or environment based new scientific evidence presented France during decision-making phase. July means of further mandate received Commission, requested provide advice if information and any other that has become available since assessment conducted for renewal in 2018 warrant re-evaluation (i) toxicological parameters used risk acetamiprid process, including endpoints; (ii) residue definition products plant origin; (iii) safety existing maximum levels (MRLs). Meanwhile, applicant EU submitted toxicology studies regarding profile metabolite IM-2-1. Furthermore, made aware several recent publications literature were after searches EFSA. As data could affect expected deliver through 2022 mandate, consider this revised September 2023. regards point statement, addressed an Working Group integrating all evidence. The results weight indicated there are major uncertainties body developmental neurotoxicity (DNT) properties therefore needed come more robust mechanistic understanding enable appropriate hazard assessment. view these uncertainties, WG proposed lower acceptable daily intake (ADI) acute reference dose (ARfD) 0.025 0.005 mg/kg (per day). A leafy fruit crops as sum N-desmethyl-acetamiprid (IM-2-1), expressed acetamiprid. Regarding pulses/oilseeds, root cereals, did not indicate need modify assessment, which remains parent enforcement, because still sufficient marker residues crop groups. Considering health-based guidance values derived present consumer been identified 38 MRLs currently place Regulation. Consequently, recommended commodities fall-back Good Agricultural Practices within ad hoc call. Some proposals require management considerations.

Language: Английский

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Engineering human cerebral organoids to explore mechanisms of arsenic-induced developmental neurotoxicity

Toxicology and Applied Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 117230 - 117230

Published: Jan. 1, 2025

Language: Английский

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Toward a Better Testing Paradigm for Developmental Neurotoxicity: OECD Efforts and Regulatory Considerations

Biology, Journal Year: 2021, Volume and Issue: 10(2), P. 86 - 86

Published: Jan. 23, 2021

Characterization of potential chemical-induced developmental neurotoxicity (DNT) hazard is considered for risk assessment purposes by many regulatory sectors. However, due to test complexity, difficulty in interpreting results and need substantial resources, the use vivo DNT guidelines has been limited animal data on are scarce. To address challenging endpoints such as DNT, Organisation Economic Co-Operation Development (OECD) chemical safety program working lately toward development integrated approaches testing (IATA) that rely a combination multiple layers (e.g., vitro, silico non-mammalian models) supported mechanistic knowledge organized according adverse outcome pathway (AOP) framework. In 2017, OECD convened dedicated expert group develop guidance document application interpretation derived from battery relies key neurodevelopmental processes complemented zebrafish assays. This review will provide brief overview project summarize various achievements relevance project. The also presents an opportunity describe considerations uptake vitro context.

Language: Английский

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