Use of new approach methodologies (NAMs) to meet regulatory requirements for the assessment of industrial chemicals and pesticides for effects on human health

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

Published: Sept. 1, 2022

New approach methodologies (NAMs) are increasingly being used for regulatory decision making by agencies worldwide because of their potential to reliably and efficiently produce information that is fit purpose while reducing animal use. This article summarizes the ability use NAMs assessment human health effects industrial chemicals pesticides within United States, Canada, European Union frameworks. While all regulations include some flexibility allow NAMs, implementation this varies across product type scheme. provides an overview various agencies' guidelines strategic plans on specific examples successful application meet requirements. It also intra- inter-agency collaborations strengthen scientific, regulatory, public confidence in thereby fostering global as reliable relevant tools toxicological evaluations. Ultimately, understanding current landscape helps inform scientific community steps needed further advance timely uptake approaches best protect environment.

Language: Английский

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A framework for establishing scientific confidence in new approach methodologies

Archives of Toxicology, Journal Year: 2022, Volume and Issue: 96(11), P. 2865 - 2879

Published: Aug. 20, 2022

Robust and efficient processes are needed to establish scientific confidence in new approach methodologies (NAMs) if they be considered for regulatory applications. NAMs need fit purpose, reliable and, the assessment of human health effects, provide information relevant biology. They must also independently reviewed transparently communicated. Ideally, NAM developers should communicate with stakeholders such as regulators industry identify question(s), specified purpose that is intended address, context which it will used. Assessment biological relevance focus on its alignment biology, mechanistic understanding, ability leads protective decisions, rather than solely comparing NAM-based chemical testing results those from traditional animal test methods. However, when compared historical results, variability observed within method used inform performance benchmarks. Building previous efforts, this paper proposes a framework comprising five essential elements use: fitness relevance, technical characterization, data integrity transparency, independent review. Universal uptake would facilitate timely development use by international community. While focuses assessing effects pesticides industrial chemicals, many suggested expected apply other types chemicals ecotoxicological effect assessments.

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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Human biomonitoring and toxicokinetics as key building blocks for next generation risk assessment

Environment International, Journal Year: 2024, Volume and Issue: 184, P. 108474 - 108474

Published: Feb. 1, 2024

Human health risk assessment is historically built upon animal testing, often following Organisation for Economic Co-operation and Development (OECD) test guidelines exposure assessments. Using combinations of human relevant in vitro models, chemical analysis computational (in silico) approaches bring advantages compared to studies. These include a greater focus on the species molecular mechanisms kinetics, identification Adverse Outcome Pathways downstream Key Events as well possibility addressing susceptible populations additional endpoints. Much advancement progress made Next Generation Risk Assessment (NGRA) have been primarily focused new approach methodologies (NAMs) physiologically based kinetic (PBK) modelling without incorporating biomonitoring (HBM). The integration toxicokinetics (TK) PBK an essential component NGRA. models are describing quantitative terms TK processes with effective dose at expected target site. Furthermore, need amplified by increasing scientific regulatory interest aggregate cumulative interactions chemicals mixtures. Since HBM data strengthens reduces uncertainties assessment, here we elaborate integrated use TK, highlighting opportunities challenges limitations. Examples provided where TK/PBK can be used both hazard characterization shifting from external dose/response assays animal-free, internal exposure-based

Language: Английский

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Addressing the safety of new food sources and production systems

Comprehensive Reviews in Food Science and Food Safety, Journal Year: 2024, Volume and Issue: 23(3)

Published: May 1, 2024

Abstract New food sources and production systems (NFPS) are garnering much attention, driven by international trade, changing consumer preferences, potential sustainability benefits, innovations in climate‐resilient systems. However, NFPS can introduce new challenges for safety agencies manufacturers. Most hazards linked to foods have been identified traditional foods. there be some that unique ingredients, inputs, processes unexpected contaminants. To realize the full of NFPS, is a need stakeholders from governments, industry, research community collectively work address communicate products. This review outlines known associated with select products on market, namely, plant‐derived proteins, seaweeds, jellyfish, insects, microbial as well derived cell‐based production, precision fermentation, vertical farming, 3D printing. We identify common elements emerging regulatory frameworks various countries/regions. Furthermore, we highlight current efforts harmonization terminologies, use recent scientific tools fill knowledge gaps, multi‐stakeholder collaborations tackle challenges. Although cannot one‐size‐fits‐all approach when it comes oversight ensuring develop consensus‐based structured protocols or workflows among facilitate comprehensive, robust, internationally harmonized approaches. These increase consumers’ confidence contribute toward fair practices trade such

Language: Английский

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Signature Analysis of High-Throughput Transcriptomics Screening Data for Mechanistic Inference and Chemical Grouping

Toxicological Sciences, Journal Year: 2024, Volume and Issue: 202(1), P. 103 - 122

Published: Aug. 23, 2024

High-throughput transcriptomics (HTTr) uses gene expression profiling to characterize the biological activity of chemicals in vitro cell-based test systems. As an extension a previous study testing 44 chemicals, HTTr was used screen additional 1,751 unique from EPA's ToxCast collection MCF7 cells using 8 concentrations and exposure duration 6 h. We hypothesized that concentration-response modeling signature scores could be identify putative molecular targets cluster with similar bioactivity. Clustering enrichment analyses were conducted based on catalog annotations ToxPrint chemotypes facilitate target prediction grouping bioactivity profiles. Enrichment analysis annotation identified known mechanisms action (MeOAs) associated well-studied generated MeOAs for other active chemicals. Chemicals predicted included those targeting estrogen receptor (ER), glucocorticoid (GR), retinoic acid (RAR), NRF2/KEAP/ARE pathway, AP-1 activation, others. Using reference ER modulation, demonstrated able stratify terms agonist potency, distinguish agonists antagonists, activities as by Pathway model. Uniform manifold approximation projection (UMAP) embedding signature-level results novel modulators no model predictions. Finally, UMAP combined chemotype explore structurally related The demonstrates can inform chemical risk assessment determining points departure, predicting chemicals' MeOA

Language: Английский

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Human and rat renal proximal tubule in vitro models for ADME applications

Archives of Toxicology, Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Abstract The kidney is a major organ dictating excretion rates of chemicals and their metabolites from the body thus renal clearance frequently component pharmaco-(toxico)-kinetic profiles. Within nephron, proximal tubule site for xenobiotic reabsorption glomerular filtrate secretion blood into lumen via expression multiple inward (lumen to interstitium) outward transport systems (interstitium lumen). While there exist several human tubular cell culture options that could be utilized modelling clearance, they do not necessarily represent full complement processes in vivo counterparts. Here, we review available rat vitro models, including subcellular fractions, immortalized lines, primary cultures, induced pluripotent stem (iPSC)-derived models also consider more organotypic environments such as microporous growth supports, organoids microfluidic systems. This focuses on levels function transporters phase I II metabolizing enzymes these order critically assess usefulness identify potential solutions overcome identified limitations.

Language: Английский

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REACH out-numbered! The future of REACH and animal numbers

ALTEX, Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 1, 2023

Policy impact analysis is needed for evidence-based policy-making.Numbers are not always fun. "Statistics the triumph of quantitative method, and method victory sterility death" a quote from Franco-English writer Hilaire Belloc (1870Belloc ( -1953)).Bad policies even less fun.There tremendous difference between statistics predictions.With more data becoming available, we can fine-tune predictions, but this requires us to look at where forecasts were off. IntroductionWe have once again (Knight et al., 2023) attempted bring animal numbers into policy discussion around Europe's Chemicals Regulation REACH.The American science fiction

Language: Английский

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A call for a Human Exposome Project

ALTEX, Journal Year: 2023, Volume and Issue: unknown, P. 4 - 33

Published: Jan. 1, 2023

Four decades of the Human Genome Project and its consequences have shown how entrepreneurial state, through significant investment into science, can drive scientific progress advance biomedicine. A certain fraction diseases now be explained as caused by genetics, a more impacted genetics. Besides another pathogens, third probably largest impactor is exposure, i.e., many physicochemical lifestyle factors. This article makes case that it time to start Exposome Project, which systematically explores catalogs exposure side human health disease.The envisioned needs than scaled exposomics approach, aiming assess totality relevant exposures ~omics body fluids forming hypotheses. Exposomics increasingly complemented science biomonitoring measure mechanistic understanding, human-relevant microphysiological systems, big data, artificial intelligence (AI) mine these data integrate pieces evidence. The potential impact AI on possible so substantial we should speak exposome (EI) because this allows us expand our limited current knowledge unknown unknowns threats health.

Language: Английский

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