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, Год журнала: 2022, Номер 4

Опубликована: Сен. 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.

Язык: Английский

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New approach methodologies (NAMs): identifying and overcoming hurdles to accelerated adoption

Toxicology Research, Год журнала: 2024, Номер 13(2)

Опубликована: Март 1, 2024

Abstract New approach methodologies (NAMs) can deliver improved chemical safety assessment through the provision of more protective and/or relevant models that have a reduced reliance on animals. Despite widely acknowledged benefits offered by NAMs, there continue to be barriers prevent or limit their application for decision-making in assessment. These include related real and perceived scientific, technical, legislative economic issues, as well cultural societal obstacles may relate inertia, familiarity, comfort with established methods, perceptions around regulatory expectations acceptance. This article focuses science, exposure, hazard, risk assessment, explores nature these how they overcome drive wider exploitation acceptance NAMs. Short-, mid- longer-term goals are outlined embrace opportunities provided NAMs protection human health environmental security part new paradigm incorporates exposure science culture promotes use toxicological assessments.

Язык: Английский

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From vision toward best practices: Evaluating in vitro transcriptomic points of departure for application in risk assessment using a uniform workflow

Frontiers in Toxicology, Год журнала: 2023, Номер 5

Опубликована: Май 23, 2023

The growing number of chemicals in the current consumer and industrial markets presents a major challenge for regulatory programs faced with need to assess potential risks they pose human ecological health. increasing demand hazard risk assessment currently exceeds capacity produce toxicity data necessary decision making, applied is commonly generated using traditional approaches animal models that have limited context terms relevance. This scenario provides opportunity implement novel, more efficient strategies purposes. study aims increase confidence implementation new approach methods by parallel analysis identify gaps experimental designs, reveal limitations common deriving transcriptomic points departure, demonstrate strengths high-throughput transcriptomics (HTTr) derive practical endpoints. A uniform workflow was across six curated gene expression datasets from concentration-response studies containing 117 diverse chemicals, three cell types, range exposure durations, determine tPODs based on profiles. After benchmark concentration modeling, used consistent reliable tPODs. High-throughput toxicokinetics were employed translate vitro (µM) human-relevant administered equivalent doses (AEDs, mg/kg-bw/day). most had AEDs lower (i.e., conservative) than apical PODs US EPA CompTox chemical dashboard, suggesting would be protective effects An multiple single revealed longer duration varied culture systems (e.g., 3D vs. 2D) lead decreased tPOD value indicated increased potency. Seven flagged as outliers when comparing ratio POD, thus indicating require further better understand their potential. Our findings build use but also must addressed prior adoption support applications.

Язык: Английский

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A pragmatic framework for the application of new approach methodologies in one health toxicological risk assessment

Toxicological Sciences, Год журнала: 2023, Номер 192(2), С. 155 - 177

Опубликована: Фев. 14, 2023

Globally, industries and regulatory authorities are faced with an urgent need to assess the potential adverse effects of chemicals more efficiently by embracing new approach methodologies (NAMs). NAMs include cell tissue methods (in vitro), structure-based/toxicokinetic models silico), that toxicant interactions biological macromolecules chemico), alternative models. Increasing knowledge on chemical toxicokinetics (what body does chemicals) toxicodynamics do body) obtained from in silico vitro systems continues provide opportunities for modernizing risk assessments. However, directly leveraging data derivation human health-based reference values has not received acceptance due uncertainties extrapolating NAM results populations, including metabolism, complex pathways, multiple exposures, interindividual susceptibility vulnerable populations. The objective this article is a standardized pragmatic framework applies integrated approaches focus quantitative vivo extrapolation (QIVIVE) extrapolate cellular exposures equivalent doses which can be derived. proposed intends systematically account complexities interpretation support sound health safety decisions diverse industrial sectors (food systems, cosmetics, chemicals, pharmaceuticals etc.). Case studies entities, using existing data, presented demonstrate utility while highlighting sources population bias uncertainty, importance Good Method Reporting Practices.

Язык: Английский

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A multiplex inhalation platform to model in situ like aerosol delivery in a breathing lung-on-chip

Frontiers in Pharmacology, Год журнала: 2023, Номер 14

Опубликована: Март 6, 2023

Prolonged exposure to environmental respirable toxicants can lead the development and worsening of severe respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) fibrosis. The limited number FDA-approved inhaled drugs for these serious lung conditions has led a shift from in vivo towards use alternative vitro human-relevant models better predict toxicity particles preclinical research. While there are several inhalation upper airways, fragile dynamic nature alveolar microenvironment reproducible distal lung. Here, we present mechanistic approach using new generation systems, Cloud α AX12. This novel tool consists cloud-based chamber (VITROCELL) that integrates breathing AX Lung-on-chip system (AlveoliX). ultrathin porous membrane AX12 plate was used create complex multicellular model enables key physiological culture conditions: air-liquid interface (ALI) three-dimensional cyclic stretch (CS). Human-relevant cellular were established a) alveolar-capillary primary cell-derived immortalized epithelial cells ( iAECs), macrophages (THP-1) endothelial (HLMVEC) cells, b) upper-airways Calu3 cells. Primary human hAEpCs) validate results obtained cell lines. To mimic relevant aerosol exposures with AX12, three different using: titanium dioxide (TiO2) zinc oxide nanoparticles polyhexamethylene guanidine toxic chemical c) an anti-inflammatory corticosteroid, fluticasone propionate (FL). Our suggest important synergistic effect on air-blood barrier sensitivity, cytotoxicity inflammation, when combined. best our knowledge, this is first time been described lung-on-chip technology. thus represents state-of-the-art pre-clinical study risks, drug safety efficacy.

Язык: Английский

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Progress in toxicogenomics to protect human health

Nature Reviews Genetics, Год журнала: 2024, Номер unknown

Опубликована: Сен. 2, 2024

Язык: Английский

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A Proof-of-Concept for Safety Evaluation of Inhalation Exposure to Known Respiratory Irritants Using In Vitro and In Silico Methods

Toxics, Год журнала: 2025, Номер 13(1), С. 35 - 35

Опубликована: Янв. 4, 2025

There is increased interest in developing non-animal test systems for inhalation exposure safety assessments. However, defined methodologies are absent predicting local respiratory effects from to irritants. The current study introduces a concept applying vitro and silico methods assessment. Three systems, representing the upper (MucilAir™-nasal epithelial tissue) lower (A549 cells human precision-cut lung slices) regions, were exposed six These irritant exposures conducted as liquid droplets, aerosol, or vapors, samples collected over 24 h. Cytotoxicity, cytokine release, resistance, oxidative stress, mitochondrial membrane potential measured. To determine relevance of exposures, airway surface depositions predicted by simulating airborne concentrations equivalent Cramer class III threshold toxicological concern limit 0.47 mg/person/day using an model. A > 100-fold margin was calculated comparing lowest showing simulated values. While further studies needed, this manuscript presents basic requirement employing inform assessments combining assays.

Язык: Английский

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Consensus findings of an International Workshops on Genotoxicity Testing workshop on using transcriptomic biomarkers to predict genotoxicity

Environmental and Molecular Mutagenesis, Год журнала: 2025, Номер unknown

Опубликована: Янв. 5, 2025

Abstract Gene expression biomarkers have the potential to identify genotoxic and non‐genotoxic carcinogens, providing opportunities for integrated testing reducing animal use. In August 2022, an International Workshops on Genotoxicity Testing (IWGT) workshop was held critically review current methods genotoxicants using transcriptomic profiling. Here, we summarize findings of workgroup state science regarding use chemicals in vitro vivo. A total 1341 papers were examined that show most promise identifying genotoxicants. This analysis revealed two independently derived vivo three that, when used conjunction with standard computational techniques, can (rat or mouse liver) human cells culture different gene profiling platforms, predictive accuracies ≥92%. These been validated differing degrees but typically high reproducibility across platforms model systems. They offer several advantages applications contexts genotoxicity including: early signal detection, moderate‐to‐high‐throughput screening capacity, adaptability cell types tissues, insights mechanistic information DNA‐damage response. Workshop participants agreed consensus statements advance regulatory adoption genotoxicity. The be other test strategies short‐term rodent exposures may cause cancer heritable genetic effects. Following are from workgroup. Transcriptomic Weight Evidence (WoE) evaluation to: determine mechanisms hazards; misleading positives assays; serve as new approach methodologies (NAMs) into battery tests. Several developed sufficiently robust training data sets, external demonstrated performance multiple laboratories. following established study designs models designated through existing validation exercises WoE evaluation. Bridging studies a selection needed deviate protocols confirm biomarker is being applied other: models, platforms. Top dose time critical should during development. conditions only ones suited unless additional bridging pharmacokinetic conducted. Temporal effects operate via distinct considered interpretation. Fixed sets analytical processes do not need rederived validation. Validation focus set sets. Robust ensure minimum spanning modes action. Genes known mechanistically involved responses. Existing frameworks described NAMs could biomarkers. Reproducibility bioinformatic application bioinformatics expert creating reproducible qualification each biomarker.

Язык: Английский

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Computational new approach methods guide focused testing and enhance understanding of chlorantraniliprole toxicity across species

Environmental Toxicology and Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 6, 2025

Diamide insecticides, specifically chlorantraniliprole (CHL), have been rising in popularity over the past decade, becoming one of most widely used insecticide classes globally. These insecticides target ryanodine receptor (RyR), primarily for control lepidopteran agricultural pests. Field studies revealed that some species developed mutations where a methionine particular position (e.g., I4790M) increases resistance to CHL. The toxicity data CHL across is limited, as case many chemicals, which creates an opportunity apply both traditional test methods and new approach (NAMs) address gaps. Here, U.S. Environmental Protection Agency's Sequence Alignment Predict Across Species Susceptibility (SeqAPASS) tool was query RyR generate susceptibility predictions exposed fill those SeqAPASS results generated testable hypotheses were guide focused acute aquatic using Daphnia magna, pulex, Pimephales promelas, Danio rerio. fish not sensitive CHL, whereas D. magna pulex found be at environmentally relevant concentrations, despite having residue I4790M mutation. Additional showed other species, including beneficial pollinators Lepidoptera, are predicted likely susceptible This study provided multiple lines evidence toward unlikelihood mutation primary cause filled knowledge gaps concerning nontarget generally amenable testing. work presents example demonstrates how NAMs can combination with types direct targeted testing build confidence predictive approaches their use risk assessment.

Язык: Английский

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Revealing Molecular Connections between Dissolved Organic Matter in Surface Water Sources and Their Cytotoxicity Influenced by Chlorination Disinfection

Environmental Science & Technology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 27, 2025

Dissolved organic matter (DOM) is the primary precursor of disinfection products (DBPs) during chlorination. However, compositional characteristics DOM transformation chlorination process in different source waters and its relationship to cytotoxicity remain understudied. Here, we used high-resolution mass spectrometry evaluate chlorination-induced molecular-level changes derived from surface water sources. We correlated components with profiles selected DBPs using new alternative methods predictive toxicological assessments. Our findings indicate a selective natural tendency for lignin protein conversion manual process. The reactivity bioactive compounds decreased order > tannin or ConAC. mainly attributed lignin- protein-like within CHO CHNO groups. Additionally, mitochondrial damage highly sensitive indicator DOM-induced cytotoxicity. toxicity revealed 37 common toxicity-driving characterized by low mass, medium H/C ratio, O/C reduction state, hydrophobicity. highlight need exploit health effects provide substantial experimental evidence necessity remove potential toxicants.

Язык: Английский

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