Incorporating new approach methods (NAMs) data in dose–response assessments: The future is now! DOI

En‐Hsuan Lu,

Ivan Rusyn, Weihsueh A. Chiu

et al.

Journal of Toxicology and Environmental Health Part B, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 35

Published: Oct. 10, 2024

Regulatory dose–response assessments traditionally rely on in vivo data and default assumptions. New Approach Methods (NAMs) present considerable opportunities to both augment traditional accelerate the evaluation of new/data-poor chemicals. This review aimed determine potential utilization NAMs through a unified conceptual framework that compartmentalizes derivation toxicity values into five sequential Key Dose–response Modules (KDMs): (1) point-of-departure (POD) determination, (2) test system-to-human (e.g. inter-species) toxicokinetics (3) toxicodynamics, (4) human population (intra-species) variability (5) toxicokinetics. After using several "traditional" dose-response illustrate this framework, is presented where existing NAMs, including silico, vitro, approaches, might be applied across KDMs. Further, false dichotomy between NAMs-derived sources broken down by organizing matrix each KDM has Tiers increasing precision confidence: Tier 0: Default/generic values, 1: Computational predictions, 2: Surrogate measurements, 3: Direct measurements. These findings demonstrated although many publications promote use KDMs for POD determination toxicokinetics, proposed reveals additional immediate integrated other critical needs were identified developing improve vitro dosimetry quantify system toxicodynamics. Overall, broadening integration steps assessment promises yield higher throughput, less animal-dependent, more science-based protecting health.

Language: Английский

Consensus findings of an International Workshops on Genotoxicity Testing workshop on using transcriptomic biomarkers to predict genotoxicity DOI Creative Commons
Roland Frötschl, J. Christopher Corton, Heng‐Hong Li

et al.

Environmental and Molecular Mutagenesis, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 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.

Language: Английский

Citations

2
Progress in toxicogenomics to protect human health DOI
Matthew J. Meier, Joshua Harrill, Kamin J. Johnson

et al.

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 2, 2024

Language: Английский

Citations

12
Mechanisms and Assessment of Genotoxicity of Metallic Engineered Nanomaterials in the Human Environment DOI Creative Commons
Baoming Liu,

A. Wallace Hayes

Biomedicines, Journal Year: 2024, Volume and Issue: 12(10), P. 2401 - 2401

Published: Oct. 20, 2024

Engineered nanomaterials (ENMs) have a broad array of applications in agriculture, engineering, manufacturing, and medicine. Decades toxicology research demonstrated that ENMs can cause genotoxic effects on bacteria, mammalian cells, animals. Some metallic (MENMs), e.g., metal or oxide nanoparticles TiO

Language: Английский

Citations

5
New Approach Methods (NAMs) for Genotoxicity Assessment of Nano- and Advanced Materials; Advantages and Challenges DOI

Arno C Gutleb,

Sivakumar Murugadoss,

Maciej Stępnik

et al.

Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Journal Year: 2025, Volume and Issue: unknown, P. 503867 - 503867

Published: March 1, 2025

Language: Английский

Citations

0
Identification of Mutagenicity, MOA, and Dose Response Analysis DOI

Christopher A. Bates,

Lynne T. Haber, Rita Schoeny

et al.

Food and Chemical Toxicology, Journal Year: 2025, Volume and Issue: unknown, P. 115441 - 115441

Published: April 1, 2025

Language: Английский

Citations

0
In vitro to in vivo extrapolation modeling to facilitate the integration of transcriptomics data into genotoxicity assessment DOI Creative Commons
Anouck Thienpont, Eunnara Cho, Andrew Williams

et al.

Toxicology, Journal Year: 2025, Volume and Issue: unknown, P. 154165 - 154165

Published: April 1, 2025

Language: Английский

Citations

0
Incorporating new approach methods (NAMs) data in dose–response assessments: The future is now! DOI

En‐Hsuan Lu,

Ivan Rusyn, Weihsueh A. Chiu

et al.

Journal of Toxicology and Environmental Health Part B, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 35

Published: Oct. 10, 2024

Regulatory dose–response assessments traditionally rely on in vivo data and default assumptions. New Approach Methods (NAMs) present considerable opportunities to both augment traditional accelerate the evaluation of new/data-poor chemicals. This review aimed determine potential utilization NAMs through a unified conceptual framework that compartmentalizes derivation toxicity values into five sequential Key Dose–response Modules (KDMs): (1) point-of-departure (POD) determination, (2) test system-to-human (e.g. inter-species) toxicokinetics (3) toxicodynamics, (4) human population (intra-species) variability (5) toxicokinetics. After using several "traditional" dose-response illustrate this framework, is presented where existing NAMs, including silico, vitro, approaches, might be applied across KDMs. Further, false dichotomy between NAMs-derived sources broken down by organizing matrix each KDM has Tiers increasing precision confidence: Tier 0: Default/generic values, 1: Computational predictions, 2: Surrogate measurements, 3: Direct measurements. These findings demonstrated although many publications promote use KDMs for POD determination toxicokinetics, proposed reveals additional immediate integrated other critical needs were identified developing improve vitro dosimetry quantify system toxicodynamics. Overall, broadening integration steps assessment promises yield higher throughput, less animal-dependent, more science-based protecting health.

Language: Английский

Citations

2