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- De Castelbajac, Thalia, et al.
(författare)
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Innovative tools and methods for toxicity testing within PARC work package 5 on hazard assessment
- 2023
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Ingår i: Frontiers in Toxicology. - : Frontiers Media S.A.. - 2673-3080. ; 5
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Forskningsöversikt (refereegranskat)abstract
- New approach methodologies (NAMs) have the potential to become a major component of regulatory risk assessment, however, their actual implementation is challenging. The European Partnership for the Assessment of Risks from Chemicals (PARC) was designed to address many of the challenges that exist for the development and implementation of NAMs in modern chemical risk assessment. PARC's proximity to national and European regulatory agencies is envisioned to ensure that all the research and innovation projects that are initiated within PARC agree with actual regulatory needs. One of the main aims of PARC is to develop innovative methodologies that will directly aid chemical hazard identification, risk assessment, and regulation/policy. This will facilitate the development of NAMs for use in risk assessment, as well as the transition from an endpoint-based animal testing strategy to a more mechanistic-based NAMs testing strategy, as foreseen by the Tox21 and the EU Chemical's Strategy for Sustainability. This work falls under work package 5 (WP5) of the PARC initiative. There are three different tasks within WP5, and this paper is a general overview of the five main projects in the Task 5.2 'Innovative Tools and methods for Toxicity Testing,' with a focus on Human Health. This task will bridge essential regulatory data gaps pertaining to the assessment of toxicological prioritized endpoints such as non-genotoxic carcinogenicity, immunotoxicity, endocrine disruption (mainly thyroid), metabolic disruption, and (developmental and adult) neurotoxicity, thereby leveraging OECD's and PARC's AOP frameworks. This is intended to provide regulatory risk assessors and industry stakeholders with relevant, affordable and reliable assessment tools that will ultimately contribute to the application of next-generation risk assessment (NGRA) in Europe and worldwide.
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| 2. |
- Gorrochategui, Eva, et al.
(författare)
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High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring
- 2023
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Ingår i: Environment International. - 0160-4120. ; 181
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Tidskriftsartikel (refereegranskat)abstract
- Paracetamol/acetaminophen (N-acetyl-p-aminophenol, APAP) is a top selling analgesic used in more than 600 prescription and non-prescription pharmaceuticals. To study efficiently some of the potential undesirable effects associated with increasing APAP consumption (e.g., developmental disorders, drug-induced liver injury), there is a need to improve current APAP biomonitoring methods that are limited by APAP short half-life. Here, we demonstrate using high-resolution mass spectrometry (HRMS) in several human studies that APAP thiomethyl metabolite conjugates (S-methyl-3-thioacetaminophen sulfate and S-methyl-3-thioacetaminophen sulphoxide sulfate) are stable biomarkers with delayed excretion rates compared to conventional APAP metabolites, that could provide a more reliable history of APAP ingestion in epidemiological studies. We also show that these biomarkers could serve as relevant clinical markers to diagnose APAP acute intoxication in overdosed patients, when free APAP have nearly disappeared from blood. Using in vitro liver models (HepaRG cells and primary human hepatocytes), we then confirm that these thiomethyl metabolites are directly linked to the toxic N-acetyl-p-benzoquinone imine (NAPQI) elimination, and produced via an overlooked pathway called the thiomethyl shunt pathway. Further studies will be needed to determine whether the production of the reactive hepatotoxic NAPQI metabolites is currently underestimated in human. Nevertheless, these biomarkers could already serve to improve APAP human biomonitoring, and investigate, for instance, inter-individual variability in NAPQI production to study underlying causes involved in APAP-induced hepatotoxicity. Overall, our findings demonstrate the potential of exposomics-based HRMS approach to advance towards a better precision for human biomonitoring.
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| 3. |
- Lizano Fallas, Verónica, 1985-
(författare)
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Toxicoproteomics, from finding molecular targets to evaluating the impact on human health
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The exposome refers to all exposures, including exposures to chemicals, that an individual may encounter over the whole life, from conception to death, that influence the individual’s health. To date, over 200,000 chemicals have been registered under the legislative framework of the European Union. Exposomics studies have revealed that individuals are exposed to chemical mixtures consisting of hundreds of compounds simultaneously. The risks to human health posed by many of these chemicals and chemical mixtures are still unknown and require evaluation. Traditional methods for assessing chemicals and chemical mixtures have been inadequate in addressing the increasing number of potentially toxic compounds in the environment. Current high-throughput toxicology methods, which involve the application of batteries of in vitro bioassays, can reduce the time and costs of analysis. However, these methods evaluate the impact on well-established pathways that have already been identified as being affected by exposure, making it difficult to discover new modes of action. The goal of this thesis is to provide a method to unravel the targets of chemicals for a better understanding of the mechanisms of action of chemicals and chemical mixtures under the scenario of the exposome. The proteome integral solubility alteration (PISA) assay is a proteome-wide approach for drug-target identification. However, implementing the PISA assay to address toxicological challenges requires different experimental considerations from chemical properties and toxicology principles. Moreover, it is necessary to translate the data from target identification to an understanding of the potential impact on human health. Therefore, three steps were followed to implement the PISA method in the field of toxicology: i) experimental considerations of the method for toxicology and chemical assessment purposes, ii) analysis of the method capability in the field of toxicology, and iii) development of pipelines from the target identification to the understanding of potential impact on human health. The results showed the capability of the PISA assay to identify the protein targets of single chemicals and chemical mixtures, extending, in an unbiased manner, the list of evaluated biological pathways in current available methodologies. The approach presented here reduces the time and cost associated with experimental and data analysis work, which could aid in the chemical risk assessment process in the context of the exposome.
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