Percorrer por autor "El Yamani, N."
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- Analysis and evaluation of genotoxicity and carcinogenicity assessment in EU legislation to improve regulatory implementation of NAMs: A focus on in silico approachesPublication . Bossa, Cecília; Raitano, Giuseppa; Benfenati, Emilio; Alivernini, Silvia; Andreoli, Cristina; Aquilina, G.; Attias, L.; Dusinska, Maria; El Yamani, N.; Louro, Henriqueta; Marcon, Francesca; Rundèn-Pran, E.; Russo, Maria Teresa; Silva, Maria João; Battistelli, Chiara LauraGenotoxicity and carcinogenicity are key endpoints for the risk assessment of all types of substances. Research on alternatives to animal testing for these endpoints has been active for decades, leading to the development of short-term in vitro tests that are integrated into current testing strategies. Nevertheless, high relevance is still devoted to data from in vivo studies. In parallel, progress in the comprehension of mechanisms underpinning genotoxicity and genotoxic carcinogenicity processes, together with the analysis of the great wealth of experimental data produced, allowed the discovery of structural determinants utilized in quantitative and qualitative structure-activity relationships and enabling in silico predictions of these endpoints. Presented here is a case study part of the collective effort carried out within the European Partnership for the Assessment of Risks from Chemicals (PARC) to address the challenges associated with innovation in chemical risk assessment, including the phasing out of animal testing through the introduction of New Approach Methodologies (NAMs) [1,2]. The case study aims to analyze current practices of the regulatory evaluation of genotoxicity and carcinogenicity hazard in several EU frameworks, in order to highlight needs and challenges in the actual or potential use of NAMs as well as short-and long- term goals towards the overcoming of animal testing. Among other NAMs, we are focusing on the role of in silico approaches highlighting strategies to increase the regulatory application and acceptance of QSAR based approaches. To this aim, the OECD QSAR Assessment Framework [3,4] has been identified as a suitable tool for evaluating the models and their predictions and will be applied to selected case studies. Moreover, a list of human relevant carcinogens has been developed as reference chemicals to evaluate and possibly refine in silico methodologies supporting a human-centric paradigm shift in toxicology.
- Fibrous shape underlies the mutagenic and carcinogenic potential of nanosilver while surface chemistry affects the biosafety of iron oxide nanoparticlesPublication . Gábelová, A.; El Yamani, N.; Alonso, T.I.; Buliaková, B.; Srančíková, A.; Bábelová, A.; Pran, E.R.; Fjellsbø, L.M.; Elje, E.; Yazdani, M.; Silva, M.J.; Dušinská, M.Nowadays engineered nanomaterials (ENMs) are increasingly used in a wide range of commercial products and biomedical applications. Despite this, the knowledge of human potential health risk as well as comprehensive biological and toxicological information is still limited. We have investigated the capacity of two frequently used metallic ENMs, nanosilver and magnetite nanoparticles (MNPs), to induce thymidine kinase (Tk+/−) mutations in L5178Y mouse lymphoma cells and transformed foci in Bhas 42 cells. Two types of nanosilver, spherical nanoparticles (AgNM300) and fibrous (AgNM302) nanorods/wires, and MNPs differing in surface modifications [MNPs coated with sodium oleate (SO-MNPs), MNPs coated with SO + polyethylene glycol (SO-PEG-MNPs) and MNPs coated with SO + PEG + poly(lactide-co-glycolic acid) SO-PEG-PLGA-MNPs] were included in this study. Spherical AgNM300 showed neither mutagenic nor carcinogenic potential. In contrast, silver nanorods/wires (AgNM302) increased significantly the number of both gene mutations and transformed foci compared with the control (untreated) cells. Under the same treatment conditions, neither SO-MNPs nor SO-PEG-PLGA-MNPs increased the mutant frequency compared with control cells though an equivocal mutagenic effect was estimated for SOPEG- MNPs. Although SO-MNPs and SO-PEG-MNPs did not show any carcinogenic potential, SO-PEG-PLGA-MNPs increased concentration dependently the number of transformed foci in Bhas 42 cells compared with the control cells. Our results revealed that fibrous shape underlies the mutagenic and carcinogenic potential of nanosilver while surface chemistry affects the biosafety of MNPs. Considering that both nanosilver and MNPs are prospective ENMs for biomedical applications, further toxicological evaluations are warranted to assess comprehensively the biosafety of these nanomaterials.
- Interlaboratory Validation of the Cell Transformation Assay (CTA) for Carcinogenic Assessment of BPA AlternativesPublication . El Yamani, N.; Aimonen, K.; Dusinska, M.; Guichard, Y.; Honza, T.; Louro, H.; Pereira, M.J.; Rundén-Pran, E.; SenGupta, T.; Tavares, A.M.; Silva, M.J.Bisphenol A (BPA) has long been used in various plastic products, resins and coatings, making human exposure to this chemical inevitable. Due to its harmful health effects, including endocrine disruption, and immunotoxicity, BPA has been increasingly replaced by several alternative compounds. However, there are still significant gaps in research regarding the safety of these BPA alternatives, particularly concerning their potential carcinogenicity. One of the in vitro assays to assess carcinogenic potential of chemicals is the Bhas-42 cell transformation assay (CTA). The assay can detect both genotoxic and non-genotoxic carcinogens It is valuable in identifying potential cancer risks before widespread exposure occurs, contributing to the development of safer chemicals and products, as well as better regulatory standards while adhering to the 3R concept. The EU-Partnership for the Assessment of Risks from Chemicals (PARC) project is addressing these research gaps to enhance the risk assessment of BPA alternatives. BPA and some alternatives, including BPZ, BPE, BPAP, BPA-MAE, BPP, and TCBPA, were selected for evaluation of their carcinogenic potential using the in vitro 2-stage Bhas-42 CTA. A key objective of the project is to validate the CTA as a reliable in vitro method for assessing carcinogenicity. To ensure consistency and accuracy across participating labs, an interlaboratory comparison was initiated and a standardized SOP was developed, including concentration ranges for controls and BPA analogues, in alignment with OECD guidance document. The first results from the protocol harmonization, using the selected controls, were consistent across all participating labs. BPA and its analogues are being tested, and the results are under evaluation. The data generated will contribute to the overall weight of evidence on the hazards posed by these chemicals and, when combined with findings from other endpoints, will provide a solid basis for refining their regulation.
- Physiologically based toxicokinetic models in aggregate exposure: A reviewPublication . Lamon, L.; Paini, A.; Siccardi, M.; Doyle, J.; McNamara, C.; Galea, K.S.; Ghosh, M.; Louro, Henriqueta; Silva, Maria Joao; El Yamani, N.; Dusinska, M.; Moeller, R.; Duca, R.C.; Cubadda, F.; Viegas, S.; Martins, C.; Price, P.This literature review explores the application of Physiologically Based Kinetic (PBK) models in aggregate exposure (AE) assessment across different chemical classes. It builds on the screening of 1119 publications and the identification of 40 relevant articles. The most frequently studied chemicals include volatile organic compounds and plant protection products, with metals, personal care products, persistent organic pollutants and plasticisers also represented. Most studies reported in this review are applied to human populations and build on human biomonitoring (HBM) data to enhance model reliability. However, some studies use animal models (primarily rat models) and apply cross-species extrapolation to the human AE scenario. Occupational exposure is taken into consideration as part of the AE scenario in a few studies. Many of the reviewed studies are designed in support of chemical risk assessment (CRA), illustrating the wide applicability of PBK models. The review discusses the joint role of HBM data and PBK model in AE scenarios, highlighting its importance for a reliable risk assessments. The studies identified and discussed in this review suggest a broad interpretation of AE. The diversity across case reported studies is attributed to varying interpretations and existing definitions of AE. Finally, the roles of forward and reverse dosimetry in refining AE assessments are discussed, highlighting their importance for future research. This scoping review provides a comprehensive overview of PBK model applications in addressing AE, serving as a valuable foundation for future research and development aimed at advancing human health protection towards the Next-Generation Risk Assessment (NGRA).