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The first Stakeholder Network Meeting of the EU Horizon 2020-funded ONTOX project was held on 13-14 March 2023, in Brussels, Belgium. The discussion centred around identifying specific challenges, barriers and drivers in relation to the implementation of non-animal new approach methodologies (NAMs) and probabilistic risk assessment (PRA), in order to help address the issues and rank them according to their associated level of difficulty. ONTOX aims to advance the assessment of chemical risk to humans, without the use of animal testing, by developing non-animal NAMs and PRA in line with 21st century toxicity testing principles. Stakeholder groups (regulatory authorities, companies, academia, non-governmental organisations) were identified and invited to participate in a meeting and a survey, by which their current position in relation to the implementation of NAMs and PRA was ascertained, as well as specific challenges and drivers highlighted. The survey analysis revealed areas of agreement and disagreement among stakeholders on topics such as capacity building, sustainability, regulatory acceptance, validation of adverse outcome pathways, acceptance of artificial intelligence (AI) in risk assessment, and guaranteeing consumer safety. The stakeholder network meeting resulted in the identification of barriers, drivers and specific challenges that need to be addressed. Breakout groups discussed topics such as hazard versus risk assessment, future reliance on AI and machine learning, regulatory requirements for industry and sustainability of the ONTOX Hub platform. The outputs from these discussions provided insights for overcoming barriers and leveraging drivers for implementing NAMs and PRA. It was concluded that there is a continued need for stakeholder engagement, including the organisation of a 'hackathon' to tackle challenges, to ensure the successful implementation of NAMs and PRA in chemical risk assessment.
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Rutas de Resultados Adversos , Inteligencia Artificial , Animales , Humanos , Pruebas de Toxicidad , Medición de Riesgo , BélgicaRESUMEN
EU regulations call for the use of alternative methods to animal testing. During the last decade, an increasing number of alternative approaches have been formally adopted. In parallel, new 3Rs-relevant technologies and mechanistic approaches have increasingly contributed to hazard identification and risk assessment evolution. In this changing landscape, an EPAA meeting reviewed the challenges that different industry sectors face in the implementation of alternative methods following a science-driven approach. Although clear progress was acknowledged in animal testing reduction and refinement thanks to an integration of scientifically robust approaches, the following challenges were identified: i) further characterization of toxicity pathways; ii) development of assays covering current scientific gaps, iii) better characterization of links between in vitro readouts and outcome in the target species; iv) better definition of alternative method applicability domains, and v) appropriate implementation of the available approaches. For areas having regulatory adopted alternative methods (e.g., vaccine batch testing), harmonised acceptance across geographical regions was considered critical for broader application. Overall, the main constraints to the application of non-animal alternatives are the still existing gaps in scientific knowledge and technological limitations. The science-driven identification of most appropriate methods is key for furthering a multi-sectorial decrease in animal testing.
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Alternativas a las Pruebas en Animales/legislación & jurisprudencia , Industrias/legislación & jurisprudencia , Animales , Europa (Continente) , Humanos , Medición de Riesgo/legislación & jurisprudencia , Pruebas de Toxicidad/normasRESUMEN
Respiratory tract sensitization can have significant acute and chronic health implications. While induction of respiratory sensitization is widely recognized for some chemicals, validated standard methods or frameworks for identifying and characterizing the hazard are not available. A workshop on assessment of respiratory sensitization was held to discuss the current state of science for identification and characterization of respiratory sensitizer hazard, identify information facilitating development of validated standard methods and frameworks, and consider the regulatory and practical risk management needs. Participants agreed on a predominant Th2 immunological mechanism and several steps in respiratory sensitization. Some overlapping cellular events in respiratory and skin sensitization are well understood, but full mechanism(s) remain unavailable. Progress on non-animal approaches to skin sensitization testing, ranging from in vitro systems, -omics, in silico profiling, and structural profiling were acknowledged. Addressing both induction and elicitation phases remains challenging. Participants identified lack of a unifying dose metric as increasing the difficulty of interpreting dosimetry across exposures. A number of research needs were identified, including an agreed list of respiratory sensitizers and other asthmagens, distinguishing between adverse effects from immune-mediated versus non-immunological mechanisms. A number of themes emerged from the discussion regarding future testing strategies, particularly the need for a tiered framework respiratory sensitizer assessment. These workshop present a basis for moving towards a weight-of-evidence assessment.
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Exposición por Inhalación/efectos adversos , Hipersensibilidad Respiratoria/inducido químicamente , Sistema Respiratorio/efectos de los fármacos , Pruebas de Toxicidad/métodos , Alternativas a las Pruebas en Animales , Animales , Asma Ocupacional/inducido químicamente , Asma Ocupacional/genética , Asma Ocupacional/inmunología , Asma Ocupacional/fisiopatología , Dermatitis Alérgica por Contacto/etiología , Humanos , Hipersensibilidad Respiratoria/genética , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/fisiopatología , Sistema Respiratorio/inmunología , Sistema Respiratorio/fisiopatología , Medición de Riesgo , Células Th2/efectos de los fármacos , Células Th2/inmunología , ToxicogenéticaRESUMEN
Celiac disease (CD) is characterized by an inappropriate immunological reaction against gluten driven by gluten-specific CD4+ T cells. We screened 25 proteases and tested 10 for their potential to degrade gluten in vitro. Five proteases were further tested for their ability to prevent the proliferative response by a gluten-specific CD4+ T cell clone and seven gluten-reactive T cell lines to protease-digested gluten peptides. A proline-specific endo-peptidase from Aspergillus niger (AnP2) was particularly efficient at diminishing proliferation after stimulation with cleaved antigen, and could completely block the response against both native and deamidated gluten peptides. We found that AnP2 was efficient down to a 1:64 protease:substrate ratio (w:w). When AnP2 was tested in assays using seven gluten-reactive T cell lines from individual CD patients (three adults and four children), the response to gluten was diminished in all cases. Our study indicates a therapeutic benefit of AnP2 to CD patients.
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Linfocitos T CD4-Positivos/inmunología , Endopeptidasas/inmunología , Proteínas Fúngicas/inmunología , Glútenes/inmunología , Péptidos/inmunología , Adulto , Secuencia de Aminoácidos , Aspergillus niger/enzimología , Linfocitos T CD4-Positivos/efectos de los fármacos , Enfermedad Celíaca/inmunología , Enfermedad Celíaca/patología , Línea Celular , Proliferación Celular/efectos de los fármacos , Niño , Células Clonales/efectos de los fármacos , Células Clonales/inmunología , Electroforesis en Gel de Poliacrilamida , Endopeptidasas/metabolismo , Endopeptidasas/farmacología , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/farmacología , Glútenes/química , Glútenes/metabolismo , Humanos , Intestinos/inmunología , Datos de Secuencia Molecular , Péptidos/metabolismo , Especificidad por SustratoRESUMEN
BACKGROUND: The onset and pathology of sporadic Alzheimer's disease (sAD) seem to be affected by both sex and genetic mechanisms. Evidence supports that the high prevalence of sAD in women, worldwide, may be attributed to an interplay among aging, sex, and lifestyle, influenced by genetics, metabolic changes, and hormones. Interestingly, epigenetic mechanisms such as microRNAs (miRNAs), known as master regulators of gene expression, may contribute to this observed sexual dimorphism in sAD. OBJECTIVES: To investigate the potential impact of sex-associated miRNAs on processes manifesting sAD pathology, as described by the Tau-driven Adverse Outcome Pathway (AOP) leading to memory loss. METHODS: Using publicly available human miRNA datasets, sex-biased miRNAs, defined as differentially expressed by sex in tissues possibly affected by sAD pathology, were collected. In addition, sex hormone-related miRNAs were also retrieved from the literature. The compiled sex-biased and sex hormone-related miRNAs were further plugged into the dysregulated processes of the Tau-driven AOP for memory loss. RESULTS: Several miRNAs, previously identified as sex-associated, were implicated in dysregulated processes associated with the manifestation of sAD pathology. Importantly, the described pathology processes were not confined to a particular sex. A mechanistic-based approach utilizing miRNAs was adopted in order to elucidate the link between sex and biological processes potentially involved in the development of memory loss. CONCLUSIONS: The identification of sex-associated miRNAs involved in the early processes manifesting memory loss may shed light to the complex molecular mechanisms underlying sAD pathogenesis in a sex-specific manner.
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Enfermedad de Alzheimer , MicroARNs , Masculino , Humanos , Femenino , MicroARNs/genética , MicroARNs/metabolismo , Enfermedad de Alzheimer/metabolismo , Envejecimiento , Amnesia , Hormonas Esteroides GonadalesRESUMEN
Alzheimer's disease (AD) is the most common cause of dementia. New strategies for the early detection of MCI and sporadic AD are crucial for developing effective treatment options. Current techniques used for diagnosis of AD are invasive and/or expensive, so they are not suitable for population screening. Cerebrospinal fluid (CSF) biomarkers such as amyloid ß1-42 (Aß1-42), total tau (T-tau), and phosphorylated tau181 (P-tau181) levels are core biomarkers for early diagnosis of AD. Several studies have proposed the use of blood-circulating microRNAs (miRNAs) as potential novel early biomarkers for AD. We therefore applied a novel approach to identify blood-circulating miRNAs associated with CSF biomarkers and explored the potential of these miRNAs as biomarkers of AD. In total, 112 subjects consisting of 28 dementia due to AD cases, 63 MCI due to AD cases, and 21 cognitively healthy controls were included. We identified seven Aß1-42-associated plasma miRNAs, six P-tau181-associated plasma miRNAs, and nine Aß1-42-associated serum miRNAs. These miRNAs were involved in AD-relevant biological processes, such as PI3K/AKT signaling. Based on this signaling pathway, we constructed an miRNA-gene target network, wherein miR-145-5p has been identified as a hub. Furthermore, we showed that miR-145-5p performs best in the prediction of both AD and MCI. Moreover, miR-145-5p also improved the prediction performance of the mini-mental state examination (MMSE) score. The performance of this miRNA was validated using different datasets including an RT-qPCR dataset from plasma samples of 23 MCI cases and 30 age-matched controls. These findings indicate that blood-circulating miRNAs that are associated with CSF biomarkers levels and specifically plasma miR-145-5p alone or combined with the MMSE score can potentially be used as noninvasive biomarkers for AD or MCI screening in the general population, although studies in other AD cohorts are necessary for further validation.
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Enfermedad de Alzheimer , Disfunción Cognitiva , MicroARNs , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Fosfatidilinositol 3-Quinasas , Disfunción Cognitiva/diagnóstico , Biomarcadores , Neuroimagen , Proteínas tau , Péptidos beta-AmiloidesRESUMEN
Exposure assessment is a crucial component of environmental health research, providing essential information on the potential risks associated with various chemicals. A systematic scoping review was conducted to acquire an overview of accessible human exposure assessment methods and computational tools to support and ultimately improve risk assessment. The systematic scoping review was performed in Sysrev, a web platform that introduces machine learning techniques into the review process aiming for increased accuracy and efficiency. Included publications were restricted to a publication date after the year 2000, where exposure methods were properly described. Exposure assessments methods were found to be used for a broad range of environmental chemicals including pesticides, metals, persistent chemicals, volatile organic compounds, and other chemical classes. Our results show that after the year 2000, for all the types of exposure routes, probabilistic analysis, and computational methods to calculate human exposure have increased. Sixty-three mathematical models and toolboxes were identified that have been developed in Europe, North America, and globally. However, only twelve occur frequently and their usefulness were associated with exposure route, chemical classes and input parameters used to estimate exposure. The outcome of the combined associations can function as a basis and/or guide for decision making for the selection of most appropriate method and tool to be used for environmental chemical human exposure assessments in Ontology-driven and artificial intelligence-based repeated dose toxicity testing of chemicals for next generation risk assessment (ONTOX) project and elsewhere. Finally, the choice of input parameters used in each mathematical model and toolbox shown by our analysis can contribute to the harmonization process of the exposure models and tools increasing the prospect for comparison between studies and consistency in the regulatory process in the future.
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Exposición a Riesgos Ambientales , Contaminantes Ambientales , Humanos , Exposición a Riesgos Ambientales/estadística & datos numéricos , Monitoreo del Ambiente/métodos , Aprendizaje Automático , Plaguicidas/toxicidad , Medición de Riesgo/métodosRESUMEN
Both because of the shortcomings of existing risk assessment methodologies, as well as newly available tools to predict hazard and risk with machine learning approaches, there has been an emerging emphasis on probabilistic risk assessment. Increasingly sophisticated AI models can be applied to a plethora of exposure and hazard data to obtain not only predictions for particular endpoints but also to estimate the uncertainty of the risk assessment outcome. This provides the basis for a shift from deterministic to more probabilistic approaches but comes at the cost of an increased complexity of the process as it requires more resources and human expertise. There are still challenges to overcome before a probabilistic paradigm is fully embraced by regulators. Based on an earlier white paper (Maertens et al., 2022), a workshop discussed the prospects, challenges and path forward for implementing such AI-based probabilistic hazard assessment. Moving forward, we will see the transition from categorized into probabilistic and dose-dependent hazard outcomes, the application of internal thresholds of toxicological concern for data-poor substances, the acknowledgement of user-friendly open-source software, a rise in the expertise of toxicologists required to understand and interpret artificial intelligence models, and the honest communication of uncertainty in risk assessment to the public.
Probabilistic risk assessment, initially from engineering, is applied in toxicology to understand chemical-related hazards and their consequences. In toxicology, uncertainties abound unclear molecular events, varied proposed outcomes, and population-level assessments for issues like neurodevelopmental disorders. Establishing links between chemical exposures and diseases, especially rare events like birth defects, often demands extensive studies. Existing methods struggle with subtle effects or those affecting specific groups. Future risk assessments must address developmental disease origins, presenting challenges beyond current capabilities. The intricate nature of many toxicological processes, lack of consensus on mechanisms and outcomes, and the need for nuanced population-level assessments highlight the complexities in understanding and quantifying risks associated with chemical exposures in the field of toxicology.
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Inteligencia Artificial , Toxicología , Animales , Humanos , Alternativas a las Pruebas en Animales , Medición de Riesgo/métodos , Incertidumbre , Toxicología/métodosRESUMEN
In the past decade, significant European calls for research proposals have supported translational collaborative research on non-communicable and infectious diseases within the biomedical life sciences by bringing together interdisciplinary and multinational consortia. This research has advanced our understanding of disease pathophysiology, marking considerable scientific progress. Yet, it is crucial to retrospectively evaluate these efforts' societal impact. Research proposals should be thoughtfully designed to ensure that the research findings can be effectively translated into actionable policies. In addition, the choice of scientific methods plays a pivotal role in shaping the societal impact of research discoveries. Understanding the factors responsible for current unmet public health issues and medical needs is crucial for crafting innovative strategies for research policy interventions. A multistakeholder survey and a roundtable helped identify potential needs for consideration in the EU research and policy agenda. Based on survey findings, mental health disorders, metabolic syndrome, cancer, antimicrobial resistance, environmental pollution, and cardiovascular diseases were considered the public health challenges deserving prioritisation. In addition, early diagnosis, primary prevention, the impact of environmental pollution on disease onset and personalised medicine approaches were the most selected unmet medical needs. Survey findings enabled the formulation of some research-policies interventions (RPIs), which were further discussed during a multistakeholder online roundtable. The discussion underscored recent EU-level activities aligned with the survey-derived RPIs and facilitated an exchange of perspectives on public health and biomedical research topics ripe for interdisciplinary collaboration and warranting attention within the EU's research and policy agenda. Actionable recommendations aimed at facilitating the translation of knowledge into transformative, science-based policies are also provided.
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Unión Europea , Salud Pública , Humanos , Encuestas y Cuestionarios , Política de Salud , Participación de los Interesados , Necesidades y Demandas de Servicios de SaludRESUMEN
The purpose of this study was to explore the possibility of combining the epidermal equivalent (EE) potency assay with the assay which assesses release of interleukin-18 (IL-18) to provide a single test for identification and classification of skin sensitizing chemicals, including chemicals of low water solubility or stability. A protocol was developed using different 3D-epidermal models including in house VUMC model, epiCS® (previously EST1000™), MatTek EpiDerm™ and SkinEthic™ RHE and also the impact of different vehicles (acetone:olive oil 4:1, 1% DMSO, ethanol, water) was investigated. Following topical exposure for 24h to 17 contact allergens and 13 non-sensitizers a robust increase in IL-18 release was observed only after exposure to contact allergens. A putative prediction model is proposed from data obtained from two laboratories yielding 95% accuracy. Correlating the in vitro EE sensitizer potency data, which assesses the chemical concentration which results in 50% cytotoxicity (EE-EC50) with human and animal data showed a superior correlation with human DSA05 (µg/cm(2)) data (Spearman r=0.8500; P value (two-tailed)=0.0061) compared to LLNA data (Spearman r=0.5968; P value (two-tailed)=0.0542). DSA05=induction dose per skin area that produces a positive response in 5% of the tested population Also a good correlation was observed for release of IL-18 (SI-2) into culture supernatants with human DSA05 data (Spearman r=0.8333; P value (two-tailed)=0.0154). This easily transferable human in vitro assay appears to be very promising, but additional testing of a larger chemical set with the different EE models is required to fully evaluate the utility of this assay and to establish a definitive prediction model.
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Alérgenos/toxicidad , Bioensayo , Dermatitis Alérgica por Contacto/etiología , Epidermis/efectos de los fármacos , Interleucina-18/metabolismo , Pruebas de Irritación de la Piel , Alérgenos/química , Ensayo de Inmunoadsorción Enzimática , Epidermis/inmunología , Humanos , Interleucina-18/inmunología , Modelos Inmunológicos , Valor Predictivo de las PruebasRESUMEN
Background: Late-onset or sporadic Alzheimer's disease (sAD) is a neurodegenerative disease leading to cognitive impairment and memory loss. The underlying pathological changes take place several years prior to the appearance of the first clinical symptoms, however, the early diagnosis of sAD remains obscure. Objective: To identify changes in circulating microRNA (miR) expression in an effort to detect early biomarkers of underlying sAD pathology. Methods: A set of candidate miRs, earlier detected in biofluids from subjects at early stage of sAD, was linked to the proposed tau-driven adverse outcome pathway for memory loss. The relative expression of the selected miRs in serum of 12 cases (mild cognitive impairment, MCI) and 27 cognitively normal subjects, recruited within the ongoing Aiginition Longitudinal Biomarker Investigation Of Neurodegeneration (ALBION) study, was measured by RT-qPCR. Data on the protein levels of amyloid-ß (Aß42) and total/phosphorylated tau (t-tau/p-tau), in cerebrospinal fluid (CSF), and the cognitive z-scores of the participants were also retrieved. Results: Each doubling in relative expression of 13 miRs in serum changed the odds of either having MCI (versus control), or having pathological Aß42 or pathological Aß42 and tau (versus normal) proteins in their CSF, or was associated with the global composite z-score. Conclusion: These candidate human circulating miRs may be of great importance in early diagnosis of sAD. There is an urgent need for confirming these proposed early predictive biomarkers for sAD, contributing not only to societal but also to economic benefits.
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This protocol describes the design and development of a tool for evaluation of the internal validity of in vitro studies, which is needed to include the data as evidence in systematic reviews and chemical risk assessments. The tool will be designed specifically to be applied to cell culture studies, including, but not restricted to, studies meeting the new approach methodology (NAM) definition. The tool is called INVITES-IN (IN VITro Experimental Studies INternal validity). In this protocol, three of the four studies that will be performed to create the release version of INVITES-IN are described. In the first study, evaluation of existing assessment tools will be combined with focus group discussions to identify how characteristics of the design or conduct of an in vitro study can affect its internal validity. Bias domains and items considered to be of relevance for in vitro studies will be identified. In the second study, group agreement on internal validity domains and items of importance for in vitro studies will be identified via a modified Delphi methodology. In the third study, the draft version of the tool will be created, based on the data on relevance and importance of bias domains and items collected in Studies 1 and 2. A separate protocol will be prepared for the fourth study, which includes the user testing and validation of the tool, and collection of users' experience.
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The adverse outcome pathway (AOP) concept was first proposed as a tool for chemical hazard assessment facilitating the regulatory decision-making in toxicology and was more recently recommended during the BioMed21 workshops as a tool for the characterization of crucial endpoints in the human disease development. This AOP framework represents mechanistically based approaches using existing data, more realistic and relevant to human biological systems. In principle, AOPs are described by molecular initiating events (MIEs) which induce key events (KEs) leading to adverse outcomes (AOs). In addition to the individual AOPs, the network of AOPs has been also suggested to beneficially support the understanding and prediction of adverse effects in risk assessment. The AOP-based networks can capture the complexity of biological systems described by different AOPs, in which multiple AOs diverge from a single MIE or multiple MIEs trigger a cascade of KEs that converge to a single AO. Here, an AOP network incorporating a recently proposed tau-driven AOP toward memory loss (AOP429) related to sporadic (late-onset) Alzheimer's disease is constructed. This proposed AOP network is an attempt to extract useful information for better comprehending the interactions among existing mechanistic data linked to memory loss as an early phase of sporadic Alzheimer's disease pathology.
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BACKGROUND: A complex network of aging-related homeostatic pathways that are sensitive to further deterioration in the presence of genetic, systemic, and environmental risk factors, and lifestyle, is implicated in the pathogenesis of progressive neurodegenerative diseases, such as sporadic (late-onset) Alzheimer's disease (sAD). OBJECTIVE: Since sAD pathology and neurotoxicity share microRNAs (miRs) regulating common as well as overlapping pathological processes, environmental neurotoxic compounds are hypothesized to exert a risk for sAD initiation and progression. METHODS: Literature search for miRs associated with human sAD and environmental neurotoxic compounds was conducted. Functional miR analysis using PathDip was performed to create miR-target interaction networks. RESULTS: The identified miRs were successfully linked to the hypothetical starting point and key events of the earlier proposed tau-driven adverse outcome pathway toward memory loss. Functional miR analysis confirmed most of the findings retrieved from literature and revealed some interesting findings. The analysis identified 40 miRs involved in both sAD and neurotoxicity that dysregulated processes governing the plausible adverse outcome pathway for memory loss. CONCLUSION: Creating miR-target interaction networks related to pathological processes involved in sAD initiation and progression, and environmental chemical-induced neurotoxicity, respectively, provided overlapping miR-target interaction networks. This overlap offered an opportunity to create an alternative picture of the mechanisms underlying sAD initiation and early progression. Looking at initiation and progression of sAD from this new angle may open for new biomarkers and novel drug targets for sAD before the appearance of the first clinical symptoms.
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Rutas de Resultados Adversos , Enfermedad de Alzheimer , MicroARNs , Síndromes de Neurotoxicidad , Enfermedad de Alzheimer/patología , Amnesia , Humanos , Trastornos de la Memoria , MicroARNs/genética , Síndromes de Neurotoxicidad/genéticaRESUMEN
Despite decades of investigation, test methods to identify respiratory sensitizers remain an unmet regulatory need. In order to support the evaluation of New Approach Methodologies in development, we sought to establish a reference set of low molecular weight respiratory sensitizers based on case reports of occupational asthma. In this context, we have developed an "in litero" approach to identify cases of low molecular weight chemical exposures leading to respiratory sensitization in clinical literature. We utilized the EPA-developed Abstract Sifter literature review tool to maximize the retrieval of publications relevant to respiratory effects in humans for each chemical in a list of chemicals suspected of inducing respiratory sensitization. The literature retrieved for each of these candidate chemicals was sifted to identify relevant case reports and studies, and then evaluated by applying defined selection criteria. Clinical diagnostic criteria were defined around exposure history, respiratory effects, and specific immune response to conclusively demonstrate occupational asthma as a result of sensitization, rather than irritation. This approach successfully identified 28 chemicals that can be considered as human respiratory sensitizers and used to evaluate the performance of NAMs as part of a weight of evidence approach to identify novel respiratory sensitizers. Further, these results have immediate implications for the development and refinement of predictive tools to distinguish between skin and respiratory sensitizers. A comparison of the protein binding mechanisms of our identified "in litero" clinical respiratory sensitizers shows that acylation is a prevalent protein binding mechanism, in contrast to Michael addition and Schiff base formation common to skin sensitizers. Overall, this approach provides an exemplary method to evaluate and apply human data as part of the weight of evidence when establishing reference chemical lists.
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The worldwide prevalence of sporadic (late-onset) Alzheimer's disease (sAD) is dramatically increasing. Aging and genetics are important risk factors, but systemic and environmental factors contribute to this risk in a still poorly understood way. Within the frame of BioMed21, the Adverse Outcome Pathway (AOP) concept for toxicology was recommended as a tool for enhancing human disease research and accelerating translation of data into human applications. Its potential to capture biological knowledge and to increase mechanistic understanding about human diseases has been substantiated since. In pursuit of the tau-cascade hypothesis, a tau-driven AOP blueprint toward the adverse outcome of memory loss is proposed. Sequences of key events and plausible key event relationships, triggered by the bidirectional relationship between brain cholesterol and glucose dysmetabolism, and contributing to memory loss are captured. To portray how environmental factors may contribute to sAD progression, information on chemicals and drugs, that experimentally or epidemiologically associate with the risk of AD and mechanistically link to sAD progression, are mapped on this AOP. The evidence suggests that chemicals may accelerate disease progression by plugging into sAD relevant processes. The proposed AOP is a simplified framework of key events and plausible key event relationships representing one specific aspect of sAD pathology, and an attempt to portray chemical interference. Other sAD-related AOPs (e.g., Aß-driven AOP) and a better understanding of the impact of aging and genetic polymorphism are needed to further expand our mechanistic understanding of early AD pathology and the potential impact of environmental and systemic risk factors.
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Rutas de Resultados Adversos , Enfermedad de Alzheimer/patología , Amnesia/patología , Encéfalo/patología , Trastornos de la Memoria/patología , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/metabolismo , Humanos , Trastornos de la Memoria/metabolismo , Medición de RiesgoRESUMEN
Contact allergy is of considerable importance to the toxicologist, and regulatory authorities worldwide require testing for skin sensitization potential and appropriate hazard labeling to enable management of the risk to human health. Although traditionally the identification of skin-sensitizing chemicals has been carried out using animal models, in Europe legislative changes have promoted, and now require, the use of non-animal methods (i.e., Cosmetic Directive, REACH). Several in vitro alternatives for hazard identification have now been validated, but do not provide information on the potency of a skin sensitizer. Here, we describe an animal model, the local lymph node assay (LLNA), and an in vitro model, the RhE IL-18 potency assay, in the context of the identification and potency classification of skin sensitizers. These two assays have been chosen among the different available tests as representative of an alternative in vivo model (the LLNA) and a promising in vitro method with the potential of both hazard identification and potency classification.
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Dermatitis Alérgica por Contacto/etiología , Interleucina-18/inmunología , Ensayo del Nódulo Linfático Local , Pruebas de Irritación de la Piel/métodos , Alérgenos/inmunología , Alérgenos/toxicidad , Animales , Células Cultivadas , Dermatitis Alérgica por Contacto/diagnóstico , Dermatitis Alérgica por Contacto/inmunología , Humanos , Irritantes/inmunología , Irritantes/toxicidad , Queratinocitos/efectos de los fármacos , Queratinocitos/inmunología , Ratones , Cultivo Primario de Células/métodosRESUMEN
The 3Rs concept, calling for replacement, reduction and refinement of animal experimentation, is receiving increasing attention around the world, and has found its way to legislation, in particular in the European Union. This is aligned by continuing high-level efforts of the European Commission to support development and implementation of 3Rs methods. In this respect, the European project called "ONTOX: ontology-driven and artificial intelligence-based repeated dose toxicity testing of chemicals for next generation risk assessment" was recently initiated with the goal to provide a functional and sustainable solution for advancing human risk assessment of chemicals without the use of animals in line with the principles of 21st century toxicity testing and next generation risk assessment. ONTOX will deliver a generic strategy to create new approach methodologies (NAMs) in order to predict systemic repeated dose toxicity effects that, upon combination with tailored exposure assessment, will enable human risk assessment. For proof-of-concept purposes, focus is put on NAMs addressing adversities in the liver, kidneys and developing brain induced by a variety of chemicals. The NAMs each consist of a computational system based on artificial intelligence and are fed by biological, toxicological, chemical and kinetic data. Data are consecutively integrated in physiological maps, quantitative adverse outcome pathway networks and ontology frameworks. Supported by artificial intelligence, data gaps are identified and are filled by targeted in vitro and in silico testing. ONTOX is anticipated to have a deep and long-lasting impact at many levels, in particular by consolidating Europe's world-leading position regarding the development, exploitation, regulation and application of animal-free methods for human risk assessment of chemicals.
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Inteligencia Artificial , Ontología de Genes , Pruebas de Toxicidad , Alternativas a las Pruebas en Animales , Animales , Simulación por Computador , Unión Europea , Humanos , Técnicas In Vitro , Medición de RiesgoRESUMEN
The growing world population and increased pressure on agricultural resources are driving a shortage of dietary protein sources. As a result, industry is developing more sustainable novel food protein sources such as insects, algae and duckweed and using new processing techniques. Consumer exposure to these novel or processed proteins, could cause new food allergies, exacerbating a public health issue which is already directly affecting an estimated 20 million Europeans. Introduction of novel foods should not add to the burden of food allergy and this calls for a reliable, harmonised, evidence-based and validated allergenicity risk assessment strategy. The COST (Cooperation in Science and Technology) Action ImpARAS (Improved Allergenicity Risk Assessment Strategy), a four-year networking project, identified gaps in current allergy risk assessment, and proposed new ideas and plans for improving it. Here, we report on the lessons learned from the ImpARAS network and suggestions for future research. The safe introduction of novel and more sustainable food protein sources, while protecting humans from food allergy, calls for a multidisciplinary approach based on an improved understanding of what determines the relative allergenic potency of proteins, novel testing and assessment methodologies, harmonized decision-making criteria, and a clear ranking approach to express the allergenicity of novel product relative to that of existing known allergenic proteins: (from 'non'/to weakly and to strongly allergenic proteins).