ALTEX最新文献 - Book学术

Evaluation of a high-throughput in-vitro-to-in-vivo extrapolation (IVIVE) workflow for the prioritization of potential developmental toxicity of chemicals. 评估高通量体外到体内外推（IVIVE）工作流程，以确定化学品潜在发育毒性的优先级。

ALTEX Pub Date : 2025-05-28 DOI: 10.14573/altex.2406281

Matthew W Linakis, Rebecca A Clewell, Jerry Campbell, P Robinan Gentry, Harvey J Clewell

{"title":"Evaluation of a high-throughput in-vitro-to-in-vivo extrapolation (IVIVE) workflow for the prioritization of potential developmental toxicity of chemicals.","authors":"Matthew W Linakis, Rebecca A Clewell, Jerry Campbell, P Robinan Gentry, Harvey J Clewell","doi":"10.14573/altex.2406281","DOIUrl":"https://doi.org/10.14573/altex.2406281","url":null,"abstract":"New approach methodologies (NAMs) are rapidly being developed to help improve the speed of risk assessment and reduce the use of animals. In vitro to in vivo extrapolation (IVIVE) is necessary to translate NAM data to human exposures. While past IVIVE efforts have demonstrated impressive success, several specialized scenarios exist where current IVIVE methods have not been tested, including pregnancy and developmental toxicity. To that end, this investigation proposes a preliminary IVIVE workflow for identification of potential developmental toxicants. Readily available in vitro and in vivo data with developmental toxicity endpoints were aggregated from the US Environmental Protection Agency's CompTox Chemicals Dashboard. In vitro distribution models (i.e. Armitage model) and both generic (httk) and bespoke physiologically-based pharmacokinetic (PBPK) models were used to estimate exposures from blood concentrations associated with in vitro bioactivity (reverse dosimetry) and NAM-based bioactive doses were compared to in vivo endpoints (LOAELs) where available. Based on literature sources, this method identified chemicals as a high, medium, or low priority for follow-up as a developmental toxicant. Of the 23 chemicals with in vitro developmental toxicity assays, 7 had a NAM-based human oral equivalent dose (hOED) that was lower for developmental assays than for all available assays, indicating that the use of all in vitro data to derive a hOED would generally provide the most conservative approach. Potential data streams and refinements for improvement of the IVIVE workflow are also discussed.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

From cellular perturbation to probabilistic risk assessments. 从细胞扰动到概率风险评估。

ALTEX Pub Date : 2025-05-26 DOI: 10.14573/altex.2501291

Alexandra Maertens, Breanne Kincaid, Eric Bridgeford, Celine Brochot, Arthur de Carvalho E Silva, Jean-Lou C M Dorne, Liesbet Geris, Trine Husøy, Nicole Kleinstreuer, Luiz C M Ladeira, Alistair Middleton, Joe Reynolds, Blanca Rodriguez, Erwin L Roggen, Giulia Russo, Kris Thayer, Thomas Hartung

{"title":"From cellular perturbation to probabilistic risk assessments.","authors":"Alexandra Maertens, Breanne Kincaid, Eric Bridgeford, Celine Brochot, Arthur de Carvalho E Silva, Jean-Lou C M Dorne, Liesbet Geris, Trine Husøy, Nicole Kleinstreuer, Luiz C M Ladeira, Alistair Middleton, Joe Reynolds, Blanca Rodriguez, Erwin L Roggen, Giulia Russo, Kris Thayer, Thomas Hartung","doi":"10.14573/altex.2501291","DOIUrl":"https://doi.org/10.14573/altex.2501291","url":null,"abstract":"Chemical risk assessment is evolving from traditional deterministic approaches to embrace probabilistic methodologies, where risk of hazard manifestation is understood as a more or less probable event depending on exposure, individual factors, and stochastic processes. This is driven by advancements in human stem cells, complex tissue engineering, high-performance computing, and cheminformatics, and is more recently facilitated by large-scale artificial intelligence models. These innovations enable a more nuanced understanding of chemical hazards, capturing the complexity of biological responses and variability within populations. However, each technology comes with its own uncertainties impacting on the estimation of hazard probabilities. This shift addresses the limitations of point estimates and thresholds that oversimplify hazard assessment, allowing for the integration of kinetic variability and uncertainty metrics into risk models. By leveraging modern technologies and expansive toxicological data, probabilistic approaches offer a comprehensive evaluation of chemical safety. This paper summarizes a workshop held in 2023 and discusses the technological and data-driven enablers, and the challenges faced in their implementation, with particular focus on perturbation of biology as the basis of hazard estimates. The future of toxicological risk assessment lies in the successful integration of these probabilistic models, promising more accurate and holistic hazard evaluations.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Determination of U-SENS™ borderline range thresholds to address uncertainty for skin sensitization assessment in a regulatory context. 确定U-SENS™边界范围阈值，以解决监管环境下皮肤致敏评估的不确定性。

ALTEX Pub Date : 2025-05-23 DOI: 10.14573/altex.2411282

Laurent Nardelli, Fleur Tourneix, Leopold Carron, Erwin van Vliet, Nathalie Alépée

{"title":"Determination of U-SENS™ borderline range thresholds to address uncertainty for skin sensitization assessment in a regulatory context.","authors":"Laurent Nardelli, Fleur Tourneix, Leopold Carron, Erwin van Vliet, Nathalie Alépée","doi":"10.14573/altex.2411282","DOIUrl":"https://doi.org/10.14573/altex.2411282","url":null,"abstract":"Skin sensitization is an endpoint in the safety evaluation of chemicals. OECD guideline 497 includes three defined approaches (DAs) integrating new approach methodologies (NAMs) for skin sensitization hazard identification or UN GHS potency categorization. The \"2 out of 3\" (2o3) DA predicts skin sensitization hazard by sequentially testing in up to three NAMs covering key events (KEs) 1-3 of the adverse outcome pathway (AOP). To increase flexibility, OECD is considering the adoption of \"alternate\" NAMs in guideline 497 targeting the same AOP KE as in test guidelines 442C, 442D, 442E. This study evaluated the feasibility of substituting the h-CLAT with U-SENS™ in the 2o3 DA as NAM for AOP KE 3. To define areas where uncertainty may exist in U-SENS™ predictions, borderline range thresholds around the 150% CD86 stimulation index (SI) cut-off were calculated using a log pooled median absolute deviation method. A revised U-SENS™ prediction model implementing these thresholds classifies a chemical as positive (SI > 176%), negative (SI < 128%), or borderline (128 ≤ SI ≤ 176%). Application of the model changed the U-SENS™ predictions for 35 of 191 chemicals in the OECD database. Substituting the h-CLAT with U-SENS™ in the 2o3 DA resulted in a balanced accuracy of 71% against LLNA (n=168) and 77% against human data (n=66), without considering borderline range thresholds. Incorporating thresholds improved the balanced accuracy to 77% (LLNA, n=142) and 88% (human, n=55). These findings support the inclusion of the U-SENS™ and its borderline range thresholds in OECD guideline 497.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

KoCVAM-led validation of KeraSkin™ Phototoxicity Assay for inclusion in OECD TG 498. kocvam主导的KeraSkin™光毒性测定法的验证，用于OECD TG 498。

ALTEX Pub Date : 2025-05-23 DOI: 10.14573/altex.2407041

Nam-Hee Kang, Chang-Eon Park, So-Hee Kim, Eunji Gwak, Seongsook Kim, Min-Gyu Go, Joohwan Kim, Sun-Wook Woo

{"title":"KoCVAM-led validation of KeraSkin™ Phototoxicity Assay for inclusion in OECD TG 498.","authors":"Nam-Hee Kang, Chang-Eon Park, So-Hee Kim, Eunji Gwak, Seongsook Kim, Min-Gyu Go, Joohwan Kim, Sun-Wook Woo","doi":"10.14573/altex.2407041","DOIUrl":"https://doi.org/10.14573/altex.2407041","url":null,"abstract":"Phototoxicity (or photoirritation) is defined as an acute toxic response elicited by topically or systematically administered photoreactive chemicals after the exposure of the body to environmental light. Korean Center for the Validation of Alternative Methods (KoCVAM) developed and optimized an in vitro phototoxicity test method using KeraSkin™, a reconstructed human epidermis model (RhE), (KeraSkin™ Phototoxicity Assay) as a 'me-too' test method in a previous study. KeraSkin™ Phototoxicity Assay was added to the OECD Workplan for inclusion in OECD test guideline (TG) 498. This study, conducted based on OECD Performance Standard No. 356 by one lead laboratory and four participating laboratories, aimed to validate the relevance and reliability of the KeraSkin™ Phototoxicity Assay for regulatory application in the safety assessment of cosmetics and drugs. Based on the test results, the 12 reference chemicals showed 91.7% to 100% within-lab reproducibility and 100% between-lab reproducibility in all participating labs. Further, the predictive capacity for the 12 reference chemicals calculated based on the total number of runs (144) showed 100% sensitivity (72/72), 98.6% specificity (71/72), and 99.3% accuracy (143/144). Overall predictive capacity (32 test chemicals) calculated based on the total number of runs (164) showed 97.6% (80/82) sensitivity, 97.6% (80/82) specificity, and 97.6% (160/164) accuracy. KeraSkin™ Phototoxicity Assay thus fulfills the requirements to be included as a 'me-too' test method in OECD TG 498.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Validation of an Endopep-suspension immunoassay for the diagnostics of human botulism. 内肽类悬液免疫分析法诊断人肉毒杆菌中毒的验证。

ALTEX Pub Date : 2025-05-19 DOI: 10.14573/altex.2412181

Maximilian Steinberg, Laura-Varenne Wilk, Daniel Stern, Jasmin Weisemann, Ute Messelhäußer, Matthias Wittwer, Maren Krüger, Hans Werner Mages, Andreas Rummel, Martin B Dorner, Brigitte G Dorner

{"title":"Validation of an Endopep-suspension immunoassay for the diagnostics of human botulism.","authors":"Maximilian Steinberg, Laura-Varenne Wilk, Daniel Stern, Jasmin Weisemann, Ute Messelhäußer, Matthias Wittwer, Maren Krüger, Hans Werner Mages, Andreas Rummel, Martin B Dorner, Brigitte G Dorner","doi":"10.14573/altex.2412181","DOIUrl":"https://doi.org/10.14573/altex.2412181","url":null,"abstract":"Botulism is a potentially life-threatening disease caused by botulinum neurotoxin (BoNT)-producing bacteria of the genus Clostridium. Laboratory detection of BoNTs in patients' samples is essential to confirm clinical diagnoses and to identify the causative BoNT serotype. The current 'gold standard' method for BoNT detection is the mouse bioassay (MBA), a highly stressful animal experiment. A viable animal experiment replacement method must demonstrate high sensitivity, specificity, reproducibility and robustness, as well as comprehensive BoNT subtype detection, and be widely accepted in the field, necessitating rigorous validation. Here, we report on the validation of a previously established in vitro endopeptidase suspension immunoassay (Endopep-SIA) for the simultaneous detection, differentiation and quantification of BoNT serotypes A and B, the most frequent serotypes associated with human botulism. This assay uses monoclonal antibodies for BoNT extraction, followed by detection of the catalytic activity using neoepitope-specific monoclonal antibodies and suspension array technology. The Endopep-SIA showed high reproducibility with intra- and inter-assay variabilities between 7 and 22%, it demonstrated a sensitivity two- to twenty-fold higher than the MBA for BoNT in buffer samples and was equally sensitive for human serum samples with a limit of detection of 0.4 MLD/mL for BoNT/A and 1.0 MLD/mL for BoNT/B. Importantly, it reliably detected all six BoNT/A and six BoNT/B subtypes tested, including clinically relevant and bivalent strains, hereby proving high diagnostic safety. Based on the results obtained, we expect the Endopep-SIA to be instrumental in markedly reducing the number of animals used in botulism diagnostics.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Making safety decisions for a sunscreen active ingredient using next-generation risk assessment: Benzophenone-4 case study. 使用新一代风险评估对防晒活性成分进行安全决策：二苯甲酮-4案例研究。

ALTEX Pub Date : 2025-05-19 DOI: 10.14573/altex.2501201

Maria T Baltazar, Sophie Cable, Richard Cubberley, Nicola J Hewitt, Jade Houghton, Predrag Kukic, Hequn Li, Sophie Malcomber, Beate Nicol, Ruth Pendlington, Ans Punt, Joe Reynolds, Sharon Scott, Sandrine Spriggs, Matthew P Dent

{"title":"Making safety decisions for a sunscreen active ingredient using next-generation risk assessment: Benzophenone-4 case study.","authors":"Maria T Baltazar, Sophie Cable, Richard Cubberley, Nicola J Hewitt, Jade Houghton, Predrag Kukic, Hequn Li, Sophie Malcomber, Beate Nicol, Ruth Pendlington, Ans Punt, Joe Reynolds, Sharon Scott, Sandrine Spriggs, Matthew P Dent","doi":"10.14573/altex.2501201","DOIUrl":"https://doi.org/10.14573/altex.2501201","url":null,"abstract":"A next generation risk assessment was carried out to evaluate the safety of benzophenone-4 (BP-4), a UV filter present at 5% in a body lotion, to compare a non-animal approach with a traditional safety assessment based on historical animal data. Exposure characterization indicated that BP-4 is poorly absorbed through the skin, poorly metabolized by the liver, a substrate of influx and efflux transporters, and excreted by the kidney. The resulting physiologically-based kinetic model predicted an upper bound (95th percentile) plasma Cmax of 1.27 µM, and liver and kidney concentrations of 0.32 µM and 0.44 µM, respectively. To characterize bioactivity, in silico and in vitro new approach methodologies were used. Points of departure (PoDs) were derived from four bioactivity platforms, including in vitro pharmacological profiling, CALUX assays, high-throughput transcriptomics, and a cell stress panel. By dividing the in vitro PoDs (PoDNAM) from these assays by the 95th percentile plasma Cmax value, so-called bioactivity:exposure ratios (BERs) were calculated. The lowest PoD was from a single gene expression change, and the highest PoD from phenotypic biomarkers using a primary renal cell model. Most BERs were above 11, except for those from gene-level PoDNAM in HepG2 and MCF-7 cells, which were 3.3 and 4.3. These lowest PoDNAMs are linked to gene transcription changes and are likely indicative of adaptive biological activity rather than adverse health effects. This work demonstrates the usefulness of next generation risk assessment in addressing pressing relevant regulatory questions without using animals.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Moving towards making (quantitative) structure-activity relationships ((Q)SARs) for toxicity-related endpoints findable, accessible, interoperable and reusable (FAIR). 朝着建立（定量的）结构-活性关系（(Q) sar）的方向发展，使毒性相关端点可找到、可访问、可互操作和可重用（FAIR）。

ALTEX Pub Date : 2025-05-19 DOI: 10.14573/altex.2411161

Samuel J Belfield, Homa Basiri, Swapnil Chavan, Georgios Chrysochoou, Steven J Enoch, James W Firman, Anish Gomatam, Barry Hardy, Palle S Helmke, Judith C Madden, Uko Maran, Eric March-Vila, Nikolai G Nikolov, Manuel Pastor, Geven Piir, Sulev Sild, Aljoša Smajić, Nicoleta Spînu, Eva B Wedebye, Mark T D Cronin

{"title":"Moving towards making (quantitative) structure-activity relationships ((Q)SARs) for toxicity-related endpoints findable, accessible, interoperable and reusable (FAIR).","authors":"Samuel J Belfield, Homa Basiri, Swapnil Chavan, Georgios Chrysochoou, Steven J Enoch, James W Firman, Anish Gomatam, Barry Hardy, Palle S Helmke, Judith C Madden, Uko Maran, Eric March-Vila, Nikolai G Nikolov, Manuel Pastor, Geven Piir, Sulev Sild, Aljoša Smajić, Nicoleta Spînu, Eva B Wedebye, Mark T D Cronin","doi":"10.14573/altex.2411161","DOIUrl":"https://doi.org/10.14573/altex.2411161","url":null,"abstract":"(Quantitative) structure-activity relationships ((Q)SARs) are widely used in chemical safety assessment to predict toxicological effects. Many thousands of (Q)SAR models have been developed and published, however, few are easily available to use. This investigation has applied previously developed Findability, Accessibility, Interoperability, and Reuse (FAIR) Principles for in silico models to six published, different, machine learning (ML) (Q)SARs for the same toxicity dataset (inhibition of growth to Tetrahymena pyriformis). The majority of principles were met, however, there are still gaps in making (Q)SARs FAIR. This study has enabled insights into, and recommendations for, the FAIRification of (Q)SARs including areas where more work and effort may be required. For instance, there is still a need for (Q)SARs to be associated with a unique identifier and full data / metadata for toxicological activity or endpoints, molecular properties and descriptors, as well as model description to be provided in a standardised manner. A number of solutions to the challenges were identified, such as building on the QSAR Model Reporting Format (QMRF) and the application of QSAR Assessment Framework (QAF). This study also demonstrated that resources such as the QSAR Databank (QsarDB, www.qsardb.org) are valuable in storing ML QSARs in a searchable database and also provide a Digital Object Identifier (DOI). Many activities related to FAIR are currently underway and (Q)SAR modellers should be encouraged to utilise these to move towards the easier access and use of models. Enabling FAIR computational toxicology models will support the overall progress towards animal free chemical safety assessment.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144130012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

How evidence-based methodologies can help identify and reduce uncertainty in chemical risk assessment. 基于证据的方法如何帮助识别和减少化学品风险评估中的不确定性。

IF 5.6

ALTEX Pub Date : 2022-01-01 Epub Date: 2022-01-31 DOI: 10.14573/altex.2201131

Sebastian Hoffmann, Paul Whaley, Katya Tsaioun

{"title":"How evidence-based methodologies can help identify and reduce uncertainty in chemical risk assessment.","authors":"Sebastian Hoffmann, Paul Whaley, Katya Tsaioun","doi":"10.14573/altex.2201131","DOIUrl":"https://doi.org/10.14573/altex.2201131","url":null,"abstract":"Evidence-based methodology, in particular systematic review, is increasingly being applied in environmental, public, and occupational health to increase the transparency, comprehensiveness, and objectivity of the processes by which existing evidence is gathered, assessed, and synthesized in answering research questions. This development is also changing risk assessment practices and will impact the assessment of uncertainties in the evidence for risks to human health that are posed by exposure to chemicals. The potential of evidence-based methodology for characterizing uncertainties in risk assessment has been widely recognized, while its contribution to uncertainty reduction is yet to be fully elucidated. We therefore present some key aspects of the evidence-based approach to risk assessment, showing how they can contribute to the identification and the assessment of uncertainties. We focus on the pre-specification of an assessment methodology in a protocol, comprehensive search strategies, study selection using predefined eligibility criteria, critical appraisal of individual studies, and an evidence integration and uncertainty characterization process based on certainty of evidence frameworks that are well-established in health care research. We also provide examples of uncertainty in risk assessment and discuss how evidence-based methodology could address those. This perspective, which neither claims to be comprehensive nor complete, is intended to stimulate discussion of the topic and to motivate detailed exploration of how evidence-based methodology contributes to characterization of uncertainties, and how it will lead to uncertainty reduction in the conduct of health risk assessment.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"175-182"},"PeriodicalIF":5.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39573216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Potential of concentration-response data to broaden regulatory application of in vitro test guidelines. 浓度反应数据在扩大体外测试准则监管应用方面的潜力。

IF 5.6

ALTEX Pub Date : 2022-01-01 Epub Date: 2021-12-09 DOI: 10.14573/altex.2107091

Miriam N Jacobs, Janine Ezendam, Betty Hakkert, Michael Oelgeschlaeger

{"title":"Potential of concentration-response data to broaden regulatory application of in vitro test guidelines.","authors":"Miriam N Jacobs, Janine Ezendam, Betty Hakkert, Michael Oelgeschlaeger","doi":"10.14573/altex.2107091","DOIUrl":"https://doi.org/10.14573/altex.2107091","url":null,"abstract":"International chemical regulatory activities are moving towards new approach methodology and away from traditional animal-based models, shifting and expanding from one single in vivo assay towards combined use of different in vitro assays within integrated approaches for testing and assessment and defined approaches to serve hazard identification, classification and selection of points of departure for risk assessment. Whilst many in vitro test guidelines were developed against specific hazard cut-off values, quantitative information is needed in data interpretation procedures for potency assessment purposes or to define points of departure so that assays can fulfill evolving regulatory needs. Utilizing four examples from skin sensitization, phototoxicity, endocrine activity, and non-genotoxic carcinogenicity, we illustrate why a shift in data generation and data interpretation procedures is needed to facilitate the full exploitation of the data that is generated using these assays. This requires the development of a practical approach that uses or expands upon existing guidance. Experience gained with such an approach can then provide a basis for an overarching strategy in test guideline development that should better facilitate combinations of in vitro test guidelines for specific endpoints that will be more transparent, robust, and adaptable for specific regulatory purposes.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"315–321"},"PeriodicalIF":5.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39582577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

On the usefulness of animals as a model system (part II): Considering benefits within distinct use domains. 关于动物作为模型系统的有用性(第二部分):在不同的使用领域内考虑利益。

IF 5.6

ALTEX Pub Date : 2022-01-01 DOI: 10.14573/altex.2207111

Giorgia Pallocca, Marcel Leist

{"title":"On the usefulness of animals as a model system (part II): Considering benefits within distinct use domains.","authors":"Giorgia Pallocca, Marcel Leist","doi":"10.14573/altex.2207111","DOIUrl":"https://doi.org/10.14573/altex.2207111","url":null,"abstract":"In many countries, animal experiments can only be performed when their necessity has been demonstrated in a legal document. As the usefulness of animals in research is also a significant societal and political issue, criteria to structure debates and evaluations are needed. Here, background information is given on laboratory animal studies. Moreover, parameters that may be considered in judging their usefulness are suggested. The discussion is strictly focused on animals used as tools/test systems/models to provide information on humans. In this context, general features and performance characteristics of models are discussed. Examples are given for well-recognized criteria (e.g., robustness, relevance, predictivity) to judge the usefulness of predictive models. The main hypothesis put forward here is that a benefits evaluation (usefulness metrics) is only possible within sharply circumscribed \"use domains\". Examples are given for the research fields of drug and vaccine research, toxicology, disease pathogenesis, and basic biological research. Efficacy, safety, and quality studies are highlighted as \"use domains\" within the field of drug discovery and production. A further separation into individual diseases, drug targets or symptoms is suggested for, e.g., efficacy studies or pathophysiology. Finally, an outlook is given on the evaluation of model advantages and disadvantages to arrive at their \"net benefit\". Moreover, the need to compare the net benefits of animal models versus that of their alternatives is highlighted.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"531-539"},"PeriodicalIF":5.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40628999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7