Regulatory Toxicology and Pharmacology最新文献_第10页

Deriving acceptable limits for non-mutagenic impurities in medicinal products – Durational adjustments 得出药用产品中非致突变杂质的可接受限值 - 持续时间调整

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-05-16 DOI: 10.1016/j.yrtph.2024.105644

Michelle O. Kenyon , Matthew Martin , Elizabeth A. Martin , Susanne Brandstetter , Teresa Wegesser , Nigel Greene , James Harvey

{"title":"Deriving acceptable limits for non-mutagenic impurities in medicinal products – Durational adjustments","authors":"Michelle O. Kenyon , Matthew Martin , Elizabeth A. Martin , Susanne Brandstetter , Teresa Wegesser , Nigel Greene , James Harvey","doi":"10.1016/j.yrtph.2024.105644","DOIUrl":"10.1016/j.yrtph.2024.105644","url":null,"abstract":"<div><p>ICH Q3A/B guidelines are not intended for application during the clinical research phase of development and durationally adjusted qualification thresholds are not included. A central tenet of ICH Q3A is that lifetime exposure to 1 mg/day of an unqualified non-mutagenic impurity (NMI) is not a safety concern. An analysis of in vivo toxicology data from 4878 unique chemicals with established NO(A)ELs was conducted to determine whether durationally adjusted qualification limits can be supported. Although not recommended in ICH Q3A/B, a conservative approach was taken by using allometric scaling in the analysis. Following allometric scaling of the 5th percentile of the distribution of NO(A)ELs from available chronic toxicology studies, it was reconfirmed that there is a safety basis for the 1 mg/day qualification threshold in ICH Q3A. Additionally, allometric scaling of the 5th percentile of the distribution of NO(A)ELs from sub-acute and sub-chronic toxicology studies could support acceptable limits of 20 and 5 mg/day for an unqualified <span>NMI</span> for dosing durations of less than or greater than one month, respectively. This analysis supports durationally adjusted <span>NMI</span> qualification thresholds for pharmaceuticals that protect patient safety and contribute to 3Rs efforts for qualifying impurities using new approach methods.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"150 ","pages":"Article 105644"},"PeriodicalIF":3.4,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141033618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A weight of evidence evaluation of the mode of action of isoeugenol 异丁香酚作用模式的证据权重评估。

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-05-11 DOI: 10.1016/j.yrtph.2024.105642

William J. Brock , Tracy Greene , Cynthia Van Landingham , Robinan Gentry

{"title":"A weight of evidence evaluation of the mode of action of isoeugenol","authors":"William J. Brock , Tracy Greene , Cynthia Van Landingham , Robinan Gentry","doi":"10.1016/j.yrtph.2024.105642","DOIUrl":"10.1016/j.yrtph.2024.105642","url":null,"abstract":"<div><p>Isoeugenol is one of several phenylpropenoid compounds that is used as a fragrance, food flavoring agent and in aquaculture as a fish anesthetic. Carcinogenicity testing in rats and mice by NTP resulted in clear evidence of carcinogenicity (hepatic adenomas/carcinomas) in male mice only. A nongenotoxic threshold mode of action (MOA) is postulated for isoeugenol and is discussed considering the IPCS MOA and Human Relevance Framework. The weight of evidence indicates that isoeugenol is not genotoxic and that the carcinogenic outcome in male mice relates directly to the metabolism of individual compounds. Benchmark Dose (BMD) modeling was conducted to determine a Point of Departure (POD) and potential threshold of carcinogenicity. The results of the BMD evaluation for isoeugenol resulted in an estimated POD for carcinogenicity in the male mouse of 8 mg/kg with a lower limit of 4 mg/kg, representing a POD for the determination of an acceptable daily intake. With application of uncertainty factors, an ADI of 40 μg/kg is calculated. This daily dose in humans would be protective of human health, including carcinogenicity. A corresponding maximum residual level (MRL) of 3200 μg/kg fish is also estimated based on this POD that considers the threshold MOA.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"150 ","pages":"Article 105642"},"PeriodicalIF":3.4,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140912550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proposals for new spray drift exposure values in orchards and vineyards for residents and bystanders 关于果园和葡萄园中居民和旁观者新的喷雾漂移暴露值的建议。

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-05-07 DOI: 10.1016/j.yrtph.2024.105643

Udo Blaschke , Edgars Felkers , Nicola J. Hewitt , Felix M. Kluxen , Neil Morgan , Christiane Wiemann

{"title":"Proposals for new spray drift exposure values in orchards and vineyards for residents and bystanders","authors":"Udo Blaschke , Edgars Felkers , Nicola J. Hewitt , Felix M. Kluxen , Neil Morgan , Christiane Wiemann","doi":"10.1016/j.yrtph.2024.105643","DOIUrl":"10.1016/j.yrtph.2024.105643","url":null,"abstract":"<div><p>In the EU, predicted exposure to spray drift for residents and bystanders from applications in orchards and vineyards is based on data from one study published in 1987, where one downwind distance (8 m) was considered. CropLife Europe conducted sixteen new GLP compliant studies in 4 EU countries, 8 in orchards, 8 in vineyards with early and late season applications, using adult and child mannequins located 5, 10 and 15 m downwind from the last row to measure dermal and inhalation exposures. The resulting “Bystander Resident Orchard Vineyard (BROV)” database comprises 288 observations and offers a more comprehensive option for exposure prediction.</p><p>There were differences between adult and child, crop type, leaf cover and distance from the sprayer, supporting the derivation of mean, median, 75th and 95th percentile exposures for each subset. Exposures did not generally correlate with wind speed, wind direction, sprayer type, spray quality, spray concentration or amount applied. Dermal and inhalation exposure were lower in vineyards than in orchards and further analysis is required to understand why.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"150 ","pages":"Article 105643"},"PeriodicalIF":3.4,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0273230024000849/pdfft?md5=78c8f51953872000dd567a71c47b9e01&pid=1-s2.0-S0273230024000849-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140899458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolism-based category formation for the prioritisation of genotoxicity hazard assessment for plant protection product residues (Part 4): α-Chloroacetamides 基于代谢的类别划分，确定植物保护产品残留物遗传毒性危害评估的优先次序（第 4 部分）：α-氯乙酰胺。

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-05-07 DOI: 10.1016/j.yrtph.2024.105641

S.J. Enoch , Z. Hasarova , M.T.D. Cronin , K. Bridgwood , S. Rao , F.M. Kluxen , M. Frericks

{"title":"Metabolism-based category formation for the prioritisation of genotoxicity hazard assessment for plant protection product residues (Part 4): α-Chloroacetamides","authors":"S.J. Enoch , Z. Hasarova , M.T.D. Cronin , K. Bridgwood , S. Rao , F.M. Kluxen , M. Frericks","doi":"10.1016/j.yrtph.2024.105641","DOIUrl":"10.1016/j.yrtph.2024.105641","url":null,"abstract":"<div><p>In dietary risk assessment of plant protection products, residues of active ingredients and their metabolites need to be evaluated for their genotoxic potential. The European Food Safety Authority recommend a tiered approach focussing assessment and testing on classes of similar chemicals. To characterise similarity, in terms of metabolism, a metabolic similarity profiling scheme has been developed from an analysis of 69 α-chloroacetamide herbicides for which either Ames, chromosomal aberration or micronucleus test results are publicly available. A set of structural space alerts were defined, each linked to a key metabolic transformation present in the α-chloroacetamide metabolic space. The structural space alerts were combined with covalent chemistry profiling to develop categories suitable for chemical prioritisation via read-across. The method is a robust and reproducible approach to such read-across predictions, with the potential to reduce unnecessary testing. The key challenge in the approach was identified as being the need for metabolism data individual groups of plant protection products as the basis for the development of the structural space alerts.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"150 ","pages":"Article 105641"},"PeriodicalIF":3.4,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0273230024000825/pdfft?md5=3d91cdafb99854bfe906dd23a7d048cd&pid=1-s2.0-S0273230024000825-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140899411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Points to consider regarding the use and implementation of virtual controls in nonclinical general toxicology studies 在非临床普通毒理学研究中使用和实施虚拟对照的注意事项

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-04-27 DOI: 10.1016/j.yrtph.2024.105632

Xavier Palazzi , Lennart T. Anger , Theresa Boulineau , Armelle Grevot , Magali Guffroy , Kristin Henson , Natalie Hoepp , Matt Jacobsen , Vijay P. Kale , John Kreeger , Joan H. Lane , Dingzhou Li , Wolfgang Muster , Brianna Paisley , Lila Ramaiah , Nicola Robertson , Valerie Shultz , Thomas Steger Hartmann , Richard Westhouse

引用次数: 0

In silico evaluation of the potential allergenicity of a fungal biomass from Rhizomucor pusillus for use as a novel food ingredient 对用作新型食品配料的根瘤藻真菌生物质的潜在过敏性进行硅学评估

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-04-22 DOI: 10.1016/j.yrtph.2024.105629

Kevin Scaife , Steve L. Taylor , Lucie Pařenicová , Richard E. Goodman , Trung D. Vo , Elisa Leune , Mohamed Abdelmoteleb , Yvonne Dommels

{"title":"In silico evaluation of the potential allergenicity of a fungal biomass from Rhizomucor pusillus for use as a novel food ingredient","authors":"Kevin Scaife , Steve L. Taylor , Lucie Pařenicová , Richard E. Goodman , Trung D. Vo , Elisa Leune , Mohamed Abdelmoteleb , Yvonne Dommels","doi":"10.1016/j.yrtph.2024.105629","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105629","url":null,"abstract":"<div><p>The world’s hunger for novel food ingredients drives the development of safe, sustainable, and nutritious novel food products. For foods containing novel proteins, potential allergenicity of the proteins is a key safety consideration. One such product is a fungal biomass obtained from the fermentation of <em>Rhizomucor pusillus</em>. The annotated whole genome sequence of this strain was subjected to sequence homology searches against the AllergenOnline database (sliding 80–amino acid windows and full sequence searches). In a stepwise manner, proteins were designated as potentially allergenic and were further compared to proteins from commonly consumed foods and from humans. From the sliding 80-mer searches, 356 proteins met the conservative >35% Codex Alimentarius threshold, 72 of which shared ≥50% identity over the full sequence. Although matches were identified between <em>R. pusillus</em> proteins and proteins from allergenic food sources, the matches were limited to minor allergens from these sources, and they shared a greater degree of sequence homology with those from commonly consumed foods and human proteins. Based on the in silico analysis and a literature review for the source organism, the risk of allergenic cross-reactivity of <em>R. pusillus</em> is low.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"150 ","pages":"Article 105629"},"PeriodicalIF":3.4,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140645295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A roadmap towards a human-centric safety assessment of advanced therapy medicinal products 以人为本的先进治疗药物安全性评估路线图

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-04-20 DOI: 10.1016/j.yrtph.2024.105631

Hsiao-Tzu Chien , Victoria C. de Leeuw , Joantine C.J. van Esterik , Frans G.M. Russel , Anne S. Kienhuis , Peter T. Theunissen , Peter van Meer

{"title":"A roadmap towards a human-centric safety assessment of advanced therapy medicinal products","authors":"Hsiao-Tzu Chien , Victoria C. de Leeuw , Joantine C.J. van Esterik , Frans G.M. Russel , Anne S. Kienhuis , Peter T. Theunissen , Peter van Meer","doi":"10.1016/j.yrtph.2024.105631","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105631","url":null,"abstract":"<div><p>Advanced therapy medicinal products (ATMPs) are among the most complex pharmaceuticals with high human specificity. Species differences severely limit the clinical relevance of <em>in vivo</em> data. We conducted interviews with stakeholders involved in ATMP development about their perspective on the use of <em>in vivo</em> studies, the perceived hurdles and associated potential solutions regarding non-clinical development of ATMPs. In total, 17 stakeholders from 9 different countries were interviewed. A workshop was held with key stakeholders to further discuss major topics identified from the interviews. Conducting <em>in vivo</em> studies remains the status quo for ATMPs development. The hurdles identified included determining the amount of information required before clinical entry and effective use of limited human samples to understand a treatment or for clinical monitoring. A number of key points defined the need for future <em>in vivo</em> studies as well as improved application and implementation of New Approach Methodology (NAM)-based approach for products within a well-known modality or technology platform. These included data transparency, understanding of the added value of <em>in vivo</em> studies, and continuous advancement, evaluation, and qualification of NAMs. Based on the outcome of the discussions, a roadmap with practical steps towards a human-centric safety assessment of ATMPs was established.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"150 ","pages":"Article 105631"},"PeriodicalIF":3.4,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0273230024000722/pdfft?md5=6cf26190c59ba73b29910e21c17fc152&pid=1-s2.0-S0273230024000722-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140646689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Challenges and gaps in immunosafety evaluation of therapeutics: An IQ DruSafe survey 治疗药物免疫安全评估方面的挑战和差距：IQ DruSafe调查

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-04-18 DOI: 10.1016/j.yrtph.2024.105630

Mark Collinge , Haley Neff-LaFord , Surekha Akella , Birgit Fogal , Kathryn Fraser , Jacob Jabbour , Kirsty Harper , Curtis C. Maier , Laurent Malherbe , Nikki Marshall , Gautham K. Rao , Kavita Raman , Hollie Skaggs , Felix Weber , Claudette L. Fuller

{"title":"Challenges and gaps in immunosafety evaluation of therapeutics: An IQ DruSafe survey","authors":"Mark Collinge , Haley Neff-LaFord , Surekha Akella , Birgit Fogal , Kathryn Fraser , Jacob Jabbour , Kirsty Harper , Curtis C. Maier , Laurent Malherbe , Nikki Marshall , Gautham K. Rao , Kavita Raman , Hollie Skaggs , Felix Weber , Claudette L. Fuller","doi":"10.1016/j.yrtph.2024.105630","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105630","url":null,"abstract":"<div><p>Immunotoxicology/immunosafety science is rapidly evolving, with novel modalities and immuno-oncology among the primary drivers of new tools and technologies. The Immunosafety Working Group of IQ/DruSafe sought to better understand some of the key challenges in immunosafety evaluation, gaps in the science, and current limitations in methods and data interpretation. A survey was developed to provide a baseline understanding of the needs and challenges faced in immunosafety assessments, the tools currently being applied across the industry, and the impact of feedback received from regulatory agencies. This survey also focused on current practices and challenges in conducting the T-cell-dependent antibody response (TDAR) and the cytokine release assay (CRA). Respondents indicated that ICH S8 guidance was insufficient for the current needs of the industry portfolio of immunomodulators and novel modalities and should be updated. Other challenges/gaps identified included translation of nonclinical immunosafety assessments to the clinic, and lack of relevant nonclinical species and models in some cases. Key areas of emerging science that will add future value to immunotoxicity assessments include development of additional in vitro and microphysiological system models, as well as application of humanized mouse models. Efforts are ongoing in individual companies and consortia to address some of these gaps and emerging science.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"150 ","pages":"Article 105630"},"PeriodicalIF":3.4,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140806927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biosimilars production in Africa opportunities & challenges 非洲生物仿制药生产的机遇与挑战

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-04-16 DOI: 10.1016/j.yrtph.2024.105626

Amany E. Abdel-Maged , Margrit F. Mikhaeil , Ahmed I. Elkordy , Amany M. Gad , Mohamed M. Elshazly

引用次数: 0

Ambient air concentrations of plant protection products: Data collection for the combined air concentration database and associated risk assessment 植物保护产品在环境空气中的浓度：为综合空气浓度数据库和相关风险评估收集数据

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-04-15 DOI: 10.1016/j.yrtph.2024.105627

Anne-Kim Vinck , Edgars Felkers , Michel Urtizberea , Nicola J. Hewitt , Kathrin Bürling , Alistair Morriss

{"title":"Ambient air concentrations of plant protection products: Data collection for the combined air concentration database and associated risk assessment","authors":"Anne-Kim Vinck , Edgars Felkers , Michel Urtizberea , Nicola J. Hewitt , Kathrin Bürling , Alistair Morriss","doi":"10.1016/j.yrtph.2024.105627","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105627","url":null,"abstract":"<div><p>CropLife Europe collected literature values from monitoring studies measuring air concentrations of Plant Protection Products (PPPs) that may be inhaled by humans located in rural areas but not immediately adjacent to PPP applications. The resulting “Combined Air Concentration Database” (CACD) was used to determine whether air concentrations of PPPs reported by the French “Agency for Food, Environmental and Occupational Health & Safety” (ANSES) are consistent with those measured by others to increase confidence in values of exposure to humans. The results were put into risk assessment context. Results show that 25–90% of samples do not contain measurable PPP concentrations. Measured respirable fractions were below EU default air concentrations used for risk assessment for resident exposure by the European Food Safety Authority. All measured exposures in the CACD were also below established toxicological endpoints, even when considering the highest maximum average reported concentrations and very conservative inhalation rates. The highest recorded air concentration was for prosulfocarb (0.696 μg/m³ measured over 48 h) which is below the EFSA default limit of 1 μg/m³ for low volatility substances. In conclusion, based on the CACD, measured air concentrations of PPPs are significantly lower than EFSA default limits and relevant toxicological reference values.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"149 ","pages":"Article 105627"},"PeriodicalIF":3.4,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0273230024000680/pdfft?md5=c8cef965a8eaa646cbc692971fc119a4&pid=1-s2.0-S0273230024000680-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140605684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0