Regulatory Toxicology and Pharmacology最新文献

{"title":"The dangerous precedent of silencing government science.","authors":"Martin van den Berg","doi":"10.1016/j.yrtph.2025.105927","DOIUrl":"10.1016/j.yrtph.2025.105927","url":null,"abstract":"","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105927"},"PeriodicalIF":3.5,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817412","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}

{"title":"Matched molecular pairs-driven read-across for the prediction of genotoxicity of plant protection product residues","authors":"S.J. Enoch ,&nbsp;Z. Hasarova ,&nbsp;M.T.D. Cronin ,&nbsp;K. Bridgwood ,&nbsp;S. Rao ,&nbsp;A. Hueser ,&nbsp;F.M. Kluxen ,&nbsp;M. Frericks","doi":"10.1016/j.yrtph.2025.105915","DOIUrl":"10.1016/j.yrtph.2025.105915","url":null,"abstract":"<div><div>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, a matched molecular pairs approach has been developed and applied to datasests of sulphonylurea herbicides, strobilurins fungicides and α-chloroacetamide herbicides for which either Ames, chromosomal aberration or micronucleus test results are publicly available. The approach is exemplified with four case studies illustrating how matched molecular pairs analysis can be used to identify analogues that cover the structural domain of the chemical for which a data-gap exists. The method is a robust and reproducible approach to such read-across predictions, with the potential to reduce unnecessary testing.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"163 ","pages":"Article 105915"},"PeriodicalIF":3.5,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144767079","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}

{"title":"Corrigendum to \"Acute and 28-days repeated dose sub-acute toxicity study of gallic acid in albino mice\" [Regulat. Toxicol. Pharmacol. RTP 101 (2019) 71-78].","authors":"Bhavesh C Variya, Anita K Bakrania, Prem Madan, Snehal S Patel","doi":"10.1016/j.yrtph.2025.105917","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105917","url":null,"abstract":"","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105917"},"PeriodicalIF":3.5,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776056","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}

{"title":"Estimates of skin and blood concentrations of UV-filters: Insights from in vitro skin experiments","authors":"Hélène P. De Luca ,&nbsp;Stéphanie Boudon ,&nbsp;Alex Odermatt ,&nbsp;Linda Schenk ,&nbsp;Nancy B. Hopf","doi":"10.1016/j.yrtph.2025.105916","DOIUrl":"10.1016/j.yrtph.2025.105916","url":null,"abstract":"<div><div>Organic ultraviolet (UV) filters mitigate radiation transmission through the skin; however, uncertainties persist regarding their ability to cross the skin barrier and induce toxicity. Our aim was to use published <em>in vitro</em> skin permeation studies to predict UV-filter concentrations in blood and skin. In our review, we identified 35 papers reporting <em>in vitro</em> skin permeation of the 12 most used organic UV-filters. We estimated the UV-filters’ theoretical concentrations in blood and skin layers for two case scenarios and compared them with <em>in vivo</em> data. Five of the UV-filters penetrated skin as the parent compound, among these the highest estimated blood concentration was for benzophenone 4 (419 mg/L). These were overestimated (up to 100 times) compared to the reported <em>in vivo</em> results. Ten of the UV-filters permeated skin, among these ethylhexyl salicylate had the highest estimated skin concentration (15.99 g/cm³). Results from literature were inconsistent, likely due to different experimental <em>in vitro</em> methods. Although skin can metabolize chemicals, none of the included studies quantified potential UV-filter metabolites. We recommend future <em>in vitro</em> skin permeation studies to standardize the methods according to existing guidelines (including quantification of the metabolites) and screen UV-filters for possible skin absorption followed by a risk evaluation.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"163 ","pages":"Article 105916"},"PeriodicalIF":3.5,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144761128","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}

{"title":"A physiologically based pharmacokinetic (PBPK) model to align dosimetry of the isobutyl metabolic series in rats and humans.","authors":"Jordan N Smith, Kimberly J Tyrrell, Karl K Weitz, Willem Faber","doi":"10.1016/j.yrtph.2025.105914","DOIUrl":"10.1016/j.yrtph.2025.105914","url":null,"abstract":"<p><p>We developed a physiologically based pharmacokinetic (PBPK) model in rats and humans for the isobutyl metabolic series, which includes isobutyl acetate, isobutanol, isobutyraldehyde, and isobutyric acid. Given chemical similarities, we used a previously developed PBPK model for the propyl metabolic series as a framework to create the isobutyl PBPK model. To support model development, we measured in vitro metabolism of isobutyl acetate in rat and human blood and liver S9 fractions. Our findings indicated that humans exhibited faster isobutyl acetate hydrolysis in liver S9 fractions compared to rats, while hydrolysis rates in blood were similar between the two species. Experiments involving closed chamber exposures of rats to isobutyl acetate or isobutanol revealed higher isobutanol concentrations in blood compared to other isobutyl compounds. Using these data to parameterize the model, the PBPK model accurately simulated available time-course concentrations of isobutyl compounds in blood of rats and humans. The isobutyl PBPK model enables comparisons of internal dose metrics across various isobutyl compound exposures and species and allows for calculation of equivalent external exposures that result in the same dose metric. Regulators can employ this PBPK model to predict and align internal dose metrics of isobutyl compounds for risk assessment purposes.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105914"},"PeriodicalIF":3.5,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732945","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}

{"title":"Protective effects of Rosa canina fruit extract against kidney damage induced by CCl4","authors":"Hanaa S.S. Gazwi ,&nbsp;Amany E. Ragab ,&nbsp;Osama I.A. Soltan ,&nbsp;Mohamed A. Abdein ,&nbsp;Bushra Shakoor ,&nbsp;Nusrat Shafiq ,&nbsp;Inas Hussein Refaat ,&nbsp;Salim S. Al-Rejaie ,&nbsp;Sinisa Djurasevic ,&nbsp;Mohamed Mohany ,&nbsp;Asmaa H. Zaki","doi":"10.1016/j.yrtph.2025.105913","DOIUrl":"10.1016/j.yrtph.2025.105913","url":null,"abstract":"<div><div>The study explored the nephroprotective potential of <em>Rosa canina</em> (dog rose) ethanolic fruit extract against carbon tetrachloride (CCl4)-induced nephrotoxicity in rats, while also analyzing its phytochemical composition using UPLC-ESI-MS/MS. Male Wistar rats were allocated into five groups: control, <em>R. canina</em> extract alone, CCl4-induced nephrotoxicity, CCl4 with <em>R. canina</em> extract and CCl4 with silymarin. UPLC-ESI-MS/MS revealed 15 compounds in <em>R. canina</em> extract, predominantly anthocyanins, flavonoids, and lycopene. Treatment with <em>R. canina</em> extract significantly ameliorated CCl4-induced kidney dysfunction, abating oxidative stress and inflammation. Enhanced expression of HO-1 (heme oxygenase-1) and Nrf2 (nuclear factor erythroid 2-related factor 2) mRNA in the kidney suggested their involvement in protective mechanisms. Inhibition of HO-1 attenuated <em>R. canina's</em> protective effect against CCl4-induced kidney injury, underscoring the significance of the Nrf2/HO-1 pathway. For further validation, high throughput molecular docking analysis were performed. The docking analysis revealed the interaction between HO-1 and Nrf2 against Pelarginidin, Malvidin and Petunidin. Among all the three compounds, pelargonidin showed the highest binding score of −9.3 kcal/mol and −7.7 kcal/mol against Nrf2 and HO-1 respectively. In conclusion, <em>R. canina</em> extract, rich in phenolics, exhibited nephroprotective effects via inflammation and oxidative stress attenuation, potentially mediated through Nrf2/HO-1 pathway modulation against CCl4-induced nephrotoxicity.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105913"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675561","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}

{"title":"Strategies to reduce the use of non-human primates in the development of oncology therapeutics: CD3-bispecifics","authors":"Smitha PS Pillai ,&nbsp;Kaushik Datta ,&nbsp;Petra Lutterbuese ,&nbsp;Smita Salian-Mehta ,&nbsp;Weimin Chen ,&nbsp;Richard Stebbings ,&nbsp;Binu Philip ,&nbsp;Caren M. Villano","doi":"10.1016/j.yrtph.2025.105910","DOIUrl":"10.1016/j.yrtph.2025.105910","url":null,"abstract":"<div><div>Pharmaceutical companies, which are IQ DruSafe/3R-TPS members, explored novel ways to reduce reliance on non-human primate (NHP) use in nonclinical drug development. These companies conducted a survey on NHP use in toxicology studies during discovery and development of CD3-bispecific antibodies (BsAbs) for the treatment of cancer. The objectives of the survey were to collect data on and case study examples of both first-in-human (FIH)-enabling (≤1-month) and Phase II/III-enabling (3-month) NHP studies conducted with CD3-BsAbs. The survey addressed study design elements, e.g. number of dose groups, number of animals/dose group, recovery arms, etc. when a study is deemed warranted. Survey questions also focused on whether data from Phase II/III-enabling studies addressed patient risk that was not identified in FIH-enabling studies, and whether Phase II/III-enabling studies impacted regulatory decisions pertaining to clinical development. The survey findings enabled the development of a Weight of Evidence (WoE) approach to assess the utility of Phase II/III-enabling toxicity studies in understanding potential safety risks with CD3-BsAbs and informing later-stage molecule development. Both study design optimization and WoE approaches offer a path for reduced NHP use without compromising nonclinical safety assessment of CD3-BsAbs for oncology indications, as illustrated by several case examples.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"163 ","pages":"Article 105910"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675562","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}

{"title":"Insights into sanguinarine toxicity in Rats: Integrating toxicokinetics, oxidative stress, and gut microbial alterations","authors":"Yufeng Xu ,&nbsp;Zhiqin Liu ,&nbsp;Wenqing Sun ,&nbsp;Lin Wang ,&nbsp;Zihui Yang ,&nbsp;Zhen Dong ,&nbsp;Jianguo Zeng","doi":"10.1016/j.yrtph.2025.105911","DOIUrl":"10.1016/j.yrtph.2025.105911","url":null,"abstract":"<div><div>Sanguinarine (SAN), a bioactive benzophenanthridine alkaloid derived from <em>Macleaya cordata</em>, has gained attention as a plant-based pesticide and veterinary therapeutic. However, its toxicity mechanisms, particularly concerning toxicokinetics (TK) and gut microbiota interactions, remain poorly understood. This research assessed the acute and subacute toxicity, toxicokinetics, oxidative stress reactions, and changes in gut microbiota associated with SAN in Sprague-Dawley rats. A single oral dose by gavage resulted in a LD₅₀ of 1000 mg/kg·bw (male) and 926 mg/kg·bw (female), classifying SAN under GHS Category 4. Subacute exposure (14 days at 1/10, 1/50, and 1/100 LD₅₀) induced multi-organ damage, including pulmonary haemorrhage, hepatic steatosis, and renal tubular necrosis, with females exhibiting relatively higher sensitivity. Surviving rats recovered from toxic damage during the 14-day recovery period. Toxicokinetic analysis demonstrated dose-dependent plasma concentration curves, nonlinear elimination kinetics, and tissue accumulation in the liver and kidneys. Assays measuring oxidative stress showed unexpected rises in overall antioxidant capacity alongside marked inhibition of glutathione peroxidase, indicating targeted redox disruption. Gut microbiota sequencing identified dose-dependent dysbiosis: high-dose SAN reduced Firmicutes/Bacteroidetes ratios, depleted Lactobacillus, and enriched opportunistic pathogens (Klebsiella, Streptococcus), alongside altered short-chain fatty acid (SCFA) profiles. These findings underscore SAN's potential to induce systemic toxicity through oxidative stress, metabolic disruption, and gut microbiome-mediated inflammation. The LOEAL observed in this study for subacute exposure (14 days) to SAN was 10 mg/kg and the safe use of SAN should be emphasized.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105911"},"PeriodicalIF":3.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656112","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}

{"title":"Platform-based opportunities to streamline animal use in support of the 3Rs – recommendations from an antibody-drug conjugate analysis","authors":"Christina L. Zuch de Zafra ,&nbsp;Christopher M. Carosino","doi":"10.1016/j.yrtph.2025.105912","DOIUrl":"10.1016/j.yrtph.2025.105912","url":null,"abstract":"<div><div>The field of antibody drug conjugates (ADCs) continues to be an active area of development which has greatly evolved over the past 25 years since the first approved ADC in 2000 (Mylotarg). Simultaneously, increasing attention is being given to the use of animals, particularly large animal species, in biopharmaceutical drug development in the wake of the global COVID-19 pandemic and legislation implemented/pending in the US Congress (the FDA Modernization Act). A recent publication summarizing data from an analysis of 14 antibody-drug conjugates (ADCs) provides a springboard for the recommendation of best practices to streamline nonclinical toxicology evaluation for these molecules. Additionally, key principles from the ADC molecule class may be applied to other biologic platforms, such as CD3 bispecific antibodies and possibly cell and gene therapy. Widespread adoption of modernized program strategies should lead both to a reduction in the use of animals in nonclinical toxicology evaluation and to more rapid delivery of new medicines to patients with unmet medical needs.</div><div>The primary goal of nonclinical toxicology evaluation in the pharmaceutical industry is the identification of hazards and characterization of their monitorability, manageability, and reversibility in support of clinical trials and the eventual marketing of new drugs. An additional key deliverable of a toxicology program is the determination of appropriate dose levels to be evaluated in clinical trials. To accomplish these goals, nonclinical toxicology studies have traditionally utilized animal models in keeping with recommendations of global health authorities (e.g., ICH M3 for small molecule drugs and ICH S6 for biologic drugs). Although the 3Rs of ethical animal use (reduce, refine, replace) have been recognized since the late 1950s (Russell and Burch, 1959), increasing attention is being given to the use of animals in pharmaceutical research. The COVID-19 pandemic and accompanying ban on the export of non-human primates (NHPs) from China highlighted the dependence of nonclinical safety evaluation on NHPs, particularly for biologics and other modalities that have limited cross-reactivity. This realization contributed to the passage of the FDA Modernization Act 2.0 and the drafting of additional legislation (FDA Modernization Act 3.0) and the recent ‘Roadmap to Reducing Animal Testing in Preclinical Safety Studies’ which codify support in the US for the refinement of nonclinical toxicology programs and signal an opportunity for decreased reliance on animal models for safety evaluation. Similarly, the European Federation of Pharmaceutical Industries and Associations (EFPIA) recently released ‘EFPIA Recommendations on Phasing Out Animal Testing for Chemical Safety Assessments’ with comparable assessments and recommendations aimed at the evolution of pharmaceutical toxicity testing away from animal studies.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105912"},"PeriodicalIF":3.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668140","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}

{"title":"Radon activity levels in beverages and drinking water in Jazan, Saudi Arabia: a health risk assessment","authors":"Entesar H. EL-Araby","doi":"10.1016/j.yrtph.2025.105909","DOIUrl":"10.1016/j.yrtph.2025.105909","url":null,"abstract":"<div><div>This study investigated radon concentrations in water and soft drinks from the Jazan region of Saudi Arabia using a CR39 detector. Sample analysis revealed radon concentrations ranging from 1.65 to 5.70 Bq/L in drinking water and 1.60–3.78 Bq/L in soft drinks, likely influenced by industrial processing. All measured values were below international safety thresholds, including USEPA limit 11.1 Bq/L and WHO guideline 100 Bq/L. Annual effective doses (AEDs) were calculated for ingestion and inhalation. Ingestion posed the greatest risk: 24.08 μSv/yr (water) and 20.32 μSv/yr (soft drinks). Inhalation doses were lower: 8.31 μSv/yr and 7.01 μSv/yr, respectively, and remained within the WHO and ICRP limits (100 μSv/yr). Ingestion doses slightly exceeded the reference value of the Scientific Committee on the Effects of Atomic Radiation (10 μSv/yr). The results highlight that ingestion is the main route of exposure and underscore the need for continuous monitoring and quality control. This is the first comprehensive assessment of radon in beverages from Jazan and provides vital baseline data for health policy and risk assessment in Saudi Arabia.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105909"},"PeriodicalIF":3.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656113","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}