Regulatory Toxicology and Pharmacology最新文献

{"title":"Chemical characterization and toxicological evaluation of acrylic-based dental implant devices used for different purposes within the scope of ISO 10993","authors":"Tuğçe Kuruca ,&nbsp;Deniz Demir ,&nbsp;Esin Akarsu ,&nbsp;Murat Akarsu","doi":"10.1016/j.yrtph.2025.105949","DOIUrl":"10.1016/j.yrtph.2025.105949","url":null,"abstract":"<div><div>Medical devices have the potential to release chemical constituents, either as residual manufacturing additives or as leachable under clinical conditions, which may pose potential toxicological risks. Therefore, comprehensive chemical characterization is crucial to identify and quantify extractable compounds that could migrate from the device during clinical use, in accordance with ISO 10993 standards.</div><div>This study provides a comprehensive chemical characterization and toxicological risk assessment of acrylic-based dental devices intended for various clinical applications. By adhering to ISO 10993–12:2021 for extraction protocols and employing both polar (water) and apolar (50:50 ethanol-water) solvents, leachable were analyzed after 72-h incubations at 50 °C. Fourier Transform Infrared Spectroscopy (FTIR) confirmed the use of polymethyl methacrylate (PMMA) in device matrices, while thermogravimetric analysis (TGA) revealed the presence of inorganic pigments.</div><div>Extractable compounds were identified by using a broad range of analytical techniques-including Gas Chromatography-Mass Spectrometry (GC-MS), High Performance Liquid Chromatography (HPLC), UV–VIS–NIR Spectrophotometry because of extractable studies, Liquid Chromatography – Tandem Mass Spectrometry (LC-MS/MS) and Inductively Coupled Plasma–Optical Emission Spectrometry (ICP-OES) techniques, detecting compounds such as phenyl benzoate, N,N-dimethyl-p-toluidine, benzoyl peroxide, ethylene glycol dimethacrylate, and benzoic acid. Toxicological risk assessments were subsequently conducted in accordance with ISO 10993–17:2023, demonstrating that all tested devices were biocompatible and posed no toxicological hazard under intended clinical conditions.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105949"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192701","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":"Safe usage levels of aqueous Hippophae rhamnoides fruit extract in cosmetics estimated by threshold of toxicological concern, point of departure, and history of safe consumption","authors":"Hyejeon Cho ,&nbsp;Ye Ji Koo ,&nbsp;Seung Ha Lee ,&nbsp;Seungjin Bae ,&nbsp;Jaeyun Choi ,&nbsp;Kyung-Min Lim","doi":"10.1016/j.yrtph.2025.105961","DOIUrl":"10.1016/j.yrtph.2025.105961","url":null,"abstract":"<div><div>Botanical ingredients pose challenges to cosmetic safety assessors due to complex and variable composition. We estimated the safe usage levels of aqueous <em>Hippophae rhamnoides</em> fruit extract (HRFE) in cosmetics using Threshold of Toxicological Concern (TTC), Point of Departure (PoD) estimation, and history of safe consumption approaches. Skin and eye irritation and genotoxicity of HRFE were excluded through <em>in vitro</em> tests, first. The safe usage level of HRFE was estimated using TTC approach through identifying 85 constituents accounting for 98.46 % of HRFE on mass basis, and calculating systemic exposure dosage levels. PoD from the rodent 90-day oral repeated-dose toxicity study and history of safe food consumption of <em>Hippophae rhamnoides</em> fruit were also utilized to derive safe usage levels of HRFE in cosmetics. Maximum safe usage levels of HRFE were estimated to be 0.125 mg/kg bw/day (extract powder), 0.5 mg/kg bw/day, and 166 mg/kg bw/day with TTC, PoD and history of safe consumption approach respectively, showing that TTC is the most conservative and history of safe consumption, the least. However, questions of material equivalence and route-difference remained for PoD and history of safe consumption. Collectively, this study may help to understand the pros and cons of current safety assessment methodologies for botanical ingredients.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105961"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280988","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":"Relationship between dietary pesticide intake and urinary excretion: a pilot study using duplicate portion analysis","authors":"Nina C. Wieland ,&nbsp;Daniel M. Figueiredo ,&nbsp;Hans Mol ,&nbsp;Neus González ,&nbsp;Nelson Abrantes ,&nbsp;Virginia Aparicio ,&nbsp;Isabel Campos ,&nbsp;Josefina Contreras ,&nbsp;Alcon Francisco ,&nbsp;Matjaž Glavan ,&nbsp;Tanja Blagus ,&nbsp;Vita Dolžan ,&nbsp;Paula Harkes ,&nbsp;Trine Nørgaard ,&nbsp;Vivi Schlünssen ,&nbsp;Igor Pasković ,&nbsp;Marija Polić Pasković ,&nbsp;Martien Graumans ,&nbsp;Ad M.J. Ragas ,&nbsp;Frans G.M. Russel ,&nbsp;Paul T.J. Scheepers","doi":"10.1016/j.yrtph.2025.105972","DOIUrl":"10.1016/j.yrtph.2025.105972","url":null,"abstract":"<div><div>Dietary uptake is estimated using residue data from food commodities and predicting the effect of food processing, such as peeling. The aim of this study was to explore the value of the analysis of duplicate portions supplemented by the analysis of urinary metabolites. Forty-three participants, consuming organic and non-organic diets collected a duplicate portion of food and beverages for 24 h. Urine was collected up to 36 h to account for metabolism and prolonged excretion of metabolites. Pesticide residues were analysed in food portions and urine samples using LC-MS/MS and GC-MS/MS. Multiple pesticide residues were detected per food portion. Out of 183 pesticides, 86 were detected in the diet. Glyphosate and AMPA were detected in 42 % and 30 % of all urine samples, respectively, while detection in the diet was low. A positive relationship between dietary intake and urinary excretion was found for 2,4-D and MCPA. No diet-urine relationship was observed for glyphosate and AMPA, indicating contribution from external routes of exposure. Hazard index (HI) indicated no exposure above the acceptable daily intake (ADI) for all participants. This study demonstrates how DPA combined with urine analysis gives insight into contribution of diet to total pesticide exposure compared to standard monitoring.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105972"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145424550","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":"Minimizing use of nonhuman primates to inform risk to fertility and of adverse pregnancy outcomes with pharmaceuticals","authors":"Christopher J. Bowman ,&nbsp;Ann Baker ,&nbsp;Diann L. Blanset ,&nbsp;Kimberly C. Brannen ,&nbsp;Gary J. Chellman ,&nbsp;Brian Enright ,&nbsp;Wendy Halpern ,&nbsp;Bethany R. Hannas ,&nbsp;Kazushige Maki ,&nbsp;Fumito Mikashima ,&nbsp;Shermaine Mitchell-Ryan ,&nbsp;Eve Mylchreest ,&nbsp;Manjunatha K. Nanjappa ,&nbsp;Helen Prior ,&nbsp;Puck Roos ,&nbsp;Dinesh Stanislaus ,&nbsp;Angela R. Stermer ,&nbsp;Jane Stewart ,&nbsp;Katie Turner ,&nbsp;Steven van Cruchten ,&nbsp;Peter Theunissen","doi":"10.1016/j.yrtph.2025.105971","DOIUrl":"10.1016/j.yrtph.2025.105971","url":null,"abstract":"<div><div>An assessment of potential developmental and reproductive toxicity (DART) is generally required to support clinical trials and marketing of pharmaceuticals. Although typically performed in rodents and rabbits, nonhuman primates (NHPs) are often used when they are the only pharmacologically relevant species. Regulatory guidances allow for weight of evidence (WoE) risk assessment for DART such that mature NHPs may not be needed to confirm expected or low risk of adverse pregnancy outcome. As such, there are numerous examples of WoE strategies to inform risk of adverse pregnancy outcome, but fewer to assess risk to male and/or female fertility, although emerging data indicate mature NHPs have limited impact on fertility risk assessment in product labels. Mature NHP data are most impactful to fill safety gaps when there are no relevant data from other species, limited information to establish WoE, and/or limited human data is available to characterize risk. In this review, we propose a detailed decision tree and examples to inform risk of adverse pregnancy outcome or male/female fertility impact by emphasizing and prioritizing WoE supplemented by experimental data where necessary, including use of NHPs as a last resort. Additional refinements to NHP use are also summarized.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105971"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145474401","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":"Beyond molecular structure: Comparing Australian and European regulatory approaches to nano-identification and classification","authors":"Sarah Wilson,&nbsp;Stephen Northey,&nbsp;Rachael Wakefield-Rann,&nbsp;Nick Florin","doi":"10.1016/j.yrtph.2025.105947","DOIUrl":"10.1016/j.yrtph.2025.105947","url":null,"abstract":"<div><div>Across regulation and toxicology, nanomaterials challenge foundational assumptions about substance identity and risk assessment. Through comparing substance identification requirements across Australian and European industrial chemical regulation – the Australian Industrial Chemicals Introduction Scheme (AICIS) and the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) respectively – this article explores how legal actors have incorporated the evolving science of nanotoxicology into the identification frameworks that establish regulatory approaches. These frameworks are important as they structure how regulators delineate between ‘new’ substances requiring novel risk assessment and regulatory approval, and ‘existing’ substances that have already been assessed.</div><div>The findings reveal REACH and AICIS have created contrasting approaches to nano-identification. REACH employs a comprehensive multifactorial method aligned with emerging nanotoxicological principles, while AICIS relies on broader structure-based CAS identifiers. These frameworks differ in both factors used and the specificity of material identification. Such regulatory data discrepancies could impact nano-risk regulation, creating potential scientific and legal vulnerabilities for managing distinct nanoforms with variable risk identities in Australia's regulatory environment. This analysis shows that the effective regulation of complex materials depends not just on accurate material characterisation, but on the structural design of legal information systems that mediate between scientific knowledge and regulatory action.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105947"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145160016","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":"Physiologically based pharmacokinetic modeling of oseltamivir in pregnant rhesus macaques to inform clinical dosing across trimesters","authors":"Darshan Mehta,&nbsp;Kiara Fairman,&nbsp;Miao Li ,&nbsp;Jeffrey Fisher ,&nbsp;Frederick A. Beland,&nbsp;Gonçalo Gamboa da Costa,&nbsp;Annie Lumen","doi":"10.1016/j.yrtph.2025.105979","DOIUrl":"10.1016/j.yrtph.2025.105979","url":null,"abstract":"<div><div>Oseltamivir phosphate is a lipophilic prodrug that is metabolized to the active form, oseltamivir carboxylate, by carboxylesterase 1 enzymes in the liver in humans and in the liver and gut in rhesus macaques. Oseltamivir carboxylate is hydrophilic and distributes extensively in extracellular fluids, including plasma, and is eliminated primarily by the kidneys through glomerular filtration and tubular secretion. Pregnant women have lower systemic exposure to oseltamivir carboxylate due to an increase in plasma volume and total body water, leading to an increased apparent volume of distribution and increased renal excretion. To evaluate the differences in oseltamivir pharmacokinetics during pregnancy, a study was conducted previously using rhesus monkeys that were administered oseltamivir phosphate via intravenous and nasogastric routes at doses of 2.5 mg/kg body weight during the three trimesters of pregnancy. In the current study, we present a physiologically based pharmacokinetic (PBPK) model to help characterize the pharmacokinetic data that were collected in the previous study and demonstrate how the model can be used to predict the pharmacokinetics of oseltamivir and oseltamivir carboxylate in pregnant women. As it can be challenging to obtain rich clinical data in pregnant women, evaluating drug pharmacokinetics in preclinical species using tools such as PBPK models can provide reliable estimates of drug disposition across species during sensitive life stages such as pregnancy. Using the PBPK modeling approach, we were able to successfully characterize a reduction in oseltamivir carboxylate exposure during pregnancy in rhesus macaques (20–25 % decrease in AUC) and satisfactorily extend the model predictions to humans by accounting for physiological changes that occur throughout the different stages of pregnancy. The rhesus macaque can thus be considered a promising animal model for extrapolating pharmacokinetic predictions during pregnancy, especially for drugs or chemicals that are metabolized by hydrolysis reactions and primarily eliminated by renal excretion.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105979"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368577","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":"2025-12-01","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":"Strengthening next generation risk decision-making: A contemporary review","authors":"Yadvinder Bhuller ,&nbsp;Raywat Deonandan ,&nbsp;Daniel Krewski","doi":"10.1016/j.yrtph.2025.105939","DOIUrl":"10.1016/j.yrtph.2025.105939","url":null,"abstract":"<div><div>Risk decision-making inherently requires consideration of fundamental principles and other factors pertinent for addressing important health and environmental risks of concern. The risk decision-making process has evolved from linear frameworks to more integrated and dynamic strategies. A recent scoping review mapped this evolution and demonstrated a transition to more holistic and complex approaches. The term next generation risk decision-making captures these contemporary strategies by incorporating all aspects of risk assessment, management, and communication involved in risk decision-making, thereby going beyond recently articulated next generation risk assessment frameworks. While this scoping review included best practices and ten attributes of risk decision-making, it did not address how to consider these factors when developing strategies for next generation risk decision-making. This contemporary review addresses this limitation by discussing the role of decision theories prior to presenting a model for characterizing, categorizing, and visualizing these ten considerations: foresight and planning, research and development, regulatory, risk, upstream and downstream attributes, risk culture, ONE Health lens, broad regulatory factors, risk management, and risk communication. The realist paradigm-based model and corresponding considerations are then analyzed using a strengths, weaknesses, opportunities, and threats analysis of top-down, bottom-up, and fully integrated risk science strategies to next generation risk decision-making.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"163 ","pages":"Article 105939"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145044766","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":"2025-12-01","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":"The dangerous precedent of silencing government science","authors":"Martin van den Berg Prof. Dr. ((Co)Editor-in-Chief)","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":"163 ","pages":"Article 105927"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","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}