Regulatory Toxicology and Pharmacology最新文献

{"title":"Subchronic oral toxicity and genotoxicity of Aurantii Fructus Immaturus water extract","authors":"So-Young An ,&nbsp;Si-Whan Song ,&nbsp;Hyun-Suk Heo ,&nbsp;Chang-Wok Park ,&nbsp;Min-Sub Kim ,&nbsp;Woo-Joo Lee ,&nbsp;Yoo-Jin Park ,&nbsp;Jae-Ho Shin ,&nbsp;Beom Seok Han ,&nbsp;Wan-Seob Cho","doi":"10.1016/j.yrtph.2025.106010","DOIUrl":"10.1016/j.yrtph.2025.106010","url":null,"abstract":"<div><div><em>Aurantii Fructus Immaturus</em> (AFI) water extract has been utilized in traditional medicine; however, its toxicity data are still lacking. In this study, we evaluated the general and genetic toxicity of the AFI water extract as a project of the Korea National Toxicology Program (KNTP). Naringin and neohesperidin, marker compounds of AFI, contained in the AFI water extract were 7.63 % and 4.51 %, respectively. These levels were higher than AFI powders, which contain about 4 % naringin and 3 % neohesperidin. The acute oral toxicity study in rats, conducted at doses of 2500–10000 mg/kg, demonstrated that the median lethal dose (LD₅₀) of AFI water extract exceeds 10000 mg/kg. Subacute oral toxicity tests at doses up to 5000 mg/kg/day and subchronic toxicity studies conducted over 13 weeks at similar dose ranges showed no treatment-related adverse effects. Thus, the no-observed-adverse-effect level (NOAEL) of AFI water extract in rats was 5000 mg/kg bw/day. Additionally, three genotoxicity assays (bacterial reverse mutation, <em>in vitro</em> chromosomal aberration, and <em>in vivo</em> micronucleus tests) confirmed that the AFI water extract is not genotoxic. These results will provide the toxicity data for the risk assessment of AFI water extract for human consumption.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106010"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744049","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":"An evaluation of the utility of blood concentration of somatic mutagens to inform germ cell mutagenic hazard","authors":"Roger Godschalk ,&nbsp;Bente Brauwers ,&nbsp;Connie L. Chen ,&nbsp;Raffaella Corvi ,&nbsp;Kerry L. Dearfield ,&nbsp;George R. Douglas ,&nbsp;Naveed Honarvar ,&nbsp;David Kirkland ,&nbsp;Frank Le Curieux ,&nbsp;Ann-Karin Olsen ,&nbsp;Stefan Pfuhler ,&nbsp;Leon F. Stankowski ,&nbsp;Paul White ,&nbsp;Jan van Benthem ,&nbsp;Francesco Marchetti","doi":"10.1016/j.yrtph.2025.105989","DOIUrl":"10.1016/j.yrtph.2025.105989","url":null,"abstract":"<div><div>The Globally Harmonized System standardizes chemical hazard communication. Within this system, germ cell mutagenicity holds unique importance due to the potential of heritable mutations. Yet, such testing is rarely performed, requiring alternative approaches to assess germ cell mutagenic potential. One strategy involves using physiological parameters to predict if somatic cell mutagens reach the gonads and induce mutations in germ cells. Therefore, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee examined whether blood concentrations of somatic cell mutagens can predict genotoxic effects in germ cells. We analyzed 11 substances with dominant lethal test data and 30 with transgenic rodent gene mutation data in male germ cells, together with blood concentrations. While significant associations were found between genotoxic outcomes in somatic tissues (e.g., micronuclei, mutation induction) and outcomes for germ cell mutagenicity, considerable variability was noted in genotoxic responses. This variability could not be explained by blood concentrations alone. Notably, blood levels of substances positive in both somatic and germ cells were similar to those that were positive for somatic cell genotoxicity and negative in germ cells. We conclude that the concentration of a somatic cell genotoxic substance in blood is insufficient to predict germ cell mutagenicity.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 105989"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588562","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":"Regulatory experience with the comparative in vitro metabolism study based on an analysis of 70 studies with pesticide active ingredients – a reality check","authors":"Umma Salma,&nbsp;Anne Schmitt,&nbsp;Soyub Rime,&nbsp;Lars Niemann,&nbsp;Carsten Kneuer","doi":"10.1016/j.yrtph.2025.105992","DOIUrl":"10.1016/j.yrtph.2025.105992","url":null,"abstract":"<div><div>The use of pesticides is an inseparable and undeniable part of modern agriculture to ensure sufficient food supply for a still-growing population but, due to their intrinsic toxic nature, rigorous testing is needed before making them available on the market. In the European Union, <em>in vitro</em> metabolism studies with the active ingredients became mandatory in 2013. Unfortunately, in contrast to most other toxicological endpoints, a harmonised test guideline for their conduct is not yet available. More than 10 years after its introduction, we aimed to analyse the practical experience with that data requirement. For this purpose, 70 comparative <em>in vitro</em> metabolism studies were reviewed. Significant methodological differences were noticed among the studies, including species selection, test systems, tested concentrations, and incubation times. These differences and the deviations from existing but not legally binding recommendations limit the use that could be made of these studies, in particular beyond a simple comparison of human and rat metabolism. There is an urgent need for a harmonised guidance how to perform the <em>in vitro</em> biotransformation studies. Its implementation would not only increase the likelihood to identify unique or disproportionate human metabolites but might also support next-generation risk assessment.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 105992"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557770","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 CDER perspective: Landscape of New Approach Methodologies (NAMs) submitted in drug development programs","authors":"Tyna Dao,&nbsp;Nakissa Sadrieh","doi":"10.1016/j.yrtph.2025.106007","DOIUrl":"10.1016/j.yrtph.2025.106007","url":null,"abstract":"<div><div>This study analyzes the landscape of studies using New Approach Methodologies (NAMs) and submitted to the FDA over the past 15 years. The study utilized a custom-developed Center for Drug Evaluation and Research (CDER) search tool to examine keywords in Module 4 of the Electronic Common Technical Document (eCTD) across various drug applications. The investigation focused on five NAM categories, including some of those identified in the 2022 Food and Drug Omnibus Reform Act (FDORA): in vitro, in silico, in chemico, nonhuman in vivo, and other NAMs. Results indicated that 93 % of NAM submissions were concentrated in two categories: in silico (49 %) and in vitro (44 %), with other categories (including in chemico, nonhuman in vivo from phylogenetically lower species and other combined methods) demonstrating significantly lower representation. In vitro NAMs, including stem cell-derived and sandwich culture models, showed higher prevalence compared to 3D models and organ chip or MPS models. The relatively high prevalence of in silico NAMs, was due to the submission of multiple study reports per application, attributed to various metabolites and the use of different in silico platforms. In chemico and nonhuman in vivo NAMs demonstrated limited submissions, with zebrafish studies predominating in the latter category. This study highlights one of CDER's activities aimed at better understanding the current usage of NAMs in drug development, while providing evidence to support areas of focus and prioritization of resources towards the validation of NAMs with significant regulatory impact potential. Despite technical limitations in the datamining work presented here, the findings confirm that CDER has been receiving NAMs data in drug applications for a long time. Nevertheless, we acknowledge that industry submits only a fraction of their NAM data to FDA, therefore we encourage increased NAM submissions which would contribute to building scientific confidence in these methods. It is only through the availability of sufficient case studies, that CDER can move towards reaching the goals of NAMs Roadmap issued in April 2025, and ultimately phasing out animal studies when possible and feasible.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106007"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708987","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":"Exploration of virtual control groups and Bayesian approaches for rat fertility studies","authors":"Christopher J. Bowman ,&nbsp;Dingzhou Li ,&nbsp;Thi Dong Binh Tran ,&nbsp;Natasha R. Catlin ,&nbsp;Christine M. Stethem ,&nbsp;William S. Nowland ,&nbsp;Sarah N. Campion","doi":"10.1016/j.yrtph.2025.106004","DOIUrl":"10.1016/j.yrtph.2025.106004","url":null,"abstract":"<div><div>This study evaluates the potential of using historical control data (HCD) in rat fertility studies to replace/reduce concurrent control animal use and improve statistical analysis. This analysis was conducted using data sourced from a single test facility using consistent animal attributes and study procedures and consisted of 13 datasets from 12 rat fertility studies conducted between 2018 and 2023. For required fertility endpoints, we have evaluated full and hybrid Virtual Control Group (VCG) and Bayesian statistical approaches compared with standard statistics used for concurrent control groups (CCG). Our findings demonstrate that the sensitivity and specificity of most required fertility endpoints were generally similar between CCG and full or hybrid VCGs of sufficient sample size. Bayesian analyses leveraging all available HCD offered similar or superior sensitivity and specificity to CCGs and VCGs (full or hybrid) for all required fertility endpoints, with some exceptions. A retrospective case study implementing these approaches with HCD illustrated similar statistical performance across all approaches in addition to the benefit of reduced animal use. Overall, this effort illustrates the potential to improve sensitivity and reduce animal use with VCG (full or hybrid) or Bayesian approaches for required fertility endpoints in the rat.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106004"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145616909","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":"Kinetics, tolerability and safety of (R)-1,3-butanediol (S)-lactate ester (LaKe): A randomized controlled cross-over trial in adults with obesity","authors":"Simon K. Kjær ,&nbsp;Nikolaj Rittig ,&nbsp;Jens M. Bruun ,&nbsp;Niels Møller ,&nbsp;Mads Svart","doi":"10.1016/j.yrtph.2025.106013","DOIUrl":"10.1016/j.yrtph.2025.106013","url":null,"abstract":"<div><div>Hyperketonemia and hyperlactatemia can be induced by exogenous supplementation of each individual compound. In this study we examined the safety profile of (R)-1,3-butanediol (S)-lactate ester, a new lactate-ketone ester (LaKe). We hypothesized that 4 weeks of LaKe supplementation would induce hyperketonemia, hyperlactatemia, be feasible, tolerable, and safe. In this randomized, double-blind, placebo-controlled cross-over study, otherwise healthy adults with obesity (N = 10) received 25 mL (∼27.75 g) LaKe or taste-matched non-caloric placebo twice daily for 28 days, followed by an additional dose in a laboratory setting on day 29 with fasting and continuous blood sampling. Compliance was ≥80 % with no dropouts. 28 days of LaKe consumption was overall well tolerated but associated with mild to moderate gastrointestinal side effects without affecting organ function biomarkers. Following a 25 mL dose of LaKe, beta-hydroxybutyrate (βHB) and lactate concentrations peaked at 0.6 mmol/L (IQR 0.5–0.675 mmol/L) and 2.15 mmol (IQR 1.5–2.65 mmol/L), respectively, while blood gases and and electrolytes remained within normal ranges. LaKe elevates blood concentrations of both βHB and lactate. The consumption of LaKe twice daily for 28 days is well tolerated and safe, although associated with mild to moderate gastrointestinal side effects.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106013"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757496","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":"Exposure and disease burden of fumonisins and aflatoxins from sorghum consumption in Ethiopia","authors":"J.A. Sadik ,&nbsp;N. Fentahun ,&nbsp;I.D. Brouwer ,&nbsp;M. Tessema ,&nbsp;H.J.van der Fels-Klerx","doi":"10.1016/j.yrtph.2025.105966","DOIUrl":"10.1016/j.yrtph.2025.105966","url":null,"abstract":"<div><div>Studies on mycotoxin exposure from sorghum consumption and related public health risk estimation are rarely available in Ethiopia. The aim of this research was to assess fumonisin and aflatoxin exposure of adults through sorghum consumption in the Amhara National Regional State (ANRS) and at national level in Ethiopia and to estimate related health risks. Data on fumonisin and aflatoxin concentrations in sorghum samples were collected from a survey and literature. Estimated fumonisin exposure in the ANRS and at national level were below the FAO/WHO limit of 2000 ng/kg bw day to be considered a health concern. The estimated aflatoxin exposure levels in the ANRS and at national level fall below the Margin of Exposure value of 10000, indicating potential health concern. The incidence of hepatocellular carcinoma due to aflatoxin exposure in the ANRS ranges from 0.0003 to 0.017 while at national level, it ranges from 0.181 to 8.47 (per100.000 persons/year). The related disability-adjusted life years estimates for the ANRS and at national level ranged from 0.0003 to 0.019 and 0.204 to 11.230, respectively. Aflatoxin exposures were driven more by sorghum intake than aflatoxin contamination. Dietary intervention could further reduce the health risk estimates.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105966"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308826","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":"Applicability of kinetically-based maximum dose studies for hazard and risk assessments of the fungicide fluoxapiprolin","authors":"Kim Z. Travis ,&nbsp;Richard W. Lewis ,&nbsp;Christine Barreau ,&nbsp;Bastian Becker ,&nbsp;Philippe F. Kennel","doi":"10.1016/j.yrtph.2025.105983","DOIUrl":"10.1016/j.yrtph.2025.105983","url":null,"abstract":"<div><div>Fluoxapiprolin is a new fungicide developed for the control of oomycetes that damage crops such as tomato, potato, grapes and leafy vegetables. Human safety studies have shown no toxicity clearly attributable to fluoxapiprolin, highlighting its favourable toxicological profile compared to many other fungicides. It meets all human health risk assessment criteria without difficulty. However, fluoxapiprolin was tested up to a Kinetically-Derived Maximum Dose (KMD) rather than the conventional limit dose, making it necessary to justify this approach in the context of regulatory hazard assessment. Official guidance documents encourage the application of KMD approaches under specific conditions. In the case of fluoxapiprolin, oral absorption was shown to become saturated as doses increased, supporting the selection of the high dose in long-term studies based on a KMD rather than using a fixed limit dose. Even if a limit dose had been used, systemic exposure would have been only about twice as high as that observed at the KMD. Given the absence of treatment-related toxicity in any study and the relatively small difference in systemic exposure, the toxicological database is considered sufficient to identify relevant hazards and to support a robust human health risk assessment.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105983"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477230","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":"Retraction notice to “Acute oral toxicity study of magnesium oxide nanoparticles and microparticles in female albino Wistar rats” [Regul. Toxicol. Pharm. 90 (2017) 170–184]","authors":"Bhanuramya Mangalampalli ,&nbsp;Naresh Dumala ,&nbsp;Paramjit Grover","doi":"10.1016/j.yrtph.2025.105986","DOIUrl":"10.1016/j.yrtph.2025.105986","url":null,"abstract":"","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105986"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145490192","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":"How many mutagens are missed under REACH due to limited low tonnage information requirements?","authors":"Rune Hjorth ,&nbsp;Joop de Knecht ,&nbsp;Eva B. Wedebye ,&nbsp;Nikolai G. Nikolov ,&nbsp;Damiën van Berlo ,&nbsp;Henrik Tyle","doi":"10.1016/j.yrtph.2025.105946","DOIUrl":"10.1016/j.yrtph.2025.105946","url":null,"abstract":"<div><div>For industrial substances registered under REACH at 1–10 tonnes per registrant/year, only the Ames test is required to address mutagenicity. When a substance tests positive in the Ames test, further testing is needed, but when the test result is negative, additional mutagenicity testing is only mandatory at a higher tonnage level. It is correspondingly known that some mutagens produced up to 10 tonnes per year/registrant are not identified. Based on battery (Q)SAR modelling, relying on agreement from both <em>in vitro</em> and <em>in vivo</em> models, advisory self-classifications (ASC) for mutagenicity are offered by the Danish EPA. In this present study, substances with ASC for mutagenicity are compared to the identified mutagens in low tonnage REACH registrations. We conclude that for only about a quarter of the low-tonnage substances with an Muta. 2 ASC, a positive experimental Ames result is available, leading to follow-up under REACH. We recommend improving the identification of mutagenic substances at the 1–10 tonnage band by including the <em>in vitro</em> micronucleus test to supplement the Ames test. Concerningly, the few low tonnage REACH dossiers that do provide <em>in vivo</em> data, mostly report negative micronucleus test results that are not conclusive due to missing information on bone marrow exposure.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105946"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138608","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}