Regulatory Toxicology and Pharmacology最新文献

{"title":"Ninety-day repeated oral toxicity and genetic toxicity studies of powderized Aurantii Fructus Immaturus","authors":"Soyoung An ,&nbsp;Songyeon Kim ,&nbsp;Si-Whan Song ,&nbsp;Hye-Seon Heo ,&nbsp;Changwook Park ,&nbsp;Minseob Kim ,&nbsp;Wooju Lee ,&nbsp;Yujin Park ,&nbsp;Jae-Ho Shin ,&nbsp;Beom Seok Han ,&nbsp;Wan-Seob Cho","doi":"10.1016/j.yrtph.2025.105837","DOIUrl":"10.1016/j.yrtph.2025.105837","url":null,"abstract":"<div><div>Aurantii Fructus Immaturus (AFI) has been widely used as an herbal medicine for health promotion and the treatment of various diseases but there is little information on its toxicity. Herein, we performed general and genetic toxicity studies on the powdered form of AFI. The lethal dose 50 % (LD₅₀) of AFI powder in Sprague-Dawley (SD) rats was &gt;4000 mg/kg for both sexes. The 28-day repeated oral toxicity study of AFI powders at 0, 125, 250, 500, 1000, and 2000 mg/kg/day showed some occasional changes including soiled perineal region, loss of fur, and weight loss. However, these changes were not considered treatment-related because the values were within the control range and responses were not dose-dependent. The 90-day repeated oral toxicity study with a 4-week recovery period of AFI powders in rats at 0, 125, 250, 500, 1000, and 2000 mg/kg/day also showed no treatment-related toxicity outcomes, although some endpoints showed significant changes such as loss of fur, increased MCH and MCV levels, and increased liver weight. Therefore, the no-observed-adverse-effect level (NOAEL) of AFI powders in rats was 2000 mg/kg/day. Finally, a battery of three genotoxicity tests showed that the AFI powder was not a genotoxic material.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"161 ","pages":"Article 105837"},"PeriodicalIF":3.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143907703","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 Alarming Consequences of Workforce Reductions at the FDA, EPA, NIH and CDC in the United States","authors":"Martin van den Berg PhD (Editor-in-Chief, Regulatory Toxicology & Pharmacology and Current Opinion in Toxicology) ,&nbsp;Daniel R. Dietrich PhD (Editor-in-Chief, Chemico-Biological Interactions, Computational Toxicology, and Journal of Toxicology and Regulatory Policy) ,&nbsp;Sonja von Aulock PhD (Editor-in-Chief, ALTEX – Alternatives to Animal Experimentation) ,&nbsp;Anna Bal-Price PhD (Editor-in-Chief, Reproductive Toxicology) ,&nbsp;Michael D. Coleman PhD (Editor-in-Chief, Environmental Toxicology and Pharmacology) ,&nbsp;Mark T.D. Cronin PhD (Editor-in-Chief, Computational Toxicology) ,&nbsp;Paul Jennings PhD (Editor-in-Chief, Toxicology in Vitro) ,&nbsp;Angela Mally PhD (Editor-in-Chief, Toxicology Letters) ,&nbsp;Mathieu Vinken PhD (Editor-in-Chief, Toxicology and NAM Journal) ,&nbsp;Matthew C. Wright PhD (Editor-in-Chief, Food and Chemical Toxicology)","doi":"10.1016/j.yrtph.2025.105827","DOIUrl":"10.1016/j.yrtph.2025.105827","url":null,"abstract":"","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"160 ","pages":"Article 105827"},"PeriodicalIF":3.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143936002","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 “The analytical evaluation threshold for inorganic metal extractables and leachables analysis of medical devices” [Regulat. Toxicol. Pharmacol. 154 (2024), 105725]","authors":"Chad P. Satori ,&nbsp;Catherine D. Christensen ,&nbsp;Stephanie M. Street ,&nbsp;Mikaelle Giffin ,&nbsp;Christopher M. Pohl ,&nbsp;Whitney V. Christian","doi":"10.1016/j.yrtph.2025.105831","DOIUrl":"10.1016/j.yrtph.2025.105831","url":null,"abstract":"","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"160 ","pages":"Article 105831"},"PeriodicalIF":3.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143936003","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":"Contributions of the joint FAO/WHO expert committee on food additives to international food safety: celebrating the 100th meeting of the committee","authors":"Diane Benford ,&nbsp;Alan Boobis ,&nbsp;Richard Cantrill ,&nbsp;Peter Cressey ,&nbsp;Eugenia Dessipri ,&nbsp;Shruti V. Kabadi ,&nbsp;Suzanne Jeurissen ,&nbsp;Utz Mueller ,&nbsp;Susan Barlow","doi":"10.1016/j.yrtph.2025.105833","DOIUrl":"10.1016/j.yrtph.2025.105833","url":null,"abstract":"<div><div>The Joint FAO/WHO Expert Committee on Food Additives (JECFA) is an international scientific committee that carries out safety and risk assessments on substances that are intended to be added to food or may be present in food. It advises the Codex Alimentarius Commission and the member countries of the Food and Agricultural Organization and the World Health Organization. In 2025, JECFA has its 100th meeting. This paper reviews the work of JECFA since its inception in 1956. The Committee has evaluated over 660 food additives, 105 enzymes, 2500 flavourings, 11 groups of natural toxicants, 12 metals, 25 groups of synthetic chemical contaminants, and residues of 115 veterinary drugs. The Committee has made major contributions internationally on risk assessment methodology for food safety, including the setting of health-based guidance values for chemicals in food, the evaluation of genotoxic and carcinogenic contaminants in food, benchmark dose analysis, use of body burden comparisons, and global approaches to dietary exposure assessment. JECFA advice is independent and based on objective, state-of-the-science assessment of the evidence. Its advice and evaluations are a freely available online resource and play a pivotal role in ensuring the protection of consumer health and enabling the international trade of safe food.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"160 ","pages":"Article 105833"},"PeriodicalIF":3.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870762","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":"Development of internal thresholds of toxicological concern (iTTC) for chemicals based on empirical exposures to pharmaceuticals","authors":"Toshihide Takeshita ,&nbsp;Yuuko Nukada ,&nbsp;Shota Nakagawa ,&nbsp;Shimpei Terasaka ,&nbsp;Masaaki Miyazawa","doi":"10.1016/j.yrtph.2025.105832","DOIUrl":"10.1016/j.yrtph.2025.105832","url":null,"abstract":"<div><div>The threshold of toxicological concern (TTC) is an approach to risk assessment that uses acceptable low-level exposure values derived from statistical information for chemicals for which insufficient toxicological information exists. Previously, the TTC for systemic toxicity was derived from the toxicological endpoints of the external dose for each administration route in animal studies. Internal TTC (iTTC), which extends the TTC concept from external to internal dosages, expands the scope of application by standardizing exposure via different routes. Information about blood exposure to pharmaceuticals used in treatment can help determine the chemical levels tolerated in humans. Using the tolerated plasma/serum blood drug concentration of the pharmaceutical as the toxicological point of departure, a new iTTC of 0.6 nM for the no effect concentration were proposed (a conservative risk assessment considers further safety margins). It is based on the 5th percentile values of the normal distribution, which approximates the cumulative empirical distribution, and an uncertainty coefficient to convert the treatment dose to the no-effect dose. Predicting blood concentrations of chemicals to which humans are exposed and comparing them to iTTC with appropriate caution can be used as an approach to risk assessment of systemic toxicity without animal-based testing.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"160 ","pages":"Article 105832"},"PeriodicalIF":3.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887766","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 pragmatic workflow for human relevance assessment of toxicological pathways and associated new approach methodologies","authors":"Christina H.J. Veltman ,&nbsp;Leo T.M. van der Ven ,&nbsp;Elena Menegola ,&nbsp;Mirjam Luijten","doi":"10.1016/j.yrtph.2025.105828","DOIUrl":"10.1016/j.yrtph.2025.105828","url":null,"abstract":"<div><div>Currently, safety assessments of chemical substances are predominantly based on animal data. Multiple considerations call for the use of alternative testing strategies that are based on new approach methodologies (NAMs). However, the human relevance of these testing strategies is usually uncertain. This necessitates a harmonized and accepted workflow for assessing their applicability for regulatory purposes. This report proposes such a workflow, applicable for assessing the human relevance of a toxicological pathway and the relevance of NAMs related to the different components of the pathway. The workflow starts with an established toxicological pathway, of which the adverse outcome is relevant for human health risk assessment and that has sufficient weight of evidence. Human relevance is assessed through three main questions, related to the different components (steps) of the pathway, the pathology of human syndromes that have a similar adverse outcome, and quantitative aspects. The latter comprise both interspecies differences and <em>in vitro</em> – <em>in vivo</em> differences. The combined evidence is scored as ‘strong’, ‘moderate’ or ‘weak’ support of human relevance, based on expert judgement. The workflow developed was tested in a case study, through application to an AOP describing craniofacial malformations after <em>in utero</em> exposure to triazoles. Based on evidence collected for two of the three main questions, the case study provided moderate to strong support for human relevance of both the various components of the AOP and its associated NAMs. Furthermore, it demonstrated that the workflow is a promising approach that allows for a more transparent scientific evaluation of human relevance of toxicological pathways and associated NAMs. Therefore, despite some areas for improvement, we consider the workflow an important step forward for application of AOPs and related NAMs in human health risk assessment.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"160 ","pages":"Article 105828"},"PeriodicalIF":3.0,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143894975","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 discovery and preclinical pharmacology of JNJ-10450232 (NTM-006), a centrally penetrant, non-opioid structural analog of acetaminophen with comparable analgesic and anti-pyretic properties but no evidence of hepatotoxicity.","authors":"Christopher M Flores, John R Carson, Ellen E Codd, Scott L Dax, Edwin K Kuffner, Paul L Stahle, Robert A Neff, Gary E Eichenbaum","doi":"10.1016/j.yrtph.2025.105830","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105830","url":null,"abstract":"<p><p>A mainstay of the analgesic pharmacopeia for nearly seven decades and alone in its class, acetaminophen relieves mild-to-moderate pain and fever, without similar adverse gastrointestinal and cardiovascular effects associated with non-steroidal anti-inflammatory drugs. While safe and effective when used as directed, acetaminophen overdose may produce liver injury. This report describes discovery and pharmacological characterization of JNJ-10450232/NTM-006, an acetaminophen structural analog designed to retain the efficacy and overall safety profile of acetaminophen without risk of hepatotoxicity following overdose. In the carrageenan and complete Freund's adjuvant models of inflammatory pain and yeast model of fever in rats, JNJ-10450232/NTM-006 exhibited statistically significant effects comparable to acetaminophen in both maximal efficacy and potency. In rat pharmacokinetic studies, JNJ-10450232/NTM-006 exhibited a comparable maximal plasma concentration but higher volume of distribution and longer half-life than acetaminophen, potentially conferring an extended duration of action. In a mouse model of liver injury, acetaminophen produced elevations in aspartate and alanine transaminase activities and signs of hepatic necrosis, whereas JNJ-10450232/NTM-006 did not. Finally, following systemic administration, JNJ-10450232/NTM-006 and acetaminophen produced comparable peripheral levels of para-aminophenol and brain levels of pharmacologically active metabolite N-arachidonoyl-phenolamine (AM404), consistent with the hypothesis that both parent molecules are prodrugs and share the same central mechanism of analgesic action. Taken together, these results suggest JNJ-10450232/NTM-006 as a potentially clinically useful analgesic/antipyretic with improved benefit-to-risk ratio compared with current standards of care.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105830"},"PeriodicalIF":3.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021505","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":"Reproductive and developmental toxicity screen (OECD TG 421) and extended one generation reproductive toxicity study (OECD TG 443) of decahydronaphthalene in Sprague Dawley rats","authors":"John M. Rogers,&nbsp;Melissa M. Heintz,&nbsp;Laurie C. Haws","doi":"10.1016/j.yrtph.2025.105829","DOIUrl":"10.1016/j.yrtph.2025.105829","url":null,"abstract":"<div><div>Decahydronaphthalene (DHN), an industrial solvent, was evaluated in OECD TG 421 and TG 443 reproductive toxicity studies in Sprague Dawley rats. In the TG 421, oral doses were 0, 100, 300, or 1000 mg DHN/kg/day. In the TG 443, initial doses of 0, 30, 100, or 300 mg/kg/day were increased to 0, 60, 200, and 600 mg/kg/day on test day 30. High dose TG 421 females exhibited estrous cycle disruption; mid and high dose dams had fewer implantations and pups/litter. High dose F0 females in the TG 443 showed signs of stress: lower body weight, disrupted estrous cycling, higher adrenal and lower thymus weights, adrenocortical hypertrophy and thymic atrophy; these effects were less severe at the mid dose. High and mid dose TG 443 F0 females also had fewer implantations and pups per litter and lower litter weight. F1 females in the TG 443 had nominally fewer F2 pups and lower litter weight. The reproductive effects of DHN indicate impaired ovarian function. Mid and high dose F0 dams in the TG 443 showed clear signs of stress, to which the ovary is known to be sensitive. Therefore, DHN's effects are considered secondary to maternal stress, and not relevant to humans.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"160 ","pages":"Article 105829"},"PeriodicalIF":3.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143850701","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":"Human health risk assessment for exposures to 1,3-butadiene in the United States with input from an independent science advisory panel","authors":"C.R. Kirman ,&nbsp;G. Boysen ,&nbsp;M.J. DiNovi ,&nbsp;R. Roy ,&nbsp;B.R. Sonawane ,&nbsp;S.M. Hays","doi":"10.1016/j.yrtph.2025.105819","DOIUrl":"10.1016/j.yrtph.2025.105819","url":null,"abstract":"<div><div>A human health risk assessment was conducted for potential cancer and noncancer effects of 1,3-butadiene (BD) using best available science, data, and methodologies. An independent panel of experts was engaged to provide input and guidance on key decisions made in the quantitative assessment. BD biomarker data played an important role in quantifying species differences, human variation, and quantifying smoking exposures. The assessment included consideration of nineteen scenarios for potential worker exposures, each of which include characterization of the impact of respirator use, and seven scenarios for aggregate exposures to BD across pathways. Monte Carlo methods were used to characterize uncertainty and variation risks and hazards from exposures to BD. The results of this assessment support three general conclusions: (1) ambient air is generally not an important source of BD exposure to the U.S. population when compared to other sources; (2) exposures to BD in the US are not expected to pose an unreasonable risk of cancer or noncancer effects; and (3) the existing OSHA PEL of 1 ppm is considered to be protective of the potential cancer risks and noncancer hazards from BD exposures.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"160 ","pages":"Article 105819"},"PeriodicalIF":3.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843195","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":"Report of the European Commission workshop on “The roadmap towards phasing out animal testing for chemical safety assessments”, Brussels, 11–12 December 2023","authors":"Mark T.D. Cronin ,&nbsp;Elisabet Berggren ,&nbsp;Sofia Camorani ,&nbsp;Christian Desaintes ,&nbsp;Marco Fabbri ,&nbsp;Julia Fabrega ,&nbsp;Matthias Herzler ,&nbsp;Jay D.E. Ingram ,&nbsp;Katia Lacasse ,&nbsp;Susanna Louhimies ,&nbsp;Gavin Maxwell ,&nbsp;Katrin Schutte ,&nbsp;Tomasz Sobanski ,&nbsp;Georg Streck ,&nbsp;Andrea Terron ,&nbsp;Andrew P. Worth","doi":"10.1016/j.yrtph.2025.105818","DOIUrl":"10.1016/j.yrtph.2025.105818","url":null,"abstract":"<div><div>This report summarises the main findings and discussion from the European Commission (EC) workshop on “The Roadmap Towards Phasing Out Animal Testing for Chemical Safety Assessments” which was held in Brussels on 11–12 December 2023. The aim of the workshop was to gather ideas and opinions from individuals, organisations and institutions, and to discuss potential approaches for incorporating non-animal methods into chemical legislation with all interested stakeholders. The roadmap will be an EC policy document which will outline milestones and specific actions, addressing all relevant pieces of chemical legislation relating to safety assessment. It intends to describe the necessary steps to replace animal testing in pieces of legislation where it is currently required for chemical safety assessments. The roadmap will outline the path to expand and accelerate the development, validation and implementation of non-animal methods as well as means to facilitate their uptake across legislation. The workshop included presentations from a wide variety of stakeholders. The contributors provided examples of how non-animal methods could be applied to replace, reduce or refine animal testing in the assessment of human health and environmental effects. Furthermore, possible guiding principles for establishing a Next-Generation Risk Assessment (NGRA) in European chemicals legislation were also discussed. The workshop provided the basis for further discussion and for structuring the roadmap work.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"161 ","pages":"Article 105818"},"PeriodicalIF":3.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796094","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}