Regulatory Toxicology and Pharmacology最新文献

{"title":"Use of NAMs in a weight of evidence approach to evaluate the safety via the inhalation route of acetylated vetiver oil, in spray products","authors":"Fanny Boisleve ,&nbsp;Hind Assaf Vandecasteele ,&nbsp;James Baily ,&nbsp;Kamil Czuchrowski ,&nbsp;Malik Diop ,&nbsp;Catherine Gadras ,&nbsp;David Herbst ,&nbsp;Christina Hickey ,&nbsp;Amaia Irizar ,&nbsp;Boris P. Müller ,&nbsp;Nikaeta Sadekar ,&nbsp;Paul Sterchele ,&nbsp;Matthias Vey ,&nbsp;Nicola J. Hewitt","doi":"10.1016/j.yrtph.2025.105905","DOIUrl":"10.1016/j.yrtph.2025.105905","url":null,"abstract":"<div><div>Acetylated Vetiver Oil (AVO) is a fragrance ingredient. We evaluated the systemic and local toxicity of AVO via inhalation from use of cosmetic spray products.</div><div>Systemic exposure after inhalation was calculated using a deterministic 2-Box model. The “local inhalation toxicological threshold of concern” (TTC_inh) was used in a weight of evidence (WoE) for the potential of AVO to cause local respiratory toxicity and the <em>in vitro</em> model, MucilAir™ was used to evaluate respiratory irritation.</div><div>AVO exposure by inhalation of sprayed cosmetic products does not add significant exposure compared to dermal exposure. The Margin of Safety (NOAEL compared to total systemic AVO exposure) is &gt; 400, indicating no concern for systemic toxicity. Regarding local toxicity, total aggregate exposure to AVO in sprayable cosmetic products is significantly lower than the TTC_inh. There were no injurious effects to MucilAir™ tissues by 0.2 % and 1 % AVO. When the NOAEL from the MucilAir™ assay (1 %) and the aggregated exposure were compared, the Margin of Exposure was 137.</div><div>In conclusion, based on a WoE approach, the concentrations of AVO used in cosmetic products are not expected to carry a risk of local irritation effects on the respiratory tract or add significantly to aggregate systemic exposure.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105905"},"PeriodicalIF":3.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144609244","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 call to action: Advancing new approach methodologies (NAMs) in regulatory toxicology through a unified framework for validation and acceptance","authors":"G. Ouedraogo ,&nbsp;N. Alépée ,&nbsp;B. Tan ,&nbsp;C.S. Roper","doi":"10.1016/j.yrtph.2025.105904","DOIUrl":"10.1016/j.yrtph.2025.105904","url":null,"abstract":"<div><div>The transition from traditional animal testing to human-relevant New Approach Methods (NAMs) in regulatory toxicology faces a significant challenge: a lack of standardized validation and acceptance criteria. This review analyses the limitations of animal test reproducibility and highlights the growing body of evidence supporting the improved reliability and relevance of NAMs for predicting human toxicity. Successful case studies of NAMs implementation across diverse industries are examined and existing regulatory perspectives and initiatives are critically evaluated. This analysis reveals a pressing need for a unified, cross-industry approach to NAMs validation, grounded in measurable quality standards and standardisation. A framework is proposed based on clearly defined standards, standardized protocols, and transparent data sharing to accelerate the integration of NAMs into regulatory decision-making, ultimately benefiting human health, animal welfare, and scientific progress. All stakeholders are urged to actively participate in this initiative by contributing their expertise, sharing data and insights, and collaborating on the development and implementation of this crucial use of NAMs in regulatory toxicology.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105904"},"PeriodicalIF":3.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144609242","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":"Considerations of non-human primate use in nonclinical toxicity study package for oncology therapeutics with well-characterized target in supports of 3Rs – an IQ DruSafe industry survey","authors":"Cleo Leung ,&nbsp;Bart Jessen ,&nbsp;Benno Rattel ,&nbsp;David Ackley ,&nbsp;Noel Dybdal ,&nbsp;Ulrike Hopfer ,&nbsp;Timothy Hart","doi":"10.1016/j.yrtph.2025.105902","DOIUrl":"10.1016/j.yrtph.2025.105902","url":null,"abstract":"<div><div>Development of monoclonal antibodies (mAbs) for oncology is increasing. An IQ DruSafe Working Group conducted an industry survey to evaluate non-human primate (NHP) use in nonclinical toxicity testing of oncology mAbs for well-characterized targets (WchT) with the aim to identify opportunities to reduce NHP use. The survey addressed sources of information used to justify WchT, weight of evidence (WoE) approaches to reduce NHP use, and design of nonclinical toxicology programs. All respondents used literature to define WchT. WoE approaches helped reduce the number and size of general toxicology studies. Most companies conducted non-Good Laboratory Practice (non-GLP) dose-range finding studies prior to GLP toxicology studies, often non-terminally, allowing for potential reuse of NHPs. For GLP studies, most companies maintained a standard design for 1-month studies (when conducted) but were more flexible with 3-month studies, often excluding recovery groups. Case studies illustrate successful regulatory acceptance of streamlined nonclinical safety packages. Engaging drug regulatory authorities (DRA) to discuss the need for additional and/or specialized studies would be beneficial to reduce NHP use. In conclusion, NHP use can be reduced in developing oncology therapeutics against WchT by optimizing nonclinical toxicology approaches with appropriate strategic planning, fit-for-purpose toxicology study designs, and discussion with DRA.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105902"},"PeriodicalIF":3.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587563","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":"Using pre-existing control data to set expectations in preclinical studies","authors":"Jenna K. Felli,&nbsp;Derek J. Leishman,&nbsp;Meredith A. Steeves","doi":"10.1016/j.yrtph.2025.105899","DOIUrl":"10.1016/j.yrtph.2025.105899","url":null,"abstract":"<div><div>This work presents a conceptual approach to limit the use of live subjects for preclinical toxicological studies by leveraging pre-existing control data. Given a valid set of pre-existing control data, one can use probabilistic methods to set expectations for targeted study outcomes prior to undertaking a study. We do not address current efforts underway to generate, simulate, validate, or otherwise model or construct such data sets (<em>e.g., mathematical models, virtual control groups</em>). Rather, we assume the existence of an appropriately collected and curated data set of relevant metrics representative of control subjects and illustrate the use of probabilistic methods to set expectations a priori for experimental outcomes for commonly measured endpoints. We explore using the T-distribution to set expectations for small sample sizes when endpoints are continuous measures (<em>e.g., organ weights</em>) and the sample average of the data set is a good proxy for the true population mean. When endpoints are discrete measures (<em>e.g., grades of specific pathologies</em>) or the sample average of the data set does not serve as a good proxy, we employ bootstrapping to generate a distribution. We conclude that these probabilistic approaches can help investigators understand the behavior of endpoints in an untreated population and help set a priori expectations for “normalcy” when interrogating study results.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105899"},"PeriodicalIF":3.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560960","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":"In vivo screening evaluation of 12 chemicals as candidate endocrine disruptors using ovariectomized mouse uterotrophic bioassay","authors":"Toshime Igarashi ,&nbsp;Satoshi Yokota ,&nbsp;Asako Aida,&nbsp;Takuya Nishimura,&nbsp;Satoshi Kitajima","doi":"10.1016/j.yrtph.2025.105900","DOIUrl":"10.1016/j.yrtph.2025.105900","url":null,"abstract":"<div><div>The rodent uterotrophic bioassay is helpful to easily predict and evaluate the estrogenic properties of chemicals by measuring changes in uterine weight as a screening test. We used this assay in ovariectomized (OVX) mice to screen 12 chemicals suspected to be estrogenic or antiestrogenic properties by <em>in vitro</em> assays in the screening project of the Ministry of Health, Labour and Welfare, Japan. We administered each chemical to 8-week-old OVX mice either orally (po) or by subcutaneous (sc) injection at 24-hr intervals for 7 consecutive days. Ethinyl estradiol was used as reference control. Our study revealed for the first time that po or sc administration of 1,1,1-tris(4-hydroxyphenyl)ethane exerted estrogenic effects at nontoxic dose, with a LOEL of 300 mg/kg for both routes. In contrast, sc administration, but not po administration, of dibenzoylmethane, tricresyl phosphate, and triphenylsilanol exerted antiestrogenic effects, with a LOEL of 30 mg/kg for each chemical. Furthermore, po and sc administration of 4,4′-butylidenebis[6-tert-butyl-3-methylphenol] exerted antiestrogenic effects, with a LOEL of 100 mg/kg for both routes. Taken together, we revealed that only 5 of the 12 substances of concern <em>in vitro</em> were active <em>in vivo</em>, which could be helpful for the effective detection of estrogenic and antiestrogenic activities. The five positive substances were considered to require further consideration in the prioritization list of higher-order toxicity testing for their endocrine disrupting effects.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105900"},"PeriodicalIF":3.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560959","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":"Safety evaluation of Nannochloropsis gaditana oil as a novel food","authors":"Jingjing Qu ,&nbsp;Taiping Zhu ,&nbsp;Xiaoya Du ,&nbsp;Yingjing Zhang ,&nbsp;Jie Tian ,&nbsp;Ying Xia ,&nbsp;Xianghong Ke ,&nbsp;Shaohua Fu ,&nbsp;Bolin Fan","doi":"10.1016/j.yrtph.2025.105901","DOIUrl":"10.1016/j.yrtph.2025.105901","url":null,"abstract":"<div><div>To assess the safety of the <em>Nannochloropsis gaditana</em> oil as a new food ingredient, we conducted a comprehensive toxicological evaluation, including acute oral toxicity study, genotoxicity studies, teratogenicity study, and subchronic toxicity study. In the acute oral toxicity study, the LD₅₀ &gt; 8.4 g/kg BW. In the genotoxicity studies (mammalian erythrocyte micronucleus, chromosomal aberrations, and Ames test), all dose groups showed no significant changes compared to negative controls. Teratogenicity study demonstrated no adverse effects on maternal body weight, reproductive capacity, or fetal development in rats, with a no-observed-adverse-effect level (NOAEL) of 2.8 g/kg BW. Similarly, the 90-day subchronic toxicity study identified a NOAEL of 2.8 g/kg BW, as no treatment-related abnormalities were observed in body weight, hematology, blood biochemistry, urinalysis, or histopathology. These findings support the safety of <em>Nannochloropsis gaditana</em> oil for human consumption.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105901"},"PeriodicalIF":3.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554299","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":"Substantiating chemical groups for read-across using molecular response profiles","authors":"Rosemary E. Barnett ,&nbsp;Thomas N. Lawson ,&nbsp;Claudia Rivetti ,&nbsp;Carlos Barata ,&nbsp;Mark T.D. Cronin ,&nbsp;Silvia Lacorte ,&nbsp;Gavin R. Lloyd ,&nbsp;Ralf J.M. Weber ,&nbsp;Matthew J. Smith ,&nbsp;Andrew D. Southam ,&nbsp;Adam Biales ,&nbsp;Kara Koehrn ,&nbsp;Bruno Campos ,&nbsp;John K. Colbourne ,&nbsp;Geoff Hodges ,&nbsp;Mark R. Viant","doi":"10.1016/j.yrtph.2025.105894","DOIUrl":"10.1016/j.yrtph.2025.105894","url":null,"abstract":"<div><div>By grouping structurally similar chemicals, toxicity endpoints from data-rich substances can be read across to data-poor substances, supporting environmental and human health risk assessment without animal testing. However, structural similarity alone is insufficient, and additional supporting data can strengthen a grouping justification. This study aimed to demonstrate how multi-omics bioactivity data can increase confidence in a grouping hypothesis, where the bioactivity profiles can reflect a chemical's mode(s) of action. We investigated three structurally similar phthalates and three uncouplers of oxidative phosphorylation, applying structure-based grouping approaches and short-term exposures of the ecotoxicological test species <em>Daphnia magna</em> to generate multi-omics data. Bioactivity similarities between the ‘omics responses to chemical exposure were assessed using t-statistics comparing treated samples to controls and visualised using hierarchical cluster analysis. Conventional structure-based grouping did not assign the phthalates and uncouplers into two anticipated categories, with the structurally more diverse uncouplers often assigned into multiple groups. Following bioactivity thresholding, which removed one uncoupler as it induced minimal molecular responses, bioactivity profile-based grouping of the remaining five substances correctly separated them into two chemical classes with high replicability confidence. However, a plausible toxicological interpretation of the reduced set of functionally annotated molecular features driving the grouping was attempted, although of limited success. This study demonstrates how multi-omics bioactivity profiles can increase confidence in chemical grouping and investigates a potential strategy for plausibly interpreting ‘omics data.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105894"},"PeriodicalIF":3.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144524155","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 value of a structured, systematic approach to benefit-risk assessment of medicines: A South African regulator case study","authors":"Lorraine Danks ,&nbsp;Boitumelo Semete-Makokotlela ,&nbsp;Donald Chuma ,&nbsp;John-Joseph Borg ,&nbsp;Star Khoza ,&nbsp;Stuart Walker ,&nbsp;Sam Salek","doi":"10.1016/j.yrtph.2025.105893","DOIUrl":"10.1016/j.yrtph.2025.105893","url":null,"abstract":"<div><div>This study investigates the utility of the Universal Methodology for Benefit-Risk Assessment (UMBRA) framework within the South African Health Products Regulatory Authority (SAHPRA) to determine whether adopting a structured approach improves consistency, transparency, and quality in benefit-risk assessments of new chemical entities (NCEs). The UMBRA eight-step framework was applied retrospectively and prospectively to six NCEs to systematically document the decision context, identify benefits and risks, and interpret the benefit-risk balance. Comparisons were made between initial SAHPRA narrative assessments and structured UMBRA-based evaluations. Reviewer feedback was collected through a questionnaire and group discussions. The retrospective study revealed that UMBRA provided greater clarity and alignment with decisions by global reference authorities, improving transparency in the weighting of benefits and risks. The prospective study demonstrated UMBRA's utility in highlighting local demographic and clinical considerations, enhancing regulatory reliance decisions. The UMBRA framework enhances the benefit-risk assessment process by providing a structured, transparent, and reproducible methodology. It facilitates comprehensive decision-making that aligns with global best practices, reducing reliance on subjective judgements. Implementing UMBRA at SAHPRA and other African regulatory authorities could promote harmonised regulatory practices, improve public trust, and enable transparent communication of decisions. The study recommends integrating UMBRA into routine assessments, training programs for new reviewers, and reliance strategies to ensure equitable benefit-risk evaluations across jurisdictions.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105893"},"PeriodicalIF":3.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529424","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":"Commentary on FDA's shift from animal testing and implications for drug attrition – The time to act is now","authors":"Eckhard von Keutz","doi":"10.1016/j.yrtph.2025.105896","DOIUrl":"10.1016/j.yrtph.2025.105896","url":null,"abstract":"<div><div>The U.S. FDA's recent policy shift toward accepting non-animal alternatives for investigational new drug (IND) applications marks a pivotal moment in regulatory science. While full replacement of animal testing will take time, the high and rising attrition rates in pharmaceutical R&amp;D demand immediate action. One of the clearest opportunities lies in the prediction of drug-induced liver injury (DILI), a key contributor to late-stage failures. Human-relevant new approach methodologies (NAMs), such as microphysiological systems and in vitro functional assays, offer enhanced mechanistic insight and population-level predictivity. This commentary explores the implications of the FDA's new policy and argues for accelerated adoption of NAMs in targeted domains where human biology-based systems can outperform traditional animal models.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105896"},"PeriodicalIF":3.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512442","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":"Assessment of human breast milk contamination with lead, mercury, cadmium, and arsenic and associated health risks in northeastern Algeria","authors":"Meriem Imen Boussadia ,&nbsp;Mohamed Amine Kerdoun ,&nbsp;Ali Boudebbouz ,&nbsp;Zinette Bensakhri ,&nbsp;Abdeldjalil Youcefi ,&nbsp;Sadek Atoussi ,&nbsp;Rabah Zebsa","doi":"10.1016/j.yrtph.2025.105891","DOIUrl":"10.1016/j.yrtph.2025.105891","url":null,"abstract":"<div><div>Lead (Pb), mercury (Hg), cadmium (Cd), and arsenic (As) pose global food safety concerns, with infants being particularly vulnerable due to exposure from maternal body burden. This study assessed health risks associated with exposure to Cd, Pb, Hg and As through breast milk consumption among women residing in Guelma, northeastern Algeria. Eighty-four breast milk samples were collected and analyzed using atomic absorption spectrometry, following microwave-assisted acid digestion. The mean concentrations of toxic metals in breast milk were as follows: Pb (15.77 ± 9.54 μg/L) &gt; Hg (3.26 ± 2.50 μg/L) &gt; Cd (2.75 ± 2.39 μg/L) &gt; As (0.35 ± 0.73 μg/L). The Target Hazard Quotient (THQ) for Hg exceeded the safety threshold of 1 across all age groups, with 83 %, 82 %, and 49 % of samples surpassing this limit for 1-month, 6-month, and 12-month-old infants, respectively. Similarly, the Hazard Index (HI) exceeded 1 in all age groups, indicating significant non-carcinogenic risks. Furthermore, the Total Carcinogenic Risk (TCR) for all metals surpassed the acceptable limit (TCR = 1 × 10⁻⁴), with Cd posing a particularly high risk, as 82 % of samples exceeded the carcinogenic threshold. These findings highlight both carcinogenic and non-carcinogenic risks from infant exposure to toxic metals via breast milk, underscoring the urgent need for nationwide monitoring programs, stricter industrial emission controls, and further research into maternal dietary exposure.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105891"},"PeriodicalIF":3.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144491991","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}