Regulatory Toxicology and Pharmacology最新文献

{"title":"Prevalence and sample sizes in pre-clinical studies","authors":"Jenna K. Felli,&nbsp;Derek J. Leishman,&nbsp;Meredith A. Steeves","doi":"10.1016/j.yrtph.2025.105817","DOIUrl":"10.1016/j.yrtph.2025.105817","url":null,"abstract":"<div><div>This work explores the relationship between event prevalence and event observation in the context of a study with a fixed number of subjects. For any given study size, one expects the number of occurrences of a given event to increase as the prevalence of that event increases. We use the Binomial distribution to characterize the likelihood of observing at least one specified event for a fixed sized study over a range of prevalence values. From this, we explore the marginal impact on that likelihood as the study size increases. We present findings regarding the value of prevalence that maximizes the marginal impact of adding one additional subject to a study. We then explicitly characterize the interaction of prevalence and sample size in yielding event observation and provide a vehicle by which study planners may design studies based on risk of non-detection as opposed to traditional power calculations.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"160 ","pages":"Article 105817"},"PeriodicalIF":3.0,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754240","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":"Enhanced pre- and postnatal developmental toxicity (ePPND) study in non-human primates: Necessity, strategic approaches, and critical considerations","authors":"Jing Lu ,&nbsp;Dehu Dou ,&nbsp;Yawen Wang ,&nbsp;Jiaao Shu ,&nbsp;Zhiqi Lei ,&nbsp;Yan Huo ,&nbsp;Xinjiang Gong","doi":"10.1016/j.yrtph.2025.105814","DOIUrl":"10.1016/j.yrtph.2025.105814","url":null,"abstract":"<div><div>Nonclinical developmental and reproductive toxicity (DART) studies are crucial components of novel drug development, as they identify reproductive and developmental risks and ensure drug safety in populations such as pregnant women and women of childbearing potential (WOCBP). Rodents or rabbits are commonly used in nonclinical studies to evaluate DART for chemical compounds. However, for most antibody-based biopharmaceuticals, non-human primates (NHPs) are the only pharmacologically relevant species, necessitating the use of NHPs in DART studies. These studies pose significant challenges due to stringent design requirements, complex protocols, prolonged timelines, and high costs. A single well-designed NHP study, in which the test substance is administered from gestational day 20 until delivery (enhanced Pre- and Postnatal Developmental study, ePPND study), is preferable to conducting separate Embryo-Fetal Developmental (EFD) and Pre- and Postnatal Developmental (PPND) studies. This review highlights the scientific rationale for NHP-based ePPND studies as mandated by major regulatory agencies, discusses advanced methodologies, key challenges (including endpoint selection, experimental design optimization, and data interpretation with case examples), and offers guidance for ePPND design across antibody-based therapeutics.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"159 ","pages":"Article 105814"},"PeriodicalIF":3.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743502","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 vitro hazard characterization of contaminants migrating from recycled paper food contact materials","authors":"Athanasios Kourkopoulos ,&nbsp;Dick T.H.M. Sijm ,&nbsp;Anastasiya Mircheva ,&nbsp;Victoria Claudino Bastos ,&nbsp;Misha F. Vrolijk","doi":"10.1016/j.yrtph.2025.105816","DOIUrl":"10.1016/j.yrtph.2025.105816","url":null,"abstract":"<div><div>The safety of paper food contact materials (FCMs) is critical for public health, necessitating precise toxicity assessments. This study investigates the impact of sample preparation methods (migration and extraction), liver metabolic enzymes, endogenous ligands, and various cell lines on the in vitro toxicity of paper FCMs. Toxicological endpoints include mutagenicity, genotoxicity, potential estrogenicity, androgenicity, aryl hydrocarbon receptor activity, and cytotoxicity to hepatocytes and the colon intestinal epithelial barrier, using HepG2 and Caco-2 cell lines. Two preparation methods were employed: migration per Commission Regulation (EU) October 2011 and exhaustive Soxhlet extraction. Extraction revealed distinct toxicological profiles compared to migration, exhibiting toxicity in more endpoints, potentially due to different sample conditions affecting chemical identity and concentration. The addition of liver metabolic enzymes altered estrogenic and androgenic activity, while endogenous ligands influenced potency in estrogenicity and androgenicity tests. Integrating extraction and migration methods with physiologically relevant models enhances the evaluation of hazards from paper FCMs. This involves incorporating cell lines that mimic target tissues, such as liver and intestinal epithelium, alongside metabolic enzymes and endogenous ligands in estrogen receptor alpha and androgen activity testing, providing a strategy for the comprehensive assessment of hazards in food contact materials.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"159 ","pages":"Article 105816"},"PeriodicalIF":3.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ethical principles for regulatory risk decision-making","authors":"Yadvinder Bhuller ,&nbsp;Marc Avey ,&nbsp;Raywat Deonandan ,&nbsp;Thomas Hartung ,&nbsp;Gina M. Hilton ,&nbsp;Robin J. Marles ,&nbsp;Stefania Trombetti ,&nbsp;Daniel Krewski","doi":"10.1016/j.yrtph.2025.105813","DOIUrl":"10.1016/j.yrtph.2025.105813","url":null,"abstract":"<div><div>Risk assessors, managers, and decision-makers are responsible for evaluating diverse human, environmental, and animal health risks. Although the critical elements of risk assessment and management are well-described in national and international documents, the ethical issues involved in risk decision-making have received comparatively little attention to date. To address this aspect, this article elaborates fundamental ethical principles designed to support fair, balanced, and equitable risk-based decision-making practices. Experts and global thinkers in risk, health, regulatory, and animal sciences were convened to share their lived experiences in relation to the intersection between risk science and analysis, regulatory science, and public health. Through a participatory and knowledge translation approach, an integrated risk decision-making model, with ethical principles and considerations, was developed and applied using diverse, contemporary risk decision-making and regulatory contexts. The ten principles - autonomy, minimize harm, maintain respect and trust, adaptability, reduce disparities, holistic, fair and just, open and transparent, stakeholder engagement, and One Health lens - demonstrate how public sector values and moral norms (i.e., ethics) are relevant to risk decision-making. We also hope these principles and considerations stimulate further discussion, debate, and an increased awareness of the application of ethics in identifying, assessing, and managing health risks.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"159 ","pages":"Article 105813"},"PeriodicalIF":3.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ex vivo prediction of the sensitization potential of biocides","authors":"Mélanie Mourot-Bousquenaud,&nbsp;Samuel Muller,&nbsp;Amélie Coiscaud,&nbsp;Julianne Mathiot,&nbsp;Aurélie Remy,&nbsp;Sandrine Jacquenet,&nbsp;Fabrice Battais","doi":"10.1016/j.yrtph.2025.105812","DOIUrl":"10.1016/j.yrtph.2025.105812","url":null,"abstract":"<div><div>Biocides are widely used in the workplace, mainly in the industrial and healthcare sectors. Because of their potential hazard for human health, their use is regulated on the European market. In particular, the sensitization potential of these substances must be identified in order to implement avoidance of exposure or measures maximizing protection of exposed employees. The objective of this study was to predict the sensitization potential of 24 biocides used in the workplace. For this purpose, the expression of two co-stimulatory markers and four chemokines was analyzed by flow cytometry in murine bone marrow-derived dendritic cells (BMDCs) exposed to the substances. Twenty-two substances induced cell activation with a concentration effect and were identified as sensitizers. Based on the BMDC model, these substances were classified into four potency categories: six extreme sensitizers, twelve strong sensitizers, two moderate and two weak sensitizers. All these biocides, except the ones classified as extreme, induced an upregulation of chemokines secretion in BMDCs. To conclude, the majority of the biocides tested were identified as potential sensitizers. These data underline the need to handle such substances with care in a preventive occupational context.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"159 ","pages":"Article 105812"},"PeriodicalIF":3.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reproductive and developmental toxicity assessment of HSK21542, a novel peripherally-restricted kappa opioid receptor agonist in rats and rabbits","authors":"Xiaoli Gou ,&nbsp;Qidi Ye ,&nbsp;Bo Chen ,&nbsp;Yu Zheng ,&nbsp;Hongyu Chen ,&nbsp;Litong Fan ,&nbsp;Qingyuan Meng ,&nbsp;Chen Zhang ,&nbsp;Yao Lu ,&nbsp;Ju Wang","doi":"10.1016/j.yrtph.2025.105811","DOIUrl":"10.1016/j.yrtph.2025.105811","url":null,"abstract":"<div><div>HSK21542, a potent and peripherally-restricted kappa opioid receptor (KOR) agonist, is currently being developed to treat postoperative pain and pruritus. Given that conventional opioids (MOR agonists) are widely recognized for their toxicological impacts on the reproductive system and embryonic development, we evaluated the effects of HSK21542 accordingly. The results showed that HSK21542 did not influence male and female fertility or early embryonic development in rats. HSK21542 also did not show significant manifestations of pre- and post-natal development toxicity in rats. In the embryo-fetal developmental study, even though there was a 3.5 % increase in incidence of fetuses with incomplete ossification of thoracic vertebral centrum in the 4 mg/kg/day group, the plasma exposure of HSK21542 in rats at the no observed adverse effect level (NOAEL) was 82.3 times higher than that of human exposure at 1 μg/kg. On the other hand, exposure to HSK21542 during pregnancy in rabbits did not show any teratogenic risk, only causing a minor impact on bone ossification in fetuses. In conclusion, HSK21542 has a favorable safety profile with only minor effects on the embryo-fetal developmental outcomes.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"159 ","pages":"Article 105811"},"PeriodicalIF":3.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670705","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":"Cross-taxa extrapolation: Is there a role for thyroid hormone conjugating liver enzymes during amphibian metamorphosis?","authors":"Christel R. Schopfer ,&nbsp;Franziska Grözinger ,&nbsp;Barbara Birk ,&nbsp;Nicola J. Hewitt ,&nbsp;Lennart Weltje ,&nbsp;Maike Habekost","doi":"10.1016/j.yrtph.2025.105810","DOIUrl":"10.1016/j.yrtph.2025.105810","url":null,"abstract":"<div><div>Chemical safety assessment includes evaluating the potential to disrupt the endocrine system in humans and wildlife. The thyroid hormone system shows high complexity which is conserved across vertebrates, allowing biological read-across between regulatory important taxa, namely mammals and amphibians. Potential thyroid disruption in aquatic vertebrates is typically investigated by activity assays (<em>Amphibian Metamorphosis Assay</em> (AMA), <em>Xenopus Eleutheroembryo Thyroid Assay)</em>. Since neither assay is designed to provide detailed mechanistic information, mode of action analyses often rely on mammalian data, assuming overall cross-vertebrate conservation. This manuscript elaborates on the imperative that, despite overall conservation, the T-modality in metamorphosing amphibians needs to be understood in detail to justify biological read-across between mammals and amphibians. To this end, we revisit the AMA regarding amphibian developmental physiology, and the T-modality regarding mechanistic cross-vertebrate conservation. The importance of a mechanistic understanding for read-across is showcased based on the AMA's apparent insensitivity to at least one category of prototypical liver enzyme inducers. From a regulatory perspective, deeper mechanistic understanding is needed, not only to strengthen the scientific basis for designing testing strategies and interpreting study results, but also to allow the identification of data gaps and thus development of New Approach Methodologies (NAMs) to minimize vertebrate testing.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"159 ","pages":"Article 105810"},"PeriodicalIF":3.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current nonclinical testing paradigm to allow clinical entry for pharmaceutical drug candidates","authors":"Paul Baldrick","doi":"10.1016/j.yrtph.2025.105809","DOIUrl":"10.1016/j.yrtph.2025.105809","url":null,"abstract":"<div><div>Nonclinical safety testing (pharmacology, ADME and toxicology studies) needs to occur to support First-In-Human clinical entry for pharmaceutical drug candidates. Examination of the study package from the content of Investigator Brochures (IBs) for 32 small (non-oncology) molecules used to support such entry over a 4-year period (2020–2023) showed that a mean of 38 nonclinical studies were performed per molecule with pharmacology, ADME and toxicology testing contributing 37 %, 39 % and 24 % of the studies, respectively. Examination of IBs used to support clinical entry of 15 small molecule oncology drugs gave similar values of 43 studies contributing 37 %, 42 % and 21 %, respectively. Examination of IBs for 16 biopharmaceuticals showed a mean number of 19 studies per molecule with pharmacology, ADME and toxicology testing contributing 84 %, 5 % and 11 % of the studies, respectively. Overall, for both small molecule and biopharmaceutical drug candidates, similar numbers of pharmacology studies were performed but the approximately 50 % fewer studies for biopharmaceuticals was due to considerably limited ADME and toxicology testing. Comment will be made on how the current study package could be refined (a 3Rs approach) to reduce animal use.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"159 ","pages":"Article 105809"},"PeriodicalIF":3.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639800","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":"Points to consider for revising the ICH S7A guideline on safety and secondary pharmacology","authors":"Jean-Pierre Valentin ,&nbsp;Derek Leishman","doi":"10.1016/j.yrtph.2025.105795","DOIUrl":"10.1016/j.yrtph.2025.105795","url":null,"abstract":"<div><div>Although the ICH S7A guideline on safety pharmacology largely achieved its objective, a proportion of remaining adverse drug reactions and attrition can be attributed in part to gaps in safety and secondary pharmacology assessments. Advances in science, technology, drug development paradigm and regulatory practices necessitate revisiting and evolving ICH S7A to address these limitations. The anticipated completion of the ICH S7B Q&amp;As by end of 2025 provides an opportunity to integrate its outcomes with ICH S7A into a comprehensive, modality-agnostic sustainable over time framework. Such consolidation could streamline guidance, enhance usability, and align regulatory expectations globally. This proposed revision should aim to address key aspects of safety and secondary pharmacology, including the definition of adversity, the integration of human-relevant <em>in vitro</em> and <em>in silico</em> models, and the adoption of state-of-the-art <em>in vivo</em> platforms. Further considerations should include the development of principles for model and assay validation, the promotion of integrated risk assessment frameworks, and incorporation of weight of evidence approaches. Revised guideline would also emphasize sustainable practices by adapting to evolving therapeutic modalities, while reducing reliance on animal testing through New Approach Methodologies. The revision seeks to enhance the benefit-risk evaluation of drug candidates, refine clinical monitoring, foster regulatory acceptance, and streamline drug development. This comprehensive update has the potential to not only optimize drug safety evaluations but also to align industry practices with modern scientific advancements and ethical considerations, ensuring a more robust and efficient pathway for therapeutic innovation.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"159 ","pages":"Article 105795"},"PeriodicalIF":3.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586442","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":"Interpretable machine learning unveils key predictors and default values in an expanded database of human in vitro dermal absorption studies with pesticides","authors":"D. Sarti ,&nbsp;J. Wagner ,&nbsp;F. Palma ,&nbsp;H. Kalvan ,&nbsp;M. Giachini ,&nbsp;D. Lautenschalaeger ,&nbsp;V. Lupianhez ,&nbsp;J. Pires ,&nbsp;M. Sales ,&nbsp;P. Faria ,&nbsp;L. Bertomeu ,&nbsp;M. Le Bras","doi":"10.1016/j.yrtph.2025.105801","DOIUrl":"10.1016/j.yrtph.2025.105801","url":null,"abstract":"<div><div>The skin is the main route of exposure to plant protection products for operators, workers, residents, and bystanders. Assessing dermal absorption is key for evaluating pesticide exposure. The initial approach to risk assessment involves using default dermal absorption values or applying read-across data from experimental results from different formulations. In this way, to support non-dietary pesticide risk assessment focused but not limited to Brazil, this project evaluated 759 GLP-compliant <em>in vitro</em> human skin dermal absorption studies covering 25 formulation types and 248 active substances at multiple concentrations using interpretable machine learning techniques. Bayesian Additive Regression Trees – BART method indicated that Log Pow and molecular weight have the highest importance when predicting dermal absorption; both parameters exhibit moderate interaction uncertainty within each other and with formulation groups water-based and organic-solvent based and with tested form (concentrates or dilutions). The default values for each formulation group were determined using the upper bound of a non-parametric confidence interval for a specified quantile, with calculations conducted via bootstrapping methods; the proposed values correspond to the upper limit of the 95% confidence interval for the 95th percentile: for concentrates, 10% for organic-solvent based, 4% for water-based and 3% for solid formulations. For dilutions, 42% for organic-solvent based, 37% for water-based and 39% for solid formulations. Organic-solvent based dermal absorption values from experimental data can be used as conservative surrogates for solid and water-based formulations. When no experimental data is available for higher spray dilutions of a given formulation type, a pro-rated correction is proposed to a 2 to 5-fold concentration difference, limited to the respective formulation group default value.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"159 ","pages":"Article 105801"},"PeriodicalIF":3.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}