Regulatory Toxicology and Pharmacology最新文献

{"title":"Minimizing the Risk of Ethylene Glycol and Diethylene Glycol Poisoning in Medications: A Regulatory and Pharmacopoeial Response.","authors":"Pawan Kumar, Shruti Rastogi, Pawan Kumar Saini, Saurabh Sahoo, Rajeev Singh Raghuvanshi, Gaurav Pratap Singh Jadaun","doi":"10.1016/j.yrtph.2024.105741","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105741","url":null,"abstract":"<p><p>Pharmaceutical and personal care products, including syrups and toothpastes, extensively use glycerin, sorbitol, and propylene glycol. However, past incidents of ethylene glycol (EG) and diethylene glycol (DEG) contamination in these products have raised serious health concerns. Recently, several child deaths linked to contaminated cough syrup consumption have heightened concerns regarding the safety of Indian pharmaceuticals. In response, Indian drug regulatory authorities and the Indian Pharmacopoeia have implemented several measures to enhance the quality, safety, and efficacy of pharmaceuticals manufactured in India. These measures encompass risk-based inspections of manufacturing facilities, rigorous quality control checks of medicinal products intended for export, and increased transparency in the supply chain of excipients prone to EG and DEG contamination. Further, the Indian Pharmacopoeia has updated monographs for five high-risk excipients: glycerin, propylene glycol, sorbitol solution (70%, both crystallizing and non-crystallizing), and liquid maltitol. These efforts are consistent with global regulatory standards and aim to ensure the overall quality and safety of pharmaceuticals produced in India.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105741"},"PeriodicalIF":3.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682610","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":"Response to Letter to Editors submitted by PE Rasmussen, P Huntsman, TM Singer, MN Jacobs, and CC Trevithick-Sutton (Aug 2024).","authors":"Adriana Oller, João Barroso, Pilar Prieto, Violaine Verougstraete, Katherine Heim, Rayetta Henderson","doi":"10.1016/j.yrtph.2024.105740","DOIUrl":"10.1016/j.yrtph.2024.105740","url":null,"abstract":"","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105740"},"PeriodicalIF":3.0,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669060","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 framework for categorizing sources of uncertainty in in silico toxicology methods: Considerations for chemical toxicity predictions","authors":"Jerry Achar ,&nbsp;James W. Firman ,&nbsp;Mark T.D. Cronin ,&nbsp;Gunilla Öberg","doi":"10.1016/j.yrtph.2024.105737","DOIUrl":"10.1016/j.yrtph.2024.105737","url":null,"abstract":"<div><div>Improving regulatory confidence and acceptance of <em>in silico</em> toxicology methods for chemical risk assessment requires assessment of associated uncertainties. Therefore, there is a need to identify and systematically categorize sources of uncertainty relevant to the methods and their predictions. In the present study, we analyzed studies that have characterized sources of uncertainty across commonly applied <em>in silico</em> toxicology methods. Our study reveals variations in the kind and number of uncertainty sources these studies cover. Additionally, the studies use different terminologies to describe similar sources of uncertainty; consequently, a majority of the sources considerably overlap. Building on an existing framework, we developed a new uncertainty categorization framework that systematically consolidates and categorizes the different uncertainty sources described in the analyzed studies. We then illustrate the importance of the developed framework through a case study involving QSAR prediction of the toxicity of five compounds, as well as compare it with the QSAR Assessment Framework (QAF). The framework can provide a structured (and potentially more transparent) understanding of where the uncertainties reside within <em>in silico</em> toxicology models and model predictions, thus promoting critical reflection on appropriate strategies to address the uncertainties.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105737"},"PeriodicalIF":3.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639665","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":"The definition of chemical contaminants in food: ambiguity and consequences.","authors":"Ivonne M C M Rietjens, Michelangelo Pascale, Gloria Pellegrino, Daniel Ribera, Armando Venâncio, Danlei Wang, Konrad Korzeniowski","doi":"10.1016/j.yrtph.2024.105739","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105739","url":null,"abstract":"<p><p>Consumers may be exposed via foods to a diverse range of substances that could be considered as contaminants. However, it is not always straightforward to understand the definition of a 'contaminant'. The present review evaluates how various categories of food-relevant substances are considered in terms of being 'contaminants'. To this end these categories of food borne constituents are evaluated against the various criteria encountered in the available definitions of a food contaminant, including unintentional presence, harmful, existence of regulatory limits, and stakeholder perception. The categories of chemicals considered include: phytotoxins, mycotoxins, (heavy) metals, persistent organic pollutants (POPs), processing aids, process related contaminants, food contact materials (FCMs), pesticides and veterinary drugs. The evaluation revealed that usage of the term appears complex, and may differ between stakeholders. A common proposed definition of the term 'contaminant' could be 'a substance considered to require control measures due to the unacceptability of its context within a food'. Use of a dimension of harm results in equivocal outcomes because risk depends on the level of exposure. As the term 'contaminant' has influence on risk management including public policy, the motivations for applying the term should be subject to more detailed analysis and understanding.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105739"},"PeriodicalIF":3.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639666","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":"Mode of action Criteria for selection of the critical effect and safe dose range for PFOA by the Alliance for risk assessment","authors":"Harvey Clewell","doi":"10.1016/j.yrtph.2024.105738","DOIUrl":"10.1016/j.yrtph.2024.105738","url":null,"abstract":"<div><div>In response to the current disparity in risk assessment values for PFOA from different agencies and countries, an international effort facilitated by the Alliance for Risk Assessment (<em>ARA</em>) was recently undertaken to characterize the range of scientifically supportable safe dose estimates. In this assessment (Burgoon et al., 2023), an evaluation of the evidence regarding the potential modes of action (MOA) for PFOA toxicity was performed first, so that it could be used to inform subsequent decisions regarding potential critical effects and studies. This review describes the evidence considered in the MOA evaluations that were performed as part of the ARA effort. The overall conclusions of this evaluation are that the available mechanistic data do not support any conclusion that reported epidemiological associations of blood concentrations of PFOA as low as 10 ng/mL with various health effects should be considered causal. It is more likely that the reported associations may instead reflect reverse causality/pharmacokinetic confounding. These conclusions are consistent with the opinions of the World Health Organization (WHO, 2022).</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105738"},"PeriodicalIF":3.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142627080","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":"Importance of tailored non-clinical safety testing of novel antimalarial drugs: Industry best-practice","authors":"Philip Hewitt ,&nbsp;Andreas Hartmann ,&nbsp;Belen Tornesi ,&nbsp;Sandrine Ferry-Martin ,&nbsp;Jean-Pierre Valentin ,&nbsp;Paul Desert ,&nbsp;Stephanie Gresham ,&nbsp;Claudia Demarta-Gatsi ,&nbsp;Vinay Kumar Venishetty ,&nbsp;Carine Kolly","doi":"10.1016/j.yrtph.2024.105736","DOIUrl":"10.1016/j.yrtph.2024.105736","url":null,"abstract":"<div><div>Malaria is an acute, debilitating parasitic illness. There were 249 million cases of malaria in 2022, resulting in 608,000 deaths globally, 76% of which were children ≤5 years. The unique nature of this disease (recurrences leading to re-treatments and numerous organ systems affected), specific clinical treatment regimens, poor compliance, and diversity of affected populations (predominantly pediatrics, women of childbearing potential, pregnant and lactating women), often makes standard testing approaches inadequate, and tailor-made safety assessments are more appropriate.</div><div>We provide best practice recommendations based on company experience for the non-clinical safety assessment of antimalarial drugs, with a focus on small molecules since they represent the majority of drug candidates for this illness. We focus on specific testing considerations for repeat dose toxicity studies, including combination toxicity assessments, since new drug treatment regimens typically foresee short treatment durations to improve compliance (i.e., 1 day) with combinations of compounds to improve efficacy and limit potential resistance. Due to the target population, the timing of reproductive, developmental, and juvenile toxicity studies may be earlier than general testing roadmaps for other small molecule drugs.</div><div>In conclusion, key recommendations presented should enable a more effective and efficient development path whilst protecting clinical trial participants and patients.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105736"},"PeriodicalIF":3.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606143","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":"Updated assessment of the genotoxic potential of titanium dioxide based on reviews of in vitro comet, mode of action and cellular uptake studies, and recent publications","authors":"David Kirkland ,&nbsp;Arne Burzlaff ,&nbsp;Andreas Czich ,&nbsp;Shareen H. Doak ,&nbsp;Paul Fowler ,&nbsp;Stefan Pfuhler ,&nbsp;Leon F. Stankowski","doi":"10.1016/j.yrtph.2024.105734","DOIUrl":"10.1016/j.yrtph.2024.105734","url":null,"abstract":"<div><div>In 2021 the European Food Safety Authority (EFSA) concluded that “<em>A concern for genotoxicity of TiO2 particles that may be present in E 171 could therefore not be ruled out.</em>”. A detailed review of the genotoxicity of titanium dioxide (TiO₂) was subsequently published by Kirkland et al. (2022) using a comprehensive weight of evidence (WoE) approach in which test systems and endpoints were allocated different levels of relevance. At that time only 34 publications met the reliability and quality criteria for being most relevant in the evaluation of genotoxicity, and based on these it was concluded that the existing evidence did not support a direct DNA damaging mechanism for TiO₂. Recently a number of regulatory opinions have been published, in which papers were cited that described <em>in vitro</em> DNA damage (mainly comet), mode of action, and cellular uptake studies that were not discussed in Kirkland et al. (2022). Furthermore, a number of additional papers have been published recently or have been identified from the regulatory opinions as a result of using extended search criteria. A total of 70 publications not previously reviewed in Kirkland et al. (2022) have been reviewed here, and again show that the published data on the genotoxicity of TiO₂ are inconsistent, often of poor quality, and in some cases difficult to interpret. The cellular uptake studies show some evidence of cytoplasmic uptake, particularly in cells treated <em>in vitro</em>, but there is no convincing evidence of nuclear uptake. In terms of genotoxicity, the conclusions of Kirkland et al. (2022) that existing evidence does not support a direct DNA damaging mechanism for titanium dioxide (including nano forms), and that the main mechanism leading to TiO₂ genotoxicity is most likely indirect damage to DNA through generation of reactive oxygen species (ROS), are still valid.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105734"},"PeriodicalIF":3.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569010","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":"Endocrine-disrupting chemicals – pesticide regulatory issues from the EU perspective","authors":"Monika Liszewska,&nbsp;Katarzyna Czaja,&nbsp;Wojciech Korcz,&nbsp;Radosław Lewiński,&nbsp;Paweł Struciński","doi":"10.1016/j.yrtph.2024.105735","DOIUrl":"10.1016/j.yrtph.2024.105735","url":null,"abstract":"<div><div>Endocrine-disrupting chemicals (EDCs), including substances used in plant protection products (PPPs), are a source of ongoing concern for the EU society. Under the EC Regulation 1107/2009, the endocrine-disrupting (ED) properties of active substances, safeners, and synergists used in PPPs shall be investigated. The scientific criteria established by the Regulation (EU) 2018/605 and the joint guidance of the European Chemicals Agency (ECHA)/European Food Safety Authority (EFSA) provide the basis for this assessment. Data requirements for the approval of safeners and synergists have been recently published in Commission Regulation (EU) 2024/1487, allowing a consistent assessment of these substances. The approach to assessing co-formulant hazards is currently a subject of EU-wide discussion. It outlines the necessity to take into account information or evaluation data from other than pesticides' EU regulatory frameworks, such as REACH or SCCS applications for cosmetic ingredients. This paper outlines: a) current EU approach applied for identification of endocrine disrupting properties of pesticides; b) issues related to European regulations that may have an indirect impact on the safe use of plant protection products and c) an analysis of the European Commission's activities aimed to limit exposure to EDCs associated with use of PPPs in the society.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105735"},"PeriodicalIF":3.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568879","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":"Statistical applications of virtual control groups to nonrodent animal toxicity studies: An initial evaluation","authors":"Dingzhou Li ,&nbsp;Jeonifer Garren ,&nbsp;Raja Mangipudy ,&nbsp;Matthew Martin ,&nbsp;Lindsay Tomlinson ,&nbsp;Nichole R. Vansell","doi":"10.1016/j.yrtph.2024.105733","DOIUrl":"10.1016/j.yrtph.2024.105733","url":null,"abstract":"<div><div>Utilization of data from historical control animals to form virtual control groups (VCGs) is an innovative approach to embody the 3Rs (reduce, refine, and replace use of control animals) principle in research. However, there is no available systematic comparison of statistical performance between concurrent control groups (CCGs) and VCGs in nonrodent safety assessment. The optimal selection criteria and combination of VCGs and CCGs also remain unclear. This study retrospectively evaluated VCGs’ statistical performance to detect test article effects on body weight and clinical pathology endpoints in dog and nonhuman primate (NHP) systemic toxicity studies. Body weight and six clinical pathology endpoints were analyzed against the reported study findings from a cohort of 22 previously reported nonrodent 1-month oral gavage toxicity using three different methods of generating VCGs. When the fold change from baseline was used, VCGs yielded a similar or higher statistical sensitivity to detect test article relatedness than CCGs. Compared to simple random sampling or using fixed criteria, the propensity score matching by BW, age, and year of study initiation yielded higher sensitivities. Our analysis supports the hypothesis that VCGs can be a viable instrument in nonrodent toxicity studies.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105733"},"PeriodicalIF":3.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564866","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":"Opportunities and challenges for use of minipigs in nonclinical pharmaceutical development: Results of a follow-up IQ DruSafe survey","authors":"David O. Clarke ,&nbsp;Kaushik Datta ,&nbsp;Kevin French ,&nbsp;Michael W. Leach ,&nbsp;Drew Olaharski ,&nbsp;Susanne Mohr ,&nbsp;Devon Strein ,&nbsp;Jeanine Bussiere ,&nbsp;Bianca Feyen ,&nbsp;Beatrice E. Gauthier ,&nbsp;Michael Graziano ,&nbsp;Joanna Harding ,&nbsp;Kenneth Hershman ,&nbsp;Binod Jacob ,&nbsp;Shaofei Ji ,&nbsp;Robert Lange ,&nbsp;Smita Salian-Mehta ,&nbsp;Brian Sayers ,&nbsp;Nicole Thomas ,&nbsp;Thierry Flandre","doi":"10.1016/j.yrtph.2024.105729","DOIUrl":"10.1016/j.yrtph.2024.105729","url":null,"abstract":"<div><div>Minipigs are valid nonrodent species infrequently utilized for pharmaceutical research and development (R&amp;D) compared with dogs or nonhuman primates (NHPs). A 2022 IQ DruSafe survey revealed a modest increase in minipig use by pharmaceutical companies compared with a prior 2014 survey, primarily in the development of oral small molecules and parenteral protein molecules. Some companies considered using minipigs more often due to NHP shortages and regional ethical concerns with using NHPs and dogs. However, for most pharmaceutical companies, minipigs still represent ≤5% of their nonrodent animal use. Key challenges noted by companies to wider adoption of minipigs were high test article requirement, limited historical control data, and lack of relevant reagents or assays. Additionally, some companies expressed uncertainties about contract research organization (CRO) capabilities and experience, a perception not shared by respondent CROs. These latest survey results indicate persistence of many concerns previously identified in 2014. Several case studies are included to illustrate areas of expanded minipig use as well as the challenges that hinder broader adoption. Ongoing, focused, and industry-wide initiatives to address the identified or perceived challenges may lead to more frequent or routine consideration of minipigs as a test species in pharmaceutical R&amp;D.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105729"},"PeriodicalIF":3.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558611","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}