Regulatory Toxicology and Pharmacology最新文献

{"title":"A Comprehensive Safety Assessment of Algae Protein from Picochlorum for Human Consumption.","authors":"Tomal Dattaroy, Manish R Shukla","doi":"10.1016/j.yrtph.2024.105753","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105753","url":null,"abstract":"<p><p>The current trend happens to be that consumers are seeking nourishing, high quality sustainable protein sources to meet their nutritional needs, thus establishing a clear intent to broaden their protein horizon. Microalgae protein holds great promise in becoming the next vegan protein option. In the present study, protein extracted from the microalga Picochlorum maculatum has been thoroughly evaluated for its safety for human consumption through a battery of in-vivo and in-vitro tests. Bacterial reverse mutation assay indicates that the test substance is non-mutagenic and studies comprising of in-vitro chromosomal aberration test and the in-vivo mammalian micronucleus test showed that the test item is non-clastogenic, and therefore, lacks genotoxicity. Based the results of an acute oral toxicity study, the test item can be classified as \"Category 5\" as designated in a globally harmonized system for classification of chemicals. Further, 28-day and 90-day repeated dose oral toxicity studies did not result in any mortality or morbidity throughout the experimental period; none of the animal groups used in the study showed any abnormal clinical signs, establishing a \"No Observed Adverse Effect Level\" of Algae Protein Powder at 3000 mg kg bw^-1. Moreover, the test item exhibited a positive impact on growth in test animals. Computational studies established extremely low allergenic potential of the test item.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105753"},"PeriodicalIF":3.0,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771745","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 and derivations of permitted daily exposure limits for impurities from intravitreal pharmaceutical products","authors":"Yi Yu Rice ,&nbsp;David G. Dolan ,&nbsp;Suren B. Bandara ,&nbsp;Ryan E. Morgan ,&nbsp;Michael Garry ,&nbsp;Joyce Tsuji","doi":"10.1016/j.yrtph.2024.105745","DOIUrl":"10.1016/j.yrtph.2024.105745","url":null,"abstract":"<div><div>Intravitreal (IVT) injection is an uncommon route of parenteral administration for therapeutic medications, but one of the most important for the treatment of ocular diseases, especially those related to macular degeneration. Nonetheless, there are currently no regulatory guidelines that specifically address how to establish a permitted daily exposure (PDE) for impurities and residual process reagents in IVT pharmaceutical drug products given the unique vulnerability of ocular tissues. The establishment of PDEs for IVT administration is complicated by the limited understanding of metabolism and clearance of small molecular weight chemicals from the human vitreous humor (VH), a problem compounded by the limited IVT-specific toxicological data. In this paper, we describe a feasible and comprehensive methodology for deriving PDE limits for impurities and residual process reagents from IVT drug products, as exemplified by five case studies, including inorganic elements, formic acid, polyethylene glycols, acetic acid, and caprolactam. The five case studies were selected to cover compounds with a wide range of impurity sources and toxicological data availability. The proposed framework considers both local ocular and systemic toxicity endpoints and advances the goal of a harmonized, science-based approach for deriving IVT PDE limits.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"155 ","pages":"Article 105745"},"PeriodicalIF":3.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710197","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":"Carcinogenicity assessment of inotersen in Tg.rasH2 mice and Sprague-Dawley rats: Implications for 2′-MOE antisense oligonucleotides","authors":"Tae-Won Kim ,&nbsp;Chris N. Papagiannis ,&nbsp;Laura S. Zwick ,&nbsp;Paul Snyder ,&nbsp;Jeffery A. Engelhardt ,&nbsp;Rosie Z. Yu ,&nbsp;Christine M. Hoffmaster ,&nbsp;Archit Rastogi ,&nbsp;Scott P. Henry","doi":"10.1016/j.yrtph.2024.105743","DOIUrl":"10.1016/j.yrtph.2024.105743","url":null,"abstract":"<div><div>Inotersen, a 2′-<em>O</em>-(2-methoxyethyl) modified antisense oligonucleotide (2′-MOE ASO), is approved for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR). It underwent a comprehensive nonclinical safety evaluation, including safety pharmacology, repeat-dose toxicity, genotoxicity, reproductive and development toxicity, and carcinogenicity studies. Tumorigenic potential was assessed through dedicated carcinogenicity studies in transgenic rasH2 (Tg.rasH2) mice and Sprague Dawley (SD) rats. In the 26-week Tg.rasH2 mouse study, inotersen and a mouse-active surrogate (ISIS 401724) were administered as weekly subcutaneous (SC) doses up to 80 mg/kg and 30 mg/kg, respectively. Proinflammatory effects and ASO accumulation in the liver and kidney, both well-documented class effects, were observed; however, no treatment-related neoplasms were noted. Similarly, the mouse surrogate did not induce any treatment-related neoplasms. In the 2-year SD rat carcinogenicity study, inotersen was administered as weekly SC doses up to 6 mg/kg. The primary dose-limiting effect at doses ≥2 mg/kg/week was an increased incidence of chronic progressive nephropathy (CPN), which contributed to decreased survival at the 6 mg/kg/week dose level. Notably, no renal neoplasia was associated with the increased CPN. Increasing mononuclear cell infiltrates at the injection site were linked to an increased incidence of subcutaneous fibrosarcoma at doses ≥2 mg/kg/week. This inflammation-associated injection site tumor in rats administered inotersen has limited relevance for humans. Additionally, the long-term assessment of ASO effects in rats is somewhat limited due to the ASO exacerbation of CPN and its impact on survival. There was no evidence of genotoxicity <em>in vitro</em> or <em>in vivo</em> at limit doses. Collectively, these data support a conclusion that a single carcinogenicity assessment in the Tg.rasH2 mouse, along with data from chronic toxicology studies in the rodent and nonrodent, is sufficient to assess carcinogenic potential for this drug class.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"155 ","pages":"Article 105743"},"PeriodicalIF":3.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695428","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":"Enhancing reliability of embryo-fetal developmental toxicity studies: A proposed design of replicate studies","authors":"L. David Wise","doi":"10.1016/j.yrtph.2024.105742","DOIUrl":"10.1016/j.yrtph.2024.105742","url":null,"abstract":"<div><h3>Background</h3><div>This report addresses the reliability of results from rat Embryo-Fetal Developmental Toxicity (EFDT) studies. Recent literature discusses the roles of reproducibility, replicability, and other influences on scientific reliability. Reproducibility is a re-analysis of the original data, while replicability addresses the same question with a separate study of some type. Concordance of rat and rabbit studies has been addressed previously, but replication of single-species EFDT studies was not found in the literature. A modest modification of the rat study is therefore proposed to assess replicability and possibly enhance reliability.</div></div><div><h3>Methods</h3><div>Regulatory guidelines were consulted and relevant literature was identified through online searches.</div></div><div><h3>Results</h3><div>Each replicate EFDT (r-EFDT) study in rats would consist of half the mated females of the definitive study. Studies would start at the same or different times in one testing facility. Separate shipments of animals (non-littermates) are required. All other procedures would be protocol-driven. The micro- and macro-environments of the animals would be held as constant as possible. Justification, design options, and interpretation methods are discussed.</div></div><div><h3>Conclusion</h3><div>Besides adding reliability, other benefits include reduced animal usage, and potentially reduced cost and time to final reports. By reducing the need for repeated studies due to questionable results, this modified study is viewed as a more efficient use of costly resources. The r-EFDT study design could easily be adapted to assess replicability of rabbit EFDT and some general toxicity studies. Future replicate studies are needed to critically evaluate replicability and the overall impact on study reliability.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"155 ","pages":"Article 105742"},"PeriodicalIF":3.0,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693453","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":"Target organ toxicity in Sprague Dawley rats following oral exposure to complex groundwater mixture: Assessment of dose-response relationships using histopathological and biochemical alterations","authors":"B. Boamah ,&nbsp;S. Siciliano ,&nbsp;N. Hogan ,&nbsp;M. Hecker ,&nbsp;M. Hanson ,&nbsp;P. Campbell ,&nbsp;R. Peters ,&nbsp;A.N. Al-Dissi ,&nbsp;L.P. Weber","doi":"10.1016/j.yrtph.2024.105744","DOIUrl":"10.1016/j.yrtph.2024.105744","url":null,"abstract":"<div><div>Exposure to contaminant mixtures from industrial legacy sites presents unique challenges that require novel approaches such as effects-directed toxicity assessment. This study characterized the target organ toxicity of groundwater from a legacy contaminated pesticide plant in male and female Sprague Dawley rats exposed to low impact (10% v/v) groundwater, high impact (0.01% v/v, 0.1% v/v, 1% v/v, and 10% v/v) groundwater or tap water (control) for 60 days. Rats exposed to high impact (1% and 10%) and 10% low impact groundwater mixture showed statistically significant increases in liver necro-inflammation relative to control. A statistically significant reduction was observed in plasma albumin of exposed rats (except 0.01% high impact) and alpha 2 macroglobulin (all exposed) when compared to the control. All groundwater-exposed rats showed glomerulopathy, but there were sex-specific differences in acute tubular necrosis. Testes showed germinal cell vacuolation, necrosis, reduced seminiferous epithelial height, and Sertoli syndrome in exposed rats, accompanied by reduced plasma testosterone and increased testicular malondialdehyde. Taken together, this sub-chronic oral exposure to groundwater from a contaminated industrial site caused dose-dependent hepatic and testicular toxicity, while nephrotoxicity was both sex-dependent and dose-dependent. This study provides support for the essentiality of using effects-driven approaches in the risk assessment of complex mixtures.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105744"},"PeriodicalIF":3.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142688462","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":"Minimizing the risk of ethylene glycol and diethylene glycol poisoning in medications: A regulatory and pharmacopoeial response","authors":"Pawan Kumar,&nbsp;Shruti Rastogi,&nbsp;Pawan Kumar Saini,&nbsp;Saurabh Sahoo,&nbsp;Rajeev Singh Raghuvanshi,&nbsp;Gaurav Pratap Singh Jadaun","doi":"10.1016/j.yrtph.2024.105741","DOIUrl":"10.1016/j.yrtph.2024.105741","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"155 ","pages":"Article 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 ,&nbsp;João Barroso ,&nbsp;Pilar Prieto ,&nbsp;Violaine Verougstraete ,&nbsp;Katherine Heim ,&nbsp;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":"154 ","pages":"Article 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":"The definition of chemical contaminants in food: Ambiguity and consequences","authors":"Ivonne M.C.M. Rietjens ,&nbsp;Michelangelo Pascale ,&nbsp;Gloria Pellegrino ,&nbsp;Daniel Ribera ,&nbsp;Armando Venâncio ,&nbsp;Danlei Wang ,&nbsp;Konrad Korzeniowski","doi":"10.1016/j.yrtph.2024.105739","DOIUrl":"10.1016/j.yrtph.2024.105739","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"155 ","pages":"Article 105739"},"PeriodicalIF":3.0,"publicationDate":"2024-11-14","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":"OA","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":"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}