Regulatory Toxicology and Pharmacology最新文献

{"title":"Control of N-nitrosamine impurities in drug products: Progressing the current CPCA framework and supporting the derivation of robust compound specific acceptable intakes.","authors":"David J Ponting, Andreas Czich, Susan P Felter, Susanne Glowienke, James S Harvey, Raphael Nudelman, Joerg Schlingemann, Stephanie Simon, Graham F Smith, Andrew Teasdale, Robert Thomas","doi":"10.1016/j.yrtph.2024.105762","DOIUrl":"10.1016/j.yrtph.2024.105762","url":null,"abstract":"<p><p>The carcinogenic potency categorisation approach (CPCA) has recently been introduced by health authorities. In this model, structural features from recent literature, industry proposals, and analyses performed by health authorities, provide a rapid assessment of the potential acceptable intake (AI) for a nitrosamine impurity. As with other screening regulatory values (such as the ICH M7 Threshold of Toxicological Concern), the CPCA is conservative and can be considered a de minimis risk management framework. In cases where a nitrosamine drug substance-related impurity (NDSRI) is present below the CPCA limit, the framework provides resolution from a toxicological perspective (i.e., no further toxicology studies are required). Where an NDSRI is above the CPCA limit, the framework provides for the initiation of additional activities (i.e., the CPCA is not the only possible limit). Read-across approaches are described in both the CPCA and M7 guidance and can provide a limit with more specific applicability than the general model. The use of available experimental data (in vitro or in vivo), is valuable in order to provide an even more specific limit. The CPCA provides a framework; however, data should permit changing the AI from initial structural assessment, based on increasing data, to ultimately increase precision of the AI.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105762"},"PeriodicalIF":3.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814074","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":"Ames mutagenicity of 15 aryl, benzyl, and aliphatic ring N-nitrosamines.","authors":"Ayako Furuhama, Kei-Ichi Sugiyama, Masamitsu Honma","doi":"10.1016/j.yrtph.2024.105763","DOIUrl":"10.1016/j.yrtph.2024.105763","url":null,"abstract":"<p><p>The Ames mutagenicity test is an effective means of screening compounds for their carcinogenic potential. Here, we conducted Ames tests on 15 aryl, benzyl, and aliphatic ring N-nitrosamines. Then, by using two indicators of mutagenicity strength calculated from the Ames test results, namely, maximum specific activity (MSA; number of revertant colonies) and maximum fold increase (MFI; relative ratio of increased colonies), we examined the relationship between Ames mutagenicity strength and Carcinogenic Potency Categorization Approach (CPCA) potency category, which is a structure-activity-relationship-based prediction of the carcinogenic potency of nitrosamines. Eleven of the test compounds were Ames positive and four were negative. Of the 11 positive compounds, three were categorized as strong positive (MSA ≥1000), five as medium positive (100 ≤ MSA <1000), and three as weak positive (MSA <100). The compounds with an aliphatic ring showed a negative relationship between mutagenicity strength (i.e., MSA or MFI) and carcinogenic potential (i.e., CPCA category), whereas, the alpha-methyl aryl N-nitrosamines did not. Overall, MSA and MFI were found to be detailed indicators of the carcinogenic potency of the N-nitrosamines and can potentially be used to support CPCA categorization.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105763"},"PeriodicalIF":3.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814067","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":"Establishment of a threshold of toxicological concern for pharmaceutical intermediates based on historical repeat-dose data and its application in setting health based exposure limits.","authors":"Zoe Dunn, Delorice Murudzwa, Kamila Blum","doi":"10.1016/j.yrtph.2024.105764","DOIUrl":"10.1016/j.yrtph.2024.105764","url":null,"abstract":"<p><p>Availability of toxicological data for pharmaceutical intermediates (IMs) used in the manufacture of small molecules is often limited. Scarcity of data - in particular, repeat-dose toxicity (RDT) - renders the calculation of health-based exposure limits (HBELs) problematic. Establishment of HBELs, including occupational exposure limits (OELs) and permitted daily exposures (PDEs) facilitating worker and patient safety respectively, is however essential. Historic 28-day oral rodent toxicity data was analysed for 103 GSK isolated IMs. No-observed (adverse) effect levels (NO(A)ELs) and critical effects were extracted. The 5th percentile (p05) of the NO(A)EL distribution was 15 mg/kg/day. Substance specific HBELs were calculated, selecting the NO(A)EL as the Point of Departure (PoD); 99% of IMs (n = 102) were assigned an oral PDE ≥1000 μg/day and OEL ≥100 μg/m³. A default oral PDE of 1000 μg/day and OEL of 100 μg/m³ is thus proposed for IMs. Evaluation of an additional PoD - benchmark dose lower confidence limit (BMDL) - further supported the default HBELs. The default oral PDE can also serve as a threshold of toxicological concern (TTC) for IMs. Default limits can aid in setting HBELs for novel data-poor IMs, as well as supporting waiving of RDT in the future through read-across.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105764"},"PeriodicalIF":3.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807901","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 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":"Incorporating Singaporean habits and practices for cosmetics and personal care products into a global consumer aggregate exposure model.","authors":"Siti Amelia Juraimi, Cesar Scrochi, Jonathan Lok, Anne Marie Api, Benjamin P C Smith","doi":"10.1016/j.yrtph.2024.105752","DOIUrl":"10.1016/j.yrtph.2024.105752","url":null,"abstract":"<p><p>Understanding consumer habits and practices of cosmetics and personal care products (PCP) is essential to generate realistic product exposure data for the safety assessment of ingredients such as fragrance materials. Product usages can vary across regions due to differences in cultural norms, seasonal and climate conditions, and the availability of different product forms, yet there is limited data published on cosmetics and PCP use outside of North America and Europe. This study reports the habits and practices of cosmetics and PCP (such as frequency and amount of use) in Singapore where participants (n = 494, aged 21-64 years) recorded their product usages and had their products weighed over a two-week period. Overall, similar use patterns were observed across demographic groups within the Singapore population for most of the products surveyed, as were the expected usage amounts. Additionally, the Singaporean dataset was mapped onto the Creme-RIFM aggregate exposure model to assess exposure estimates. Preliminary comparisons with product exposures observed in the United States (US) and Europe suggest that exposures in Singapore are comparable. Findings from this study will contribute to the Creme-RIFM model, expanding its geographic scope and applicability for the global safety assessment of fragrance ingredients and fragranced products.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105752"},"PeriodicalIF":3.0,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755115","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}