Regulatory Toxicology and Pharmacology最新文献_第3页

Analysis of predictive value of animal repeated dose toxicity study results for clinical safety of US FDA-approved anticancer drugs between 2019 and 2023 动物重复剂量毒性研究结果对2019 - 2023年美国fda批准的抗癌药物临床安全性的预测价值分析

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-03-01 Epub Date: 2026-01-12 DOI: 10.1016/j.yrtph.2026.106031

Gyeyoung Choi , Seungjin Bae , Kyung-Min Lim

{"title":"Analysis of predictive value of animal repeated dose toxicity study results for clinical safety of US FDA-approved anticancer drugs between 2019 and 2023","authors":"Gyeyoung Choi , Seungjin Bae , Kyung-Min Lim","doi":"10.1016/j.yrtph.2026.106031","DOIUrl":"10.1016/j.yrtph.2026.106031","url":null,"abstract":"<div><div>The translational relevance of nonclinical animal studies in predicting clinical safety outcomes remains poorly understood in oncology drug development. This study aimed to qualitatively assess the concordance between toxicological findings from animal repeat-dose toxicity studies and treatment-emergent adverse events (TEAEs) in clinical trials of 63 anticancer drugs approved by the U.S. FDA from 2019 to 2023. We extracted nonclinical and clinical safety data from FDA review documents and categorized observations across 20 organ systems using a Concordant Positive/Concordant Negative/Animal-only Positive/Clinical-only Positive classification framework. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated by organ class and animal species. Among 63 anti-cancer drugs analyzed, hematologic, hepatobiliary, and gastrointestinal systems exhibited high concordance (notably high PPV and sensitivity), while bone/tooth and lymphatic systems showed low translational predictivity. Predictive performance was similar across rats, dogs, and monkeys, with no statistically significant interspecies differences. These findings suggest that current animal models offer organ-specific, but not species-specific, translational value for anti-cancer drugs. A shift toward validated, human-relevant alternative models is recommended for organ classes with low predictive performance in animal studies, to enhance translational accuracy while reducing animal sacrifice.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106031"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978591","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}

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Adulterated cough syrup caused acute kidney failure deaths in children: lessons have still not been learnt 掺假止咳糖浆导致儿童急性肾衰竭死亡：至今仍未吸取教训。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-03-01 Epub Date: 2025-12-19 DOI: 10.1016/j.yrtph.2025.106015

Devaraj Ezhilarasan, Munusamy Karthick

引用次数: 0

Four-year monitoring of pesticide residues in Egyptian sweet peppers 埃及甜椒四年农药残留监测

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-03-01 Epub Date: 2025-12-30 DOI: 10.1016/j.yrtph.2025.106027

Farag Malhat , Shokr Abdel Salam Shokr , Fawzy Eissa

{"title":"Four-year monitoring of pesticide residues in Egyptian sweet peppers","authors":"Farag Malhat , Shokr Abdel Salam Shokr , Fawzy Eissa","doi":"10.1016/j.yrtph.2025.106027","DOIUrl":"10.1016/j.yrtph.2025.106027","url":null,"abstract":"<div><div>This study monitored pesticide residues in 1826 sweet pepper samples from Egyptian markets (2021–2024), screening for 430 pesticides using QuEChERS extraction with LC-MS/MS and GC-MS/MS. Results revealed concerning contamination trends, with samples exceeding EU Maximum Residue Limits (MRLs) increasing from 14.95 % (2021) to 37.38 % (2023), before declining to 28.74 % (2024). Between 42 and 97 different pesticides were detected annually, with acetamiprid consistently the most prevalent (21.5–29.51 %). Neonicotinoids dominated detections, representing two to four compounds in annual top-10 rankings. Multiple residue contamination escalated dramatically from 45.79 % (2021) to 69.35 % (2023), with samples containing up to 16 pesticides simultaneously. Chlorpyrifos and bifenazate showed severe MRL violations, exceeding limits by 6.2-fold and 25.9-fold, respectively. Despite extensive contamination, chronic dietary risk assessment across 13 population groups indicated acceptable exposure levels, with all calculated %ADI values below the 100 % safety threshold. The highest exposure corresponded to 3.47 % of the ADI for chlorpyrifos in the GEMS/Food G15 population. While current consumption poses negligible health risks, the high prevalence of MRL violations and multiple residues highlights urgent needs for enhanced agricultural practices and regulatory enforcement to ensure long-term food safety.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106027"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145885956","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}

引用次数: 0

Prolonged exposure to nitrate in drinking water does not adversely impact prenatal or birth outcomes in a rat model 在大鼠模型中，长期暴露于饮用水中的硝酸盐不会对产前或分娩结果产生不利影响

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-03-01 Epub Date: 2026-01-09 DOI: 10.1016/j.yrtph.2026.106030

Leaf R. Kardol , Avalon Gray , Amina Rhaman , Alexander N. Larcombe , Christine Jeffries-Stokes , Annette Stokes , Sarah Bourke , Sujata Shinde , Kevin Croft , Caitlin S. Wyrwoll

{"title":"Prolonged exposure to nitrate in drinking water does not adversely impact prenatal or birth outcomes in a rat model","authors":"Leaf R. Kardol , Avalon Gray , Amina Rhaman , Alexander N. Larcombe , Christine Jeffries-Stokes , Annette Stokes , Sarah Bourke , Sujata Shinde , Kevin Croft , Caitlin S. Wyrwoll","doi":"10.1016/j.yrtph.2026.106030","DOIUrl":"10.1016/j.yrtph.2026.106030","url":null,"abstract":"<div><div>Nitrate (NO<sub>3</sub><sup>−</sup>) is a common drinking water contaminant associated with increased risks of adverse pregnancy outcomes at concentrations below the World Health Organisation (WHO) drinking water guidelines (50 mg/L NO<sub>3</sub><sup>−</sup>). However, causal evidence at relevant concentrations is sparse. This study aimed to characterise the effects of prolonged exposure to drinking water nitrate at concentrations relevant to human exposure on maternal, fetal, and birth outcomes. Wistar rats were exposed to 0, 50 or 100 mg/L NO<sub>3</sub><sup>−</sup> as sodium nitrate in drinking water three weeks pre-conception and throughout gestation. At 21 days gestation, fetal and placental weights and morphology, maternal outcomes including plasma nitrate and nitrite, endocrine and inflammatory markers, and uterine artery haemodynamics were analysed. In a second cohort, birth timing and weight were assessed. While nitrate exposure substantially increased maternal plasma nitrate and nitrite concentrations, no consistent effects were seen on fetal or placental outcomes or endocrine/inflammatory markers. Several birth complications, small litters and higher uterine artery blood velocities were noted in nitrate-exposed groups, but these outcomes were highly variable. These results show that chronic exposure to nitrate at or above the WHO drinking water guidelines subtly impacts rat pregnancy and do not provide causal support for the findings of epidemiological studies.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106030"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145927527","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}

引用次数: 0

Analysis of occupational exposure limits for hazardous chemical agents of African countries: A comparative study 非洲国家危险化学剂职业接触限值分析：比较研究

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-03-01 Epub Date: 2026-01-06 DOI: 10.1016/j.yrtph.2026.106029

Nadia Suzette Botha, Ilzé Engelbrecht, Suranie Rachel Horn

{"title":"Analysis of occupational exposure limits for hazardous chemical agents of African countries: A comparative study","authors":"Nadia Suzette Botha, Ilzé Engelbrecht, Suranie Rachel Horn","doi":"10.1016/j.yrtph.2026.106029","DOIUrl":"10.1016/j.yrtph.2026.106029","url":null,"abstract":"<div><div>Occupational exposure limits (OELs) are a valuable tool used by occupational hygiene professionals to assess exposure and determine when measures should be employed to control exposure to hazardous chemical agents (HCAs) in the workplace. Many countries have OELs that are included in their respective occupational health and safety legislation. In South Africa, the Regulations for Hazardous Chemical Substances (RHCS SA, 1995) were first published in 1995. It was repealed and replaced with the Regulations for Hazardous Chemical Agents (RHCA SA, 2021). This study aimed to comparatively evaluate the progress of OELs in South Africa for certain HCAs as stated in the RHCA SA 2021 in terms of the previous version (RHCS SA, 1995) and other countries in Africa with OELs. This was done to provide insights into the gap in OEL development in Africa. The findings show that of the 54 countries in Africa, only 10 have OELs included in their occupational health and safety legislation. Legislative documents from five African countries were compared to the RHCA SA 2021 using the geometric mean method. The results indicate that South Africa has less stringent OELs than the other African countries to which it was compared, with the exception of Lesotho. This highlights the work that still needs to be done to improve OELs in African countries.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106029"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145927528","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}

引用次数: 0

Confidence in new approach methods (NAMs): Ensuring reproducibility, operationalising context-of-use and alignment with decision-making needs 对新方法（NAMs）的信心：确保可重复性，操作使用环境和与决策需求的一致性。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-03-01 Epub Date: 2025-12-20 DOI: 10.1016/j.yrtph.2025.106016

Miriam N. Jacobs , Heli M. Hollnagel , Karma Fussel , Giel Hendriks , Ioanna Katsiadaki , Susanne N. Kolle , Morné E. van der Mescht , Andreas Natsch , Hans Raabe , Amanda Ulrey , Robert Landsiedel

引用次数: 0

Nonclinical development of advanced therapies: Best practices for translational and regulatory success 先进疗法的非临床开发：转化和监管成功的最佳实践

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-03-01 Epub Date: 2026-01-12 DOI: 10.1016/j.yrtph.2026.106032

Piyan Zhang

{"title":"Nonclinical development of advanced therapies: Best practices for translational and regulatory success","authors":"Piyan Zhang","doi":"10.1016/j.yrtph.2026.106032","DOIUrl":"10.1016/j.yrtph.2026.106032","url":null,"abstract":"<div><div>Advanced therapeutics—including cell and gene therapies, antibody–drug conjugates, and RNA-based medicines—present unique in vivo pharmacology, safety, and translational challenges that require tailored nonclinical programs aligned with global regulatory expectations. This review synthesizes best practices for designing IND/CTA-enabling studies, integrating biodistribution, pharmacokinetics/pharmacodynamics, immunogenic assessment, safety pharmacology, toxicology, and dose selection into a cohesive strategy. Regulatory frameworks from the FDA, EMA, and PMDA emphasize early engagement, modality-specific risk assessment, and harmonization through ICH guidance (e.g., S12). Key recommendations include using relevant animal models, novel analytical methods, and conservative first-in-human dosing to mitigate translational uncertainties. Distinct considerations for oncology versus non-oncology indications are highlighted, reflecting differing risk tolerances and data requirements. Case studies of clinical holds and successful submissions underscore the importance of anticipating regulatory concerns, ensuring manufacturing readiness, and implementing robust risk mitigation. By adopting these integrated scientific and regulatory strategies, developers can streamline translation from preclinical studies to human trials, ultimately accelerating the delivery of safe, effective advanced therapies.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106032"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978590","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}

引用次数: 0

Establishing best practice for N-nitrosamine read-across and surrogate selection 建立n -亚硝胺读取和替代选择的最佳实践。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-03-01 Epub Date: 2025-12-20 DOI: 10.1016/j.yrtph.2025.106009

David J. Ponting , Gabriela de Oliveira Silveira , Philip Rowell , Crina I. Heghes , Adrian Fowkes , Christopher G. Barber

{"title":"Establishing best practice for N-nitrosamine read-across and surrogate selection","authors":"David J. Ponting , Gabriela de Oliveira Silveira , Philip Rowell , Crina I. Heghes , Adrian Fowkes , Christopher G. Barber","doi":"10.1016/j.yrtph.2025.106009","DOIUrl":"10.1016/j.yrtph.2025.106009","url":null,"abstract":"<div><div>Read-across is, ultimately, achieving a confident decision on the activity of a compound based on an analogue compound with robust toxicity data. The use of read-across assessments for the determination of acceptable intakes for <em>N</em>-nitrosamine compounds is recommended in regulatory guidance for this critical impurity class and is given an equal weight to the tier-0 screening approach, the Carcinogenic Potency Categorization Approach (CPCA), as well as <em>in vitro</em> and <em>in vivo</em> toxicological studies. However, read-across assessment is a multifaceted, manual process which requires the expert assessment of many factors. The complexities of performing read-across have been acknowledged as a driving force for the introduction of the CPCA. Prior to this there was a significant backlog of compounds needing a read-across assessment for a compound-specific acceptable intake (AI) as control to the class-specific threshold of toxicological concern (TTC) was unachievable. It was however clear from subjective assessment that control to the class-specific limit was unwarranted from a safety perspective. In this article the authors propose factors that should be considered in both the manual read-across and the new generation of semi-automated <em>in silico</em> tools for read-across assessment, in order to ensure that a robust assessment is performed, and a confident conclusion can be both reached and documented. Key case studies are presented for several NDSRIs, showing the applicability of this approach.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106009"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810972","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}

引用次数: 0

Nitroparaffin transcriptional profiles and toxicokinetics support chemical-specific carcinogenicity assessment 硝基石蜡转录谱和毒性动力学支持化学特异性致癌性评估。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-03-01 Epub Date: 2026-01-19 DOI: 10.1016/j.yrtph.2026.106035

A. Rasim Barutcu , Jamie Scaglione , Marjory Moreau , Elizabeth Hofstetter , Todor Antonijevic , Andrew Maier , Pierre Serfass , Leslie Recio , Pamela J. Spencer

{"title":"Nitroparaffin transcriptional profiles and toxicokinetics support chemical-specific carcinogenicity assessment","authors":"A. Rasim Barutcu , Jamie Scaglione , Marjory Moreau , Elizabeth Hofstetter , Todor Antonijevic , Andrew Maier , Pierre Serfass , Leslie Recio , Pamela J. Spencer","doi":"10.1016/j.yrtph.2026.106035","DOIUrl":"10.1016/j.yrtph.2026.106035","url":null,"abstract":"<div><div>The toxicological profiles of nitroparaffins—nitromethane (NM), nitroethane (NE), and 1-nitropropane (1NP)—remain incompletely characterized. This has led to reliance on read-across approaches, extrapolating carcinogenicity data from NM to NE and 1NP, though the validity of such extrapolations is uncertain. In this study, we examined the concentration-dependent transcriptional effects of NM, NE, and 1NP in primary rat hepatocytes to clarify their cellular impact and mechanisms of toxicity. We assessed cytotoxicity, differential gene expression, and pathway enrichment, and applied in vitro to in vivo extrapolation (IVIVE) to estimate systemic bioavailability and clearance rates. Cytotoxicity was observed at 3 mM for NM and NE but not up to 10 mM for 1NP. Transcriptomic profiling revealed minimal overlap in dysregulated genes and enriched pathways among the three compounds. NE elicited the broadest transcriptional response, whereas NM and 1NP showed more limited effects. IVIVE further indicated distinct systemic bioavailability and clearance, suggesting toxicokinetic differences. Taken together, these results demonstrate that structural similarity alone does not predict comparable toxicological behavior. Each nitroparaffin exhibited unique molecular activity and toxicokinetics, indicating that read-across within this class requires demonstrated concordance in both bioactivity and toxicokinetic profiles, which are currently absent for NE, NM and 1NP. Thus, reliance on read-across from NM to NE or 1NP may misrepresent health risks and carries significant regulatory implications.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106035"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019562","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}

引用次数: 0

Dietary administration of α-terpineol to Sprague-Dawley rats for 90 days α-松油醇对sd大鼠90 d的影响。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-03-01 Epub Date: 2025-12-20 DOI: 10.1016/j.yrtph.2025.106017

Michel Aubanel , Christopher Choi , Jan Demyttenaere , Maodo Malick Diop , Sylvain Etter , Alexandra Blanchard , Christie L. Harman , Mihoko Koyanagi , Gerhard Krammer , Gregory Ladics , Severin Müller , George Pugh , Mark R. Bauter , Shannon E. Beck , Jeanne M. Davidsen , Suzanne F. Wilson , Sean V. Taylor

{"title":"Dietary administration of α-terpineol to Sprague-Dawley rats for 90 days","authors":"Michel Aubanel , Christopher Choi , Jan Demyttenaere , Maodo Malick Diop , Sylvain Etter , Alexandra Blanchard , Christie L. Harman , Mihoko Koyanagi , Gerhard Krammer , Gregory Ladics , Severin Müller , George Pugh , Mark R. Bauter , Shannon E. Beck , Jeanne M. Davidsen , Suzanne F. Wilson , Sean V. Taylor","doi":"10.1016/j.yrtph.2025.106017","DOIUrl":"10.1016/j.yrtph.2025.106017","url":null,"abstract":"<div><div>α-Terpineol is a flavoring ingredient that occurs naturally in spices and foods. It has been evaluated by regulatory and scientific expert bodies such as the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1999 and the European Food Safety Authority (EFSA) in 2006 and has been determined safe under the conditions of intended use. To ensure the continued safety of high-usage flavoring ingredients, a 90-day Organization for Economic Co-operation and Development (OECD) 408 and Good Laboratory Practice (GLP) compliant study was conducted in Sprague-Dawley (SD) rats (10/sex/groups) at target dietary intakes to achieve doses of 0, 50, 150 or 500 mg/kg bw/day. There were no unscheduled deaths and no adverse changes in ophthalmological examinations, body weight, food consumption, food efficiency, hematology, serum chemistry, urinalysis parameters and macroscopic and microscopic observations. While not statistically significant, excessive fragmentation of sperm (head and tail separating) was observed in high-dose males, resulting in reduced or zero sperm mobility. Based on the specific sperm abnormalities observed, the no-observed-adverse-effect level (NOAEL) was determined to be the middle dose, 146 mg/kg bw/day for male SD rats and 500 mg/kg bw/day, the highest dose tested, for female SD rats.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106017"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805392","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}

引用次数: 0