Pub Date : 2025-11-26DOI: 10.1016/j.yrtph.2025.106004
Christopher J. Bowman , Dingzhou Li , Thi Dong Binh Tran , Natasha R. Catlin , Christine M. Stethem , William S. Nowland , Sarah N. Campion
This study evaluates the potential of using historical control data (HCD) in rat fertility studies to replace/reduce concurrent control animal use and improve statistical analysis. This analysis was conducted using data sourced from a single test facility using consistent animal attributes and study procedures and consisted of 13 datasets from 12 rat fertility studies conducted between 2018 and 2023. For required fertility endpoints, we have evaluated full and hybrid Virtual Control Group (VCG) and Bayesian statistical approaches compared with standard statistics used for concurrent control groups (CCG). Our findings demonstrate that the sensitivity and specificity of most required fertility endpoints were generally similar between CCG and full or hybrid VCGs of sufficient sample size. Bayesian analyses leveraging all available HCD offered similar or superior sensitivity and specificity to CCGs and VCGs (full or hybrid) for all required fertility endpoints, with some exceptions. A retrospective case study implementing these approaches with HCD illustrated similar statistical performance across all approaches in addition to the benefit of reduced animal use. Overall, this effort illustrates the potential to improve sensitivity and reduce animal use with VCG (full or hybrid) or Bayesian approaches for required fertility endpoints in the rat.
{"title":"Exploration of virtual control groups and Bayesian approaches for rat fertility studies","authors":"Christopher J. Bowman , Dingzhou Li , Thi Dong Binh Tran , Natasha R. Catlin , Christine M. Stethem , William S. Nowland , Sarah N. Campion","doi":"10.1016/j.yrtph.2025.106004","DOIUrl":"10.1016/j.yrtph.2025.106004","url":null,"abstract":"<div><div>This study evaluates the potential of using historical control data (HCD) in rat fertility studies to replace/reduce concurrent control animal use and improve statistical analysis. This analysis was conducted using data sourced from a single test facility using consistent animal attributes and study procedures and consisted of 13 datasets from 12 rat fertility studies conducted between 2018 and 2023. For required fertility endpoints, we have evaluated full and hybrid Virtual Control Group (VCG) and Bayesian statistical approaches compared with standard statistics used for concurrent control groups (CCG). Our findings demonstrate that the sensitivity and specificity of most required fertility endpoints were generally similar between CCG and full or hybrid VCGs of sufficient sample size. Bayesian analyses leveraging all available HCD offered similar or superior sensitivity and specificity to CCGs and VCGs (full or hybrid) for all required fertility endpoints, with some exceptions. A retrospective case study implementing these approaches with HCD illustrated similar statistical performance across all approaches in addition to the benefit of reduced animal use. Overall, this effort illustrates the potential to improve sensitivity and reduce animal use with VCG (full or hybrid) or Bayesian approaches for required fertility endpoints in the rat.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106004"},"PeriodicalIF":3.5,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145616909","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}
Pub Date : 2025-11-22DOI: 10.1016/j.yrtph.2025.105989
Roger Godschalk , Bente Brauwers , Connie L. Chen , Raffaella Corvi , Kerry L. Dearfield , George R. Douglas , Naveed Honarvar , David Kirkland , Frank Le Curieux , Ann-Karin Olsen , Stefan Pfuhler , Leon F. Stankowski , Paul White , Jan van Benthem , Francesco Marchetti
The Globally Harmonized System standardizes chemical hazard communication. Within this system, germ cell mutagenicity holds unique importance due to the potential of heritable mutations. Yet, such testing is rarely performed, requiring alternative approaches to assess germ cell mutagenic potential. One strategy involves using physiological parameters to predict if somatic cell mutagens reach the gonads and induce mutations in germ cells. Therefore, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee examined whether blood concentrations of somatic cell mutagens can predict genotoxic effects in germ cells. We analyzed 11 substances with dominant lethal test data and 30 with transgenic rodent gene mutation data in male germ cells, together with blood concentrations. While significant associations were found between genotoxic outcomes in somatic tissues (e.g., micronuclei, mutation induction) and outcomes for germ cell mutagenicity, considerable variability was noted in genotoxic responses. This variability could not be explained by blood concentrations alone. Notably, blood levels of substances positive in both somatic and germ cells were similar to those that were positive for somatic cell genotoxicity and negative in germ cells. We conclude that the concentration of a somatic cell genotoxic substance in blood is insufficient to predict germ cell mutagenicity.
{"title":"An evaluation of the utility of blood concentration of somatic mutagens to inform germ cell mutagenic hazard","authors":"Roger Godschalk , Bente Brauwers , Connie L. Chen , Raffaella Corvi , Kerry L. Dearfield , George R. Douglas , Naveed Honarvar , David Kirkland , Frank Le Curieux , Ann-Karin Olsen , Stefan Pfuhler , Leon F. Stankowski , Paul White , Jan van Benthem , Francesco Marchetti","doi":"10.1016/j.yrtph.2025.105989","DOIUrl":"10.1016/j.yrtph.2025.105989","url":null,"abstract":"<div><div>The Globally Harmonized System standardizes chemical hazard communication. Within this system, germ cell mutagenicity holds unique importance due to the potential of heritable mutations. Yet, such testing is rarely performed, requiring alternative approaches to assess germ cell mutagenic potential. One strategy involves using physiological parameters to predict if somatic cell mutagens reach the gonads and induce mutations in germ cells. Therefore, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee examined whether blood concentrations of somatic cell mutagens can predict genotoxic effects in germ cells. We analyzed 11 substances with dominant lethal test data and 30 with transgenic rodent gene mutation data in male germ cells, together with blood concentrations. While significant associations were found between genotoxic outcomes in somatic tissues (e.g., micronuclei, mutation induction) and outcomes for germ cell mutagenicity, considerable variability was noted in genotoxic responses. This variability could not be explained by blood concentrations alone. Notably, blood levels of substances positive in both somatic and germ cells were similar to those that were positive for somatic cell genotoxicity and negative in germ cells. We conclude that the concentration of a somatic cell genotoxic substance in blood is insufficient to predict germ cell mutagenicity.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 105989"},"PeriodicalIF":3.5,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588562","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}
Pub Date : 2025-11-20DOI: 10.1016/j.yrtph.2025.105993
Dayton M. Petibone , Jennifer M. Shemansky , Timothy W. Robison , Aisar H. Atrakchi , Robert H. Heflich
Phase 1 clinical trial participants could potentially be exposed to significant health risks. Findings from a standard battery of genetic toxicology tests typically are the only data available to inform about cancer hazards at the initiation of clinical trials. Although uncommon, a question occasionally arises that is not clearly defined in current guidance: how many doses of an Ames-positive (potentially DNA-reactive) drug can be administered safely to healthy adult subjects during Phase 1 clinical trials? A literature survey was undertaken to identify information on carcinogenic risks from short-term exposures to Ames-positive agents, which might inform about administering an Ames-positive drug as a single dose or over a period of up to 14 days in healthy adult subjects. Limited information was identified on risk predictions for short-term exposures from modeling applications and from human studies, with more extensive data available using animal models. Relevant information on cancer outcomes following short-term exposures to Ames-positive agents suggest there is an increased cancer risk for administering even a single dose of an Ames-positive drug to healthy adult subjects. These findings indicate that Phase 1 studies with Ames-positive drug candidates should be exceedingly rare, and that additional mutagenicity testing should be performed before drug administration.
{"title":"Assessing carcinogenic outcomes following short-term exposure to potentially DNA-reactive drugs: Are available data sufficient to inform risk assessment?","authors":"Dayton M. Petibone , Jennifer M. Shemansky , Timothy W. Robison , Aisar H. Atrakchi , Robert H. Heflich","doi":"10.1016/j.yrtph.2025.105993","DOIUrl":"10.1016/j.yrtph.2025.105993","url":null,"abstract":"<div><div>Phase 1 clinical trial participants could potentially be exposed to significant health risks. Findings from a standard battery of genetic toxicology tests typically are the only data available to inform about cancer hazards at the initiation of clinical trials. Although uncommon, a question occasionally arises that is not clearly defined in current guidance: how many doses of an Ames-positive (potentially DNA-reactive) drug can be administered safely to healthy adult subjects during Phase 1 clinical trials? A literature survey was undertaken to identify information on carcinogenic risks from short-term exposures to Ames-positive agents, which might inform about administering an Ames-positive drug as a single dose or over a period of up to 14 days in healthy adult subjects. Limited information was identified on risk predictions for short-term exposures from modeling applications and from human studies, with more extensive data available using animal models. Relevant information on cancer outcomes following short-term exposures to Ames-positive agents suggest there is an increased cancer risk for administering even a single dose of an Ames-positive drug to healthy adult subjects. These findings indicate that Phase 1 studies with Ames-positive drug candidates should be exceedingly rare, and that additional mutagenicity testing should be performed before drug administration.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 105993"},"PeriodicalIF":3.5,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582335","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}
Pub Date : 2025-11-19DOI: 10.1016/j.yrtph.2025.105994
L.M. Brewster , A. Ishwardat , B.J. van den Born , M.M.A.L. Pelsers , H. Galenkamp , G.A. van Montfrans
Policymakers in Europe utilize biomonitoring to regulate exposure to arsenic and protect public health, but potentially high exposure levels among ancestral subgroups remain understudied.
We assessed arsenic exposure in a random population sample of Amsterdam, the Netherlands, stratified by European-Dutch vs Asian and African-Dutch ancestry (n = 60, 30 women, aged 40–63 years). We analyzed total spot urinary arsenic with inductively coupled plasma mass spectrometry and used food frequency questionnaires to calculate the exposure to inorganic arsenic (reference point <0.8 nmol/kg body mass/day) from rice, fish, and water consumption.
Urinary arsenic (40–4828 nmol/L, mean 532 (SE 116); respectively 312 (60) in European-Dutch vs. 642 (169) in Asian and African-Dutch), was independently associated with rice consumption (343 nmol/L (95 % CI, 112–575)/100 g rice).
Inorganic arsenic intake (87–976 nmol/day, mean 397, SE 32), respectively 175 (14) in European-Dutch (2.4 (0.2) nmol/kg body mass/day) vs 508 (37) in Asian and African-Dutch (6.7 (0.5) nmol/kg body mass/day), was independently associated with systolic blood pressure (3.1 (1.5–4.8) mm Hg/100 nmol iAs).
The high dietary arsenic exposure among certain ancestry subgroups living in Europe is concerning. Health policies should be developed to monitor these subgroups and reduce their inorganic arsenic intake to the unavoidable minimum.
{"title":"Biomonitoring arsenic exposure by ancestry: the healthy life in an urban setting (HELIUS) study","authors":"L.M. Brewster , A. Ishwardat , B.J. van den Born , M.M.A.L. Pelsers , H. Galenkamp , G.A. van Montfrans","doi":"10.1016/j.yrtph.2025.105994","DOIUrl":"10.1016/j.yrtph.2025.105994","url":null,"abstract":"<div><div>Policymakers in Europe utilize biomonitoring to regulate exposure to arsenic and protect public health, but potentially high exposure levels among ancestral subgroups remain understudied.</div><div>We assessed arsenic exposure in a random population sample of Amsterdam, the Netherlands, stratified by European-Dutch vs Asian and African-Dutch ancestry (n = 60, 30 women, aged 40–63 years). We analyzed total spot urinary arsenic with inductively coupled plasma mass spectrometry and used food frequency questionnaires to calculate the exposure to inorganic arsenic (reference point <0.8 nmol/kg body mass/day) from rice, fish, and water consumption.</div><div>Urinary arsenic (40–4828 nmol/L, mean 532 (SE 116); respectively 312 (60) in European-Dutch vs. 642 (169) in Asian and African-Dutch), was independently associated with rice consumption (343 nmol/L (95 % CI, 112–575)/100 g rice).</div><div>Inorganic arsenic intake (87–976 nmol/day, mean 397, SE 32), respectively 175 (14) in European-Dutch (2.4 (0.2) nmol/kg body mass/day) vs 508 (37) in Asian and African-Dutch (6.7 (0.5) nmol/kg body mass/day), was independently associated with systolic blood pressure (3.1 (1.5–4.8) mm Hg/100 nmol iAs).</div><div>The high dietary arsenic exposure among certain ancestry subgroups living in Europe is concerning. Health policies should be developed to monitor these subgroups and reduce their inorganic arsenic intake to the unavoidable minimum.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 105994"},"PeriodicalIF":3.5,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145565194","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}
Pub Date : 2025-11-17DOI: 10.1016/j.yrtph.2025.105992
Umma Salma, Anne Schmitt, Soyub Rime, Lars Niemann, Carsten Kneuer
The use of pesticides is an inseparable and undeniable part of modern agriculture to ensure sufficient food supply for a still-growing population but, due to their intrinsic toxic nature, rigorous testing is needed before making them available on the market. In the European Union, in vitro metabolism studies with the active ingredients became mandatory in 2013. Unfortunately, in contrast to most other toxicological endpoints, a harmonised test guideline for their conduct is not yet available. More than 10 years after its introduction, we aimed to analyse the practical experience with that data requirement. For this purpose, 70 comparative in vitro metabolism studies were reviewed. Significant methodological differences were noticed among the studies, including species selection, test systems, tested concentrations, and incubation times. These differences and the deviations from existing but not legally binding recommendations limit the use that could be made of these studies, in particular beyond a simple comparison of human and rat metabolism. There is an urgent need for a harmonised guidance how to perform the in vitro biotransformation studies. Its implementation would not only increase the likelihood to identify unique or disproportionate human metabolites but might also support next-generation risk assessment.
{"title":"Regulatory experience with the comparative in vitro metabolism study based on an analysis of 70 studies with pesticide active ingredients – a reality check","authors":"Umma Salma, Anne Schmitt, Soyub Rime, Lars Niemann, Carsten Kneuer","doi":"10.1016/j.yrtph.2025.105992","DOIUrl":"10.1016/j.yrtph.2025.105992","url":null,"abstract":"<div><div>The use of pesticides is an inseparable and undeniable part of modern agriculture to ensure sufficient food supply for a still-growing population but, due to their intrinsic toxic nature, rigorous testing is needed before making them available on the market. In the European Union, <em>in vitro</em> metabolism studies with the active ingredients became mandatory in 2013. Unfortunately, in contrast to most other toxicological endpoints, a harmonised test guideline for their conduct is not yet available. More than 10 years after its introduction, we aimed to analyse the practical experience with that data requirement. For this purpose, 70 comparative <em>in vitro</em> metabolism studies were reviewed. Significant methodological differences were noticed among the studies, including species selection, test systems, tested concentrations, and incubation times. These differences and the deviations from existing but not legally binding recommendations limit the use that could be made of these studies, in particular beyond a simple comparison of human and rat metabolism. There is an urgent need for a harmonised guidance how to perform the <em>in vitro</em> biotransformation studies. Its implementation would not only increase the likelihood to identify unique or disproportionate human metabolites but might also support next-generation risk assessment.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 105992"},"PeriodicalIF":3.5,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557770","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}
Pub Date : 2025-11-17DOI: 10.1016/j.yrtph.2025.105991
Laura Ghanem , Antonia Moubarak , Jana Kotaich , Marianne Mouannes , Amir Ghanem , Soulaima Chamat , Nizar Bitar
The impact of firsthand and secondhand smoking on the development of various types of cancer is well established. However, the association of thirdhand smoke (THS) with malignant diseases has only recently been recognized, with limited research investigating the underlying mechanisms. THS refers to the dynamic mixture of residual tobacco smoke constituents that persist in air, dust, and on surfaces, and can occur through dermal absorption, inhalation of re-emitted gases and particles, and ingestion - particularly via dust intake. Tobacco smoke contains hundreds of toxic compounds, 60 of which are classified as carcinogens. These include aromatic amines, nicotine, nitrosamines, nitric oxide and polycyclic aromatic hydrocarbons. These substances can react with environmental chemicals, forming highly toxic secondary pollutants that can be released from surfaces over months and be absorbed through the skin or mucosa. The metabolization of tobacco smoke components can increase the incidence of cancer by altering key molecular pathways. Main mechanisms of carcinogenesis include DNA adduct formation and DNA structural changes, interference with tumor suppressor genes, and chronic inflammation. This review examines the risks of THS exposure, the potential mechanisms of carcinogenesis associated with THS and the role of THS in the development of different cancers linked to tobacco use.
{"title":"Evaluating cancer risks: The impact of thirdhand smoke exposure on carcinogenesis","authors":"Laura Ghanem , Antonia Moubarak , Jana Kotaich , Marianne Mouannes , Amir Ghanem , Soulaima Chamat , Nizar Bitar","doi":"10.1016/j.yrtph.2025.105991","DOIUrl":"10.1016/j.yrtph.2025.105991","url":null,"abstract":"<div><div>The impact of firsthand and secondhand smoking on the development of various types of cancer is well established. However, the association of thirdhand smoke (THS) with malignant diseases has only recently been recognized, with limited research investigating the underlying mechanisms. THS refers to the dynamic mixture of residual tobacco smoke constituents that persist in air, dust, and on surfaces, and can occur through dermal absorption, inhalation of re-emitted gases and particles, and ingestion - particularly via dust intake. Tobacco smoke contains hundreds of toxic compounds, 60 of which are classified as carcinogens. These include aromatic amines, nicotine, nitrosamines, nitric oxide and polycyclic aromatic hydrocarbons. These substances can react with environmental chemicals, forming highly toxic secondary pollutants that can be released from surfaces over months and be absorbed through the skin or mucosa. The metabolization of tobacco smoke components can increase the incidence of cancer by altering key molecular pathways. Main mechanisms of carcinogenesis include DNA adduct formation and DNA structural changes, interference with tumor suppressor genes, and chronic inflammation. This review examines the risks of THS exposure, the potential mechanisms of carcinogenesis associated with THS and the role of THS in the development of different cancers linked to tobacco use.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105991"},"PeriodicalIF":3.5,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557686","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}
Pub Date : 2025-11-15DOI: 10.1016/j.yrtph.2025.105990
N. Choksi , D. McMillan , D. Schmitt , C. Doepker , R.G. Henderson
Novel waxes require safety documentation, which traditionally involves using a battery of assays in experimental animals. For a class of well-studied substances (e.g., waxes) generally recognized to be of low or no toxicity, bridging methods that leverage safety information to fill data gaps for new substances may be considered. The aim of this assessment was to use a bridging assessment procedure to fill data gaps to demonstrate safety for two novel plant waxes (rice bran wax and sunflower wax). Using the European Chemicals Agency (ECHA) framework methodology, compositional similarity was established between the novel waxes and four well-evaluated plant waxes. Using the evidence bases for the evaluated plant waxes, the bridging assessment predicted that rice bran and sunflower waxes would have limited absorption. The bridging assessments also predicted that rice bran and sunflower waxes had limited repeat-dose oral toxicity, and were not reproductive or developmental toxicants or carcinogenic. Predicted lack of acute and mutagenic activity by rice bran wax was supported by experimental data. In conclusion, this case study shows that the bridging approach can fill toxicity data gaps, supporting a waiver of additional in vivo tests, thus ensuring safety, as well as reducing the use of animal testing.
{"title":"Demonstration of safety for rice bran wax and sunflower wax based on bridging to other naturally derived waxes used in foods","authors":"N. Choksi , D. McMillan , D. Schmitt , C. Doepker , R.G. Henderson","doi":"10.1016/j.yrtph.2025.105990","DOIUrl":"10.1016/j.yrtph.2025.105990","url":null,"abstract":"<div><div>Novel waxes require safety documentation, which traditionally involves using a battery of assays in experimental animals. For a class of well-studied substances (e.g., waxes) generally recognized to be of low or no toxicity, bridging methods that leverage safety information to fill data gaps for new substances may be considered. The aim of this assessment was to use a bridging assessment procedure to fill data gaps to demonstrate safety for two novel plant waxes (rice bran wax and sunflower wax). Using the European Chemicals Agency (ECHA) framework methodology, compositional similarity was established between the novel waxes and four well-evaluated plant waxes. Using the evidence bases for the evaluated plant waxes, the bridging assessment predicted that rice bran and sunflower waxes would have limited absorption. The bridging assessments also predicted that rice bran and sunflower waxes had limited repeat-dose oral toxicity, and were not reproductive or developmental toxicants or carcinogenic. Predicted lack of acute and mutagenic activity by rice bran wax was supported by experimental data. In conclusion, this case study shows that the bridging approach can fill toxicity data gaps, supporting a waiver of additional <em>in vivo</em> tests, thus ensuring safety, as well as reducing the use of animal testing.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 105990"},"PeriodicalIF":3.5,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145542065","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}
Pub Date : 2025-11-11DOI: 10.1016/j.yrtph.2025.105988
Yanzhe Xu, Yun Zhu, Jianyang Lin, Jürgen Borlak
Serial blood collection is a key requirement for pharmacological and toxicological studies in rodents, but existing approaches such as tail vein, retro-orbital, or catheter-based sampling are constrained by limited sample volume, variability, and welfare concerns. We developed a percutaneous technique for serial blood sampling from the external jugular vein in male Wistar rats under isoflurane anaesthesia. The method was evaluated over 14 days by monitoring body weight, behaviour, haematological and clinical chemistry parameters in a preclinical safety study at a No-Observable-Adverse-Effect-Level dose setting. Rats tolerated repeated sampling without distress, skin lesions, or behavioural abnormalities. Isoflurane induction was rapid and uneventful, and blood samples (0.5–1 ml) were consistently obtained within 2 min. Body weight changes were minimal across sessions (1.2 % after the first to 0.2 % after the sixth), indicating procedural adaptation. Haematological values remained within reference ranges, with only a significant reduction in RDW-CV, while biochemical parameters including AST, CK, and lipids showed no significant alterations; minor, non-adverse trends included reduced ALT (p < 0.041) and non-significant cholesterol and minimal non-significant increases in plasma creatinine. This study establishes repeated percutaneous jugular vein puncture as a minimally invasive, welfare-compliant, and reliable method for longitudinal blood sampling in anaesthetised rats without catheterisation, supporting robust preclinical research.
{"title":"Serial blood collection in anaesthetised rats: Enhancing animal welfare without the need for jugular vein catheterisation","authors":"Yanzhe Xu, Yun Zhu, Jianyang Lin, Jürgen Borlak","doi":"10.1016/j.yrtph.2025.105988","DOIUrl":"10.1016/j.yrtph.2025.105988","url":null,"abstract":"<div><div>Serial blood collection is a key requirement for pharmacological and toxicological studies in rodents, but existing approaches such as tail vein, retro-orbital, or catheter-based sampling are constrained by limited sample volume, variability, and welfare concerns. We developed a percutaneous technique for serial blood sampling from the external jugular vein in male Wistar rats under isoflurane anaesthesia. The method was evaluated over 14 days by monitoring body weight, behaviour, haematological and clinical chemistry parameters in a preclinical safety study at a No-Observable-Adverse-Effect-Level dose setting. Rats tolerated repeated sampling without distress, skin lesions, or behavioural abnormalities. Isoflurane induction was rapid and uneventful, and blood samples (0.5–1 ml) were consistently obtained within 2 min. Body weight changes were minimal across sessions (1.2 % after the first to 0.2 % after the sixth), indicating procedural adaptation. Haematological values remained within reference ranges, with only a significant reduction in RDW-CV, while biochemical parameters including AST, CK, and lipids showed no significant alterations; minor, non-adverse trends included reduced ALT (p < 0.041) and non-significant cholesterol and minimal non-significant increases in plasma creatinine. This study establishes repeated percutaneous jugular vein puncture as a minimally invasive, welfare-compliant, and reliable method for longitudinal blood sampling in anaesthetised rats without catheterisation, supporting robust preclinical research.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105988"},"PeriodicalIF":3.5,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513679","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}
Pub Date : 2025-11-10DOI: 10.1016/j.yrtph.2025.105987
Andressa Glinski , Jessica Zablocki da Luz , Aliciane de Almeida Roque , Tugstênio Lima de Souza , Arandi Ginane Bezerra Junior , Carolina Camargo de Oliveira , Ciro Alberto de Oliveira Ribeiro , Francisco Filipak Neto
Silver nanoparticles (AgNPs) are widely used in nanotechnology products. However, the health risks associated with co-exposure to these emerging contaminants and environmental pollutants, such as non-essential metals, are poorly understood. The present study aimed to investigate the cytotoxicity and toxicological interaction of AgNPs (0.36 and 3.6 μg mL−1) + lead (Pb2+, 25 and 250 μM) and AgNPs + mercury (Hg2+, 15 and 150 μM) using the macrophage cell line RAW 264.7 as a model. Effects were observed after a few hours (4 h) on NO levels, phagocytic activity, and DNA damage. Cell viability (24 h-exposure) was affected mainly by the higher concentrations of the contaminants and their mixtures, preceded by increases in NO levels and DNA damage, but without effects on ROS levels. Co-exposure potentiated some effects (ROS and NO levels and DNA damage), indicating toxicological interaction. These important findings must be further investigated, since the interaction of Pb2+ and Hg2+ with AgNPs from nanoproducts may impair the function of macrophages and represent a health risk for humans.
{"title":"Cytotoxic effects of silver nanoparticles and non-essential metals in murine macrophages","authors":"Andressa Glinski , Jessica Zablocki da Luz , Aliciane de Almeida Roque , Tugstênio Lima de Souza , Arandi Ginane Bezerra Junior , Carolina Camargo de Oliveira , Ciro Alberto de Oliveira Ribeiro , Francisco Filipak Neto","doi":"10.1016/j.yrtph.2025.105987","DOIUrl":"10.1016/j.yrtph.2025.105987","url":null,"abstract":"<div><div>Silver nanoparticles (AgNPs) are widely used in nanotechnology products. However, the health risks associated with co-exposure to these emerging contaminants and environmental pollutants, such as non-essential metals, are poorly understood. The present study aimed to investigate the cytotoxicity and toxicological interaction of AgNPs (0.36 and 3.6 μg mL<sup>−1</sup>) + lead (Pb<sup>2+</sup>, 25 and 250 μM) and AgNPs + mercury (Hg<sup>2+</sup>, 15 and 150 μM) using the macrophage cell line RAW 264.7 as a model. Effects were observed after a few hours (4 h) on NO levels, phagocytic activity, and DNA damage. Cell viability (24 h-exposure) was affected mainly by the higher concentrations of the contaminants and their mixtures, preceded by increases in NO levels and DNA damage, but without effects on ROS levels. Co-exposure potentiated some effects (ROS and NO levels and DNA damage), indicating toxicological interaction. These important findings must be further investigated, since the interaction of Pb<sup>2+</sup> and Hg<sup>2+</sup> with AgNPs from nanoproducts may impair the function of macrophages and represent a health risk for humans.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105987"},"PeriodicalIF":3.5,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145506568","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号