In view of the exploration of sirolimus (rapamycin) as balloon coating for peripheral intravasal treatment and the reports on unfavorable tolerance of daily low-dose sirolimus, the aim of the study was to investigate potential toxicological effects of a single intravascular dose of sirolimus in comparison to paclitaxel and vehicle in the rat.
Methods
Rats were treated intravenously with a single dose of 20 mg/kg sirolimus or paclitaxel dissolved in identical vehicle and sacrificed 5- or 14-days post treatment. Vehicle (Cremophor EL/Ethanol diluted with saline) treated rats served as a control. Potential effects on survival, hematology, organ weights, organ histology were analyzed.
Results
Single dose i.v. injection of sirolimus, paclitaxel and vehicle induced temporary sedation after treatment. One animal treated with paclitaxel died, probably due to solvent toxicity. Sirolimus, paclitaxel and the vehicle control were tolerated. Animals treated with sirolimus or paclitaxel showed temporary hematological effects and thymic atrophy that subsided after 14 days. Sirolimus induced a temporary weight reduction of ovaries and uterus. Male rats showed histological changes of testes at 14 days after sirolimus treatment. Notably, sirolimus induced a prolonged body weight reduction compared to paclitaxel and vehicle treatment in male rats.
Conclusion
Both substances showed similar and acceptable tolerability after high single-dose intravenous treatment. The results of this study do not indicate safety concerns that would preclude the use of sirolimus as an active ingredient on balloon catheters as an alternative to paclitaxel.
{"title":"Comparative acute toxicity of intravenous paclitaxel and sirolimus in rats","authors":"Jing Xie , Denise Schuett , Ulrich Speck , Tobias Haase","doi":"10.1016/j.crtox.2025.100248","DOIUrl":"10.1016/j.crtox.2025.100248","url":null,"abstract":"<div><h3>Aim</h3><div>In view of the exploration of sirolimus (rapamycin) as balloon coating for peripheral intravasal treatment and the reports on unfavorable tolerance of daily low-dose sirolimus, the aim of the study was to investigate potential toxicological effects of a single intravascular dose of sirolimus in comparison to paclitaxel and vehicle in the rat.</div></div><div><h3>Methods</h3><div>Rats were treated intravenously with a single dose of 20 mg/kg sirolimus or paclitaxel dissolved in identical vehicle and sacrificed 5- or 14-days post treatment. Vehicle (Cremophor<!--> <!-->EL/Ethanol diluted with saline) treated rats served as a control. Potential effects on survival, hematology, organ weights, organ histology were analyzed.</div></div><div><h3>Results</h3><div>Single dose i.v. injection of sirolimus, paclitaxel and vehicle induced temporary sedation after treatment. One animal treated with paclitaxel died, probably due to solvent toxicity. Sirolimus, paclitaxel and the vehicle control were tolerated. Animals treated with sirolimus or paclitaxel showed temporary hematological effects and thymic atrophy that subsided after 14 days. Sirolimus induced a temporary weight reduction of ovaries and uterus. Male rats showed histological changes of testes at 14 days after sirolimus treatment. Notably, sirolimus induced a prolonged body weight reduction compared to paclitaxel and vehicle treatment in male rats.</div></div><div><h3>Conclusion</h3><div>Both substances showed similar and acceptable tolerability after high single-dose intravenous treatment. The results of this study do not indicate safety concerns that would preclude the use of sirolimus as an active ingredient on balloon catheters as an alternative to paclitaxel.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"9 ","pages":"Article 100248"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2025.100269
Wanting Xie , Shuo Yang , Xin Wang , Jinting Liu , Wen Gao , Yan Shi
Fentanyl analogs present a significant global risk to public health and safety due to their high abuse potential and related mortality. However, the absence of a structured research framework focused on their clinical pharmacology and toxicology has led to a scarcity of studies on the mechanisms underlying the toxicity of and addiction to these substances, particularly regarding the rapidly emerging new fentanyl analogs. In this study, we employed a nontargeted metabolomics strategy. By conducting multivariate statistical analysis on ultrahigh performance liquid chromatography–high resolution mass spectrometry (UHPLC-HRMS) data from rat urine and plasma to elucidate the metabolic disruptions induced by fentanyl and carfentanyl. Adult male SD rats were randomly assigned to four groups: low-dose fentanyl group, high-dose fentanyl group, low-dose carfentanyl group, and high-dose carfentanyl group. All groups underwent continuous tail vein injection of toxicants for 5 consecutive days. Plasma and urine samples were collected from the rats before the first administration and at different time points after the last administration, followed by detection and analysis. Specifically, we aimed to elucidate the dose- and time-dependent metabolic toxicity of fentanyl and carfentanyl through a nontargeted metabolomics strategy. Oxidative stress, immunosuppression, and energy dysregulation were identified as core toxic effects of fentanyl and carfentanyl, tightly linked to perturbations in taurine and glutathione pathways, taurine regulating immune function and neuronal homeostasis, glutathione maintaining redox homeostasis. Succinic acid and taurine were confirmed as common biomarkers in urine and plasma. Succinic acid showed decreased plasma levels and increased urine levels, directly indicating fentanyl and carfentanyl-induced energy metabolism impairment. Taurine exhibited similar dysregulation, reflecting drug-induced immunosuppression and neuronal excitability abnormalities. These findings provide critical references and experimental support for studies on fentanyl-related hazards, toxicological mechanisms, and forensic detection.
{"title":"Novel dose- and time-dependent toxicity biomarkers of fentanyl/carfentanyl: uncovered by urine-plasma metabolomics for forensics","authors":"Wanting Xie , Shuo Yang , Xin Wang , Jinting Liu , Wen Gao , Yan Shi","doi":"10.1016/j.crtox.2025.100269","DOIUrl":"10.1016/j.crtox.2025.100269","url":null,"abstract":"<div><div>Fentanyl analogs present a significant global risk to public health and safety due to their high abuse potential and related mortality. However, the absence of a structured research framework focused on their clinical pharmacology and toxicology has led to a scarcity of studies on the mechanisms underlying the toxicity of and addiction to these substances, particularly regarding the rapidly emerging new fentanyl analogs. In this study, we employed a nontargeted metabolomics strategy. By conducting multivariate statistical analysis on ultrahigh performance liquid chromatography–high resolution mass spectrometry (UHPLC-HRMS) data from rat urine and plasma to elucidate the metabolic disruptions induced by fentanyl and carfentanyl. Adult male SD rats were randomly assigned to four groups: low-dose fentanyl group, high-dose fentanyl group, low-dose carfentanyl group, and high-dose carfentanyl group. All groups underwent continuous tail vein injection of toxicants for 5 consecutive days. Plasma and urine samples were collected from the rats before the first administration and at different time points after the last administration, followed by detection and analysis. Specifically, we aimed to elucidate the dose- and time-dependent metabolic toxicity of fentanyl and carfentanyl through a nontargeted metabolomics strategy. Oxidative stress, immunosuppression, and energy dysregulation were identified as core toxic effects of fentanyl and carfentanyl, tightly linked to perturbations in taurine and glutathione pathways, taurine regulating immune function and neuronal homeostasis, glutathione maintaining redox homeostasis. Succinic acid and taurine were confirmed as common biomarkers in urine and plasma. Succinic acid showed decreased plasma levels and increased urine levels, directly indicating fentanyl and carfentanyl-induced energy metabolism impairment. Taurine exhibited similar dysregulation, reflecting drug-induced immunosuppression and neuronal excitability abnormalities. These findings provide critical references and experimental support for studies on fentanyl-related hazards, toxicological mechanisms, and forensic detection.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"9 ","pages":"Article 100269"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2024.100210
Job H. Berkhout , James A. Glazier , Aldert H. Piersma , Julio M. Belmonte , Juliette Legler , Richard M. Spencer , Thomas B. Knudsen , Harm J. Heusinkveld
Neural tube closure is a critical morphogenetic event during early vertebrate development. This complex process is susceptible to perturbation by genetic errors and chemical disruption, which can induce severe neural tube defects (NTDs) such as spina bifida. We built a computational agent-based model (ABM) of neural tube development based on the known biology of morphogenetic signals and cellular biomechanics underlying neural fold elevation, bending and fusion. The computer model functionalizes cell signals and responses to render a dynamic representation of neural tube closure. Perturbations in the control network can then be introduced synthetically or from biological data to yield quantitative simulation and probabilistic prediction of NTDs by incidence and degree of defect. Translational applications of the model include mechanistic understanding of how singular or combinatorial alterations in gene-environmental interactions and animal-free assessment of developmental toxicity for an important human birth defect (spina bifida) and potentially other neurological problems linked to development of the brain and spinal cord.
{"title":"A computational dynamic systems model for in silico prediction of neural tube closure defects","authors":"Job H. Berkhout , James A. Glazier , Aldert H. Piersma , Julio M. Belmonte , Juliette Legler , Richard M. Spencer , Thomas B. Knudsen , Harm J. Heusinkveld","doi":"10.1016/j.crtox.2024.100210","DOIUrl":"10.1016/j.crtox.2024.100210","url":null,"abstract":"<div><div>Neural tube closure is a critical morphogenetic event during early vertebrate development. This complex process is susceptible to perturbation by genetic errors and chemical disruption, which can induce severe neural tube defects (NTDs) such as spina bifida. We built a computational agent-based model (ABM) of neural tube development based on the known biology of morphogenetic signals and cellular biomechanics underlying neural fold elevation, bending and fusion. The computer model functionalizes cell signals and responses to render a dynamic representation of neural tube closure. Perturbations in the control network can then be introduced synthetically or from biological data to yield quantitative simulation and probabilistic prediction of NTDs by incidence and degree of defect. Translational applications of the model include mechanistic understanding of how singular or combinatorial alterations in gene-environmental interactions and animal-free assessment of developmental toxicity for an important human birth defect (spina bifida) and potentially other neurological problems linked to development of the brain and spinal cord.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100210"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2025.100232
Furqan Alam , Tahani Saleh Mohammed Alnazzawi , Rashid Mehmood , Ahmed Al-maghthawi
Sustainable toxicology is vital for living species and the environment because it guarantees the safety, efficacy, and regulatory compliance of drugs, treatments, vaccines, and chemicals in living organisms and the environment. Conventional toxicological methods often lack sustainability as they are costly, time-consuming, and sometimes inaccurate. It means delays in producing new drugs, vaccines, and treatments and understanding the adverse effects of the chemicals on the environment. To address these challenges, the healthcare sector must leverage the power of the Generative-AI (GenAI) paradigm. This paper aims to help understand how the healthcare field can be revolutionized in multiple ways by using GenAI to facilitate sustainable toxicological developments. This paper first reviews the present literature and identifies the possible classes of GenAI that can be applied to toxicology. A generalized and holistic visualization of various toxicological processes powered by GenAI is presented in tandem. The paper discussed toxicological risk assessment and management, spotlighting how global agencies and organizations are forming policies to standardize and regulate AI-related development, such as GenAI, in these fields. The paper identifies and discusses the advantages and challenges of GenAI in toxicology. Further, the paper outlines how GenAI empowers Conversational-AI, which will be critical for highly tailored toxicological solutions. This review will help to develop a comprehensive understanding of the impacts and future potential of GenAI in the field of toxicology. The knowledge gained can be applied to create sustainable GenAI applications for various problems in toxicology, ultimately benefiting our societies and the environment.
{"title":"A Review of the Applications, Benefits, and Challenges of Generative AI for Sustainable Toxicology","authors":"Furqan Alam , Tahani Saleh Mohammed Alnazzawi , Rashid Mehmood , Ahmed Al-maghthawi","doi":"10.1016/j.crtox.2025.100232","DOIUrl":"10.1016/j.crtox.2025.100232","url":null,"abstract":"<div><div>Sustainable toxicology is vital for living species and the environment because it guarantees the safety, efficacy, and regulatory compliance of drugs, treatments, vaccines, and chemicals in living organisms and the environment. Conventional toxicological methods often lack sustainability as they are costly, time-consuming, and sometimes inaccurate. It means delays in producing new drugs, vaccines, and treatments and understanding the adverse effects of the chemicals on the environment. To address these challenges, the healthcare sector must leverage the power of the Generative-AI (GenAI) paradigm. This paper aims to help understand how the healthcare field can be revolutionized in multiple ways by using GenAI to facilitate sustainable toxicological developments. This paper first reviews the present literature and identifies the possible classes of GenAI that can be applied to toxicology. A generalized and holistic visualization of various toxicological processes powered by GenAI is presented in tandem. The paper discussed toxicological risk assessment and management, spotlighting how global agencies and organizations are forming policies to standardize and regulate AI-related development, such as GenAI, in these fields. The paper identifies and discusses the advantages and challenges of GenAI in toxicology. Further, the paper outlines how GenAI empowers Conversational-AI, which will be critical for highly tailored toxicological solutions. This review will help to develop a comprehensive understanding of the impacts and future potential of GenAI in the field of toxicology. The knowledge gained can be applied to create sustainable GenAI applications for various problems in toxicology, ultimately benefiting our societies and the environment.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100232"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2024.100206
Ruth Daniels , Wim Van der Elst , Chi K. So , Liesbeth Voeten , Philip Breugelmans , Marijke W.A. Molenaar-de Backer , Stephen Poole , Mehul Patel
The present study describes the “fit for purpose” testing and the independent product-specific GMP validation of the monocyte activation test (MAT) to detect pyrogenic and pro-inflammatory contaminants, MAT Method A, Quantitative Test (European Pharmacopoeia, Ph. Eur. chapter 2.6.30, 2017). A fit for purpose study was carried out to ensure that the chosen MAT set-up (cryopreserved PBMC, IL-6 detection) can reliably discriminate between batches of product containing pyrogenic contaminants below the contaminants limit concentration, CLC, from batches containing pyrogenic contaminants above the CLC. Such testing is carried out once, before the chosen MAT set-up is used for subsequent product testing to show that the incidence of false positives (pyrogen-negative (<CLC) batches testing as pyrogen-positive (>CLC) batches) and – especially – false negatives (pyrogen-positive (>CLC) testing as pyrogen-negative (<CLC)) is low. This study also afforded the opportunity to collect an independent body of validation data for comparison with that obtained previously (Daniels et al., 2022) to evaluate the robustness of MAT Method A and its fitness to replace the rabbit pyrogen test (RPT) where this has not already happened.
{"title":"Fit for purpose testing and independent GMP validation of the monocyte activation test","authors":"Ruth Daniels , Wim Van der Elst , Chi K. So , Liesbeth Voeten , Philip Breugelmans , Marijke W.A. Molenaar-de Backer , Stephen Poole , Mehul Patel","doi":"10.1016/j.crtox.2024.100206","DOIUrl":"10.1016/j.crtox.2024.100206","url":null,"abstract":"<div><div>The present study describes the “fit for purpose” testing and the independent product-specific GMP validation of the monocyte activation test (MAT) to detect pyrogenic and pro-inflammatory contaminants, MAT Method A, Quantitative Test (<span><span>European Pharmacopoeia, Ph. Eur. chapter 2.6.30, 2017</span></span>). A fit for purpose study was carried out to ensure that the chosen MAT set-up (cryopreserved PBMC, IL-6 detection) can reliably discriminate between batches of product containing pyrogenic contaminants below the contaminants limit concentration, CLC, from batches containing pyrogenic contaminants above the CLC. Such testing is carried out once, before the chosen MAT set-up is used for subsequent product testing to show that the incidence of false positives (pyrogen-negative (<CLC) batches testing as pyrogen-positive (>CLC) batches) and – especially – false negatives (pyrogen-positive (>CLC) testing as pyrogen-negative (<CLC)) is low. This study also afforded the opportunity to collect an independent body of validation data for comparison with that obtained previously (<span><span>Daniels et al., 2022</span></span>) to evaluate the robustness of MAT Method A and its fitness to replace the rabbit pyrogen test (RPT) where this has not already happened.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100206"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2025.100253
Marie de Deus , Charlotte Petit , Eve Cosker , Amandine Luc , Cédric Baumann , Thomas Schwitzer
Background
Major depressive disorder (MDD) treatment can be long and difficult to obtain. Thus, alternative non-pharmacological treatments, such as light therapy (LT), are increasingly recommended to treat MDD. For better treatment adherence, portable LT devices have been developed. However, more research is needed to better understand their safety of their use on patients’ physiology. One way to explore it is evaluating the retina function. That is why the aim of the study presented was to assess, thanks to Electroretinography (ERG), the impact on retinal function of an 8 weeks exposure to an active or a placebo LT portable device in MDD patients.
Method
MDD patients were treated with an active portable LT device or with a placebo LT device. The LT device tested was Luminette®. ERG measurements were carried out before the start of the LT treatment and 4 and 8 weeks afterwards.
Results
No significant differences were found in the ERG waveforms between the patients treated with active Luminette® and patients treated with the placebo device.
Conclusions
The use of the Luminette® device for 8 weeks, combined with usual care, did not result in any morphological or quantitative alterations in ERG waveforms in our cohort of MDD patients. This portable LT device would therefore be well tolerated at retinal level in MDD patients.
{"title":"Evaluation of the impact of a 8 week exposure to a portable light therapy device, Luminette®, on retinal function assessed by ElectroRetinoGraphy","authors":"Marie de Deus , Charlotte Petit , Eve Cosker , Amandine Luc , Cédric Baumann , Thomas Schwitzer","doi":"10.1016/j.crtox.2025.100253","DOIUrl":"10.1016/j.crtox.2025.100253","url":null,"abstract":"<div><h3>Background</h3><div>Major depressive disorder (MDD) treatment can be long and difficult to obtain. Thus, alternative non-pharmacological treatments, such as light therapy (LT), are increasingly recommended to treat MDD. For better treatment adherence, portable LT devices have been developed. However, more research is needed to better understand their safety of their use on patients’ physiology. One way to explore it is evaluating the retina function. That is why the aim of the study presented was to assess, thanks to Electroretinography (ERG), the impact on retinal function of an 8 weeks exposure to an active or a placebo LT portable device in MDD patients.</div></div><div><h3>Method</h3><div>MDD patients were treated with an active portable LT device or with a placebo LT device. The LT device tested was Luminette®. ERG measurements were carried out before the start of the LT treatment and 4 and 8 weeks afterwards.</div></div><div><h3>Results</h3><div>No significant differences were found in the ERG waveforms between the patients treated with active Luminette® and patients treated with the placebo device.</div></div><div><h3>Conclusions</h3><div>The use of the Luminette® device for 8 weeks, combined with usual care, did not result in any morphological or quantitative alterations in ERG waveforms in our cohort of MDD patients. This portable LT device would therefore be well tolerated at retinal level in MDD patients.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"9 ","pages":"Article 100253"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2025.100236
David G. Belair , Rebecca Kohnken , Rebecca L. McCloud , Stephanie Sandoval , Jonathon Green , Wayne R. Buck , James S. Polakowski
Unintended central nervous system (CNS) effects of small molecule drugs can lead to costly attrition during drug development. CNS liability can be assessed with biochemical assays, as part of routine nonclinical toxicology studies, or via a battery of rodent CNS tests. Alternative in vitro methods have been developed for assessing CNS liability of small molecule drugs though their use in drug development has lagged relative to other organ systems of interest including cardiac, hepatic, and gastrointestinal. In the present study, 13 commercially available small molecule drugs and 15 experimental AbbVie compounds were evaluated in an in vitro seizure assay consisting of human-induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons cultured on a multi-electrode array (MEA). Across all 28 compounds, the in vitro seizure assay exhibited 58% sensitivity and 78% specificity. A mathematical model of brain penetrance was used to predict brain exposures in cynomolgus monkey and improved the concordance of the in vitro seizure assay with in vivo seizure liability, highlighting that the in vitro assay together with CNS exposure prediction could serve as a useful tool for characterizing seizure liability of a small molecule drug candidate.
{"title":"Predicting seizure liability of small molecules using an in vitro multi-electrode array based assay coupled with modeling of brain disposition","authors":"David G. Belair , Rebecca Kohnken , Rebecca L. McCloud , Stephanie Sandoval , Jonathon Green , Wayne R. Buck , James S. Polakowski","doi":"10.1016/j.crtox.2025.100236","DOIUrl":"10.1016/j.crtox.2025.100236","url":null,"abstract":"<div><div>Unintended central nervous system (CNS) effects of small molecule drugs can lead to costly attrition during drug development. CNS liability can be assessed with biochemical assays, as part of routine nonclinical toxicology studies, or via a battery of rodent CNS tests. Alternative in vitro methods have been developed for assessing CNS liability of small molecule drugs though their use in drug development has lagged relative to other organ systems of interest including cardiac, hepatic, and gastrointestinal. In the present study, 13 commercially available small molecule drugs and 15 experimental AbbVie compounds were evaluated in an in vitro seizure assay consisting of human-induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons cultured on a multi-electrode array (MEA). Across all 28 compounds, the in vitro seizure assay exhibited 58% sensitivity and 78% specificity. A mathematical model of brain penetrance was used to predict brain exposures in cynomolgus monkey and improved the concordance of the in vitro seizure assay with in vivo seizure liability, highlighting that the in vitro assay together with CNS exposure prediction could serve as a useful tool for characterizing seizure liability of a small molecule drug candidate.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100236"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143900388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2025.100220
I.A. Lea , A.N. Buerger , D. Feifarek , A. Mihalchik , M.M. Heintz , L.C. Haws , H. Nyambego , K. Goyak , C. Palermo , S.J. Borghoff
Low molecular weight ortho-phthalate compounds have been implicated in disruption of androgen pathways when exposure occurs during the masculinization programming window. Di-isononyl phthalate (DINP) is a high molecular weight phthalate and a high production volume chemical. To understand the potential for DINP and its metabolites to disrupt endocrine pathways, a weight of evidence assessment was conducted according to the European Chemicals Agency (ECHA)/ European Food Safety Authority (EFSA) Endocrine Disruptor Guidance (2018). Toxicological data related to estrogen (E), androgen (A), thyroid (T), or steroidogenesis (S) pathways was assessed. Literature searches returned 110 articles from which data were extracted and assessed in conjunction with 105 high-throughput assays. An in-silico assessment of the EATS activity for DINP metabolites also was conducted. Based on the available evidence, DINP did not elicit thyroid- or estrogen-related apical outcomes in vivo. There were no studies evaluating thyroid hormone levels in vivo which, according to the ECHA/EFSA guidance, constitutes a data gap and prevents a conclusion being drawn on the T-pathway. The E, A, and S-pathways were sufficiently assessed to conclude on the endocrine disrupting potential of DINP. Based on the lack of apical outcomes, DINP did not disrupt the E-pathway. For the A and S-pathways, there was limited evidence to support adverse apical outcomes, so a mode of action assessment using a structured adverse outcome pathway (AOP) framework was performed. No biologically plausible link could be established between the key events in the hypothesized AOP that lead to adverse outcomes. Further, no dose or temporal concordance for A- and S-mediated findings were identified. Therefore, DINP does not meet the ECHA/EFSA criteria to be considered an endocrine disruptor.
{"title":"Evaluation of the endocrine disrupting potential of Di-isononyl phthalate","authors":"I.A. Lea , A.N. Buerger , D. Feifarek , A. Mihalchik , M.M. Heintz , L.C. Haws , H. Nyambego , K. Goyak , C. Palermo , S.J. Borghoff","doi":"10.1016/j.crtox.2025.100220","DOIUrl":"10.1016/j.crtox.2025.100220","url":null,"abstract":"<div><div>Low molecular weight <em>ortho</em>-phthalate compounds have been implicated in disruption of androgen pathways when exposure occurs during the masculinization programming window. Di-isononyl phthalate (DINP) is a high molecular weight phthalate and a high production volume chemical. To understand the potential for DINP and its metabolites to disrupt endocrine pathways, a weight of evidence assessment was conducted according to the European Chemicals Agency (ECHA)/ European Food Safety Authority (EFSA) Endocrine Disruptor Guidance (2018). Toxicological data related to estrogen (E), androgen (A), thyroid (T), or steroidogenesis (S) pathways was assessed. Literature searches returned 110 articles from which data were extracted and assessed in conjunction with 105 high-throughput assays. An <em>in-silico</em> assessment of the EATS activity for DINP metabolites also was conducted. Based on the available evidence, DINP did not elicit thyroid- or estrogen-related apical outcomes <em>in vivo.</em> There were no studies evaluating thyroid hormone levels <em>in vivo</em> which, according to the ECHA/EFSA guidance, constitutes a data gap and prevents a conclusion being drawn on the T-pathway. The E, A, and S-pathways were sufficiently assessed to conclude on the endocrine disrupting potential of DINP. Based on the lack of apical outcomes, DINP did not disrupt the E-pathway. For the A and S-pathways, there was limited evidence to support adverse apical outcomes, so a mode of action assessment using a structured adverse outcome pathway (AOP) framework was performed. No biologically plausible link could be established between the key events in the hypothesized AOP that lead to adverse outcomes. Further, no dose or temporal concordance for A- and S-mediated findings were identified. Therefore, DINP does not meet the ECHA/EFSA criteria to be considered an endocrine disruptor.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100220"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143510178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Exposure of pregnant rats to some phthalates during the masculinization programming window (MPW) can lower fetal testis testosterone production and adversely affect development of the fetal male reproductive tract. Some of the effects in rats are androgen-dependent, while others also occur in mice without lower testosterone production. An adverse outcome pathway (AOP) network has been proposed for these developmental effects that includes both androgen-dependent and androgen-independent pathways, the latter of which includes a short list of putative molecular initiating events (MIEs) including peroxisome proliferator activated receptor (PPAR) activation, and effects on Sertoli cells in the developing testes as early key events (KEs) (PMID 34314370). Data from peer-reviewed literature, publicly cited toxicology reports, and EPA’s Toxicity Forecaster (ToxCast) were evaluated in the context of this hypothesized Sertoli cell-based AOP and exposure to diisononyl phthalate (DINP). Each of the fifteen identified studies underwent a risk of bias (RoB) assessment, which revealed a high risk of bias for all but one study endpoint. In vitro evidence in kidney, liver, and fibroblast-like cell lines indicates that the DINP metabolites mono-isononyl phthalate (MINP) and mono-hydroxyisononyl phthalate (MHINP) activate PPARα/γ and that mouse PPARα/γ are more sensitive than human PPARα/γ. However, DINP did not activate PPARα-related genes in rat fetal testes at high maternal dosages (PMID 22112501), and it remains unknown whether PPARs are expressed in fetal Sertoli cells. Overall, there is insufficient evidence to evaluate whether PPAR activation in the developing male reproductive tract is causally linked to the KEs in the hypothesized AOP. Regarding the KEs, no in vivo studies were identified that examined the effects of DINP on Sertoli cell proliferation or cytoskeleton; a single in vitro study found no effect of DINP on Sertoli cell proliferation. There was limited and conflicting evidence for the effects of DINP on tubulogenesis, but strong in vivo evidence for increased multinucleated germ (MNG) cells. No evidence was found concerning germ cell apoptosis. For the adverse outcomes (AOs), there was limited in vivo evidence for testicular dysgenesis following altered tubulogenesis, and impaired spermatogenesis following increased MNGs. There was strong evidence against reduced fertility, but this is not a sensitive endpoint in rats given their robust sperm production and excess capacity. In conclusion, following in utero DINP exposure, while PPAR activation (MIE) is plausible, linkage to effects on Sertoli cells and downstream AOPs is lacking. The sparse evidence currently available is insufficient to support the applicability of the hypothesized Sertoli cell-based AOP to DINP.
{"title":"Evaluation of a hypothesized Sertoli cell-based adverse outcome pathway for effects of diisononyl phthalate on the developing testis","authors":"J.M. Rogers , A.N. Buerger , M.M. Heintz , C.M. Palermo , L.C. Haws , I.A. Lea","doi":"10.1016/j.crtox.2025.100219","DOIUrl":"10.1016/j.crtox.2025.100219","url":null,"abstract":"<div><div>Exposure of pregnant rats to some phthalates during the masculinization programming window (MPW) can lower fetal testis testosterone production and adversely affect development of the fetal male reproductive tract. Some of the effects in rats are androgen-dependent, while others also occur in mice without lower testosterone production. An adverse outcome pathway (AOP) network has been proposed for these developmental effects that includes both androgen-dependent and androgen-independent pathways, the latter of which includes a short list of putative molecular initiating events (MIEs) including peroxisome proliferator activated receptor (PPAR) activation, and effects on Sertoli cells in the developing testes as early key events (KEs) (PMID 34314370). Data from peer-reviewed literature, publicly cited toxicology reports, and EPA’s Toxicity Forecaster (ToxCast) were evaluated in the context of this hypothesized Sertoli cell-based AOP and exposure to diisononyl phthalate (DINP). Each of the fifteen identified studies underwent a risk of bias (RoB) assessment, which revealed a high risk of bias for all but one study endpoint. <em>In vitro</em> evidence in kidney, liver, and fibroblast-like cell lines indicates that the DINP metabolites mono-isononyl phthalate (MINP) and mono-hydroxyisononyl phthalate (MHINP) activate PPARα/γ and that mouse PPARα/γ are more sensitive than human PPARα/γ. However, DINP did not activate PPARα-related genes in rat fetal testes at high maternal dosages (PMID 22112501), and it remains unknown whether PPARs are expressed in fetal Sertoli cells. Overall, there is insufficient evidence to evaluate whether PPAR activation in the developing male reproductive tract is causally linked to the KEs in the hypothesized AOP. Regarding the KEs, no <em>in vivo</em> studies were identified that examined the effects of DINP on Sertoli cell proliferation or cytoskeleton; a single <em>in vitro</em> study found no effect of DINP on Sertoli cell proliferation. There was limited and conflicting evidence for the effects of DINP on tubulogenesis, but strong <em>in vivo</em> evidence for increased multinucleated germ (MNG) cells. No evidence was found concerning germ cell apoptosis. For the adverse outcomes (AOs), there was limited <em>in vivo</em> evidence for testicular dysgenesis following altered tubulogenesis, and impaired spermatogenesis following increased MNGs. There was strong evidence against reduced fertility, but this is not a sensitive endpoint in rats given their robust sperm production and excess capacity. In conclusion, following <em>in utero</em> DINP exposure, while PPAR activation (MIE) is plausible, linkage to effects on Sertoli cells and downstream AOPs is lacking. The sparse evidence currently available is insufficient to support the applicability of the hypothesized Sertoli cell-based AOP to DINP.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100219"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crtox.2025.100231
Giovanni Tossetta , Sonia Fantone , Antonio Domenico Procopio , Armanda Pugnaloni , Alessandro Francesco Gualtieri , Daniela Marzioni
It is known that mineral fibres can be found in placental tissues, but their effect is not known on these tissues. BeWo in vitro model of syncytiotrophoblast, the outer layer of maternal-foetal barrier, is necessary to understand if mineral fibres can alter placental cell turnover and consequently to influence the outcome of pregnancy. We performed in vitro experiments using chrysotile UICC (UICC), chrysotile Valmalenco (VM) and erionite (ERI) to investigate the potential cytotoxic effects of these mineral fibres on BeWo cells. We demonstrated that all fibres are toxic while only UICC fibres caused a DNA damage that the cells were not able to repair through RAD51 activity. In addition, we demonstrated that DNA replication is not altered while cyclin D1 showed a significant decrease in VM and UICC suggesting that the cell cycle is altered in G1 phase. Moreover, UICC increased active form of caspase 3 demonstrating that apoptosis can be induced in BeWo cells. We suggest that although morphological changes are not visible in BeWo cells treated with these mineral fibres, DNA damage can lead to altered placenta physiology that can be seen late when the damage at the foetal tissues has already occurred.
{"title":"Effects of mineral fibres in an in vitro placental syncytiotrophoblast model","authors":"Giovanni Tossetta , Sonia Fantone , Antonio Domenico Procopio , Armanda Pugnaloni , Alessandro Francesco Gualtieri , Daniela Marzioni","doi":"10.1016/j.crtox.2025.100231","DOIUrl":"10.1016/j.crtox.2025.100231","url":null,"abstract":"<div><div>It is known that mineral fibres can be found in placental tissues, but their effect is not known on these tissues. BeWo in vitro model of syncytiotrophoblast, the outer layer of maternal-foetal barrier, is necessary to understand if mineral fibres can alter placental cell turnover and consequently to influence the outcome of pregnancy. We performed in vitro experiments using chrysotile UICC (UICC), chrysotile Valmalenco (VM) and erionite (ERI) to investigate the potential cytotoxic effects of these mineral fibres on BeWo cells. We demonstrated that all fibres are toxic while only UICC fibres caused a DNA damage that the cells were not able to repair through RAD51 activity. In addition, we demonstrated that DNA replication is not altered while cyclin D1 showed a significant decrease in VM and UICC suggesting that the cell cycle is altered in G1 phase. Moreover, UICC increased active form of caspase 3 demonstrating that apoptosis can be induced in BeWo cells. We suggest that although morphological changes are not visible in BeWo cells treated with these mineral fibres, DNA damage can lead to altered placenta physiology that can be seen late when the damage at the foetal tissues has already occurred.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100231"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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