Journal of Toxicological Sciences最新文献

{"title":"Evaluation of toxicokinetic interactions mediated by plasma protein binding during amoxapine intoxication.","authors":"Akifumi Okamoto, Yoshitaka Yamazaki, Natsumi Hattori-Usami, Kenji Momo, Asuka Kaizaki-Mitsumoto, Satoshi Numazawa","doi":"10.2131/jts.51.31","DOIUrl":"10.2131/jts.51.31","url":null,"abstract":"<p><p>Toxicity enhancement mediated by plasma protein binding during intoxication remains poorly understood. It is known that in mice, brain penetration of amoxapine (AMX) increases nonlinearly with increasing doses; therefore, this study investigated its potential to enhance toxicity via plasma protein binding. AMX was added to mouse or human plasma and adjusted to therapeutic, toxic, and lethal concentrations. The plasma protein-binding ratio and free AMX concentration were measured using ultrafiltration and equilibrium dialysis. Furthermore, the binding ratios of varying concentrations of chlorpromazine, which is often co-administered with AMX in cases of overdose, was analyzed in the presence of therapeutic AMX concentrations. The binding ratio of AMX exceeded 90%, thereby demonstrating a high binding rate; however, this ratio was lower in human plasma than in mice. A nonlinear increase in free AMX concentration was observed in mouse plasma, particularly at high concentrations. In contrast, free AMX concentration showed a linear increase in human plasma. Neither the therapeutic nor toxic concentration of chlorpromazine produced any visible effects on the plasma protein binding ratio or the free AMX concentration. These results suggest that protein binding of AMX is more readily saturated in mouse plasma than in human plasma. In addition, chlorpromazine inhibits AMX binding to α₁-acid glycoprotein; however, AMX may alternatively binds to albumin, which results in no apparent change in the total binding ratio. Further insights into the toxicokinetic interactions mediated by plasma protein binding are also needed for various toxic substances other than AMX.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 1","pages":"31-44"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integration of QSAR modeling and in vitro validation for identification of food-derived Nrf2 activators against arsenic-induced toxicity.","authors":"Ngo Thanh Huong, Susumu Kodama, Atsushi Ono","doi":"10.2131/jts.51.533","DOIUrl":"https://doi.org/10.2131/jts.51.533","url":null,"abstract":"<p><p>Arsenic exposure is a major public health concern due to its toxicity and carcinogenicity, largely mediated by oxidative stress, and activation of the Nrf2 signaling pathway is considered a promising strategy to mitigate such damage. In this study, a quantitative structure-activity relationship (QSAR) model was developed to identify potential Nrf2 activators from food-derived compounds. Machine learning algorithms, including Random Forest (RF), Support Vector Machine (SVM), Linear Discriminant Analysis (LDA), and a stacking model, were developed and optimized. The optimized RF, SVM, and LDA models were subsequently integrated into a stacking framework, which was selected as the final predictive model for virtual screening based on its robust and balanced predictive performance. The stacking model achieved the highest accuracy during five-fold cross-validation (0.77) and demonstrated competitive performance on the independent test set (0.742 ± 0.040), with balanced precision, sensitivity, and F-measure. Consequently, the stacking model was selected as the final model for virtual screening. A total of 70,926 compounds retrieved from a food-derived database were filtered based on physicochemical criteria, and QSAR-based virtual screening predicted 920 compounds as potential activators of the Nrf2 signaling pathway, from which 5,7-Dimethylchrysin (FooDB ID: FDB015537) and Demethylvestitol (FooDB ID: FDB012218) were selected for experimental validation. In vitro assays using HepG2 cells demonstrated that 5,7-Dimethylchrysin significantly enhanced cell viability against sodium arsenite (150 μM)-induced cytotoxicity, with an effective concentration (EC50) of 0.54 μM, whereas Demethylvestitol exhibited only limited protective effects. Furthermore, luciferase reporter assays confirmed that 5,7-Dimethylchrysin activated antioxidant response element (ARE)-driven transcription in a concentration-dependent manner, producing a 1.5 to 2.4-fold increase at concentrations ranging from 0.78 to 6.25 μM. Overall, these findings highlight the effectiveness of integrating QSAR modeling with experimental validation to identify food-derived compounds with protective potential against arsenic-induced toxicity, with 5,7-Dimethylchrysin emerging as a promising candidate for further investigation.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 10","pages":"533-547"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of blood microsampling (50 μL) on toxicological assessment in rats treated with tacrine, a drug known to have adverse effects that increase neutrophils.","authors":"Norimichi Hattori, Yusuke Shibui, Yoichi Tanaka, Yoshiro Saito","doi":"10.2131/jts.51.19","DOIUrl":"10.2131/jts.51.19","url":null,"abstract":"<p><p>To promote the 3Rs in toxicological assessment, the recommendation for blood microsampling in toxicokinetic evaluation is noted in the ICH Harmonized Guideline S3A Q&As. However, there are only a few articles reporting the practical application of microsampling in the toxicological assessment with toxic drugs. In this study, we investigate the effect of microsampling on toxicological assessment in rats treated with tacrine, which is known to have toxic effects that induce an increase in neutrophils and behavioral abnormalities. Thirty female Sprague-Dawley rats were divided into microsampling (MS) and non-microsampling (non-MS) groups, and orally administered tacrine once daily at dose levels of 0 (vehicle only), 3 and 10 mg/kg bw for 28 days (each group: n=5). In the MS group, blood samples (50 μL/time point) were collected at 6 time points on day 1 and 7 time points on day 28 to 29. All the animals underwent necropsy on day 29. By comparing the results of toxicological and toxicokinetic analysis between the MS and non-MS groups, we validated effects of microsampling for toxicological assessment. Although increase in neutrophils and repeated stereotypic behaviors were observed as toxic effects in the rats administered tacrine, we could not find any difference between the MS and non-MS groups, and also found that microsampling did not affect any other data from toxicological and toxicokinetic analysis. In conclusion, blood microsampling appeared to be a feasible technique for the toxicity study of tacrine and was considered to be applicable in the toxicity study of even drugs with toxic effects on hematological parameters, such as an increase in neutrophils.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 1","pages":"19-30"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linalool inhalation‒induced anxiety-like effects occur independently of olfactory input and require cytochrome P450 activity.","authors":"Hideaki Sato, Ami Oguro, Masatsugu Miyara, Yaichiro Kotake","doi":"10.2131/jts.51.393","DOIUrl":"https://doi.org/10.2131/jts.51.393","url":null,"abstract":"<p><p>Multiple chemical sensitivity (MCS) is characterized by neuropsychological symptoms including anxiety, depression, and fatigue following exposure to environmental chemicals, yet its underlying mechanisms remain poorly understood. Linalool, a monoterpene alcohol widely used in consumer products, has been suggested as a potential contributor to MCS. To elucidate its neural effects, we examined the behavioral effects of linalool inhalation in mice. Linalool exposure induced both anxiety- and depression-like behaviors. While the depression-like behavior required olfactory input, the anxiety-like behavior occurred independently of olfactory perception. Our previous studies demonstrated that inhaled linalool accumulates in the brain and undergoes cytochrome P450 (P450)-dependent metabolism. We therefore tested whether P450-mediated metabolism contributes to the behavioral effects of linalool. Significantly, inhibition of P450 activity abolished the anxiety-like behavior. These findings reveal an olfactory-independent mechanism by which inhaled linalool induces anxiety-like behavior in mice and suggest that P450 activity is required for this effect, providing a basis for investigating fragrance-induced MCS-like neurobehavioral responses.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 7","pages":"393-402"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148368762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A high-fat/high-sucrose/high-cholesterol diet leads to early indications of metabolic dysfunction-associated steatohepatitis-like lesions in obese diabetic mice.","authors":"Kinuko Uno, Kodai Shirasaka, Yamato Muro, Fuko Kuroki, Mei Nishida, Kumiko Yamaguchi, Kouhei Mandai, Keita Sekiguchi, Tomohiko Sasase, Masami Shinohara, Miki Sugimoto, Tatsuya Maekawa, Katsuhiro Miyajima, Takeshi Ohta","doi":"10.2131/jts.51.367","DOIUrl":"https://doi.org/10.2131/jts.51.367","url":null,"abstract":"<p><p>Chronic hyperlipidemia and/ or hyperglycemia can impair various organs, such as the liver, kidney, and pancreas, through metabolic abnormalities. Metabolic dysfunction-associated steatohepatitis (MASH), related from nonalcoholic steatohepatitis (NASH), exhibits complex pathophysiological features, and animal models of MASH are essential for elucidating its underlying mechanisms. This study aimed to induce MASH-like lesions in obese type 2 diabetic mice by feeding them a high-fat/high-sucrose/high-cholesterol (HFSC) diet. C57BL/6J, db/db, and KK-Ay mice at 6 weeks of age were fed an HFSC diet for 8 weeks. Collected samples were subjected to hematobiochemical, gene expression, and histopathological analyses. At 14 weeks of age, both diabetic mouse models showed hyperglycemia and hyperlipidemia, with hypercholesterolemia observed in HFSC-fed groups. HFSC-fed db/db and KK-Ay mice showed increased hepatic steatosis, and KK-Ay mice also showed partial hepatic fibrosis in pericentral venous and perivascular areas. mRNA analysis revealed upregulation of hepatic genes involved in lipid synthesis, inflammation, and fibrosis in diabetic mice fed the HFSC diet. Obese type 2 diabetic mice fed a high-fat/high-sucrose/high-cholesterol diet showed early indications of MASH-like lesions, supporting their utility as MASH animal models.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 7","pages":"367-377"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148368847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel ICP-MS strategy identifies arsenite as an inhibitor of selenocysteine-tRNA^Sec charging.","authors":"Hayato Takashima, Reiko Makino, Hiroki Taguchi, Yoshika Takenaka, Yasutoshi Akiyama, Yoshihisa Tomikoka, Daigo Sumi, Takashi Toyama, Yoshiro Saito","doi":"10.2131/jts.51.331","DOIUrl":"10.2131/jts.51.331","url":null,"abstract":"<p><p>Arsenite (As(III)) is a widespread environmental contaminant that increases susceptibility to oxidative stress. We recently reported that As(III) suppresses the induction of glutathione peroxidases (GPx) by various selenium sources in cultured cells; however, its underlying mechanism remains unclear. GPx contains a selenocysteine (Sec) residue essential for catalytic activity, and Sec biosynthesis requires multiple steps of selenium metabolism. Selenite is directly incorporated into the Sec biosynthetic pathway via selenophosphate synthetase 2 (SEPHS2) and utilized for Sec-tRNA^Sec formation. Because Sec-tRNA^Sec decodes UGA codons, impaired synthesis of Sec-tRNA^Sec leads to nonsense-mediated decay or truncated translation of selenoprotein mRNAs. Here, we developed an inductively coupled plasma (ICP)-MS based method to evaluate Sec-tRNA^Sec and found that As(III) inhibits Sec charging of tRNA. As(III) markedly suppressed GPx protein induction with minimal effects on mRNA abundance. As(III) did not affect total tRNA^Sec levels; however, As(III) significantly decreased RNA-bound selenium released by deacylation, indicating reduced Sec-tRNA^Sec formation. These results suggest that As(III) impairs selenoprotein translation by inhibiting Sec charging of tRNA.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 6","pages":"331-338"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148138467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic protective effects of melatonin and ascorbic acid against benzene-induced genotoxicity, oxidative stress, and activin A/follistatin dysregulation in a rat model of pre-leukemia.","authors":"Mohammed M Hussein M Raouf, Ismail M Maulood, Zrar Saleem Marzani","doi":"10.2131/jts.51.449","DOIUrl":"https://doi.org/10.2131/jts.51.449","url":null,"abstract":"<p><p>Benzene exposure is a major risk factor for hematologic malignancies, including acute myeloid leukemia (AML), through mechanisms involving genotoxicity, oxidative stress, and dysregulation of hematopoietic signaling pathways. This study investigated the protective effects of melatonin, vitamin C, and their combination against benzene-induced pre-leukemic alterations in rats, with emphasis on bone marrow genotoxicity, oxidative stress, and activin A/follistatin expression. Forty male Wistar rats were allocated into five groups (n=8): control, benzene, benzene + melatonin, benzene + vitamin C, and benzene + combined treatment. Genotoxicity was assessed using bone marrow micronucleus assays, while oxidative stress biomarkers, serum activin A/follistatin levels, and bone marrow gene expression were evaluated using biochemical assays, ELISA, and qPCR, respectively. Benzene exposure significantly increased micronucleus frequency, reduced %PCE and PCE/NCE ratio, elevated %NCE, and suppressed activin A and follistatin expression. Melatonin or vitamin C alone partially attenuated these abnormalities, whereas combined treatment demonstrated the strongest protective effects, including marked improvement of genotoxicity indices, restoration of catalase activity, and significant upregulation of activin A and follistatin gene expression. Combined melatonin and vitamin C supplementation attenuated benzene-associated pre-leukemic alterations, particularly genotoxic and oxidative stress-related abnormalities. Combined melatonin and vitamin C supplementation attenuated benzene-associated pre-leukemic alterations in rats, particularly genotoxic and oxidative stress-related abnormalities. These protective effects were accompanied by modulation of activin A/follistatin expression patterns, suggesting a potential association between restoration of this signaling axis and improved bone marrow homeostasis. However, further mechanistic studies are required to determine whether activin A/follistatin signaling directly contributes to the observed protective effects.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 8","pages":"449-461"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148664168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogen sulfide donor GYY4137 attenuates RANKL-induced osteoclast differentiation and multi-nucleation.","authors":"Tomohiro Takagi, Hirofumi Inoue, Hiromu Morimoto, Nobuyuki Takahashi, Mariko Uehara","doi":"10.2131/jts.51.267","DOIUrl":"10.2131/jts.51.267","url":null,"abstract":"<p><p>Hydrogen sulfide (H₂S) is a novel gasotransmitter produced in mammalian cells and is known to various regulate physiological functions. Previous study reported that an imbalance in H₂S metabolism is associated with defective bone homeostasis. However, the detailed mechanism of how H₂S affect osteoclast differentiation remains unclear. In the present study, we demonstrated that the effect of H₂S donor GYY4137 on osteoclast differentiation and multi-nucleation. Treatment of GYY4137 significantly decreased the number of receptor activator of nuclear factor kappa-B ligand (RANKL)-induced tartrate-resistant acid phosphatase (TRAP)-positive cells and inhibited the expression of osteoclast-related genes, nuclear factor of activated T-cells 1 (NFATc1) and Cathepsin K(Ctsk). Additionally, the increased gene expression of dendritic cell-specific transmembrane protein (DC-STAMP), osteoclast stimulatory transmembrane protein (OC-STAMP), and v-ATPase V0 subunit d2 (Atp6v0d2), which are cell-cell fusion-related molecules by RANKL treatment, was attenuated by GYY4137. Furthermore, GYY4137 suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including ERK1/2, JNK1/2, and p38MAPK, compared to RANKL-treated cells. Thus, our data suggested that H₂S donor GYY4137 as a novel osteoclast genesis inhibitor, significantly decreases osteoclast differentiation and multi-nucleation by inhibiting the expression of the cell-cell fusion molecules.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 4","pages":"267-274"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Screening for putative epimutagens in neural stem cells derived from human induced pluripotent stem cells.","authors":"Yoshikazu Arai, Koichiro Nishino","doi":"10.2131/jts.51.427","DOIUrl":"https://doi.org/10.2131/jts.51.427","url":null,"abstract":"<p><p>The prevalence of pediatric neurological disorders has increased in recent years and has emerged as a major social concern. While genetic factors play a role, environmental factors may also contribute to these disorders, particularly exposure to harmful chemicals in the fetal environment during pregnancy. However, the concentrations of these chemicals in the fetal environment are extremely low compared with those in experimental conditions, and their influence on the development of neurological disorders after birth remains unclear. Epigenetic regulation plays a crucial role in gene expression and/or chromatin formation, ensuring normal cellular development and differentiation. The relationship between impaired epigenetic regulation and neurological disorders has been previously reported. Therefore, this study aimed to identify chemicals that disrupt epigenetic systems at detectable concentrations in pregnant mothers' serum using a human neural differentiation model. Among the 11 chemicals, including pesticides and heavy metals, exposure to octachlorodipropyl ether (S-421) altered heterochromatin formation in neural stem cells at concentrations found in maternal and umbilical cord blood serum. Additionally, exposure to several chemicals, including S-421, affected neural differentiation, leading to excessive neural fiber growth. Furthermore, S-421 exposure induced DNA hypermethylation of the neural-related genes Cadherin 2 (CDH2) and Sry-related HMG-Box gene 10 (SOX10) in neural stem cells. These findings suggest that S-421, which is present in the fetal environment, functions as an epimutagen that disrupts the epigenetic system within biologically relevant exposure levels. The established epimutagenic screening is expected to provide new insights into the relationship between prenatal chemical exposure and postnatal childhood neurological disorders.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 8","pages":"427-440"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148664218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Considerations for infection risks identified in target safety review.","authors":"Yuichiro Amano, Yoshitaka Inui, Satoko Yoshioka, Jodi Goodwin","doi":"10.2131/jts.51.251","DOIUrl":"10.2131/jts.51.251","url":null,"abstract":"<p><p>Target Safety Review (TSR) is a document that triggers the Target Safety Assessment and is designed to predict and identify on-target safety risks. However, with regard to the anticipated on-target risks extracted by TSR, nonclinical toxicity studies sometimes have limitations in predicting clinical safety risks. In this study, we investigated whether nonclinical toxicity studies could predict clinical infection risks expected in TSR. Using the OFF-X database, we identified 942 targets and 1323 drugs associated with infection risks. Through successive filters, i.e., applying \"drug alert\", \"on-target\", \"causality with severity\", \"class score\", and \"evidence levels\", biologics became the focus, resulting in six targets and 17 drugs approved by PMDA. From PMDA reports, package inserts, and interview forms, we extracted immune-related findings in nonclinical toxicity studies and infection risks in clinical settings to analyze predictivity by target. Our survey shows clear immune-related toxicity in nonclinical studies of CD20 inhibitors (obinutuzumab, ofatumumab, rituximab), TNF-alpha inhibitors (adalimumab, golimumab), and IL-6R antagonists (sarilumab, tocilizumab). Indicators included B cell depletion, thymus atrophy, and decreased neutrophils. For IL-17, IL-23, and IL-1beta inhibitors, nonclinical studies did not always predict the infection risks observed in clinical settings. Although nonclinical toxicity studies sometimes provided insights into potential infection risks which can be anticipated by its target, their predictive power for specific mechanism of actions and infections appeared limited. Understanding the MOAs and biological background of the drug through the TSR and identifying and mitigating risks early in the project are essential for the safe development of new therapeutic agents.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 4","pages":"251-258"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592919","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}