Journal of Applied Toxicology最新文献

{"title":"The Development of Yellow Mealworm (Tenebrio molitor) as a Cheap and Simple Model to Evaluate Acute Toxicity, Locomotor Activity Changes, and Metabolite Profile Alterations Induced by Nanoplastics of Different Sizes.","authors":"Miao Sun, Xiaomei Zhao, Sihuan Luo, Miao Jiang, Qing Liu, Yi Cao","doi":"10.1002/jat.4764","DOIUrl":"https://doi.org/10.1002/jat.4764","url":null,"abstract":"<p><p>Due to the wide uses of plastic products, nanoplastics are ubiquitous contaminants in the environment. Hence, extensive studies used various models to evaluate the toxicity of nanoplastics. In the present study, we developed yellow mealworm (Tenebrio molitor) as an alternative model to investigate the acute toxicity of nanoplastics. Our results showed that microinjection with 500 mg/kg nanoplastics significantly increased death rate of yellow mealworms after 24 or 48 h, with 100 nm particles being more effective compared with 20 nm ones. Meanwhile, dose-dependent increase of death rate was observed in yellow mealworms after injection with 2-200 mg/kg 100 nm nanoplastics. Exposure to 2 mg/kg 100 nm but not 20 nm nanoplastics also led to hyperactivity of yellow mealworms. Both types of nanoplastics altered metabolite profiles, that 20 nm nanoplastics significantly up-regulated and down-regulated 9 and 12 metabolites, whereas 100 nm nanoplastics significantly up-regulated and down-regulated 16 and 25 metabolites, respectively. Enrichment analysis revealed that 100 nm but not 20 nm nanoplastics significantly affected alpha-linolenic acid metabolism (ko00592) and purine metabolism (ko00230). For the metabolites belonging to these pathways, 100 nm nanoplastics significantly up-regulated stearidonic acid but down-regulated guanine. Combined, these results revealed size-dependent effects of nanoplastics on acute toxicity, hyperactivity and metabolite profile changes in yellow mealworms. These results also indicated the potential uses of yellow mealworms as a cheap and simple model to evaluate the toxicity of nanoplastics.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382519","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":"Toll-Like Receptors in Pentachlorophenol- and Dibutyltin-Induced Production of Pro-Inflammatory Cytokines, Interleukin (IL)-1β, and IL-6, by Human Immune Cells.","authors":"Aleshia Seaton-Terry, Zinia Hunter, Meaghan Lewis, Sophia Fisher, Ellie Bray, Brian Townsend, Saleban Gabure, Latoya Daniel, Margaret Whalen","doi":"10.1002/jat.4762","DOIUrl":"https://doi.org/10.1002/jat.4762","url":null,"abstract":"<p><p>Pentachlorophenol (PCP) and dibutyltin dichloride (DBT) contaminate the environment due to their diverse applications. PCP has been found from 0.26 to 5 μM in the serum of exposed individuals and at an average of 0.15 μM in the unexposed. DBT has been detected in human blood at levels up to 0.3 μM. Exposure to these contaminants is linked to pathological conditions including cancer. Interleukin-1 beta (IL-1β) and IL-6 are pro-inflammatory cytokines that when produced inappropriately can cause chronic inflammation, which is linked to pathologies including autoimmune diseases and cancer. PCP and DBT have been shown to increase the production of IL-1β and IL-6 by immune cells in a MAP kinase (MAPK) dependent process. Toll-like receptors (TLRs) activate the signaling pathways linked to MAPK that lead to production of these cytokines. This study demonstrates that PCP-induced production of IL-1β and IL-6 is dependent on TLR4 and TLR8, and independent of TLR1/2, TLR2, and TLR3. Additionally, DBT-induced IL-6 production depends on TLR1/2, whereas IL-1β production does not. Blocking the TLR-linked adapter protein, MyD88, lead to a loss of both PCP and DBT stimulation of IL-1β and IL-6. These findings indicate that both PCP and DBT interact with selected TLRs as part of their mechanisms of elevating the levels of critical pro-inflammatory cytokines, which may contribute to chronic inflammation and its related pathologies.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364794","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":"Oxidative Stress in Kidney of Zebrafish due to Individual and Combined Exposure to Amoxicillin, Arsenic, and Fluoride: Involving Nrf2-Keap1-ARE Pathway.","authors":"Sunanda Mukherjee, Shehnaz Islam, Olivia Sarkar, Ansuman Chattopadhyay","doi":"10.1002/jat.4763","DOIUrl":"https://doi.org/10.1002/jat.4763","url":null,"abstract":"<p><p>Toxic manifestations of different antibiotics and metal compounds have been studied comprehensively in the last decades; however, their co-toxicity on aquatic organisms is poorly investigated. This study aimed to evaluate the oxidative stress imposed on zebrafish kidney tissue when exposed to amoxicillin (AMX, 10 μg/L) alone or in combination with 50 μg/L of As₂O₃ (equivalent to 37.87 μg/L of As) and/or 15 mg/L of NaF (equivalent to 6.8 mg/L of F) for 15 days. We observed increased levels of cellular ROS, MDA, and GSH along with increased activity of CAT enzyme in all the treated groups. Disrupted histoarchitecture, including degeneration of tubular cells, vacuolation, and necrotic spots, was indicative of oxidative damage. mRNA expression of stress responsive genes like nrf2, gpx1, hsp70, keap1, nqo1, cat, and ho1 corroborated the data. Translocation of Nrf2 from cytoplasm to nucleus and its subsequent expression was higher for all the treated groups. Moreover, the mixture effects of AMX + As + F were more severe than the other combinations, while unique exposure with AMX had minimum effects. Highlighting the involvement of the Nrf2-Keap1-ARE pathway, these findings make us aware of the synergistic response of AMX, As, and F in the ecosystem, putting forward a great threat to humankind.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255677","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":"Effects of Non-Feeding on Development in a Teleost, Minami-Medaka, Oryzias latipes: Identification of Eleutheroembryonic Stage for Potential Alternative Regulatory Toxicology Tests Along the 3R Principles.","authors":"Taijun Myosho, Makoto Kashima, Taisen Iguchi, Tohru Kobayashi","doi":"10.1002/jat.4757","DOIUrl":"https://doi.org/10.1002/jat.4757","url":null,"abstract":"<p><p>Fish in the eleutheroembryonic life stage are defined as embryos or hatched fry before external self-feeding begins, and this stage is not classified as a protected life stage according to the EU (Directive 2010/63/EU) because of its alignment with the 3R principles (replacement, reduction, and refinement). In Minami-medaka (Oryzias latipes), the eleutheroembryonic stage is considered to extend until hatching, according to OECD TG210, whereas no supporting evidence to identify this stage has yet been reported. To clarify the medaka eleutheroembryonic stage, we investigated the effects of non-feeding on survival, growth, and gene expression in the NIES-R, Hd-rR, and d-rR strains. Non-feeding did not affect survival up to 6 days post-hatching (dph) in any strain, with survival rates exceeding 80%. However, non-feeding beyond 8 dph reduced the survival rates to below 50% at 30 dph. Fish growth, measured as total length, was not significantly affected by non-feeding up to 6 dph, except for the Hd-rR. Analysis of differentially expressed genes (DEGs) in response to non-feeding revealed that autophagy-related DEGs (wipi2, wdr45, wipi1, atg14, and map1lc3b) were found from 43 autophagy-related genes. map1lc3b and the other DEGs were upregulated after 4 and 6 days of non-feeding, respectively. However, the effect of non-feeding up to 6 dph was rescued by feeding. Together, the medaka fry < 6 dph were considered to be in the eleutheroembryonic stage for at least up to 4 dph, suggesting that hatched fry can be used to evaluate chemical toxicity and endocrine-disrupting activity according to the 3R principles. This study indicated that non-feeding did not affect survival up to 6 dph in NIES-R, Hd-rR, and d-rR strains of Minami-medaka, and fish growth was not affected by non-feeding up to 6 dph, except in the Hd-rR strain. Additionally, autophagy-related gene expression upregulated by non-feeding but was rescued by feeding. Together, we demonstrate for the first time that fry < 6 dph are in the eleutheroembryonic stage for at least up to 4 dph in Minami-medaka (Oryzias latipes).</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065976","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":"Thyroid Endocrine Disrupting Potential of Fluoxetine in Zebrafish Larvae.","authors":"Jin Huang, Kunyun Liu, Shan Chen, Huijia Tang, Ruiwen Li, Xianzheng Wang, Heying Sun","doi":"10.1002/jat.4755","DOIUrl":"https://doi.org/10.1002/jat.4755","url":null,"abstract":"<p><p>Fluoxetine (FLX), a typical selective serotonin reuptake inhibitors, has been frequently detected in aquatic environment and wild fish. However, little is known about its effect on thyroid endocrine system. In the present study, zebrafish (Danio rerio) embryos were exposed to 1, 3, 10, and 30 μg/L of FLX for 6 days. Chemical analysis demonstrated that FLX and its metabolic product (nonfluoxetine, NFLX) were accumulated in zebrafish larvae. The exposure resulted in decreased thyroid hormones (THs) levels, indicating thyroid endocrine disruption. Moreover, thyroid-stimulating hormone (TSH) content was significantly inhibited in a concentration-dependent manner after exposure to FLX. Gene transcription in the hypothalamic-pituitary-thyroid (HPT) axis was further examined, and the results showed that the genes encoding corticotrophin-releasing hormone (crh) and thyrotropin-releasing hormone (trh) were significantly up-regulated as a compensatory mechanism for the decreased TH contents accompanied with decreased tshβ mRNA expression. In addition, genes involved in thyroid hormone synthesis (sodium/iodide symporter, nis, thyroglobulin, tg) and transport (transthyretin, ttr) were down-regulated after exposure to FLX in a concentration-dependent manner. The increased gene transcription of deiodinases (dio2) and uridinediphosphate-glucuronosyltransferase (ugt1ab) might be responsible for the decrease of TH contents. In addition, a significant inhibition in thyroid hormone receptors (trα and trβ) gene expression was observed upon treatment with FLX. All these results demonstrated that FLX could alter THs and TSH content as well as gene transcription in the HPT axis, exerting an endocrine disruption of the thyroid system in zebrafish larvae.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059286","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":"Preclinical Toxicological Assessment of 2-(Benzoxazol-2-yl)[(2-hydroxynaphthyl)diazenyl]phenol Derivatives for Blue Light and UV Radiation Photoprotection Applications.","authors":"Karen Sousa, Dione Silva Corrêa, João Denis Medeiros de Oliveira, Gabriel Beilfuss Rieth, Juliana da Silva, Ingrid Maliszewski Paczkowski, Leandra Franciscato Campo, Ivana Grivicich, Jaqueline Nascimento Picada","doi":"10.1002/jat.4756","DOIUrl":"https://doi.org/10.1002/jat.4756","url":null,"abstract":"<p><p>The widespread use of electronic devices has led to increased blue light exposure, highlighting the need for effective radiation blockers with blue light protection. Two synthetic 2-(2'-hydroxyphenyl)benzoxazole derivatives named azo-4'-benzoxazole and azo-5'-benzoxazole have shown an unprecedented blue light absorption capacity but had not been subjected to a safety evaluation. This study aimed to evaluate the cytotoxic, genotoxic, and mutagenic activities of these compounds. The cytotoxic and genotoxic activities were evaluated using MTT assay and comet assay in L929 fibroblast cells. Salmonella/microsome assay and micronucleus test were performed to detect gene and chromosomal mutations. The IC₅₀ was 87.9 μg/mL for azo-4'-benzoxazole and 79.5 μg/mL for azo-5'-benzoxazole. In the Salmonella/microsome assay, the azo-5'-benzoxazole compound induced frameshift mutations in the TA97a strain in the presence of metabolic activation (S9 mix), while azo-4'-benzoxazole did not show mutagenic activities in all five strains tested. The azo-5'-benzoxazole showed genotoxic and mutagenic effects in L929 cells that were probably associated to the cleavage of azo-5' into its analogs 2-(4'-amino-2'-hydroxyphenyl)benzoxazole and 2-amino-1-naphthol. In conclusion, the azo-substituted group at the 5' position of the phenyl ring appears to have greater toxicological risks than substituents at the 4' position of 2-(phenyl)benzoxazole. The findings warrant further preclinical studies to ensure the safety of these compounds for use as blue light filters.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059277","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":"Dose-Dependent Hepatorenal Damage Induced by Erythrosine: A Study of Biochemical, Oxidative Stress, DNA Damage, and Histopathological Effects in Wistar Rats.","authors":"Mandeep Singh, Pooja Chadha","doi":"10.1002/jat.4754","DOIUrl":"https://doi.org/10.1002/jat.4754","url":null,"abstract":"<p><p>This study aimed to provide insights into the hepatorenal toxicity induced by erythrosine, a synthetic red dye commonly used in food and pharmaceuticals, which has raised concerns over its potential health risks. Twenty-four rats were randomly divided into four groups (n = 6). The first group was the control group and the other group received one of three doses of erythrosine based on acceptable daily intake (¼ ADI, ½ ADI, and ADI, 0.1 mg/kg body weight). This study examined biological activity via biochemical enzyme analysis, oxidative stress indices, DNA damage, and histopathology. Compared with the control group, erythrosine administration increased the serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, total protein, urea, creatinine, and uric acid at the highest erythrosine dose. The catalase and the superoxide dismutase activity decreased in both tissues at the highest dose. The glutathione-S-transferase activity increased at the ¼ ADI dose and decreased at higher doses in both tissues. In contrast, acetylcholinesterase activity was greater in erythrosine-treated rats than in control rats. Oxidative stress indices indicated increased lipid peroxidation, hydrogen peroxide content, and lactate dehydrogenase activity. The comet assay was used to assess DNA damage, revealing significant damage in the erythrosine-treated groups. Histopathological examination revealed necrotic and degenerative changes in the liver and kidney tissues. The findings underscore dose-dependent hepatorenal toxicity and highlight the novelty of demonstrating a comprehensive link between erythrosine exposure, oxidative stress, and DNA damage. These results emphasize the need for cautious evaluation of synthetic dye consumption due to potential health risks.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023443","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":"Systematic Review of the Epidemiology of Hair Relaxer Use and Hormone-Sensitive Reproductive Outcomes Among Black Adult Women in the United States.","authors":"Ashley M Hernandez, Sierra J Smith, Moin S Vahora, Devan Campbell, Callan F Krevanko, Ryan C Lewis, Jennifer S Pierce","doi":"10.1002/jat.4744","DOIUrl":"https://doi.org/10.1002/jat.4744","url":null,"abstract":"<p><p>Hair relaxers are predominantly used by Black women in the United States. It has been recently suggested that exposure to potential endocrine-disrupting compounds from the use of these products may be associated with the development of gynecological and breast cancers and anatomically relevant nonmalignancies. We conducted a systematic literature review using PubMed to identify original studies reporting measures of association between hair relaxer use and relevant adverse outcomes, focusing specifically on Black women in the United States. A total of 1382 studies were initially identified, and after consideration of the exclusion and inclusion criteria, the final set of studies consisted of seven cohort studies and one case-control study. The overall findings suggest that Black women in the United States do not experience an increased risk of breast cancer, ovarian cancer, or uterine cancer due to hair relaxers. One study found a statistically significant association between hair relaxer use and uterine leiomyomata, but there were no other studies identified to support these findings. None of the studies characterized the chemical constituents of hair relaxers. From an epidemiologic perspective, the weight of the evidence does not support the hypothesis that the use of hair relaxers is a risk factor for gynecological and breast cancers in US Black women.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006030","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":"The Impact of Genetic Polymorphisms on Genotoxicity (DNA Damage) Induced by Cigarette Smoke in Humans: A Systematic Review.","authors":"Thiago Guedes Pinto, Lorrany da Silva Avanci, Ana Claudia Muniz Renno, Debora Cristina Hipolide, Jean Nunes Dos Santos, Patricia Ramos Cury, Rogerio Aparecido Dedivitis, Daniel Araki Ribeiro","doi":"10.1002/jat.4753","DOIUrl":"https://doi.org/10.1002/jat.4753","url":null,"abstract":"<p><p>The present systematic review aims to put together human population studies that include some relationship between genetic polymorphisms and genotoxicity as well as to evaluate the quality of the published studies induced by cigarette smoke exposure in vivo. The present systematic review was built according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Different genotoxicity assays were used by different authors, although the major goal was the genotoxicity assessment by means of micronucleus, comet, sister chromatid exchange, and chromosomal aberration assays. Also, different genetic polymorphisms were analyzed by different authors, being closely related to xenobiotics metabolizing and DNA repair genes. Our aim, therefore, was to collect these data so that a quality assessment could be properly carried out. Out of the 18 included studies, 15 reported genotoxicity due to cigarette smoking, and all of these reported some association between a genetic polymorphism and the aforementioned genotoxicity. Also, 14 studies were classified as either strong or moderate, which suggests the aforementioned findings can be trusted in regard to the studies' quality. Taken as a whole, the results suggest that genes associated with detoxification genes and DNA repair genes play a substantial role in the determination of an individual's susceptibility to genomic damage due to cigarette smoking.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006061","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":"26-Week Repeated-Dose Toxicity Study of a Novel Antiarrhythmic Drug Sulcardine Sulfate in Sprague-Dawley Rats.","authors":"Liangyu Zhang, Leilei Gu, Hongqun Qiao","doi":"10.1002/jat.4750","DOIUrl":"https://doi.org/10.1002/jat.4750","url":null,"abstract":"<p><p>Sulcardine sulfate (Sul) is a novel antiarrhythmic agent blocking multiple channels and exhibits unique pharmacological properties such as lower APD-dependent prolongation and reduced arrhythmia risk. Sul is currently in Phase III clinical trials, yet studies on its long-term toxicological profile and potential target organs remain unexplored. This study investigated the related toxicity of Sul in Sprague Dawley (SD) rats through repeated oral administration for 26 weeks, followed by a 4-week recovery period. Consistent with the clinical intended mode of administration, Sul was administered via oral gavage at daily doses of 0, 175, 350, and 700/525 mg/kg in rats. On account of clinically observed body weight loss of male and female rats in the high-dose group compared with the control group, with one female rat in the high-dose group dying after 8 weeks of administration, the high dose was adjusted to 525 mg/kg. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in male rats significantly increased in the medium- and high-dose groups, whereas female rats in these groups showed a significant rise in alkaline phosphatase (ALP) levels, accompanied by varying degrees of weight gain in the liver and lungs. Additionally, brownish-red pigment deposition was observed in hepatocytes and Kupffer cells across all dosing groups, along with foam cell deposition in the alveolar cavities. Concomitant toxicokinetics showed that the drug accumulated to some extent in the animals. Consequently, the liver and lungs were identified as potential target organs, and the no observed adverse effect level (NOAEL) was determined to be 175 mg/kg.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005954","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}