International Journal of Toxicology最新文献

The Tg.rasH2 mouse is a validated bioassay system for evaluation of carcinogenic potential, and it is confirmed to be sensitive to both genotoxic and nongenotoxic carcinogens. This is also one of the models specified in ICH S1B Guidance, enabling 6-month carcinogenicity studies as an alternative to traditional 2-year bioassays. We conducted a 26-week carcinogenicity study at our test facility on Tg.rasH2 mice sourced from CLEA Japan Inc., in a process to generate historical control database. Although historical control data have been published for these mice sourced from Taconic Biosciences Inc., USA, there is a dearth of published literature citing spontaneous incidence of neoplastic findings in Tg.rasH2 mice sourced from CLEA Japan. We have therefore presented the spontaneous tumor incidence in our study and compared it with the previously published tumor incidence for Tg.rasH2 mice sourced from Taconic, USA. The comparison reveals a similarity of tumor incidence between the mice from these two sources.

The rasH2^TM mouse model has become the primary alternative to a 2-year mouse carcinogenicity study in safety testing of human pharmaceuticals. In this publication, we present the neoplastic incidence for 2291 control males, 2191 control females, 575 MNU-treated males, 559 MNU-treated females, and 210 urethane-treated males and females in rasH2^TM carcinogenicity studies conducted from 2012 to 2024 as well as survival, body weights, and selected non-neoplastic microscopic findings for control and positive control mice. Inclusion of a positive control group is recommended to ensure regulatory acceptance. Survival of controls at the end of 26 weeks was approximately 96% with similar percentages of survivors in the 13-week urethane-treated positive controls in contrast to a survival percentage of approximately 17% in MNU-treated positive controls. Malignant neoplasms accounted for most early deaths in control and positive control mice. Major neoplasms in control mice included Harderian gland adenomas, bronchioloalveolar adenomas and carcinomas, and splenic hemangiosarcomas, while the predominant neoplasms in MNU-treated mice included squamous cell papillomas and carcinomas of the nonglandular stomach and malignant lymphomas. The percentage of urethane-treated mice developing bronchioloalveolar neoplasms was over 98% in both sexes. When compared to control mice, MNU-treated mice had lower mean body weights while urethane-treated mice had higher mean body weights. Major non-neoplastic findings in control mice were subcapsular cell hyperplasia (51.78% to 89.41%) and skeletal muscle myopathy (77.17% to 80.71%). Other non-neoplastic findings included retinal degeneration in MNU-treated mice (∼87% in both sexes) and bronchioloalveolar hyperplasia in urethane-treated mice (≥53% in both sexes).

Although Bisphenol A (BPA) is still used in consumer products, concerns about its toxicity led to the adoption of structurally related replacement products such as Bisphenol F (BPF) and Bisphenol S (BPS). Unfortunately, comparing the biological responses to BPA and BPA substitutes in vivo can be challenging, as the available information is often derived from different studies using various animal strains and experimental protocols. To address this issue, we directly compared the impacts of BPA, BPF, and BPS in the same in vivo exposure study. Briefly, 8-week-old male Fischer rats were exposed to BPA, BPF, or BPS (at five different doses) and to 17α-ethinylestradiol (positive control for estrogenicity) by gavage for 28 consecutive days. Rat health, dietary intakes, and weight gains were monitored, 24-hour urine samples were collected, and blood and tissues were harvested at the terminal necropsy. The impacts of BPA, BPF, and BPS on rat weight gains, organ weights and histology, liver enzymatic activities, hematology, clinical chemistry, and serum hormone levels were relatively modest and mostly limited to the highest doses administered. However, bisphenol cross-contamination observed in urine samples from the vehicle control group may have interfered with the evaluation of their effects at lower doses. Although BPA, BPF, and BPS exposures all shared similarities with the 17α-ethinylestradiol positive control group, their impacts on serum hormone levels and endocrine-responsive tissues also presented noticeable differences. This suggests that BPA, BPF, and BPS may interfere with endocrine functions through slightly different molecular mechanisms.

Parkinson's disease (PD) is characterized by the abnormal aggregation of α-synuclein, which can originate in the gut and propagate to the brain. Recent evidence suggests a correlation between metabolic disorders, particularly diabetes, and PD pathogenesis through the gut-brain axis. Methylglyoxal (MGO), a glucose-derived metabolite produced by gut bacteria such as Proteus mirabilis, is implicated in protein misfolding and glycation. This study investigated whether MGO induced α-synuclein aggregation in intestinal enteroendocrine cells and explored the underlying mechanisms. Mouse enteroendocrine STC-1 cells were treated with MGO (0.01-1 mM) for 36 h, and changes in α-synuclein aggregation, neuronal markers, and relevant signaling pathways were assessed. MGO at 1 mM significantly reduced cell viability and neuronal marker expression, and concentrations of 0.1 and 1 mM increased α-synuclein aggregation. MGO also inhibited SIRT1 expression, leading to increased Hif-1α transcription and reduced expression of autophagy-related proteins Beclin1 and LC3B. These changes were accompanied by mitochondrial dysfunction, as evidenced by decreased Bcl2, increased cytochrome C expression, and reduced levels of the antioxidant factor HO-1. Our findings provide the first evidence that MGO directly induces α-synuclein aggregation in enteroendocrine cells via the SIRT1-Hif-1α-autophagy pathway dysregulation, establishing a potential mechanistic link between gut microbiome-derived metabolites and PD pathogenesis. These results suggest that intestinal glycation may be a critical target for preventing α-synuclein pathology originating in the gut.

Traditional tobacco products are harmful to the body, especially the respiratory system. In recent years, different kinds of novel and emerging nicotine and tobacco products have emerged on the market and are becoming increasingly popular with young people. Some regulatory policies have been implemented, but the public still lacks a systematic understanding of the health risks of these novel products. To provide a summary of these topics to date, we performed a literature review, in which we summarized studies on novel and emerging nicotine and tobacco products in terms of cell models, three-dimensional models, animal models, and population and their potential advantages and disadvantages, which will provide support for the market supervision and policy control and the comprehensive health risks of novel and emerging nicotine and tobacco products to the public.

2-Deoxy-D-Glucose (2-DG) has anticonvulsant and antiseizure effects in rodent models and is in the development phase for novel antiseizure treatment. To evaluate potential toxicity, Beagle dogs (five/sex/group) were orally gavaged with either vehicle (deionized water) or 2-DG (5, 30, and 90 mg/kg BID) for 28 days followed by a 14-day recovery period. The safety endpoints evaluated were mortality, clinical observations, body temperature, respiratory assessment, body weights, food consumption, ophthalmic examinations, electrocardiograph (ECG), blood pressure, cardiac biomarker (NT-proBNP), and pathology. Toxicokinetic analysis was conducted after the first dose on days 1 and 28. The dose formulation analysis confirmed that 2-DG concentrations were within 93%-107% of the target concentrations. There were no 2-DG associated effects observed in mortality, clinical signs, body temperature, respiratory parameters, body weights, food consumption, ophthalmic examination, ECG, blood pressure, and NT-proBNP. There was an increase (∼1.7X) in aspartate transaminase on day 29, while histopathological evaluation revealed hepatic cytoplasmic alterations in 2 of 6 dogs on day 29 and only in 1 of 4 dogs on day 43 at 90 mg/kg BID. These changes were considered non-adverse because of minimal severity, reversibility trend after recovery period and no correlative increase in alanine transaminase. Toxicokinetic evaluation revealed dose dependent increases in C_max of ∼7.8, 39.5, and 114 μg/mL, and AUCs of 12.2, 70.8, and 202 h*μg/mL at 5, 30, and 90 mg/kg, respectively with T_max of ∼0.5-0.9 h and T_1/2 of ∼3.8-5.4 h. In conclusion, 90 mg/kg BID of 2-DG was considered as the No Observed Adverse Effect Level following 28-day administration in dogs.

The Crl:CD(SD) Sprague Dawley rat and the Crl:WI(Han) Wistar Hannover (Wistar Han) rat are two outbred rat models commonly used in 2-year carcinogenicity testing. In this presentation, the spontaneous incidences of common, rare, and fatal neoplasms in the two models in 2-year carcinogenicity studies were compared from 51 Sprague Dawley rat studies and 31 Wistar Han rat studies that were completed from 2016 to 2023. All Wistar Han rat studies completed the intended 104 weeks of dosing, whereas 47 of the 51 Sprague Dawley rat studies were terminated early in both sexes or terminated early in one sex. The incidence of total spontaneous neoplasms was greater in Sprague Dawley rats when compared to Wistar Han rats of either sex, with the greatest incidence found in female Sprague Dawley rats (95.93%). Of palpable masses that corresponded to neoplasms, approximately 85-90% of masses were mammary tumors in females of either strain, while a similar percentage of masses corresponded to skin tumors in male rats of either strain. Common fatal tumors included pituitary adenoma of the pars distalis, carcinoma of the pars distalis, mammary adenocarcinoma, and mammary fibroadenoma, and were found at a lower incidence in Wistar Han rats; where calculable, the onset of these neoplasms was earlier in Sprague Dawley rats.

Orodispersible films (ODFs) are advanced drug delivery systems that consist of thin, mechanically robust polymeric films designed to dissolve or disintegrate quickly in the oral cavity, facilitating local and systemic drug administration. Orphyllo™ is a novel ODF vehicle developed to enhance the stability and delivery efficiency of active pharmaceutical ingredients. This study aimed to assess the safety profile of Orphyllo™ through a comprehensive evaluation of its cytotoxicity and genotoxicity on human oral mucosa cell lines. The cytotoxicity was evaluated using (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) MTT, Neutral Red Uptake (NR), and Lactate Dehydrogenase (LDH) assays, which tested the impact of Orphyllo™ at concentrations of 5.0% and 10.0% over 24, 48, and 72 hours. Results indicated no significant reduction in cell viability (P > 0.05), demonstrating the formulation's biocompatibility. To evaluate genotoxicity, the micronucleus test was performed, showing no significant increase in the frequency of micronuclei compared to the control group, thus indicating no DNA damage. Additionally, the Annexin/7-AAD assay was employed to assess apoptosis and necrosis, revealing no significant induction of cell death at the tested concentrations (P > 0.05). These findings highlight that Orphyllo™ presents, even at an early stage, the potential to become a promising vehicle for oral drug administration applications, with potential benefits in several therapeutic areas, especially for populations that require ease of administration.

Physiologically based pharmacokinetic (PBPK) modeling is increasingly used to anticipate, quantify, and strategically manage drug-drug (DDI) and herb-drug (HDI) interactions that can alter the exposure of chemotherapy agents together with co-administered phytochemicals or nutraceuticals. To evaluate current knowledge, we performed a comprehensive Google Scholar search (2003-2024) and selected studies that employed PBPK platforms, reported quantitative validation, and focused on chemotherapy-related interactions. From these reports, key modeling parameters, validation metrics, and clinically relevant outcomes were extracted, and then the information was synthesized to identify common trends. Collectively, the evidence indicates that unintended changes in drug exposure-most often mediated by CYP3A4 inhibition or induction-may modify efficacy, toxicity, and overall anticancer response; nevertheless, PBPK models reproduce these effects with high accuracy, and emerging AI-enhanced approaches promise even finer precision. Accordingly, our synthesis underscores how PBPK modeling can help clinicians forecast interaction risk, individualize dosing, and avert therapeutic failure, especially in polypharmacy settings. Integrating these models into routine oncology practice therefore offers a proactive path toward safer, more personalized chemotherapy and, ultimately, better patient outcomes within an increasingly complex therapeutic landscape.

A nanoparticle-based immunization strategy offers a promising treatment for opioid use disorder (OUD). This study tested the in vivo safety of subunit keyhole limpet hemocyanin-loaded lipid-PLGA hybrid nanoparticles (sKLH-hNPs) as a nanocarrier for OUD vaccine in adult male BALB/c mice by subcutaneous administration at an effective low dose (60 μg) and a dose 5-fold higher (300 μg), with cohorts of animals (n = 10/group, including controls) observed and evaluated for behavioral changes. At 3, 14, 28, and 56 days after dosing, mice (n = 3/dose) were sacrificed, and serum was collected for evaluation of electrolytes, minerals, proteins, liver function, renal function, and energy metabolism. Histological examination included all critical organs, gastrocnemius muscle, and skin from the site of injection. For behavioral evaluation, home cage, open field, and reflex observations were compared among the groups. Results demonstrated no statistical differences among the groups, with the exception of respirations observed in the home cage (O-RESP) on Day 3 (P = 0.03). There was no evidence of any effect of the test product on energy (glucose, cholesterol, triglycerides) or mineral metabolism (phosphorus, calcium) and hepatic function (urea nitrogen, albumin, total bilirubin), and no indication that the test agent caused liver injury, cholestasis, muscle damage, or acid-base imbalance. Histological analysis in control and treated mice generally revealed no significant findings, although small areas of hemorrhage, lymphocyte infiltration, and thick areas in the subcutis were noted in a subset of samples from both control and treated animals. These experiments suggest that the nanoparticle-based product would be safe for vaccines treating OUD.