International Journal of Toxicology最新文献

Drug discovery and development is a complex, lengthy, and expensive process that takes on average 10-15 years and approximately $1-2 billion USD for approval of a new drug. While the studies needed to support clinical development are generally outlined in guidance documents, there is much less guidance on how to translate the nonclinical data into clinical designs. Nonclinical studies are performed to conduct the First-in-Human clinical trial, which is the first major milestone to advance new promising drug candidates, and are conducted primarily to determine the safe dose range for clinical development. Resolving how to move forward, and even when to move forward, requires significant cross-functional collaboration with pathologists, ADME scientists, biologists, and clinical staff. There are many reasons why drug candidates may fail; these could be as simple as insufficient understanding of the nature of the translational process, failure to effectively integrate the data from different pharmacologically relevant species, or erosion of the margin of safety during chronic toxicology studies. The case studies described here were designed to help participants in the 2024 American College of Toxicology (ACT) Continuing Education course "Translational Challenges from Nonclinical to Clinical Program: Case Study Examples" to improve their skills in managing translational challenges from nonclinical to clinical program encountered during drug development.

The U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), and Office of New Drugs (OND) has continuously encouraged the submission of nonclinical tests utilizing new approach methodologies (NAMs) and sponsor engagement with regulators to optimize NAM utility in supporting the safety and efficacy of new drugs. Previously, we published an FDA/CDER perspective on nonclinical testing strategies, discussed the opportunities and challenges of using NAMs to replace, reduce, and refine animal testing in drug development, and reported gaps and challenges underserved by existing nonclinical testing approaches that CDER Pharmacology/Toxicology reviewers face. Here, we demonstrate how FDA/CDER has historically incorporated NAMs into standard nonclinical assessments, describing how specific tests became validated and internationally accepted alternatives to animal testing for regulatory decision-making. We also provide a CDER/OND Pharmacology/Toxicology reviewer perspective on NAMs submitted to support new drug development, in an effort to provide insight into our experience with NAMs submitted for CDER-regulated products. Furthermore, we provide a CDER/OND Pharmacology/Toxicology reviewer perspective on the future of NAM incorporation into nonclinical development programs for new drugs as scientific technology continues to evolve. Ultimately, we hope that by sharing the FDA/CDER/OND experience with NAMs thus far and providing considerations for refining NAM submissions, we will (1) illustrate our scientific approach to evaluating NAM submissions, (2) reiterate FDA/CDER's steadfast commitment to the 3Rs, and (3) foster confidence in our continued efforts to encourage nonclinical test NAM submissions for regulatory decision-making, while maintaining our mission to protect public health and patients from unintended harm.

Exposure to diesel exhaust air pollutants is a key environmental threat for pulmonary and cardiovascular diseases. Oxidative stress and Transient Receptor Potential Vanilloid-1 (TRPV1) receptors exhibit pivotal contributions in mediating lung injury induced by environmental pollutants. This study investigates the histological changes in lung tissue induced by short-term particulate-free filtered diesel exhaust (FDE) exposure, with a focus on TRPV1 receptor expression and oxidative stress pathways. Male rats were allocated to four groups randomly: Non-exposed (NE), clean air exposed (CAE), FDE-exposed, and NAC pre-treated FDE-exposed groups. FDE exposure lasted 5 hours per day for five days, with histological examination and TRPV1 expression analysis conducted on day six. The NAC pre-treated group received NAC (200 mg/kg) for five days prior to each exposure. Lung tissue samples were analyzed using hematoxylin and eosin staining, and immunofluorescence for TRPV1 expression. FDE exposure caused significant histological alterations, including alveolar septal thickening, interstitial inflammation, capillary congestion, perivascular inflammation, bronchial epithelial necrosis, endothelial discontinuity, and interstitial fibrosis, as classified by a semi-quantitative INHAND (International Harmonization of Nomenclature and Diagnostic) scoring criteria for rats, visualized on a heat map. TRPV1 expression was upregulated in FDE-exposed lung tissues, particularly around congested vessels and thickened septa. NAC pre-treatment significantly reduced both histological damage and TRPV1 expression. Our study highlights a potential mechanistic relationship between TRPV1 receptor expression and oxidative stress pathways in the lung damage induced by FDE exposure, underscoring the therapeutic potential of NAC in countering these effects.

Chronic ozone exposure in urban environments compromises lung function, predisposing individuals to severe sepsis outcomes from common infections. Pyroptosis, a type of programmed cell death, is implicated in sepsis and lung injury, and its regulation is crucial for understanding disease severity. We focused on pyroptosis due to its role in inflammation, tissue damage, and organ dysfunction in septic patients, as well as its link to ozone exposure through inflammasome activation. To elucidate the underlying molecular mechanisms, we integrated bioinformatics and experimental approaches. We analyzed public genomic data repositories to identify pyroptosis-related genes and those linked to sepsis and ozone-induced lung injury. Three pyroptosis-related genes (caspase-1, interleukin-1β, and gasdersmin D) were upregulated, while adenosine deaminase acting on RNA 1 (ADAR1) was downregulated. To validate these findings, mice were exposed to ozone followed by lipopolysaccharide-induced sepsis. After 12 hours, lung tissue damage, inflammation, and pyroptosis were assessed. Two-way ANOVA revealed significant LPS × ozone interactions, with one-way ANOVA showing dose-dependent ozone effects on inflammation and pyroptosis. Results confirmed the bioinformatics predictions, showing ADAR1 levels initially increased in septic mice but declined with ozone exposure. Concurrently, ozone exacerbated caspase-1-mediated pyroptosis in lung tissue. Our findings demonstrate that ozone preexposure worsens septic lung injury by modulating ADAR1 and pyroptosis. By elucidating the ADAR1-pyroptosis interplay, this study highlights a novel mechanism contributing to the pathogenesis of ozone-induced lung injury in sepsis, revealing ADAR1 as a key regulatory molecule.

Per- and polyfluoroalkylated substances (PFAS) are persistent anthropogenic chemicals widely distributed in the environment that are known to have toxic effects in animals and humans following exposure. Some PFAS have been shown to activate peroxisome proliferator-activated receptor α (PPARα), a transcription factor involved in lipid metabolism, leading to dyslipidemia or liver toxicity. PFAS comprise a wide range of compounds, and variations in their structural characteristics could reveal important details regarding the level of PPARα activation. In this work, using a Chemically Activated LUciferase eXpression (CALUX) assay, we experimentally tested the PPARα activation efficiency of several PFAS compounds of varying chain lengths and functional groups. Activation and potency were compared across and within PFAS class based on chemical differences. When compounds with the same number of carbons or perfluorinated carbons were compared across class, the rank from high to low activator class remained the same. Perfluorocarboxylated ether was found to be the strongest class, while polyfluorotelomer was the weakest, suggesting the importance of structural features in PPARa activation. Perfluorocarboxylates were consistently better PPARα activators than perfluorosulfonates. Comparing within these 2 classes, the number of perfluorinated carbon atoms better predicted activation than the number of carbon atoms. In the perfluorocarboxylated ether, perfluorocarboxylate, and perfluorosulfonate classes, a direct correlation existed between potency and the percentage of PPARα activation (R² = 0.702), a novel observation. These findings provide new insights regarding distinct chemical characteristics of PFAS compounds which may be predictive of PPARα activation level.

Interleukin-13 (IL-13) is a cytokine implicated in the pathophysiology of type 2 inflammatory diseases and is a clinically validated target in atopic dermatitis. APG777 is a humanized IgG1 monoclonal antibody with an optimized pharmacokinetic profile. APG777 has high affinity to IL-13 and includes a triple amino acid modification (the "YTE" modification) in its Fc region that is designed to extend its half-life. The current study examined the safety and potential toxicity of APG777 when given by once-weekly subcutaneous injection for 27 weeks to cynomolgus monkeys, and the potential reversibility of any findings following a 2-month recovery period. Toxicokinetic characteristics of APG777 were also determined. APG777 exhibited dose-proportional systemic exposure, with a half-life of approximately 28 days. No APG777-related adverse effects were noted in clinical observations, body weight, ophthalmology, electrocardiogram readings, neurologic parameters, hematology, coagulation, clinical chemistry, urinalysis, organ weights, or histopathology. Anti-drug antibodies were not detected in any APG777-exposed animals. Drug accumulation was evident over the study duration; however, there were no APG777-related adverse findings in any of the parameters analyzed. The no-observed-adverse-effect level (NOAEL) was 150 mg/kg/week. These findings provide preclinical evidence supporting continued clinical development of APG777 for IL-13-mediated diseases. The extended half-life of APG777 suggests potential benefits in reducing dosing frequency compared with existing IL-13-targeting therapies, which could improve treatment adherence and patient outcomes. The safety and efficacy of APG777 are currently being investigated in a Phase 2 clinical trial (NCT06395948) in patients with moderate-to-severe atopic dermatitis.

BackgroundPlastics have been widely used for several decades, but their persistence in the environment has resulted in the widespread presence of microplastics (MPs) in the air, water, and soil. With particle sizes smaller than 5 mm, MPs are now recognized as emerging contaminants of concern owing to their potential impact on human health.ObjectiveThis study aimed to conduct a critical narrative umbrella review of published reviews and primary studies on microplastic exposure and human health. Specifically, the objective was to synthesize evidence across the major exposure pathways (ingestion, inhalation, and dermal), summarize the associated health outcomes, and critically appraise common themes, inconsistencies, and knowledge gaps. This review provides guidance for future research and policy directions by aligning findings with methodological strengths and limitations.ResultsMPs are consistently detected in food, water, air, human stool, blood, placenta, and breast milk. Reported outcomes include gastrointestinal inflammation, gut microbiota disruption, respiratory diseases, endocrine and reproductive dysfunction, and possible neurotoxicity. Inhalation is increasingly recognized as significant, and ingestion remains the most studied, whereas dermal exposure is underexplored.ConclusionMicroplastics represent a pervasive and complex public health challenge. This umbrella review underscores the need for harmonized methodologies, epidemiological investigations, and mechanistic studies that reflect real-world exposure. Strengthening this evidence base is essential for risk assessment, regulation, and public awareness of the health impacts of microplastics.

Anaerostipes caccae CLB101 (CLB101) is an obligate, anaerobic bacteria that was isolated from the stool of a healthy infant. Due to its ability to produce butyrate and its potential promotion of microbiome health through multiple homeostatic interactions there is interest in its consumption by humans. No toxicity data are publicly available for any strain of A. caccae. Therefore, its genotoxic and toxicological potential was investigated in the current study. Due to its anaerobic nature, a genotoxicity evaluation was performed using the in vivo comet assay and the in vivo mammalian micronucleus assay, which found no evidence of clastogenicity or aneugenicity. General toxicity and potential target organs were assessed in a 90-day, repeated-dose, oral toxicity study using 0, 250, 500, and 1000 mg/kg bw/day in Wistar rats. CLB101 exposure did not result in adverse effects in male or female rats when evaluated for clinical signs, body weight, food consumption, clinical pathology, organ weight, and histopathology after administration, at any dose. Therefore, a NOAEL of 1000 mg/kg bw/day, equivalent to 1.9 × 10¹¹ CFU/kg bw/day for all cells and, based on ∼32% cell viability in the buffer used (Mitsuoka), ∼6.1 × 10¹⁰ CFU/kg bw/d for living cells.

ZYGK1 is a novel small molecule glucokinase (GK) activator. The purpose of this study was to assess the repeated dose toxicity of ZYGK1 in male and female Wistar rats and its effect on pregnancy and embryo-fetal development in pregnant female Wistar rats. ZYGK1 was administered by oral gavage to rats at 15, 30, 60, and 120 mg/kg, once a day, for 28 consecutive days. For studying the effect on pregnancy and embryo-fetal development, ZYGK1 was administered by oral gavage at 60 and 120 mg/kg from gestation day (GD) 6 to 15, to presumed pregnant female Wistar rats. Hypoglycemia was observed at all doses of ZYGK1 in male and female rats in the general toxicity study, but no toxic effects were observed, except partially reversible axonal degeneration in peripheral nerves. ZYGK1 treatment in pregnant female rats caused hypoglycemia and decreased the fetal body weight. Treatment from GD 6 to 15 caused no significant fetal abnormalities, except incidental fetal skeleton anomalies. Thus, ZYGK1 may lead to maternal hypoglycemia, but no significant developmental toxicity was observed.

Compiling evidence strongly suggests the involvement of environmental toxicants, including heavy metals (aluminum, arsenic, lead, copper, cadmium, mercury, and manganese), pesticides, and solvents, as the prime culprits of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. The pathogenesis of environmental toxicant-induced neurodegenerative disease remains elusive. Studies carried out in the last decade suggest that dysfunctional mitochondria are increasingly recognized as a key factor in the progression of neurodegenerative diseases. Mitochondria, the essential organelles that regulate cellular energy production, are particularly vital in neurons, which have high energy demands and depend on proper mitochondrial function for survival. Environmental toxicants have been shown to impair mitochondrial membranes, disrupt the electron transport chain, increase oxidative stress, and damage mitochondrial DNA, leading to progressive neurodegeneration, with mitochondrial fragmentation and oxidative stress that worsens neurodegeneration. There are currently no disease-modifying treatments available for most neurodegenerative disorders, largely due to the lack of suitable molecular targets. Targeting mitochondria presents a rational strategy for neuroprotective therapy, with the potential to slow or halt disease progression. In view of this, this review highlights the central role of mitochondria in environmental toxicant-induced neurodegeneration, emphasizing how environmental exposures drive mitochondrial dysfunction and accelerate disease progression. Understanding these mechanisms is crucial for identifying environmental risk factors and developing targeted interventions. This will provide a foundation for future research targeting mitochondria and developing suitable therapeutic interventions for neurodegenerative diseases.