Toxicological Sciences最新文献

{"title":"Emergent latent neurotoxic effects of manganese following nominal chronic exposures in human stem cell and Caenorhabditis elegans models.","authors":"Xueqi Tang, Airton C Martins, Anke M Tukker, Hyunjin Kim, Michael Aschner, Aaron B Bowman","doi":"10.1093/toxsci/kfag040","DOIUrl":"10.1093/toxsci/kfag040","url":null,"abstract":"<p><p>Behavioral deficits can emerge after the removal of manganese (Mn) exposures in humans and other mammals. Although epidemiological studies provide substantial evidence supporting latency, challenges reproducing such effects in alternative models have slowed mechanistic understanding. Here, we report in 2 systems, human-induced pluripotent stem cell (hiPSC)-derived and Caenorhabditis elegans, that prior chronic exposure elicits clear latent neurotoxic effects in gene expression and functional outcomes. To identify these effects and investigate underlying mechanisms, single-cell RNA sequencing was employed in hiPSC-derived cortical culture to provide comparisons of transcriptomic changes immediately following versus after cessation of chronic Mn exposures. Transcriptomic alterations revealed latent effects after cessation of elevated Mn that were not detected immediately following 40-day exposures. To confirm the reproducibility of the observed latent magnification of chronic Mn-induced neurotoxicity, behavioral endpoints were evaluated in C. elegans. We detected a significant amplification of 2 motor phenotypes after a period of exposure cessation. These data demonstrate, in 2 genetic and mechanistically tractable systems, the detection of novel latent neurotoxic effects not detected until the cessation of a chronic exposure at a magnitude well beyond the effects of the chronic Mn exposure itself. Identified alterations support a linkage between the latent effects following chronic Mn exposure and a broad range of neurodegenerative etiologies and provide insight into the cellular pathways involved. Using both in vitro and in vivo experimental models provides complementary evidence that substantially strengthens the robustness and translational relevance of these novel findings.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":"209 4","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13127424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative estimates of inter-individual variability for new approach methodologies-based systemic safety toolbox using a population-based human in vitro model.","authors":"Ibrahim Alshammari, Lucie C Ford, Han-Hsuan D Tsai, Hsing-Chieh Lin, Chander K Negi, Allison N Dickey, Fred A Wright, Alistair M Middleton, Maria T Baltazar, Joe Reynolds, Sophie Cable, Ans Punt, Weihsueh A Chiu, Ivan Rusyn","doi":"10.1093/toxsci/kfag038","DOIUrl":"10.1093/toxsci/kfag038","url":null,"abstract":"<p><p>Next-generation risk assessment (NGRA) frameworks use new approach methodologies (NAMs) to support regulatory decisions without animal testing. Although NAM-based approaches are well established for hazard and dose-response assessment, inter-individual variability is still typically addressed using default uncertainty factors for inter-individual variability. This study evaluated an NAM-based strategy to quantify chemical-specific variability using a human cell model. We hypothesized that integrating chemical-specific variability data into NGRA would yield more protective risk estimates. Using 131 human lymphoblastoid cell lines (LCLs) from four European and African subpopulations, we assessed differences in cytotoxic responses to 53 substances, including industrial chemicals, pharmaceuticals, pesticides, and consumer-use compounds. Concentration-response testing (0.3 nM to 300 μM) data were analyzed using Bayesian modeling to calculate points of departure per cell line. Of the substances tested, 18 exhibited cytotoxic effects, enabling the derivation of chemical-specific variability factors. These factors were designated as toxicodynamic variability factors at the 5th percentile (TDVF05) because of the limited metabolic capacity of lymphoblast cell lines. The median TDVF05 was 3.8 (range 1 to 46), largely consistent with default assumptions. A genome-wide association study (GWAS) identified genomic loci, primarily containing transporter and metabolism genes, associated with variability in cytotoxicity, suggesting mechanistic bases for inter-individual differences. Overall, this study shows that human LCLs are a practical high-throughput in vitro model for quantifying inter-individual variability, strengthening confidence in NGRA risk predictions and supporting hypothesis generation on chemical-specific genetic and mechanistic drivers of human variability. However, cell-based systems have limited coverage of adverse effects and require careful alignment with in vivo dosimetry.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13099385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147514903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alleviating effects of fat mass and obesity-associated protein on fluoride-induced neurotoxicity in rat brain, primary neurons, and SH-SY5Y cells.","authors":"Xiao-Xiao Zeng, Wen-Wen He, Wei Liao, Xiao Xiao, Xi Tu, Jie Deng, Xiao-Lan Qi, Yang-Ting Dong, Wei Hong, Yan He, Yan Xiao, Na Wei, Zhi-Zhong Guan","doi":"10.1093/toxsci/kfag031","DOIUrl":"10.1093/toxsci/kfag031","url":null,"abstract":"<p><p>Chronic fluorosis can cause injury to the central nervous system. Because fat mass and obesity-associated protein (FTO) connected with demethylation of N6-methyladenosine (m6A) plays a crucial role in maintaining brain function, we examined whether FTO might help resist the neurotoxicity of fluoride. Sprague-Dawley rats with chronic fluorosis and cultured nerve cells exposed to fluoride with overexpression or knockdown of FTO were employed. The Morris water maze test was employed to assess learning and memory. Expressions of FTO, m6A, postsynaptic density protein 95 (PSD95) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) and its subunit GluR2 mRNA stability, apoptosis, and reactive oxygen species (ROS) were determined by Western blotting, RT-PCR, and biochemical methods, respectively. The results showed that the impaired learning and memory of rats with chronic fluorosis, the decreased FTO, PSD95 and AMPARs, the elevated m6A, and the disrupted synapse morphology as well as apoptosis in their brains were determined. Similar abnormal changes were further confirmed in primary neurons and SH-SY5Y cells exposed to fluoride, accompanied by a significant decline of GluR2 and high ROS. Notably, overexpression of FTO reduced m6A, enhanced GluR2, and attenuated neurotoxicity induced by fluoride, whereas knockdown had the opposite effects. FTO can alleviate the neurotoxicity induced by fluoride, in which the mechanism may be involved in its regulating m6A to enhance expression of GluR2.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147460243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of hemopexin in protoporphyrin IX distribution and cholestatic liver injury.","authors":"Ruizhi Gu, Fu-Ying Qin, Zeyu Sun, Xujian Wang, Elim Chen, Jie Lu, Junmei Wang, Xiaochao Ma","doi":"10.1093/toxsci/kfag041","DOIUrl":"10.1093/toxsci/kfag041","url":null,"abstract":"<p><p>Deficiency of ferrochelatase (FECH) in erythropoietic protoporphyria (EPP) leads to accumulation of its substrate, protoporphyrin IX (PPIX), the final intermediate in the heme biosynthesis pathway. PPIX is produced primarily in the bone marrow and subsequently delivered to the liver, where it can cause cholestatic liver injury and, in severe cases, liver failure. A key unresolved question is how circulating PPIX is transported to the liver to initiate hepatic damage. Given the structural similarity between PPIX and heme, we investigated whether the heme carrier hemopexin (HPX) mediates this process. Using an EPP mouse model carrying a Fech mutation (Fech-mut), we generated mice additionally lacking Hpx (Fech-mut/Hpx-null). As expected, Fech-mut mice exhibited markedly elevated PPIX levels in both the circulation and liver. However, Hpx deficiency did not alter PPIX distribution in Fech-mut/Hpx-null mice, indicating that HPX is not required for the delivery of circulating PPIX to the liver. Similarly, Hpx deficiency did not modify the severity of PPIX-induced cholestatic liver injury. Computational modeling further revealed that PPIX-HPX binding is energetically unfavorable, making HPX-mediated uptake unlikely. In summary, HPX does not contribute to hepatic PPIX uptake or influence cholestatic liver injury in EPP. These findings redirect attention to alternative hepatic uptake mechanisms and underscore the need to define the pathways that modulate PPIX delivery to the liver and shape susceptibility to EPP-associated liver injury.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13103549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147646665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isolated and combined exposure to polystyrene nanoplastics and a phthalate metabolite mixture disrupts antral follicle growth and function of mice in vitro.","authors":"Patrick V Souza, Ramsés Santacruz-Márquez, Mary J Laws, Jodi A Flaws, Wellerson R Scarano","doi":"10.1093/toxsci/kfag036","DOIUrl":"10.1093/toxsci/kfag036","url":null,"abstract":"<p><p>Polystyrene nanoplastics (PS-NPs) are small particles derived from plastic degradation that have been detected in several human tissues. Phthalates are ubiquitous plasticizers used to increase flexibility in polymers which act as endocrine disruptors, impacting hormonal homeostasis. Considering that both pollutants have been detected in human follicular fluid, there is increasing concern regarding their potential effects on female reproductive health. This study evaluated the isolated and combined effects of environmentally relevant doses of PS-NPs and a phthalate metabolite mixture (MM) on antral follicle growth, hormone production, and the expression of genes involved in apoptosis, oxidative stress, steroidogenesis, and hormone receptor signaling. Antral follicles from adult CD-1 mice were cultured with vehicle control (DMSO and water), metabolite mixture (0.01, 0.1, 1, and 10 μg/ml), or PSNPs (5, 25, 50, and 100 μg/ml) or MM + PS-NPs (5 µg/ml PS-NPs + 0.01 µg/ml MM; 100 μg/ml PS-NPs + 10 μg/ml MM). Follicle growth was monitored every 24 h for 96 h. PS-NPs and MM were internalized by follicles and they inhibited follicle growth alone and in co-exposure. Both pollutants altered the expression of apoptosis-related (Casp3, Casp8, Bcl2) and oxidative stress-related (Cat, Nrf2, Gpx1) genes without significantly affecting steroid hormone levels. Co-exposure also reduced Esr2 and Ar expression, demonstrating more pronounced effects under low-dose combined exposure. Altogether, these findings indicate that environmentally relevant exposure to PS-NPs and phthalate mixtures impairs antral follicle growth and disrupts molecular pathways essential for ovarian function, highlighting potential pathways and the importance of understanding combined exposures in reproductive toxicity.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147499783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating exposomics and multi-omics with dysbiosis biomarkers for clinical and environmental connections implicated in neuropathology. Cause and cure cluses.","authors":"Hajar Heidari, Marah Vincent, David A Lawrence","doi":"10.1093/toxsci/kfag034","DOIUrl":"10.1093/toxsci/kfag034","url":null,"abstract":"<p><p>Multi-omic investigations into environmental effects on health and disease are aided by inclusion of microbial microbiomes with assessment of mirobes producing metabolites that differentially modulate host organ functions. The gut microbiome is key because many environmental toxicants enter the body orally and may disrupt gut microbes that help digest food, as well as the microbiome-gut-brain axis, which produces regulatory metabolites with systemic effects. Environmental stressors may differentially alter brain development and function, even among identical twins, in that over time, there may be divergence due to epigenetic effects from the environment, including microbes within the microbiome. The diversity of microbiomes is presented as playing a key role in the influence of organs on each other, health, and the development of disorders. The gut microbes and their metabolites may cause mitochondria to produce less ATP and more reactive oxygen species (ROS). The metabolites produced by microbes during the digestion of foods can nourish or harm a person's cellular and molecular functions and vary depending on each person's exposome. The detrimental effects of environmental stressors are discussed, focusing on how altered levels of neuropeptides, neurotransmitters, and the inflammatory/anti-inflammatory balance affect health and disorders. During ATP production, dysfunctional mitochondria may produce more ROS, which can lead to inflammation and oxidative stress, causing cell damage and disrupting products needed for neuronal development, connections, and functions. The balance between inflammatory/anti-inflammatory biomarkers and metabolites and between oxidants/antioxidants is discussed in relation to some clinical connections; for example, the proportions of CD4 and CD8 T cells in HIV patients and the ROS-to-glutathione ratio in inflammatory bowel disease and septic patients. These imbalances are reviewed regarding brain development and functions leading to anxiety, depression, and dementia. The integration of multi-omics, dysbiosis, and mitochondrial dysfunction with a person's clinical evaluation is discussed to inform the formulation of prevention measures and therapeutic interventions regarding environmental effects on the microbiome-gut-brain axis and physical and mental health.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147487431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic and circadian bioenergetic alterations following perfluorooctanoic acid exposure and high-fat diet in female C57BL/6 mice.","authors":"Aya Ahmed, Matthew Wittenborn, Jamie Dewitt, Tracey Woodlief","doi":"10.1093/toxsci/kfag025","DOIUrl":"10.1093/toxsci/kfag025","url":null,"abstract":"<p><p>Exposure to per- and polyfluoroalkyl substances (PFAS) elicits changes in various metabolic responses but few studies have evaluated whole-body metabolic changes. This study compared whole-body bioenergetics in adult female C57BL/6 mice orally dosed with 0 or 7.5 mg/kg perfluorooctanoic acid (PFOA) or fed a 60% high fat diet (HFD) for 24 h or 15 d. After 24 h, HFD mice showed increased oxygen consumption (VO2) and reduced active-phase respiratory exchange ratio (RER), indicating early lipid utilization. After 15 d, PFOA-exposed mice exhibited decreased resting RER and suppressed active VO2, suggesting impaired circadian metabolic activation. In contrast, HFD mice maintained elevated VO2 across both resting and active cycles and showed reduced RER variation between phases, indicating metabolic inflexibility. PFOA exposure also increased relative liver weights and ACOX-1 activity. HFD resulted in an increase in body weight and increase in fat mass without hepatomegaly. These results indicate that both exposure paradigms disrupt whole-body metabolism and circadian bioenergetics. PFOA induced pronounced peroxisomal proliferation and suppressed resting-cycle energy expenditure without weight gain, whereas HFD drove obesogenic effects with impaired substrate switching. These findings provide mechanistic insight into how environmental and dietary stressors alter metabolic rhythms.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147390999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repeated bronchoalveolar lavage variability and impact in a 2-week nonclinical toxicology study.","authors":"Emily Hackshaw, James Nelson, Molly H Boyle","doi":"10.1093/toxsci/kfag044","DOIUrl":"10.1093/toxsci/kfag044","url":null,"abstract":"<p><p>Nonclinical inhalation studies often rely on systemic biomarkers of exposure and pharmacology for serial evaluations, since local pulmonary effects are generally limited to assessment by terminal procedures. In addition, invasive procedures raise concern with health impact for subsequent inhalation doses and artifacts in tissue histology that could confound interpretation of toxicity. To test a non-terminal lung monitoring technique for use in non-human primate repeat-dose inhalation toxicology studies, bronchoalveolar lavage was performed during the pretest phase (twice), following 7 d of treatment with saline or albuterol, and the day after the final dose. Evaluations included clinical observations and histopathology, as well as differential cell counts and quantification of protein, lactate dehydrogenase, and urea in bronchoalveolar lavage fluid. Animals sufficiently recovered from the procedure were dosed by conscious facemask inhalation several hours later, without incident, and had slightly lower lavage total cell counts. Bronchoalveolar lavage the day before necropsy was associated with mixed cell infiltrates or inflammation in 2 of 8 animals. Total white cell counts in lavage fluid were higher but more variable when collected as a terminal rather than survival procedure, although intra-animal variability between pretest occasions was notable as well. Urea concentration showed greater variability than total protein and lactate dehydrogenase, although values were near the method's limit of detection. In summary, this study showed that bronchoalveolar lavage can be performed as a serial evaluation in nonclinical studies, without benefit from multiple baseline occasions and with some effect on lung histopathology.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147662915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An adverse outcome pathway-aligned ex vivo mouse testicular organ culture platform for mechanistic integration of multi-level endpoints with recovery assessment.","authors":"Hideaki Nakagiri, Kyoichi Kodama, Shimpei Terasaka, Makoto Kashima, Naohiro Ikeda, Yuko Nukada, Kenkichi Fujii, Yoshikazu Nagao","doi":"10.1093/toxsci/kfag037","DOIUrl":"10.1093/toxsci/kfag037","url":null,"abstract":"<p><p>Mechanistic understanding is important for improving the safety assessment of male reproductive toxicity; however, current evaluations still rely primarily on in vivo studies. Therefore, the development of new approach methodologies (NAMs) requires test systems capable of capturing key events organized within adverse outcome pathways (AOPs). The PDMS ceiling (PC) method is a testicular organ culture technique previously used to detect testicular toxicity. However, its applicability as an AOP-aligned platform for multi-level mechanistic assessment, including recovery evaluation, has not been fully examined. Here, we evaluated the utility of the PC-based organ culture system for AOP-aligned assessment of testicular toxicity. Methoxyacetic acid (MAA), a testicular toxicant with established AOPs, was used as a reference compound. Molecular, cellular, and histological endpoints were assessed under identical conditions, and a membrane-supported PC (msPC) configuration was introduced to enable controlled recovery assessment. Testes from Acro3-EGFP transgenic mice, in which EGFP expression driven by the acrosin promoter accumulates in developing acrosomes, were cultured and exposed to MAA. GFP fluorescence indicating spermatogenic progression decreased in a concentration-dependent manner. Histological and immunohistochemical analyses demonstrated selective loss of pachytene spermatocytes with apoptosis, whereas transcriptomic profiling suggested disruption of cell cycle- and meiosis-related pathways consistent with established AOP-defined key events. Recovery of GFP fluorescence and tissue morphology occurred earlier in the msPC system than in the conventional PC method. These findings support the PC-based organ culture system as an AOP-aligned platform within NAMs for evaluating testicular toxicity and recovery.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147575329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Withdrawal interval estimations of oxytetracycline and chlortetracycline in swine using physiologically based pharmacokinetic models: a global trade perspective.","authors":"Kun Mi, Hiroko Enomoto, Ronald E Baynes, Zhoumeng Lin","doi":"10.1093/toxsci/kfag042","DOIUrl":"10.1093/toxsci/kfag042","url":null,"abstract":"<p><p>Violative drug residues in animal-derived food are a global food safety concern. Physiologically based pharmacokinetic (PBPK) modeling is a valuable tool for predicting drug residues in edible tissues and determining withdrawal intervals (WDIs). This study aimed to develop a PBPK model for oxytetracycline (OTC) and chlortetracycline (CTC) in swine to determine WDIs based on different regulatory requirements of different countries. The models were calibrated and evaluated with the pharmacokinetic data after oral administration via feed and drinking water collected from the Food Animal Residue Avoidance Databank (FARAD). The models can accurately capture the observed kinetics in plasma and edible tissues (liver, muscle, kidney, and fat), and most of the model predictions were within a 3-fold factor of observed data (87.9% for OTC and 88.9% for CTC). WDIs of OTC and CTC were determined using the population PBPK models based on maximum residue limits (MRLs) from 13 countries or regions under the label dosage regimens. The models were converted to a web-based PBPK dashboard. The models are a useful tool for predicting tissue residues and estimating WDIs based on different MRLs across countries, thereby supporting food safety assessment and international trade of meat products derived from swine treated with OTC and CTC.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147662967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}