Toxicology Mechanisms and Methods最新文献

{"title":"Molecular insights and translational potential of ferulic acid in radiation protection.","authors":"Tamizh Selvan Gnanasekaran","doi":"10.1080/15376516.2026.2726973","DOIUrl":"https://doi.org/10.1080/15376516.2026.2726973","url":null,"abstract":"<p><p>Ferulic acid, a common dietary phenolic abundant in plant cell walls, has been identified as a potential drug candidate with radiation-protective effects in experimental models. This review summarizes new developments regarding the molecular mechanisms, experimental models and translational potential of ferulic acid-induced radioprotection. Mechanistically, ferulic acid attenuates ionizing radiation-induced damage by scavenging free radicals, inhibiting lipid peroxidation, maintaining mitochondrial fitness, modulating inflammation signaling pathways and upregulating endogenous antioxidant systems partially through nuclear translocation of the Nrf2 pathway. Preclinical studies across <i>in vitro</i> (human and animal cell lines), <i>ex vivo</i> (human blood chromosomal aberration, micronucleus, and γ-H2AX assays), and <i>in vivo</i> rodent models consistently show that ferulic acid reduces DNA damage and chromosomal alterations, supports cell survival pathways, and, in some conditions, enhances DNA repair, translating into improved tissue histology, hematopoietic recovery, and post-irradiation survival. Despite promising efficacy signals, there are still issues with pharmacokinetics, optimal dosing schedules, long-term safety/adverse events, and bioavailability in humans. This review discusses the priority directions for translation: (1) systematic pharmacokinetic and toxicology profiling, (2) discovery of ferulic acid derivatives and delivery systems (e.g. nanoparticles, prodrugs) that facilitate tissue targeting, and (3) rigorous clinical trials in prophylactic and post-exposure settings, with combination strategies involving established radioprotectors. Bridging preclinical mechanistic insights with rigorous clinical evaluation could position ferulic acid as a safe, low-cost, and widely accessible radioprotective adjunct suitable for both medical and occupational applications.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-19"},"PeriodicalIF":2.7,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892244","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":"Acute oral toxicity evaluation of microencapsulated semi-purified fibrinolytic proteases using a modified OECD 423-aligned design for biotechnological applications.","authors":"Ragil Saptaningtyas, Sri Rejeki, Ana Hidayati Mukaromah, Amin Samiasih, Nanik Rahmani, Maya Dian Rakhmawatie, Stalis Norma Ethica","doi":"10.1080/15376516.2026.2666608","DOIUrl":"10.1080/15376516.2026.2666608","url":null,"abstract":"<p><p>The present study evaluated the acute oral toxicity profile of microencapsulated semi-purified fibrinolytic proteases derived from <i>Bacillus tequilensis</i> HSFI-5 (Indonesian Patent Application No. S00202313485) using a modified OECD Guideline 423-aligned fixed-dose parallel design. BALB/c mice (<i>n</i> = 50; equal sex distribution) received single oral doses of 50, 300, 2000, or 5000 mg/kg body weight and were monitored for 14 days for clinical signs, body weight progression, hematological indices, clinical biochemistry parameters, organ weights, and gross pathological changes. No mortality or treatment-related clinical abnormalities were observed at any dose level. Body weight gain remained progressive and comparable to controls. Hematological and biochemical parameters showed no consistent dose-dependent deviations indicative of systemic inflammatory, metabolic, hepatic, or renal dysfunction. Absolute and relative organ weights, including liver and kidneys, remained within physiological ranges, and necropsy revealed no macroscopic lesions. Based on OECD decision criteria, the median lethal dose (LD₅₀) was estimated to exceed 5000 mg/kg body weight, indicating that the formulation is not classified for acute oral toxicity under the Globally Harmonized System. Collectively, these findings indicate no evidence of acute treatment-related toxicological effects under the conditions of this study. Interpretation is limited to single-dose exposure and should be confirmed by further investigations incorporating detailed histopathological and extended toxicity assessments.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1183-1198"},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781980","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":"Targeting lipid-fibrotic signaling crosstalk for antifibrotic therapy.","authors":"Sandeepa K N, Shilpa S Shetty","doi":"10.1080/15376516.2026.2659870","DOIUrl":"10.1080/15376516.2026.2659870","url":null,"abstract":"<p><p>Fibrosis is essentially a compromised wound-healing process in which fibroblasts remain engaged for an extended period of time, resulting in an excessive accumulation of extracellular matrix and ultimately leading to organ failure. Although well-known drivers, including transforming growth factor-β, Wnt/β-catenin, nuclear factor kappa-B, and sphingosine-1-phosphate signaling, are well-established, studies reveal that lipid metabolism is crucial for regulating these pathways. Inflammation, oxidative stress, cell energy consumption, and the conversion of cells into scar-forming myofibroblasts are all influenced by lipids, which are no longer only inert building blocks or fuel. Changes in phospholipids, fatty acids, sphingolipids, and cholesterol are examples of dysregulated lipid synthesis, remodeling, and oxidation that produce a metabolic milieu that supports fibrotic signaling and accelerates the course of the disease. This review deciphers the bidirectional crosstalk between fibrotic signaling pathways and how lipids are involved in different fibrotic signaling pathways in different organ systems, enumerating how profibrotic transcriptional programs and metabolic reprogramming are combined by lipid-derived mediators to form feed-forward loops that sustain fibrosis. Unraveling the underpinnings in lipid-fibrosis axis provides testament of lipid signaling and involvement as viable pathways for precision medicine and antifibrotic intervention by revealing new biomarkers and therapeutic targets.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1029-1044"},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781970","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":"Mouse precision-cut liver and kidney slices: an optimized <i>ex vivo</i> model for organotoxicity testing.","authors":"Christiane Spruck, Ghizlan Bousejra, Ahmed Erbay, Sonja Herbrich, Andreas Dimitriadis, Zoe Röntgen, Frauke Roolfs, Isaac Musong Mboni-Johnston, Gerhard Fritz, Seddik Hammad, Nicole Schupp","doi":"10.1080/15376516.2026.2670503","DOIUrl":"10.1080/15376516.2026.2670503","url":null,"abstract":"<p><p>As excretion organs, the kidneys and liver are exposed to high concentrations of potentially toxic substances. While animal models remain the gold standard for organ-specific toxicity testing, meaningful alternative <i>ex vivo</i> approaches are essential in order to align with the 3 R principles (refinement, reduction, replacement). Precision-cut tissue slices (PCTS) retain native tissue architecture, cellular heterogeneity, the interplay of different cell types, and metabolic capacity, offering a promising link between <i>in vitro</i> and <i>in vivo</i> models. Here, we aimed to establish an optimized protocol for preparation and cultivation of precision-cut kidney and liver slices (PCKS and PCLS) from mice for use in substance-oriented toxicity testing. Key parameters - including slice thickness, media composition and oxygenation, glucose levels, and incubation time - were refined to preserve tissue viability and metabolic function. Five known prototypical toxins - acetaminophen, cyclosporin A, cisplatin, arsenic trioxide, and aristolochic acid I - were tested. While PCKS showed comparable sensitivity to established kidney cell lines, PCLS achieved IC₅₀ values closely matching <i>in vivo</i> toxicity data. High reproducibility across different experimenters was achieved, highlighting the robustness of the model. In conclusion, the optimization of this <i>ex vivo</i> system makes this valuable, reproducible, and ethically approved platform for testing nephrotoxicity and hepatotoxicity accessible to more laboratories, for example for dose finding or compound prioritization, thereby supporting 3 R-conform preclinical drug screening as well as hazard identification and potentially reducing reliance on animal experiments.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1211-1225"},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147933862","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":"Sevoflurane pre-treatment attenuates myocardial cell ferroptosis caused by hypoxia and reoxygenation <i>via</i> regulating lncRNA NNT-AS1.","authors":"Zanhui Gong, Yajun Wu, Yongsheng Wang, Zhiwei Huang, Jianxing Chen, Lijuan Pan, Zhijian Chen","doi":"10.1080/15376516.2026.2668535","DOIUrl":"10.1080/15376516.2026.2668535","url":null,"abstract":"<p><p>Myocardial ischemia-reperfusion injury (MIRI) is the primary cause of death for acute myocardial infarction. LncRNA NNT-AS1 was upregulated in the H9c2 hypoxia-reoxygenation (H/R) model. However, the interaction between sevoflurane and NNT-AS1 is unknown in MIRI. The specific aim of this study was to explore the mechanism by which sevoflurane regulates cardiomyocyte injury <i>via</i> the NNT-AS1/miR-23a-3p/USP24 axis. The Caspase-3 level and apoptosis rate were used to assess the cell apoptosis level. Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), glutathione disulfide (GSSG), GSH/GSSG ratio, the total iron content, and Glutathione Peroxidase 4 (GPX4) protein content were measured to evaluate the level of ferroptosis. The targeting relationship was detected by the dual-luciferase reporter gene assay. In the H9c2 H/R model, the NNT-AS1 and USP24 levels were increased, but miR-23a-3p was decreased. The cell damage was aggravated, and apoptosis and ferroptosis were promoted. However, the NNT-AS1 and USP24 expression was downregulated, and miR-23a-3p expression was upregulated by sevoflurane pre-treatment. Cell damage, apoptosis, and ferroptosis were also improved. NNT-AS1 functions as a molecular sponge for miR-23a-3p. The NNT-AS1 overexpression further aggravated cell damage, apoptosis, and ferroptosis, while miR-23a-3p overexpression reversed the damaging effect of NNT-AS1. In summary, sevoflurane pretreatment alleviates apoptosis and ferroptosis in H/R-stimulated cardiomyocytes by regulating the NNT-AS1/miR-23a-3p/USP24 signaling axis, which may provide a potential target for MIRI treatment.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1199-1210"},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148151400","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":"Glycycoumarin ameliorates pyroptosis in autoimmune hepatitis by activating autophagy and reducing NLRP3 inflammasome activation.","authors":"Qian Gao, Yiqun Zhou, Jun Shi, Fang Yuan, Yanping Shen","doi":"10.1080/15376516.2026.2664034","DOIUrl":"10.1080/15376516.2026.2664034","url":null,"abstract":"<p><strong>Objective: </strong>This study explored the protective effect of glycycoumarin (GCM) against autoimmune hepatitis (AIH) and its underlying mechanisms.</p><p><strong>Methods: </strong>An AIH mouse model was established by concanavalin A induction and treated with GCM or methylprednisolone (MP) positive control. Liver index and serum levels of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase (LDH) were measured. Histopathological changes in liver tissues were observed <i>via</i> H&E staining. Pyroptosis-associated proteins and inflammatory cytokines in liver tissues were assessed by Western blot, RT-qPCR, and ELISA. <i>In vitro</i>, AML12 cells were stimulated with lipopolysaccharide and Nigericin to construct an inflammatory pyroptosis model. Cell viability, LDH release, autophagic flux, pyroptosis-related protein expression, Caspase-1 activity, and mitochondrial function were assessed. To assess the autophagy-dependence of GCM's effect, cells were treated with 3-methyladenine, an inhibitor of autophagy.</p><p><strong>Results: </strong>In AIH mice, GCM treatment reduced liver index, serum transaminases, and LDH levels while alleviating hepatic necrosis and inflammatory infiltration. GCM downregulated NLRP3, Caspase-1, and GSDMD mRNA expression, reduced NLRP3, Cleaved Caspase-1, and GSDMD-NT protein expression, and suppressed IL-1β and IL-18 release in liver tissues of mice. <i>In vitro</i>, GCM improved cell viability, reduced LDH release, and inhibited Caspase-1 activation and pyroptosis in LPS+NIG-induced AML12 cells. GCM restored autophagic flux, alleviated oxidative stress, and mitigated mitochondrial damage <i>in vivo</i> and <i>in vitro</i>. Autophagy inhibition partially counteracted the effects of GCM on promoting autophagy, protecting against mitochondrial damage, and suppressing NLRP3 inflammasome-induced pyroptosis.</p><p><strong>Conclusion: </strong>GCM protects against AIH by restoring autophagic flux and mitigating oxidative stress, thereby suppressing NLRP3 inflammasome-mediated pyroptosis.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1115-1129"},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278953","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":"Tobacco-specific nitrosamine '4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)': toxicological mechanisms, carcinogenicity, and chemopreventive approaches.","authors":"Divya Kumari, Pracheta Janmeda, Devendra Singh","doi":"10.1080/15376516.2026.2668531","DOIUrl":"10.1080/15376516.2026.2668531","url":null,"abstract":"<p><p>The tobacco-specific nitrosamine, 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone has been identified as potent lung carcinogen in laboratory animals. Bioactivation of nicotine-derived nitrosamine ketone occurs <i>via</i> cytochrome P450-mediated hydroxylation of carbon atoms adjacent to the nitrosamino group, generating reactive methylating and pyridyloxobutylating intermediates. NNK can be metabolically reduced to NNAL, which retains carcinogenic potential and undergoes similar activation. Like NNK, NNAL also requires the metabolic activation to DNA alkylating agents. When NNAL is methyl hydroxylated, pyridinyl-hydroxy-butyl DNA adducts are formed, and methylene hydroxylation results in DNA methyl adducts. NNK's metabolic complexity leads to a variety of DNA lesions, increasing its overall carcinogenic potency. From this angle, the chemistry and genotoxic properties of many DNA adduct generated from NNK are discussed. Adducts that contribute to the genotoxic effects of NNK include the gene targeted for mutation, amounts, and genetic variants of critical repair enzymes. NNK, present in modern smokeless tobacco products, plays a central role in cancer risk among users. The mechanisms by which NNK induces cancer in humans are discussed in this paper, along with the factors influencing NNK development at various phases of tobacco manufacturing.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1059-1089"},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843226","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":"Computational toxicology analysis of candidate drivers and pathways in HRZE-associated drug-induced liver injury.","authors":"Yehua Lai, Xinyi Yang, Hua Tian, Yuhong Zhou, Fu Liu","doi":"10.1080/15376516.2026.2670504","DOIUrl":"10.1080/15376516.2026.2670504","url":null,"abstract":"<p><p>The first-line anti-tuberculosis regimen HRZE (isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), ethambutol (EMB)) frequently causes drug-induced liver injury (DILI). However, the mechanisms underlying this combination hepatotoxicity remain unclear. Therefore, this study used a hierarchical network toxicology and molecular docking approach to systematically investigate the hepatotoxic mechanisms of the HRZE regimen, aiming to identify core and non-core hepatotoxic drugs and elucidate their synergistic effects. We identified 315 DILI-related targets associated with the HRZE regimen. Protein-protein interaction network analysis revealed seven hub genes, and enrichment analysis identified the biological processes involved and signaling pathways. Isoniazid, RIF, and PZA were classified as core hepatotoxic drugs due to the significant enrichment of their targets in DILI pathways and their high clinical risk. In contrast, EMB was identified as a non-core hepatotoxic drug, with lower target enrichment and a lower risk of liver injury. The targets of the core hepatotoxic drugs were widely distributed across major DILI pathways, while EMB may synergistically modulate pathway activity through a limited set of targets, including carbonic anhydrase II (CA2). Molecular docking confirmed that all four drugs bind stably to cytochrome P450 family 2 subfamily E member 1 (CYP2E1); the high affinity of EMB for CA2 suggests its involvement in cholestatic injury. In conclusion, HRZE-induced hepatotoxicity is a multi-pathway process driven predominantly by INH, RIF, and PZA, with EMB playing a synergistic role and potentially contributing to cholestatic injury. By establishing a multi-level toxicological framework, this study provides a theoretical basis for understanding combination hepatotoxicity and offers potential targets for DILI intervention.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1226-1242"},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147869483","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":"E-cigarette aerosols as systemic metabolic disruptors: integrated mitochondrial, circadian, and neurobehavioral mechanisms.","authors":"Ardie Barry Sailis","doi":"10.1080/15376516.2026.2658739","DOIUrl":"10.1080/15376516.2026.2658739","url":null,"abstract":"<p><p>E-cigarettes are promoted as reduced-harm alternatives to combustible tobacco, yet their aerosols contain metals, aldehydes, solvents, and other bioactive chemicals capable of disrupting metabolic regulation. This review synthesizes evidence from cellular, animal, and early human studies on how e-cigarette aerosol exposure affects metabolic homeostasis across mitochondrial, redox, circadian, and neurobehavioral systems. A systems-level model is proposed in which mitochondrial dysfunction, oxidative stress, circadian misalignment, and neurobehavioral alterations form a feed-forward network that drives metabolic inflexibility. Across experimental systems, e-cigarette exposure is associated with mitochondrial impairment, oxidative stress, AMPK suppression, disrupted lipid oxidation, adipose inflammation, and reduced thermogenic capacity, changes consistent with insulin resistance. Evidence also indicates disruption of circadian clock signaling and modulation of reward and appetite circuits, further biasing energy balance. These findings support a model in which e-cigarette aerosols act as multi-system metabolic disruptors affecting both peripheral organs and central regulatory pathways. However, important uncertainties remain regarding dose-response relationships, exposure patterns, device variability, and long-term human risk. This review provides an integrated framework to clarify potential links between e-cigarette aerosol exposure and metabolic dysfunction and highlights priorities for future translational and human research.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1003-1028"},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147692315","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":"Quantitative methods for the risk assessment of drinking water contact chemicals following the NSF/ANSI/CAN 600 Standard - Part II: advanced methods.","authors":"Bradley Lampe, J Caroline English, L T Haber, Kelly Magurany","doi":"10.1080/15376516.2026.2672014","DOIUrl":"10.1080/15376516.2026.2672014","url":null,"abstract":"<p><p>Health-based criteria have been developed using quantitative methods for over 370 unregulated chemicals that have been detected in extraction testing of products certified or being certified to NSF/ANSI/CAN 60 (<i>Drinking Water Treatment Chemicals - Health Effects</i>) and NSF/ANSI/CAN 61 (<i>Drinking Water System Components - Health Effects</i>), public health-based drinking water standards. These criteria are derived in accordance with the requirements of NSF/ANSI/CAN 600, <i>Health Effects Evaluation and Criteria for Chemicals in Drinking Water</i> and undergo external peer review by an independent Health Advisory Board. However, a complete and unified description of how these criteria are derived is not available in the scientific literature. This is the second part of a two-part publication that describes specialized methods that may be applied in drinking water risk assessments conducted according to NSF/ANSI/CAN 600, depending on data availability and understanding of the mode of action. The specialized methods discussed herein include the use of data-derived extrapolation factors (including dosimetric adjustment factors and chemical-specific adjustment factors), inhalation-to-oral route extrapolation, the use of threshold versus non-threshold approaches in evaluating dose-response, study mortality adjustments, benchmark dose modeling, and carcinogen-specific approaches such as the use of the cancer slope factor and lifestage adjustment for cancer potency.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1090-1114"},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148138960","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}