Toxicology Mechanisms and Methods最新文献

{"title":"Antigenotoxicity of extracts and metabolites of <i>Lippia spp.:</i> phytochemical basis, experimental evidence, and molecular mechanisms of genomic protection.","authors":"Norberto Alarcón-Herrera, Guillermo Ávila-Acevedo, Saúl Flores-Maya, Edgar A Estrella-Parra, Paulina Abrica-González","doi":"10.1080/15376516.2026.2698040","DOIUrl":"https://doi.org/10.1080/15376516.2026.2698040","url":null,"abstract":"<p><p>Genotoxicity is a fundamental biological process linked to the development of numerous diseases, particularly cancer, due to its impact on the integrity and stability rof genetic material. In this context, natural compounds with antigenotoxic properties have gained increasing attention as potential agents for preventing or mitigating DNA damage. Species of the genus <i>Lippia</i> (Verbenaceae) have emerged as a relevant source of bioactive metabolites with promising genoprotective effects. This review provides a comprehensive analysis of the antigenotoxic activity of <i>Lippia</i> spp., focusing on key species such as <i>Lippia alba</i>, <i>Lippia citriodora</i>, <i>Lippia graveolens</i>, and <i>Lippia sidoides</i>. Special emphasis is placed on their phytochemical composition, particularly flavonoids and phenolic acids, including quercetin, luteolin, apigenin, caffeic acid, and rosmarinic acid, which are responsible for their biological activity. Evidence from <i>in vitro</i> and <i>in vivo</i> studies indicates that <i>Lippia</i> extracts exhibit low genotoxic potential and can reduce DNA damage induced by chemical and physical agents. The molecular mechanisms underlying these effects involve reactive oxygen species scavenging, activation of endogenous antioxidant systems, modulation of DNA repair pathways, metal chelation, and regulation of cellular signaling and epigenetic processes. Additionally, potential applications in chemoprevention, environmental health, and nutraceutical development are discussed. Overall, <i>Lippia</i> species represent a valuable source of natural antigenotoxic compounds; however, further studies in complex biological models and clinical settings are required to validate their efficacy, safety, and applicability in human health.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-25"},"PeriodicalIF":2.7,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148670719","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 and subchronic oral toxicity study, phytochemical profiling of a herbal formulation containing Taxus, astragalus, asparagus, and liquorice in mice.","authors":"Muhammad Yousif, Samuel Kumi Okyere, Dongqiong Xiao, Yanchun Hu","doi":"10.1080/15376516.2026.2711723","DOIUrl":"https://doi.org/10.1080/15376516.2026.2711723","url":null,"abstract":"<p><p>Zishangan Granule (ZSG) is a plant-derived formulation containing <i>Taxus, Astragalus, Asparagus,</i> and licorice. Its phytochemical composition and oral toxicological safety remain insufficiently characterized. This study profiled ZSG constituents and evaluated acute and subchronic oral toxicity in Kunming mice using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and <i>in vivo</i> safety assessments. UPLC-MS/MS detected 15 candidate serum-detectable constituents in ZSG and post-administration mouse serum, including Salvianolic acid L, Lithospermic acid B, Taxine A, Liquiritin, Hyperin, and Calycosin-7-O-glucoside. In the acute study, no mortality occurred after 14 days of ZSG administration at 0.43-27.52 g/kg/day. No abnormal clinical signs were observed up to 3.44 g/kg/day; however, higher doses (6.88-27.52 g/kg/day) produced dose-related reductions in food intake, slower body-weight gain, hypoactivity, and piloerection. In the 90-day subchronic study, repeated administration at the no-observed-adverse-effect level (NOAEL; 3.44 g/kg/day) caused no treatment-related changes in body weight, food intake, organ coefficients, hematology, serum biochemistry, or histopathology. These findings indicate a wide oral safety margin for ZSG at up to eight-fold the recommended mouse dose and support further preclinical development, while additional genotoxicity, reproductive toxicity, and longer-duration studies remain needed.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-17"},"PeriodicalIF":2.7,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148621530","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":"Perspective for breaching the positive feedback loop between necroptosis and pyroptosis with spirulina in alcoholic liver injury induced in mice.","authors":"Ghada S El-Tanbouly","doi":"10.1080/15376516.2026.2706564","DOIUrl":"10.1080/15376516.2026.2706564","url":null,"abstract":"<p><p>The functional nutraceutical Spirulina (SP) was evaluated against alcohol intoxication in mice livers, concurrently striving to elucidate its protective mechanisms in cellular death pathways: necroptosis and pyroptosis. Ethanol (ET) intoxication was induced <i>via</i> intake of 5% ethanol in drinking water for 10 days, succeeded by a substantial dose of 50% ethanol (4 g/kg, i.p.) on day 11. SP (250 and 300 mg/kg, p.o.) were administered to the ET-intoxicated mice one hour prior to ethanol consumption for 11 days. The two submaximal doses effectively modulated the ET-instigated hepatic abnormalities. Both doses restored the disrupted hepatic function and architecture. SP mitigated serum liver biomarkers: ALT, AST and ALP, in addition to improving survival. SP substantially modified hepatic oxidative stress by inhibiting the lipid peroxidation product MDA and elevating the antioxidant levels of SOD and GSH. Meanwhile, SP counteracted the ET-induced elevated levels of hepatic TNF-α, the necroptosis-related molecular signals; RIPK1/RIPK3/MLKL and the pyroptosis biomarkers: NLRP3/caspase-1/IL-1β. However, no extra benefit was detected with the higher dose. These findings robustly imply the hepatoprotective properties of Spirulina in alcoholism at a dose correspondent to 250 mg/kg <i>via</i> revoking hepatic cell death chains: necroptosis and pyroptosis. Thereby, opens a new avenue for assisting cellular repair mechanisms.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-14"},"PeriodicalIF":2.7,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520948","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":"Combined molecular fingerprint and descriptor features enable classical machine learning to match deep learning performance across the Tox21 toxicity panel.","authors":"Oluwaseun E Agboola, Samuel S Agboola, Adekunle T Adegbuyi, Zainab A Ayinla","doi":"10.1080/15376516.2026.2703006","DOIUrl":"10.1080/15376516.2026.2703006","url":null,"abstract":"<p><strong>Background and objective: </strong>Molecular fingerprints and physicochemical descriptors encode complementary structural information, yet most Tox21 benchmarks evaluate only one representation at a time. This study examined whether integrating both closes the reported gap between classical and graph-based deep learning.</p><p><strong>Methods: </strong>Six algorithms (Random Forest, XGBoost, LightGBM, SVM, MLP, Logistic Regression) were trained on a 3,131-dimensional feature vector combining 59 RDKit descriptors with ECFP4, ECFP6, and RDKit topological fingerprints (1,024 bits each), across 8,014 Tox21 compounds and 12 endpoints, evaluated under both stratified 5-fold cross-validation and a Bemis-Murcko scaffold split. Bootstrap resampling (<i>n</i> = 1,000) gave 95% confidence intervals.</p><p><strong>Results: </strong>Random Forest achieved the highest mean AUC-ROC of 0.846 (SD = 0.053) under stratified 5-fold cross-validation, with 10 of 12 endpoints exceeding 0.80. Under a Bemis-Murcko scaffold split matching the deep learning benchmark protocol, RF mean AUC was 0.839, at or slightly above the published aggregate means of AttentiveFP (0.829) and GROVER (0.831); because these benchmarks report only a single aggregate mean, comparison is aggregate-level only. Adding fingerprints to the descriptor-only baseline improved RF on 10 of 12 endpoints (maximum gain +0.028 on SR-ATAD5). A linear-kernel SVM (0.752) outperformed the originally reported RBF-kernel SVM (0.710), a kernel-calibration artifact; SVM remained the weakest baseline.</p><p><strong>Conclusion: </strong>An integrated fingerprint-descriptor representation lets classical machine learning match published graph neural networks on Tox21 under matched scaffold-split evaluation, without specialized hardware, offering a reproducible, interpretable alternative for computational toxicology.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-12"},"PeriodicalIF":2.7,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148431164","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 prioritization of CYP3A4 and DPP7 as candidate triclosan-relevant molecular targets in ulcerative colitis.","authors":"Jiafeng Wang, Songsong Jiang, Yingying Zhang, Hao Gao, Xiaoqi Zhao, Lixiang Liu, Zijian Li","doi":"10.1080/15376516.2026.2698865","DOIUrl":"10.1080/15376516.2026.2698865","url":null,"abstract":"<p><p>Triclosan (TCS), a synthetic broad-spectrum antimicrobial and novel persistent organic pollutant, is detected in over 75% of human urine samples, yet its molecular targets in ulcerative colitis (UC) remain unclear. We integrated network toxicology, multi-cohort machine learning, molecular docking, 100-ns all-atom molecular dynamics (MD) simulation, and single-cell transcriptomics to address this gap.Intersecting UC differentially expressed genes with database-derived TCS targets yielded 479 shared candidate targets; because these databases include indirect and probabilistic associations,this set was treated as hypothesis-generating. KEGG enrichment identified the AGE-RAGE signaling pathway, PPAR signaling, and TNF signaling among the top enriched pathways. LASSO regression and random forest algorithms distilled a 10-gene diagnostic signature that achieved cross-cohort AUC of 0.910-1.000 across six independent GEO datasets, consistent with strong discriminative performance.Molecular docking predicted Vina scores of -7.1 kcal/mol (CYP3A4) and -7.0 kcal/mol (DPP7);redocking and decoy analyses supported protocol specificity but not biochemical binding or inhibition. Over 100 ns of MD simulation, the docked poses remained stable for both targets. Single-cell RNA sequencing GSE214695 independently corroborated cell-type-specific CYP3A4 downregulation in epithelial cells and broad DPP7 upregulation across immune subsets in UC.CellOracle-based in silico perturbation predicted that CYP3A4 suppression would impair cytoplasmic translation, while DPP7 suppression would polarize innate inflammation toward an IL-1β-driven phenotype. Together, these analyses computationally prioritize CYP3A4 and DPP7 as candidate TCS-relevant targets in UC and generate testable hypotheses for future experimental validation; they do not by themselves establish direct target engagement, inhibition, or causal contribution to UC.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-14"},"PeriodicalIF":2.7,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148405898","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":"Systemic histopathological responses to nanoplastic exposure: a review of cellular toxicity and organ-level pathology in mammalian systems.","authors":"Sijoon Lee","doi":"10.1080/15376516.2026.2699441","DOIUrl":"10.1080/15376516.2026.2699441","url":null,"abstract":"<p><p>Nanoplastics (NPs), a subfraction of microplastics (MPs) smaller than 1 μm, are increasingly recognized for their ability to cross biological barriers and induce organ-level toxicity; however, their systemic histopathological effects remain fragmented across individual studies. This review summarizes current <i>in vivo</i> mammalian evidence on NP-induced cellular toxicity and organ-specific histopathological changes based on a structured literature search of PubMed, Scopus, and Web of Science covering studies published between 2000 and 2024. The findings were narratively organized by organ system. Across the nervous, respiratory, gastrointestinal, hepatobiliary/renal, and reproductive systems, NPs consistently induce common pathological signatures, including immune cell infiltration, apoptosis, fibrosis, epithelial barrier disruption, and ultrastructural organelle damage. These lesions indicate conserved mechanisms involving oxidative stress, inflammatory signaling, impaired cellular homeostasis, and organ-organ crosstalk, such as gut-liver and hepato-renal interactions, which may amplify systemic toxicity. Collectively, the evidence demonstrates that NPs act as system-wide toxicants capable of multi-organ histopathological disruption, distinct from larger MPs or other nanoparticles, underscoring the need for further mechanistic and pathology-driven evaluation.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-15"},"PeriodicalIF":2.7,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391710","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":"Reclassification of the main impurity (-)-scopolamine hydrobromide trihydrate in scopolamine butylbromide: an integrated ICH M7 guideline assessment combining <i>in silico</i>, <i>in vitro</i>, and <i>in vivo</i> studies.","authors":"Rui Li, Su Zhou, Hongyan Zhu, Jing Fang, Minyang Gu, Zhiwen Ji, Liming Tang, Qingfen Zhu, Zhen Feng","doi":"10.1080/15376516.2026.2697220","DOIUrl":"10.1080/15376516.2026.2697220","url":null,"abstract":"<p><p>Following the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) multidisciplinary guideline M7 (R2), <i>in silico</i> prediction, <i>in vitro</i> and <i>in vivo</i> genotoxicity evaluations were used to evaluate the potential genotoxic risk of (-)-scopolamine hydrobromide trihydrate (SHT), the main impurity of scopolamine butylbromide in the Chinese Pharmacopeia (ChP). The 2018 <i>in silico</i> models for genotoxicity (Derek Nexus and Sarah Nexus) predicted SHT to be a Class 4 impurity. Subsequent <i>in vitro</i> and <i>in vivo</i> genotoxicity tests (bacterial reverse mutation test, <i>in vitro</i> mammalian chromosomal aberration test, <i>in vitro</i> mammalian cell gene mutation test and mammalian erythrocyte micronucleus test) showed no positive findings, indicating that SHT has no evidence of genotoxic potential under the tested conditions. Therefore, SHT could be tentatively categorized as a Class 5 impurity according to the ICH multidisciplinary guideline M7 (R2), with a threshold according to ICH quality guideline Q3B (R2). <i>In silico</i> prediction in 2026 confirmed this classification, demonstrating the high reliability of the Nexus software database for classification according to ICH multidisciplinary guideline M7 (R2). In the ChP, the SHT threshold in scopolamine butylbromide falls between the identification thresholds and the qualification thresholds of ICH quality guideline Q3B (R2), which is accurate and reasonable.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-10"},"PeriodicalIF":2.7,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148353755","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":"Toxic effects of perfluoroalkyl and polyfluoroalkyl substances (PFAS) on the gut microenvironment and their potential association with colorectal cancer.","authors":"Xiufen Tang, Lixin Tang","doi":"10.1080/15376516.2026.2695156","DOIUrl":"10.1080/15376516.2026.2695156","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are persistent surfactants with ingestion as a major exposure route, positioning the intestine as a primary site of contact. This narrative review integrates mechanistic toxicology, multi-omics microbiology, and human observational studies to evaluate whether PFAS-associated disruption of intestinal homeostasis could contribute to colorectal cancer (CRC). <i>In vitro</i> epithelial systems and animal models indicate that selected PFAS can impair barrier function through altered membrane properties and reduced tight-junction expression, increasing paracellular permeability and luminal antigen translocation. PFAS may also perturb goblet-cell secretion and mucus organization, in part through endoplasmic reticulum (ER) stress and altered autophagy, thereby facilitating mucosa-associated bacterial adherence. Stress signaling can converge on mitochondrial dysfunction and reactive oxygen species (ROS) generation that primes inflammasome activity and cytokine-mediated inflammation. In colon cell models, PFOA and PFOS have been associated with modulation of Wnt/β-catenin signaling and downstream transcriptional programs linked to proliferative and invasive phenotypes. At the community level, exposure-associated dysbiosis includes loss of butyrate-producing taxa and disruption of bile acid pools, consistent with reduced short-chain fatty acids (SCFAs) and altered farnesoid X receptor signaling. However, epidemiologic findings remain inconsistent, including null and inverse associations that may reflect reverse causation from occult bleeding, exposure misclassification, residual dietary confounding, non-monotonic dose responses, congener heterogeneity, and species-specific toxicokinetics. We propose priorities for future work including long-lag prospective sampling, physiologically based pharmacokinetic (PBPK)-informed exposure reconstruction, and adverse outcome pathway (AOP)-anchored multi-omics endpoints for causal inference and regulation.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-18"},"PeriodicalIF":2.7,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148333172","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":"Combined exposure effects and potential mechanisms of volatile organic compounds on liver fibrosis in the US population: an integrative epidemiological and computational toxicology analysis.","authors":"Yinhang Cui, Xiaoyi Yan, Xiaocong Ma, Jiacheng Xie, Tingwei Quan, Lian Gu","doi":"10.1080/15376516.2026.2648850","DOIUrl":"10.1080/15376516.2026.2648850","url":null,"abstract":"<p><strong>Background: </strong>Volatile organic compounds (VOCs) are widespread environmental pollutants that can cause oxidative stress and hepatocellular damage. However, epidemiological evidence linking VOC exposure to liver fibrosis and the underlying molecular mechanisms remains limited.</p><p><strong>Methods: </strong>Data were obtained from the 2017-2020 National Health and Nutrition Examination Survey (NHANES). Liver fibrosis was defined using the NAFLD fibrosis score (NFS > 0.676). Weighted logistic regression, restricted cubic spline (RCS), and weighted quantile sum (WQS) models were applied to evaluate individual and combined associations of nine blood VOCs with liver fibrosis after adjusting for demographic, lifestyle, and biochemical covariates. To explore potential mechanisms, network toxicology and molecular docking were conducted.</p><p><strong>Results: </strong>VOCs were moderately correlated, indicating common co-exposure sources. The WQS model revealed a positive overall association between mixed VOC exposure and liver fibrosis, with 1,4-Dichlorobenzene contributing the greatest weight. In fully adjusted models, higher blood 1,4-Dichlorobenzene levels were significantly associated with increased odds of liver fibrosis (<i>p</i>-trend < 0.05). RCS analysis showed a nonlinear dose-response relationship between 1,4-Dichlorobenzene and liver fibrosis risk. Network toxicology identified 176 overlapping targets enriched in PI3K-AKT and MAPK signaling pathways, with SRC, AKT1, AKT3, PIK3CA, and PIK3CD as hub genes. Molecular docking confirmed stable binding between 1,4-Dichlorobenzene and these proteins, with binding energies ranging from -7.5 to -8.5 kcal/mol.</p><p><strong>Conclusion: </strong>Blood 1,4-dichlorobenzene exposure is positively associated with an increased risk of liver fibrosis in the U.S. population, potentially through PI3K-AKT and MAPK pathway activation. This integrative approach provides new insights into VOC-induced hepatic fibrosis.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"904-918"},"PeriodicalIF":2.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147575568","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":"Cosmetic preservatives: physicochemical descriptors, mechanistic toxicity, and methodological approaches.","authors":"Wiktoria Omachel, Patrycja Pietruszewska, Anna Barbasz","doi":"10.1080/15376516.2026.2656478","DOIUrl":"10.1080/15376516.2026.2656478","url":null,"abstract":"<p><p>Cosmetic preservatives are widely used to ensure microbiological stability, yet their health risk assessment requires an understanding of dermal penetration mechanisms, interactions with the skin barrier, and cellular responses. This review presents mechanistic aspects of toxicity across major preservative classes, including parabens, formaldehyde donors, benzyl alcohol and its derivatives, isothiazolinones, sorbic acid, and benzoic acid systems, integrating physicochemical descriptors with data on percutaneous penetration, stratum corneum (SC) retention, and systemic distribution. Key parameters such as log <i>P</i>, log <i>D</i>, bioconcentration factor, and molecular weight are discussed as predictors of preservative behavior within the SC and their toxicodynamic potential. Mechanisms of cytotoxicity, sensitization, and membrane disruption are examined in relation to the chemical structure and reactivity of individual compounds. Alternative preservation strategies, including bioactive substances, multifunctional agents, and self-preserving systems, are evaluated with respect to their physicochemical properties and biological activity. Broader determinants of preservative use, such as exposure patterns, regulatory pressures, and environmental considerations, are outlined to contextualize mechanistic findings within real-world applications. The conclusion highlights future research directions, including the potential of methods such as Langmuir monolayer modeling, lipidomics, and established <i>in vitro</i> and <i>ex vivo</i> systems to support more precise characterization of preservative-barrier interactions and advance predictive toxicology.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"801-827"},"PeriodicalIF":2.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147692286","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}