Current Research in Toxicology最新文献

{"title":"RhoA/ROCK2 signaling pathway regulates Mn-induced alterations in tight junction proteins leading to cognitive dysfunction in mice","authors":"Yan Ma ,&nbsp;Honggang Chen ,&nbsp;Yuxin Jiang ,&nbsp;Diya Wang ,&nbsp;Michael Aschner ,&nbsp;Wenjing Luo ,&nbsp;Peng Su","doi":"10.1016/j.crtox.2024.100207","DOIUrl":"10.1016/j.crtox.2024.100207","url":null,"abstract":"<div><div>Elevated manganese (Mn) exposure has been implicated in a broad spectrum of neurological disorders, including motor dysfunction and cognitive deficits. Previous studies have demonstrated that Mn induces neurotoxicity by disrupting the integrity of the blood–brain barrier (BBB), a critical regulator in maintaining central nervous system homeostasis and a contributing factor in the pathogenesis of numerous neurological disorders. However, the precise molecular mechanisms underlying Mn-induced BBB disruption and its role in facilitating neurotoxicity remain incompletely understood. The primary objectives of this study were to elucidate the mechanisms underlying the relationship between Mn exposure and BBB tight junction proteins (TJPs), and to further investigate potential neuroprotective strategies for mitigating Mn-induced cognitive impairments. In this investigation, we developed Mn exposure models utilizing both murine subjects and cell culture systems to elucidate the mechanisms underlying TJPs involvement and to assess the potential neuroprotective effects of gastrodin (GAS), a bioactive compound extracted from traditional Chinese medicine. Our findings revealed a significant reduction in TJPs expression, both <em>in vivo</em> and <em>in vitro</em>, in Mn-induced BBB disruption. The overexpression of Occludin (OCLN), a crucial component of TJPs, mitigated Mn-induced BBB damage. GAS administration effectively attenuated Mn-induced disruption of the BBB, enhanced the expression of TJPs, and mitigated Mn-induced cognitive dysfunctions, potentially through the modulation of the RhoA/ROCK2 signaling pathway. This research sought to advance our understanding of the molecular pathways involved in Mn-mediated BBB disruption and to identify novel therapeutic approaches for mitigating the deleterious effects of Mn exposure on cognitive function.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100207"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of a hydrogen–oxygen generator in treating cigarette smoke–induced chronic obstructive pulmonary disease in rats","authors":"Wan-Ting Huang ,&nbsp;Tzong-Jih Cheng ,&nbsp;Lin-Hsiang Huang ,&nbsp;Yung-Te Hou","doi":"10.1016/j.crtox.2024.100214","DOIUrl":"10.1016/j.crtox.2024.100214","url":null,"abstract":"<div><div>Current treatments for chronic obstructive pulmonary disease (COPD), a common respiratory condition, include oxygen therapy and steroids for temporary relief. In this study, we established a rat model of cigarette smoke (CS)–induced COPD and investigated the benefits of a hydrogen–oxygen generator in this model. CS–exposed rats were treated using either a hydrogen–oxygen generator or a steroid. A hydrogen–oxygen generator reduced the neutrophil, lymphocyte, and eosinophil counts compared to natural recovery, whereas steroid treatment increased the total white blood cell, neutrophil, lymphocyte, monocyte and eosinophil counts. Furthermore, the mean linear intercept and the mean alveolar number were 59.8%, and 188.3%, respectively, after treatment with the generator, compared to the values observed with natural recovery. Finally, the generator increased the tricuspid annular plane systolic excursion values by 113.1% compared with the values in natural recovery. Our findings indicate successful establishment of a rat model of CS–induced COPD and demonstrate the potential benefits of using a hydrogen–oxygen generator for COPD patients.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100214"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A simple, reliable and easily generalizable cell-based assay for screening potential drugs that inhibit lipid accumulation","authors":"Weili Yang,&nbsp;Qiuyue Pan,&nbsp;Qi Li,&nbsp;Sirui Zhou,&nbsp;Xi Cao","doi":"10.1016/j.crtox.2024.100213","DOIUrl":"10.1016/j.crtox.2024.100213","url":null,"abstract":"<div><div>Ectopic lipid deposition in the hepatocyte plays an important role in the development of nonalcoholic fatty liver disease (NAFLD), which has become one of the most common causes of chronic liver disease worldwide yet no approved drugs are currently available. In this study, a cell-based method was developed to screen potential drugs with low toxicity that inhibit lipid accumulation. In the same 96-well plate, cytotoxicity was measured using CCK8 assay, followed by lipid content detection using BODIPY 493/503 via fluorometry assay, a lipid droplet-specific fluorescent dye commonly used in microscopy and flow cytometry, but not previously reported in fluorometry. Lipid content was normalized to DAPI staining to control for cell number. The results of this assay were highly consistent with the fluorescence microscopy, with significantly lower intra-group variability in detecting lipid accumulation induced by free fatty acids in Huh7 cells. Validation was conducted using 10 well documented steatotic compounds and 5 negative controls, all of which were correctly identified by the assay. In addition, the inhibitory effect of ML261, a well-known inhibitor of hepatic lipid droplets formation, was also confirmed by the assay both in AML12 cells and Hepa1-6 cells. To our knowledge, this study is the first to quantify lipid droplets using BODIPY 493/503 by fluorometry assay, and to demonstrate that CCK8 does not interfere with subsequent BODIPY 493/503 staining, both of which will reduce the cost and increase the efficiency. In conclusion, the method is simple, reliable, efficient and does not rely on expensive instruments, making it an easily generalizable approach to identify potential drug candidates for NAFLD treatment.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100213"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fit for purpose testing and independent GMP validation of the monocyte activation test","authors":"Ruth Daniels ,&nbsp;Wim Van der Elst ,&nbsp;Chi K. So ,&nbsp;Liesbeth Voeten ,&nbsp;Philip Breugelmans ,&nbsp;Marijke W.A. Molenaar-de Backer ,&nbsp;Stephen Poole ,&nbsp;Mehul Patel","doi":"10.1016/j.crtox.2024.100206","DOIUrl":"10.1016/j.crtox.2024.100206","url":null,"abstract":"<div><div>The present study describes the “fit for purpose” testing and the independent product-specific GMP validation of the monocyte activation test (MAT) to detect pyrogenic and pro-inflammatory contaminants, MAT Method A, Quantitative Test (<span><span>European Pharmacopoeia, Ph. Eur. chapter 2.6.30, 2017</span></span>). A fit for purpose study was carried out to ensure that the chosen MAT set-up (cryopreserved PBMC, IL-6 detection) can reliably discriminate between batches of product containing pyrogenic contaminants below the contaminants limit concentration, CLC, from batches containing pyrogenic contaminants above the CLC. Such testing is carried out once, before the chosen MAT set-up is used for subsequent product testing to show that the incidence of false positives (pyrogen-negative (&lt;CLC) batches testing as pyrogen-positive (&gt;CLC) batches) and – especially – false negatives (pyrogen-positive (&gt;CLC) testing as pyrogen-negative (&lt;CLC)) is low. This study also afforded the opportunity to collect an independent body of validation data for comparison with that obtained previously (<span><span>Daniels et al., 2022</span></span>) to evaluate the robustness of MAT Method A and its fitness to replace the rabbit pyrogen test (RPT) where this has not already happened.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100206"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotoxicity testing of the anthraquinone dye Alizarin Red S","authors":"Benedikt Bauer,&nbsp;Helena Rossi,&nbsp;Henning Hintzsche","doi":"10.1016/j.crtox.2024.100208","DOIUrl":"10.1016/j.crtox.2024.100208","url":null,"abstract":"<div><div>The anthraquinone dye Alizarin Red S (ARS) is used for marking live animals, specifically as a tool for monitoring the stock of the endangered European eel by marking caught fish with ARS before releasing the eels back into the wild. As ARS can be found in recaptured eels even years later, knowledge of potential health hazards of ARS is essential for assessing the food safety of eels marked with ARS. As the compound class of anthraquinones is known for their genotoxic and carcinogenic properties, concerns were raised regarding the food safety of marked eels. Up to now, no data for characterizing the hazard potential of ARS is available. In this study, we aimed at closing this data gap. We tested ARS in liver (HepG2), cervix (HeLa) and lymphoblast (TK-6) cells and identified HepG2 cells as the cell line most sensitive to ARS-induced cytotoxicity. We then investigated oxidative stress, DNA strand breaks, and micronucleus formation in these cells and did not observe effects at sub-cytotoxic concentrations.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100208"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of the gut microbiota and the nicotinate/nicotinamide pathway in rotenone-induced neurotoxicity","authors":"Yan Sai,&nbsp;Wei Ge,&nbsp;Li Zhong,&nbsp;Qifu Zhang,&nbsp;Jingsong Xiao,&nbsp;Yaohui Shan,&nbsp;Wenqi Ye,&nbsp;Haoyin Liu,&nbsp;Shulin Liu,&nbsp;Feng Ye,&nbsp;Xiaogang Wang,&nbsp;He Tang,&nbsp;Yuanpeng Zhao,&nbsp;Guorong Dan","doi":"10.1016/j.crtox.2024.100212","DOIUrl":"10.1016/j.crtox.2024.100212","url":null,"abstract":"<div><div>Rotenone is a natural compound from plants. It is widely used in pesticides because of highly toxic to insects and fish. However, lots of research has reported that rotenone has neurotoxic effects in humans. It is confirmed there is a correlation between rotenone exposure and Parkinson’s disease (PD). Therefore, the role of gut microbiota and related metabolic pathways was investigated in rotenone-induced neurotoxicity. The results showed that the abundance of gut microbiota changed significantly. The differential metabolites were enriched in the nicotinate and nicotinamide metabolism pathways, which had the greatest impact on the entire metabolic system. The contents of acetic acid and butyric acid in intestinal tissues decreased significantly. Additionally, Interleukin-6 (IL-6), Tumor necrosis factor alpha (TNF-α) and vasoactive intestinal peptide (VIP) were significantly up-regulated, while gastrin (GAS) and Ghrelin were significantly down-regulated. Expression of intestinal tight junction protein was significantly reduced. Moreover, nicotinamide adenine dinucleotide (NAD⁺), a the product of the nicotinate/nicotinamide pathways, decreased significantly. And the expression levels of nicotinamide phosphoribosyl transferase (NAMPT) and Solute Carrier Family 25 Member 51 (SLC25A51) also reduced significantly. Therefore, gut microbiota was influenced obviously in rats exposed to rotenone, leading to a decrease of acetic acid and butyric acid contents, which might in turn affect the change of intestinal barrier permeability and induce inflammatory reactions. Meanwhile, the nicotinate/nicotinamide metabolic pathways might play an important role in rats exposed to rotenone.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100212"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomic profiling reveals systemic metabolic disruptions induced by combined exposure to particulate matter and ozone","authors":"Yue Ge ,&nbsp;Maliha S. Nash ,&nbsp;Aimen K. Farraj","doi":"10.1016/j.crtox.2025.100216","DOIUrl":"10.1016/j.crtox.2025.100216","url":null,"abstract":"<div><div>Air pollution exposure, especially particulate matter (PM) and ozone (O₃), poses significant health risks, but the systemic metabolic consequences of combined exposures to PM and O₃, remain poorly understood. This study investigated systemic metabolic changes in male spontaneously hypertensive (SH) rats following inhalation exposure to concentrated ambient particles (CAPs) (PM2.5, 150 μg/m³), ozone (O₃) (0.2 ppm), and their combination. Rats were exposed for 4 h, and serum samples were collected 1-hour post-exposure. Using targeted metabolomics, we identified significant alterations in metabolites involved in lipid metabolism (phosphatidylcholines), energy metabolism (acylcarnitine C3), and oxidative stress (glutamine). Notably, the combination exposure induced distinct metabolic changes, including increased acylcarnitine C3 levels, suggesting heightened mitochondrial dysfunction. Principal component analysis revealed overlapping profiles between CAPs and controls, indicating a subtler impact of CAPs compared to ozone or combined exposure. These systemic metabolic alterations are aligned with our previously published proteomics findings in cardiac tissues from the same rats, which showed elevated inflammatory markers (e.g., IL-6, TNF-α) and mitochondrial dysfunction. In conclusion, this study provides new insights into the systemic metabolic effects of air pollutant exposure, identifies novel metabolic targets of pollutant-induced toxicity, highlights the complex interactions resulting from combined exposure to multiple pollutants, and underscores the importance of assessing the combined effects of multiple pollutants in air pollution risk assessments.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100216"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143161099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exacerbation of polyethylene microplastics in animal models of DSS-induced colitis through damage to intestinal epithelial cell conjunctions","authors":"Minkyoung Sung ,&nbsp;Yeon-Ji Lee ,&nbsp;Soo-Eun Sung ,&nbsp;Kyung-Ku Kang ,&nbsp;Jae Woo Park ,&nbsp;Yujeong Lee ,&nbsp;Dongmin Kim ,&nbsp;Sunjong Lee ,&nbsp;Joo-Hee Choi ,&nbsp;Sijoon Lee","doi":"10.1016/j.crtox.2025.100217","DOIUrl":"10.1016/j.crtox.2025.100217","url":null,"abstract":"<div><div>Microplastics are pollutants that occur in various environments and habitats. Inflammatory bowel disease (IBD) is a chronic inflammatory disease accompanied with diarrhea, and the number of patients has increased worldwide. In this study, manufactured fragmented polyethylene-microplastics in the size range of 10–30 ㎛, were oxidized by exposure to ultraviolet light, and then administered to a dextran sodium sulfate-induced colitis mouse model to observe the effects of polyethylene-microplastics on IBD. In the microplastics-treated groups, an increase in disease activity index score, histopathological score, and a decrease in the areas of goblet cells were observed. In addition, the tight junction proteins, ZO-1 and Occludin, were significantly decreased, whereas MPO was significantly increased. Interestingly, E-cadherin, which is an adheren junction, was also decreased, presumably because of the physical effects of microplastics. The results suggest that polyethylene-microplastics worsen IBD and microplastics can affect not only tight junctions, but also adheren junctions.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100217"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143161100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"L-3-n-butylphthalide alleviates intermittent alcohol exposure-induced hypothalamic cell apoptosis via inhibiting the IRE1α-ASK1-JNK pathway in adolescent rats","authors":"Shanyong Yi ,&nbsp;Lai Wei ,&nbsp;Bin Zhao ,&nbsp;Zhijun Yao ,&nbsp;Bin Yang","doi":"10.1016/j.crtox.2024.100211","DOIUrl":"10.1016/j.crtox.2024.100211","url":null,"abstract":"<div><div>Exposure to alcohol can induce different degrees of damage to various tissues and organs, and brain is the most vulnerable part affected by alcohol. However, there is no detailed report on whether intermittent alcohol exposure can result in pathological changes in the hypothalamus of adolescent rats and the detailed mechanism. This study investigated pathological changes in the hypothalamus, probed the levels of inflammatory factors, and detected the expression of proteins related to endoplasmic reticulum stress (ERS) to determine whether ERS is involved in the injury process of the hypothalamus and the protective mechanism of L-3-n-butylphthalide (L-NBP). The results showed that intermittent alcohol exposure induced hypothalamic nerve injury, including cell apoptosis, increased the levels of inflammatory factors, and upregulated the expression of glucose-regulated protein 78 (GRP78), p-Inositol Requiring Enzyme 1α (p-IRE1α), apoptosis signal-regulating kinase 1 (ASK1), and p-c-Jun N-terminal kinase (p-JNK)). Tauroursodeoxycholic acid (TUDCA), an ERS inhibitor, significantly reduced the pathological damage described above. The increases in the levels of inflammatory factors, pathological injury, and increased levels of proteins associated with the IRE1α-ASK1-JNK pathway were alleviated by L-NBP. The present study indicated that intermittent alcohol exposure could lead to hypothalamic cell apoptosis in adolescent rats and L-NBP could alleviate the above injury by inhibiting the IRE1α-ASK1-JNK pathway.</div><div>Abbreviations: Ang-2, Angiopoietin-2; ASK1, Apoptosis signal-regulating kinase 1; ER, Endoplasmic reticulum; ERS, Endoplasmic reticulum stress; ELISA, Enzyme-linked immunosorbent assay; GFAP, Glial fibrillary acidic protein; GRP78, Glucose-regulated protein 78; IBA1, Ionized calcium binding adapter molecule 1; i.p., Intraperitoneal; IRE1α, Inositol Requiring Enzyme 1α; JNK, c-Jun N-terminal kinase; L-NBP, L-3-n-butylphthalide; PND, Postnatal day; PVDF, Polyvinylidene difluoride; SDS-PAGE, Sodium dodecyl sulfate–polyacrylamide gel electrophoresis; TRAF2, TNF-receptor associated factor 2; TUDCA, Tauroursodeoxycholic acid; VEGF, Vascular endothelial growth factor.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100211"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The skin allergy risk assessment-integrated chemical environment (SARA-ICE) defined approach to derive points of departure for skin sensitization","authors":"Emily N. Reinke ,&nbsp;Joe Reynolds ,&nbsp;Nicola Gilmour ,&nbsp;Georgia Reynolds ,&nbsp;Judy Strickland ,&nbsp;Dori Germolec ,&nbsp;David G. Allen ,&nbsp;Gavin Maxwell ,&nbsp;Nicole C. Kleinstreuer","doi":"10.1016/j.crtox.2024.100205","DOIUrl":"10.1016/j.crtox.2024.100205","url":null,"abstract":"<div><div>Mechanistically based non-animal methods for assessing skin sensitization hazard have been developed, but are not considered sufficient, individually, to conclusively define the skin sensitization potential or potency of a chemical. This resulted in the development of defined approaches (DAs), as documented in OECD TG 497, for combining information sources in a prescriptive manner to provide a determination of risk or potency. However, there are currently no DAs within OECD TG 497 that can derive a point of departure (POD) for risk assessment. The Skin Allergy Risk Assessment – Integrated Chemical Environment (SARA-ICE) DA for skin sensitization is a Bayesian statistical model that estimates a human-relevant metric of sensitizer potency, the ED₀₁, an estimate of the human predictive patch test dermal dose at which there is 1% chance of inducing sensitization, which can be used in a risk assessment paradigm. The model accounts for variability of input data and explicitly quantifies uncertainty. SARA-ICE derives the ED₀₁ from a variety of <em>in vitro</em> and <em>in vivo</em> test method data and is built upon historical human, murine, and <em>in vitro</em> test data for 434 chemicals. In addition to the ED₀₁ POD SARA-ICE DA also provides a Globally Harmonized System of Classification and Labelling of Chemicals (GHS) classification probability for GHS subcategories 1A, 1B and not classified (NC). Here we describe the SARA-ICE model and its evaluation, including performance versus benchmark PODs. In addition, via a case study with isothiazolinones (ITs), we demonstrate the utility of SARA-ICE for integrating different data inputs and compare the ED₀₁ for six ITs to existing historical data.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100205"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11719337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}