Toxicological Sciences最新文献

{"title":"Expansion of preexisting cancer driver mutant clones is induced by the genotoxic carcinogen benzo[b]fluoranthene in MutaMouse lung.","authors":"Jennifer B Faske, Binsheng Gong, Danielle P LeBlanc, Juergen Funk, Gu Zhou, Sabrina Kehm, Paul A White, Timothy Robison, Andreas Zeller, Carole L Yauk, Francesco Marchetti, Barbara L Parsons","doi":"10.1093/toxsci/kfag030","DOIUrl":"10.1093/toxsci/kfag030","url":null,"abstract":"<p><p>Clonal expansion (CE) of cells carrying cancer driver mutations (CDMs) is being developed as a biomarker of cancer risk. CE in lung of MutaMouse males treated with 0, 6.25, 12.5, and 25 mg/kg/d benzo[b]fluoranthene (B[b]F) by gavage for 90 and 180 d was assessed by CarcSeq. DNA regions encompassing mouse correlates of human hotspot CDMs were PCR amplified, attaching 18-base unique molecular identifiers (UMIs) during the PCR. Following library preparation and sequencing, UMI-defined read families were assembled to produce single-strand consensus sequences (SSCSs). Recovered mutants with mutant fractions (MFs) ≥10-4 were stratified based on their occurrence in lung-specific or nonlung driver sequences and CE was assessed on a per mouse basis as median absolute deviation in mutant fraction (MAD). A significant, dose-dependent increase in MAD was observed for lung-specific MFs after 180 d of B[b]F treatment, a duration that did not cause a significant increase in lung lesions. Dose- and treatment duration-related increases in MF were observed for Egfr, the mouse correlate of a known human lung tumor driver gene. MF and mutation counts were significantly decreased in response to longer treatment duration for some nonlung drivers, suggesting negative selection. Importantly, the normalized trinucleotide mutation spectrum derived from CDMs reflects amplification of preexisting spontaneous mutations, distinct from those induced by B[b]F mutagenesis. These results show CarcSeq detects CE of preexisting cancer driver gene mutants induced by the genotoxic carcinogen B[b]F and suggest a CE endpoint may be useful for evaluating cancer risk associated with tumor promoters or complete carcinogens.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13011165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147487472","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":"The International Collaborative Animal Study of the carcinogenicity and genotoxicity of mobile phone radiofrequency radiation: the Korean study.","authors":"Hye Sun Kim, Kang-Hyun Han, Yong-Bum Kim, Sang Bong Jeon, Ae-Kyoung Lee, Jung-Ick Moon, Hyung Do Choi, Katsumi Imaida, Masanao Yokohira, Mayumi Kawabe, Norio Imai, Jianqing Wang, Young Hwan Ahn","doi":"10.1093/toxsci/kfag001","DOIUrl":"10.1093/toxsci/kfag001","url":null,"abstract":"<p><p>A chronic bioassay investigating radiofrequency (RF) carcinogenicity, intentionally designed to be conducted simultaneously in Korea and Japan, using the same research protocol and experimental environment. The study aimed to assess the potential carcinogenicity of Code Division Multiple Access (CDMA)-modulated 900 MHz RF signals at a whole-body specific absorption rate (SAR) of 4 W/kg, which is the reference level of the international human safety guideline, and to verify the key findings from the National Toxicology Program (NTP) study at that SAR level. Two reverberation chamber systems were used for RF exposures, and the same study protocols were followed. Male Harlan Sprague-Dawley (Hsd:Sprague Dawley SD) rats were randomly assigned to cage-control, sham-exposed, or RF-exposed groups. The exposure started on gestational day 5 and lasted for 18 h and 20 min each day, with 10-min on/off cycles. The project included a 28-d toxicity study, a 2-yr carcinogenicity study, and a 14-wk genotoxicity test. Histopathological evaluations were conducted in a partially blinded manner. The results were independently analyzed and submitted separately based on each country's research findings. In the Korean study, no statistically significant changes in tumor incidence or survival rates were observed. No significant RF-related effects were detected in the heart, brain, or adrenal glands. No changes in body temperature. Genotoxicity tests showed no evidence of DNA damage or mutation. In conclusion, the Korean part found that long-term exposure to CDMA-modulated 900 MHz RF was neither carcinogenic nor genotoxic at a SAR of 4 W/kg in male rats. An international animal study was jointly conducted as a chronic bioassay in Japan and Korea to evaluate the carcinogenicity of mobile phone RF signals and to verify key findings from the NTP study using identical protocols and exposure systems.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13017829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990768","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":"Application of in vitro to in vivo extrapolation (IVIVE) to inform chemical health guidance value derivation-sample case studies comparing neuro-, hepato-, and developmental toxicities.","authors":"Xiaoqing Chang, David G Allen, Nicole C Kleinstreuer, Moiz M Mumtaz","doi":"10.1093/toxsci/kfag017","DOIUrl":"10.1093/toxsci/kfag017","url":null,"abstract":"<p><p>Traditional chemical risk assessment is often based on published mammalian in vivo toxicity data, which are used to identify a point-of-departure (PoD) to derive the minimal risk level (MRL) and similar health guidance values. However, time and resource requirements prohibit efficient multi-target-organ toxicity assessments for a large number of environmental chemical pollutants. In vitro high-throughput screening assays and other new approach methodologies could address this problem by using reverse dosimetry to contextualize activity concentrations obtained from the in vitro assays to in vivo settings. In this study, we selected sample priority of diverse chemicals for which both curated high-throughput screening (cHTS) assay data and acute oral MRLs were available for neurotoxicity, hepatotoxicity, and developmental toxicity. We obtained in vitro activity concentrations for these chemicals and conducted in vitro to in vivo extrapolation (IVIVE) to estimate the daily equivalent administered dose (EAD) that would result in rat or human plasma concentrations equivalent to the in vitro activity concentrations. The range of EAD values across various cHTS assays was then compared with in vivo PoDs, MRLs, and predicted human exposure levels. Although variations existed depending on toxicity endpoints evaluated, our results showed that PoDs for a majority of chemicals can be predicted using such data. Our results also demonstrated that a majority of MRL and EAD values fall well below predicted human exposure levels. In summary, our findings demonstrate the usefulness and limitations of using cHTS data and IVIVE approaches for the derivation of health guidance values.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13017706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146214276","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":"Comparative investigation of the potential of glyphosate and glyphosate-based formulations to cause oxidative stress and DNA damage in human skin and liver cell systems.","authors":"Stephanie L Smith-Roe, Michael J DeVito, Caroll Co, Sreenivasa C Ramaiahgari, Michael Easterling, Julie R Rice, Paul E Dunlap, David M Crizer, Zhifeng Zhou, Bruce Alex Merrick, Guanhua Xie, Shawn F Harris, Keith R Shockley, Arpit Tandon, Ayse Oktay, Deepak Mav, Ruchir Shah, Alexandre Borrel, Vijay Gombar, Scott A Masten, Richard S Paules, Stephen S Ferguson","doi":"10.1093/toxsci/kfag029","DOIUrl":"10.1093/toxsci/kfag029","url":null,"abstract":"<p><p>Glyphosate is an herbicide found worldwide in glyphosate-based formulations (GBFs). Although glyphosate appears to have a low toxicity profile for humans and mammals, conflicting reports exist regarding the risk for cancer in humans. US-EPA and European regulatory agencies have described glyphosate as unlikely to pose a carcinogenic hazard to humans. However, the International Agency for Research on Cancer (IARC) classified glyphosate as \"probably carcinogenic to humans (Group 2A),\" citing \"mechanistic data provide strong evidence for genotoxicity and oxidative stress.\" Given these discrepancies, the Division of Translational Toxicology at NIEHS designed an experimental strategy to expand mechanistic evidence and address critical gaps within existing literature (e.g. mechanistic evaluations of glyphosate alongside GBFs, inclusion of context-defining positive controls). Cell morphology, viability, H2O2, and γH2AX formation were assayed in human keratinocytes (HaCaT), previously cited by IARC, and human hepatocytes (HepaRG) to derive benchmark concentrations and fold-change response metrics. Our findings revealed glyphosate alone was weakly and inconsistently bioactive for oxidative stress and DNA damage when compared with positive controls. In contrast, most of the 13 GBFs evaluated were more clearly bioactive with no apparent correlation to varied glyphosate concentrations. Hierarchical clustering of biological responses revealed some bioactive GBFs to cluster near well-characterized positive controls for oxidative stress, whereas 4 GBFs clustered more similarly to negative controls and glyphosate. Collectively, this study provides a robust dataset with context-defining results that advance our understanding of the hazard potential of GBFs while revealing that glyphosate is likely not a primary driver of oxidative stress from GBF exposures.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13026420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147460192","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":"Characterization of an anti-STEAP1 T-cell dependent bispecific antibody for the treatment of prostate cancer and associated toxicity in cynomolgus monkeys.","authors":"Elizabeth G Tonkin, Michelle Lepherd, John Davies, Gautham Gampa, Isidro Hötzel, Hartmut Koeppen, Wenyu Liu, Fjodor Melnikov, Xiang Niu, Dorothee Nickles, Monica Romero-Lopez, Lily Shao, Klara Totpal, Gabriele Schaefer","doi":"10.1093/toxsci/kfag015","DOIUrl":"10.1093/toxsci/kfag015","url":null,"abstract":"<p><p>BSTP0204A is a T-cell dependent-bispecific (TCB) antibody targeting 6-transmembrane epithelial antigen of the prostate 1 (STEAP1) that induces T-cell mediated killing of STEAP1 expressing cancer cells. STEAP1 is considered an attractive target for prostate cancer due to its high expression in the prostate and prostate cancer. Characterization of BSTP0204A showed potent T-cell-mediated killing in vitro and anti-tumor activity in mouse xenograft models against prostate cancer cell lines with both moderate and high STEAP1 expression. Analysis of STEAP1 protein expression in human and monkey tissues confirmed low STEAP1 expression outside of the prostate, suggesting a low potential for on-target/off-tumor toxicity. However, administration of BSTP0204A in a repeat-dose toxicity study in cynomolgus monkeys revealed adverse vascular inflammation that was inconsistent with STEAP1 expression observed in normal tissues. Additional assessments of STEAP1 expression in the vascular lesions from the toxicity study in monkeys and in human inflammatory disease conditions showed increased STEAP1 expression associated with inflammation and/or injury in both species. Furthermore, upregulation of STEAP1 was observed in both human and monkey primary cells in the presence of inflammatory stimuli. These findings suggest that systemic inflammation induced by T-cell activation following BSTP0204A treatment may have resulted in increased STEAP1 expression, inducing additional inflammation and tissue damage. This work demonstrated the need to understand not only baseline target expression for T-cell-engaging therapies, but also expression under conditions such as inflammation, injury, or disease.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158528","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":"Exposure of endothelial cells to doxorubicin inhibits extracellular matrix production by dermal fibroblasts in a paracrine manner.","authors":"Zhu Jiang, Giulia Sorrentino, Madalena Lopes Natário Pinto Gomes, Amber Swan-Taylor, Suat Simsek, Joris J T H Roelofs, Hans W M Niessen, Paul A J Krijnen","doi":"10.1093/toxsci/kfag027","DOIUrl":"10.1093/toxsci/kfag027","url":null,"abstract":"<p><p>Doxorubicin (Dox) is a potent chemotherapeutic with known vascular toxicity and connective-tissue damage. Endothelial cells (EC) and fibroblasts crosstalk is essential for vascular homeostasis and extracellular matrix (ECM) remodeling. This study aimed to explore whether Dox induces endothelial-to-mesenchymal transition (EndMT) and the paracrine effects of Dox-exposed EC on fibroblasts activation, senescence, and ECM synthesis. Human umbilical vein endothelial cells (HUVECs) were treated with Dox, and conditioned medium (CM) from EC was applied to human dermal fibroblasts for short- and long-term culture. Dox induced EndMT in ECs. Fibroblasts exposed to CM from Dox-treated EC exhibited early activation with increased fibroblast activation protein (FAP) and α-smooth muscle actin (α-SMA) at day 3, followed by a progressive senescent phenotype marked by elevated p21 and reduced Lamin B1 at day 21. ECM formation was impaired, with reduced collagen and increased transcriptional expression of matrix-degrading enzymes (MMP1 and MMP9). Cytokines profiling of the CM revealed decreased interleukin-1β (IL-1β), C-C motif ligand 2 (CCL2), and C-X-C motif ligand 10 (CXCL10), and elevated interleukin-6 (IL-6) levels. These findings demonstrate that exposure of EC to Dox induced endothelial dysfunction and elicited pathological paracrine signaling, driving fibroblast activation, myofibroblast transition, senescence, and ECM disruption. This mechanism may underlie Dox-related skin aging and delayed wound healing, and emphasizes the importance of endothelial dysfunction in chemotherapy-associated connective tissue damage and impaired repair.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13017147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147349003","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":"Comparison of physiologically based pharmacokinetic modeling platforms for developmental neurotoxicity in vitro to in vivo extrapolation.","authors":"Anna Kreutz, Xiaoqing Chang, Michael Lawless, Susana Proença, Stephan Schaller, Nicole Kleinstreuer, Helena T Hogberg","doi":"10.1093/toxsci/kfaf147","DOIUrl":"10.1093/toxsci/kfaf147","url":null,"abstract":"<p><p>An extensive battery of 17 in vitro assays has been developed for assessing developmental neurotoxicity (DNT), with the aim of replacing or supplementing traditional in vivo guideline studies for risk assessment, as these mechanistic assays provide advantages over costly, lengthy in vivo studies. However, 1 major challenge in employing in vitro assays is the translation of in vitro bioactive concentrations into in vivo doses that can be compared with human exposures. This study describes an in vitro to in vivo extrapolation (IVIVE) approach to derive human-relevant administered equivalent doses based on chemical partitioning into DNT target organs during the critical period of brain development. We used data from chemicals previously found to elicit bioactivity in a subset (7 of 17) of the in vitro DNT battery assays conducted at the US Environmental Protection Agency. Three physiologically based pharmacokinetic modeling platforms were evaluated for their suitability for this DNT-IVIVE approach. Chemical predictions for administered equivalent doses were compared against in vivo effect levels, where available, and found to be within 3-fold for 78% of chemicals. To provide metrics for risk assessment considerations, administered equivalent doses were compared with predicted human exposures. Overall, this DNT-IVIVE approach was found to be relatively transferable among modeling platforms, albeit with varying limitations and considerations that should be taken into account for specific contexts of use.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145378694","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":"Computational integration of in vivo single cell and in vitro bulk transcriptomics across 236 human and mouse datasets differentiates physiological versus non-physiological hepatic cell lines for hepatotoxicity screening.","authors":"Thomas Kowal, Susanna Wang, Michael Cheng, Ruoshui Liu, Montgomery Blencowe, Xia Yang","doi":"10.1093/toxsci/kfaf171","DOIUrl":"10.1093/toxsci/kfaf171","url":null,"abstract":"<p><p>New approach methods (NAMs), including in vitro paradigms, are needed to increase throughput, sustainability, and ethicality in toxicity research. However, selecting optimal cell culture models that mimic in vivo physiological conditions is challenging. To identify cell lines that best recapitulate physiological cells, we compared gene expression signatures of cell lines and in vivo tissues. We curated 214 transcriptomics datasets from 17 human and mouse hepatic cell lines representing hepatocytes, hepatic stellate cells, and cholangiocytes and determined basal gene expression profiles for each. We also collected 7 in vivo single-cell RNA sequencing (scRNAseq) datasets from human and mouse livers, which provide physiologically relevant transcriptome profiles for hepatic cell types. We compared cell line transcriptome profiles to liver scRNAseq data to determine which cell lines best represent in vivo physiology for each cell type and compared genes, regulatory networks, and biological pathways between cell lines and hepatic cell types. We further analyzed 15 cell lines, in vivo, and primary hepatocyte datasets from hepatotoxicity studies to relate baseline patterns to toxicological responses. We identified HepaRG as optimal to model hepatocytes both at baseline and in hepatotoxicity application studies of diverse toxicants, and further provided biological insights into the key differences of some of the widely used hepatic cell lines from in vivo biology. Overall, we present a new in silico approach that leverages existing big data to guide the selection of cell lines with better functional relevance, which can be applied to in vitro modeling of other tissues and broad biomedical applications.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757793","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":"β-lactoglobulin-per- and polyfluoroalkyl substance-binding interactions identifies the calyx domain as a determinant of contaminated milk exposure and the calycin protein family as potential mediators of per- and polyfluoroalkyl substance toxicity.","authors":"Zachary S McLean, Mallory E Thomas, Scott M Belcher","doi":"10.1093/toxsci/kfaf178","DOIUrl":"10.1093/toxsci/kfaf178","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are a diverse class of highly fluorinated persistent synthetic chemical pollutants. Major routes of human exposure include ingestion of contaminated drinking water and foods including dairy. Consumption of PFAS-contaminated milk and dairy is especially concerning for infants and children who are particularly sensitive and most highly exposed. Here, we report findings of quantitative analysis of PFAS binding to β-lactoglobulin (β-Lg), the major whey protein in bovine milk, using differential scanning fluorimetry to determine binding affinities for 17 PFAS; except for uncharged fluorotelomer alcohols, β-Lg bound each PFAS congener tested, supporting a key role of charged functional groups in binding. The perfluoroalkyl carboxylic acid trifluoroacetic acid (TFA) bound with lowest affinity (Kd=8.6 mM) and long-chain congeners PFNA, PFDA, and PFUnDA bound with highest affinities. Evidence of significant cooperative binding was found for TFA, PFDA, PFUnDA, and PFOS. Molecular docking was used to define molecular mechanisms of PFAS binding by β-Lg and across the calycin super family of lipocalins and fatty acid-binding proteins. All calycins were predicted to bind PFAS in the calyx domain with ΔG of binding ranging from -5.3 to -9.4 kcal/mol, revealing that the binding affinity for many PFAS is greater than those for binding albumin. In total, this study has identified the calycin protein superfamily as PFAS-binding proteins, most of which have well-characterized functions related to key endocrine and toxicological pathways associated with the adverse consequences of PFAS exposure.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850580","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":"Interlaboratory validation of the human thyroid microtissue assay.","authors":"Chad Deisenroth, Briana Foley, Eda Rogers, Julia Kühnlenz, Wei Chen, Madison Feshuk, Enrica Bianchi, Josiah McKenna, Bridgett N Hill, Jessica Larocca, Edward L LeCluyse, Nicole Kleinstreuer, Russell S Thomas, Helena T Hogberg","doi":"10.1093/toxsci/kfaf166","DOIUrl":"10.1093/toxsci/kfaf166","url":null,"abstract":"<p><p>The U.S. Environmental Protection Agency (EPA) continues to evaluate strategies to implement new approach methods (NAMs) for screening chemicals that disrupt the thyroid endocrine system. Validation of NAMs is a critical milestone toward establishing confidence in data sources that could be used in a regulatory decision-making context. The objective of this study was to conduct an interlaboratory validation of the human thyroid microtissue assay to evaluate its relevance and reliability. In coordination with the US validation authority, NICEATM, and collaboration with industry partners (LifeNet Health, Bayer Crop Science, Corteva Agrisciences), the study aims were to (1) define the study design and establish standard operating procedures, (2) conduct test method transfer, training, and within-laboratory model performance evaluation, (3) perform interlaboratory reference chemical testing and assay performance evaluation. Progress was independently monitored by a validation management team comprised of an international group of experts in thyroid physiology, in vitro test methods, and regulatory toxicology. Results indicated the thyroid microtissue model could be reliably transferred to new laboratories with reproducible effects on thyroid hormone synthesis. Interlaboratory testing of 4 blinded reference chemicals (3 true positive, 1 true negative) across 3 independent human donors revealed consistent bioactivity across the reference set and performance metrics (dynamic range, precision, screening quality) that met acceptance criteria and shed insight into areas for improvement. In the context of a NAM-based testing strategy, a validated human thyroid microtissue assay enables direct measurement of thyroid hormone synthesis perturbations, reducing reliance on animal testing and addressing a critical mode-of-action that is of regulatory concern.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678120","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}