Toxicological Sciences最新文献

{"title":"Comparative Review of Human Health Reference Values of the United States.","authors":"George M Woodall, Sarah E Kobylewski-Saucier, Rachel M Shaffer, April M Luke, Laura M Carlson","doi":"10.1093/toxsci/kfaf092","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf092","url":null,"abstract":"<p><p>Human health-based reference values (HHRVs) developed by United States (U.S.) governmental agencies and professional organizations are derived for specific purposes related to their organizational or statutory mandates, and for individual chemicals or substance groups (e.g., manganese compounds). Choosing an appropriate chemical-specific value should be based on the risk assessment need and the specific exposure context, along with a basic understanding of the various types and the intended purposes of each available HHRV. In this overview, HHRVs have been broadly organized into three main categories: Values for the general public; occupational exposure limits; and emergency response values. The goal of this overview is to equip the reader with a greater understanding of HHRVs, how they are meant to be applied, and key aspects to consider in selecting the most appropriate value. These key aspects include target population (e.g., general public of all ages vs. working-age adults), duration and frequency of exposure, health effect severity, confidence in the data set, use of well-documented and contemporary derivation methods, transparency and documentation of the value derivation, and the thoroughness of the review process. Chemical- and exposure scenario-specific needs should determine which HHRV is most appropriate; however, a most appropriate HHRV may not be available for every chemical and situation. Therefore, we present both considerations and limitations to guide selection of an alternate HHRV based on suitability for the assessment scenario from among the available chemical-specific values.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718731","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":"High-Content Imaging and Transcriptomic Analyses of the Effects of Bisphenol S and Alternative Color Developers on KGN Granulosa Cells.","authors":"Lama Iskandarani, Stéphane Bayen, Barbara F Hales, Bernard Robaire","doi":"10.1093/toxsci/kfaf096","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf096","url":null,"abstract":"<p><p>Concerns about the adverse effects of bisphenol A (BPA), a chemical used for the production of polycarbonate plastics, epoxy resins, and as a color developer in thermal papers, have led to an increase in the use of 4,4-sulfonyldiphenol (bisphenol S; BPS), bis(3-allyl-4-hydroxyphenyl) sulfone (TGSA), 4-hydroxyphenyl 4-isoprooxyphenylsulfone (D-8), and [3-[(4-methylphenyl)sulfonylcarbamoylamino]phenyl] 4-methylbenzenesulfonate (Pergafast-201; PF-201), and 2,4-bis(phenylsulfonyl)phenol (DBSP) as alternative color developers. Data on these chemicals is scarce and little is known about their potential toxicity. We determined the effects of BPS, TGSA, D-8, PF-201, and DBSP on the phenotype, function, and transcriptome of KGN human granulosa cells. Using high-content imaging, we observed that TGSA was the most cytotoxic compound tested, followed by D-8, DBSP, PF-201, and BPS. While the effects of these compounds on lysosomes, mitochondria, and oxidative stress were minimal, TGSA, D-8, and PF-201 drastically increased the number and total area of lipid droplets compared to control. RNA sequencing analyses revealed that TGSA and D-8 exposure differentially regulated 2,414 and 2,563 genes, respectively. PF-201 was the least transcriptionally active chemical, significantly affecting only six transcripts. The predominant effect of TGSA was the activation of pathways related to the extracellular matrix, while both TGSA and D-8 inhibited pathways involved in cell cycle regulation, DNA replication, and DNA repair. Such mechanisms may be underlying the cytotoxicity and lipid droplet accumulation observed in KGN cells. These data suggest that alternative color developers such as TGSA, D-8, and PF-201 act by different mechanisms and may not be responsible replacements for BPA and BPS in thermal papers.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718732","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":"De-Risking Seizure Liability: Integrating Adverse Outcome Pathways (AOPs), New Approach Methodologies (NAMs) and In Silico Approaches while Highlighting Knowledge Gaps.","authors":"Mamta Behl, Agnes Karmaus, Mohan Rao, Thomas Lane, Joshua Harris, Clifford Sachs, Alexandre Borrel, Oluwakemi Oyetade, Aswani Unnikrishnan, Jonathan Hamm, Helena T Hogberg","doi":"10.1093/toxsci/kfaf109","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf109","url":null,"abstract":"<p><p>Animal studies are commonly used in drug development, chemical, and environmental toxicology to predict human toxicity, but their reliability, particularly in the central nervous system (CNS) is limited. For example, animal models often fail to predict drug-induced seizures, leading to unforeseen convulsions in clinical trials. Evaluating environmental compounds, such as pesticides, also poses challenges due to time and resource constraints, resulting in compounds remaining untested. To address these limitations, a government-industry collaboration identified 25 biological target families linked to seizure mechanisms by combining key events from adverse outcome pathways (AOPs) with drug discovery data. Over a hundred vitro assay endpoints were identified, covering 24 of the target families, including neurotransmitter receptors, transporters, and voltage-gated calcium channels. A review of reference compounds identified 196 seizure-inducing and 34 seizure-negative chemicals revealed that fewer than 30% of the targets had been tested, highlighting significant data gaps. This proof-of-concept study demonstrates how mechanistic seizure liability can be assessed using an AOP framework and in vitro data. It underscores the need for expanded screening panels to include additional seizure-relevant targets. By integrating mechanistic insights into early drug development and environmental risk assessment, this approach enhances compound prioritization, complements animal studies, and optimizes resource use. Ultimately, this strategy refines CNS safety evaluation in drug development, improves public health protection to neurotoxicants, and bridges knowledge gaps.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715193","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":"Evaluating the role of alveolar macrophages in tolerance to ozone.","authors":"Gregory J Smith, Morgan Nalesnik, Robert M Immormino, Jeremy M Simon, Jack R Harkema, Jason R Mock, Timothy P Moran, Samir N P Kelada","doi":"10.1093/toxsci/kfaf095","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf095","url":null,"abstract":"<p><p>Acute exposure to ozone (O3) causes pulmonary inflammation and injury in humans and animal models. In rodents, acute O3-induced inflammation and injury can be mitigated by pre-exposure to relatively low concentration O3, a phenomenon referred to as tolerance. While tolerance was first described long ago, the underlying mechanisms are not known. We hypothesized that alveolar macrophages (AMs) play a key role in tolerance to O3 based on prior studies with other exposures. To enable our studies, we first generated a mouse model in which female C57BL6/NJ mice were pre-exposed to filtered air (FA) or 0.8 ppm O3 for four days (4 hours/day), then challenged with 2 ppm O3 (3 hours) 2 days later, and phenotyped for airway inflammation and injury 6 or 24 hours thereafter. As expected, pre-exposure to O3 resulted in significantly reduced airway inflammation and injury 24 hours following O3-challenge. Tolerance was associated with regenerative hyperplasia in the terminal bronchioles and changes in the frequency of proliferating alveolar type 2 cells. O3 pre-exposure altered the expression of ∼1500 genes in AMs, most notably down regulation of Toll-like receptor and proinflammatory cytokine signaling pathways, suggesting AMs had become hypo-responsive. Depletion of tolerized AMs prior to acute O3 challenge did not, however, alter inflammation and injury. Additionally, adoptive transfer of tolerized AM to naïve, recipient mice failed to alter responses to acute O3 challenge. In total, our results argue against an important role for AMs in tolerance to ozone and suggest that other cell types are involved.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715194","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":"Chemosensory Tobacco Product Toxicology Part 2: Toxicological Testing, Assays, and State of the Science.","authors":"Weihong Lin, Thomas Hill, Andrea M Stroup, S Emma Sarles, Tatsuya Ogura, Farhan Augustine, Sean O'Sullivan, Irfan Rahman, Risa Robinson, Sairam V Jabba, Caleb Nuss, Edward Hensel","doi":"10.1093/toxsci/kfaf091","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf091","url":null,"abstract":"<p><p>The toxicologic impacts to normative function of the chemosensory system and loss of its contribution to organism protection and homeostasis remain an underrepresented area of interest in the published literature. The impact of chemical constituents in ENDS e-liquids or aerosol on the chemosensory system is even less known, as are the effects on product selection and use behavior-and may be an overlooked impact on the public health. This review is a snapshot of the current state of the science and opportunities for improving and increasing the volume of publications in chemosensory toxicology, on the potential impacts of tobacco products. The proposed solutions rely on the determination of the scientific community to take advantage of an unexplored field of opportunity. Active research engagement and use of an integrative, risk-driven planning framework to address harmonization and data gaps in neurosensory research programs would support harmonization, improve scientific visibility in the published literature, and recruit additional investigators to this research community.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708833","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":"Chemosensory Tobacco Product Toxicology Part 1: Sensory Mechanisms.","authors":"Weihong Lin, Thomas Hill, Andrea M Stroup, S Emma Sarles, Tatsuya Ogura, Farhan Augustine, Sean O'Sullivan, Irfan Rahman, Risa Robinson, Sairam V Jabba, Caleb Nuss, Edward Hensel","doi":"10.1093/toxsci/kfaf090","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf090","url":null,"abstract":"<p><p>Chemosensory systems detect and discriminate a wide variety of molecules to monitor internal and external chemical environments. They initiate olfactory, gustatory, and chemesthetic sensations, influence human brain cognition and emotion, and guide a wide variety of behaviors essential for survival, including protective reactions, such as avoidance of contaminated foods and potential toxicants. Electronic nicotine delivery systems (ENDS) aerosolize e-liquids for inhaled consumption that typically contain flavorants, propylene glycol (PG), vegetable glycerin (VG), and nicotine. E-liquid aerosols also contain toxicants, such as formaldehyde, acetaldehyde, acrolein, and heavy metals. Chemosensory evaluation of ENDS aerosol plays an essential role in the assessment of whether a product will attract new users of all ages, as well as determining their likely use patterns, perceptions of product harm, satisfaction, and product selection. Nicotine and individual flavorant constituents stimulate multiple sensory receptor systems in complex patterns, initiating distinctive sensory perceptions depending on the chemical properties and quantity in the aerosol. There are limited data on chemosensory evaluation of ENDS aerosols and their influence on ENDS use and protective biologic mechanisms. This two-part manuscript provides an overview of i) the physiology of the olfactory, gustatory, and chemesthetic chemosensory systems and their detection mechanisms, and their role in protective defenses; and ii) the in vitro, in vivo, and in silico computer-based methodology available to evaluate ENDS irritants and toxicants and their impact on chemosensory pathways, the current state of the science related to e-liquid and ENDS aerosols, and challenges for future studies and scientific innovation.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708881","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":"Perfluorooctanesulfonic acid (PFOS) antagonizes gamma-aminobutyric acid (GABA) receptors in larval zebrafish and mammalian models.","authors":"Renee Owen, Gabriel de Macedo, Jana Nerlich, Ilka Scharkin, Kristina Bartmann, Jonas Döbler, Beatrice Engelmann, Ulrike E Rolle-Kampczyk, David Leuthold, Sebastian Gutsfeld, Nicole Schweiger, Tamara Tal","doi":"10.1093/toxsci/kfaf101","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf101","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals detected ubiquitously in the environment, humans, and wildlife. Perfluorooctanesulfonic acid (PFOS) is one prevalent chemical previously shown to cause adverse effects on nervous system function across in vivo and in vitro models, including dark-phase hyperactivity in larval zebrafish. The objective of this study was to evaluate the role of gamma-aminobutyric acid receptors (GABARs), GABAAR and GABABR, as mediators of dark-phase hyperactivity in PFOS-exposed larval zebrafish. Zebrafish were acutely exposed to 7.87-120 μM PFOS, 0.68-12.4 μM picrotoxin (GABAAR antagonist), 0.77-14.05 μM propofol (GABAAR positive allosteric modulator), 4.4-80 μM saclofen (GABABR antagonist), 0.43-7.87 μM CGP13501 (GABABR positive allosteric modulator), or the solvent control 0.4% dimethyl sulfoxide (DMSO) 60 min before behavior assessment at 5 days post fertilization (dpf). Co-exposures to positive allosteric modulators and PFOS were performed. Acute exposure to PFOS caused transient dark-phase hyperactivity. Concentration-dependent dark-phase hypoactivity was observed following acute propofol or CGP13501 exposure, in contrast to the concentration-dependent hyperactivity caused by acute picrotoxin exposure. Saclofen exposure provoked a modest reduction in dark-phase motor activity at the highest concentration tested. PFOS-induced hyperactivity was rescued to baseline activity by co-exposure to propofol or CGP13501. To assess relevance across species, electrophysiological measurements were performed in cultured mouse cortical neurons, and BrainSpheres derived from human-induced pluripotent stem cells (hiPSC). PFOS exposure reduced GABAAR-mediated currents in mouse neurons. GABAAR- and GABABR-dependent units in BrainSphere-derived neural networks exhibited increased spiking activity following PFOS exposure. This study demonstrates that PFOS antagonizes GABARs in zebrafish, mouse, and human experimental systems. Taken together, this supports the concept that early life stage zebrafish can be used to rapidly identify causative mechanisms, conserved across taxa, by which xenobiotic agents alter neuroactivity.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699631","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":"Culture Media Influences Primary Human Bronchial Epithelial Cell Morphology, Differentiation Status, and Transcriptional Response to Ozone Exposure.","authors":"Sarah A Lester, Sabri H Abdelwahab, Scott H Randell, Samir N P Kelada","doi":"10.1093/toxsci/kfaf089","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf089","url":null,"abstract":"<p><p>Exposure to the ambient air pollutant ozone induces acute and chronic respiratory health effects in part by causing inflammation of the airways. Several aspects of the inflammatory response to ozone can be modeled in vitro using primary human bronchial epithelial cells (HBECs) cultured at an air-liquid interface. We tested two commonly used HBEC culture media systems, one proprietary and one non-proprietary, to identify which system yielded the most in vivo-like pro-inflammatory response to acute ozone exposure as reflected by gene expression. Cells from six donors were grown in each culture system in parallel followed by examination of epithelial morphology and cell type proportions prior to ozone exposure. Cultures grown in the proprietary system were notably thicker and contained more ciliated and secretory cells, as well as internal cyst-like structures. The transcriptomic response to acute ozone exposure (0.5 parts per million ozone x 2 hours) was strongly affected by media. HBECs grown in the proprietary system exhibited minimal changes after ozone, with only 7 differentially expressed genes (DEGs). In contrast, HBECs grown in the non-proprietary system exhibited a more dynamic response with 128 DEGs, including hallmark response genes indicative of inflammation (CXCL8) and oxidative stress (HMOX1). Gene set enrichment analysis using the 128 DEGs further corroborated upregulation of oxidative stress and inflammation pathways. In total, our results indicate that the choice of HBEC culture media should be carefully considered to best model the in vivo response to ozone.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699630","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":"Preimplantational ethanol exposure causes disturbances in gene expression and abnormalities in cerebral cortex morphogenesis and behavior.","authors":"Rei Sugiyamai, Mizuki Tanizaki, Munekazu Komada","doi":"10.1093/toxsci/kfaf104","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf104","url":null,"abstract":"<p><p>Preimplantational ethanol exposure during the early stages of pregnancy is associated with significant developmental abnormalities in the cerebral cortex and behavioral changes. This study explores the impact of such exposure on neurogenesis, cortical morphogenesis, neuronal development, and behavioral outcomes. Ethanol exposure impairs the proliferation of radial glial and intermediate progenitor cells, disrupting neurogenesis in the dorsal telencephalon. Histological analysis reveals reduced neuronal distribution and decreased microglia numbers, highlighting neuroinflammation's role in these abnormalities. Gene expression studies show disrupted BDNF expression and upregulation of neurogenesis-related genes like Ngn2 and NeuroD, suggesting a potential imbalance in neuronal differentiation. Behavioral assessments in postnatal mice indicate significant impairments in locomotor and psychomotor activities and altered social proximity, though overall social interaction remains largely unchanged. Observations from open field tests demonstrate reduced spontaneous and psychomotor activity in alcohol-exposed mice. In multi-individual settings, these mice show decreased inter-individual distance, suggesting altered social proximity preferences. These findings underscore the long-term consequences of early prenatal ethanol exposure on brain development and behavior. The disruption in cortical morphogenesis, along with neuroinflammation and altered gene expression, is linked to neurodevelopmental deficits characteristic of fetal alcohol spectrum disorders (FASD). 10205Further studies are necessary to better understand the mechanisms involved and mitigate long-term impacts.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699632","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":"Refining High-Throughput In Vitro-In vivo Extrapolation Modeling through Incorporation of Intestinal Toxicokinetics.","authors":"Evgenia Korol-Bexell, Anna S Jarnagin, Amanda Brennan, Jermaine Ford, Jackson Bounds, Denise M MacMillan, Michael F Hughes, Barbara A Wetmore","doi":"10.1093/toxsci/kfaf105","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf105","url":null,"abstract":"<p><p>New approach methods (NAMs) that combine high-throughput toxicity and toxicokinetic data have gained prominence as federal entities attempt to evaluate tens of thousands of commercial chemicals for human health hazard. In vitro-in vivo extrapolation employing a generic high-throughput toxicokinetic (HTTK) model to convert in vitro points of departure (POD) to human equivalent doses (ie, PODNAMs) has proven successful translating in vitro data to real-world exposures; however, conservative assumptions, including consideration of only hepatic metabolism, has resulted in PODNAMs that are 10 to 100-fold more conservative when compared to available in vivo-based PODs. This effort evaluates the impact of incorporating intestinal metabolism through consideration of CYP3A4, a cytochrome P450 isozyme responsible for over 80% of intestinal clearance. For 11 chemicals, intrinsic clearance rates were derived in human liver and intestinal microsomes with and without inhibition of CYP3A4 to quantitate relative CYP3A4 contribution. Physiologically-based TK simulations were conducted using Simcyp Simulator to 1) recapitulate the HTTK approach and 2) incorporate CYP3A4 contribution into the elimination model, which by extension incorporates intestinal clearance occurring via CYP3A4. CYP3A4 contribution ranged from 0 to 71% across the chemicals tested, and estimates of oral bioavailability, steady-state concentration, and fraction escaping gut metabolism typically decreasing with increasing CYP3A4 involvement. Further, incorporation of in vitro PODs with this refined model showed a concomitant increase in PODNAMs, indicating that incorporating such information into HTTK provides more predictive risk-based prioritization of the commercial chemical space.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683157","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}