Chemical Research in Toxicology最新文献

{"title":"Toxicokinetics and Perfluorooctanesulfonic Acid-Induced Liver Protein Expression Are Markedly Altered in Mice Lacking Albumin.","authors":"Emily M Kaye, Jitka Becanova, Simon Vojta, Rainer Lohmann, Fabian Christoph Fischer, Angela Slitt","doi":"10.1021/acs.chemrestox.4c00508","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00508","url":null,"abstract":"<p><p>Perfluorooctanesulfonic acid (PFOS) is a ubiquitous perfluoroalkyl substance (PFAS) linked to liver disease and obesity in humans. Binding studies suggest that albumin is a crucial blood protein influencing PFOS toxicokinetics and hepatotoxicity; however, its role has not been mechanistically tested in vivo. This study used an albumin-deficient mouse model to investigate the relevance of albumin in PFOS tissue distribution and liver disease end points. Adult male C57BL/6J wild-type (Alb^+/+) and albumin-deficient (Alb^-/-) mice were orally gavaged daily for 7 days with either vehicle or PFOS at 0.5 or 10 mg/kg body weight. The measured PFOS concentrations in plasma were significantly lower in Alb^-/- mice compared to those in Alb^+/+ mice, while liver concentrations were significantly higher in Alb^-/- mice. Binding experiments confirmed these findings, indicating that PFOS toxicokinetics are driven by plasma and tissue binding. Significant changes in liver protein expression did not translate into differences in liver disease end points between genotypes, suggesting the need for chronic exposure studies. Our data imply that disease-related albumin deficiency in humans can influence PFAS toxicokinetics and susceptibility to hepatotoxicity. Our framework using knockout mice can be adapted in future studies to assess the relevance of protein binding and membrane transporters in PFAS distribution and elimination.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256637","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":"Facile Biological Oxidation of Dopamine to 6-Hydroxydopamine p-Quinone in a Sequential Two-Step Process: Implications for Parkinson’s Disease","authors":"Xiang-Rong Jiang,&nbsp; and ,&nbsp;Bao Ting Zhu*,&nbsp;","doi":"10.1021/acs.chemrestox.5c0005810.1021/acs.chemrestox.5c00058","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00058https://doi.org/10.1021/acs.chemrestox.5c00058","url":null,"abstract":"<p >6-Hydroxydopamine (6-OHDA), a hydroxyl-derivative of the endogenous neurotransmitter dopamine, can selectively induce Parkinsonian symptoms in animal models. At present, most researchers consider 6-OHDA a man-made neurotoxicant, due to the lack of strong evidence for its presence and/or formation in biological systems. The present study aims to determine whether 6-OHDA can be formed under physiologically relevant conditions. Here, we report in the Fenton reaction system (containing 15 μM Fe²⁺, 142 μM ascorbic acid and 80 μM EDTA in 50 mM phosphate buffer, pH 7.4), dopamine can undergo facile oxidation to 6-OHDA <i>p</i>-quinone (a stable, oxidized form of 6-OHDA) in a sequential two-step process: the first step involves dopamine oxidation to its <i>o</i>-quinone (DAQ), and this process is facilitated by oxidants like transition metal ions Fe^2+/3+ and Mn^2+/3+; and the second step involves the further oxidization of DAQ to 6-OHDA <i>p</i>-quinone by hydroxyl radical or hydrogen peroxide. The chemical mechanism by which H₂O₂ oxidizes DAQ to 6-OHDA <i>p</i>-quinone likely results from the attack of H₂O₂-derived ⁻OOH at the C–6 position of DAQ. We also demonstrate that while catalase abolishes 6-OHDA <i>p</i>-quinone formation by removing hydrogen peroxide or hydroxyl radical, glutathione and cysteine provide effective protection by forming conjugates with DAQ and 6-OHDA <i>p</i>-quinone. The results of this study demonstrate that 6-OHDA can be readily formed from dopamine under physiologically relevant conditions, and thus provide important tangible support for the long-held speculation that 6-OHDA is an intrinsic etiological factor in Parkinson’s disease.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"1082–1090 1082–1090"},"PeriodicalIF":3.7,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290416","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":"A Review of the Most Frequent Compounds, Metals, and Compound and Metal Mixtures Found at U.S. Superfund Sites and Their Carcinogenic Potential","authors":"June K. Dunnick*,&nbsp;Charles P. Schmitt and Darlene Dixon*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0050610.1021/acs.chemrestox.4c00506","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00506https://doi.org/10.1021/acs.chemrestox.4c00506","url":null,"abstract":"<p >The United States Environmental Protection Agency’s (U.S. EPA) National Priorities List (NPL) is a list of sites in the U.S. and its territories of national priority that are sources of known hazardous contaminants, pollutants, or substances that pose a significant risk to human health and the environment. These sites are commonly termed U.S. Superfund sites and contain many harmful compounds and metals. This paper reviews the carcinogenic potential of the most frequent compounds, metals, and mixtures at U.S. Superfund sites. Of the most frequent compounds and metals identified at U.S. Superfund sites, some are classified as human carcinogens and some as probable/possible human carcinogens. The most frequent mixtures of three individual carcinogenic compound or metals at U.S. Superfund sites include: nickel, arsenic, and cadmium (496 sites); benzene, arsenic, trichloroethene (451 sites); benzene, vinyl chloride, trichloroethene (420 sites); and arsenic, vinyl chloride, trichloroethene (386 sites). Many compounds or metals that are frequently found at U.S. Superfund Sites have not been evaluated for carcinogenic activity because of limited data including copper, xylene, mercury, barium, and iron. Factors in human cancer development include both environmental factors and genetic disease susceptibility backgrounds. Thus, future mixture toxicology studies should be conducted with a design that looks at mixture toxicology in a variety of models with varied genetic backgrounds.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"963–974 963–974"},"PeriodicalIF":3.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00506","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290402","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":"Evaluation of the Effectiveness of l-Ergothioneine in Conjunction with Reactive Intermediates Derived from Model Pharmaceuticals","authors":"Jianyao Wang*,&nbsp;Lu Chen and Kaushik Mitra,&nbsp;","doi":"10.1021/acs.chemrestox.5c0011210.1021/acs.chemrestox.5c00112","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00112https://doi.org/10.1021/acs.chemrestox.5c00112","url":null,"abstract":"<p >During our investigation into a compound’s disposition within our discovery portfolio, we identified an <span>l</span>-ergothioneine to generate reactive intermediates. These drugs included acetaminophen, diclofenac, carbamazepine, clozapine, nefazodone, raloxifene, tamoxifen, ticlopidine, troglitazone, and ethacrynic acid. The drugs were incubated with human liver microsomes supplemented with NADPH and ET, followed by analysis with liquid chromatography–mass spectrometry (LC-MS). This process led to the detection of ET conjugates in six of the ten compounds, which exhibited structural differences: for instance, acetaminophen, raloxifene, and troglitazone presented with +ET-2H, while diclofenac, nefazodone, troglitazone, and tamoxifen showed +O + ET-2H. Additionally, nefazodone yielded +ET + O-HCl. The paper discusses structure–activity relationships (SAR) and underlying mechanisms. The proposed structures indicate that ET effectively incorporates reactive intermediates featuring highly conjugated moieties, such as quinones and quinone-imines, yet is less effective with epoxides, α-β-unsaturated ketones, and nitrenium ions. To further investigate ET’s detoxification capabilities, we analyzed metabolic products from acetaminophen, diclofenac, nefazodone, and raloxifene using rat, monkey, and human hepatocytes without GSH and ET supplementation. Interestingly, we detected conjugates of ET and GSH corresponding to +ET/GSH-2H and +O + ET/GSH-2H. Notably, our findings suggest that, in addition to scavenging reactive oxygen species, ET can also shield cells from reactive xenobiotic intermediates, similar to GSH. This research presents the first evidence of ET’s role as a trapping agent for reactive drug intermediates.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"1113–1121 1113–1121"},"PeriodicalIF":3.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290329","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":"Per- and Polyfluoroalkyl Substances Suppress Macrophage Alternative Activation to Disrupt Hepatic Lipid Metabolism","authors":"Lijuan You,&nbsp;Xiaohong Wang,&nbsp;Yuan Zhi,&nbsp;Huiling Wang,&nbsp;Zhisen Zhuang,&nbsp;Jing Yang,&nbsp;Qiannan Zhang,&nbsp;Hailin Shang,&nbsp;Yongning Li,&nbsp;Yi Wan,&nbsp;Xudong Jia and Hui Yang*,&nbsp;","doi":"10.1021/acs.chemrestox.5c0006610.1021/acs.chemrestox.5c00066","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00066https://doi.org/10.1021/acs.chemrestox.5c00066","url":null,"abstract":"<p >Per- and polyfluoroalkyl substances (PFAS) are pervasive environmental pollutants with diverse toxic effects (e.g., hepatotoxicity and metabolism disorder). Macrophages played a key role in metabolic response; however, the effect of macrophage on PFAS-induced toxicity and the underlying mechanisms remain poorly understood. In this study, we constructed a high-content cell model by utilizing the activation and differentiation of human THP-1 monocytes into alternative activation of macrophages, enabling rapid quantitative screening of numerous PFAS. We applied the cell model to screen 10 PFASs and identified that PFOA and PFUnDA significantly suppressed alternative activation of macrophages by disrupting the PPAR signaling pathway. Oral exposure to PFOA and PFUnDA in WT mice also significantly impaired alternative activation of macrophages in the liver and induced hepatocyte hypertrophy, liver dysfunction, and systemic lipid metabolism disorders. Moreover, macrophage-specific knockout of PPARγ exacerbated PFOA and PFUnDA-induced suppression of macrophage alternative activation and subsequent hepatotoxicity. Activation balance between PPARα and PPARγ may be a critical factor by PFOA and PFUnDA to affect the alternative activation of macrophage. These findings highlight the immunometabolism regulatory role of macrophage activation in PFAS-induced hepatotoxicity in humans.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"1091–1102 1091–1102"},"PeriodicalIF":3.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290278","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 the Amino Reactivity-Based Identification of Respiratory Sensitizers","authors":"Martin Simoneit,&nbsp;Helene Langer,&nbsp;Nadin Ulrich and Alexander Böhme*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0054510.1021/acs.chemrestox.4c00545","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00545https://doi.org/10.1021/acs.chemrestox.4c00545","url":null,"abstract":"<p >The sensitization of the respiratory tract may lead to various pulmonary diseases such as asthma. It can be triggered by the chemical reaction of organic electrophiles with nucleophiles of lung proteins with amino groups being of particular interest in this case. For assessing the dermal sensitization potential of chemicals, the direct peptide reactivity assay (DPRA) has become an OECD-accepted nonanimal test system. However, issues with the identification of known respiratory sensitizers such as isocyanates and anhydrides based on their amino reactivity in the DPRA have been reported. Hence, in this study the chemoassay employing glycine-<i>para</i>-nitroanilide (Gly-pNA) as model nucleophile is applied to eight iso(thio)cyanates, seven anhydrides, four dinitrobenzenes, one triazine, five acrylates, glutaraldehyde, and chloramine T to quantify their amino reactivity in terms of the second order rate constant <i>k</i>_Gly and the DPRA-like 24 h percent depletion <i>D</i>_Gly. A comparison of <i>D</i>_Gly with respective DPRA amino reactivity data (<i>D</i>_DPRA) showed that in particular iso(thio)cyanates and anhydrides are substantially more reactive toward Gly-pNA. This can be rationalized by the unintentional and so far not considered reaction of the test compounds with the ammonium acetate buffer used for DPRA testing. A detailed analysis of this reaction includes half-lives and analytically determined adduct patterns and indicates that it can hamper the envisaged depletion of the DPRA amino nucleophile. Finally, the obtained log <i>k</i>_Gly values range from −3.73 to ≥ 4.52 and allow for an improved identification of respiratory sensitizers. Hence, the Gly-pNA chemoassay may serve as a nonanimal screening method as one part of a mechanism-informed integrated testing and assessment strategy for respiratory sensitizers.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"1046–1060 1046–1060"},"PeriodicalIF":3.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00545","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290296","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":"Toward Metabolic Similarity in Read-Across: A Case Study Using Graph Convolutional Networks to Predict Genotoxicity Outcomes from Simulated Metabolic Networks","authors":"Brett Hagan,&nbsp;Louis Groff,&nbsp;Grace Patlewicz and Imran Shah*,&nbsp;","doi":"10.1021/acs.chemrestox.5c0012010.1021/acs.chemrestox.5c00120","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00120https://doi.org/10.1021/acs.chemrestox.5c00120","url":null,"abstract":"<p >Metabolic similarity is a key consideration in evaluating candidate source analogues for read-across (RAx), but approaches to systematically characterize metabolism for read-across prediction are still evolving. Metabolic similarity is multifaceted, considering the similarity of the metabolic tree, the metabolites simulated, and the transformation pathways. The structure of metabolic trees lends itself naturally to graph representations, for which several methods, including graph convolutional networks (GCNs), can be applied to quantify the pairwise similarity between the target and source analogue(s) within an analogue or category approach. In this study, we compared metabolic graph representations of metabolites with structural similarities in predicting genotoxicity outcomes using a data set comprising 5403 chemicals. Xenobiotic metabolism pathways were predicted using the rat liver models within the commercial expert system, TIssue MEtabolism Simulator (TIMES), and the phase I and II xenobiotic metabolism modules within the freely available system BioTransformer. Metabolic pathways were converted to graphs and used to train GCNs, generating embeddings for each chemical. The classification performance of generalized read-across (GenRA), random forest (RF), logistic regression (LR), and multilayer perceptron (MLP) was compared using GCN-derived embeddings versus both Morgan and MACCS chemical fingerprints to identify genotoxic chemicals. GCN embeddings with LR, based on in vivo TIMES metabolism predictions using MACCS fingerprints as node features, achieved the highest area under the curve of the receiver operating characteristic of 0.807, outperforming GenRA and LR with MACCS fingerprints by 14.47% and 5.49%, respectively. Our findings suggest that GCN embeddings of predicted metabolism pathways perform substantially better than structural features of the parent chemicals in predicting genotoxicity outcomes. Such GCN embeddings offer new avenues of systematically encoding end point metabolic information to facilitate analogue identification for read-across.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"1122–1133 1122–1133"},"PeriodicalIF":3.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290261","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":"Catalytic-Dependent Role of DNA Polymerase κ in Nucleotide Excision Repair","authors":"Abbey Rebok,&nbsp;Mariela C. Torres,&nbsp;Julia R. Ambrose and Thomas E. Spratt*,&nbsp;","doi":"10.1021/acs.chemrestox.5c0008510.1021/acs.chemrestox.5c00085","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00085https://doi.org/10.1021/acs.chemrestox.5c00085","url":null,"abstract":"<p >DNA polymerase kappa (pol κ) is an error-prone Y-family polymerase primarily associated with translesion DNA synthesis (TLS), a DNA damage tolerance mechanism that prevents replication fork stalling. Pol κ has been implicated in other DNA repair and tolerance pathways such as nucleotide excision repair (NER). However, the role of error-prone pol κ in the NER pathway remains unclear. We sought to investigate if pol κ had a catalytic role in NER by using the pol κ selective nucleoside analogue, <i>N</i>²-(4-ethynylbenzyl)-2′-deoxyguanosine (EBndG). Here, we identified robust, cell cycle-independent catalytic activity of pol κ in cells not treated with DNA-damaging agents. We identified approximately 40% of pol κ catalytic activity was reduced with loss of either XPC or XPA, but not CSB, indicating pol κ has a role in global genome-NER. We monitored pol κ catalytic activity after treatment with benzo(<i>a</i>)pyrene diol epoxide and UVB radiation, and we observed that pol κ catalytic activity increased in an NER-dependent manner. Our study highlights that pol κ is consistently active in cells and possesses a key catalytic role in NER.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"1103–1112 1103–1112"},"PeriodicalIF":3.7,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290258","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":"Short-Term and Long-Term Effects of Electronic Cigarettes on Mouse Lungs Following Nose-Only Exposures","authors":"Indu Sinha,&nbsp;Zachary Bitzer,&nbsp;Stephanie Barnett,&nbsp;Lisa Reinhart,&nbsp;Todd M. Umstead,&nbsp;Zissis C. Chroneos,&nbsp;Matthew Lanza,&nbsp;Dongxiao Sun,&nbsp;Junjia Zhu,&nbsp;John P. Richie Jr. and Raghu Sinha*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0052510.1021/acs.chemrestox.4c00525","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00525https://doi.org/10.1021/acs.chemrestox.4c00525","url":null,"abstract":"<p >Health effects of electronic cigarettes (ECs) remain unknown, despite their popularity. We have determined that ECs produce highly reactive free radicals that could potentially cause damage in exposed tissues, mainly lungs. Goal for this study was to investigate the short- and long-term effects of ECs in mouse lungs. We focused on evaluating lung functions, oxidative stress related markers, and lung injury following nose-only exposures in male and female mice after 4- and 12-week periods. The EC exposure was modeled <i>in vivo</i> using nose-only exposures to C57BL/6 mice. For all studies, E-liquid (60:40; PG:VG) aerosols were compared to sham (compressed air) and to very low non-nicotine cigarette smoke (CS) controls in both sexes. Oxidative stress biomarkers (GSH, 8-Isoprostane, REDD1, and pGSK3β) and their selected downstream (RPS6) as well as upstream (AKT) target proteins in addition to pH2AX were measured by Western blot analysis. Lung function in mice was assessed by flexiVent and the injury scores were calculated following lung histology. Changes in cytology were also observed in cytospins from bronchoalveolar lavage (BALF). The lung injury (LI) score following 12-week exposures was significantly higher with EC and CS in female mice. Higher cell counts in BALF were mainly observed in CS exposed males and females at 4 and 12 weeks. 8-Isoprostane levels were significantly higher in EC and CS exposed males at 12 weeks. pGSK3β/GSK3β was low in males and higher in female mice at 4 weeks, and this difference was more pronounced at 12 weeks in CS exposed mice. Some mice exposed to EC and CS also showed DNA damage, as measured by pH2AX/H2AX expression. Based on the LI score, ECs were placed in between compressed air and CS. Our results showed the differentially expressed inflammation and oxidative stress/damage-related pathways from <i>in vivo</i> exposures to EC aerosols vs CS that could be an effective strategy for identifying EC relevant biomarkers of exposure and potential harm.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"1019–1036 1019–1036"},"PeriodicalIF":3.7,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290308","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":"A Comparative Assessment of the FDA List of 93 HPHCs in Aerosol Generated by Tobacco Heating System 2.2 versus 3R4F Reference Cigarette Smoke","authors":"Serge Maeder*,&nbsp; and ,&nbsp;Cyril Jeannet,&nbsp;","doi":"10.1021/acs.chemrestox.4c0054410.1021/acs.chemrestox.4c00544","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00544https://doi.org/10.1021/acs.chemrestox.4c00544","url":null,"abstract":"<p >The US Food and Drug Administration (FDA) published an inventory of harmful and potentially harmful constituents (HPHCs), which lists 93 chemicals (FDA 93) linked to the serious health effects of tobacco use. Some of the chemical compounds in the FDA 93 list were not characterized in earlier studies due to methodological limitations at that time. Leveraging new analytical methods, the current study quantitatively assessed an expanded list of 108 HPHCs in the tobacco heating system (THS) aerosol compared with smoke from the 3R4F reference cigarette. Analyses were conducted by Labstat International ULC, an independent laboratory accredited by the Standard Council of Canada to ISO/IEC 17025:2017, on two different THS HeatStick variants (regular and menthol) together with the THS version 2.2 and the 3R4F reference cigarette smoke using a Health Canada Intense smoking regime. Of the 108 HPHCs assessed in this study, 105 were either below the limits of quantification or showed substantial reductions in THS aerosol relative to cigarette smoke (all &gt;45%), with no increased HPHC levels in the THS aerosol relative to cigarette smoke. Aside from nicotine, anabasine, and polonium-210 (210Po) which was near the limits of detection), the average reduction in the levels of HPHCs in the aerosol of THS compared with 3R4F reference cigarette smoke was &gt;91.6% (Regular) and &gt;92.2% (Menthol). The results for the two THS tobacco stick variants were remarkably similar. These results confirm that the elimination of combustion in THS results in a substantial reduction of HPHCs relative to cigarette smoke.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 6","pages":"1037–1045 1037–1045"},"PeriodicalIF":3.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00544","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290269","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}