Regulatory Toxicology and Pharmacology最新文献_第2页

Nitrosamine drug substance-related impurities cause DNA methylation adducts in vitro and in primary hepatocytes upon Cytochrome P450-dependend metabolic activation 亚硝胺类药物相关杂质在体外和原代肝细胞中通过细胞色素p450依赖的代谢激活引起DNA甲基化加合物。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-05-01 Epub Date: 2026-01-20 DOI: 10.1016/j.yrtph.2026.106036

Matthias Vogel , Max J. Carlsson , Claudia Skowron , Christina Felske , Rhys Whomsley , Jörg Fahrer

{"title":"Nitrosamine drug substance-related impurities cause DNA methylation adducts in vitro and in primary hepatocytes upon Cytochrome P450-dependend metabolic activation","authors":"Matthias Vogel , Max J. Carlsson , Claudia Skowron , Christina Felske , Rhys Whomsley , Jörg Fahrer","doi":"10.1016/j.yrtph.2026.106036","DOIUrl":"10.1016/j.yrtph.2026.106036","url":null,"abstract":"<div><div><em>N</em>-nitrosamines are DNA alkylating agents found in food, cosmetics, tobacco products and, more recently, drugs. Following Cytochrome P450 (CYP)-mediated metabolic activation, these compounds cause DNA damage and mutations. Unlike well-characterized compounds like <em>N</em>-nitrosodimethylamine (NDMA), data on the genotoxicity of nitrosamine drug substance-related impurities (NDSRIs) remain limited. Given their regulatory relevance, this study assessed the genotoxic potential of three NDSRIs —<em>N</em>-nitrosobetahistine (NBH), <em>N</em>-nitrosofluoxetine (NFluo), and <em>N</em>-nitrosonortriptyline (NNT) —compared to NDMA. The NDSRIs demonstrated distinct DNA methylating potential, confirmed by elevated levels of <em>N</em>7-methyl-deoxyguanosine (<em>N7</em>-MedG) and <em>O</em><sup>6</sup>-methyl-deoxyguanosine (<em>O</em><sup>6</sup>-MedG) in a DNA alkylation assay with metabolic activation. Recombinant CYP isoforms contributed differentially to the bioactivation of each NDSRI, highlighting enzyme-specific pathways of toxification. Subsequently, we demonstrated that all NDSRIs cause DNA methylation adducts (<em>N</em>7-MedG > <em>O</em><sup>6</sup>-MedG) in primary rat hepatocytes, with generally higher levels than those caused by NDMA. Consistently, the NDSRIs generated more DNA strand breaks than NDMA, which followed the DNA adduct kinetics. Furthermore, all NDSRIs showed cytotoxicity after 24 h, whereas no cytotoxic effect was observed for NDMA. Taken together, our study provided evidence that the three NDSRIs are genotoxic in primary rat hepatocytes, which warrants further investigation with regard to their mutagenic potential.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106036"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evidence integration in TSCA risk evaluation: The value of tiered risk assessment – A case study using HHCB TSCA风险评估中的证据整合：分层风险评估的价值——以HHCB为例

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-05-01 Epub Date: 2026-01-27 DOI: 10.1016/j.yrtph.2026.106039

Paul C. DeLeo , Darci Ferrer , Aurelia Lapczynski , Stella Wang

{"title":"Evidence integration in TSCA risk evaluation: The value of tiered risk assessment – A case study using HHCB","authors":"Paul C. DeLeo , Darci Ferrer , Aurelia Lapczynski , Stella Wang","doi":"10.1016/j.yrtph.2026.106039","DOIUrl":"10.1016/j.yrtph.2026.106039","url":null,"abstract":"<div><div>As part of the evidence integration step of its proposed systematic review protocol supporting chemical risk evaluations under the Toxic Substances Control Act (TSCA), the United States Environmental Protection Agency (EPA) describes a data hierarchy for various sources within the risk assessment. EPA identifies “less preferred” exposure data sources (e.g., modeled data) and “more preferred” sources (e.g., monitoring data). This approach to risk assessment data contrasts with substantial EPA guidance regarding tiered approaches for risk-based decision-making. We examined environmental exposure data for the fragrance material 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[g]-2-benzopyran (HHCB), a TSCA high-priority substance, using EPA's deterministic model the Exposure and Fate Assessment Screening Tool (E-FAST), a publicly available probabilistic environmental exposure model (iSTREEM), and data from the United States Geological Survey's National Water Information System. Exposure estimates for HHCB decreased progressively from deterministic modeling to probabilistic modeling to monitoring data. However, this case study illustrates that higher-tier analyses may reduce uncertainty but may not improve the risk conclusions. Over the course of an iterative risk characterization, the need for higher tier data may be demonstrated. However, in other cases, it may be more efficient and effective to draw risk conclusions at a lower tier of assessment and forego further analysis of existing data.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106039"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Towards EU regulatory hazard assessment of metabolic endocrine disrupters: Integrating new biomarkers into OECD test guidelines 对代谢内分泌干扰物的欧盟监管危害评估：将新的生物标志物整合到经合组织测试指南中。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-05-01 Epub Date: 2026-01-28 DOI: 10.1016/j.yrtph.2026.106041

Claire Beausoleil , Christophe Rousselle , Eren Ozcagli , Miriam N. Jacobs

{"title":"Towards EU regulatory hazard assessment of metabolic endocrine disrupters: Integrating new biomarkers into OECD test guidelines","authors":"Claire Beausoleil , Christophe Rousselle , Eren Ozcagli , Miriam N. Jacobs","doi":"10.1016/j.yrtph.2026.106041","DOIUrl":"10.1016/j.yrtph.2026.106041","url":null,"abstract":"<div><div>Exposure to ‘metabolic disrupting chemicals’ (MDCs) are increasingly implicated in obesity, diabetes and/or fatty liver disease; indeed, these metabolic changes may play a role in the global metabolic disorders' epidemic. To better assess and manage the health risks of MDCs, improved hazard identification is needed. This review describes how current <em>in vivo</em> OECD Test Guidelines (TGs) can better capture MDC effects. The biological and clinical evidence to support the inclusion of promising human relevant biomarkers, blood parameters, endpoints and relevant tissues for MDCs for potential inclusion in OECD TGs is documented. Current clinical chemistry routine requirements could be utilised further, and the additional assessment of relevant hormones such as a decrease in adiponectin, increase in resistin and leptin, which impact satiety, could be additionally included. Additionally, assessment of fatty tissue distribution in alert animals and insulin resistance, is recommended, and histological parameters in relation to the different types of adipose tissue. How specific biomarkers and endpoints could be incorporated into OECD mammalian <em>in vivo</em> assays, and how they can be included in the EU strategy for Endocrine Disrupting Chemicals identification and the forthcoming update to the OECD Guidance Document on the Testing and Assessment of Endocrine Disruption chemicals, are discussed.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106041"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Smoke Flavoring-a case study demonstrating the value of using Benefit-risk analysis for foods (BRAFO) to provide transparency for risk management decisions 烟熏调味——一个案例研究，展示了使用食品利益风险分析（BRAFO）为风险管理决策提供透明度的价值。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-05-01 Epub Date: 2026-01-21 DOI: 10.1016/j.yrtph.2026.106033

Candace Doepker , Allison Franzen , Gregory Brorby , Lauren Brown , Neepa Choksi , Alexander East , Daniele Wikoff

{"title":"Smoke Flavoring-a case study demonstrating the value of using Benefit-risk analysis for foods (BRAFO) to provide transparency for risk management decisions","authors":"Candace Doepker , Allison Franzen , Gregory Brorby , Lauren Brown , Neepa Choksi , Alexander East , Daniele Wikoff","doi":"10.1016/j.yrtph.2026.106033","DOIUrl":"10.1016/j.yrtph.2026.106033","url":null,"abstract":"<div><div>Efforts to renew existing authorizations of smoke flavoring primary products (SFPPs) were recently finalized in the European Union. Herein, a Benefit Risk Assessment for Foods (BRAFO) was conducted for smoke flavorings using three specific SFPPs. Four metrics were evaluated between a reference scenario (legislation allowing both conventional smoking of foods and SFPPs) and an alternative scenario (SFPPs in meat, fish, and cheese are scheduled to be removed from the market after July 1, 2029, and only conventional smoking of foods is allowed): 1) whole mixture risk, 2) risk from polycyclic aromatic hydrocarbons (PAHs), 3) risk from constituents other than PAHs, and 4) environmental considerations. Systematic literature searches were used to identify information pertinent to each metric and scenario; direct testing data for the SFPPs was also used. All metrics were assessed qualitatively; quantitative assessment was also conducted when sufficient data were available. For each metric, the reference scenario prevailed, presenting the benefit of less risk than the alternative scenario. Key considerations involved the robust characterization of the SFPPs and direct testing data to inform safety, which are less controlled in conventional smoking of foods. The results of this assessment demonstrate the importance of risk-benefit considerations and should be helpful to policy makers globally.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106033"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Talc fits the framework of poorly soluble low-toxicity particles - implications for hazard classification 滑石符合难溶性低毒性颗粒的框架-危害分类的含义

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-05-01 Epub Date: 2026-02-11 DOI: 10.1016/j.yrtph.2026.106060

Kevin E. Driscoll , Jeffrey I. Everitt , Paul J.A. Borm

{"title":"Talc fits the framework of poorly soluble low-toxicity particles - implications for hazard classification","authors":"Kevin E. Driscoll , Jeffrey I. Everitt , Paul J.A. Borm","doi":"10.1016/j.yrtph.2026.106060","DOIUrl":"10.1016/j.yrtph.2026.106060","url":null,"abstract":"<div><div>An extensive toxicology database demonstrates talc exhibits the defining characteristics of poorly soluble, low-toxicity particles (PSLTs), including slow dissolution in biological fluids; macrophage-mediated clearance as the key determinant of lung residence time; significant inflammatory and proliferative responses only at lung burdens that overload normal particle clearance capacity; and, lung tumors in rats—but not in mice or hamsters—under conditions of excessive overload. This profile mirrors that documented for other PSLTs, such as titanium dioxide, carbon black, and diesel soot. Consistent with other PSLTs, talc has not been associated with increased lung cancer risk in humans, even after prolonged occupational exposure. Collectively, these observations demonstrate adverse rat lung responses to talc and other PSLTs are a consequence of lung overload rather than intrinsic toxicity, and the tumor response is unique to rats. Accordingly, hazard classification and risk assessment for PSLTs should explicitly consider the overload-dependent nature of responses. In the absence of evidence for intrinsic carcinogenic activity, lung tumors occurring only in rats and only under conditions of lung overload should not be interpreted as evidence of a human cancer hazard. Despite the well-established understanding of overload-driven PSLT responses in rats, recent IARC and ECHA/RAC evaluations interpreted rat lung tumors in the NTP study as evidence of inherent carcinogenicity. These assessments did not rigorously account for the PSLT properties of talc, the extensive evidence on lung particle overload, or that tumors occurred only at lung burdens greatly exceeding normal clearance capacity. Consequently, interpretations of the NTP findings conflict with the current state of the science.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106060"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146191112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ames concordance with the in vivo transgenic rodent (TGR) gene mutation assay for NDSRIs and relative in vivo TGR potency with nitrosamines with robust dose-response carcinogenicity data NDSRIs的体内转基因啮齿动物（TGR）基因突变测定与Ames的一致性，以及与亚硝胺相关的体内TGR效价具有可靠的剂量-反应致癌性数据。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-05-01 Epub Date: 2026-01-30 DOI: 10.1016/j.yrtph.2026.106051

Robert A. Jolly , Alejandra Trejo-Martin , Joel P. Bercu , Mark W. Powley , Rachael E. Tennant , David J. Ponting , Raphael Nudelman , Zhanna Sobol , Andreas Czich , George E. Johnson , Yi Yang , Tetyana Kobets , Paul A. White , Sheroy Minocherhomji , Anthony M. Lynch , Andreas Zeller , Gregory R. Ott , Patricia A. Escobar , Cheryl Hobbs , Maik Schuler , Raechel Puglisi

{"title":"Ames concordance with the in vivo transgenic rodent (TGR) gene mutation assay for NDSRIs and relative in vivo TGR potency with nitrosamines with robust dose-response carcinogenicity data","authors":"Robert A. Jolly , Alejandra Trejo-Martin , Joel P. Bercu , Mark W. Powley , Rachael E. Tennant , David J. Ponting , Raphael Nudelman , Zhanna Sobol , Andreas Czich , George E. Johnson , Yi Yang , Tetyana Kobets , Paul A. White , Sheroy Minocherhomji , Anthony M. Lynch , Andreas Zeller , Gregory R. Ott , Patricia A. Escobar , Cheryl Hobbs , Maik Schuler , Raechel Puglisi","doi":"10.1016/j.yrtph.2026.106051","DOIUrl":"10.1016/j.yrtph.2026.106051","url":null,"abstract":"<div><div>Nitrosamines (NAs) are a diverse class of mutagenic impurities encompassing both small molecules and structurally complex drug-related NAs, referred to as nitrosamine drug substance-related impurities (NDSRIs). NAs display a broad range of carcinogenic potential, from high carcinogenic potency to being weak or even non-carcinogenic. <em>In vitro</em> Ames tests, conducted with both rat and hamster liver-induced S9, and <em>in vivo</em> transgenic rodent (TGR) mutation assays have been used by pharmaceutical sponsors for hazard identification of NDSRIs. A comparative analysis of Ames tests and TGR results for 33 NDSRIs was performed and revealed an accuracy of 79 % between the overall mutagenic calls in the two assays. For NDSRIs with positive TGR results, mutagenic potency estimates were calculated and compared to NAs with robust carcinogenicity and TGR dose-response data. Results from these NAs demonstrated a strong correlation between carcinogenic potency (TD<sub>50</sub>) and TGR mutagenic potency (BMDL<sub>50</sub>) (r<sup>2</sup> = 0.95), which supports the use of TGR data for both hazard identification and acceptable intake (AI) determination. By integrating quantitative risk assessment tools with TGR assays, this work contributes to a more robust framework for evaluating NA-associated risks.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106051"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Do co-formulants influence plant protection product genotoxicity? 共制剂是否影响植保产品的遗传毒性？

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-05-01 Epub Date: 2026-02-09 DOI: 10.1016/j.yrtph.2026.106059

Alkiviadis Stagkos-Georgiadis , Vishal Raolji , Jeannette Koenig , Philip Marx-Stoelting , Sabine Martin , Tewes Tralau , Carsten Kneuer , Alfonsina Paola D'Ambrosio Melendrez , Christian Tobias Willenbockel , Veronika Städele , Tanja Schwerdtle , Denise Bloch

{"title":"Do co-formulants influence plant protection product genotoxicity?","authors":"Alkiviadis Stagkos-Georgiadis , Vishal Raolji , Jeannette Koenig , Philip Marx-Stoelting , Sabine Martin , Tewes Tralau , Carsten Kneuer , Alfonsina Paola D'Ambrosio Melendrez , Christian Tobias Willenbockel , Veronika Städele , Tanja Schwerdtle , Denise Bloch","doi":"10.1016/j.yrtph.2026.106059","DOIUrl":"10.1016/j.yrtph.2026.106059","url":null,"abstract":"<div><div>Plant protection products (PPPs) contain active substances (AS) providing pesticidal activity and co-formulants supporting efficacy. AS undergo extensive safety assessment, including genotoxicity testing, while PPPs are assessed only for acute and local toxicity. Genotoxicity may contribute to long-term effects like carcinogenesis, and as operators are exposed to concentrated PPPs and spray dilutions, co-formulant toxicity and interactions require attention. An <em>in silico</em> analysis was conducted to identify potentially genotoxic co-formulants and prioritise PPPs for <em>in vitro</em> testing. Four prioritised co-formulants exceeded 1 % concentration in eight PPPs, but existing data ruled out further investigation. AS with known <em>in vitro</em> genotoxic potential were assessed for toxicokinetic interaction with co-formulants. The genotoxic potential of PPPs containing metiram, a dithiocarbamate fungicide, and pendimethalin, a dinitroaniline herbicide, was assessed in V79 cells using <em>in vitro</em> micronucleus test. No difference was observed between metiram and its PPP, whereas a 2-fold increase in micronuclei formation occurred in formulated PPP compared to pendimethalin alone at highest tested concentration. These findings indicate that co-formulants, although unlikely to be genotoxic on their own, may influence the genotoxic potential of pendimethalin in the tested PPP. Therefore, AS showing genotoxic potential <em>in vitro</em> should be considered for testing in respective formulated PPPs.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106059"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development and evaluation of a novel consensus in silico model within the OECD GL497 defined approach for skin sensitization prediction 在OECD GL497定义的皮肤致敏预测方法中开发和评估一种新的共识硅模型。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-03-01 Epub Date: 2026-01-05 DOI: 10.1016/j.yrtph.2026.106028

Mika Imamura , Ryoichi Murakami , Masakazu Tateshita , Yasushi Hikida

{"title":"Development and evaluation of a novel consensus in silico model within the OECD GL497 defined approach for skin sensitization prediction","authors":"Mika Imamura , Ryoichi Murakami , Masakazu Tateshita , Yasushi Hikida","doi":"10.1016/j.yrtph.2026.106028","DOIUrl":"10.1016/j.yrtph.2026.106028","url":null,"abstract":"<div><div>Skin sensitization is a key endpoint in chemical safety assessment, involving multiple key events (KEs) in the adverse outcome pathway. The integrated testing strategy defined approach (ITS-DA) in OECD GL497 combines non-animal methods addressing KE1 and KE3 with an <em>in silico</em> component to predict sensitization. We developed a novel consensus <em>in silico</em> model integrating a rule-based system with metabolic simulation and two statistical models trained on local lymph node assay (LLNA) and guinea pig maximization test (GPMT) data.</div><div>When applied as the <em>in silico</em> element of the ITS-DA, the model achieved balanced accuracies of 77 % for LLNA and 70 % for human data, surpassing existing <em>in silico</em> approaches. Furthermore, we developed a rule- and statistics-based KE1 replacement model (RSRKE1) that estimates protein-binding potential without <em>in chemico</em> KE1 assays. Combining RSRKE1 with the human Cell Line Activation Test (h-CLAT, KE3) and the consensus model yielded sensitivities of ∼80 % and potency classification accuracies of ∼70 % for LLNA, with similar performance for human data.</div><div>These results demonstrate that the consensus model and RSRKE1 can maintain predictive performance comparable to established ITS-DA workflows, while eliminating the need for certain <em>in vitro</em> assays. This approach supports regulatory acceptance of non-animal testing strategies for skin sensitization assessment.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106028"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Risk assessment and pharmacokinetic modeling of incidental ingestion of ethanol from mouthwash 漱口水中偶然摄入乙醇的风险评估和药代动力学模型。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-03-01 Epub Date: 2025-12-23 DOI: 10.1016/j.yrtph.2025.106018

Daniel G. Kougias , Michael Kovochich , Sadaff Ejaz , Abdulkarim Najjar , Smruti Nair , Boris Michelin , Christopher Chu , Michael D. Southall

{"title":"Risk assessment and pharmacokinetic modeling of incidental ingestion of ethanol from mouthwash","authors":"Daniel G. Kougias , Michael Kovochich , Sadaff Ejaz , Abdulkarim Najjar , Smruti Nair , Boris Michelin , Christopher Chu , Michael D. Southall","doi":"10.1016/j.yrtph.2025.106018","DOIUrl":"10.1016/j.yrtph.2025.106018","url":null,"abstract":"<div><div>Mouthwashes containing ethanol for antiseptic properties have a long history of use and well-established oral hygiene benefits by significantly enhancing the control of dental biofilm and reducing gingival inflammation. Despite the substantial health benefits from ethanol-containing mouthwashes, there has been ongoing scrutiny by regulatory and health authorities of products containing ethanol resulting from the classification of consumption of alcohol-containing beverages as a potential carcinogen. Unlike alcohol-containing beverages, mouthwash products are not intended to be ingested, and the potential ethanol exposure is substantially lower for mouthwash products. Therefore, we conducted a risk assessment that benchmarked estimated and modeled incidental exposure to ethanol in mouthwash products against endogenous blood levels, dietary exposure, and health-based guidance values for ethanol. All mouthwash-use scenarios, including average, 90th-percentile, and maximum-label use, resulted in relatively low estimated ethanol exposures that were below various reference and health-based guidance values (HBGVs), including the HBGV of 1 g/day for ethanol (16.7 mg/kg/day in a 60-kg human), a conservative value that is considered to be protective against all chronic health endpoints, including cancer. The findings suggest that ethanol from mouthwash does not significantly contribute to systemic levels of ethanol, falls within dietary intake levels, and remains below HBGVs. Taken together, this assessment concludes that incidental oral exposure of ethanol-containing mouthwashes represents a <em>de minimis</em> health risk.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106018"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inter-species variability in 4,4′-methylenedianiline metabolism: insights from human and rat precision-cut liver slices 4,4'-亚甲二苯胺代谢的物种间变异：来自人类和大鼠精确切割肝脏切片的见解。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-03-01 Epub Date: 2026-01-17 DOI: 10.1016/j.yrtph.2026.106034

Marieke A.J. Hof , Jeffrey Sewdihal , Stepan Stepanovic , Jos H. Hermans , Péter Horvatovich , Peter Olinga , Frank Klont

{"title":"Inter-species variability in 4,4′-methylenedianiline metabolism: insights from human and rat precision-cut liver slices","authors":"Marieke A.J. Hof , Jeffrey Sewdihal , Stepan Stepanovic , Jos H. Hermans , Péter Horvatovich , Peter Olinga , Frank Klont","doi":"10.1016/j.yrtph.2026.106034","DOIUrl":"10.1016/j.yrtph.2026.106034","url":null,"abstract":"<div><div>Occupational exposure to 4,4′-methylenedianiline (MDA), a precursor in polyurethane foam production, has been linked to liver disease and cancer. Most evidence, however, comes from underpowered epidemiological studies, while empirical data are mainly from animal models, which point toward liver metabolism generating reactive metabolites. We thus used precision-cut liver slices (PCLS) from human and rat donors which we exposed to MDA at 10 and 100 μM for 24 h, and supernatants were analyzed by liquid chromatography-‘SWATH’ mass spectrometry. The major metabolite detected in hPCLS and rPCLS was MDA's known N-acetyl derivative, comprising approximately 80–90 % of metabolites at 10 μM and 50–60 % at 100 μM. Other metabolites were phase II conjugates, including putative N-formylation and urea-glutamine and urea-ethanolamine adducts. The latter accounted for ∼10 % of metabolites at 10 μM, increasing to 50 % at 100 μM in rPCLS but only reaching ∼25 % in hPCLS. Cell viability remained at 100 % across all human conditions and in rPCLS at 10 μM, but it dropped below 5 % at 100 μM. In conclusion, this study confirmed MDA's well-known N-acetyl metabolite across both species, while also unveiling rather unusual, previously unreported conjugates. Additionally, distinct interspecies differences were observed, underscoring the need for human-based studies.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106034"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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