Regulatory Toxicology and Pharmacology最新文献_第8页

Impurity qualification requirements for drug-linkers related impurities used to generate antibody-drug conjugates 用于产生抗体-药物偶联物的药物连接物相关杂质的杂质鉴定要求。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-01-01 Epub Date: 2025-10-23 DOI: 10.1016/j.yrtph.2025.105974

Osama Chahrour , Paul D. Cornwell , Penny Leavitt , Elizabeth A. Martin , Christina de Zafra , Susanne Glowienke , Angela White , Andrew Teasdale , Bruce Trela , Mayur S. Mitra , Wolfgang Muster , Jim Harvey

{"title":"Impurity qualification requirements for drug-linkers related impurities used to generate antibody-drug conjugates","authors":"Osama Chahrour , Paul D. Cornwell , Penny Leavitt , Elizabeth A. Martin , Christina de Zafra , Susanne Glowienke , Angela White , Andrew Teasdale , Bruce Trela , Mayur S. Mitra , Wolfgang Muster , Jim Harvey","doi":"10.1016/j.yrtph.2025.105974","DOIUrl":"10.1016/j.yrtph.2025.105974","url":null,"abstract":"<div><div>This position paper presents a science-based, holistic assessment of the toxicological risks posed by organic impurities in drug-linkers (D-L) used as intermediates in the production of Antibody-Drug Conjugates (ADCs) for oncology indications. The analysis outlined in this manuscript demonstrates that organic impurities present at levels at or below 1.0 % w/w in D-L intermediates are unlikely to result in adverse toxicological effects upon administration of the final ADC drug product. Due to the extremely low exposure (molar and weight) associated with 1.0 % w/w impurity level in the D-Ls, the authors propose to maintain the ICH Q3A criteria of not more than 1 mg/day limit however increase the qualification limit criteria for D-L related impurities from 0.15 % to 1.0 % w/w. Additionally, a methodology is introduced to assess the level of concern for non-conjugatable organic impurities, utilizing process-specific and ADC-specific factors to justify specifications for these impurities in D-L intermediates. Based on the minimal risk associated with D-L impurities at or below the discussed levels, the paper proposes a workflow for quality risk management of such impurities in D-Ls.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105974"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370444","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

Quantitative next generation risk assessment for skin sensitization - application of regression models based on in vitro data to estimate point of departure 定量下一代皮肤致敏风险评估-应用基于体外数据的回归模型来估计起点。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-01-01 Epub Date: 2025-10-14 DOI: 10.1016/j.yrtph.2025.105964

Isabelle Lee , Mihwa Na , Maura Lavelle , Isabella Schember , Marissa A. Guttenberg , G Frank Gerberick , Andreas Natsch , Cindy Ryan , Anne Marie Api

{"title":"Quantitative next generation risk assessment for skin sensitization - application of regression models based on in vitro data to estimate point of departure","authors":"Isabelle Lee , Mihwa Na , Maura Lavelle , Isabella Schember , Marissa A. Guttenberg , G Frank Gerberick , Andreas Natsch , Cindy Ryan , Anne Marie Api","doi":"10.1016/j.yrtph.2025.105964","DOIUrl":"10.1016/j.yrtph.2025.105964","url":null,"abstract":"<div><div>Quantitative risk assessment (QRA) for dermal sensitization is essential for determining safe concentrations of skin sensitizers in consumer products. The fragrance industry developed the QRA2 approach, which uses the No Expected Sensitization Induction Level (NESIL) as a starting reference dose or point of departure (PoD). Animal alternatives for potency assessment have emerged to calculate quantitative PoDs. One such alternative is <em>in vitro</em>-based regression models.</div><div>Herein, a framework for incorporating regression models into next-generation risk assessment (NGRA) is presented. The framework begins with hazard assessment using <em>in vitro</em> methods (OECD Guideline 497), followed by PoD calculation through regression models, and completed with QRA2. After determining a PoD, uncertainty factors may be considered to derive a new approach methodology NESIL (NAM-NESIL). Case studies are presented with two sensitizers, <em>p</em>-mentha-1,8-dien-7-al (CAS # 2111-75-3) and 3-propylidenephthalide (CAS # 17369-59-4), calculating acceptable exposure levels (AELs) for products like deodorants and bar soaps. Ratios of the AELs to consumer exposure levels (CELs) were then calculated to determine whether the current use is safe. Comparison of QRA based on NAM-NESILs to historically human-derived NESILs supports the reliability of <em>in vitro</em> models. This approach offers a promising alternative for PoD derivation, potentially eliminating the dependence on in-vivo data.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105964"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308926","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

Expert panel evaluation of the tumor modes of action for 1,4-dioxane and their implications for human risk assessment 专家小组对1,4-二恶烷的肿瘤作用方式及其对人类风险评估的影响的评估。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-01-01 Epub Date: 2025-09-25 DOI: 10.1016/j.yrtph.2025.105950

C.R. Kirman , J.S. Bus , S. Gupta , J.E. Klaunig , M.E. Meek , S.M. Hays

{"title":"Expert panel evaluation of the tumor modes of action for 1,4-dioxane and their implications for human risk assessment","authors":"C.R. Kirman , J.S. Bus , S. Gupta , J.E. Klaunig , M.E. Meek , S.M. Hays","doi":"10.1016/j.yrtph.2025.105950","DOIUrl":"10.1016/j.yrtph.2025.105950","url":null,"abstract":"<div><div>Mode of action (MOA) plays an important role in key decisions made in risk assessments, including that for low-dose extrapolation. To support MOA-dependent decisions for 1,4-dioxane (1,4-DX), an independent panel of topic experts evaluated the available evidence on the MOA and human relevance of 1,4-DX tumors reported in rodent studies. The panel considered MOA data on liver tumors in rodents, as well as for other tissue sites (nasal cavity, peritoneal mesothelioma). For liver tumors, the panelists found strongest support for an indirect genotoxic MOA involving metabolic saturation of the enzyme that metabolizes 1,4-DX (CYP2E1), followed by induction of CYP2E1, oxidative stress, cytotoxicity, and regenerative proliferation. Metabolic saturation was identified as an early key event. Although available evidence for nasal and peritoneal tumors was limited, similar non-genotoxic MOAs were considered plausible. For all three tumor types, confidence ratings (scale of −5 to +5) from the panel for the best supported MOAs (+2.5 to +3.3) were significantly higher than the confidence rating for a direct genotoxic MOA (−3.8 to −4.5). The conclusions from this independent panel, which included careful consideration of recently published studies, provide support for use of non-linear extrapolation methods in human health risk assessment for 1,4-DX rodent tumors.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105950"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182211","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

Occupational asthma: dust exposure as a contributory factor and implications for classification of respiratory sensitisers 职业性哮喘：粉尘暴露作为一个促成因素和对呼吸道致敏物分类的影响。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-01-01 Epub Date: 2025-10-13 DOI: 10.1016/j.yrtph.2025.105962

Mark A. Pemberton , Ian Kimber

{"title":"Occupational asthma: dust exposure as a contributory factor and implications for classification of respiratory sensitisers","authors":"Mark A. Pemberton , Ian Kimber","doi":"10.1016/j.yrtph.2025.105962","DOIUrl":"10.1016/j.yrtph.2025.105962","url":null,"abstract":"<div><div>Occupational asthma (AO) is an important chronic respiratory disease associated with airway narrowing. Chemicals that cause OA are regulated under the UN GHS endpoint of respiratory sensitisation. Such chemicals are typically identified using evidence suggesting work-related exposure resulting in the <em>ab initio</em> development of asthma, rather than simply aggravating pre-existing asthma (work exacerbated asthma; WEA). There exist predisposing and aggravating factors within and outside the workplace that influence the development and severity of the disease. Inhalation exposure to dusts is one factor and is recognised as directly causing respiratory disease, and also aggravating pre-existing disease, including asthma. Here the contribution of dusts to the development of work-related asthma has been re-examined with reference to published clinical case studies. The data reveal a link between exposure to dusts and OA, suggesting an additional role of dust in this respect may be the presentation of irritant or sensitising agents in a way that promotes the development of OA, even under conditions where exposure to those agents alone does not. We propose that the significance of co-exposure to dusts may be currently under-estimated in health management of OA, clinical identification of chemicals suspected of causing OA, and classification of true respiratory sensitisers.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105962"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145302926","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

Case studies on skin sensitization risk assessment: estimating the PoD using artificial neural network-based models for substances with known and unknown structure 皮肤致敏风险评估的案例研究：使用基于人工神经网络的模型估算已知和未知结构物质的PoD。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-01-01 Epub Date: 2025-10-22 DOI: 10.1016/j.yrtph.2025.105978

Kosuke Imai , Yuri Hatakeyama , Tomomi Atobe, Toshiyuki Ohtake, Shiho Oeda, Morihiko Hirota

{"title":"Case studies on skin sensitization risk assessment: estimating the PoD using artificial neural network-based models for substances with known and unknown structure","authors":"Kosuke Imai , Yuri Hatakeyama , Tomomi Atobe, Toshiyuki Ohtake, Shiho Oeda, Morihiko Hirota","doi":"10.1016/j.yrtph.2025.105978","DOIUrl":"10.1016/j.yrtph.2025.105978","url":null,"abstract":"<div><div>Non-animal methods for skin sensitization assessment have been developed and adopted as OECD test guidelines. However, no single new approach methodology (NAM) can fully replace animal-based methods, leading to the development of defined approaches like OECD GL497. This study advances quantitative risk assessment (QRA) for skin sensitization using Artificial Neural Network (ANN) models to predict LLNA EC3 values. As a case study, six substances were evaluated using ANN models based on the Direct Peptide Reactivity Assay (DPRA) and the Amino acid Derivative Reactivity Assay (ADRA). These substances included four with known structures (Metol, Dibenzyl Ether, Safranal, and Lyral) and two with unknown structures (Verbena Oil and Oakmoss Extract). Most predicted EC3 values were within a 10-fold range of observed values, demonstrating model reliability. Incorporating ADRA molar and gravimetric method data, ANN models successfully predicted EC3 values for both substances with known and unknown structure, showing their applicability to natural complex substances like botanical extracts. A new skin sensitization risk assessment flow incorporating ANN models is proposed, contributing to the 3Rs by providing a reliable, non-animal method for determining Points of Departure (PoD) and advancing Next Generation Risk Assessment (NGRA) for cosmetic ingredients.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105978"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368602","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

The Decision Tree approach as a strategy for the global phase out of animal testing for acute and local toxicity for chemicals: recommendations from an expert workshop 决策树方法作为全球逐步淘汰化学品急性毒性和局部毒性动物试验的战略：专家讲习班的建议。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-01-01 Epub Date: 2025-10-22 DOI: 10.1016/j.yrtph.2025.105969

Catherine Willett , Giorgia Pallocca , Annamaria Carusi , Nathalie Alépée , Patience Browne , Marie Darracq-Ghitalla-Ciock , Fabian A. Grimm , Jay Ingram , Laura Holden , Kamel Mansouri , Hans Raabe , Clive Roper , Katherine Santizo , Barbara G. Schmitt , Li Xiang , Thomas A. Ward , Bryan Zhou

{"title":"The Decision Tree approach as a strategy for the global phase out of animal testing for acute and local toxicity for chemicals: recommendations from an expert workshop","authors":"Catherine Willett , Giorgia Pallocca , Annamaria Carusi , Nathalie Alépée , Patience Browne , Marie Darracq-Ghitalla-Ciock , Fabian A. Grimm , Jay Ingram , Laura Holden , Kamel Mansouri , Hans Raabe , Clive Roper , Katherine Santizo , Barbara G. Schmitt , Li Xiang , Thomas A. Ward , Bryan Zhou","doi":"10.1016/j.yrtph.2025.105969","DOIUrl":"10.1016/j.yrtph.2025.105969","url":null,"abstract":"<div><div>The Animal-Free Safety Assessment (AFSA) Collaboration invited a select group of international experts, representing regulatory bodies, industry, method developers, and academia, to a workshop to develop a regulatory strategy implementing non-animal approaches to assess acute toxicity endpoints. The workshop, held in Loch Lomond, Scotland, from 28 April to 1 May, 2025, aimed to develop a decision tree (DT) approach that could support the implementation of non-animal methods and the phased-out use of animal testing for systemic acute and local toxicity.</div><div>This DT approach provides a transparent decision-making workflow that assists users in applying appropriate opportunities for waiving testing, non-animal testing methods (NAMs), and other adaptations consistently across chemical regulations. DTs also serve to increase awareness of the application of non-animal approaches and ensure compliance with the last resort requirement for animal studies. This workshop aimed to review the suitability of the proposed framework, formulate overarching recommendations for its implementation and provide specific feedback and timelines to finalise endpoint-specific DTs for acute oral toxicity, eye irritation and corrosion, skin irritation and corrosion, and skin sensitisation. This report summarises the overarching discussions and findings tackled during the meeting. The individual endpoint-specific DTs will be described in follow-up scientific publications.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105969"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368575","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

Retrospective evaluation of the use of non-human primates for fertility assessment of pharmaceuticals submitted for marketing approval in the EU 非人类灵长类动物用于欧盟上市批准药品生育能力评估的回顾性评估。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-01-01 Epub Date: 2025-10-23 DOI: 10.1016/j.yrtph.2025.105967

Puck Roos , Diann L. Blanset , Peter JK. van Meer , Shermaine Mitchell-Ryan , Peter T. Theunissen , Katie J. Turner , Ronald L. Wange , Christopher J. Bowman

{"title":"Retrospective evaluation of the use of non-human primates for fertility assessment of pharmaceuticals submitted for marketing approval in the EU","authors":"Puck Roos , Diann L. Blanset , Peter JK. van Meer , Shermaine Mitchell-Ryan , Peter T. Theunissen , Katie J. Turner , Ronald L. Wange , Christopher J. Bowman","doi":"10.1016/j.yrtph.2025.105967","DOIUrl":"10.1016/j.yrtph.2025.105967","url":null,"abstract":"<div><div>During development, potential adverse effects of pharmaceuticals on male and female fertility are evaluated. Although non-human primates (NHP) can be an appropriate model for some pharmaceuticals, there are scientific, ethical and practical limitations. We performed a retrospective analysis of the use of NHP for fertility assessment.</div><div>A database was created, consisting of pharmaceuticals submitted to the European Medicines Agency (2011–2022). Pharmaceuticals with repeat-dose toxicity studies or dedicated studies to evaluate surrogate fertility endpoints in NHP were included. Publicly available data on product characteristics, study design, observations on standard surrogate fertility endpoints (changes in reproductive organ weight and histopathology), additional surrogate fertility endpoints (changes in reproductive hormone levels, menstrual cycle, and sperm parameters), and labeling were collected.</div><div>In total, 263 pharmaceuticals were included. For 22 pharmaceuticals, adverse effects on surrogate fertility endpoints in NHP were reflected in the label. In all 22 cases, effects were predictable based on mechanism of action or rodent studies provided sufficient information on fertility. Hence, no clear scientific value of fertility assessment in sexually mature NHP was determined.</div><div>In conclusion, using NHP to evaluate effects on surrogate fertility endpoints of pharmaceuticals did not have a significant impact on fertility labeling.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105967"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370430","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

Mode of action analysis for induction of mouse lung tumors by permethrin: Involvement of CYP2F2 enzyme and human relevancy 氯菊酯诱导小鼠肺肿瘤的作用模式分析：CYP2F2酶的参与与人的相关性。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-01-01 Epub Date: 2025-10-04 DOI: 10.1016/j.yrtph.2025.105958

Dai Hasegawa , Kensuke Kawamoto , Keiko Ogata , Satoki Fukunaga , Samuel M. Cohen , Hiroyuki Asano

{"title":"Mode of action analysis for induction of mouse lung tumors by permethrin: Involvement of CYP2F2 enzyme and human relevancy","authors":"Dai Hasegawa , Kensuke Kawamoto , Keiko Ogata , Satoki Fukunaga , Samuel M. Cohen , Hiroyuki Asano","doi":"10.1016/j.yrtph.2025.105958","DOIUrl":"10.1016/j.yrtph.2025.105958","url":null,"abstract":"<div><div>Permethrin increases the incidence of bronchiolo-alveolar adenomas in female mice. The proposed mode of action (MOA) for permethrin-induced lung tumorigenesis involves increased mitogenesis in Club cells. Additionally, CYP2F2, which is particularly expressed in mouse lung Club cells and different from human CYP2F1, is considered to be a key factor in mouse-specific lung tumorigenesis. In this study, we investigated the relationship between permethrin-induced mouse lung tumorigenesis and CYP2F2 in CYP2f2 knockout (KO) mice. Fluensulfone and isoniazid were selected as positive controls. We showed that the increased proliferation of Club cells and increased proliferation of smooth endoplasmic reticulum (SER) within them were abolished in permethrin-treated CYP2f2 KO mice, while these changes were clearly observed in permethrin- and positive control-treated wild type mice. Additionally, the disappearance of the Club cell reaction was also observed in positive control-treated CYP2f2 KO mice. Based on these results, it was concluded that CYP2F2 is essential in the MOA of mouse lung tumorigenesis by permethrin, also suggesting that permethrin metabolism by CYP2F2 corresponds to a chain of early key events, including the molecular initiating event (MIE). Furthermore, the data suggested that CYP2F2 played a crucial role in mouse lung tumorigenesis induced by isoniazid, which is known to cause lung tumors in mice but not in humans. The collective data on permethrin-treated mouse lung tumorigenesis, including findings from this study, would lead to the conclusion that the lung tumors induced by permethrin treatment are mouse-specific and not relevant to human lung cancer risk.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105958"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239524","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

Evaluating cancer risks: The impact of thirdhand smoke exposure on carcinogenesis 评估癌症风险：三手烟暴露对致癌的影响。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-01-01 Epub Date: 2025-11-17 DOI: 10.1016/j.yrtph.2025.105991

Laura Ghanem , Antonia Moubarak , Jana Kotaich , Marianne Mouannes , Amir Ghanem , Soulaima Chamat , Nizar Bitar

{"title":"Evaluating cancer risks: The impact of thirdhand smoke exposure on carcinogenesis","authors":"Laura Ghanem , Antonia Moubarak , Jana Kotaich , Marianne Mouannes , Amir Ghanem , Soulaima Chamat , Nizar Bitar","doi":"10.1016/j.yrtph.2025.105991","DOIUrl":"10.1016/j.yrtph.2025.105991","url":null,"abstract":"<div><div>The impact of firsthand and secondhand smoking on the development of various types of cancer is well established. However, the association of thirdhand smoke (THS) with malignant diseases has only recently been recognized, with limited research investigating the underlying mechanisms. THS refers to the dynamic mixture of residual tobacco smoke constituents that persist in air, dust, and on surfaces, and can occur through dermal absorption, inhalation of re-emitted gases and particles, and ingestion - particularly via dust intake. Tobacco smoke contains hundreds of toxic compounds, 60 of which are classified as carcinogens. These include aromatic amines, nicotine, nitrosamines, nitric oxide and polycyclic aromatic hydrocarbons. These substances can react with environmental chemicals, forming highly toxic secondary pollutants that can be released from surfaces over months and be absorbed through the skin or mucosa. The metabolization of tobacco smoke components can increase the incidence of cancer by altering key molecular pathways. Main mechanisms of carcinogenesis include DNA adduct formation and DNA structural changes, interference with tumor suppressor genes, and chronic inflammation. This review examines the risks of THS exposure, the potential mechanisms of carcinogenesis associated with THS and the role of THS in the development of different cancers linked to tobacco use.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105991"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557686","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

MODEXMO: A modular non-dietary exposure assessment approach for pesticides using dose-based dermal absorption prediction MODEXMO：一种基于剂量的皮肤吸收预测的模块化非膳食农药暴露评估方法。

IF 3.5 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2026-01-01 Epub Date: 2025-11-09 DOI: 10.1016/j.yrtph.2025.105984

Felix M. Kluxen , Korinna Wend , Christiane Wiemann , Edgars Felkers , Neil Morgan

{"title":"MODEXMO: A modular non-dietary exposure assessment approach for pesticides using dose-based dermal absorption prediction","authors":"Felix M. Kluxen , Korinna Wend , Christiane Wiemann , Edgars Felkers , Neil Morgan","doi":"10.1016/j.yrtph.2025.105984","DOIUrl":"10.1016/j.yrtph.2025.105984","url":null,"abstract":"<div><div>A modular non-dietary exposure assessment approach for pesticides (PPPs) is proposed, emphasizing a dose-based prediction of dermal absorption. The Modular Dermal Exposure Model (MODEXMO) defines new nomenclature: exposure, dermal absorption and surface distribution prediction models, respectively abbreviated as EXPREMOs, DAPREMOs, SUDIPREMOs. Approach and nomenclature are generic and can be used for probabilistic models or simulation-based approaches. The modularity aids the integration of refined exposure data and enhances the adaptability of risk assessments to better reflect dynamic real-world scenarios. DAPREMOs could replace relative dermal absorption values (DAVs) by directly predicting internal exposure from external doses with a statistical model. It is well-known that absolute dermal penetration depends primarily on applied dose. EXPREMOs can predict relatively low area doses, since exposure estimates are averaged over large body surfaces, regardless of the actual residue surface distribution. While this has no consequence in the current assessment approach using DAVs, it ignores the exposure scenario-dependent spatial distributions of residue on skin, e.g., due to individual splash events during mixing and loading operations. SUDIPREMOs can refine EXPREMO-assumed default surface areas to provide DAPREMOs with more accurate inputs for different area doses in multiple exposure sub-streams.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105984"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145496499","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