Pub Date : 2026-01-30DOI: 10.1016/j.yrtph.2026.106038
Mineo Matsumoto, J Ryan Polli, Suresh Swaminathan, Kaushik Datta, Cris Kamperschroer, Marie C Fortin, Smita Salian-Mehta, Rutwij Dave, Zheng Yang, Payal Arora, Masanori Hiura, Mizuho Suzuki, Christine E Crute, Frank R Brennan, Jean Sathish
Selecting first-in-human (FIH) doses for immunomodulators presents significant challenges. Conservative approaches, which rely on the minimal anticipated biological effect level (MABEL), emphasize safety but often result in sub-therapeutic starting doses. These doses limit patients' benefit in severe diseases and prolong dose escalation. To address these limitations, we previously introduced a refined integrative approach from an expert working group. This commentary highlights key enhancements of this refined framework for FIH dose selection, including a revised decision tree, industry case studies, and pharmacokinetic/pharmacodynamic (PK/PD) modeling. This approach allows for careful consideration of immunomodulator mechanisms of action and balances risk-benefit profiles. The case studies illustrate the utility of these strategies. Furthermore, the commentary discusses how emerging concepts like Model-Informed Drug Development (MIDD) and quantitative systems pharmacology (QSP) models can inform and potentially strengthen FIH starting dose selection, aiming to optimize the balance between patient safety and therapeutic efficacy in early-phase trials (148 words).
{"title":"FIH Dose Selection Beyond MABEL: Optimizing Phase 1 clinical trial Starting Dose Whilst Protecting Patient Safety.","authors":"Mineo Matsumoto, J Ryan Polli, Suresh Swaminathan, Kaushik Datta, Cris Kamperschroer, Marie C Fortin, Smita Salian-Mehta, Rutwij Dave, Zheng Yang, Payal Arora, Masanori Hiura, Mizuho Suzuki, Christine E Crute, Frank R Brennan, Jean Sathish","doi":"10.1016/j.yrtph.2026.106038","DOIUrl":"https://doi.org/10.1016/j.yrtph.2026.106038","url":null,"abstract":"<p><p>Selecting first-in-human (FIH) doses for immunomodulators presents significant challenges. Conservative approaches, which rely on the minimal anticipated biological effect level (MABEL), emphasize safety but often result in sub-therapeutic starting doses. These doses limit patients' benefit in severe diseases and prolong dose escalation. To address these limitations, we previously introduced a refined integrative approach from an expert working group. This commentary highlights key enhancements of this refined framework for FIH dose selection, including a revised decision tree, industry case studies, and pharmacokinetic/pharmacodynamic (PK/PD) modeling. This approach allows for careful consideration of immunomodulator mechanisms of action and balances risk-benefit profiles. The case studies illustrate the utility of these strategies. Furthermore, the commentary discusses how emerging concepts like Model-Informed Drug Development (MIDD) and quantitative systems pharmacology (QSP) models can inform and potentially strengthen FIH starting dose selection, aiming to optimize the balance between patient safety and therapeutic efficacy in early-phase trials (148 words).</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"106038"},"PeriodicalIF":3.5,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100754","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}
Pub Date : 2026-01-30DOI: 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
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. In vitro Ames tests, conducted with both rat and hamster liver-induced S9, and in vivo 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 (TD50) and TGR mutagenic potency (BMDL50) (r2 = 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.
亚硝胺（Nitrosamines, NAs）是一类多样的致突变杂质，包括小分子和结构复杂的药物相关NAs，称为亚硝胺类药物相关杂质（nitrosamine drug substance related杂质，NDSRIs）。NAs具有广泛的致癌潜力，从高致癌性到弱致癌性甚至无致癌性。用大鼠和仓鼠肝脏诱导的S9进行的体外Ames试验，以及体内转基因啮齿动物（TGR）突变试验，已被制药公司用于NDSRIs的危害鉴定。对33种NDSRIs的Ames试验和TGR结果进行了比较分析，结果显示两种分析的总体诱变要求之间的准确性为79%。对于TGR结果为阳性的NDSRIs，计算致突变效力估计值，并将其与具有强大致癌性和TGR剂量反应数据的NAs进行比较。这些NAs的结果表明，致癌效力（TD50）和TGR致突变效力（BMDL50）之间存在很强的相关性（r2 = 0.95），这支持将TGR数据用于危害识别和可接受摄入量（AI）确定。通过将定量风险评估工具与TGR分析相结合，这项工作有助于建立一个更健全的评估dna相关风险的框架。
{"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":"2026-01-30","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}
Pub Date : 2026-01-29DOI: 10.1016/j.yrtph.2026.106050
Heenam Seo , Mel Kim , Eunyoung Kim
Most accelerated approvals for oncology drugs have been granted, few studies have characterized the regulatory outcomes of non-oncology drugs within this framework. To examine regulatory outcome and approval timelines of non-oncology drug indications, a cross-sectional analysis was performed using the Food and Drug Administration's accelerated approval database from 1992 to 2024. Among 328 accelerated approval indications, 98 (30 %) were for non-oncology drugs. Overall, 63/98 (64 %) were converted to full approval with systemic anti-infectives accounting for 50 %. Among the 77 (79 %) original indications, 55 (71 %) were converted to full approval, compared to only 8 (38 %) of the 21 supplemental indications. The median times to accelerated approval and convert to full approval for all non-oncology indications were 7.9 (IQR, 5.9–10.0) and 38.8 (IQR, 22.5–63.9) months, respectively. The median time to accelerated approval was 6.8 (IQR, 5.9–10.0) months for 90 (92 %) chemical drug indications and 8.6 (IQR, 7.9–11.0) for 8 (8 %) biologic drug indications; conversion to full approval took 38.8 (IQR, 22.8–63.8) and 42.6 (IQR, 21.3–100.6) months, respectively. Accelerated approvals for non-oncology biologic drug indications took significantly longer than those for oncology biologic indications (8.6 vs. 6.0 months; p = 0.003). These findings underscore the importance of enhanced regulatory oversight and continued post-marketing evaluation to confirm the clinical benefits of non-oncology drugs approved via the accelerated pathway.
{"title":"A comprehensive review of regulatory outcomes and timelines of accelerated FDA approvals for non-oncology therapeutics","authors":"Heenam Seo , Mel Kim , Eunyoung Kim","doi":"10.1016/j.yrtph.2026.106050","DOIUrl":"10.1016/j.yrtph.2026.106050","url":null,"abstract":"<div><div>Most accelerated approvals for oncology drugs have been granted, few studies have characterized the regulatory outcomes of non-oncology drugs within this framework. To examine regulatory outcome and approval timelines of non-oncology drug indications, a cross-sectional analysis was performed using the Food and Drug Administration's accelerated approval database from 1992 to 2024. Among 328 accelerated approval indications, 98 (30 %) were for non-oncology drugs. Overall, 63/98 (64 %) were converted to full approval with systemic anti-infectives accounting for 50 %. Among the 77 (79 %) original indications, 55 (71 %) were converted to full approval, compared to only 8 (38 %) of the 21 supplemental indications. The median times to accelerated approval and convert to full approval for all non-oncology indications were 7.9 (IQR, 5.9–10.0) and 38.8 (IQR, 22.5–63.9) months, respectively. The median time to accelerated approval was 6.8 (IQR, 5.9–10.0) months for 90 (92 %) chemical drug indications and 8.6 (IQR, 7.9–11.0) for 8 (8 %) biologic drug indications; conversion to full approval took 38.8 (IQR, 22.8–63.8) and 42.6 (IQR, 21.3–100.6) months, respectively. Accelerated approvals for non-oncology biologic drug indications took significantly longer than those for oncology biologic indications (8.6 vs. 6.0 months; <em>p</em> = 0.003). These findings underscore the importance of enhanced regulatory oversight and continued post-marketing evaluation to confirm the clinical benefits of non-oncology drugs approved via the accelerated pathway.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106050"},"PeriodicalIF":3.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097171","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}
Pub Date : 2026-01-28DOI: 10.1016/j.yrtph.2026.106041
Claire Beausoleil , Christophe Rousselle , Eren Ozcagli , Miriam N. Jacobs
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 in vivo 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 in vivo 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.
{"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":"2026-01-28","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}
Pub Date : 2026-01-27DOI: 10.1016/j.yrtph.2026.106040
L.P. Sheets , M. Patel , L. Zorrilla , K. Bothe
Imidacloprid is a neonicotinoid insecticide that was first registered in the early 1990's, with global registrations that include agricultural, residential and veterinary uses. In 2001, Bayer reported a developmental neurotoxicity (DNT) study with imidacloprid that complied with U.S. EPA and OECD guidelines to support global registrations. The report concluded that there were slight effects in the offspring at the highest dietary level related to general or acute (neuro)-toxicity and no evidence of DNT at any dose; however, the European Food Safety Authority (EFSA) questioned certain findings at the high dose and whether the study established a clear NOAEL. More recently, the Jai Research Foundation (JRF) independently conducted a guideline-compliant DNT study with imidacloprid for other registrants, with elements incorporated into the study design to facilitate comparison with the Bayer study that could address these issues. This paper examines the findings from both studies, in the context of an updated literature review, to address regulatory uncertainty and persistent claims from non-governmental organizations that imidacloprid is a developmental neurotoxicant. The present analysis supports the interpretation that differences in brain measurements at the high dose in the Bayer study were incidental and unrelated to treatment and that imidacloprid is not a developmental neurotoxicant.
{"title":"Analysis of two guideline-compliant developmental neurotoxicity studies with imidacloprid to assist the interpretation of findings that impact global registrations","authors":"L.P. Sheets , M. Patel , L. Zorrilla , K. Bothe","doi":"10.1016/j.yrtph.2026.106040","DOIUrl":"10.1016/j.yrtph.2026.106040","url":null,"abstract":"<div><div>Imidacloprid is a neonicotinoid insecticide that was first registered in the early 1990's, with global registrations that include agricultural, residential and veterinary uses. In 2001, Bayer reported a developmental neurotoxicity (DNT) study with imidacloprid that complied with U.S. EPA and OECD guidelines to support global registrations. The report concluded that there were slight effects in the offspring at the highest dietary level related to general or acute (neuro)-toxicity and no evidence of DNT at any dose; however, the European Food Safety Authority (EFSA) questioned certain findings at the high dose and whether the study established a clear NOAEL. More recently, the Jai Research Foundation (JRF) independently conducted a guideline-compliant DNT study with imidacloprid for other registrants, with elements incorporated into the study design to facilitate comparison with the Bayer study that could address these issues. This paper examines the findings from both studies, in the context of an updated literature review, to address regulatory uncertainty and persistent claims from non-governmental organizations that imidacloprid is a developmental neurotoxicant. The present analysis supports the interpretation that differences in brain measurements at the high dose in the Bayer study were incidental and unrelated to treatment and that imidacloprid is not a developmental neurotoxicant.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106040"},"PeriodicalIF":3.5,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086903","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}
Pub Date : 2026-01-27DOI: 10.1016/j.yrtph.2026.106039
Paul C. DeLeo , Darci Ferrer , Aurelia Lapczynski , Stella Wang
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.
{"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":"2026-01-27","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}
This study assessed the occurrence and dietary risk of pesticide residues in bananas and kiwifruits marketed in Turkey. A total of 50 banana and 50 kiwifruit samples were analyzed for 235 pesticide residues using LC-MS/MS. The analytical method exhibited satisfactory recoveries, acceptable precision, and adequate sensitivity, in full compliance with the European SANTE/11312/2021 Guidelines. Pesticide residues were detected in 82 % of banana and 46 % of kiwifruit samples, with 28 % and 30 % of samples exceeding the EU maximum residue levels (MRLs), respectively. Triadimefon and fenarimol were the most frequently detected compounds in bananas, while acetamiprid and cycloate were the predominant residues in kiwifruits. Chronic dietary exposure assessment, conducted using both deterministic and probabilistic (Monte Carlo simulation) approaches, indicated that chronic hazard indices (HIc) remained well below the threshold value of 1 for both adults and children. Probabilistic modeling revealed right-skewed exposure distributions, with 95th percentile HIc values of 0.0068 and 0.0094 for adults and children, respectively, for bananas, and 0.0013 and 0.0033 for kiwifruit, thereby confirming negligible chronic health risks even under high-exposure scenarios. Acute hazard quotients (HQa) were generally below 1 for adults, whereas a potential acute risk (HQa > 1) was identified for children in a single kiwifruit sample due to indoxacarb, indicating that acute concerns may arise for vulnerable populations under worst-case exposure conditions.
{"title":"Occurrence and dietary risk assessment of pesticide residues in bananas and kiwifruits from Turkey","authors":"Fatma Oznur Afacan , Nimo Hussain Yussuf , Tuba Buyuksirit-Bedir , Cagla Kayisoglu , Eylem Odabas , Ozgur Golge , Bulent Kabak","doi":"10.1016/j.yrtph.2026.106037","DOIUrl":"10.1016/j.yrtph.2026.106037","url":null,"abstract":"<div><div>This study assessed the occurrence and dietary risk of pesticide residues in bananas and kiwifruits marketed in Turkey. A total of 50 banana and 50 kiwifruit samples were analyzed for 235 pesticide residues using LC-MS/MS. The analytical method exhibited satisfactory recoveries, acceptable precision, and adequate sensitivity, in full compliance with the European SANTE/11312/2021 Guidelines. Pesticide residues were detected in 82 % of banana and 46 % of kiwifruit samples, with 28 % and 30 % of samples exceeding the EU maximum residue levels (MRLs), respectively. Triadimefon and fenarimol were the most frequently detected compounds in bananas, while acetamiprid and cycloate were the predominant residues in kiwifruits. Chronic dietary exposure assessment, conducted using both deterministic and probabilistic (Monte Carlo simulation) approaches, indicated that chronic hazard indices (<em>HIc</em>) remained well below the threshold value of 1 for both adults and children. Probabilistic modeling revealed right-skewed exposure distributions, with 95th percentile <em>HIc</em> values of 0.0068 and 0.0094 for adults and children, respectively, for bananas, and 0.0013 and 0.0033 for kiwifruit, thereby confirming negligible chronic health risks even under high-exposure scenarios. Acute hazard quotients (<em>HQa</em>) were generally below 1 for adults, whereas a potential acute risk (<em>HQa</em> > 1) was identified for children in a single kiwifruit sample due to indoxacarb, indicating that acute concerns may arise for vulnerable populations under worst-case exposure conditions.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106037"},"PeriodicalIF":3.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146039875","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}
Pub Date : 2026-01-21DOI: 10.1016/j.yrtph.2026.106033
Candace Doepker , Allison Franzen , Gregory Brorby , Lauren Brown , Neepa Choksi , Alexander East , Daniele Wikoff
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.
{"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":"2026-01-21","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}
Pub Date : 2026-01-20DOI: 10.1016/j.yrtph.2026.106036
Matthias Vogel , Max J. Carlsson , Claudia Skowron , Christina Felske , Rhys Whomsley , Jörg Fahrer
N-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 N-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 —N-nitrosobetahistine (NBH), N-nitrosofluoxetine (NFluo), and N-nitrosonortriptyline (NNT) —compared to NDMA. The NDSRIs demonstrated distinct DNA methylating potential, confirmed by elevated levels of N7-methyl-deoxyguanosine (N7-MedG) and O6-methyl-deoxyguanosine (O6-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 (N7-MedG > O6-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.
{"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":"2026-01-20","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}
Pub Date : 2026-01-19DOI: 10.1016/j.yrtph.2026.106035
A. Rasim Barutcu , Jamie Scaglione , Marjory Moreau , Elizabeth Hofstetter , Todor Antonijevic , Andrew Maier , Pierre Serfass , Leslie Recio , Pamela J. Spencer
The toxicological profiles of nitroparaffins—nitromethane (NM), nitroethane (NE), and 1-nitropropane (1NP)—remain incompletely characterized. This has led to reliance on read-across approaches, extrapolating carcinogenicity data from NM to NE and 1NP, though the validity of such extrapolations is uncertain. In this study, we examined the concentration-dependent transcriptional effects of NM, NE, and 1NP in primary rat hepatocytes to clarify their cellular impact and mechanisms of toxicity. We assessed cytotoxicity, differential gene expression, and pathway enrichment, and applied in vitro to in vivo extrapolation (IVIVE) to estimate systemic bioavailability and clearance rates. Cytotoxicity was observed at 3 mM for NM and NE but not up to 10 mM for 1NP. Transcriptomic profiling revealed minimal overlap in dysregulated genes and enriched pathways among the three compounds. NE elicited the broadest transcriptional response, whereas NM and 1NP showed more limited effects. IVIVE further indicated distinct systemic bioavailability and clearance, suggesting toxicokinetic differences. Taken together, these results demonstrate that structural similarity alone does not predict comparable toxicological behavior. Each nitroparaffin exhibited unique molecular activity and toxicokinetics, indicating that read-across within this class requires demonstrated concordance in both bioactivity and toxicokinetic profiles, which are currently absent for NE, NM and 1NP. Thus, reliance on read-across from NM to NE or 1NP may misrepresent health risks and carries significant regulatory implications.
{"title":"Nitroparaffin transcriptional profiles and toxicokinetics support chemical-specific carcinogenicity assessment","authors":"A. Rasim Barutcu , Jamie Scaglione , Marjory Moreau , Elizabeth Hofstetter , Todor Antonijevic , Andrew Maier , Pierre Serfass , Leslie Recio , Pamela J. Spencer","doi":"10.1016/j.yrtph.2026.106035","DOIUrl":"10.1016/j.yrtph.2026.106035","url":null,"abstract":"<div><div>The toxicological profiles of nitroparaffins—nitromethane (NM), nitroethane (NE), and 1-nitropropane (1NP)—remain incompletely characterized. This has led to reliance on read-across approaches, extrapolating carcinogenicity data from NM to NE and 1NP, though the validity of such extrapolations is uncertain. In this study, we examined the concentration-dependent transcriptional effects of NM, NE, and 1NP in primary rat hepatocytes to clarify their cellular impact and mechanisms of toxicity. We assessed cytotoxicity, differential gene expression, and pathway enrichment, and applied in vitro to in vivo extrapolation (IVIVE) to estimate systemic bioavailability and clearance rates. Cytotoxicity was observed at 3 mM for NM and NE but not up to 10 mM for 1NP. Transcriptomic profiling revealed minimal overlap in dysregulated genes and enriched pathways among the three compounds. NE elicited the broadest transcriptional response, whereas NM and 1NP showed more limited effects. IVIVE further indicated distinct systemic bioavailability and clearance, suggesting toxicokinetic differences. Taken together, these results demonstrate that structural similarity alone does not predict comparable toxicological behavior. Each nitroparaffin exhibited unique molecular activity and toxicokinetics, indicating that read-across within this class requires demonstrated concordance in both bioactivity and toxicokinetic profiles, which are currently absent for NE, NM and 1NP. Thus, reliance on read-across from NM to NE or 1NP may misrepresent health risks and carries significant regulatory implications.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106035"},"PeriodicalIF":3.5,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019562","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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