Pub Date : 2025-12-09DOI: 10.1016/j.yrtph.2025.106010
So-Young An , Si-Whan Song , Hyun-Suk Heo , Chang-Wok Park , Min-Sub Kim , Woo-Joo Lee , Yoo-Jin Park , Jae-Ho Shin , Beom Seok Han , Wan-Seob Cho
Aurantii Fructus Immaturus (AFI) water extract has been utilized in traditional medicine; however, its toxicity data are still lacking. In this study, we evaluated the general and genetic toxicity of the AFI water extract as a project of the Korea National Toxicology Program (KNTP). Naringin and neohesperidin, marker compounds of AFI, contained in the AFI water extract were 7.63 % and 4.51 %, respectively. These levels were higher than AFI powders, which contain about 4 % naringin and 3 % neohesperidin. The acute oral toxicity study in rats, conducted at doses of 2500–10000 mg/kg, demonstrated that the median lethal dose (LD50) of AFI water extract exceeds 10000 mg/kg. Subacute oral toxicity tests at doses up to 5000 mg/kg/day and subchronic toxicity studies conducted over 13 weeks at similar dose ranges showed no treatment-related adverse effects. Thus, the no-observed-adverse-effect level (NOAEL) of AFI water extract in rats was 5000 mg/kg bw/day. Additionally, three genotoxicity assays (bacterial reverse mutation, in vitro chromosomal aberration, and in vivo micronucleus tests) confirmed that the AFI water extract is not genotoxic. These results will provide the toxicity data for the risk assessment of AFI water extract for human consumption.
{"title":"Subchronic oral toxicity and genotoxicity of Aurantii Fructus Immaturus water extract","authors":"So-Young An , Si-Whan Song , Hyun-Suk Heo , Chang-Wok Park , Min-Sub Kim , Woo-Joo Lee , Yoo-Jin Park , Jae-Ho Shin , Beom Seok Han , Wan-Seob Cho","doi":"10.1016/j.yrtph.2025.106010","DOIUrl":"10.1016/j.yrtph.2025.106010","url":null,"abstract":"<div><div><em>Aurantii Fructus Immaturus</em> (AFI) water extract has been utilized in traditional medicine; however, its toxicity data are still lacking. In this study, we evaluated the general and genetic toxicity of the AFI water extract as a project of the Korea National Toxicology Program (KNTP). Naringin and neohesperidin, marker compounds of AFI, contained in the AFI water extract were 7.63 % and 4.51 %, respectively. These levels were higher than AFI powders, which contain about 4 % naringin and 3 % neohesperidin. The acute oral toxicity study in rats, conducted at doses of 2500–10000 mg/kg, demonstrated that the median lethal dose (LD<sub>50</sub>) of AFI water extract exceeds 10000 mg/kg. Subacute oral toxicity tests at doses up to 5000 mg/kg/day and subchronic toxicity studies conducted over 13 weeks at similar dose ranges showed no treatment-related adverse effects. Thus, the no-observed-adverse-effect level (NOAEL) of AFI water extract in rats was 5000 mg/kg bw/day. Additionally, three genotoxicity assays (bacterial reverse mutation, <em>in vitro</em> chromosomal aberration, and <em>in vivo</em> micronucleus tests) confirmed that the AFI water extract is not genotoxic. These results will provide the toxicity data for the risk assessment of AFI water extract for human consumption.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106010"},"PeriodicalIF":3.5,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744049","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 : 2025-12-06DOI: 10.1016/j.yrtph.2025.106007
Tyna Dao, Nakissa Sadrieh
This study analyzes the landscape of studies using New Approach Methodologies (NAMs) and submitted to the FDA over the past 15 years. The study utilized a custom-developed Center for Drug Evaluation and Research (CDER) search tool to examine keywords in Module 4 of the Electronic Common Technical Document (eCTD) across various drug applications. The investigation focused on five NAM categories, including some of those identified in the 2022 Food and Drug Omnibus Reform Act (FDORA): in vitro, in silico, in chemico, nonhuman in vivo, and other NAMs. Results indicated that 93 % of NAM submissions were concentrated in two categories: in silico (49 %) and in vitro (44 %), with other categories (including in chemico, nonhuman in vivo from phylogenetically lower species and other combined methods) demonstrating significantly lower representation. In vitro NAMs, including stem cell-derived and sandwich culture models, showed higher prevalence compared to 3D models and organ chip or MPS models. The relatively high prevalence of in silico NAMs, was due to the submission of multiple study reports per application, attributed to various metabolites and the use of different in silico platforms. In chemico and nonhuman in vivo NAMs demonstrated limited submissions, with zebrafish studies predominating in the latter category. This study highlights one of CDER's activities aimed at better understanding the current usage of NAMs in drug development, while providing evidence to support areas of focus and prioritization of resources towards the validation of NAMs with significant regulatory impact potential. Despite technical limitations in the datamining work presented here, the findings confirm that CDER has been receiving NAMs data in drug applications for a long time. Nevertheless, we acknowledge that industry submits only a fraction of their NAM data to FDA, therefore we encourage increased NAM submissions which would contribute to building scientific confidence in these methods. It is only through the availability of sufficient case studies, that CDER can move towards reaching the goals of NAMs Roadmap issued in April 2025, and ultimately phasing out animal studies when possible and feasible.
{"title":"A CDER perspective: Landscape of New Approach Methodologies (NAMs) submitted in drug development programs","authors":"Tyna Dao, Nakissa Sadrieh","doi":"10.1016/j.yrtph.2025.106007","DOIUrl":"10.1016/j.yrtph.2025.106007","url":null,"abstract":"<div><div>This study analyzes the landscape of studies using New Approach Methodologies (NAMs) and submitted to the FDA over the past 15 years. The study utilized a custom-developed Center for Drug Evaluation and Research (CDER) search tool to examine keywords in Module 4 of the Electronic Common Technical Document (eCTD) across various drug applications. The investigation focused on five NAM categories, including some of those identified in the 2022 Food and Drug Omnibus Reform Act (FDORA): in vitro, in silico, in chemico, nonhuman in vivo, and other NAMs. Results indicated that 93 % of NAM submissions were concentrated in two categories: in silico (49 %) and in vitro (44 %), with other categories (including in chemico, nonhuman in vivo from phylogenetically lower species and other combined methods) demonstrating significantly lower representation. In vitro NAMs, including stem cell-derived and sandwich culture models, showed higher prevalence compared to 3D models and organ chip or MPS models. The relatively high prevalence of in silico NAMs, was due to the submission of multiple study reports per application, attributed to various metabolites and the use of different in silico platforms. In chemico and nonhuman in vivo NAMs demonstrated limited submissions, with zebrafish studies predominating in the latter category. This study highlights one of CDER's activities aimed at better understanding the current usage of NAMs in drug development, while providing evidence to support areas of focus and prioritization of resources towards the validation of NAMs with significant regulatory impact potential. Despite technical limitations in the datamining work presented here, the findings confirm that CDER has been receiving NAMs data in drug applications for a long time. Nevertheless, we acknowledge that industry submits only a fraction of their NAM data to FDA, therefore we encourage increased NAM submissions which would contribute to building scientific confidence in these methods. It is only through the availability of sufficient case studies, that CDER can move towards reaching the goals of NAMs Roadmap issued in April 2025, and ultimately phasing out animal studies when possible and feasible.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106007"},"PeriodicalIF":3.5,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708987","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 : 2025-12-05DOI: 10.1016/j.yrtph.2025.106006
Gary M. Williams , Robert Kroes , Ian C. Munro
{"title":"Retraction notice to“Safety evaluation and risk assessment of the herbicide roundup and its active ingredient, glyphosate, for humans” [Regul. Toxicol. Pharm. 31 (2000) 117–165]","authors":"Gary M. Williams , Robert Kroes , Ian C. Munro","doi":"10.1016/j.yrtph.2025.106006","DOIUrl":"10.1016/j.yrtph.2025.106006","url":null,"abstract":"","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106006"},"PeriodicalIF":3.5,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805519","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 : 2025-12-03DOI: 10.1016/j.yrtph.2025.106008
Kelly E. Carstens, Timothy J. Shafer
The Network Formation Assay (NFA) is part of a battery of in vitro assays developed to evaluate chemicals for the potential to cause developmental neurotoxicity. This assay follows the formation of interconnected networks of rat neurons using microelectrode array recordings, deriving up to 17 different endpoints informing different aspects of network activity, bursting, and connectivity. As such, it is one of the most complex assays in the battery, and interpretation of the data from this assay can be challenging. This work provides recommendations on a fit-for-purpose approach for the interpretation of data from the NFA, including the basics of the NFA experimental design, data analysis approaches, and concentration-response modeling with the ToxCast Pipeline. This manuscript also provides a workflow for data interpretation and discusses common issues that are often confronted when evaluating the data from this assay.
{"title":"Current approaches to the interpretation of bioactivity data from a neural network formation assay to inform developmental neurotoxicity potential of chemical exposure","authors":"Kelly E. Carstens, Timothy J. Shafer","doi":"10.1016/j.yrtph.2025.106008","DOIUrl":"10.1016/j.yrtph.2025.106008","url":null,"abstract":"<div><div>The Network Formation Assay (NFA) is part of a battery of <em>in vitro</em> assays developed to evaluate chemicals for the potential to cause developmental neurotoxicity. This assay follows the formation of interconnected networks of rat neurons using microelectrode array recordings, deriving up to 17 different endpoints informing different aspects of network activity, bursting, and connectivity. As such, it is one of the most complex assays in the battery, and interpretation of the data from this assay can be challenging. This work provides recommendations on a fit-for-purpose approach for the interpretation of data from the NFA, including the basics of the NFA experimental design, data analysis approaches, and concentration-response modeling with the ToxCast Pipeline. This manuscript also provides a workflow for data interpretation and discusses common issues that are often confronted when evaluating the data from this assay.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106008"},"PeriodicalIF":3.5,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687917","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 : 2025-12-01Epub Date: 2025-07-26DOI: 10.1016/j.yrtph.2025.105914
Jordan N Smith, Kimberly J Tyrrell, Karl K Weitz, Willem Faber
We developed a physiologically based pharmacokinetic (PBPK) model in rats and humans for the isobutyl metabolic series, which includes isobutyl acetate, isobutanol, isobutyraldehyde, and isobutyric acid. Given chemical similarities, we used a previously developed PBPK model for the propyl metabolic series as a framework to create the isobutyl PBPK model. To support model development, we measured in vitro metabolism of isobutyl acetate in rat and human blood and liver S9 fractions. Our findings indicated that humans exhibited faster isobutyl acetate hydrolysis in liver S9 fractions compared to rats, while hydrolysis rates in blood were similar between the two species. Experiments involving closed chamber exposures of rats to isobutyl acetate or isobutanol revealed higher isobutanol concentrations in blood compared to other isobutyl compounds. Using these data to parameterize the model, the PBPK model accurately simulated available time-course concentrations of isobutyl compounds in blood of rats and humans. The isobutyl PBPK model enables comparisons of internal dose metrics across various isobutyl compound exposures and species and allows for calculation of equivalent external exposures that result in the same dose metric. Regulators can employ this PBPK model to predict and align internal dose metrics of isobutyl compounds for risk assessment purposes.
{"title":"A physiologically based pharmacokinetic (PBPK) model to align dosimetry of the isobutyl metabolic series in rats and humans.","authors":"Jordan N Smith, Kimberly J Tyrrell, Karl K Weitz, Willem Faber","doi":"10.1016/j.yrtph.2025.105914","DOIUrl":"10.1016/j.yrtph.2025.105914","url":null,"abstract":"<p><p>We developed a physiologically based pharmacokinetic (PBPK) model in rats and humans for the isobutyl metabolic series, which includes isobutyl acetate, isobutanol, isobutyraldehyde, and isobutyric acid. Given chemical similarities, we used a previously developed PBPK model for the propyl metabolic series as a framework to create the isobutyl PBPK model. To support model development, we measured in vitro metabolism of isobutyl acetate in rat and human blood and liver S9 fractions. Our findings indicated that humans exhibited faster isobutyl acetate hydrolysis in liver S9 fractions compared to rats, while hydrolysis rates in blood were similar between the two species. Experiments involving closed chamber exposures of rats to isobutyl acetate or isobutanol revealed higher isobutanol concentrations in blood compared to other isobutyl compounds. Using these data to parameterize the model, the PBPK model accurately simulated available time-course concentrations of isobutyl compounds in blood of rats and humans. The isobutyl PBPK model enables comparisons of internal dose metrics across various isobutyl compound exposures and species and allows for calculation of equivalent external exposures that result in the same dose metric. Regulators can employ this PBPK model to predict and align internal dose metrics of isobutyl compounds for risk assessment purposes.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105914"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732945","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 : 2025-11-26DOI: 10.1016/j.yrtph.2025.106005
Yunjin Choi , Seonghui Kim , Duhyeon Kim , Kyoung Sik Park , Mi-Young Lee , Suengmok Cho
Key lime (Citrus aurantiifolia) peel, a major by-product of juice processing, is rich in flavonoids and other bioactives. To support its safe use as a food-derived ingredient, we chemically characterized key lime peel ethanol extract (KLPE) and conducted a full toxicological evaluation under OECD Test Guidelines (No. 420, 408, 471, 473, 474) and in compliance with GLP. The program included acute oral toxicity, a 90-day repeated-dose study with a 28-day recovery, and in vitro and in vivo genotoxicity assays. KLPE caused no mortality or clinical signs, and body weight, food intake, hematology, and organ weights were comparable to controls. No histopathological lesions or genotoxic effects were observed. Both the LD50 and the No Observed Adverse Effect Level (NOAEL) exceeded 2000 mg/kg BW/day, the highest dose tested, indicating a wide safety margin. These results provide regulatory-grade evidence confirming the safety of KLPE for human consumption and support its application as a functional food and nutraceutical ingredient in global markets.
{"title":"Regulatory safety evaluation of key lime (Citrus aurantiifolia) peel ethanol extract: Acute, 90-day repeated-dose, and genotoxicity studies","authors":"Yunjin Choi , Seonghui Kim , Duhyeon Kim , Kyoung Sik Park , Mi-Young Lee , Suengmok Cho","doi":"10.1016/j.yrtph.2025.106005","DOIUrl":"10.1016/j.yrtph.2025.106005","url":null,"abstract":"<div><div>Key lime (<em>Citrus aurantiifolia</em>) peel, a major by-product of juice processing, is rich in flavonoids and other bioactives. To support its safe use as a food-derived ingredient, we chemically characterized key lime peel ethanol extract (KLPE) and conducted a full toxicological evaluation under OECD Test Guidelines (No. 420, 408, 471, 473, 474) and in compliance with GLP. The program included acute oral toxicity, a 90-day repeated-dose study with a 28-day recovery, and in vitro and in vivo genotoxicity assays. KLPE caused no mortality or clinical signs, and body weight, food intake, hematology, and organ weights were comparable to controls. No histopathological lesions or genotoxic effects were observed. Both the LD<sub>50</sub> and the No Observed Adverse Effect Level (NOAEL) exceeded 2000 mg/kg BW/day, the highest dose tested, indicating a wide safety margin. These results provide regulatory-grade evidence confirming the safety of KLPE for human consumption and support its application as a functional food and nutraceutical ingredient in global markets.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106005"},"PeriodicalIF":3.5,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145638124","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 : 2025-11-26DOI: 10.1016/j.yrtph.2025.106004
Christopher J. Bowman , Dingzhou Li , Thi Dong Binh Tran , Natasha R. Catlin , Christine M. Stethem , William S. Nowland , Sarah N. Campion
This study evaluates the potential of using historical control data (HCD) in rat fertility studies to replace/reduce concurrent control animal use and improve statistical analysis. This analysis was conducted using data sourced from a single test facility using consistent animal attributes and study procedures and consisted of 13 datasets from 12 rat fertility studies conducted between 2018 and 2023. For required fertility endpoints, we have evaluated full and hybrid Virtual Control Group (VCG) and Bayesian statistical approaches compared with standard statistics used for concurrent control groups (CCG). Our findings demonstrate that the sensitivity and specificity of most required fertility endpoints were generally similar between CCG and full or hybrid VCGs of sufficient sample size. Bayesian analyses leveraging all available HCD offered similar or superior sensitivity and specificity to CCGs and VCGs (full or hybrid) for all required fertility endpoints, with some exceptions. A retrospective case study implementing these approaches with HCD illustrated similar statistical performance across all approaches in addition to the benefit of reduced animal use. Overall, this effort illustrates the potential to improve sensitivity and reduce animal use with VCG (full or hybrid) or Bayesian approaches for required fertility endpoints in the rat.
{"title":"Exploration of virtual control groups and Bayesian approaches for rat fertility studies","authors":"Christopher J. Bowman , Dingzhou Li , Thi Dong Binh Tran , Natasha R. Catlin , Christine M. Stethem , William S. Nowland , Sarah N. Campion","doi":"10.1016/j.yrtph.2025.106004","DOIUrl":"10.1016/j.yrtph.2025.106004","url":null,"abstract":"<div><div>This study evaluates the potential of using historical control data (HCD) in rat fertility studies to replace/reduce concurrent control animal use and improve statistical analysis. This analysis was conducted using data sourced from a single test facility using consistent animal attributes and study procedures and consisted of 13 datasets from 12 rat fertility studies conducted between 2018 and 2023. For required fertility endpoints, we have evaluated full and hybrid Virtual Control Group (VCG) and Bayesian statistical approaches compared with standard statistics used for concurrent control groups (CCG). Our findings demonstrate that the sensitivity and specificity of most required fertility endpoints were generally similar between CCG and full or hybrid VCGs of sufficient sample size. Bayesian analyses leveraging all available HCD offered similar or superior sensitivity and specificity to CCGs and VCGs (full or hybrid) for all required fertility endpoints, with some exceptions. A retrospective case study implementing these approaches with HCD illustrated similar statistical performance across all approaches in addition to the benefit of reduced animal use. Overall, this effort illustrates the potential to improve sensitivity and reduce animal use with VCG (full or hybrid) or Bayesian approaches for required fertility endpoints in the rat.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106004"},"PeriodicalIF":3.5,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145616909","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 : 2025-11-22DOI: 10.1016/j.yrtph.2025.105989
Roger Godschalk , Bente Brauwers , Connie L. Chen , Raffaella Corvi , Kerry L. Dearfield , George R. Douglas , Naveed Honarvar , David Kirkland , Frank Le Curieux , Ann-Karin Olsen , Stefan Pfuhler , Leon F. Stankowski , Paul White , Jan van Benthem , Francesco Marchetti
The Globally Harmonized System standardizes chemical hazard communication. Within this system, germ cell mutagenicity holds unique importance due to the potential of heritable mutations. Yet, such testing is rarely performed, requiring alternative approaches to assess germ cell mutagenic potential. One strategy involves using physiological parameters to predict if somatic cell mutagens reach the gonads and induce mutations in germ cells. Therefore, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee examined whether blood concentrations of somatic cell mutagens can predict genotoxic effects in germ cells. We analyzed 11 substances with dominant lethal test data and 30 with transgenic rodent gene mutation data in male germ cells, together with blood concentrations. While significant associations were found between genotoxic outcomes in somatic tissues (e.g., micronuclei, mutation induction) and outcomes for germ cell mutagenicity, considerable variability was noted in genotoxic responses. This variability could not be explained by blood concentrations alone. Notably, blood levels of substances positive in both somatic and germ cells were similar to those that were positive for somatic cell genotoxicity and negative in germ cells. We conclude that the concentration of a somatic cell genotoxic substance in blood is insufficient to predict germ cell mutagenicity.
{"title":"An evaluation of the utility of blood concentration of somatic mutagens to inform germ cell mutagenic hazard","authors":"Roger Godschalk , Bente Brauwers , Connie L. Chen , Raffaella Corvi , Kerry L. Dearfield , George R. Douglas , Naveed Honarvar , David Kirkland , Frank Le Curieux , Ann-Karin Olsen , Stefan Pfuhler , Leon F. Stankowski , Paul White , Jan van Benthem , Francesco Marchetti","doi":"10.1016/j.yrtph.2025.105989","DOIUrl":"10.1016/j.yrtph.2025.105989","url":null,"abstract":"<div><div>The Globally Harmonized System standardizes chemical hazard communication. Within this system, germ cell mutagenicity holds unique importance due to the potential of heritable mutations. Yet, such testing is rarely performed, requiring alternative approaches to assess germ cell mutagenic potential. One strategy involves using physiological parameters to predict if somatic cell mutagens reach the gonads and induce mutations in germ cells. Therefore, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee examined whether blood concentrations of somatic cell mutagens can predict genotoxic effects in germ cells. We analyzed 11 substances with dominant lethal test data and 30 with transgenic rodent gene mutation data in male germ cells, together with blood concentrations. While significant associations were found between genotoxic outcomes in somatic tissues (e.g., micronuclei, mutation induction) and outcomes for germ cell mutagenicity, considerable variability was noted in genotoxic responses. This variability could not be explained by blood concentrations alone. Notably, blood levels of substances positive in both somatic and germ cells were similar to those that were positive for somatic cell genotoxicity and negative in germ cells. We conclude that the concentration of a somatic cell genotoxic substance in blood is insufficient to predict germ cell mutagenicity.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 105989"},"PeriodicalIF":3.5,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588562","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 : 2025-11-20DOI: 10.1016/j.yrtph.2025.105993
Dayton M. Petibone , Jennifer M. Shemansky , Timothy W. Robison , Aisar H. Atrakchi , Robert H. Heflich
Phase 1 clinical trial participants could potentially be exposed to significant health risks. Findings from a standard battery of genetic toxicology tests typically are the only data available to inform about cancer hazards at the initiation of clinical trials. Although uncommon, a question occasionally arises that is not clearly defined in current guidance: how many doses of an Ames-positive (potentially DNA-reactive) drug can be administered safely to healthy adult subjects during Phase 1 clinical trials? A literature survey was undertaken to identify information on carcinogenic risks from short-term exposures to Ames-positive agents, which might inform about administering an Ames-positive drug as a single dose or over a period of up to 14 days in healthy adult subjects. Limited information was identified on risk predictions for short-term exposures from modeling applications and from human studies, with more extensive data available using animal models. Relevant information on cancer outcomes following short-term exposures to Ames-positive agents suggest there is an increased cancer risk for administering even a single dose of an Ames-positive drug to healthy adult subjects. These findings indicate that Phase 1 studies with Ames-positive drug candidates should be exceedingly rare, and that additional mutagenicity testing should be performed before drug administration.
{"title":"Assessing carcinogenic outcomes following short-term exposure to potentially DNA-reactive drugs: Are available data sufficient to inform risk assessment?","authors":"Dayton M. Petibone , Jennifer M. Shemansky , Timothy W. Robison , Aisar H. Atrakchi , Robert H. Heflich","doi":"10.1016/j.yrtph.2025.105993","DOIUrl":"10.1016/j.yrtph.2025.105993","url":null,"abstract":"<div><div>Phase 1 clinical trial participants could potentially be exposed to significant health risks. Findings from a standard battery of genetic toxicology tests typically are the only data available to inform about cancer hazards at the initiation of clinical trials. Although uncommon, a question occasionally arises that is not clearly defined in current guidance: how many doses of an Ames-positive (potentially DNA-reactive) drug can be administered safely to healthy adult subjects during Phase 1 clinical trials? A literature survey was undertaken to identify information on carcinogenic risks from short-term exposures to Ames-positive agents, which might inform about administering an Ames-positive drug as a single dose or over a period of up to 14 days in healthy adult subjects. Limited information was identified on risk predictions for short-term exposures from modeling applications and from human studies, with more extensive data available using animal models. Relevant information on cancer outcomes following short-term exposures to Ames-positive agents suggest there is an increased cancer risk for administering even a single dose of an Ames-positive drug to healthy adult subjects. These findings indicate that Phase 1 studies with Ames-positive drug candidates should be exceedingly rare, and that additional mutagenicity testing should be performed before drug administration.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 105993"},"PeriodicalIF":3.5,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582335","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 : 2025-11-19DOI: 10.1016/j.yrtph.2025.105994
L.M. Brewster , A. Ishwardat , B.J. van den Born , M.M.A.L. Pelsers , H. Galenkamp , G.A. van Montfrans
Policymakers in Europe utilize biomonitoring to regulate exposure to arsenic and protect public health, but potentially high exposure levels among ancestral subgroups remain understudied.
We assessed arsenic exposure in a random population sample of Amsterdam, the Netherlands, stratified by European-Dutch vs Asian and African-Dutch ancestry (n = 60, 30 women, aged 40–63 years). We analyzed total spot urinary arsenic with inductively coupled plasma mass spectrometry and used food frequency questionnaires to calculate the exposure to inorganic arsenic (reference point <0.8 nmol/kg body mass/day) from rice, fish, and water consumption.
Urinary arsenic (40–4828 nmol/L, mean 532 (SE 116); respectively 312 (60) in European-Dutch vs. 642 (169) in Asian and African-Dutch), was independently associated with rice consumption (343 nmol/L (95 % CI, 112–575)/100 g rice).
Inorganic arsenic intake (87–976 nmol/day, mean 397, SE 32), respectively 175 (14) in European-Dutch (2.4 (0.2) nmol/kg body mass/day) vs 508 (37) in Asian and African-Dutch (6.7 (0.5) nmol/kg body mass/day), was independently associated with systolic blood pressure (3.1 (1.5–4.8) mm Hg/100 nmol iAs).
The high dietary arsenic exposure among certain ancestry subgroups living in Europe is concerning. Health policies should be developed to monitor these subgroups and reduce their inorganic arsenic intake to the unavoidable minimum.
{"title":"Biomonitoring arsenic exposure by ancestry: the healthy life in an urban setting (HELIUS) study","authors":"L.M. Brewster , A. Ishwardat , B.J. van den Born , M.M.A.L. Pelsers , H. Galenkamp , G.A. van Montfrans","doi":"10.1016/j.yrtph.2025.105994","DOIUrl":"10.1016/j.yrtph.2025.105994","url":null,"abstract":"<div><div>Policymakers in Europe utilize biomonitoring to regulate exposure to arsenic and protect public health, but potentially high exposure levels among ancestral subgroups remain understudied.</div><div>We assessed arsenic exposure in a random population sample of Amsterdam, the Netherlands, stratified by European-Dutch vs Asian and African-Dutch ancestry (n = 60, 30 women, aged 40–63 years). We analyzed total spot urinary arsenic with inductively coupled plasma mass spectrometry and used food frequency questionnaires to calculate the exposure to inorganic arsenic (reference point <0.8 nmol/kg body mass/day) from rice, fish, and water consumption.</div><div>Urinary arsenic (40–4828 nmol/L, mean 532 (SE 116); respectively 312 (60) in European-Dutch vs. 642 (169) in Asian and African-Dutch), was independently associated with rice consumption (343 nmol/L (95 % CI, 112–575)/100 g rice).</div><div>Inorganic arsenic intake (87–976 nmol/day, mean 397, SE 32), respectively 175 (14) in European-Dutch (2.4 (0.2) nmol/kg body mass/day) vs 508 (37) in Asian and African-Dutch (6.7 (0.5) nmol/kg body mass/day), was independently associated with systolic blood pressure (3.1 (1.5–4.8) mm Hg/100 nmol iAs).</div><div>The high dietary arsenic exposure among certain ancestry subgroups living in Europe is concerning. Health policies should be developed to monitor these subgroups and reduce their inorganic arsenic intake to the unavoidable minimum.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 105994"},"PeriodicalIF":3.5,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145565194","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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