Pub Date : 2026-01-01Epub Date: 2025-10-26DOI: 10.1016/j.yrtph.2025.105959
Gina M. Hilton , Penelope A. Fenner-Crisp , William L. Jordan , Amy J. Clippinger , Douglas C. Wolf
The United States Environmental Protection Agency (USEPA) has long championed the use of the most modern toxicity testing approaches to meet its pesticide registration mandates, often collaborating with stakeholders to develop and implement innovative approaches that strengthen environmental and human health protections. Despite these efforts, the adoption of 21st-century testing approaches in pesticide registration has been slowed by various factors, including limited resources, inefficient processes for establishing confidence in new methods, and the retention of outdated data requirements codified in the Code of Federal Regulations. This paper provides a brief overview of the current USEPA legislative landscape for pesticide toxicity testing, describes the progress and remaining challenges in using new testing approaches to fulfill regulatory requirements, and highlights opportunities to address these challenges and enhance protection of human health and the environment.
{"title":"Enhancing pesticide risk assessment processes at the US Environmental Protection Agency","authors":"Gina M. Hilton , Penelope A. Fenner-Crisp , William L. Jordan , Amy J. Clippinger , Douglas C. Wolf","doi":"10.1016/j.yrtph.2025.105959","DOIUrl":"10.1016/j.yrtph.2025.105959","url":null,"abstract":"<div><div>The United States Environmental Protection Agency (USEPA) has long championed the use of the most modern toxicity testing approaches to meet its pesticide registration mandates, often collaborating with stakeholders to develop and implement innovative approaches that strengthen environmental and human health protections. Despite these efforts, the adoption of 21st-century testing approaches in pesticide registration has been slowed by various factors, including limited resources, inefficient processes for establishing confidence in new methods, and the retention of outdated data requirements codified in the Code of Federal Regulations. This paper provides a brief overview of the current USEPA legislative landscape for pesticide toxicity testing, describes the progress and remaining challenges in using new testing approaches to fulfill regulatory requirements, and highlights opportunities to address these challenges and enhance protection of human health and the environment.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105959"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145392475","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 : 2026-01-01Epub Date: 2025-10-13DOI: 10.1016/j.yrtph.2025.105963
Martyn L. Chilton , Tasha Jones , Adrian Fowkes , Donna S. Macmillan , Darren Kidd
Much progress has been made in the development and validation of New Approach Methodologies (NAMs) for assessing skin sensitisation, as part of the global move away from animal testing. While there are now numerous in silico models and in chemico/in vitro assays available, none are currently thought to be a one-for-one replacement for the animal tests, but rather several NAMs are combined within a Defined Approach (DA), such as those described in OECD guideline 497. In this study, 22 chemicals were chosen which have known human sensitisation potential, but which have not previously been tested in NAMs, to the best of the authors’ knowledge. New in chemico/in vitro data were generated for each chemical in three assays, and this was combined with in silico predictions from two models to generate predictions from four DAs. The data was used to assess the performance of the individual NAMs and DAs within a less well understood area of chemical space, and to learn more about their applicability domains. The newly generated data are made available herein in the expectation that they will be useful to others who are developing and/or validating DAs which assess the risk of chemicals causing human skin sensitisation.
{"title":"Evaluating the ability of defined approaches to predict the human skin sensitisation potential of chemicals previously untested in new approach methodologies","authors":"Martyn L. Chilton , Tasha Jones , Adrian Fowkes , Donna S. Macmillan , Darren Kidd","doi":"10.1016/j.yrtph.2025.105963","DOIUrl":"10.1016/j.yrtph.2025.105963","url":null,"abstract":"<div><div>Much progress has been made in the development and validation of New Approach Methodologies (NAMs) for assessing skin sensitisation, as part of the global move away from animal testing. While there are now numerous <em>in silico</em> models and <em>in chemico/in vitro</em> assays available, none are currently thought to be a one-for-one replacement for the animal tests, but rather several NAMs are combined within a Defined Approach (DA), such as those described in OECD guideline 497. In this study, 22 chemicals were chosen which have known human sensitisation potential, but which have not previously been tested in NAMs, to the best of the authors’ knowledge. New <em>in chemico/in vitro</em> data were generated for each chemical in three assays, and this was combined with <em>in silico</em> predictions from two models to generate predictions from four DAs. The data was used to assess the performance of the individual NAMs and DAs within a less well understood area of chemical space, and to learn more about their applicability domains. The newly generated data are made available herein in the expectation that they will be useful to others who are developing and/or validating DAs which assess the risk of chemicals causing human skin sensitisation.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105963"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145302959","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 : 2026-01-01Epub Date: 2025-11-10DOI: 10.1016/j.yrtph.2025.105987
Andressa Glinski , Jessica Zablocki da Luz , Aliciane de Almeida Roque , Tugstênio Lima de Souza , Arandi Ginane Bezerra Junior , Carolina Camargo de Oliveira , Ciro Alberto de Oliveira Ribeiro , Francisco Filipak Neto
Silver nanoparticles (AgNPs) are widely used in nanotechnology products. However, the health risks associated with co-exposure to these emerging contaminants and environmental pollutants, such as non-essential metals, are poorly understood. The present study aimed to investigate the cytotoxicity and toxicological interaction of AgNPs (0.36 and 3.6 μg mL−1) + lead (Pb2+, 25 and 250 μM) and AgNPs + mercury (Hg2+, 15 and 150 μM) using the macrophage cell line RAW 264.7 as a model. Effects were observed after a few hours (4 h) on NO levels, phagocytic activity, and DNA damage. Cell viability (24 h-exposure) was affected mainly by the higher concentrations of the contaminants and their mixtures, preceded by increases in NO levels and DNA damage, but without effects on ROS levels. Co-exposure potentiated some effects (ROS and NO levels and DNA damage), indicating toxicological interaction. These important findings must be further investigated, since the interaction of Pb2+ and Hg2+ with AgNPs from nanoproducts may impair the function of macrophages and represent a health risk for humans.
{"title":"Cytotoxic effects of silver nanoparticles and non-essential metals in murine macrophages","authors":"Andressa Glinski , Jessica Zablocki da Luz , Aliciane de Almeida Roque , Tugstênio Lima de Souza , Arandi Ginane Bezerra Junior , Carolina Camargo de Oliveira , Ciro Alberto de Oliveira Ribeiro , Francisco Filipak Neto","doi":"10.1016/j.yrtph.2025.105987","DOIUrl":"10.1016/j.yrtph.2025.105987","url":null,"abstract":"<div><div>Silver nanoparticles (AgNPs) are widely used in nanotechnology products. However, the health risks associated with co-exposure to these emerging contaminants and environmental pollutants, such as non-essential metals, are poorly understood. The present study aimed to investigate the cytotoxicity and toxicological interaction of AgNPs (0.36 and 3.6 μg mL<sup>−1</sup>) + lead (Pb<sup>2+</sup>, 25 and 250 μM) and AgNPs + mercury (Hg<sup>2+</sup>, 15 and 150 μM) using the macrophage cell line RAW 264.7 as a model. Effects were observed after a few hours (4 h) on NO levels, phagocytic activity, and DNA damage. Cell viability (24 h-exposure) was affected mainly by the higher concentrations of the contaminants and their mixtures, preceded by increases in NO levels and DNA damage, but without effects on ROS levels. Co-exposure potentiated some effects (ROS and NO levels and DNA damage), indicating toxicological interaction. These important findings must be further investigated, since the interaction of Pb<sup>2+</sup> and Hg<sup>2+</sup> with AgNPs from nanoproducts may impair the function of macrophages and represent a health risk for humans.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105987"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145506568","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 : 2026-01-01Epub Date: 2025-11-04DOI: 10.1016/j.yrtph.2025.105982
{"title":"Retraction notice to “Repeated dose 28-day oral toxicity study of DEAE-Dextran in mice: An advancement in safety chemotherapeutics” [Regul. Toxicol. Pharm. 88 (2017) 262–272]","authors":"","doi":"10.1016/j.yrtph.2025.105982","DOIUrl":"10.1016/j.yrtph.2025.105982","url":null,"abstract":"","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105982"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452872","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 : 2026-01-01Epub Date: 2025-10-21DOI: 10.1016/j.yrtph.2025.105975
Pablo Fernández del Olmo, Julián Sánchez-Hermosilla, Ángel Callejón-Ferre, Marta Gómez-Galán, José Pérez-Alonso
Accurate assessment of occupational exposure to plant protection products in greenhouses poses specific challenges due to confined environments, operator variability, and the limited suitability of existing models under real working conditions. This study presents the development of a digital tool that implements a semi-quantitative model for evaluating pesticide exposure risk among greenhouse workers. The model integrates task-specific variables across four exposure scenarios: mixing and loading, application, maintenance and re-entry; and applies a logarithmic scoring system to calculate an exposure index. This index is then combined with a toxicity score derived from product hazard classifications to obtain a comprehensive risk level, interpreted using a five-tier classification scheme with corresponding preventive recommendations. The application includes a preliminary questionnaire to ensure basic safety conditions are met and incorporates an automated update mechanism that maintains an up-to-date list of authorized products based on official registries. The tool was developed with a focus on usability and structured logic, supporting efficient data entry and interpretability of results. Field testing was carried out in different greenhouses under commercial production located in southeast Spain, confirming the coherence and functionality of the tool under practical conditions.
{"title":"Development of a digital tool for semi-quantitative assessment of pesticide exposure risk in greenhouses","authors":"Pablo Fernández del Olmo, Julián Sánchez-Hermosilla, Ángel Callejón-Ferre, Marta Gómez-Galán, José Pérez-Alonso","doi":"10.1016/j.yrtph.2025.105975","DOIUrl":"10.1016/j.yrtph.2025.105975","url":null,"abstract":"<div><div>Accurate assessment of occupational exposure to plant protection products in greenhouses poses specific challenges due to confined environments, operator variability, and the limited suitability of existing models under real working conditions. This study presents the development of a digital tool that implements a semi-quantitative model for evaluating pesticide exposure risk among greenhouse workers. The model integrates task-specific variables across four exposure scenarios: mixing and loading, application, maintenance and re-entry; and applies a logarithmic scoring system to calculate an exposure index. This index is then combined with a toxicity score derived from product hazard classifications to obtain a comprehensive risk level, interpreted using a five-tier classification scheme with corresponding preventive recommendations. The application includes a preliminary questionnaire to ensure basic safety conditions are met and incorporates an automated update mechanism that maintains an up-to-date list of authorized products based on official registries. The tool was developed with a focus on usability and structured logic, supporting efficient data entry and interpretability of results. Field testing was carried out in different greenhouses under commercial production located in southeast Spain, confirming the coherence and functionality of the tool under practical conditions.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105975"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355878","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 : 2026-01-01Epub Date: 2025-10-24DOI: 10.1016/j.yrtph.2025.105980
Mark T.D. Cronin , Sophie Cable , Christian Desaintes , Sylvia E. Escher , Ellen Hessel , Ellen Fritsche , Petra Kern , Gavin Maxwell , Gladys Ouedraogo , Tomasz Sobanski , Matthias Wehr , Andrew White
The European Partnership for Alternative Approaches to Animal Testing (EPAA) held the “New Approach Methodology (NAMs) User Forum” at the European Chemicals Agency, Helsinki, Finland on 30–October 31, 2024. The User Forum brought together stakeholders from regulatory agencies, industry, non-governmental organisations (NGOs) and academia, as well as European Union competent authorities. Lessons learned from applying NAMs for regulatory use were provided by the European Food Safety Authority (EFSA) and European Chemicals Agency (ECHA). Progress in the development of the developmental and neurotoxicity in vitro battery (DNT IVB) and Alternative Safety Profiling Algorithm (ASPA) were described, as well as five case studies describing uses of NAMs for chemical safety assessment. The presentations confirmed progress in NAMs and, in particular, the value of tiered testing strategies to bring together different lines of evidence. Specifically, tiered testing strategies for non-animal information are organised into three tiers, which may be relevant to hazard, exposure and toxicokinetic information. Progress into, and the needs for improvement of, the tiered strategies were discussed with a particular focus on the types of NAMs (in silico and in vitro) that may be required at each tier and the how confidence may be assigned to making a decision.
{"title":"Report on the European Partnership for Alternative Approaches to Animal Testing (EPAA) “New Approach Methodology (NAMs) User Forum”, 30–31 October 2024, Helsinki, Finland","authors":"Mark T.D. Cronin , Sophie Cable , Christian Desaintes , Sylvia E. Escher , Ellen Hessel , Ellen Fritsche , Petra Kern , Gavin Maxwell , Gladys Ouedraogo , Tomasz Sobanski , Matthias Wehr , Andrew White","doi":"10.1016/j.yrtph.2025.105980","DOIUrl":"10.1016/j.yrtph.2025.105980","url":null,"abstract":"<div><div>The European Partnership for Alternative Approaches to Animal Testing (EPAA) held the “New Approach Methodology (NAMs) User Forum” at the European Chemicals Agency, Helsinki, Finland on 30–October 31, 2024. The User Forum brought together stakeholders from regulatory agencies, industry, non-governmental organisations (NGOs) and academia, as well as European Union competent authorities. Lessons learned from applying NAMs for regulatory use were provided by the European Food Safety Authority (EFSA) and European Chemicals Agency (ECHA). Progress in the development of the developmental and neurotoxicity <em>in vitro</em> battery (DNT IVB) and Alternative Safety Profiling Algorithm (ASPA) were described, as well as five case studies describing uses of NAMs for chemical safety assessment. The presentations confirmed progress in NAMs and, in particular, the value of tiered testing strategies to bring together different lines of evidence. Specifically, tiered testing strategies for non-animal information are organised into three tiers, which may be relevant to hazard, exposure and toxicokinetic information. Progress into, and the needs for improvement of, the tiered strategies were discussed with a particular focus on the types of NAMs (<em>in silico</em> and <em>in vitro</em>) that may be required at each tier and the how confidence may be assigned to making a decision.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105980"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145424548","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 : 2026-01-01Epub Date: 2025-10-22DOI: 10.1016/j.yrtph.2025.105976
Mao-wen Weng, Xiaoling (Sharlene) Dai, Shaoping Wu, Jared Wilsey, Matt Lewis, Robert F. Shulfer, Marika Kamberi
Cohort of concern substances (CoCs) present challenges in medical device toxicological risk assessment. They are excluded from the lifetime threshold of toxicological concern (TTC) per ISO/TS 21726, because their toxic dose is < 1.5 μg/day and they may present a higher cancer risk. Relying solely on structural similarities with known toxicants is inadequate for assessing carcinogenic potency. This study selected chemicals from the Carcinogenic Potency Database (CPDB) to establish a framework for identifying potential CoCs. To do that, a threshold of Cancer Risk Specific Dose (CRSD) < 0.025 μg/kg/day was initially applied. Chemicals meeting this criterion are recognized as CoCs. However, the risk assessment could be impeded by particular uncertainties, such as the inability to determine the CRSD. In such cases, the identified CoCs were further categorized based on their mutagenicity determined by the Ames test results. A scatterplot reveals a significant correlation between the carcinogenic potency [ Log(0.5/TD50)+7] and acute systemic toxicity [Log(LD50)] in the CoCs-Ames (−) group (R2 = 0.72). For the CoCs-Ames (+) group (n = 124), 18 CoCs with available mutation slope data show cancer risk greater than the default risk of 1 in 100,000. This study provides a framework integrating scientific evidence and regulatory guidelines to identify potential CoCs.
{"title":"Exploration of a framework to identify cohort of concern substances in medical device risk assessment","authors":"Mao-wen Weng, Xiaoling (Sharlene) Dai, Shaoping Wu, Jared Wilsey, Matt Lewis, Robert F. Shulfer, Marika Kamberi","doi":"10.1016/j.yrtph.2025.105976","DOIUrl":"10.1016/j.yrtph.2025.105976","url":null,"abstract":"<div><div>Cohort of concern substances (CoCs) present challenges in medical device toxicological risk assessment. They are excluded from the lifetime threshold of toxicological concern (TTC) per ISO/TS 21726, because their toxic dose is < 1.5 μg/day and they may present a higher cancer risk. Relying solely on structural similarities with known toxicants is inadequate for assessing carcinogenic potency. This study selected chemicals from the Carcinogenic Potency Database (CPDB) to establish a framework for identifying potential CoCs. To do that, a threshold of Cancer Risk Specific Dose (CRSD) < 0.025 μg/kg/day was initially applied. Chemicals meeting this criterion are recognized as CoCs. However, the risk assessment could be impeded by particular uncertainties, such as the inability to determine the CRSD. In such cases, the identified CoCs were further categorized based on their mutagenicity determined by the Ames test results. A scatterplot reveals a significant correlation between the carcinogenic potency [ Log(0.5/TD<sub>50</sub>)+7] and acute systemic toxicity [Log(LD<sub>50</sub>)] in the CoCs-Ames (−) group (R<sup>2</sup> = 0.72). For the CoCs-Ames (+) group (n = 124), 18 CoCs with available mutation slope data show cancer risk greater than the default risk of 1 in 100,000. This study provides a framework integrating scientific evidence and regulatory guidelines to identify potential CoCs.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105976"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368588","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 : 2026-01-01Epub Date: 2025-09-13DOI: 10.1016/j.yrtph.2025.105941
Ladan Fakhrzadeh , Otto Mills , Jim Bowman , Michael J. Cork , Alain Khaiat , James A. McGuire , Teginder Singh , Evren Atillasoy
Skin sensitization testing to ensure the safety of skincare products for public consumption has largely relied on human repeat insult patch test (HRIPT). The desire to minimize reliance on HRIPT has prompted a search for alternative methods to assess the sensitization risk of consumer products to inform decision-making about their suitability before being brought to market. The novel Skin Sensitization Prediction Model (SSPM) is a methodology that draws upon a database consisting of more than 20 years of historical HRIPT data pertaining to 1274 unique product formulations, comprising 1226 common ingredients, for which HRIPT testing has been performed on 203,640 human subjects. The SSPM sets modifiable thresholds for each individual ingredient of a proposed formulation and for the formulation as a whole, applying risk calculations based on dosage density, potential for skin occlusion, potential for skin barrier impairment, and potential effects on immune-primed skin. Tabulations of a formulation's risk characteristics allow for a numerical risk calculation that is compared to the preset thresholds to determine whether the product may continue its development or should be reformulated or discontinued. This methodology points to a new model for sensitization testing for a wide array of products without recourse to in vivo testing.
{"title":"The skin sensitization prediction model: an algorithm for real-world prediction of skin sensitization risk and minimization of human sensitization testing","authors":"Ladan Fakhrzadeh , Otto Mills , Jim Bowman , Michael J. Cork , Alain Khaiat , James A. McGuire , Teginder Singh , Evren Atillasoy","doi":"10.1016/j.yrtph.2025.105941","DOIUrl":"10.1016/j.yrtph.2025.105941","url":null,"abstract":"<div><div>Skin sensitization testing to ensure the safety of skincare products for public consumption has largely relied on human repeat insult patch test (HRIPT). The desire to minimize reliance on HRIPT has prompted a search for alternative methods to assess the sensitization risk of consumer products to inform decision-making about their suitability before being brought to market. The novel Skin Sensitization Prediction Model (SSPM) is a methodology that draws upon a database consisting of more than 20 years of historical HRIPT data pertaining to 1274 unique product formulations, comprising 1226 common ingredients, for which HRIPT testing has been performed on 203,640 human subjects. The SSPM sets modifiable thresholds for each individual ingredient of a proposed formulation and for the formulation as a whole, applying risk calculations based on dosage density, potential for skin occlusion, potential for skin barrier impairment, and potential effects on immune-primed skin. Tabulations of a formulation's risk characteristics allow for a numerical risk calculation that is compared to the preset thresholds to determine whether the product may continue its development or should be reformulated or discontinued. This methodology points to a new model for sensitization testing for a wide array of products without recourse to <em>in vivo</em> testing.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105941"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070369","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 : 2026-01-01Epub Date: 2025-09-24DOI: 10.1016/j.yrtph.2025.105948
Nicola J. Hewitt , Hind Assaf Vandecasteele , Paul Benndorf , Rolf Fautz , Anne Fuchs , Karma Fussell , Carsten Goebel , Torben König , Fabrice Nesslany , Juliane Werner , Paul Fowler
New in vivo data cannot be generated for cosmetics. New safety assessments for genotoxicity must rely on in vivo data from the in vivo Mammalian Erythrocyte Micronucleus (MN) Test generated before the ban. Many used intraperitoneal (i.p.) administration, which is no longer recommended without scientific justification. Therefore, we investigated whether these studies are still valid for evaluating genotoxicity of hair dyes. Small to medium size molecules, including hair dyes, are preferentially absorbed via the portal vein and undergo first-pass metabolism, whereas large molecules are taken up by the lymphatics directly into the systemic circulation. Plasma concentrations of small molecules are generally similar, if not higher, after i.p. than after p.o. administration. Importantly, outcomes from in vivo MN Test using the i.p. and p.o. routes were equivalent. Most genotoxic carcinogens with positive outcomes in the in vivo MN Test were administered by i.p. injection. Differences between in vivo genotoxicity assay results using administration routes are attributed to the Mode of Action and/or tissue-specific effects. In conclusion, the i.p. route achieves sufficiently high internal exposure i.e., in the plasma and bone marrow. Therefore, legacy OECD test guideline compliant studies using the i.p. route are valid for current safety assessments of hair dyes.
{"title":"Suitability of the use of the intraperitoneal route in the in vivo micronucleus test to evaluate the genotoxicity of hair dyes","authors":"Nicola J. Hewitt , Hind Assaf Vandecasteele , Paul Benndorf , Rolf Fautz , Anne Fuchs , Karma Fussell , Carsten Goebel , Torben König , Fabrice Nesslany , Juliane Werner , Paul Fowler","doi":"10.1016/j.yrtph.2025.105948","DOIUrl":"10.1016/j.yrtph.2025.105948","url":null,"abstract":"<div><div>New <em>in vivo</em> data cannot be generated for cosmetics. New safety assessments for genotoxicity must rely on <em>in vivo</em> data from the <em>in vivo</em> Mammalian Erythrocyte Micronucleus (MN) Test generated before the ban. Many used intraperitoneal (i.p.) administration, which is no longer recommended without scientific justification. Therefore, we investigated whether these studies are still valid for evaluating genotoxicity of hair dyes. Small to medium size molecules, including hair dyes, are preferentially absorbed via the portal vein and undergo first-pass metabolism, whereas large molecules are taken up by the lymphatics directly into the systemic circulation. Plasma concentrations of small molecules are generally similar, if not higher, after i.p. than after p.o. administration. Importantly, outcomes from <em>in vivo</em> MN Test using the i.p. and p.o. routes were equivalent. Most genotoxic carcinogens with positive outcomes in the <em>in vivo</em> MN Test were administered by i.p. injection. Differences between <em>in vivo</em> genotoxicity assay results using administration routes are attributed to the Mode of Action and/or tissue-specific effects. In conclusion, the i.p. route achieves sufficiently high internal exposure i.e., in the plasma and bone marrow. Therefore, legacy OECD test guideline compliant studies using the i.p. route are valid for current safety assessments of hair dyes.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105948"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145160017","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 : 2026-01-01Epub Date: 2025-10-14DOI: 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
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 in vitro-based regression models.
Herein, a framework for incorporating regression models into next-generation risk assessment (NGRA) is presented. The framework begins with hazard assessment using in vitro 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, p-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 in vitro models. This approach offers a promising alternative for PoD derivation, potentially eliminating the dependence on in-vivo data.
{"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}
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