Pub Date : 2025-12-20DOI: 10.1016/j.yrtph.2025.106017
Michel Aubanel , Christopher Choi , Jan Demyttenaere , Maodo Malick Diop , Sylvain Etter , Alexandra Blanchard , Christie L. Harman , Mihoko Koyanagi , Gerhard Krammer , Gregory Ladics , Severin Müller , George Pugh , Mark R. Bauter , Shannon E. Beck , Jeanne M. Davidsen , Suzanne F. Wilson , Sean V. Taylor
α-Terpineol is a flavoring ingredient that occurs naturally in spices and foods. It has been evaluated by regulatory and scientific expert bodies such as the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1999 and the European Food Safety Authority (EFSA) in 2006 and has been determined safe under the conditions of intended use. To ensure the continued safety of high-usage flavoring ingredients, a 90-day Organization for Economic Co-operation and Development (OECD) 408 and Good Laboratory Practice (GLP) compliant study was conducted in Sprague-Dawley (SD) rats (10/sex/groups) at target dietary intakes to achieve doses of 0, 50, 150 or 500 mg/kg bw/day. There were no unscheduled deaths and no adverse changes in ophthalmological examinations, body weight, food consumption, food efficiency, hematology, serum chemistry, urinalysis parameters and macroscopic and microscopic observations. While not statistically significant, excessive fragmentation of sperm (head and tail separating) was observed in high-dose males, resulting in reduced or zero sperm mobility. Based on the specific sperm abnormalities observed, the no-observed-adverse-effect level (NOAEL) was determined to be the middle dose, 146 mg/kg bw/day for male SD rats and 500 mg/kg bw/day, the highest dose tested, for female SD rats.
{"title":"Dietary administration of α-terpineol to Sprague-Dawley rats for 90 days","authors":"Michel Aubanel , Christopher Choi , Jan Demyttenaere , Maodo Malick Diop , Sylvain Etter , Alexandra Blanchard , Christie L. Harman , Mihoko Koyanagi , Gerhard Krammer , Gregory Ladics , Severin Müller , George Pugh , Mark R. Bauter , Shannon E. Beck , Jeanne M. Davidsen , Suzanne F. Wilson , Sean V. Taylor","doi":"10.1016/j.yrtph.2025.106017","DOIUrl":"10.1016/j.yrtph.2025.106017","url":null,"abstract":"<div><div>α-Terpineol is a flavoring ingredient that occurs naturally in spices and foods. It has been evaluated by regulatory and scientific expert bodies such as the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1999 and the European Food Safety Authority (EFSA) in 2006 and has been determined safe under the conditions of intended use. To ensure the continued safety of high-usage flavoring ingredients, a 90-day Organization for Economic Co-operation and Development (OECD) 408 and Good Laboratory Practice (GLP) compliant study was conducted in Sprague-Dawley (SD) rats (10/sex/groups) at target dietary intakes to achieve doses of 0, 50, 150 or 500 mg/kg bw/day. There were no unscheduled deaths and no adverse changes in ophthalmological examinations, body weight, food consumption, food efficiency, hematology, serum chemistry, urinalysis parameters and macroscopic and microscopic observations. While not statistically significant, excessive fragmentation of sperm (head and tail separating) was observed in high-dose males, resulting in reduced or zero sperm mobility. Based on the specific sperm abnormalities observed, the no-observed-adverse-effect level (NOAEL) was determined to be the middle dose, 146 mg/kg bw/day for male SD rats and 500 mg/kg bw/day, the highest dose tested, for female SD rats.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106017"},"PeriodicalIF":3.5,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805392","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 : 2025-12-19DOI: 10.1016/j.yrtph.2025.106015
Devaraj Ezhilarasan, Munusamy Karthick
In 2025, 24 children in India died after consuming COLDRIF, a paediatric cough syrup, due to acute kidney failure. Batch SR-13 from Sresan Pharmaceuticals in Tamil Nadu, India,was contaminated with 46.28 % diethylene glycol (DEG), a toxic solvent used in place of pharmaceutical-grade excipients. Kidney biopsies from children confirmed acute tubular necrosis. DEG toxicity, via its metabolites 2-hydroxyethoxyacetic acid and diglycolic acid, causes metabolic acidosis and nephrotoxicity. Global incidents highlight repeated risks of DEG adulteration in children medicines. Regulatory lapses and poor-quality control remain major contributors. Strict adherence to Good Manufacturing Practices and vigilant regulatory oversight are essential to prevent such fatal outbreaks.
{"title":"Adulterated cough syrup caused acute kidney failure deaths in children: lessons have still not been learnt","authors":"Devaraj Ezhilarasan, Munusamy Karthick","doi":"10.1016/j.yrtph.2025.106015","DOIUrl":"10.1016/j.yrtph.2025.106015","url":null,"abstract":"<div><div>In 2025, 24 children in India died after consuming COLDRIF, a paediatric cough syrup, due to acute kidney failure. Batch SR-13 from Sresan Pharmaceuticals in Tamil Nadu, India,was contaminated with 46.28 % diethylene glycol (DEG), a toxic solvent used in place of pharmaceutical-grade excipients. Kidney biopsies from children confirmed acute tubular necrosis. DEG toxicity, via its metabolites 2-hydroxyethoxyacetic acid and diglycolic acid, causes metabolic acidosis and nephrotoxicity. Global incidents highlight repeated risks of DEG adulteration in children medicines. Regulatory lapses and poor-quality control remain major contributors. Strict adherence to Good Manufacturing Practices and vigilant regulatory oversight are essential to prevent such fatal outbreaks.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106015"},"PeriodicalIF":3.5,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805364","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 : 2025-12-13DOI: 10.1016/j.yrtph.2025.106014
Chad M. Thompson , Melissa M. Heintz , John M. Cullen , Laurie C. Haws
Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (HFPO-DA; CAS#: 62037-80-3) was tested for potential toxicity and carcinogenicity in CD-1 mice administered 0, 0.05, 0.1, 0.5, or 5 mg/kg-day HFPO-DA via oral gavage for 9 or 18 months. Histopathological examinations were conducted at each time point along with clinical chemistry measurements. Reduced survival was observed in male mice exposed to 5 mg/kg-day for 18 months but not 9 months. Hepatocellular hypertrophy was the most sensitive histopathological response to HFPO-DA and was significantly increased in both sexes at 9 and 18 months of exposure. At 18 months, hepatocellular hypertrophy was not observed below 0.1 mg/kg-day. Liver tumors were significantly increased at 5 mg/kg-day in males at both timepoints and in females at 18 months. No other treatment related tumors were observed. Consistent with previously published studies in mice, transcriptomic responses in the liver of both sexes showed enrichment of peroxisome proliferator-activated receptor alpha (PPARα) signaling pathways. These changes demonstrate that the tumor response in the liver is consistent with a PPARα mode of action. Other noncancer histopathological effects were limited to the adrenal gland (5 mg/kg-day at ≥9 months) and testes (≥0.5 mg/kg-day at 18 months) of male mice.
{"title":"Evaluation of chronic toxicity and carcinogenicity of HFPO-DA in mice","authors":"Chad M. Thompson , Melissa M. Heintz , John M. Cullen , Laurie C. Haws","doi":"10.1016/j.yrtph.2025.106014","DOIUrl":"10.1016/j.yrtph.2025.106014","url":null,"abstract":"<div><div>Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (HFPO-DA; CAS#: 62037-80-3) was tested for potential toxicity and carcinogenicity in CD-1 mice administered 0, 0.05, 0.1, 0.5, or 5 mg/kg-day HFPO-DA via oral gavage for 9 or 18 months. Histopathological examinations were conducted at each time point along with clinical chemistry measurements. Reduced survival was observed in male mice exposed to 5 mg/kg-day for 18 months but not 9 months. Hepatocellular hypertrophy was the most sensitive histopathological response to HFPO-DA and was significantly increased in both sexes at 9 and 18 months of exposure. At 18 months, hepatocellular hypertrophy was not observed below 0.1 mg/kg-day. Liver tumors were significantly increased at 5 mg/kg-day in males at both timepoints and in females at 18 months. No other treatment related tumors were observed. Consistent with previously published studies in mice, transcriptomic responses in the liver of both sexes showed enrichment of peroxisome proliferator-activated receptor alpha (PPARα) signaling pathways. These changes demonstrate that the tumor response in the liver is consistent with a PPARα mode of action. Other noncancer histopathological effects were limited to the adrenal gland (5 mg/kg-day at ≥9 months) and testes (≥0.5 mg/kg-day at 18 months) of male mice.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106014"},"PeriodicalIF":3.5,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757547","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 : 2025-12-12DOI: 10.1016/j.yrtph.2025.106013
Simon K. Kjær , Nikolaj Rittig , Jens M. Bruun , Niels Møller , Mads Svart
Hyperketonemia and hyperlactatemia can be induced by exogenous supplementation of each individual compound. In this study we examined the safety profile of (R)-1,3-butanediol (S)-lactate ester, a new lactate-ketone ester (LaKe). We hypothesized that 4 weeks of LaKe supplementation would induce hyperketonemia, hyperlactatemia, be feasible, tolerable, and safe. In this randomized, double-blind, placebo-controlled cross-over study, otherwise healthy adults with obesity (N = 10) received 25 mL (∼27.75 g) LaKe or taste-matched non-caloric placebo twice daily for 28 days, followed by an additional dose in a laboratory setting on day 29 with fasting and continuous blood sampling. Compliance was ≥80 % with no dropouts. 28 days of LaKe consumption was overall well tolerated but associated with mild to moderate gastrointestinal side effects without affecting organ function biomarkers. Following a 25 mL dose of LaKe, beta-hydroxybutyrate (βHB) and lactate concentrations peaked at 0.6 mmol/L (IQR 0.5–0.675 mmol/L) and 2.15 mmol (IQR 1.5–2.65 mmol/L), respectively, while blood gases and and electrolytes remained within normal ranges. LaKe elevates blood concentrations of both βHB and lactate. The consumption of LaKe twice daily for 28 days is well tolerated and safe, although associated with mild to moderate gastrointestinal side effects.
{"title":"Kinetics, tolerability and safety of (R)-1,3-butanediol (S)-lactate ester (LaKe): A randomized controlled cross-over trial in adults with obesity","authors":"Simon K. Kjær , Nikolaj Rittig , Jens M. Bruun , Niels Møller , Mads Svart","doi":"10.1016/j.yrtph.2025.106013","DOIUrl":"10.1016/j.yrtph.2025.106013","url":null,"abstract":"<div><div>Hyperketonemia and hyperlactatemia can be induced by exogenous supplementation of each individual compound. In this study we examined the safety profile of (R)-1,3-butanediol (S)-lactate ester, a new lactate-ketone ester (LaKe). We hypothesized that 4 weeks of LaKe supplementation would induce hyperketonemia, hyperlactatemia, be feasible, tolerable, and safe. In this randomized, double-blind, placebo-controlled cross-over study, otherwise healthy adults with obesity (N = 10) received 25 mL (∼27.75 g) LaKe or taste-matched non-caloric placebo twice daily for 28 days, followed by an additional dose in a laboratory setting on day 29 with fasting and continuous blood sampling. Compliance was ≥80 % with no dropouts. 28 days of LaKe consumption was overall well tolerated but associated with mild to moderate gastrointestinal side effects without affecting organ function biomarkers. Following a 25 mL dose of LaKe, beta-hydroxybutyrate (βHB) and lactate concentrations peaked at 0.6 mmol/L (IQR 0.5–0.675 mmol/L) and 2.15 mmol (IQR 1.5–2.65 mmol/L), respectively, while blood gases and and electrolytes remained within normal ranges. LaKe elevates blood concentrations of both βHB and lactate. The consumption of LaKe twice daily for 28 days is well tolerated and safe, although associated with mild to moderate gastrointestinal side effects.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106013"},"PeriodicalIF":3.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757496","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 : 2025-12-11DOI: 10.1016/j.yrtph.2025.106012
Michael A. Austin , Somalin Mao , Jonathan MacLeod , Zachary Cantor
Methoxyflurane, a self-administered fluorinated hydrocarbon, provides rapid, relief for traumatic pain. While low-dose methoxyflurane poses minimal risk, paramedics may experience intermittent exposure. This study assesses occupational risks to enhance paramedic safety, health standards, and patient care directives.
Active air sampling was conducted in a Ministry of Health-approved ambulance, in the driver and patient compartment, under controlled conditions, both with and without ventilation. Twelve healthy participants inhaled for 15 min, with samples collected per EPA and ISO standards. Results were adjusted for time weighted average (TWA) exposure.
Twenty-four air samples were collected (median age 30.5 years, 50 % female). Exposure concentrations remained below 8-h TWA occupational limits and NIOSH 60-min ceiling limits. With ventilation, 8-h TWA levels were 0.001 ppm (driver) and 0.033 ppm (patient compartment), rising to 0.017 ppm and 0.057 ppm without ventilation. Maximum TWA levels for 22 transports (30-min duration) reached 0.019 ppm (driver) and 0.736 ppm (patient) with ventilation, increasing to 0.377 ppm and 1.254 ppm without. These were based upon worst-case assumptions of 22 treatment and transport events, each lasting 30 min, over a 12 h work shift. Ventilation significantly reduced exposure, with 99.1 % protocol adherence and no adverse events.
This controlled study confirms methoxyflurane's safe use in ambulances with exposure well below safety thresholds. Ventilation minimizes potential risk(s), ensuring paramedic safety and uninterrupted pain management.
{"title":"Methoxyflurane exposure in ambulances: a controlled laboratory study on paramedic safety","authors":"Michael A. Austin , Somalin Mao , Jonathan MacLeod , Zachary Cantor","doi":"10.1016/j.yrtph.2025.106012","DOIUrl":"10.1016/j.yrtph.2025.106012","url":null,"abstract":"<div><div>Methoxyflurane, a self-administered fluorinated hydrocarbon, provides rapid, relief for traumatic pain. While low-dose methoxyflurane poses minimal risk, paramedics may experience intermittent exposure. This study assesses occupational risks to enhance paramedic safety, health standards, and patient care directives.</div><div>Active air sampling was conducted in a Ministry of Health-approved ambulance, in the driver and patient compartment, under controlled conditions, both with and without ventilation. Twelve healthy participants inhaled for 15 min, with samples collected per EPA and ISO standards. Results were adjusted for time weighted average (TWA) exposure.</div><div>Twenty-four air samples were collected (median age 30.5 years, 50 % female). Exposure concentrations remained below 8-h TWA occupational limits and NIOSH 60-min ceiling limits. With ventilation, 8-h TWA levels were 0.001 ppm (driver) and 0.033 ppm (patient compartment), rising to 0.017 ppm and 0.057 ppm without ventilation. Maximum TWA levels for 22 transports (30-min duration) reached 0.019 ppm (driver) and 0.736 ppm (patient) with ventilation, increasing to 0.377 ppm and 1.254 ppm without. These were based upon worst-case assumptions of 22 treatment and transport events, each lasting 30 min, over a 12 h work shift. Ventilation significantly reduced exposure, with 99.1 % protocol adherence and no adverse events.</div><div>This controlled study confirms methoxyflurane's safe use in ambulances with exposure well below safety thresholds. Ventilation minimizes potential risk(s), ensuring paramedic safety and uninterrupted pain management.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106012"},"PeriodicalIF":3.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744005","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 : 2025-12-09DOI: 10.1016/j.yrtph.2025.106011
Giulia Collatuzzo , Paolo Boffetta
Pesticides are suspected to cause health effects in humans, but human-based data on their toxicity are often insufficient to establish associations and quantify risks. We reviewed literature on trichlorfon and investigated methodological aspects of risk assessment for pesticides based on human data. We provided an overview of epidemiology of pesticide toxicity, with focus on methodological features of the available studies, combined with a systematic review of the health effects of the pesticide, trichlorfon in humans, focusing on studies published after 1990. Studies on dichlorvos, the metabolite of trichlorfon, as well as metrifonate, a medication with the identical formula as trichlorfon, were included. A total of 60 publications were identified on health effects of trichlorfon, dichlorvos and metrifonate. Studies on acute effects (N = 23 publications) comprised mainly case-reports related to accidents and suicidal attempts, and were connoted by cholinergic syndrome, gastrointestinal and general symptoms. Evidence on chronic effects derived from analyses of the Agricultural Health Study (28 publications), as well as case-control and cross-sectional studies (9 publications). Evidence of possible associations between trichlorfon or dichlorvos exposure and various outcomes was heterogeneous and insufficient to establish causality. Critical features of epidemiology studies used for pesticide risk assessment include study design, exposure misclassification, lack of quantitative exposure data, and lack of consideration to potential confounders. Few high-quality epidemiology studies are available on potential health effects of trichlorfon. Future studies conducted according to established guidelines and supported by artificial intelligence might help to fill the gap on human health risks from pesticides.
{"title":"Use of human data for risk assessment of pesticides: A review including an evaluation of trichlorfon as case study","authors":"Giulia Collatuzzo , Paolo Boffetta","doi":"10.1016/j.yrtph.2025.106011","DOIUrl":"10.1016/j.yrtph.2025.106011","url":null,"abstract":"<div><div>Pesticides are suspected to cause health effects in humans, but human-based data on their toxicity are often insufficient to establish associations and quantify risks. We reviewed literature on trichlorfon and investigated methodological aspects of risk assessment for pesticides based on human data. We provided an overview of epidemiology of pesticide toxicity, with focus on methodological features of the available studies, combined with a systematic review of the health effects of the pesticide, trichlorfon in humans, focusing on studies published after 1990. Studies on dichlorvos, the metabolite of trichlorfon, as well as metrifonate, a medication with the identical formula as trichlorfon, were included. A total of 60 publications were identified on health effects of trichlorfon, dichlorvos and metrifonate. Studies on acute effects (N = 23 publications) comprised mainly case-reports related to accidents and suicidal attempts, and were connoted by cholinergic syndrome, gastrointestinal and general symptoms. Evidence on chronic effects derived from analyses of the Agricultural Health Study (28 publications), as well as case-control and cross-sectional studies (9 publications). Evidence of possible associations between trichlorfon or dichlorvos exposure and various outcomes was heterogeneous and insufficient to establish causality. Critical features of epidemiology studies used for pesticide risk assessment include study design, exposure misclassification, lack of quantitative exposure data, and lack of consideration to potential confounders. Few high-quality epidemiology studies are available on potential health effects of trichlorfon. Future studies conducted according to established guidelines and supported by artificial intelligence might help to fill the gap on human health risks from pesticides.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 106011"},"PeriodicalIF":3.5,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744027","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 : 2025-12-09DOI: 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}
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