Pub Date : 2026-03-01Epub 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":"2026-03-01","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 : 2026-02-28DOI: 10.1016/j.yrtph.2026.106067
A Sanz-Pérez, T Pérez, E González-Burgos
Although cannabis exposure is linked to oxidative stress, no systematic analysis has evaluated its effects on ROS production, lipid peroxidation, and antioxidant defenses. We conducted a systematic review and meta-analysis of recent in vivo and in vitro studies. Of 9775 records identified across six databases, 51 met inclusion criteria and 49 were quantitatively analyzed (23 in vitro, 26 in vivo). In vitro studies exposed cell lines to phytocannabinoids and measured ROS, MDA, and GSH. In vivo studies included 1258 animals, mainly rats (52.7%) and mice (27%), treated with THC, CBD, THC + CBD, crude extracts, or synthetic cannabinoids via intraperitoneal, oral, or aqueous routes. Assessed biomarkers included MDA/TBARS, CAT, SOD, GSH, and GPx. Meta-analyses showed cannabis exposure was associated with ROS production in vitro (SMD = 0.04, 95% CI 0.02-0.06), a small, context-dependent effect, and in vivo (SMD = 0.93, 95% CI 0.10-1.75), along with increased lipid peroxidation in both systems. Cannabis reduced GSH and antioxidant enzymes, decreasing GR and CAT in vitro and SOD and GPx in vivo. Overall, cannabinoid exposure was associated with changes in oxidative stress markers in preclinical models. These findings suggest a possible biological pathway but do not provide definitive evidence of a consistent effect.
虽然大麻暴露与氧化应激有关，但没有系统的分析评估其对活性氧产生、脂质过氧化和抗氧化防御的影响。我们对最近的体内和体外研究进行了系统回顾和荟萃分析。在6个数据库中鉴定的9775条记录中，51条符合纳入标准，49条进行了定量分析（23条体外，26条体内）。体外研究将细胞系暴露于植物大麻素并测量ROS， MDA和GSH。体内研究包括1258只动物，主要是大鼠（52.7%）和小鼠（27%），通过腹腔、口服或水溶途径分别给予THC、CBD、THC+CBD、粗提取物或合成大麻素。评估的生物标志物包括MDA/TBARS、CAT、SOD、GSH和GPx。荟萃分析显示，大麻暴露与体外（SMD = 0.04, 95% CI 0.02-0.06）和体内（SMD = 0.93, 95% CI 0.10-1.75）的ROS产生有关，并与两个系统中脂质过氧化增加有关。大麻降低GSH和抗氧化酶，降低体外GR和CAT以及体内SOD和GPx。总体而言，大麻素暴露与临床前模型中氧化应激标志物的变化有关。这些发现提示了一种可能的生物学途径，但没有提供一致效果的明确证据。
{"title":"Preclinical evidence of cannabis-induced oxidative stress: A systematic review and meta-analysis.","authors":"A Sanz-Pérez, T Pérez, E González-Burgos","doi":"10.1016/j.yrtph.2026.106067","DOIUrl":"10.1016/j.yrtph.2026.106067","url":null,"abstract":"<p><p>Although cannabis exposure is linked to oxidative stress, no systematic analysis has evaluated its effects on ROS production, lipid peroxidation, and antioxidant defenses. We conducted a systematic review and meta-analysis of recent in vivo and in vitro studies. Of 9775 records identified across six databases, 51 met inclusion criteria and 49 were quantitatively analyzed (23 in vitro, 26 in vivo). In vitro studies exposed cell lines to phytocannabinoids and measured ROS, MDA, and GSH. In vivo studies included 1258 animals, mainly rats (52.7%) and mice (27%), treated with THC, CBD, THC + CBD, crude extracts, or synthetic cannabinoids via intraperitoneal, oral, or aqueous routes. Assessed biomarkers included MDA/TBARS, CAT, SOD, GSH, and GPx. Meta-analyses showed cannabis exposure was associated with ROS production in vitro (SMD = 0.04, 95% CI 0.02-0.06), a small, context-dependent effect, and in vivo (SMD = 0.93, 95% CI 0.10-1.75), along with increased lipid peroxidation in both systems. Cannabis reduced GSH and antioxidant enzymes, decreasing GR and CAT in vitro and SOD and GPx in vivo. Overall, cannabinoid exposure was associated with changes in oxidative stress markers in preclinical models. These findings suggest a possible biological pathway but do not provide definitive evidence of a consistent effect.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"106067"},"PeriodicalIF":3.5,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147327058","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 : 2026-02-23DOI: 10.1016/j.yrtph.2026.106064
Chukwujindu M A Iwegbue, Victor E Ajokperiniovo, Olubunmi A Adewusi, Onome Edigbina, Enebi E Jasper, Jeremiah Eko, Bice S Martincigh
Daily use of oral hygiene products (OHPs) contaminated with potentially toxic elements (PTEs) can cause acute or long-term intoxication. This study investigated the occurrence and human health risks associated with potential toxic metals such as Fe, Pb, Mn, Ni, Co, Cu, Cr, Zn and Cd in 55 commonly used OHPs such as dental powders (DP), toothpastes and mouth wash (MW) in Nigeria. The types of toothpastes include herbal toothpaste (HT), smokers/medicated toothpaste (SMT), children toothpaste (CT) and regular toothpaste (RT). The metal concentrations in the OHPs varied from 4.94 to 81.8, -1 for Fe, Pb, Mn, Ni, Co, Cu, Cr, Zn and Cd, respectively. The order of metal concentrations in the OHPs was Fe > Pb > Zn > Cu > Mn > Cr > Cd > Co > Ni. The hazard index (HI) values for the total metals and that of hazard quotients (HQs) of the individual metals resulting from the use of the OHPs by adults and children were below the risk threshold of 1, suggesting negligible non-carcinogenic risk. Carcinogenic risk (TCR) for Pb was several orders of magnitude below 10-6, confirming negligible cancer risk.
日常使用被潜在有毒元素（pte）污染的口腔卫生产品（ohp）可导致急性或长期中毒。本研究调查了尼日利亚55种常用ohp（如牙粉、牙膏和漱口水）中铁、铅、锰、镍、钴、铜、铬、锌和镉等潜在有毒金属的发生情况和与之相关的人类健康风险。牙膏的种类包括草药牙膏（HT），吸烟者/药物牙膏（SMT），儿童牙膏（CT）和普通牙膏（RT）。ohp中Fe、Pb、Mn、Ni、Co、Cu、Cr、Zn和Cd的金属浓度变化范围为4.94 ~ 81.8,-1。金属在OHPs中的浓度顺序为Fe > Pb > Zn > Cu > Mn > Cr > Cd > Co > Ni。成人和儿童使用OHPs导致的总金属危害指数（HI）值和单个金属危害商（hq）值均低于1的风险阈值，非致癌风险可以忽略不计。铅的致癌风险（TCR）低于10-6几个数量级，证实可忽略不计的癌症风险。
{"title":"Occurrence and exposure risk to potentially toxic metals from oral hygiene products in Nigeria.","authors":"Chukwujindu M A Iwegbue, Victor E Ajokperiniovo, Olubunmi A Adewusi, Onome Edigbina, Enebi E Jasper, Jeremiah Eko, Bice S Martincigh","doi":"10.1016/j.yrtph.2026.106064","DOIUrl":"https://doi.org/10.1016/j.yrtph.2026.106064","url":null,"abstract":"<p><p>Daily use of oral hygiene products (OHPs) contaminated with potentially toxic elements (PTEs) can cause acute or long-term intoxication. This study investigated the occurrence and human health risks associated with potential toxic metals such as Fe, Pb, Mn, Ni, Co, Cu, Cr, Zn and Cd in 55 commonly used OHPs such as dental powders (DP), toothpastes and mouth wash (MW) in Nigeria. The types of toothpastes include herbal toothpaste (HT), smokers/medicated toothpaste (SMT), children toothpaste (CT) and regular toothpaste (RT). The metal concentrations in the OHPs varied from 4.94 to 81.8, <LOQ to 33.8, 0.31 to 10.8, 0.08 to 2.44, 0.06 to 3.05, 0.83 to 11.9, 1.51 to 10.9 and 0.53 to 6.24 mg kg<sup>-1</sup> for Fe, Pb, Mn, Ni, Co, Cu, Cr, Zn and Cd, respectively. The order of metal concentrations in the OHPs was Fe > Pb > Zn > Cu > Mn > Cr > Cd > Co > Ni. The hazard index (HI) values for the total metals and that of hazard quotients (HQs) of the individual metals resulting from the use of the OHPs by adults and children were below the risk threshold of 1, suggesting negligible non-carcinogenic risk. Carcinogenic risk (TCR) for Pb was several orders of magnitude below 10<sup>-6</sup>, confirming negligible cancer risk.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"106064"},"PeriodicalIF":3.5,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147309572","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 : 2026-02-01Epub 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":"2026-02-01","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 : 2026-02-01Epub 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":"2026-02-01","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 : 2026-02-01Epub Date: 2025-11-15DOI: 10.1016/j.yrtph.2025.105990
N. Choksi , D. McMillan , D. Schmitt , C. Doepker , R.G. Henderson
Novel waxes require safety documentation, which traditionally involves using a battery of assays in experimental animals. For a class of well-studied substances (e.g., waxes) generally recognized to be of low or no toxicity, bridging methods that leverage safety information to fill data gaps for new substances may be considered. The aim of this assessment was to use a bridging assessment procedure to fill data gaps to demonstrate safety for two novel plant waxes (rice bran wax and sunflower wax). Using the European Chemicals Agency (ECHA) framework methodology, compositional similarity was established between the novel waxes and four well-evaluated plant waxes. Using the evidence bases for the evaluated plant waxes, the bridging assessment predicted that rice bran and sunflower waxes would have limited absorption. The bridging assessments also predicted that rice bran and sunflower waxes had limited repeat-dose oral toxicity, and were not reproductive or developmental toxicants or carcinogenic. Predicted lack of acute and mutagenic activity by rice bran wax was supported by experimental data. In conclusion, this case study shows that the bridging approach can fill toxicity data gaps, supporting a waiver of additional in vivo tests, thus ensuring safety, as well as reducing the use of animal testing.
{"title":"Demonstration of safety for rice bran wax and sunflower wax based on bridging to other naturally derived waxes used in foods","authors":"N. Choksi , D. McMillan , D. Schmitt , C. Doepker , R.G. Henderson","doi":"10.1016/j.yrtph.2025.105990","DOIUrl":"10.1016/j.yrtph.2025.105990","url":null,"abstract":"<div><div>Novel waxes require safety documentation, which traditionally involves using a battery of assays in experimental animals. For a class of well-studied substances (e.g., waxes) generally recognized to be of low or no toxicity, bridging methods that leverage safety information to fill data gaps for new substances may be considered. The aim of this assessment was to use a bridging assessment procedure to fill data gaps to demonstrate safety for two novel plant waxes (rice bran wax and sunflower wax). Using the European Chemicals Agency (ECHA) framework methodology, compositional similarity was established between the novel waxes and four well-evaluated plant waxes. Using the evidence bases for the evaluated plant waxes, the bridging assessment predicted that rice bran and sunflower waxes would have limited absorption. The bridging assessments also predicted that rice bran and sunflower waxes had limited repeat-dose oral toxicity, and were not reproductive or developmental toxicants or carcinogenic. Predicted lack of acute and mutagenic activity by rice bran wax was supported by experimental data. In conclusion, this case study shows that the bridging approach can fill toxicity data gaps, supporting a waiver of additional <em>in vivo</em> tests, thus ensuring safety, as well as reducing the use of animal testing.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 105990"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145542065","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 : 2026-02-01Epub 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":"2026-02-01","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 : 2026-02-01Epub 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":"2026-02-01","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 : 2026-02-01Epub Date: 2025-10-23DOI: 10.1016/j.yrtph.2025.105970
David J. Snodin
In ICH Q3C five residual solvents are classified as “should be avoided” and are designated as Class 1 solvents. The solvents in question are: benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene and 1,1,1-trichloroethane. Although multiple revisions to ICH Q3C have been made, PDE (permitted daily exposure) limits for Class 1 solvents remain unchanged from those originally proposed in 1997. Since that time, new toxicological data have become available, and additional expert assessments have been published. A detailed review of information currently available indicates that there is a case for a change to limits for all Class 1 solvents except benzene. Two of the solvents can be classified as mutagenic carcinogens making them eligible for determination of AI (acceptable intake) limits as described in ICH M7(R2). In addition, the concept of expressing limits as concentrations, based on the assumption of a daily drug-substance dose of 10 g, is challenged.
{"title":"ICH Q3C revisited part I: Evaluation of class 1 residual solvents","authors":"David J. Snodin","doi":"10.1016/j.yrtph.2025.105970","DOIUrl":"10.1016/j.yrtph.2025.105970","url":null,"abstract":"<div><div>In ICH Q3C five residual solvents are classified as “should be avoided” and are designated as Class 1 solvents. The solvents in question are: benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene and 1,1,1-trichloroethane. Although multiple revisions to ICH Q3C have been made, PDE (permitted daily exposure) limits for Class 1 solvents remain unchanged from those originally proposed in 1997. Since that time, new toxicological data have become available, and additional expert assessments have been published. A detailed review of information currently available indicates that there is a case for a change to limits for all Class 1 solvents except benzene. Two of the solvents can be classified as mutagenic carcinogens making them eligible for determination of AI (acceptable intake) limits as described in ICH M7(R2). In addition, the concept of expressing limits as concentrations, based on the assumption of a daily drug-substance dose of 10 g, is challenged.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 105970"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370380","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 : 2026-02-01Epub 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":"2026-02-01","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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