Pub Date : 2026-05-01Epub Date: 2026-01-21DOI: 10.1016/j.yrtph.2026.106033
Candace Doepker , Allison Franzen , Gregory Brorby , Lauren Brown , Neepa Choksi , Alexander East , Daniele Wikoff
Efforts to renew existing authorizations of smoke flavoring primary products (SFPPs) were recently finalized in the European Union. Herein, a Benefit Risk Assessment for Foods (BRAFO) was conducted for smoke flavorings using three specific SFPPs. Four metrics were evaluated between a reference scenario (legislation allowing both conventional smoking of foods and SFPPs) and an alternative scenario (SFPPs in meat, fish, and cheese are scheduled to be removed from the market after July 1, 2029, and only conventional smoking of foods is allowed): 1) whole mixture risk, 2) risk from polycyclic aromatic hydrocarbons (PAHs), 3) risk from constituents other than PAHs, and 4) environmental considerations. Systematic literature searches were used to identify information pertinent to each metric and scenario; direct testing data for the SFPPs was also used. All metrics were assessed qualitatively; quantitative assessment was also conducted when sufficient data were available. For each metric, the reference scenario prevailed, presenting the benefit of less risk than the alternative scenario. Key considerations involved the robust characterization of the SFPPs and direct testing data to inform safety, which are less controlled in conventional smoking of foods. The results of this assessment demonstrate the importance of risk-benefit considerations and should be helpful to policy makers globally.
{"title":"Smoke Flavoring-a case study demonstrating the value of using Benefit-risk analysis for foods (BRAFO) to provide transparency for risk management decisions","authors":"Candace Doepker , Allison Franzen , Gregory Brorby , Lauren Brown , Neepa Choksi , Alexander East , Daniele Wikoff","doi":"10.1016/j.yrtph.2026.106033","DOIUrl":"10.1016/j.yrtph.2026.106033","url":null,"abstract":"<div><div>Efforts to renew existing authorizations of smoke flavoring primary products (SFPPs) were recently finalized in the European Union. Herein, a Benefit Risk Assessment for Foods (BRAFO) was conducted for smoke flavorings using three specific SFPPs. Four metrics were evaluated between a reference scenario (legislation allowing both conventional smoking of foods and SFPPs) and an alternative scenario (SFPPs in meat, fish, and cheese are scheduled to be removed from the market after July 1, 2029, and only conventional smoking of foods is allowed): 1) whole mixture risk, 2) risk from polycyclic aromatic hydrocarbons (PAHs), 3) risk from constituents other than PAHs, and 4) environmental considerations. Systematic literature searches were used to identify information pertinent to each metric and scenario; direct testing data for the SFPPs was also used. All metrics were assessed qualitatively; quantitative assessment was also conducted when sufficient data were available. For each metric, the reference scenario prevailed, presenting the benefit of less risk than the alternative scenario. Key considerations involved the robust characterization of the SFPPs and direct testing data to inform safety, which are less controlled in conventional smoking of foods. The results of this assessment demonstrate the importance of risk-benefit considerations and should be helpful to policy makers globally.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106033"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-05-01Epub Date: 2026-02-11DOI: 10.1016/j.yrtph.2026.106060
Kevin E. Driscoll , Jeffrey I. Everitt , Paul J.A. Borm
An extensive toxicology database demonstrates talc exhibits the defining characteristics of poorly soluble, low-toxicity particles (PSLTs), including slow dissolution in biological fluids; macrophage-mediated clearance as the key determinant of lung residence time; significant inflammatory and proliferative responses only at lung burdens that overload normal particle clearance capacity; and, lung tumors in rats—but not in mice or hamsters—under conditions of excessive overload. This profile mirrors that documented for other PSLTs, such as titanium dioxide, carbon black, and diesel soot. Consistent with other PSLTs, talc has not been associated with increased lung cancer risk in humans, even after prolonged occupational exposure. Collectively, these observations demonstrate adverse rat lung responses to talc and other PSLTs are a consequence of lung overload rather than intrinsic toxicity, and the tumor response is unique to rats. Accordingly, hazard classification and risk assessment for PSLTs should explicitly consider the overload-dependent nature of responses. In the absence of evidence for intrinsic carcinogenic activity, lung tumors occurring only in rats and only under conditions of lung overload should not be interpreted as evidence of a human cancer hazard. Despite the well-established understanding of overload-driven PSLT responses in rats, recent IARC and ECHA/RAC evaluations interpreted rat lung tumors in the NTP study as evidence of inherent carcinogenicity. These assessments did not rigorously account for the PSLT properties of talc, the extensive evidence on lung particle overload, or that tumors occurred only at lung burdens greatly exceeding normal clearance capacity. Consequently, interpretations of the NTP findings conflict with the current state of the science.
{"title":"Talc fits the framework of poorly soluble low-toxicity particles - implications for hazard classification","authors":"Kevin E. Driscoll , Jeffrey I. Everitt , Paul J.A. Borm","doi":"10.1016/j.yrtph.2026.106060","DOIUrl":"10.1016/j.yrtph.2026.106060","url":null,"abstract":"<div><div>An extensive toxicology database demonstrates talc exhibits the defining characteristics of poorly soluble, low-toxicity particles (PSLTs), including slow dissolution in biological fluids; macrophage-mediated clearance as the key determinant of lung residence time; significant inflammatory and proliferative responses only at lung burdens that overload normal particle clearance capacity; and, lung tumors in rats—but not in mice or hamsters—under conditions of excessive overload. This profile mirrors that documented for other PSLTs, such as titanium dioxide, carbon black, and diesel soot. Consistent with other PSLTs, talc has not been associated with increased lung cancer risk in humans, even after prolonged occupational exposure. Collectively, these observations demonstrate adverse rat lung responses to talc and other PSLTs are a consequence of lung overload rather than intrinsic toxicity, and the tumor response is unique to rats. Accordingly, hazard classification and risk assessment for PSLTs should explicitly consider the overload-dependent nature of responses. In the absence of evidence for intrinsic carcinogenic activity, lung tumors occurring only in rats and only under conditions of lung overload should not be interpreted as evidence of a human cancer hazard. Despite the well-established understanding of overload-driven PSLT responses in rats, recent IARC and ECHA/RAC evaluations interpreted rat lung tumors in the NTP study as evidence of inherent carcinogenicity. These assessments did not rigorously account for the PSLT properties of talc, the extensive evidence on lung particle overload, or that tumors occurred only at lung burdens greatly exceeding normal clearance capacity. Consequently, interpretations of the NTP findings conflict with the current state of the science.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106060"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146191112","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 : 2026-05-01Epub Date: 2026-01-30DOI: 10.1016/j.yrtph.2026.106051
Robert A. Jolly , Alejandra Trejo-Martin , Joel P. Bercu , Mark W. Powley , Rachael E. Tennant , David J. Ponting , Raphael Nudelman , Zhanna Sobol , Andreas Czich , George E. Johnson , Yi Yang , Tetyana Kobets , Paul A. White , Sheroy Minocherhomji , Anthony M. Lynch , Andreas Zeller , Gregory R. Ott , Patricia A. Escobar , Cheryl Hobbs , Maik Schuler , Raechel Puglisi
Nitrosamines (NAs) are a diverse class of mutagenic impurities encompassing both small molecules and structurally complex drug-related NAs, referred to as nitrosamine drug substance-related impurities (NDSRIs). NAs display a broad range of carcinogenic potential, from high carcinogenic potency to being weak or even non-carcinogenic. In vitro Ames tests, conducted with both rat and hamster liver-induced S9, and in vivo transgenic rodent (TGR) mutation assays have been used by pharmaceutical sponsors for hazard identification of NDSRIs. A comparative analysis of Ames tests and TGR results for 33 NDSRIs was performed and revealed an accuracy of 79 % between the overall mutagenic calls in the two assays. For NDSRIs with positive TGR results, mutagenic potency estimates were calculated and compared to NAs with robust carcinogenicity and TGR dose-response data. Results from these NAs demonstrated a strong correlation between carcinogenic potency (TD50) and TGR mutagenic potency (BMDL50) (r2 = 0.95), which supports the use of TGR data for both hazard identification and acceptable intake (AI) determination. By integrating quantitative risk assessment tools with TGR assays, this work contributes to a more robust framework for evaluating NA-associated risks.
亚硝胺（Nitrosamines, NAs）是一类多样的致突变杂质，包括小分子和结构复杂的药物相关NAs，称为亚硝胺类药物相关杂质（nitrosamine drug substance related杂质，NDSRIs）。NAs具有广泛的致癌潜力，从高致癌性到弱致癌性甚至无致癌性。用大鼠和仓鼠肝脏诱导的S9进行的体外Ames试验，以及体内转基因啮齿动物（TGR）突变试验，已被制药公司用于NDSRIs的危害鉴定。对33种NDSRIs的Ames试验和TGR结果进行了比较分析，结果显示两种分析的总体诱变要求之间的准确性为79%。对于TGR结果为阳性的NDSRIs，计算致突变效力估计值，并将其与具有强大致癌性和TGR剂量反应数据的NAs进行比较。这些NAs的结果表明，致癌效力（TD50）和TGR致突变效力（BMDL50）之间存在很强的相关性（r2 = 0.95），这支持将TGR数据用于危害识别和可接受摄入量（AI）确定。通过将定量风险评估工具与TGR分析相结合，这项工作有助于建立一个更健全的评估dna相关风险的框架。
{"title":"Ames concordance with the in vivo transgenic rodent (TGR) gene mutation assay for NDSRIs and relative in vivo TGR potency with nitrosamines with robust dose-response carcinogenicity data","authors":"Robert A. Jolly , Alejandra Trejo-Martin , Joel P. Bercu , Mark W. Powley , Rachael E. Tennant , David J. Ponting , Raphael Nudelman , Zhanna Sobol , Andreas Czich , George E. Johnson , Yi Yang , Tetyana Kobets , Paul A. White , Sheroy Minocherhomji , Anthony M. Lynch , Andreas Zeller , Gregory R. Ott , Patricia A. Escobar , Cheryl Hobbs , Maik Schuler , Raechel Puglisi","doi":"10.1016/j.yrtph.2026.106051","DOIUrl":"10.1016/j.yrtph.2026.106051","url":null,"abstract":"<div><div>Nitrosamines (NAs) are a diverse class of mutagenic impurities encompassing both small molecules and structurally complex drug-related NAs, referred to as nitrosamine drug substance-related impurities (NDSRIs). NAs display a broad range of carcinogenic potential, from high carcinogenic potency to being weak or even non-carcinogenic. <em>In vitro</em> Ames tests, conducted with both rat and hamster liver-induced S9, and <em>in vivo</em> transgenic rodent (TGR) mutation assays have been used by pharmaceutical sponsors for hazard identification of NDSRIs. A comparative analysis of Ames tests and TGR results for 33 NDSRIs was performed and revealed an accuracy of 79 % between the overall mutagenic calls in the two assays. For NDSRIs with positive TGR results, mutagenic potency estimates were calculated and compared to NAs with robust carcinogenicity and TGR dose-response data. Results from these NAs demonstrated a strong correlation between carcinogenic potency (TD<sub>50</sub>) and TGR mutagenic potency (BMDL<sub>50</sub>) (r<sup>2</sup> = 0.95), which supports the use of TGR data for both hazard identification and acceptable intake (AI) determination. By integrating quantitative risk assessment tools with TGR assays, this work contributes to a more robust framework for evaluating NA-associated risks.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106051"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Plant protection products (PPPs) contain active substances (AS) providing pesticidal activity and co-formulants supporting efficacy. AS undergo extensive safety assessment, including genotoxicity testing, while PPPs are assessed only for acute and local toxicity. Genotoxicity may contribute to long-term effects like carcinogenesis, and as operators are exposed to concentrated PPPs and spray dilutions, co-formulant toxicity and interactions require attention. An in silico analysis was conducted to identify potentially genotoxic co-formulants and prioritise PPPs for in vitro testing. Four prioritised co-formulants exceeded 1 % concentration in eight PPPs, but existing data ruled out further investigation. AS with known in vitro genotoxic potential were assessed for toxicokinetic interaction with co-formulants. The genotoxic potential of PPPs containing metiram, a dithiocarbamate fungicide, and pendimethalin, a dinitroaniline herbicide, was assessed in V79 cells using in vitro micronucleus test. No difference was observed between metiram and its PPP, whereas a 2-fold increase in micronuclei formation occurred in formulated PPP compared to pendimethalin alone at highest tested concentration. These findings indicate that co-formulants, although unlikely to be genotoxic on their own, may influence the genotoxic potential of pendimethalin in the tested PPP. Therefore, AS showing genotoxic potential in vitro should be considered for testing in respective formulated PPPs.
{"title":"Do co-formulants influence plant protection product genotoxicity?","authors":"Alkiviadis Stagkos-Georgiadis , Vishal Raolji , Jeannette Koenig , Philip Marx-Stoelting , Sabine Martin , Tewes Tralau , Carsten Kneuer , Alfonsina Paola D'Ambrosio Melendrez , Christian Tobias Willenbockel , Veronika Städele , Tanja Schwerdtle , Denise Bloch","doi":"10.1016/j.yrtph.2026.106059","DOIUrl":"10.1016/j.yrtph.2026.106059","url":null,"abstract":"<div><div>Plant protection products (PPPs) contain active substances (AS) providing pesticidal activity and co-formulants supporting efficacy. AS undergo extensive safety assessment, including genotoxicity testing, while PPPs are assessed only for acute and local toxicity. Genotoxicity may contribute to long-term effects like carcinogenesis, and as operators are exposed to concentrated PPPs and spray dilutions, co-formulant toxicity and interactions require attention. An <em>in silico</em> analysis was conducted to identify potentially genotoxic co-formulants and prioritise PPPs for <em>in vitro</em> testing. Four prioritised co-formulants exceeded 1 % concentration in eight PPPs, but existing data ruled out further investigation. AS with known <em>in vitro</em> genotoxic potential were assessed for toxicokinetic interaction with co-formulants. The genotoxic potential of PPPs containing metiram, a dithiocarbamate fungicide, and pendimethalin, a dinitroaniline herbicide, was assessed in V79 cells using <em>in vitro</em> micronucleus test. No difference was observed between metiram and its PPP, whereas a 2-fold increase in micronuclei formation occurred in formulated PPP compared to pendimethalin alone at highest tested concentration. These findings indicate that co-formulants, although unlikely to be genotoxic on their own, may influence the genotoxic potential of pendimethalin in the tested PPP. Therefore, AS showing genotoxic potential <em>in vitro</em> should be considered for testing in respective formulated PPPs.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106059"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166389","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 : 2026-03-18DOI: 10.1016/j.yrtph.2026.106083
Edgars Felkers, Clare Butler Ellis, Marc Kennedy, Siân Wright-Williams, Sarah Adham
A database was compiled with field measurement studies which were conducted by CropLife Europe (CLE) member companies between 2011 and 2019 to refine product-specific bystander and resident risk assessments and studies previously used to develop and test BREAM and BROWSE models. Bayesian analysis of the database suggests that the most important variables influencing drift are drift reduction, boom height, wind speed, mannequin height, distance downwind, crop class and formulation class. A comparison between BREAM 2 predictions and field measurements of potential bystander exposure have shown that the level of conservatism in the model is satisfactory and is therefore the most appropriate model currently available for risk assessment for bystanders and residents. Comparing spray drift values as median, 75th and 95th percentiles derived from the CLE data show that current EFSA guidance values significantly overestimate bystander/resident exposure.
{"title":"Dermal exposure of bystanders and residents to direct spray drift in low crops during pesticide application.","authors":"Edgars Felkers, Clare Butler Ellis, Marc Kennedy, Siân Wright-Williams, Sarah Adham","doi":"10.1016/j.yrtph.2026.106083","DOIUrl":"10.1016/j.yrtph.2026.106083","url":null,"abstract":"<p><p>A database was compiled with field measurement studies which were conducted by CropLife Europe (CLE) member companies between 2011 and 2019 to refine product-specific bystander and resident risk assessments and studies previously used to develop and test BREAM and BROWSE models. Bayesian analysis of the database suggests that the most important variables influencing drift are drift reduction, boom height, wind speed, mannequin height, distance downwind, crop class and formulation class. A comparison between BREAM 2 predictions and field measurements of potential bystander exposure have shown that the level of conservatism in the model is satisfactory and is therefore the most appropriate model currently available for risk assessment for bystanders and residents. Comparing spray drift values as median, 75th and 95th percentiles derived from the CLE data show that current EFSA guidance values significantly overestimate bystander/resident exposure.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"106083"},"PeriodicalIF":3.5,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147491562","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 : 2026-03-18DOI: 10.1016/j.yrtph.2026.106084
Mehmet Cihan Yavaş, Cumali Keskin, Salih Varol, Fazile Cantürk Tan, Selim Demirtaş
This study evaluated tartrazine-induced nephrotoxicity and the protective effects of curcumin in rats. Thirty-five male Wistar albino rats were assigned to five groups (n = 7): control; tartrazine 10 mg/kg/day; tartrazine 100 mg/kg/day; tartrazine 10 mg/kg/day + curcumin 20 mg/kg/day; and tartrazine 100 mg/kg/day + curcumin 20 mg/kg/day. After 21 days, blood and kidney samples were analyzed for biochemical, oxidative, genotoxic, and histopathological changes. High-dose tartrazine significantly elevated serum urea and creatinine levels compared with controls (urea, p=0.033; creatinine, p < 0.001), indicating renal dysfunction. Curcumin co-treatment mitigated these elevations. Total antioxidant status (TAS) was elevated by tartrazine exposure but decreased with curcumin supplementation (p < 0.001), total oxidant status (TOS) showed a non-significant increasing trend and was reduced by curcumin. Compared to the control group, MDA levels decreased with low-dose tartrazine and increased with high-dose tartrazine, while curcumin supplementation increased levels (p < 0.05). Comet assay and histopathological analyses confirmed dose-dependent DNA and tissue damage, both of which were alleviated by curcumin. Overall, short-term tartrazine exposure may induce renal biochemical, oxidative, and genotoxic alterations in rats under experimental conditions, particularly at doses exceeding the ADI level. The antioxidant properties of curcumin may mitigate the negative effects of food dyes.
{"title":"Tartrazine-induced nephrotoxicity via oxidative and genotoxic pathways in rats: Regulatory insights and the nephroprotective role of curcumin.","authors":"Mehmet Cihan Yavaş, Cumali Keskin, Salih Varol, Fazile Cantürk Tan, Selim Demirtaş","doi":"10.1016/j.yrtph.2026.106084","DOIUrl":"https://doi.org/10.1016/j.yrtph.2026.106084","url":null,"abstract":"<p><p>This study evaluated tartrazine-induced nephrotoxicity and the protective effects of curcumin in rats. Thirty-five male Wistar albino rats were assigned to five groups (n = 7): control; tartrazine 10 mg/kg/day; tartrazine 100 mg/kg/day; tartrazine 10 mg/kg/day + curcumin 20 mg/kg/day; and tartrazine 100 mg/kg/day + curcumin 20 mg/kg/day. After 21 days, blood and kidney samples were analyzed for biochemical, oxidative, genotoxic, and histopathological changes. High-dose tartrazine significantly elevated serum urea and creatinine levels compared with controls (urea, p=0.033; creatinine, p < 0.001), indicating renal dysfunction. Curcumin co-treatment mitigated these elevations. Total antioxidant status (TAS) was elevated by tartrazine exposure but decreased with curcumin supplementation (p < 0.001), total oxidant status (TOS) showed a non-significant increasing trend and was reduced by curcumin. Compared to the control group, MDA levels decreased with low-dose tartrazine and increased with high-dose tartrazine, while curcumin supplementation increased levels (p < 0.05). Comet assay and histopathological analyses confirmed dose-dependent DNA and tissue damage, both of which were alleviated by curcumin. Overall, short-term tartrazine exposure may induce renal biochemical, oxidative, and genotoxic alterations in rats under experimental conditions, particularly at doses exceeding the ADI level. The antioxidant properties of curcumin may mitigate the negative effects of food dyes.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"106084"},"PeriodicalIF":3.5,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147491580","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 : 2026-03-12DOI: 10.1016/j.yrtph.2026.106082
Keith Morris-Schaffer, Neslihan Aygun Kocabas, Sara Hearon, Larry G Higgins, Sarah Dahlberg, Frank Faulhammer, Elaine Freeman, Janine Cubello, Martijn Rooseboom
Xylene substances (xylene) are high production chemicals that are currently undergoing new data generation and dossier evaluation under European Regulation on the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) including consideration of an additional immunotoxicity testing cohort to an extended one-generation reproduction toxicity study (EOGRTS). To address the need for an additional EOGRTS cohort, a weight of evidence assessment was conducted on xylene's immunosuppression potential using ToxRTool, and the World Health Organization (WHO) International Programme on Chemical Safety (IPCS) framework. The evaluation included a review of historical human and experimental animal literature as well as new toxicity data from guideline studies. Two limited epidemiology studies showed no xylene exposure-related effects on white blood cell counts. Reliable study results from a mouse host resistance model were negative. No mammalian T-cell dependent antibody response assays were located for xylene in the literature review. No xylene-related immunological change was observed in an avian immunotoxicity study. In addition, a review of immune functional data on structural analogues did not indicate a signal for immunosuppression. Lastly, in guideline studies, several statistically spurious, isolated, and/or inconsistent immune system findings were observed, but overall, the dataset in its totality demonstrated no signal of xylene-mediated immunosuppression. In conclusion, xylene shows no evidence of immunosuppression and there is no need for an immunotoxicity cohort evaluation in any subsequent EOGRTS.
{"title":"A Weight of Evidence Evaluation on the Immunosuppressive Potential of Xylene.","authors":"Keith Morris-Schaffer, Neslihan Aygun Kocabas, Sara Hearon, Larry G Higgins, Sarah Dahlberg, Frank Faulhammer, Elaine Freeman, Janine Cubello, Martijn Rooseboom","doi":"10.1016/j.yrtph.2026.106082","DOIUrl":"https://doi.org/10.1016/j.yrtph.2026.106082","url":null,"abstract":"<p><p>Xylene substances (xylene) are high production chemicals that are currently undergoing new data generation and dossier evaluation under European Regulation on the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) including consideration of an additional immunotoxicity testing cohort to an extended one-generation reproduction toxicity study (EOGRTS). To address the need for an additional EOGRTS cohort, a weight of evidence assessment was conducted on xylene's immunosuppression potential using ToxRTool, and the World Health Organization (WHO) International Programme on Chemical Safety (IPCS) framework. The evaluation included a review of historical human and experimental animal literature as well as new toxicity data from guideline studies. Two limited epidemiology studies showed no xylene exposure-related effects on white blood cell counts. Reliable study results from a mouse host resistance model were negative. No mammalian T-cell dependent antibody response assays were located for xylene in the literature review. No xylene-related immunological change was observed in an avian immunotoxicity study. In addition, a review of immune functional data on structural analogues did not indicate a signal for immunosuppression. Lastly, in guideline studies, several statistically spurious, isolated, and/or inconsistent immune system findings were observed, but overall, the dataset in its totality demonstrated no signal of xylene-mediated immunosuppression. In conclusion, xylene shows no evidence of immunosuppression and there is no need for an immunotoxicity cohort evaluation in any subsequent EOGRTS.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"106082"},"PeriodicalIF":3.5,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147459105","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 : 2026-03-11DOI: 10.1016/j.yrtph.2026.106081
Lynea Murphy, Robert Mingoia, Enrica Bianchi, Viera Lukacova, Jeanne Domoradzki, Claire Terry, Sean Gehen, Rachel Brunner, Angela Myer, Brandall L Ingle, Daniel Hoer, Yu-Mei Tan
Regulatory testing for agrochemicals has traditionally included a 90-day toxicity study in a non-rodent species, usually the dog. With growing emphasis on the 3Rs-replacement, reduction, and refinement of animal use-and increased adoption of New Approach Methodologies (NAMs), there is interest in determining when such studies are truly necessary. This case study on florpyrauxifen-benzyl ester uses a weight-of-evidence (WoE) framework integrating short-term in vivo, in vitro, and in silico data to evaluate the need for a 90-day dog study in human health risk assessment. In 28-day studies, rats and dogs showed no adverse effects up to approximately 1000 mg/kg/day, so the assessment focused on toxicokinetic sensitivity. Rat and dog toxicokinetic data-from metabolism, dose-range-finding, and 28-day studies-were combined with in vitro plasma protein binding and microsomal clearance data in physiologically based pharmacokinetic (PBPK) models. These models predicted 90-day internal exposure and showed higher exposures in rats than dogs at comparable doses, with no evidence of accumulation. The model predictions aligned with observed data and supported waiving the 90-day dog study. The existing study also did not change human health risk conclusions. Overall, this WoE framework shows how integrated data can justify waiving subchronic dog studies while maintaining protection of human health and reducing animal use.
{"title":"Integrating systemic toxicity and toxicokinetic data to inform the need for subchronic dog studies in human health safety assessments of agrochemicals.","authors":"Lynea Murphy, Robert Mingoia, Enrica Bianchi, Viera Lukacova, Jeanne Domoradzki, Claire Terry, Sean Gehen, Rachel Brunner, Angela Myer, Brandall L Ingle, Daniel Hoer, Yu-Mei Tan","doi":"10.1016/j.yrtph.2026.106081","DOIUrl":"10.1016/j.yrtph.2026.106081","url":null,"abstract":"<p><p>Regulatory testing for agrochemicals has traditionally included a 90-day toxicity study in a non-rodent species, usually the dog. With growing emphasis on the 3Rs-replacement, reduction, and refinement of animal use-and increased adoption of New Approach Methodologies (NAMs), there is interest in determining when such studies are truly necessary. This case study on florpyrauxifen-benzyl ester uses a weight-of-evidence (WoE) framework integrating short-term in vivo, in vitro, and in silico data to evaluate the need for a 90-day dog study in human health risk assessment. In 28-day studies, rats and dogs showed no adverse effects up to approximately 1000 mg/kg/day, so the assessment focused on toxicokinetic sensitivity. Rat and dog toxicokinetic data-from metabolism, dose-range-finding, and 28-day studies-were combined with in vitro plasma protein binding and microsomal clearance data in physiologically based pharmacokinetic (PBPK) models. These models predicted 90-day internal exposure and showed higher exposures in rats than dogs at comparable doses, with no evidence of accumulation. The model predictions aligned with observed data and supported waiving the 90-day dog study. The existing study also did not change human health risk conclusions. Overall, this WoE framework shows how integrated data can justify waiving subchronic dog studies while maintaining protection of human health and reducing animal use.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"106081"},"PeriodicalIF":3.5,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147459188","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}
Skin sensitization is a key endpoint in chemical safety assessment, involving multiple key events (KEs) in the adverse outcome pathway. The integrated testing strategy defined approach (ITS-DA) in OECD GL497 combines non-animal methods addressing KE1 and KE3 with an in silico component to predict sensitization. We developed a novel consensus in silico model integrating a rule-based system with metabolic simulation and two statistical models trained on local lymph node assay (LLNA) and guinea pig maximization test (GPMT) data.
When applied as the in silico element of the ITS-DA, the model achieved balanced accuracies of 77 % for LLNA and 70 % for human data, surpassing existing in silico approaches. Furthermore, we developed a rule- and statistics-based KE1 replacement model (RSRKE1) that estimates protein-binding potential without in chemico KE1 assays. Combining RSRKE1 with the human Cell Line Activation Test (h-CLAT, KE3) and the consensus model yielded sensitivities of ∼80 % and potency classification accuracies of ∼70 % for LLNA, with similar performance for human data.
These results demonstrate that the consensus model and RSRKE1 can maintain predictive performance comparable to established ITS-DA workflows, while eliminating the need for certain in vitro assays. This approach supports regulatory acceptance of non-animal testing strategies for skin sensitization assessment.
{"title":"Development and evaluation of a novel consensus in silico model within the OECD GL497 defined approach for skin sensitization prediction","authors":"Mika Imamura , Ryoichi Murakami , Masakazu Tateshita , Yasushi Hikida","doi":"10.1016/j.yrtph.2026.106028","DOIUrl":"10.1016/j.yrtph.2026.106028","url":null,"abstract":"<div><div>Skin sensitization is a key endpoint in chemical safety assessment, involving multiple key events (KEs) in the adverse outcome pathway. The integrated testing strategy defined approach (ITS-DA) in OECD GL497 combines non-animal methods addressing KE1 and KE3 with an <em>in silico</em> component to predict sensitization. We developed a novel consensus <em>in silico</em> model integrating a rule-based system with metabolic simulation and two statistical models trained on local lymph node assay (LLNA) and guinea pig maximization test (GPMT) data.</div><div>When applied as the <em>in silico</em> element of the ITS-DA, the model achieved balanced accuracies of 77 % for LLNA and 70 % for human data, surpassing existing <em>in silico</em> approaches. Furthermore, we developed a rule- and statistics-based KE1 replacement model (RSRKE1) that estimates protein-binding potential without <em>in chemico</em> KE1 assays. Combining RSRKE1 with the human Cell Line Activation Test (h-CLAT, KE3) and the consensus model yielded sensitivities of ∼80 % and potency classification accuracies of ∼70 % for LLNA, with similar performance for human data.</div><div>These results demonstrate that the consensus model and RSRKE1 can maintain predictive performance comparable to established ITS-DA workflows, while eliminating the need for certain <em>in vitro</em> assays. This approach supports regulatory acceptance of non-animal testing strategies for skin sensitization assessment.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106028"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918250","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 : 2026-03-01Epub Date: 2025-12-23DOI: 10.1016/j.yrtph.2025.106018
Daniel G. Kougias , Michael Kovochich , Sadaff Ejaz , Abdulkarim Najjar , Smruti Nair , Boris Michelin , Christopher Chu , Michael D. Southall
Mouthwashes containing ethanol for antiseptic properties have a long history of use and well-established oral hygiene benefits by significantly enhancing the control of dental biofilm and reducing gingival inflammation. Despite the substantial health benefits from ethanol-containing mouthwashes, there has been ongoing scrutiny by regulatory and health authorities of products containing ethanol resulting from the classification of consumption of alcohol-containing beverages as a potential carcinogen. Unlike alcohol-containing beverages, mouthwash products are not intended to be ingested, and the potential ethanol exposure is substantially lower for mouthwash products. Therefore, we conducted a risk assessment that benchmarked estimated and modeled incidental exposure to ethanol in mouthwash products against endogenous blood levels, dietary exposure, and health-based guidance values for ethanol. All mouthwash-use scenarios, including average, 90th-percentile, and maximum-label use, resulted in relatively low estimated ethanol exposures that were below various reference and health-based guidance values (HBGVs), including the HBGV of 1 g/day for ethanol (16.7 mg/kg/day in a 60-kg human), a conservative value that is considered to be protective against all chronic health endpoints, including cancer. The findings suggest that ethanol from mouthwash does not significantly contribute to systemic levels of ethanol, falls within dietary intake levels, and remains below HBGVs. Taken together, this assessment concludes that incidental oral exposure of ethanol-containing mouthwashes represents a de minimis health risk.
{"title":"Risk assessment and pharmacokinetic modeling of incidental ingestion of ethanol from mouthwash","authors":"Daniel G. Kougias , Michael Kovochich , Sadaff Ejaz , Abdulkarim Najjar , Smruti Nair , Boris Michelin , Christopher Chu , Michael D. Southall","doi":"10.1016/j.yrtph.2025.106018","DOIUrl":"10.1016/j.yrtph.2025.106018","url":null,"abstract":"<div><div>Mouthwashes containing ethanol for antiseptic properties have a long history of use and well-established oral hygiene benefits by significantly enhancing the control of dental biofilm and reducing gingival inflammation. Despite the substantial health benefits from ethanol-containing mouthwashes, there has been ongoing scrutiny by regulatory and health authorities of products containing ethanol resulting from the classification of consumption of alcohol-containing beverages as a potential carcinogen. Unlike alcohol-containing beverages, mouthwash products are not intended to be ingested, and the potential ethanol exposure is substantially lower for mouthwash products. Therefore, we conducted a risk assessment that benchmarked estimated and modeled incidental exposure to ethanol in mouthwash products against endogenous blood levels, dietary exposure, and health-based guidance values for ethanol. All mouthwash-use scenarios, including average, 90th-percentile, and maximum-label use, resulted in relatively low estimated ethanol exposures that were below various reference and health-based guidance values (HBGVs), including the HBGV of 1 g/day for ethanol (16.7 mg/kg/day in a 60-kg human), a conservative value that is considered to be protective against all chronic health endpoints, including cancer. The findings suggest that ethanol from mouthwash does not significantly contribute to systemic levels of ethanol, falls within dietary intake levels, and remains below HBGVs. Taken together, this assessment concludes that incidental oral exposure of ethanol-containing mouthwashes represents a <em>de minimis</em> health risk.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"166 ","pages":"Article 106018"},"PeriodicalIF":3.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834662","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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