Pub Date : 2026-05-01Epub Date: 2026-02-09DOI: 10.1016/j.yrtph.2026.106055
Michael D. Dutton , Chris Bacigalupo
Toxicity reference value (TRV) is a general term for an exposure limit below which health impairment is not expected. TRVs are used to develop environmental quality standards and for other risk-based activities. Nickel (Ni) TRVs developed by several influential regulatory agencies have used toxicity data from rats orally exposed to nickel sulfate hexahydrate (NSHH). These TRVs converted doses from an NSHH-basis to an ‘as-nickel’ basis, under the belief that controls received no Ni, which is not the case. The extrapolation from a point-of-departure to a human-relevant limit has resulted in TRVs that are, in some instances, less than the estimated normal daily dietary nickel intake observed in certain human life stages. As a result, Ni that is present naturally in food has been incorrectly believed to be contributing to human health risk. The now common risk assessment practice of applying these Ni TRVs on an ‘inclusive of baseline diet’ basis, contrasts with the Institute of Medicine (IOM) perspective that there is no evidence of adverse effects associated with a normal diet: rather, human health risk is associated with excess nickel intake as soluble nickel salts. TRVs based on soluble Ni salts are to be distinguished from the normal Ni-containing diet.
{"title":"Lack of significant risk from everyday dietary nickel: Rethinking the application of oral toxicity reference values","authors":"Michael D. Dutton , Chris Bacigalupo","doi":"10.1016/j.yrtph.2026.106055","DOIUrl":"10.1016/j.yrtph.2026.106055","url":null,"abstract":"<div><div>Toxicity reference value (TRV) is a general term for an exposure limit below which health impairment is not expected. TRVs are used to develop environmental quality standards and for other risk-based activities. Nickel (Ni) TRVs developed by several influential regulatory agencies have used toxicity data from rats orally exposed to nickel sulfate hexahydrate (NSHH). These TRVs converted doses from an NSHH-basis to an ‘as-nickel’ basis, under the belief that controls received no Ni, which is not the case. The extrapolation from a point-of-departure to a human-relevant limit has resulted in TRVs that are, in some instances, less than the estimated normal daily dietary nickel intake observed in certain human life stages. As a result, Ni that is present naturally in food has been incorrectly believed to be contributing to human health risk. The now common risk assessment practice of applying these Ni TRVs on an ‘inclusive of baseline diet’ basis, contrasts with the Institute of Medicine (IOM) perspective that there is no evidence of adverse effects associated with a normal diet: rather, human health risk is associated with excess nickel intake as soluble nickel salts. TRVs based on soluble Ni salts are to be distinguished from the normal Ni-containing diet.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106055"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166492","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: 2026-01-29DOI: 10.1016/j.yrtph.2026.106050
Heenam Seo , Mel Kim , Eunyoung Kim
Most accelerated approvals for oncology drugs have been granted, few studies have characterized the regulatory outcomes of non-oncology drugs within this framework. To examine regulatory outcome and approval timelines of non-oncology drug indications, a cross-sectional analysis was performed using the Food and Drug Administration's accelerated approval database from 1992 to 2024. Among 328 accelerated approval indications, 98 (30 %) were for non-oncology drugs. Overall, 63/98 (64 %) were converted to full approval with systemic anti-infectives accounting for 50 %. Among the 77 (79 %) original indications, 55 (71 %) were converted to full approval, compared to only 8 (38 %) of the 21 supplemental indications. The median times to accelerated approval and convert to full approval for all non-oncology indications were 7.9 (IQR, 5.9–10.0) and 38.8 (IQR, 22.5–63.9) months, respectively. The median time to accelerated approval was 6.8 (IQR, 5.9–10.0) months for 90 (92 %) chemical drug indications and 8.6 (IQR, 7.9–11.0) for 8 (8 %) biologic drug indications; conversion to full approval took 38.8 (IQR, 22.8–63.8) and 42.6 (IQR, 21.3–100.6) months, respectively. Accelerated approvals for non-oncology biologic drug indications took significantly longer than those for oncology biologic indications (8.6 vs. 6.0 months; p = 0.003). These findings underscore the importance of enhanced regulatory oversight and continued post-marketing evaluation to confirm the clinical benefits of non-oncology drugs approved via the accelerated pathway.
{"title":"A comprehensive review of regulatory outcomes and timelines of accelerated FDA approvals for non-oncology therapeutics","authors":"Heenam Seo , Mel Kim , Eunyoung Kim","doi":"10.1016/j.yrtph.2026.106050","DOIUrl":"10.1016/j.yrtph.2026.106050","url":null,"abstract":"<div><div>Most accelerated approvals for oncology drugs have been granted, few studies have characterized the regulatory outcomes of non-oncology drugs within this framework. To examine regulatory outcome and approval timelines of non-oncology drug indications, a cross-sectional analysis was performed using the Food and Drug Administration's accelerated approval database from 1992 to 2024. Among 328 accelerated approval indications, 98 (30 %) were for non-oncology drugs. Overall, 63/98 (64 %) were converted to full approval with systemic anti-infectives accounting for 50 %. Among the 77 (79 %) original indications, 55 (71 %) were converted to full approval, compared to only 8 (38 %) of the 21 supplemental indications. The median times to accelerated approval and convert to full approval for all non-oncology indications were 7.9 (IQR, 5.9–10.0) and 38.8 (IQR, 22.5–63.9) months, respectively. The median time to accelerated approval was 6.8 (IQR, 5.9–10.0) months for 90 (92 %) chemical drug indications and 8.6 (IQR, 7.9–11.0) for 8 (8 %) biologic drug indications; conversion to full approval took 38.8 (IQR, 22.8–63.8) and 42.6 (IQR, 21.3–100.6) months, respectively. Accelerated approvals for non-oncology biologic drug indications took significantly longer than those for oncology biologic indications (8.6 vs. 6.0 months; <em>p</em> = 0.003). These findings underscore the importance of enhanced regulatory oversight and continued post-marketing evaluation to confirm the clinical benefits of non-oncology drugs approved via the accelerated pathway.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106050"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097171","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: 2026-02-02DOI: 10.1016/j.yrtph.2026.106052
Andreas Natsch , Peter Griem , Amaia Irizar , James Bridges , Matthias Vey , Isabelle Lee , Anne Marie Api , Petra Kern , Ian Kimber
Skin sensitization is a key endpoint for the safety assessment of topical consumer products. Ingredients with the potential to act as skin sensitizers differ markedly in their threshold for induction but can be used safely if their potency is characterized and exposure remains within an appropriate margin of safety. To this end, the fragrance industry co-developed Quantitative Risk Assessment (QRA) which starts with the No-Expected-Sensitization-Induction-Level (NESIL). Historically, QRA relies on a weight of evidence approach based on animal data, human confirmatory tests and read across. To allow an approach based solely on New Approach Methodologies (NAMs), the International Dialogue for the Evaluation of Allergens (IDEA) initiative, developed an extended Reference Chemical Potency List (RCPL) integrating human and animal data to derive potency values (PV). Here, we use PVs to evaluate the suitability of quantitative NAMs, including Defined Approaches (DAs), to derive a Point-of-Departure (NAM-PoD) for skin sensitization potency assessment. Evaluation of NAM-PoD derived by SARA-ICE DA, Regression DA and GARDskin dose-response assay (GSDR), indicates that the sensitization potency of fragrance chemicals can be reliably predicted using each approach. Through comparison of NAM-PoDs with in vivo human sensitization thresholds, NAM-specific adjustment factors were derived to convert NAM-PoDs into NAM-NESILs for QRA.
{"title":"Derivation of a Point of Departure using NAMs for application in Quantitative Risk Assessment of fragrance materials","authors":"Andreas Natsch , Peter Griem , Amaia Irizar , James Bridges , Matthias Vey , Isabelle Lee , Anne Marie Api , Petra Kern , Ian Kimber","doi":"10.1016/j.yrtph.2026.106052","DOIUrl":"10.1016/j.yrtph.2026.106052","url":null,"abstract":"<div><div>Skin sensitization is a key endpoint for the safety assessment of topical consumer products. Ingredients with the potential to act as skin sensitizers differ markedly in their threshold for induction but can be used safely if their potency is characterized and exposure remains within an appropriate margin of safety. To this end, the fragrance industry co-developed Quantitative Risk Assessment (QRA) which starts with the No-Expected-Sensitization-Induction-Level (NESIL). Historically, QRA relies on a weight of evidence approach based on animal data, human confirmatory tests and read across. To allow an approach based solely on New Approach Methodologies (NAMs), the International Dialogue for the Evaluation of Allergens (IDEA) initiative, developed an extended Reference Chemical Potency List (RCPL) integrating human and animal data to derive potency values (PV). Here, we use PVs to evaluate the suitability of quantitative NAMs, including Defined Approaches (DAs), to derive a Point-of-Departure (NAM-PoD) for skin sensitization potency assessment. Evaluation of NAM-PoD derived by SARA-ICE DA, Regression DA and GARDskin dose-response assay (GSDR), indicates that the sensitization potency of fragrance chemicals can be reliably predicted using each approach. Through comparison of NAM-PoDs with <em>in vivo</em> human sensitization thresholds, NAM-specific adjustment factors were derived to convert NAM-PoDs into NAM-NESILs for QRA.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106052"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119968","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}
Microplastics (MPs) pollution is a growing environmental issue due to excessive plastic use and improper waste disposal. While early studies focused on MPs in aquatic and terrestrial ecosystems, recent research has expanded to include air quality. This comprehensive narrative review examines MP concentrations in both indoor and outdoor air, highlighting that poorly ventilated indoor spaces have the highest levels of MPs, while good ventilation helps reduce pollution. Factors such as humidity and precipitation decrease MP concentrations through particle deposition, while temperature, wind, and environmental conditions influence their dispersion and persistence. Effective management of environmental conditions and ventilation design is essential to reduce human exposure to MPs. MPs in indoor and outdoor environments show distinct characteristics. Indoor MPs are mostly small (<30 μm), transparent or black, and mainly appear as fibers, originating from textiles, carpets, and furniture. Outdoor MPs are more diverse, often found as fragments and composed of polymers like polystyrene (PS), polyethylene (PE), and polyethylene terephthalate (PET). Human exposure to MPs occurs primarily through inhalation and ingestion, with indoor environments posing higher risks due to particle accumulation and prolonged human presence. Fine MPs (<10 μm, especially ≤2.5 μm) can penetrate deep into the lungs, causing inflammation, oxidative stress, and systemic toxicity. Ingestion through dust is particularly concerning for infants and toddlers. Despite increasing evidence of health risks, the lack of standardized methods and regulatory limits highlights the urgent need for harmonized exposure assessment and targeted public health interventions. By synthesizing existing literature, this review provides a qualitative assessment of the current state of knowledge, identifies key research gaps, and discusses implications for future policy and exposure mitigation strategies.
{"title":"Atmospheric microplastics: A review of pollution characteristics, human exposure pathways, and emerging health risks","authors":"MohammadAmin Azizi , Zahra Khashi , Razieh Ashoori , Farzaneh Rostami , Abooalfazl Azhdarpoor","doi":"10.1016/j.yrtph.2026.106053","DOIUrl":"10.1016/j.yrtph.2026.106053","url":null,"abstract":"<div><div>Microplastics (MPs) pollution is a growing environmental issue due to excessive plastic use and improper waste disposal. While early studies focused on MPs in aquatic and terrestrial ecosystems, recent research has expanded to include air quality. This comprehensive narrative review examines MP concentrations in both indoor and outdoor air, highlighting that poorly ventilated indoor spaces have the highest levels of MPs, while good ventilation helps reduce pollution. Factors such as humidity and precipitation decrease MP concentrations through particle deposition, while temperature, wind, and environmental conditions influence their dispersion and persistence. Effective management of environmental conditions and ventilation design is essential to reduce human exposure to MPs. MPs in indoor and outdoor environments show distinct characteristics. Indoor MPs are mostly small (<30 μm), transparent or black, and mainly appear as fibers, originating from textiles, carpets, and furniture. Outdoor MPs are more diverse, often found as fragments and composed of polymers like polystyrene (PS), polyethylene (PE), and polyethylene terephthalate (PET). Human exposure to MPs occurs primarily through inhalation and ingestion, with indoor environments posing higher risks due to particle accumulation and prolonged human presence. Fine MPs (<10 μm, especially ≤2.5 μm) can penetrate deep into the lungs, causing inflammation, oxidative stress, and systemic toxicity. Ingestion through dust is particularly concerning for infants and toddlers. Despite increasing evidence of health risks, the lack of standardized methods and regulatory limits highlights the urgent need for harmonized exposure assessment and targeted public health interventions. By synthesizing existing literature, this review provides a qualitative assessment of the current state of knowledge, identifies key research gaps, and discusses implications for future policy and exposure mitigation strategies.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106053"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119951","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}
This study assessed the occurrence and dietary risk of pesticide residues in bananas and kiwifruits marketed in Turkey. A total of 50 banana and 50 kiwifruit samples were analyzed for 235 pesticide residues using LC-MS/MS. The analytical method exhibited satisfactory recoveries, acceptable precision, and adequate sensitivity, in full compliance with the European SANTE/11312/2021 Guidelines. Pesticide residues were detected in 82 % of banana and 46 % of kiwifruit samples, with 28 % and 30 % of samples exceeding the EU maximum residue levels (MRLs), respectively. Triadimefon and fenarimol were the most frequently detected compounds in bananas, while acetamiprid and cycloate were the predominant residues in kiwifruits. Chronic dietary exposure assessment, conducted using both deterministic and probabilistic (Monte Carlo simulation) approaches, indicated that chronic hazard indices (HIc) remained well below the threshold value of 1 for both adults and children. Probabilistic modeling revealed right-skewed exposure distributions, with 95th percentile HIc values of 0.0068 and 0.0094 for adults and children, respectively, for bananas, and 0.0013 and 0.0033 for kiwifruit, thereby confirming negligible chronic health risks even under high-exposure scenarios. Acute hazard quotients (HQa) were generally below 1 for adults, whereas a potential acute risk (HQa > 1) was identified for children in a single kiwifruit sample due to indoxacarb, indicating that acute concerns may arise for vulnerable populations under worst-case exposure conditions.
{"title":"Occurrence and dietary risk assessment of pesticide residues in bananas and kiwifruits from Turkey","authors":"Fatma Oznur Afacan , Nimo Hussain Yussuf , Tuba Buyuksirit-Bedir , Cagla Kayisoglu , Eylem Odabas , Ozgur Golge , Bulent Kabak","doi":"10.1016/j.yrtph.2026.106037","DOIUrl":"10.1016/j.yrtph.2026.106037","url":null,"abstract":"<div><div>This study assessed the occurrence and dietary risk of pesticide residues in bananas and kiwifruits marketed in Turkey. A total of 50 banana and 50 kiwifruit samples were analyzed for 235 pesticide residues using LC-MS/MS. The analytical method exhibited satisfactory recoveries, acceptable precision, and adequate sensitivity, in full compliance with the European SANTE/11312/2021 Guidelines. Pesticide residues were detected in 82 % of banana and 46 % of kiwifruit samples, with 28 % and 30 % of samples exceeding the EU maximum residue levels (MRLs), respectively. Triadimefon and fenarimol were the most frequently detected compounds in bananas, while acetamiprid and cycloate were the predominant residues in kiwifruits. Chronic dietary exposure assessment, conducted using both deterministic and probabilistic (Monte Carlo simulation) approaches, indicated that chronic hazard indices (<em>HIc</em>) remained well below the threshold value of 1 for both adults and children. Probabilistic modeling revealed right-skewed exposure distributions, with 95th percentile <em>HIc</em> values of 0.0068 and 0.0094 for adults and children, respectively, for bananas, and 0.0013 and 0.0033 for kiwifruit, thereby confirming negligible chronic health risks even under high-exposure scenarios. Acute hazard quotients (<em>HQa</em>) were generally below 1 for adults, whereas a potential acute risk (<em>HQa</em> > 1) was identified for children in a single kiwifruit sample due to indoxacarb, indicating that acute concerns may arise for vulnerable populations under worst-case exposure conditions.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106037"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146039875","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: 2026-02-06DOI: 10.1016/j.yrtph.2026.106054
Alla Ahmed Muhamad Amin , Hiwa Mohammad Qadr
Naturally occurring radioactive materials, particularly radon (222Rn) gas, can accumulate in carbonated beverages through source water and carbonation processes, potentially exposing consumers through ingestion and inhalation pathways. This investigation measured 222Rn activity concentrations and physicochemical parameters in 25 commercially available non-alcoholic carbonated beverages from Iraqi Kurdistan and evaluated associated radiological health risks. 222Rn concentrations ranged between 20.4 and 48.5 mBq/L, averaging 34.0 mBq/L. All measurements remained considerably below drinking water reference limits established by USEPA (11,100 mBq/L), WHO (100,000 mBq/L), and UNSCEAR (40,000 mBq/L). Physicochemical analysis revealed pH values of 2.2–4.5, electrical conductivity of 603–2622 μS/cm, total dissolved solids of 515–2250 mg/L, and Brix values of 0.4–12.3%. Calculated annual effective doses for adults, considering both ingestion and inhalation routes, stayed well beneath the WHO reference level of 100 μSv/y. Excess lifetime cancer risk values were approximately three orders of magnitude lower than USEPA's acceptable threshold. Statistical analysis showed no significant correlations between 222Rn concentrations and physicochemical properties. These non-alcoholic carbonated beverages present negligible radiological health risks to consumers. However, periodic monitoring of 222Rn concentrations in commercial beverages and continued surveillance of source water quality remain recommended to ensure ongoing compliance with safety standards and maintain public health protection.
{"title":"Physicochemical and radon analysis of commercial non-alcoholic carbonated beverages in Iraqi Kurdistan","authors":"Alla Ahmed Muhamad Amin , Hiwa Mohammad Qadr","doi":"10.1016/j.yrtph.2026.106054","DOIUrl":"10.1016/j.yrtph.2026.106054","url":null,"abstract":"<div><div>Naturally occurring radioactive materials, particularly radon (<sup>222</sup>Rn) gas, can accumulate in carbonated beverages through source water and carbonation processes, potentially exposing consumers through ingestion and inhalation pathways. This investigation measured <sup>222</sup>Rn activity concentrations and physicochemical parameters in 25 commercially available non-alcoholic carbonated beverages from Iraqi Kurdistan and evaluated associated radiological health risks. <sup>222</sup>Rn concentrations ranged between 20.4 and 48.5 mBq/L, averaging 34.0 mBq/L. All measurements remained considerably below drinking water reference limits established by USEPA (11,100 mBq/L), WHO (100,000 mBq/L), and UNSCEAR (40,000 mBq/L). Physicochemical analysis revealed pH values of 2.2–4.5, electrical conductivity of 603–2622 μS/cm, total dissolved solids of 515–2250 mg/L, and Brix values of 0.4–12.3%. Calculated annual effective doses for adults, considering both ingestion and inhalation routes, stayed well beneath the WHO reference level of 100 μSv/y. Excess lifetime cancer risk values were approximately three orders of magnitude lower than USEPA's acceptable threshold. Statistical analysis showed no significant correlations between <sup>222</sup>Rn concentrations and physicochemical properties. These non-alcoholic carbonated beverages present negligible radiological health risks to consumers. However, periodic monitoring of <sup>222</sup>Rn concentrations in commercial beverages and continued surveillance of source water quality remain recommended to ensure ongoing compliance with safety standards and maintain public health protection.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106054"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142439","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: 2026-01-27DOI: 10.1016/j.yrtph.2026.106040
L.P. Sheets , M. Patel , L. Zorrilla , K. Bothe
Imidacloprid is a neonicotinoid insecticide that was first registered in the early 1990's, with global registrations that include agricultural, residential and veterinary uses. In 2001, Bayer reported a developmental neurotoxicity (DNT) study with imidacloprid that complied with U.S. EPA and OECD guidelines to support global registrations. The report concluded that there were slight effects in the offspring at the highest dietary level related to general or acute (neuro)-toxicity and no evidence of DNT at any dose; however, the European Food Safety Authority (EFSA) questioned certain findings at the high dose and whether the study established a clear NOAEL. More recently, the Jai Research Foundation (JRF) independently conducted a guideline-compliant DNT study with imidacloprid for other registrants, with elements incorporated into the study design to facilitate comparison with the Bayer study that could address these issues. This paper examines the findings from both studies, in the context of an updated literature review, to address regulatory uncertainty and persistent claims from non-governmental organizations that imidacloprid is a developmental neurotoxicant. The present analysis supports the interpretation that differences in brain measurements at the high dose in the Bayer study were incidental and unrelated to treatment and that imidacloprid is not a developmental neurotoxicant.
{"title":"Analysis of two guideline-compliant developmental neurotoxicity studies with imidacloprid to assist the interpretation of findings that impact global registrations","authors":"L.P. Sheets , M. Patel , L. Zorrilla , K. Bothe","doi":"10.1016/j.yrtph.2026.106040","DOIUrl":"10.1016/j.yrtph.2026.106040","url":null,"abstract":"<div><div>Imidacloprid is a neonicotinoid insecticide that was first registered in the early 1990's, with global registrations that include agricultural, residential and veterinary uses. In 2001, Bayer reported a developmental neurotoxicity (DNT) study with imidacloprid that complied with U.S. EPA and OECD guidelines to support global registrations. The report concluded that there were slight effects in the offspring at the highest dietary level related to general or acute (neuro)-toxicity and no evidence of DNT at any dose; however, the European Food Safety Authority (EFSA) questioned certain findings at the high dose and whether the study established a clear NOAEL. More recently, the Jai Research Foundation (JRF) independently conducted a guideline-compliant DNT study with imidacloprid for other registrants, with elements incorporated into the study design to facilitate comparison with the Bayer study that could address these issues. This paper examines the findings from both studies, in the context of an updated literature review, to address regulatory uncertainty and persistent claims from non-governmental organizations that imidacloprid is a developmental neurotoxicant. The present analysis supports the interpretation that differences in brain measurements at the high dose in the Bayer study were incidental and unrelated to treatment and that imidacloprid is not a developmental neurotoxicant.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106040"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086903","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: 2026-01-20DOI: 10.1016/j.yrtph.2026.106036
Matthias Vogel , Max J. Carlsson , Claudia Skowron , Christina Felske , Rhys Whomsley , Jörg Fahrer
N-nitrosamines are DNA alkylating agents found in food, cosmetics, tobacco products and, more recently, drugs. Following Cytochrome P450 (CYP)-mediated metabolic activation, these compounds cause DNA damage and mutations. Unlike well-characterized compounds like N-nitrosodimethylamine (NDMA), data on the genotoxicity of nitrosamine drug substance-related impurities (NDSRIs) remain limited. Given their regulatory relevance, this study assessed the genotoxic potential of three NDSRIs —N-nitrosobetahistine (NBH), N-nitrosofluoxetine (NFluo), and N-nitrosonortriptyline (NNT) —compared to NDMA. The NDSRIs demonstrated distinct DNA methylating potential, confirmed by elevated levels of N7-methyl-deoxyguanosine (N7-MedG) and O6-methyl-deoxyguanosine (O6-MedG) in a DNA alkylation assay with metabolic activation. Recombinant CYP isoforms contributed differentially to the bioactivation of each NDSRI, highlighting enzyme-specific pathways of toxification. Subsequently, we demonstrated that all NDSRIs cause DNA methylation adducts (N7-MedG > O6-MedG) in primary rat hepatocytes, with generally higher levels than those caused by NDMA. Consistently, the NDSRIs generated more DNA strand breaks than NDMA, which followed the DNA adduct kinetics. Furthermore, all NDSRIs showed cytotoxicity after 24 h, whereas no cytotoxic effect was observed for NDMA. Taken together, our study provided evidence that the three NDSRIs are genotoxic in primary rat hepatocytes, which warrants further investigation with regard to their mutagenic potential.
{"title":"Nitrosamine drug substance-related impurities cause DNA methylation adducts in vitro and in primary hepatocytes upon Cytochrome P450-dependend metabolic activation","authors":"Matthias Vogel , Max J. Carlsson , Claudia Skowron , Christina Felske , Rhys Whomsley , Jörg Fahrer","doi":"10.1016/j.yrtph.2026.106036","DOIUrl":"10.1016/j.yrtph.2026.106036","url":null,"abstract":"<div><div><em>N</em>-nitrosamines are DNA alkylating agents found in food, cosmetics, tobacco products and, more recently, drugs. Following Cytochrome P450 (CYP)-mediated metabolic activation, these compounds cause DNA damage and mutations. Unlike well-characterized compounds like <em>N</em>-nitrosodimethylamine (NDMA), data on the genotoxicity of nitrosamine drug substance-related impurities (NDSRIs) remain limited. Given their regulatory relevance, this study assessed the genotoxic potential of three NDSRIs —<em>N</em>-nitrosobetahistine (NBH), <em>N</em>-nitrosofluoxetine (NFluo), and <em>N</em>-nitrosonortriptyline (NNT) —compared to NDMA. The NDSRIs demonstrated distinct DNA methylating potential, confirmed by elevated levels of <em>N</em>7-methyl-deoxyguanosine (<em>N7</em>-MedG) and <em>O</em><sup>6</sup>-methyl-deoxyguanosine (<em>O</em><sup>6</sup>-MedG) in a DNA alkylation assay with metabolic activation. Recombinant CYP isoforms contributed differentially to the bioactivation of each NDSRI, highlighting enzyme-specific pathways of toxification. Subsequently, we demonstrated that all NDSRIs cause DNA methylation adducts (<em>N</em>7-MedG > <em>O</em><sup>6</sup>-MedG) in primary rat hepatocytes, with generally higher levels than those caused by NDMA. Consistently, the NDSRIs generated more DNA strand breaks than NDMA, which followed the DNA adduct kinetics. Furthermore, all NDSRIs showed cytotoxicity after 24 h, whereas no cytotoxic effect was observed for NDMA. Taken together, our study provided evidence that the three NDSRIs are genotoxic in primary rat hepatocytes, which warrants further investigation with regard to their mutagenic potential.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106036"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030510","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: 2026-01-27DOI: 10.1016/j.yrtph.2026.106039
Paul C. DeLeo , Darci Ferrer , Aurelia Lapczynski , Stella Wang
As part of the evidence integration step of its proposed systematic review protocol supporting chemical risk evaluations under the Toxic Substances Control Act (TSCA), the United States Environmental Protection Agency (EPA) describes a data hierarchy for various sources within the risk assessment. EPA identifies “less preferred” exposure data sources (e.g., modeled data) and “more preferred” sources (e.g., monitoring data). This approach to risk assessment data contrasts with substantial EPA guidance regarding tiered approaches for risk-based decision-making. We examined environmental exposure data for the fragrance material 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[g]-2-benzopyran (HHCB), a TSCA high-priority substance, using EPA's deterministic model the Exposure and Fate Assessment Screening Tool (E-FAST), a publicly available probabilistic environmental exposure model (iSTREEM), and data from the United States Geological Survey's National Water Information System. Exposure estimates for HHCB decreased progressively from deterministic modeling to probabilistic modeling to monitoring data. However, this case study illustrates that higher-tier analyses may reduce uncertainty but may not improve the risk conclusions. Over the course of an iterative risk characterization, the need for higher tier data may be demonstrated. However, in other cases, it may be more efficient and effective to draw risk conclusions at a lower tier of assessment and forego further analysis of existing data.
{"title":"Evidence integration in TSCA risk evaluation: The value of tiered risk assessment – A case study using HHCB","authors":"Paul C. DeLeo , Darci Ferrer , Aurelia Lapczynski , Stella Wang","doi":"10.1016/j.yrtph.2026.106039","DOIUrl":"10.1016/j.yrtph.2026.106039","url":null,"abstract":"<div><div>As part of the evidence integration step of its proposed systematic review protocol supporting chemical risk evaluations under the Toxic Substances Control Act (TSCA), the United States Environmental Protection Agency (EPA) describes a data hierarchy for various sources within the risk assessment. EPA identifies “less preferred” exposure data sources (e.g., modeled data) and “more preferred” sources (e.g., monitoring data). This approach to risk assessment data contrasts with substantial EPA guidance regarding tiered approaches for risk-based decision-making. We examined environmental exposure data for the fragrance material 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[g]-2-benzopyran (HHCB), a TSCA high-priority substance, using EPA's deterministic model the Exposure and Fate Assessment Screening Tool (E-FAST), a publicly available probabilistic environmental exposure model (iSTREEM), and data from the United States Geological Survey's National Water Information System. Exposure estimates for HHCB decreased progressively from deterministic modeling to probabilistic modeling to monitoring data. However, this case study illustrates that higher-tier analyses may reduce uncertainty but may not improve the risk conclusions. Over the course of an iterative risk characterization, the need for higher tier data may be demonstrated. However, in other cases, it may be more efficient and effective to draw risk conclusions at a lower tier of assessment and forego further analysis of existing data.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106039"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081188","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: 2026-01-28DOI: 10.1016/j.yrtph.2026.106041
Claire Beausoleil , Christophe Rousselle , Eren Ozcagli , Miriam N. Jacobs
Exposure to ‘metabolic disrupting chemicals’ (MDCs) are increasingly implicated in obesity, diabetes and/or fatty liver disease; indeed, these metabolic changes may play a role in the global metabolic disorders' epidemic. To better assess and manage the health risks of MDCs, improved hazard identification is needed. This review describes how current in vivo OECD Test Guidelines (TGs) can better capture MDC effects. The biological and clinical evidence to support the inclusion of promising human relevant biomarkers, blood parameters, endpoints and relevant tissues for MDCs for potential inclusion in OECD TGs is documented. Current clinical chemistry routine requirements could be utilised further, and the additional assessment of relevant hormones such as a decrease in adiponectin, increase in resistin and leptin, which impact satiety, could be additionally included. Additionally, assessment of fatty tissue distribution in alert animals and insulin resistance, is recommended, and histological parameters in relation to the different types of adipose tissue. How specific biomarkers and endpoints could be incorporated into OECD mammalian in vivo assays, and how they can be included in the EU strategy for Endocrine Disrupting Chemicals identification and the forthcoming update to the OECD Guidance Document on the Testing and Assessment of Endocrine Disruption chemicals, are discussed.
{"title":"Towards EU regulatory hazard assessment of metabolic endocrine disrupters: Integrating new biomarkers into OECD test guidelines","authors":"Claire Beausoleil , Christophe Rousselle , Eren Ozcagli , Miriam N. Jacobs","doi":"10.1016/j.yrtph.2026.106041","DOIUrl":"10.1016/j.yrtph.2026.106041","url":null,"abstract":"<div><div>Exposure to ‘metabolic disrupting chemicals’ (MDCs) are increasingly implicated in obesity, diabetes and/or fatty liver disease; indeed, these metabolic changes may play a role in the global metabolic disorders' epidemic. To better assess and manage the health risks of MDCs, improved hazard identification is needed. This review describes how current <em>in vivo</em> OECD Test Guidelines (TGs) can better capture MDC effects. The biological and clinical evidence to support the inclusion of promising human relevant biomarkers, blood parameters, endpoints and relevant tissues for MDCs for potential inclusion in OECD TGs is documented. Current clinical chemistry routine requirements could be utilised further, and the additional assessment of relevant hormones such as a decrease in adiponectin, increase in resistin and leptin, which impact satiety, could be additionally included. Additionally, assessment of fatty tissue distribution in alert animals and insulin resistance, is recommended, and histological parameters in relation to the different types of adipose tissue. How specific biomarkers and endpoints could be incorporated into OECD mammalian <em>in vivo</em> assays, and how they can be included in the EU strategy for Endocrine Disrupting Chemicals identification and the forthcoming update to the OECD Guidance Document on the Testing and Assessment of Endocrine Disruption chemicals, are discussed.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"167 ","pages":"Article 106041"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093481","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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