Pub Date : 2024-10-28DOI: 10.1016/j.yrtph.2024.105732
Charlotte E Laupheimer, Yana Kolianchuk, Rex E FitzGerald, Martin F Wilks, Arne Jaksch
Vanadium is used in alloys, batteries as well as catalyst and is a known impurity in medical devices and pharmaceuticals. The present work describes the calculation of a parenteral tolerable intake (TI) for vanadium by chronic exposure in implantable medical devices per ISO 10993-17:2023, the applicable standard. The 2023 update of ISO 10993-17 [1] introduces new uncertainty factors (UFs) for calculating a TI. Therefore, we noted differences between the ISO guidance and the ICH Q3D guidance on Permissible Daily Exposure (PDE) for parental elemental pharmaceutical impurities. We derived a TI of 0.20 μg V/kg/day based on the updated ISO guidance, and a PDE of 0.24 μg V/kg/day based on ICH guidance. The latter is considered a more realistic estimate.
钒用于合金、电池和催化剂，也是医疗器械和药品中的一种已知杂质。本研究介绍了根据 ISO 10993-17:2023（适用标准）计算植入式医疗器械中长期接触钒的肠外耐受摄入量（TI）。ISO 10993-17[1]的2023更新版引入了计算TI的新不确定系数（UF）。因此，我们注意到 ISO 指南与 ICH Q3D 指南中关于亲元素药物杂质每日允许暴露量 (PDE) 的不同之处。根据最新的 ISO 指南，我们得出 TI 为 0.20 μg V/kg/day，而根据 ICH 指南，PDE 为 0.24 μg V/kg/day。后者被认为是更切合实际的估计值。
{"title":"Toxicological evaluation of vanadium and derivation of a parenteral tolerable intake value for medical devices.","authors":"Charlotte E Laupheimer, Yana Kolianchuk, Rex E FitzGerald, Martin F Wilks, Arne Jaksch","doi":"10.1016/j.yrtph.2024.105732","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105732","url":null,"abstract":"<p><p>Vanadium is used in alloys, batteries as well as catalyst and is a known impurity in medical devices and pharmaceuticals. The present work describes the calculation of a parenteral tolerable intake (TI) for vanadium by chronic exposure in implantable medical devices per ISO 10993-17:2023, the applicable standard. The 2023 update of ISO 10993-17 [1] introduces new uncertainty factors (UFs) for calculating a TI. Therefore, we noted differences between the ISO guidance and the ICH Q3D guidance on Permissible Daily Exposure (PDE) for parental elemental pharmaceutical impurities. We derived a TI of 0.20 μg V/kg/day based on the updated ISO guidance, and a PDE of 0.24 μg V/kg/day based on ICH guidance. The latter is considered a more realistic estimate.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105732"},"PeriodicalIF":3.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547051","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 : 2024-10-26DOI: 10.1016/j.yrtph.2024.105725
Chad P. Satori , Catherine D. Christensen , Stephanie M. Street , Mikaelle Giffin , Christopher M. Pohl , Whitney V. Christian
Chemical characterization of medical devices uses the analytical evaluation threshold (AET) to determine reportable organic extractables, as these chemicals may be of toxicological concern and should be addressed via toxicological risk assessment. The AET is not applicable to metal extractables due to the exclusion of toxicity data on inorganics from the dataset used to derive dose-based threshold (DBT) values. This results in minimal guidance for reporting metal extractables. Herein, an AET for metals, or mAET, is proposed as a reporting threshold for individual metal extractables. The mAET can ensure metals are reported that are at quantities that may present a patient safety risk. This may reduce the number of metals reported in a chemical characterization report, improving the efficiency of the overall biocompatibility evaluation by removing unneeded effort and resource time. Conversely, an analytical method's ability to report all metals at toxicologically relevant levels can be confirmed by comparing method sensitivity to mAET values. DBTs were developed for 70 metals, permitting mAET values to be determined. These mAET values were then compared to metal reporting limits from 13 previously conducted chemical characterization studies, which used varying extraction designs and analytical methods, to determine the impact of the mAET.
{"title":"The analytical evaluation threshold for inorganic metal extractables and leachables analysis of medical devices","authors":"Chad P. Satori , Catherine D. Christensen , Stephanie M. Street , Mikaelle Giffin , Christopher M. Pohl , Whitney V. Christian","doi":"10.1016/j.yrtph.2024.105725","DOIUrl":"10.1016/j.yrtph.2024.105725","url":null,"abstract":"<div><div>Chemical characterization of medical devices uses the analytical evaluation threshold (AET) to determine reportable organic extractables, as these chemicals may be of toxicological concern and should be addressed via toxicological risk assessment. The AET is not applicable to metal extractables due to the exclusion of toxicity data on inorganics from the dataset used to derive dose-based threshold (DBT) values. This results in minimal guidance for reporting metal extractables. Herein, an AET for metals, or mAET, is proposed as a reporting threshold for individual metal extractables. The mAET can ensure metals are reported that are at quantities that may present a patient safety risk. This may reduce the number of metals reported in a chemical characterization report, improving the efficiency of the overall biocompatibility evaluation by removing unneeded effort and resource time. Conversely, an analytical method's ability to report all metals at toxicologically relevant levels can be confirmed by comparing method sensitivity to mAET values. DBTs were developed for 70 metals, permitting mAET values to be determined. These mAET values were then compared to metal reporting limits from 13 previously conducted chemical characterization studies, which used varying extraction designs and analytical methods, to determine the impact of the mAET.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105725"},"PeriodicalIF":3.0,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-23DOI: 10.1016/j.yrtph.2024.105731
Xiaoli Gou , Ying Chen , Qidi Ye , Qingyuan Meng , Yanli Jia , Peiyun Li , Quanjun Wang , JianMin Wang , Chen Zhang , Ju Wang , Yansheng Dong
HSK21542 is a peripherally-restricted kappa opioid receptor (KOR) agonist developed for pain treatment. Because of the CNS pharmacological concern of opioid receptor activation, such as physical dependence and addiction potential, an assessment of abuse potential of HSK21542 was required prior to marketing approval. The preclinical abuse potential assessments for HSK21542 included the following studies: 1) intravenous self-administration study to explore the relative reinforcing efficacy in rats self-administering remifentanil; 2) rat drug discrimination study to examine the pharmacological similarity of the interoceptive or subjective effects of HSK21542 in rats discriminating pentazocine; 3) rat conditioned place preference (CPP) paradigm to test the rewarding effects; 4) rat natural physical dependence-spontaneous withdrawal study in rats chronically treated with HSK21542; 5) naloxone-precipitated withdrawal assay following chronic HSK21542 exposure to evaluate its physical dependence potential. The results showed that HSK21542 was devoid of behavioral evidence of positive reinforcing effect and did not share similar discriminative stimulus effects with pentazocine. HSK21542 also did not produce CPP in rats. In addition, HSK21542 did not produce spontaneous withdrawal or naloxone-precipitated withdrawal in rats with chronic treatments. Collectively, these preclinical findings suggest that HSK21542 has no abuse potential in animals, which demonstrate low abuse potential in humans.
{"title":"Preclinical evaluation of abuse potential of the peripherally-restricted kappa opioid receptor agonist HSK21542","authors":"Xiaoli Gou , Ying Chen , Qidi Ye , Qingyuan Meng , Yanli Jia , Peiyun Li , Quanjun Wang , JianMin Wang , Chen Zhang , Ju Wang , Yansheng Dong","doi":"10.1016/j.yrtph.2024.105731","DOIUrl":"10.1016/j.yrtph.2024.105731","url":null,"abstract":"<div><div>HSK21542 is a peripherally-restricted kappa opioid receptor (KOR) agonist developed for pain treatment. Because of the CNS pharmacological concern of opioid receptor activation, such as physical dependence and addiction potential, an assessment of abuse potential of HSK21542 was required prior to marketing approval. The preclinical abuse potential assessments for HSK21542 included the following studies: 1) intravenous self-administration study to explore the relative reinforcing efficacy in rats self-administering remifentanil; 2) rat drug discrimination study to examine the pharmacological similarity of the interoceptive or subjective effects of HSK21542 in rats discriminating pentazocine; 3) rat conditioned place preference (CPP) paradigm to test the rewarding effects; 4) rat natural physical dependence-spontaneous withdrawal study in rats chronically treated with HSK21542; 5) naloxone-precipitated withdrawal assay following chronic HSK21542 exposure to evaluate its physical dependence potential. The results showed that HSK21542 was devoid of behavioral evidence of positive reinforcing effect and did not share similar discriminative stimulus effects with pentazocine. HSK21542 also did not produce CPP in rats. In addition, HSK21542 did not produce spontaneous withdrawal or naloxone-precipitated withdrawal in rats with chronic treatments. Collectively, these preclinical findings suggest that HSK21542 has no abuse potential in animals, which demonstrate low abuse potential in humans.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105731"},"PeriodicalIF":3.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506670","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 : 2024-10-22DOI: 10.1016/j.yrtph.2024.105728
Luiza Novaes Borges , Eduardo Agostinho Freitas Fernandes , Érico Miroro de Oliveira , Victor Gomes Pereira , Andréa Diniz
The landscape of drug product development and regulatory sciences is evolving, driven by the increasing application of systems thinking and modeling and simulation (M&S) techniques, especially from a biopharmaceutics perspective. Patient-centric quality standards can be achieved within this context through the application of quality by design (QbD) principles and M&S, specifically by defining clinically relevant dissolution specifications (CRDS). To this end, it is essential to bridge in vitro results to drug product in vivo performance, emphasizing the need to explore the translational capacity of biopharmaceutics tools. Physiologically based M&S analyses offer a unique avenue for integrating the drug, drug product, and biological properties of a target organism to study their interactions on the pharmacokinetic response. Accordingly, Physiologically Based Biopharmaceutics Modeling (PBBM) has seen increasing use to support drug development and regulatory applications globally. In Brazil, a Model-Informed Drug Development (MIDD) policy and strategic project are not yet established, limiting applicability of M&S techniques. Drawing from the experience of the ANVISA-Academia PBBM Working Group (WG), this article assesses the opportunities and challenges for pharmacometrics (PMx) in Brazil and proposes strategies to advance the adoption of M&S analyses into regulatory decision-making.
{"title":"Experiences and initiatives on pharmacokinetic modeling and simulation data analysis: Perspectives from the Brazilian Health Regulatory Agency (ANVISA)","authors":"Luiza Novaes Borges , Eduardo Agostinho Freitas Fernandes , Érico Miroro de Oliveira , Victor Gomes Pereira , Andréa Diniz","doi":"10.1016/j.yrtph.2024.105728","DOIUrl":"10.1016/j.yrtph.2024.105728","url":null,"abstract":"<div><div>The landscape of drug product development and <strong>regulatory sciences</strong> is evolving, driven by the increasing application of systems thinking and <strong>modeling and simulation (M&S)</strong> techniques, especially from a <strong>biopharmaceutics</strong> perspective. <strong>Patient-centric quality standards</strong> can be achieved within this context through the application of <strong>quality by design (QbD)</strong> principles and M&S, specifically by defining <strong>clinically relevant dissolution specifications (CRDS)</strong>. To this end, it is essential to bridge <em>in vitro</em> results to drug product <em>in vivo</em> performance, emphasizing the need to explore the <strong>translational capacity</strong> of biopharmaceutics tools. Physiologically based M&S analyses offer a unique avenue for integrating the drug, drug product, and biological properties of a target organism to study their interactions on the pharmacokinetic response. Accordingly, <strong>Physiologically Based Biopharmaceutics Modeling (PBBM)</strong> has seen increasing use to support drug development and regulatory applications globally. In Brazil, a <strong>Model-Informed Drug Development (MIDD)</strong> policy and strategic project are not yet established, limiting applicability of M&S techniques. Drawing from the experience of the ANVISA-Academia PBBM Working Group (WG), this article assesses the opportunities and challenges for pharmacometrics (PMx) in Brazil and proposes strategies to advance the adoption of M&S analyses into regulatory decision-making.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105728"},"PeriodicalIF":3.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506669","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 : 2024-10-20DOI: 10.1016/j.yrtph.2024.105727
Neil Morgan , Sarah Adham , Edgars Felkers , Felix M. Kluxen , Christian J. Kuster , Christiane Wiemann
Plant protection products (PPPs) undergo rigorous safety assessments. In Europe, non-dietary risk assessments for operators, workers, bystanders and residents are highly conservative as this area of exposure science has historically been data poor. CropLife Europe (CLE) companies have collaborated to generate new data and pool existing data to refine the approaches prescribed by the European Food Safety Authority (EFSA) guidance on non-dietary exposure (2022).
This article summarises key activities, beginning with the development of the Agricultural Operator Exposure Model (AOEM) and covers projects which refine current approaches to bystander, resident and re-entry worker assessment, including the Bystander Resident Orchards Vineyards (BROV) project, improvements to the Bystander and Resident Exposure Assessment Model for spray drift (BREAM), proposals for refined vapour inhalation assessments, and a meta-analysis of Dislodgeable Foliar Residue (DFR) data. A study quantifying the benefits of using closed transfer systems, an appraisal of the inherent compounded conservatism in current risk assessment paradigms and the development of a new seed treatment model by the SeedTROPEX taskforce are also introduced.
These industry-led activities underscore the critical role of non-dietary exposure in the registration process for PPPs and reflect an ongoing commitment to provide farmers with effective crop protection solutions while ensuring safety.
{"title":"Data collection initiatives of the crop protection industry – A mission to improve non-dietary risk assessment in Europe","authors":"Neil Morgan , Sarah Adham , Edgars Felkers , Felix M. Kluxen , Christian J. Kuster , Christiane Wiemann","doi":"10.1016/j.yrtph.2024.105727","DOIUrl":"10.1016/j.yrtph.2024.105727","url":null,"abstract":"<div><div>Plant protection products (PPPs) undergo rigorous safety assessments. In Europe, non-dietary risk assessments for operators, workers, bystanders and residents are highly conservative as this area of exposure science has historically been data poor. CropLife Europe (CLE) companies have collaborated to generate new data and pool existing data to refine the approaches prescribed by the European Food Safety Authority (EFSA) guidance on non-dietary exposure (2022).</div><div>This article summarises key activities, beginning with the development of the Agricultural Operator Exposure Model (AOEM) and covers projects which refine current approaches to bystander, resident and re-entry worker assessment, including the Bystander Resident Orchards Vineyards (BROV) project, improvements to the Bystander and Resident Exposure Assessment Model for spray drift (BREAM), proposals for refined vapour inhalation assessments, and a meta-analysis of Dislodgeable Foliar Residue (DFR) data. A study quantifying the benefits of using closed transfer systems, an appraisal of the inherent compounded conservatism in current risk assessment paradigms and the development of a new seed treatment model by the SeedTROPEX taskforce are also introduced.</div><div>These industry-led activities underscore the critical role of non-dietary exposure in the registration process for PPPs and reflect an ongoing commitment to provide farmers with effective crop protection solutions while ensuring safety.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105727"},"PeriodicalIF":3.0,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-20DOI: 10.1016/j.yrtph.2024.105730
Xilin Li , Yuan Le , Xiaoqing Guo , Sruthi T. King , Robert T. Dorsam , Aisar H. Atrakchi , Timothy J. McGovern , Karen L. Davis-Bruno , David A. Keire , Robert H. Heflich , Nan Mei
Nitrosamine drug substance-related impurities (NDSRIs) are a sub-category of N-nitrosamine drug impurities that share structural similarity to the corresponding active pharmaceutical ingredient. The mutagenicity of NDSRIs is poorly understood. We previously tested a series of NDSRIs using the Enhanced Ames Test (EAT). In this follow-up study, we further examined the genotoxicity and mutagenicity of 15 of these NDSRIs in human TK6 cells. Seven EAT-positive NDSRIs, including N-nitroso-nortriptyline, N-nitroso-fluoxetine, N-nitroso-desmethyl-diphenhydramine, N-nitroso-duloxetine, N-nitroso-lorcaserin, N-nitroso-varenicline, and N-nitroso-sertraline, induced concentration-dependent increases in micronuclei after bioactivation with hamster liver S9. These NDSRIs were also mutagenic in the TK and HPRT gene mutation assays, consistent with their positive EAT results. In the presence of hamster liver S9, the eight EAT-negative NDSRIs were negative in the micronucleus assay and negative for mutation induction. Using TK6 cells endogenously expressing a single human cytochrome P450 (CYP), we found that CYP2C19, CYP2B6, CYP2A6, and CYP3A4 are key enzymes activating the genotoxicity and mutagenicity of these NDSRIs. Overall, the hamster S9-mediated TK6 cell mutagenicity results agreed with those observed in the EAT, indicating consistency in the mutagenic responses produced by NDSRIs across different testing systems. These data support the use of EAT for hazard identification and safety assessment of NDSRIs.
{"title":"Mutagenicity and genotoxicity evaluation of 15 nitrosamine drug substance-related impurities in human TK6 cells","authors":"Xilin Li , Yuan Le , Xiaoqing Guo , Sruthi T. King , Robert T. Dorsam , Aisar H. Atrakchi , Timothy J. McGovern , Karen L. Davis-Bruno , David A. Keire , Robert H. Heflich , Nan Mei","doi":"10.1016/j.yrtph.2024.105730","DOIUrl":"10.1016/j.yrtph.2024.105730","url":null,"abstract":"<div><div>Nitrosamine drug substance-related impurities (NDSRIs) are a sub-category of <em>N</em>-nitrosamine drug impurities that share structural similarity to the corresponding active pharmaceutical ingredient. The mutagenicity of NDSRIs is poorly understood. We previously tested a series of NDSRIs using the Enhanced Ames Test (EAT). In this follow-up study, we further examined the genotoxicity and mutagenicity of 15 of these NDSRIs in human TK6 cells. Seven EAT-positive NDSRIs, including <em>N</em>-nitroso-nortriptyline, <em>N</em>-nitroso-fluoxetine, <em>N</em>-nitroso-desmethyl-diphenhydramine, <em>N</em>-nitroso-duloxetine, <em>N</em>-nitroso-lorcaserin, <em>N</em>-nitroso-varenicline, and <em>N</em>-nitroso-sertraline, induced concentration-dependent increases in micronuclei after bioactivation with hamster liver S9. These NDSRIs were also mutagenic in the <em>TK</em> and <em>HPRT</em> gene mutation assays, consistent with their positive EAT results. In the presence of hamster liver S9, the eight EAT-negative NDSRIs were negative in the micronucleus assay and negative for mutation induction. Using TK6 cells endogenously expressing a single human cytochrome P450 (CYP), we found that CYP2C19, CYP2B6, CYP2A6, and CYP3A4 are key enzymes activating the genotoxicity and mutagenicity of these NDSRIs. Overall, the hamster S9-mediated TK6 cell mutagenicity results agreed with those observed in the EAT, indicating consistency in the mutagenic responses produced by NDSRIs across different testing systems. These data support the use of EAT for hazard identification and safety assessment of NDSRIs.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105730"},"PeriodicalIF":3.0,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473314","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 : 2024-10-19DOI: 10.1016/j.yrtph.2024.105726
Nicholas L. Drury , Robyn L. Prueitt , Barbara D. Beck
In November 2023, the International Agency for Research on Cancer (IARC) classified PFOA as “carcinogenic to humans” (Group 1) and PFOS as “possibly carcinogenic to humans” (Group 2B). We evaluated these classifications, considering the epidemiology, experimental animal, and mechanistic evidence. It is our opinion that the IARC Working Group overstated the available evidence for the carcinogenicity of PFOA and PFOS. Epidemiology studies have shown weak and inconsistent associations across studies. Studies reporting increased incidences of tumors in experimental animals exposed to PFOA or PFOS had statistically significant results that were driven by the presence of benign adenomas. The IARC Working Group used the key characteristics of carcinogens (KCCs, which comprise 10 chemical and/or biological properties of known human carcinogens) approach to upgrade the carcinogenicity classifications for PFOA and PFOS from initially lower classifications that were based on the strength of the epidemiology and experimental animal evidence. However, this is not a robust assessment of mechanistic evidence, as it fails to consider the quality, external validity, and relevance of the evidence. Rather than use the KCCs as a checklist of potential carcinogenic mechanisms, IARC should use a rigorous method to evaluate the plausibility and human relevance of mechanistic evidence.
{"title":"Commentary: Understanding IARC's PFOA and PFOS carcinogenicity assessments","authors":"Nicholas L. Drury , Robyn L. Prueitt , Barbara D. Beck","doi":"10.1016/j.yrtph.2024.105726","DOIUrl":"10.1016/j.yrtph.2024.105726","url":null,"abstract":"<div><div>In November 2023, the International Agency for Research on Cancer (IARC) classified PFOA as “carcinogenic to humans” (Group 1) and PFOS as “possibly carcinogenic to humans” (Group 2B). We evaluated these classifications, considering the epidemiology, experimental animal, and mechanistic evidence. It is our opinion that the IARC Working Group overstated the available evidence for the carcinogenicity of PFOA and PFOS. Epidemiology studies have shown weak and inconsistent associations across studies. Studies reporting increased incidences of tumors in experimental animals exposed to PFOA or PFOS had statistically significant results that were driven by the presence of benign adenomas. The IARC Working Group used the key characteristics of carcinogens (KCCs, which comprise 10 chemical and/or biological properties of known human carcinogens) approach to upgrade the carcinogenicity classifications for PFOA and PFOS from initially lower classifications that were based on the strength of the epidemiology and experimental animal evidence. However, this is not a robust assessment of mechanistic evidence, as it fails to consider the quality, external validity, and relevance of the evidence. Rather than use the KCCs as a checklist of potential carcinogenic mechanisms, IARC should use a rigorous method to evaluate the plausibility and human relevance of mechanistic evidence.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105726"},"PeriodicalIF":3.0,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473311","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 : 2024-10-18DOI: 10.1016/j.yrtph.2024.105724
Jürg A. Zarn, Sebastian L.B. König, Holly V. Shaw, H. Christoph Geiser
The concurrent control group is the most important reference for the interpretation of toxicity studies. However, pooled information on control animals from independent studies, i.e., historical control data (HCD), is also used for the interpretation of results. Currently, an overview on actual HCD use in regulatory toxicology is lacking. Therefore, we evaluated the HCD use of the Joint FAO/WHO Meeting on Pesticide Residues from 2004 to 2021 and compared it with recommendations in regulatory guidelines and in the literature. We found that HCD was used routinely and exclusively to avoid potential false positive decisions regarding the treatment-relatedness of effects, mostly using the HCD range, i.e., the most extreme values, as a benchmark. HCD were not used to avoid potential false negative decisions or for quality control of the index study. The central assumption of the HCD use, namely that the HCD and control group of the index study follow the same underlying distribution because they are samples of the same data generation process, was not investigated, although numerous factors potentially contribute to effect variation between the different control groups pooled in the HCD. We recommend that the existing guidelines be revised to improve the robustness and transparency of toxicological assessments.
{"title":"An analysis of the use of historical control data in the assessment of regulatory pesticide toxicity studies","authors":"Jürg A. Zarn, Sebastian L.B. König, Holly V. Shaw, H. Christoph Geiser","doi":"10.1016/j.yrtph.2024.105724","DOIUrl":"10.1016/j.yrtph.2024.105724","url":null,"abstract":"<div><div>The concurrent control group is the most important reference for the interpretation of toxicity studies. However, pooled information on control animals from independent studies, <em>i.e.</em>, historical control data (HCD), is also used for the interpretation of results. Currently, an overview on actual HCD use in regulatory toxicology is lacking. Therefore, we evaluated the HCD use of the Joint FAO/WHO Meeting on Pesticide Residues from 2004 to 2021 and compared it with recommendations in regulatory guidelines and in the literature. We found that HCD was used routinely and exclusively to avoid potential false positive decisions regarding the treatment-relatedness of effects, mostly using the HCD range, <em>i.e.,</em> the most extreme values, as a benchmark. HCD were not used to avoid potential false negative decisions or for quality control of the index study. The central assumption of the HCD use, namely that the HCD and control group of the index study follow the same underlying distribution because they are samples of the same data generation process, was not investigated, although numerous factors potentially contribute to effect variation between the different control groups pooled in the HCD. We recommend that the existing guidelines be revised to improve the robustness and transparency of toxicological assessments.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105724"},"PeriodicalIF":3.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-11DOI: 10.1016/j.yrtph.2024.105717
Sue A. Hubbard , Kevin Klipsch , Michael S. Cockburn , Sandra Carey
In this paper we present methodological and experimental details and results from an OECD Test Guideline 474 and GLP-compliant in vivo micronucleus study on sodium molybdate dihydrate in Sprague Dawley rats. Prior to the conduct of this study, there was a data-gap for reliable in vivo genotoxicity data for molybdenum substances. The presentation of the new study is complemented by a review of other available in vitro and in vivo data on the genotoxicity of molybdenum substances, focussing on substances where the contained or released molybdate ion, MoO42−, is considered the responsible moiety for any toxicological effect (grouping/category approach). After consideration of the relevance and reliability of all available data, the absence of a concern for genotoxicity of molybdate in vitro and in vivo is concluded.
{"title":"In vivo micronucleus assay on sodium molybdate in rats and its impact on the overall assessment of the genotoxicity of molybdenum substances","authors":"Sue A. Hubbard , Kevin Klipsch , Michael S. Cockburn , Sandra Carey","doi":"10.1016/j.yrtph.2024.105717","DOIUrl":"10.1016/j.yrtph.2024.105717","url":null,"abstract":"<div><div>In this paper we present methodological and experimental details and results from an OECD Test Guideline 474 and GLP-compliant <em>in vivo</em> micronucleus study on sodium molybdate dihydrate in Sprague Dawley rats. Prior to the conduct of this study, there was a data-gap for reliable <em>in vivo</em> genotoxicity data for molybdenum substances. The presentation of the new study is complemented by a review of other available <em>in vitro</em> and <em>in vivo</em> data on the genotoxicity of molybdenum substances, focussing on substances where the contained or released molybdate ion, MoO<sub>4</sub><sup>2−</sup>, is considered the responsible moiety for any toxicological effect (grouping/category approach). After consideration of the relevance and reliability of all available data, the absence of a concern for genotoxicity of molybdate <em>in vitro</em> and <em>in vivo</em> is concluded.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105717"},"PeriodicalIF":3.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-10DOI: 10.1016/j.yrtph.2024.105716
Jerry Achar , James W. Firman , Chantelle Tran , Daniella Kim , Mark T.D. Cronin , Gunilla Öberg
Although uncertainties expressed in texts within QSAR studies can guide quantitative uncertainty estimations, they are often overlooked during uncertainty analysis. Using neurotoxicity as an example, this study developed a method to support analysis of implicitly and explicitly expressed uncertainties in QSAR modeling studies. Text content analysis was employed to identify implicit and explicit uncertainty indicators, whereafter uncertainties within the indicator-containing sentences were identified and systematically categorized according to 20 uncertainty sources. Our results show that implicit uncertainty was more frequent within most uncertainty sources (13/20), while explicit uncertainty was more frequent in only three sources, indicating that uncertainty is predominantly expressed implicitly in the field. The most highly cited sources included Mechanistic plausibility, Model relevance and Model performance, suggesting they constitute sources of most concern. The fact that other sources like Data balance were not mentioned, although it is recognized in the broader QSAR literature as an area of concern, demonstrates that the output from the type of analysis conducted here must be interpreted in the context of the broader QSAR literature before conclusions are drawn. Overall, the method established here can be applied in other QSAR modeling contexts and ultimately guide efforts targeted towards addressing the identified uncertainty sources.
{"title":"Analysis of implicit and explicit uncertainties in QSAR prediction of chemical toxicity: A case study of neurotoxicity","authors":"Jerry Achar , James W. Firman , Chantelle Tran , Daniella Kim , Mark T.D. Cronin , Gunilla Öberg","doi":"10.1016/j.yrtph.2024.105716","DOIUrl":"10.1016/j.yrtph.2024.105716","url":null,"abstract":"<div><div>Although uncertainties expressed in texts within QSAR studies can guide quantitative uncertainty estimations, they are often overlooked during uncertainty analysis. Using neurotoxicity as an example, this study developed a method to support analysis of implicitly and explicitly expressed uncertainties in QSAR modeling studies. Text content analysis was employed to identify implicit and explicit uncertainty indicators, whereafter uncertainties within the indicator-containing sentences were identified and systematically categorized according to 20 uncertainty sources. Our results show that implicit uncertainty was more frequent within most uncertainty sources (13/20), while explicit uncertainty was more frequent in only three sources, indicating that uncertainty is predominantly expressed implicitly in the field. The most highly cited sources included Mechanistic plausibility, Model relevance and Model performance, suggesting they constitute sources of most concern. The fact that other sources like Data balance were not mentioned, although it is recognized in the broader QSAR literature as an area of concern, demonstrates that the output from the type of analysis conducted here must be interpreted in the context of the broader QSAR literature before conclusions are drawn. Overall, the method established here can be applied in other QSAR modeling contexts and ultimately guide efforts targeted towards addressing the identified uncertainty sources.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105716"},"PeriodicalIF":3.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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