Regulatory Toxicology and Pharmacology最新文献

Isolation and investigation of anti-tubercular ilicic acid from Sphaeranthus indicus against Mycobacterium tuberculosis H37Rv and MDR strains

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-03-03 DOI: 10.1016/j.yrtph.2025.105800

Alex Yagoo , M.C. John Milton , Jelin Vilvest , A. Arokia Ahino Jessie , Kedike Balakrishna

The global burden of tuberculosis, particularly multidrug-resistant (MDR) strains of Mycobacterium tuberculosis, necessitates the urgent development of novel and effective therapeutic agents. Natural products derived from plants have long served as an essential resource for drug discovery, offering structurally diverse bioactive compounds. Sphaeranthus indicus, a plant traditionally valued for its medicinal properties, has shown promise as a source of antimicrobial agents. This study evaluated the antimycobacterial potential of S. indicus extracts and the isolated compound ilicic acid against M. tuberculosis H₃₇Rv and MDR isolates. Hexane, chloroform, and methanol extracts were screened using the microbroth dilution assay, with the hexane extract demonstrating superior activity (MIC: 125 μg/mL) against the H₃₇Rv strain. Purification of the hexane extract led to the isolation of ilicic acid, which exhibited significant antimycobacterial activity, inhibiting H₃₇Rv at 125 μg/mL. Against MDR isolates, ilicic acid displayed MIC values of 500 μg/mL for isolate 1, 125 μg/mL for isolate 2, and 250 μg/mL for isolate 3. These findings underscore the therapeutic potential of ilicic acid as a lead compound for developing anti-TB drugs, especially against drug-resistant strains. The study highlights S. indicus as a valuable source for discovering novel antimycobacterial agents, contributing to global efforts to combat TB resistance.

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引用次数: 0

Subchronic safety assessment of CIGB-500 in beagle dog after repeated daily dose administration over 28 days CIGB-500 在小猎犬中进行亚慢性安全性评估，每天重复给药 28 天

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-02-28 DOI: 10.1016/j.yrtph.2025.105798

Jorge Castro , Imran Shaikh , Sherwin Silo , Carolyn Hum , Michel Carrier , Rocky DiFruscia , Fred Thouin , Jeremy Chan , Lizet Aldana , Ariana Garcia , Jorge Berlanga , Leigh Berryman

CIGB-500 is a product whose active pharmaceutical ingredient is GHRP-6, (Growth Hormone Releasing Peptide-6), a synthetic peptide that allows the rescue of cardiac mass affected during Acute Myocardial Infarction. The objective of the study was to determine the toxicity profile of CIGB-500 in dogs. As general methodology, CIGB-500 was administered daily to dogs by intravenous route for 28 consecutive days. All animals were allocated to four groups: Control, Low-Dose (300 μg/kg/day), Mid dose (1000 μg/kg/day) and High-Dose (2000 μg/μg/day). Hypersalivation, hypoactivity, reduced heart rate, changes in respiration, pale gums and erythema of the head region were observed in some animals administered at 1000 and 2000 μg/kg/day. These clinical signs were transient, and were therefore considered non-adverse. Treatment with CIGB-500 did not result in any adverse macroscopic or microscopic changes. A decrease in heart rate value was noted following CIGB-500 treatment at all dose levels an at the end of recovery period, the heart rate effects at 2000 μg/kg/day were comparable to controls. In conclusion, the daily administration of CIGB-500 at doses up to 2000 μg/kg/day was well-tolerated, findings noted were transient, minor, non-adverse and reversible, and the no observable adverse effect level (NOAEL) was considered to be 2000 μg/kg/day.

{"title":"Subchronic safety assessment of CIGB-500 in beagle dog after repeated daily dose administration over 28 days","authors":"Jorge Castro , Imran Shaikh , Sherwin Silo , Carolyn Hum , Michel Carrier , Rocky DiFruscia , Fred Thouin , Jeremy Chan , Lizet Aldana , Ariana Garcia , Jorge Berlanga , Leigh Berryman","doi":"10.1016/j.yrtph.2025.105798","DOIUrl":"10.1016/j.yrtph.2025.105798","url":null,"abstract":"<div><div>CIGB-500 is a product whose active pharmaceutical ingredient is GHRP-6, (Growth Hormone Releasing Peptide-6), a synthetic peptide that allows the rescue of cardiac mass affected during Acute Myocardial Infarction. The objective of the study was to determine the toxicity profile of CIGB-500 in dogs. As general methodology, CIGB-500 was administered daily to dogs by intravenous route for 28 consecutive days. All animals were allocated to four groups: Control, Low-Dose (300 μg/kg/day), Mid dose (1000 μg/kg/day) and High-Dose (2000 μg/μg/day). Hypersalivation, hypoactivity, reduced heart rate, changes in respiration, pale gums and erythema of the head region were observed in some animals administered at 1000 and 2000 μg/kg/day. These clinical signs were transient, and were therefore considered non-adverse. Treatment with CIGB-500 did not result in any adverse macroscopic or microscopic changes. A decrease in heart rate value was noted following CIGB-500 treatment at all dose levels an at the end of recovery period, the heart rate effects at 2000 μg/kg/day were comparable to controls. In conclusion, the daily administration of CIGB-500 at doses up to 2000 μg/kg/day was well-tolerated, findings noted were transient, minor, non-adverse and reversible, and the no observable adverse effect level (NOAEL) was considered to be 2000 μg/kg/day.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"158 ","pages":"Article 105798"},"PeriodicalIF":3.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143535226","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}

引用次数: 0

Report on the European Partnership for Alternative Approaches to Animal Testing (EPAA) "New Approach Methodologies (NAMs) User Forum Kick-off Workshop".

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-02-28 DOI: 10.1016/j.yrtph.2025.105796

Mark T D Cronin, Maria T Baltazar, Tara S Barton-Maclaren, Ofelia Bercaru, K Nadira De Abrew, Christian Desaintes, Sylvia E Escher, Petra Kern, Gavin Maxwell, Vera Rogiers, Katrin Schutte, Tomasz Sobanski

The European Partnership for Alternative Approaches to Animal Testing (EPAA) held the "New Approach Methodologies (NAMs) User Forum Kick-off Workshop", at the European Chemicals Agency (ECHA), Helsinki, Finland on 7-8 December 2023. The aim of the User Forum was to gain insight into the regulatory use of NAMs, with a particular reference to Next Generation Risk Assessment (NGRA), for chemical safety assessment. To achieve this, presentations summarised the learnings and experiences of previous EPAA Skin Sensitisation User Forums as well as that of the European Commission's Scientific Committee on Consumer Safety (SCCS). The findings of five case studies were summarised that illustrated the use of NAMs. The presentations and subsequent discussions allowed for learnings and insights to be compiled from all stakeholders with regard to the use of NAMs. Recommendations for the regulatory use of NAMs in NGRA were made namely for exposure assessment; hazard identification; using tiered and targeted testing strategies; performing risk assessment using NAM data; the practical implementation of NAMs; the use of -omics technologies; and the needs for capacity building and training. The EPAA User Forum provided an open platform for safety assessors to share learnings and experiences. Recommendations for the format and topics of future EPAA User Forums were also made.

2023 年 12 月 7-8 日，欧洲动物试验替代方法合作伙伴关系（EPAA）在芬兰赫尔辛基的欧洲化学品管理局（ECHA）举办了 "新方法（NAMs）用户论坛启动研讨会"。用户论坛的目的是深入了解新方法方法在监管方面的应用，特别是下一代风险评估 (NGRA) 在化学品安全评估方面的应用。为实现这一目标，演讲总结了之前 EPAA 皮肤过敏用户论坛以及欧盟委员会消费者安全科学委员会 (SCCS) 的学习成果和经验。会议还总结了五个案例研究的结果，说明了非杀伤性物质的使用情况。通过发言和随后的讨论，汇集了所有利益相关方在使用营养物质管理方面的经验和见解。会议提出了在国家地质评估中规范使用国家记录和档案的建议，即暴露评估、危害识别、使用分级和有针对性的测试策略、使用国家记录和档案数据进行风险评估、国家记录和档案的实际实施、组学技术的使用以及能力建设和培训需求。EPAA 用户论坛为安全评估人员提供了一个交流学习和经验的开放平台。还就未来 EPAA 用户论坛的形式和主题提出了建议。

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引用次数: 0

A review of the genotoxic effects of antiparasitic drugs on parasites and their hosts 抗寄生虫药物对寄生虫及其宿主的基因毒性影响综述

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-02-28 DOI: 10.1016/j.yrtph.2025.105797

Nikolajs Sjakste , Domagoj Dinter , Goran Gajski

Antiparasitic medications are drugs used to treat infections caused by parasites like protozoa, helminths, and ectoparasites by either killing the parasite or inhibiting its growth and reproduction. These medications are crucial for treating parasitic diseases and can vary in dosage and administration depending on the type of infection with proper diagnosis being essential for effective treatment. Nevertheless, such drugs can also cause a range of side effects including genotoxicity, depending on the type of medication and the individual's response. Therefore, here we will summarize data on the genotoxic effects of some antiparasitic drugs since many parasites provoke DNA damage per se, and therapy can enhance such genotoxic effects. The DNA-damaging effects of antiparasitic drugs enable the use of some of them for cancer treatment. Since a parasitic disease comes with severe consequences, the cost-benefit should be considered when taking drugs against such a disease even in terms of their potential genotoxicity. While some antiparasitic drugs have shown genotoxic potential in laboratory studies, most are considered safe for human use at therapeutic doses. Long-term or high-dose exposure may carry more risk; moreover, the genotoxic effects of the drugs can interfere with the genotoxicity of the parasitic infection. More research is needed to fully understand the implications for human health. Nevertheless, the present study has confirmed the need for further cytogenetic research and regular patient monitoring to minimize the risk of an adverse event, especially among frequent travellers visiting parasite-affected areas.

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引用次数: 0

Next Generation Risk Assessment of Hair Dye HC Yellow No. 13: Ensuring Protection From Liver Steatogenic Effects.

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-02-28 DOI: 10.1016/j.yrtph.2025.105794

Sara Sepehri, Dinja De Win, Anja Heymans, Freddy Van Goethem, Robim M Rodrigues, Vera Rogiers, Tamara Vanhaecke

This study employs animal-free Next Generation Risk Assessment (NGRA) principles to evaluate the safety of repeated dermal exposure to 2.5% (w/w) HC Yellow No. 13 (HCY13) hair dye. As multiple in silico tools consistently flagged hepatotoxic potential, likely due to HCY13's trifluoromethyl group, which is known to interfere with hepatic lipid metabolism, liver steatosis was chosen as the primary mode of action for evaluation. AOP-guided in vitro tests were conducted, exposing human stem cell-derived hepatic cells to varying HCY13 concentrations over 72 hours. The expression of 11 lipid metabolism-related marker genes (AHR, PPARA, LXRA, APOB, ACOX1, CPT1A, FASN, SCD1, DGAT2, CD36, and PPARG) and triglyceride accumulation, a phenotypic hallmark of steatosis, were measured. PROAST software was used to calculate in vitro Points of Departure (PoD_NAM) for each biomarker. Using GastroPlus 9.9, physiologically-based pharmacokinetic (PBPK) models estimated internal liver concentrations (C_{max liver}) of HCY13, ranging from 4 to 20 pM. All PoD_NAM values significantly exceeded the predicted C_{max liver}, indicating that HCY13 at 2.5% (w/w) is unlikely to induce liver steatosis under the assumed conditions. This research demonstrates the utility of NGRA, integrating AOP-based in vitro assays and computational models to protect human health and support regulatory decision-making without animal testing.

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引用次数: 0

Nonclinical teratogenicity safety assessment of CRBN-engaging targeted protein degraders: Points to consider

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-02-25 DOI: 10.1016/j.yrtph.2025.105793

Lise I. Loberg , William R. Proctor , Andrew D. Burdick , Annick Cauvin , Anthony M. DeLise , Michelle Hemkens , Andreas M. Hohlbaum , Renee Hukkanen , Alanna E. Sedgwick , Dana Shuey , Doris T. Zane , Katie Stamp

Targeted protein degraders (or degraders) are an emerging small molecule drug modality with transformative therapeutic potential. Currently, most degraders are developed for severe life-threatening disorders and engage the E3 ligase cereblon. One barrier to the broader use of degraders is the potential risk of embryofetal toxicity with cereblon-engaging degraders, exemplified by thalidomide. Thalidomide (and analogs, known as immunomodulatory drugs) binds cereblon and modifies its substrate repertoire, leading to degradation of intended and multiple unintended neosubstrates. Some cereblon-engaging degraders have been engineered to avoid the degradation of unintended neosubstrates implicated in teratogenicity, specifically SALL4. Mechanistic links between SALL4 degradation by thalidomide and human teratogenicity have been established; further, SALL4 degradation by thalidomide (and its analogs) has been linked to teratogenicity in susceptible nonclinical species. It is generally accepted that SALL4 degradation is unlikely to be the only mechanism of teratogenicity associated with thalidomide and its analogs. Currently, best practices to evaluate the teratogenicity risk of cereblon-engaging degraders have not been established. Here, we present points to consider in the teratogenicity safety assessment of cereblon-engaging degraders from the perspective of an IQ consortium working group.

{"title":"Nonclinical teratogenicity safety assessment of CRBN-engaging targeted protein degraders: Points to consider","authors":"Lise I. Loberg , William R. Proctor , Andrew D. Burdick , Annick Cauvin , Anthony M. DeLise , Michelle Hemkens , Andreas M. Hohlbaum , Renee Hukkanen , Alanna E. Sedgwick , Dana Shuey , Doris T. Zane , Katie Stamp","doi":"10.1016/j.yrtph.2025.105793","DOIUrl":"10.1016/j.yrtph.2025.105793","url":null,"abstract":"<div><div>Targeted protein degraders (or degraders) are an emerging small molecule drug modality with transformative therapeutic potential. Currently, most degraders are developed for severe life-threatening disorders and engage the E3 ligase cereblon. One barrier to the broader use of degraders is the potential risk of embryofetal toxicity with cereblon-engaging degraders, exemplified by thalidomide. Thalidomide (and analogs, known as immunomodulatory drugs) binds cereblon and modifies its substrate repertoire, leading to degradation of intended and multiple unintended neosubstrates. Some cereblon-engaging degraders have been engineered to avoid the degradation of unintended neosubstrates implicated in teratogenicity, specifically SALL4. Mechanistic links between SALL4 degradation by thalidomide and human teratogenicity have been established; further, SALL4 degradation by thalidomide (and its analogs) has been linked to teratogenicity in susceptible nonclinical species. It is generally accepted that SALL4 degradation is unlikely to be the only mechanism of teratogenicity associated with thalidomide and its analogs. Currently, best practices to evaluate the teratogenicity risk of cereblon-engaging degraders have not been established. Here, we present points to consider in the teratogenicity safety assessment of cereblon-engaging degraders from the perspective of an IQ consortium working group.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"158 ","pages":"Article 105793"},"PeriodicalIF":3.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524287","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}

引用次数: 0

Comparison of carbonyls and tobacco-specific nitrosamines in aerosols of heated tobacco products and conventional cigarette smoke using both targeted and untargeted analytical methods

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-02-13 DOI: 10.1016/j.yrtph.2025.105786

Hsiang-Tsui Wang , Ping-Huai Wang , Chun-Yu Chen , Tsung-Yun Liu , Han-Hsing Tsou

Cigarette smoke (CS) exposes users to harmful substances, contributing to chronic lung diseases. Heated tobacco products (HTPs) are marketed as safer alternatives due to their lower toxicant emissions from heating rather than burning tobacco. However, HTPs may produce unique toxicants that are not found in CS. The emissions of carbonyls and tobacco-specific nitrosamines (TSNAs) were compared using targeted analysis using liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry (UPLC-MS/MS) and untargeted analysis with UPLC-QToF and Progenesis® QI software. Targeted analysis revealed that HTP aerosol emissions contain significantly lower levels of harmful compounds compared to CS, with reductions of 8.7%–91.6% in 11 carbonyls and 85.7%–95.4% in four TSNAs) Untargeted analysis identified 25 carbonyls and seven nitrosamines in both HTPs and conventional cigarettes, with acetoin, dimethylbenzaldehyde, furfural, and diisopropanolnitrosamine (DIPN) found at relatively high levels in HTPs. While untargeted methods introduce some uncertainty, these findings underscore distinct chemical differences between HTPs and conventional cigarettes. Long-term studies are essential to fully understand the health implications of HTP use.

{"title":"Comparison of carbonyls and tobacco-specific nitrosamines in aerosols of heated tobacco products and conventional cigarette smoke using both targeted and untargeted analytical methods","authors":"Hsiang-Tsui Wang , Ping-Huai Wang , Chun-Yu Chen , Tsung-Yun Liu , Han-Hsing Tsou","doi":"10.1016/j.yrtph.2025.105786","DOIUrl":"10.1016/j.yrtph.2025.105786","url":null,"abstract":"<div><div>Cigarette smoke (CS) exposes users to harmful substances, contributing to chronic lung diseases. Heated tobacco products (HTPs) are marketed as safer alternatives due to their lower toxicant emissions from heating rather than burning tobacco. However, HTPs may produce unique toxicants that are not found in CS. The emissions of carbonyls and tobacco-specific nitrosamines (TSNAs) were compared using targeted analysis using liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry (UPLC-MS/MS) and untargeted analysis with UPLC-QToF and Progenesis® QI software. Targeted analysis revealed that HTP aerosol emissions contain significantly lower levels of harmful compounds compared to CS, with reductions of 8.7%–91.6% in 11 carbonyls and 85.7%–95.4% in four TSNAs) Untargeted analysis identified 25 carbonyls and seven nitrosamines in both HTPs and conventional cigarettes, with acetoin, dimethylbenzaldehyde, furfural, and diisopropanolnitrosamine (DIPN) found at relatively high levels in HTPs. While untargeted methods introduce some uncertainty, these findings underscore distinct chemical differences between HTPs and conventional cigarettes. Long-term studies are essential to fully understand the health implications of HTP use.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"157 ","pages":"Article 105786"},"PeriodicalIF":3.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143422315","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}

引用次数: 0

Accurate regulatory classification of chemical respiratory allergens: The case for robust characterisation of causation

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-02-12 DOI: 10.1016/j.yrtph.2025.105785

Mark A. Pemberton , Ian Kimber

Occupational health standards, worker safety and effective regulatory classification relies upon characterisation of occupational asthma and discrimination between allergic asthma, irritant-induced asthma, and work-exacerbated asthma, and the accurate identification of chemical allergens of the respiratory tract.

No in silico, in vitro or in vivo experimental method can, either alone or in combination, accurately identify chemical respiratory allergens and provide a sound basis for regulatory classification. Measurement of IgE antibody and skin prick testing can characterise allergy to proteins, but not to chemical respiratory allergens.

Therefore, characterisation of causation and accurate regulatory classification of work-related asthma relies upon characterisation of clinical and workplace histories and specific inhalation challenge tests conforming to current guidelines and best practice.

This manuscript reviews the important of accurate characterisation of causation in cases of work-related asthma to ensure accurate classification and robust regulation, and to promote a sound basis for clinical and experimental research. Commentaries on selected clinical case studies are provided that highlight key issues that confound attribution of causation. Specific recommendations are made regarding the design, conduct and interpretation of clinical investigations of work-related asthma that could provide a basis of more robust regulatory practice, and the more reliable identification of chemical respiratory allergens.

{"title":"Accurate regulatory classification of chemical respiratory allergens: The case for robust characterisation of causation","authors":"Mark A. Pemberton , Ian Kimber","doi":"10.1016/j.yrtph.2025.105785","DOIUrl":"10.1016/j.yrtph.2025.105785","url":null,"abstract":"<div><div>Occupational health standards, worker safety and effective regulatory classification relies upon characterisation of occupational asthma and discrimination between allergic asthma, irritant-induced asthma, and work-exacerbated asthma, and the accurate identification of chemical allergens of the respiratory tract.</div><div>No <em>in silico, in vitro or in vivo</em> experimental method can, either alone or in combination, accurately identify chemical respiratory allergens and provide a sound basis for regulatory classification. Measurement of IgE antibody and skin prick testing can characterise allergy to proteins, but not to chemical respiratory allergens.</div><div>Therefore, characterisation of causation and accurate regulatory classification of work-related asthma relies upon characterisation of clinical and workplace histories and specific inhalation challenge tests conforming to current guidelines and best practice.</div><div>This manuscript reviews the important of accurate characterisation of causation in cases of work-related asthma to ensure accurate classification and robust regulation, and to promote a sound basis for clinical and experimental research. Commentaries on selected clinical case studies are provided that highlight key issues that confound attribution of causation. Specific recommendations are made regarding the design, conduct and interpretation of clinical investigations of work-related asthma that could provide a basis of more robust regulatory practice, and the more reliable identification of chemical respiratory allergens.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"157 ","pages":"Article 105785"},"PeriodicalIF":3.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143422316","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}

引用次数: 0

Applicability of the in vitro skin irritation methods (EpiSkin™, EpiDerm™ SIT) to organosilicon-based substances

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-02-07 DOI: 10.1016/j.yrtph.2025.105778

Carole Forlini , Farah Koraichi-Emeriau , Barbara G. Schmitt , Wendy Koch , Shawn Seidel , Eckart Gura , Michael Haack , Dorothea Eigler

It is now widely accepted that the reconstructed human epidermis models (OECD TG 439) can be used as a standalone replacement of the in vivo rabbit assay (OECD TG 404) to accurately predict skin irritancy. Many legislations have now introduced the legal requirement to use in vitro methods as the first step. The applicability of these methods to organosilicon-based substances was not evaluated during the validation of this guideline. Therefore, the aim of the current work was to assess the applicability of EpiSkin™ and EpiDerm™ SIT in vitro methods for organosilicons. Ten substances were evaluated, and results were compared with existing rabbit data. The data showed that both test methods failed to accurately predict the in vivo skin irritation potential, with predictive capacities below the minimum test guideline requirements. The two models delivered consistent results in only 60% of the cases. Several hypotheses were explored to explain this high rate of discordance without success. As EpiDerm™ SIT showed 100% sensitivity, a new stepwise testing strategy is proposed for organosilicons consisting of starting with EpiDerm™ SIT, following by EpiSkin™ in case of positive outcome. While keeping protective, this adapted strategy avoids unnecessary animal testing.

{"title":"Applicability of the in vitro skin irritation methods (EpiSkin™, EpiDerm™ SIT) to organosilicon-based substances","authors":"Carole Forlini , Farah Koraichi-Emeriau , Barbara G. Schmitt , Wendy Koch , Shawn Seidel , Eckart Gura , Michael Haack , Dorothea Eigler","doi":"10.1016/j.yrtph.2025.105778","DOIUrl":"10.1016/j.yrtph.2025.105778","url":null,"abstract":"<div><div>It is now widely accepted that the reconstructed human epidermis models (OECD TG 439) can be used as a standalone replacement of the <em>in vivo</em> rabbit assay (OECD TG 404) to accurately predict skin irritancy. Many legislations have now introduced the legal requirement to use <em>in vitro</em> methods as the first step. The applicability of these methods to organosilicon-based substances was not evaluated during the validation of this guideline. Therefore, the aim of the current work was to assess the applicability of EpiSkin™ and EpiDerm™ SIT <em>in vitro</em> methods for organosilicons. Ten substances were evaluated, and results were compared with existing rabbit data. The data showed that both test methods failed to accurately predict the <em>in vivo</em> skin irritation potential, with predictive capacities below the minimum test guideline requirements. The two models delivered consistent results in only 60% of the cases. Several hypotheses were explored to explain this high rate of discordance without success. As EpiDerm™ SIT showed 100% sensitivity, a new stepwise testing strategy is proposed for organosilicons consisting of starting with EpiDerm™ SIT, following by EpiSkin™ in case of positive outcome. While keeping protective, this adapted strategy avoids unnecessary animal testing.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"157 ","pages":"Article 105778"},"PeriodicalIF":3.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143383094","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}

引用次数: 0

Establishment of a threshold of toxicological concern for pharmaceutical intermediates based on historical repeat-dose data and its application in setting health based exposure limits 基于历史重复剂量数据的药物中间体毒理学关注阈值的建立及其在设定健康暴露限值中的应用。

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2024.105764

Zoe Dunn , Delorice Murudzwa , Kamila Blum

Availability of toxicological data for pharmaceutical intermediates (IMs) used in the manufacture of small molecules is often limited. Scarcity of data – in particular, repeat-dose toxicity (RDT) – renders the calculation of health-based exposure limits (HBELs) problematic. Establishment of HBELs, including occupational exposure limits (OELs) and permitted daily exposures (PDEs) facilitating worker and patient safety respectively, is however essential. Historic 28-day oral rodent toxicity data was analysed for 103 GSK isolated IMs. No-observed (adverse) effect levels (NO(A)ELs) and critical effects were extracted. The 5th percentile (p05) of the NO(A)EL distribution was 15 mg/kg/day. Substance specific HBELs were calculated, selecting the NO(A)EL as the Point of Departure (PoD); 99% of IMs (n = 102) were assigned an oral PDE ≥1000 μg/day and OEL ≥100 μg/m³. A default oral PDE of 1000 μg/day and OEL of 100 μg/m³ is thus proposed for IMs. Evaluation of an additional PoD – benchmark dose lower confidence limit (BMDL) – further supported the default HBELs. The default oral PDE can also serve as a threshold of toxicological concern (TTC) for IMs. Default limits can aid in setting HBELs for novel data-poor IMs, as well as supporting waiving of RDT in the future through read-across.

用于制造小分子的药物中间体（IMs）的毒理学数据通常是有限的。数据的缺乏——特别是重复剂量毒性（RDT）——使得基于健康的暴露限值（hbel）的计算存在问题。然而，建立hbel，包括职业暴露限值（oel）和允许的每日暴露（PDEs），分别促进工人和患者的安全是至关重要的。对103例GSK分离的IMs进行28天口服啮齿动物毒性数据分析。提取未观察到的（不良）效应水平（NO(A) el）和临界效应。NO(A)EL分布的第5百分位（p0.05）为15 mg/kg/d。计算物质特异性hbel，选择NO(A)EL作为出发点（PoD）；99%的IMs （n = 102）口服PDE≥1000 μg/d， OEL≥100 μg/m3。因此，建议IMs的默认口服PDE为1000 μg/d， OEL为100 μg/m3。额外PoD的评估——基准剂量下限（BMDL）——进一步支持了默认的hbel。默认的口服PDE也可以作为IMs毒理学关注（TTC）的阈值。默认限制可以帮助为新的数据贫乏的im设置hbel，并支持将来通过读透免除RDT。

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引用次数: 0