Regulatory Toxicology and Pharmacology最新文献_第2页

Smoke Flavoring-a case study demonstrating the value of using Benefit-risk analysis for foods (BRAFO) to provide transparency for risk management decisions. 烟熏调味——一个案例研究，展示了使用食品利益风险分析（BRAFO）为风险管理决策提供透明度的价值。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2026-01-21 DOI: 10.1016/j.yrtph.2026.106033

Candace Doepker, Allison Franzen, Gregory Brorby, Lauren Brown, Neepa Choksi, Alexander East, Daniele Wikoff

Efforts to renew existing authorizations of smoke flavoring primary products (SFPPs) were recently finalized in the European Union. Herein, a Benefit Risk Assessment for Foods (BRAFO) was conducted for smoke flavorings using three specific SFPPs. Four metrics were evaluated between a reference scenario (legislation allowing both conventional smoking of foods and SFPPs) and an alternative scenario (SFPPs in meat, fish, and cheese are scheduled to be removed from the market after July 1, 2029, and only conventional smoking of foods is allowed): 1) whole mixture risk, 2) risk from polycyclic aromatic hydrocarbons (PAHs), 3) risk from constituents other than PAHs, and 4) environmental considerations. Systematic literature searches were used to identify information pertinent to each metric and scenario; direct testing data for the SFPPs was also used. All metrics were assessed qualitatively; quantitative assessment was also conducted when sufficient data were available. For each metric, the reference scenario prevailed, presenting the benefit of less risk than the alternative scenario. Key considerations involved the robust characterization of the SFPPs and direct testing data to inform safety, which are less controlled in conventional smoking of foods. The results of this assessment demonstrate the importance of risk-benefit considerations and should be helpful to policy makers globally.

欧盟最近完成了更新现有烟味初级产品（SFPPs）授权的工作。本文对使用三种特定SFPPs的烟熏香料进行了食品效益风险评估（BRAFO）。在参考情景（立法允许对食品和SFPPs进行传统熏制）和替代情景（肉类、鱼类和奶酪中的SFPPs计划在2029年7月1日之后从市场上移除，只允许对食品进行传统熏制）之间评估了四个指标：1)全混合物风险，2)多环芳烃（PAHs）风险，3)多环芳烃以外成分风险，4)环境考虑因素。系统文献检索用于识别与每个指标和场景相关的信息；还使用了SFPPs的直接测试数据。所有指标都进行了定性评估；在获得足够数据时也进行了定量评价。对于每一个度量，参考方案都占了上风，呈现出比备选方案风险更小的好处。关键的考虑因素包括SFPPs的强大特性和直接测试数据，以告知安全性，这在传统的食品熏制中控制较少。这一评估的结果表明了风险-收益考虑的重要性，应该对全球决策者有所帮助。

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引用次数: 0

Nitrosamine drug substance-related impurities cause DNA methylation adducts in vitro and in primary hepatocytes upon Cytochrome P450-dependend metabolic activation 亚硝胺类药物相关杂质在体外和原代肝细胞中通过细胞色素p450依赖的代谢激活引起DNA甲基化加合物。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2026-01-20 DOI: 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.

n -亚硝胺是一种DNA烷基化剂，在食品、化妆品、烟草产品以及最近的药物中都有发现。随着细胞色素P450 （CYP）介导的代谢激活，这些化合物引起DNA损伤和突变。与n -亚硝基二甲胺（NDMA）等表征良好的化合物不同，亚硝胺类药物相关杂质（NDSRIs）的遗传毒性数据仍然有限。考虑到它们的调控相关性，本研究评估了三种NDSRIs——n -亚硝基倍他组氨酸（NBH）、n -亚硝基氟西汀（NFluo）和n -亚硝基索替林（NNT）——与NDMA相比的遗传毒性潜力。在代谢激活的DNA烷基化实验中，n7 -甲基-脱氧鸟苷（N7-MedG）和o6 -甲基-脱氧鸟苷（O6-MedG）水平升高证实了NDSRIs具有明显的DNA甲基化潜力。重组CYP异构体对每种NDSRI的生物激活有不同的贡献，突出了酶特异性的毒性途径。随后，我们证明了所有NDSRIs在原代大鼠肝细胞中引起DNA甲基化加合物（N7-MedG >O6-MedG），其水平普遍高于NDMA引起的水平。一致地，NDSRIs比NDMA产生更多的DNA链断裂，这遵循DNA加合动力学。此外，所有NDSRIs在24 h后都表现出细胞毒性，而NDMA没有细胞毒性作用。综上所述，我们的研究提供了证据，证明三种NDSRIs在原代大鼠肝细胞中具有遗传毒性，这需要进一步研究它们的致突变潜力。

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引用次数: 0

Nitroparaffin transcriptional profiles and toxicokinetics support chemical-specific carcinogenicity assessment 硝基石蜡转录谱和毒性动力学支持化学特异性致癌性评估。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2026-01-19 DOI: 10.1016/j.yrtph.2026.106035

A. Rasim Barutcu , Jamie Scaglione , Marjory Moreau , Elizabeth Hofstetter , Todor Antonijevic , Andrew Maier , Pierre Serfass , Leslie Recio , Pamela J. Spencer

The toxicological profiles of nitroparaffins—nitromethane (NM), nitroethane (NE), and 1-nitropropane (1NP)—remain incompletely characterized. This has led to reliance on read-across approaches, extrapolating carcinogenicity data from NM to NE and 1NP, though the validity of such extrapolations is uncertain. In this study, we examined the concentration-dependent transcriptional effects of NM, NE, and 1NP in primary rat hepatocytes to clarify their cellular impact and mechanisms of toxicity. We assessed cytotoxicity, differential gene expression, and pathway enrichment, and applied in vitro to in vivo extrapolation (IVIVE) to estimate systemic bioavailability and clearance rates. Cytotoxicity was observed at 3 mM for NM and NE but not up to 10 mM for 1NP. Transcriptomic profiling revealed minimal overlap in dysregulated genes and enriched pathways among the three compounds. NE elicited the broadest transcriptional response, whereas NM and 1NP showed more limited effects. IVIVE further indicated distinct systemic bioavailability and clearance, suggesting toxicokinetic differences. Taken together, these results demonstrate that structural similarity alone does not predict comparable toxicological behavior. Each nitroparaffin exhibited unique molecular activity and toxicokinetics, indicating that read-across within this class requires demonstrated concordance in both bioactivity and toxicokinetic profiles, which are currently absent for NE, NM and 1NP. Thus, reliance on read-across from NM to NE or 1NP may misrepresent health risks and carries significant regulatory implications.

硝基石蜡的毒理学特征-硝基甲烷（NM），硝基乙烷（NE）和1-硝基丙烷(1NP)-仍然不完全表征。这导致了对跨读方法的依赖，将从NM到NE和1NP的致癌性数据外推，尽管这种外推的有效性尚不确定。在这项研究中，我们检测了NM、NE和1NP在原代大鼠肝细胞中的浓度依赖性转录效应，以阐明它们的细胞影响和毒性机制。我们评估了细胞毒性、差异基因表达和途径富集，并应用体外到体内外推法（IVIVE）来估计系统生物利用度和清除率。NM和NE在3 mM时观察到细胞毒性，而1NP在10 mM时则没有。转录组学分析显示，三种化合物之间的失调基因和富集途径的重叠最小。NE引起了最广泛的转录反应，而NM和1NP的作用更有限。IVIVE进一步显示出不同的系统生物利用度和清除率，表明毒性动力学差异。综上所述，这些结果表明，结构相似性本身并不能预测相似的毒理学行为。每个硝基石蜡都表现出独特的分子活性和毒性动力学，这表明在这类中进行跨读需要证明生物活性和毒性动力学特征的一致性，这是目前NE， NM和1NP所缺乏的。因此，依赖从NM到NE或1NP的读取可能会歪曲健康风险，并带来重大的监管影响。

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引用次数: 0

Inter-species variability in 4,4′-methylenedianiline metabolism: insights from human and rat precision-cut liver slices 4,4'-亚甲二苯胺代谢的物种间变异：来自人类和大鼠精确切割肝脏切片的见解。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2026-01-17 DOI: 10.1016/j.yrtph.2026.106034

Marieke A.J. Hof , Jeffrey Sewdihal , Stepan Stepanovic , Jos H. Hermans , Péter Horvatovich , Peter Olinga , Frank Klont

Occupational exposure to 4,4′-methylenedianiline (MDA), a precursor in polyurethane foam production, has been linked to liver disease and cancer. Most evidence, however, comes from underpowered epidemiological studies, while empirical data are mainly from animal models, which point toward liver metabolism generating reactive metabolites. We thus used precision-cut liver slices (PCLS) from human and rat donors which we exposed to MDA at 10 and 100 μM for 24 h, and supernatants were analyzed by liquid chromatography-‘SWATH’ mass spectrometry. The major metabolite detected in hPCLS and rPCLS was MDA's known N-acetyl derivative, comprising approximately 80–90 % of metabolites at 10 μM and 50–60 % at 100 μM. Other metabolites were phase II conjugates, including putative N-formylation and urea-glutamine and urea-ethanolamine adducts. The latter accounted for ∼10 % of metabolites at 10 μM, increasing to 50 % at 100 μM in rPCLS but only reaching ∼25 % in hPCLS. Cell viability remained at 100 % across all human conditions and in rPCLS at 10 μM, but it dropped below 5 % at 100 μM. In conclusion, this study confirmed MDA's well-known N-acetyl metabolite across both species, while also unveiling rather unusual, previously unreported conjugates. Additionally, distinct interspecies differences were observed, underscoring the need for human-based studies.

职业暴露于4,4'-亚甲二苯胺（MDA）——聚氨酯泡沫生产中的一种前体——与肝脏疾病和癌症有关。然而，大多数证据来自缺乏动力的流行病学研究，而经验数据主要来自动物模型，这些数据指向肝脏代谢产生反应性代谢物。因此，我们使用来自人类和大鼠供体的精确切割肝脏切片（PCLS），我们将其暴露于10和100 μM的MDA中24小时，并通过液相色谱-'SWATH'质谱分析上清。在hPCLS和rPCLS中检测到的主要代谢物是MDA的已知n -乙酰基衍生物，在10 μM范围内约占80-90%，在100 μM范围内约占50-60%。其他代谢物是II期偶联物，包括假定的n -甲酰化和尿素-谷氨酰胺和尿素-乙醇胺加合物。后者在10 μM时占代谢物的约10%，在rPCLS中在100 μM时增加到50%，而在hPCLS中仅达到约25%。在所有人类条件下，细胞活力保持在100%，在10 μM的rPCLS中，但在100 μM时，细胞活力下降到5%以下。总之，这项研究证实了MDA在两个物种中众所周知的n -乙酰代谢物，同时也揭示了相当不寻常的，以前未报道的偶联物。此外，观察到明显的种间差异，强调了以人类为基础的研究的必要性。

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引用次数: 0

Analysis of predictive value of animal repeated dose toxicity study results for clinical safety of US FDA-approved anticancer drugs between 2019 and 2023 动物重复剂量毒性研究结果对2019 - 2023年美国fda批准的抗癌药物临床安全性的预测价值分析

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2026-01-12 DOI: 10.1016/j.yrtph.2026.106031

Gyeyoung Choi , Seungjin Bae , Kyung-Min Lim

The translational relevance of nonclinical animal studies in predicting clinical safety outcomes remains poorly understood in oncology drug development. This study aimed to qualitatively assess the concordance between toxicological findings from animal repeat-dose toxicity studies and treatment-emergent adverse events (TEAEs) in clinical trials of 63 anticancer drugs approved by the U.S. FDA from 2019 to 2023. We extracted nonclinical and clinical safety data from FDA review documents and categorized observations across 20 organ systems using a Concordant Positive/Concordant Negative/Animal-only Positive/Clinical-only Positive classification framework. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated by organ class and animal species. Among 63 anti-cancer drugs analyzed, hematologic, hepatobiliary, and gastrointestinal systems exhibited high concordance (notably high PPV and sensitivity), while bone/tooth and lymphatic systems showed low translational predictivity. Predictive performance was similar across rats, dogs, and monkeys, with no statistically significant interspecies differences. These findings suggest that current animal models offer organ-specific, but not species-specific, translational value for anti-cancer drugs. A shift toward validated, human-relevant alternative models is recommended for organ classes with low predictive performance in animal studies, to enhance translational accuracy while reducing animal sacrifice.

在肿瘤药物开发中，非临床动物研究在预测临床安全性结果中的转化相关性仍然知之甚少。本研究旨在定性评估2019年至2023年美国FDA批准的63种抗癌药物临床试验中动物重复剂量毒性研究毒理学结果与治疗发生不良事件（teae）之间的一致性。我们从FDA审查文件中提取了非临床和临床安全性数据，并使用协和阳性/协和阴性/仅动物阳性/仅临床阳性分类框架对20个器官系统的观察结果进行了分类。按器官分类和动物种类计算敏感性、特异性、阳性预测值（PPV）和阴性预测值（NPV）。在分析的63种抗癌药物中，血液系统、肝胆系统和胃肠道系统表现出高度的一致性（特别是高PPV和敏感性），而骨/牙齿和淋巴系统表现出较低的翻译预测性。大鼠、狗和猴子的预测性能相似，在物种间没有统计学上的显著差异。这些发现表明，目前的动物模型为抗癌药物提供了器官特异性而非物种特异性的转化价值。对于动物研究中预测性能较低的器官类别，建议转向经过验证的、与人类相关的替代模型，以提高翻译准确性，同时减少动物牺牲。

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引用次数: 0

Nonclinical development of advanced therapies: Best practices for translational and regulatory success 先进疗法的非临床开发：转化和监管成功的最佳实践

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2026-01-12 DOI: 10.1016/j.yrtph.2026.106032

Piyan Zhang

Advanced therapeutics—including cell and gene therapies, antibody–drug conjugates, and RNA-based medicines—present unique in vivo pharmacology, safety, and translational challenges that require tailored nonclinical programs aligned with global regulatory expectations. This review synthesizes best practices for designing IND/CTA-enabling studies, integrating biodistribution, pharmacokinetics/pharmacodynamics, immunogenic assessment, safety pharmacology, toxicology, and dose selection into a cohesive strategy. Regulatory frameworks from the FDA, EMA, and PMDA emphasize early engagement, modality-specific risk assessment, and harmonization through ICH guidance (e.g., S12). Key recommendations include using relevant animal models, novel analytical methods, and conservative first-in-human dosing to mitigate translational uncertainties. Distinct considerations for oncology versus non-oncology indications are highlighted, reflecting differing risk tolerances and data requirements. Case studies of clinical holds and successful submissions underscore the importance of anticipating regulatory concerns, ensuring manufacturing readiness, and implementing robust risk mitigation. By adopting these integrated scientific and regulatory strategies, developers can streamline translation from preclinical studies to human trials, ultimately accelerating the delivery of safe, effective advanced therapies.

先进疗法——包括细胞和基因疗法、抗体-药物偶联物和基于rna的药物——呈现出独特的体内药理学、安全性和转化挑战，需要量身定制符合全球监管期望的非临床项目。这篇综述综合了设计IND/ cta研究的最佳实践，将生物分布、药代动力学/药效学、免疫原性评估、安全药理学、毒理学和剂量选择整合到一个统一的策略中。FDA、EMA和PMDA的监管框架强调早期参与、特定模式的风险评估，以及通过ICH指导进行协调（例如，S12）。主要建议包括使用相关的动物模型、新的分析方法和保守的首次人体给药来减轻转化的不确定性。强调了肿瘤与非肿瘤适应症的不同考虑，反映了不同的风险承受能力和数据要求。临床持有和成功提交的案例研究强调了预测监管问题、确保生产准备和实施强有力的风险缓解的重要性。通过采用这些综合的科学和监管策略，开发人员可以简化从临床前研究到人体试验的转换，最终加速安全、有效的先进疗法的交付。

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引用次数: 0

Prolonged exposure to nitrate in drinking water does not adversely impact prenatal or birth outcomes in a rat model 在大鼠模型中，长期暴露于饮用水中的硝酸盐不会对产前或分娩结果产生不利影响

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2026-01-09 DOI: 10.1016/j.yrtph.2026.106030

Leaf R. Kardol , Avalon Gray , Amina Rhaman , Alexander N. Larcombe , Christine Jeffries-Stokes , Annette Stokes , Sarah Bourke , Sujata Shinde , Kevin Croft , Caitlin S. Wyrwoll

Nitrate (NO₃⁻) is a common drinking water contaminant associated with increased risks of adverse pregnancy outcomes at concentrations below the World Health Organisation (WHO) drinking water guidelines (50 mg/L NO₃⁻). However, causal evidence at relevant concentrations is sparse. This study aimed to characterise the effects of prolonged exposure to drinking water nitrate at concentrations relevant to human exposure on maternal, fetal, and birth outcomes. Wistar rats were exposed to 0, 50 or 100 mg/L NO₃⁻ as sodium nitrate in drinking water three weeks pre-conception and throughout gestation. At 21 days gestation, fetal and placental weights and morphology, maternal outcomes including plasma nitrate and nitrite, endocrine and inflammatory markers, and uterine artery haemodynamics were analysed. In a second cohort, birth timing and weight were assessed. While nitrate exposure substantially increased maternal plasma nitrate and nitrite concentrations, no consistent effects were seen on fetal or placental outcomes or endocrine/inflammatory markers. Several birth complications, small litters and higher uterine artery blood velocities were noted in nitrate-exposed groups, but these outcomes were highly variable. These results show that chronic exposure to nitrate at or above the WHO drinking water guidelines subtly impacts rat pregnancy and do not provide causal support for the findings of epidemiological studies.

硝酸盐（NO3−）是一种常见的饮用水污染物，浓度低于世界卫生组织（WHO）饮用水指南（50 mg/L NO3−）时，与不良妊娠结局的风险增加有关。然而，相关浓度的因果证据很少。本研究旨在描述长期暴露于与人类暴露浓度相关的饮用水硝酸盐对母体、胎儿和分娩结果的影响。Wistar大鼠在孕前三周和整个妊娠期间分别在饮用水中暴露于0、50或100 mg/L NO3−硝酸钠。在妊娠第21天，分析胎儿和胎盘的重量和形态，产妇结局包括血浆硝酸盐和亚硝酸盐，内分泌和炎症标志物，子宫动脉血流动力学。在第二个队列中，对出生时间和体重进行了评估。虽然硝酸盐暴露大大增加了母体血浆硝酸盐和亚硝酸盐浓度，但对胎儿或胎盘结局或内分泌/炎症标志物没有一致的影响。在硝酸盐暴露组中注意到一些分娩并发症，产仔少和子宫动脉血流速度加快，但这些结果变化很大。这些结果表明，长期暴露于达到或高于世卫组织饮用水指南的硝酸盐对大鼠妊娠有微妙的影响，并不能为流行病学研究的结果提供因果支持。

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引用次数: 0

Analysis of occupational exposure limits for hazardous chemical agents of African countries: A comparative study 非洲国家危险化学剂职业接触限值分析：比较研究

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2026-01-06 DOI: 10.1016/j.yrtph.2026.106029

Nadia Suzette Botha, Ilzé Engelbrecht, Suranie Rachel Horn

Occupational exposure limits (OELs) are a valuable tool used by occupational hygiene professionals to assess exposure and determine when measures should be employed to control exposure to hazardous chemical agents (HCAs) in the workplace. Many countries have OELs that are included in their respective occupational health and safety legislation. In South Africa, the Regulations for Hazardous Chemical Substances (RHCS SA, 1995) were first published in 1995. It was repealed and replaced with the Regulations for Hazardous Chemical Agents (RHCA SA, 2021). This study aimed to comparatively evaluate the progress of OELs in South Africa for certain HCAs as stated in the RHCA SA 2021 in terms of the previous version (RHCS SA, 1995) and other countries in Africa with OELs. This was done to provide insights into the gap in OEL development in Africa. The findings show that of the 54 countries in Africa, only 10 have OELs included in their occupational health and safety legislation. Legislative documents from five African countries were compared to the RHCA SA 2021 using the geometric mean method. The results indicate that South Africa has less stringent OELs than the other African countries to which it was compared, with the exception of Lesotho. This highlights the work that still needs to be done to improve OELs in African countries.

职业暴露限值（OELs）是职业卫生专业人员用来评估暴露和确定何时应采取措施来控制工作场所危险化学剂（hca）暴露的宝贵工具。许多国家在各自的职业健康和安全立法中都纳入了OELs。在南非，1995年首次出版了《危险化学物质条例》（RHCS SA, 1995）。它被废除并被《危险化学剂条例》（RHCA SA, 2021）所取代。本研究旨在对比评估南非在RHCA SA 2021中所述的某些HCAs的OELs进展与之前版本（RHCS SA, 1995）和其他具有OELs的非洲国家。这样做是为了深入了解非洲OEL发展的差距。调查结果表明，在非洲54个国家中，只有10个国家的职业健康和安全立法中纳入了OELs。使用几何平均方法将五个非洲国家的立法文件与RHCA SA 2021进行了比较。结果表明，除莱索托外，南非的OELs比与之比较的其他非洲国家不那么严格。这凸显了改善非洲国家OELs的工作任重而道远。

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引用次数: 0

Development and evaluation of a novel consensus in silico model within the OECD GL497 defined approach for skin sensitization prediction 在OECD GL497定义的皮肤致敏预测方法中开发和评估一种新的共识硅模型。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2026-01-05 DOI: 10.1016/j.yrtph.2026.106028

Mika Imamura , Ryoichi Murakami , Masakazu Tateshita , Yasushi Hikida

Skin sensitization is a key endpoint in chemical safety assessment, involving multiple key events (KEs) in the adverse outcome pathway. The integrated testing strategy defined approach (ITS-DA) in OECD GL497 combines non-animal methods addressing KE1 and KE3 with an in silico component to predict sensitization. We developed a novel consensus in silico model integrating a rule-based system with metabolic simulation and two statistical models trained on local lymph node assay (LLNA) and guinea pig maximization test (GPMT) data.

When applied as the in silico element of the ITS-DA, the model achieved balanced accuracies of 77 % for LLNA and 70 % for human data, surpassing existing in silico approaches. Furthermore, we developed a rule- and statistics-based KE1 replacement model (RSRKE1) that estimates protein-binding potential without in chemico KE1 assays. Combining RSRKE1 with the human Cell Line Activation Test (h-CLAT, KE3) and the consensus model yielded sensitivities of ∼80 % and potency classification accuracies of ∼70 % for LLNA, with similar performance for human data.

These results demonstrate that the consensus model and RSRKE1 can maintain predictive performance comparable to established ITS-DA workflows, while eliminating the need for certain in vitro assays. This approach supports regulatory acceptance of non-animal testing strategies for skin sensitization assessment.

皮肤致敏是化学品安全性评估的关键终点，涉及不良结果通路中的多个关键事件（KEs）。OECD GL497中的综合测试策略定义方法（ITS-DA）将非动物方法与硅成分结合起来，解决KE1和KE3的问题，以预测致敏性。我们开发了一个新的共识硅模型，集成了基于规则的代谢模拟系统和两个基于局部淋巴结测定（LLNA）和豚鼠最大化试验（GPMT）数据训练的统计模型。当应用于ITS-DA的计算机元素时，该模型在LLNA和人类数据上实现了77%的平衡精度，超过了现有的计算机方法。此外，我们开发了一个基于规则和统计的KE1替代模型（RSRKE1），该模型可以在没有化学KE1检测的情况下估计蛋白质结合潜力。将RSRKE1与人类细胞系激活试验（h-CLAT, KE3）和共识模型结合使用，LLNA的灵敏度为80%，效力分类精度为70%，对人类数据具有相似的性能。这些结果表明，共识模型和RSRKE1可以保持与已建立的ITS-DA工作流程相当的预测性能，同时消除了对某些体外检测的需要。这种方法支持监管机构接受非动物试验策略进行皮肤致敏评估。

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引用次数: 0

Four-year monitoring of pesticide residues in Egyptian sweet peppers 埃及甜椒四年农药残留监测

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-30 DOI: 10.1016/j.yrtph.2025.106027

Farag Malhat , Shokr Abdel Salam Shokr , Fawzy Eissa

This study monitored pesticide residues in 1826 sweet pepper samples from Egyptian markets (2021–2024), screening for 430 pesticides using QuEChERS extraction with LC-MS/MS and GC-MS/MS. Results revealed concerning contamination trends, with samples exceeding EU Maximum Residue Limits (MRLs) increasing from 14.95 % (2021) to 37.38 % (2023), before declining to 28.74 % (2024). Between 42 and 97 different pesticides were detected annually, with acetamiprid consistently the most prevalent (21.5–29.51 %). Neonicotinoids dominated detections, representing two to four compounds in annual top-10 rankings. Multiple residue contamination escalated dramatically from 45.79 % (2021) to 69.35 % (2023), with samples containing up to 16 pesticides simultaneously. Chlorpyrifos and bifenazate showed severe MRL violations, exceeding limits by 6.2-fold and 25.9-fold, respectively. Despite extensive contamination, chronic dietary risk assessment across 13 population groups indicated acceptable exposure levels, with all calculated %ADI values below the 100 % safety threshold. The highest exposure corresponded to 3.47 % of the ADI for chlorpyrifos in the GEMS/Food G15 population. While current consumption poses negligible health risks, the high prevalence of MRL violations and multiple residues highlights urgent needs for enhanced agricultural practices and regulatory enforcement to ensure long-term food safety.

本研究对埃及市场1826份甜椒样品（2021-2024）的农药残留进行了监测，采用QuEChERS萃取、LC-MS/MS和GC-MS/MS对430种农药进行了筛选。结果显示了污染趋势，超过欧盟最大残留限量（MRLs）的样品从14.95%（2021年）增加到37.38%（2023年），然后下降到28.74%（2024年）。每年共检出42 ~ 97种农药，其中以啶虫脒的检出率最高（21.5 ~ 29.51%）。新烟碱类在检测中占主导地位，在年度前10名中占2到4个化合物。多重残留污染从45.79%（2021年）急剧上升至69.35%（2023年），样品中同时含有多达16种农药。毒死蜱和联苯肼严重违反MRL，分别超标6.2倍和25.9倍。尽管存在广泛的污染，但对13个人群进行的慢性饮食风险评估表明，暴露水平是可以接受的，所有计算出的%ADI值都低于100%安全阈值。在GEMS/Food G15人群中，毒死蜱的最高暴露量相当于每日摄入量的3.47%。虽然目前的消费构成的健康风险可以忽略不计，但严重违反MRL规定和多种残留的情况突出表明，迫切需要加强农业实践和监管执法，以确保长期食品安全。

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