Current opinion in toxicology最新文献

英文中文

IUTOX 2023: Addressing complex toxicological endpoints with new approach methodologies IUTOX 2023：用新的方法方法解决复杂的毒理学终点

IF 4.6

Current opinion in toxicology

Pub Date : 2025-09-27 DOI: 10.1016/j.cotox.2025.100550

Emanuela Corsini, Heather Wallace

引用次数: 0

Issues around the deterministic reference dose for lead and human safety concerns regarding its continued utilization 关于铅的确定参考剂量的问题以及继续使用铅的人体安全问题

IF 4.6

Current opinion in toxicology

Pub Date : 2025-09-18 DOI: 10.1016/j.cotox.2025.100549

Wells Utembe

Lead (Pb) continues to be a contaminant of public health concern throughout the world. This narrative review identified electronic papers on the risk assessment of Pb to assess the impact of the lack of a reference dose (RfD) for Pb on the methods and approaches of its risk assessment. Although the World Health Organization (WHO) withdrew the provisional tolerable weekly intake (PTWI) and the United States Environmental Protection Agency (USEPA) desisted from issuing an RfD for Pb, the use of these parameters has continued to be prevalent in the literature. This is worrisome and concerning as these parameters are not sufficiently protective, have no scientific basis, and may lead to misleading conclusions and recommendations. On the other hand, using a predetermined risk level, benchmark dose (BMD), and probabilistic approaches offer viable alternatives to the risk assessment of Pb. Remarkably, the use of a probabilistic RfD and the use of a deterministic RfD along with probabilistic exposure data can be observed in the literature, with the latter failing to address the risk assessment challenges that arise from lead's lack of no-observed-adverse-effect level (NOAEL). Biokinetic models are also often used to convert environmental Pb to blood lead, with appropriate actions taken to reduce exposure at the WHO-recommended blood Pb concentration of ≥5 ug/dl (observed or predicted).

铅（Pb）仍然是世界各地令人关注的公共卫生污染物。本叙述性审查确定了关于铅风险评估的电子论文，以评估缺乏铅参考剂量对其风险评估方法和途径的影响。虽然世界卫生组织（世卫组织）取消了临时每周可容忍摄入量（PTWI），美国环境保护署（USEPA）也不再发布铅的每日推荐摄入量，但这些参数的使用在文献中仍然普遍存在。这是令人担忧和关切的，因为这些参数没有足够的保护，没有科学依据，并可能导致误导性的结论和建议。另一方面，使用预先确定的风险水平、基准剂量（BMD）和概率方法为铅的风险评估提供了可行的替代方法。值得注意的是，在文献中可以观察到使用概率RfD和使用确定性RfD以及概率暴露数据，后者未能解决因铅缺乏未观察到的不良影响水平（NOAEL）而产生的风险评估挑战。生物动力学模型也经常用于将环境铅转化为血铅，并采取适当行动，以减少在世卫组织推荐的血铅浓度≥5微克/分升（观察或预测）时的暴露。

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引用次数: 0

“More toxic than thought!” “毒性比想象的还要大！”

IF 4.6

Current opinion in toxicology

Pub Date : 2025-06-30 DOI: 10.1016/j.cotox.2025.100542

R. Fotler, D.R. Dietrich

Climate change enhances the formation and duration of toxin producing cyanobacterial blooms. Although toxins, e.g. Microcystins (MC), and their maximum levels in drinking water (1μg MC-LR_equiv./Liter) and foodstuffs are regulated and controlled, the basis for this regulation is questionable. Nearly all governmental regulations rely on WHO guidance values (GV) that were derived from an in vivo mouse study using a single MC congener (MC-LR). However cellular uptake (and thus toxicity) is governed by organic anion transporting polypeptides (OATPs), whereby rodents and humans differ drastically with regard to the expression and transport affinity and capacity of OATPs, and thus mice appear less susceptible to MC. Accordingly, the current questionable GVs provided by WHO must be replaced ad interim with a Toxicity Equivalence Factor (TEF) approach, whereby as a consequence current GVs need to be lowered by at least a factor 22 as shown here. The latter would result in a GV for drinking water of 0.045μg MC-LR_equiv./Liter to ensure safety of humans. As not all MC congeners can be tested, a new assessment approach using modern toxicology methods e.g. in vitro and in silico tools including artificial intelligence approaches must be undertaken to better characterize risks from exposure to toxic.

气候变化增强了产生毒素的蓝藻华的形成和持续时间。虽然毒素，如微囊藻毒素（MC）及其在饮用水和食品中的最高水平（1μg MC- lrequirequiv / l）受到监管和控制，但这种监管的依据是值得怀疑的。几乎所有政府法规都依赖于世卫组织指导值（GV），这些指导值是从使用单一MC同系物（MC- lr）的小鼠体内研究中得出的。然而，细胞摄取（因此毒性）是由有机阴离子转运多肽（OATPs）控制的，因此啮齿动物和人类在OATPs的表达、转运亲和力和能力方面存在巨大差异，因此小鼠似乎不太容易受到MC的影响。因此，目前世卫组织提供的有问题的gv必须暂时用毒性等效系数（TEF）方法取代。因此，当前的GVs需要降低至少22倍，如图所示。后者将导致饮用水的GV为0.045μg MC-LRequiv。/升，确保人身安全。由于并非所有的MC同系物都可以进行测试，因此必须采用一种新的评估方法，使用现代毒理学方法，例如体外和计算机工具，包括人工智能方法，以更好地表征接触有毒物质的风险。

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引用次数: 0

Factors influencing chemical relative potency in mixture toxicity risk assessment 影响混合物毒性风险评价中化学相对效力的因素

IF 4.6

Current opinion in toxicology

Pub Date : 2025-06-30 DOI: 10.1016/j.cotox.2025.100541

Frances Widjaja-van den Ende

The concept of relative potency (REP) is well established through terms like REP, relative potency factor (RPF), and toxic equivalency factor (TEF). REP is often determined using in vivo data, such as for dioxins. However, many factors such as dose, species, endpoint, interindividual variability, and chemical structure can influence REP values. This mini review examines REP values for pyrrolizidine alkaloid N-oxides (PA-N-oxides) versus their parent alkaloids. Using physiologically based kinetic (PBK) model simulations, the impact of dose, species, endpoint, interindividual variability, and chemical structure on REP values could be quantified. Results show that interindividual variability and chemical structure are the most influential. This highlights PBK modeling as a valuable tool for predicting REP, especially when animal data are limited and in vitro tests alone are insufficient.

相对效力（REP）的概念通过REP、相对效力因子（RPF）和毒性等效因子（TEF）等术语得到了很好的确立。通常使用体内数据（如二恶英）来确定REP。然而，许多因素，如剂量、物种、终点、个体间变异性和化学结构都会影响REP值。这篇综述检查了吡咯利西啶生物碱n -氧化物（pa - n -氧化物）与其母体生物碱的REP值。利用基于生理的动力学（PBK）模型模拟，可以量化剂量、物种、终点、个体间变异和化学结构对REP值的影响。结果表明，个体间变异和化学结构的影响最大。这突出了PBK模型作为预测REP的一种有价值的工具，特别是在动物数据有限且单独体外试验不足的情况下。

引用次数: 0

The Alarming Consequences of Workforce Reductions at the FDA, EPA, NIH and CDC in the United States☆ 美国FDA、EPA、NIH和CDC裁员的惊人后果☆

IF 4.6

Current opinion in toxicology

Pub Date : 2025-05-02 DOI: 10.1016/j.cotox.2025.100530

Martin van den Berg PhD (Editor-in-Chief, Regulatory Toxicology & Pharmacology and Current Opinion in Toxicology), Daniel R. Dietrich PhD (Editor-in-Chief, Chemico-Biological Interactions, Computational Toxicology, and Journal of Toxicology and Regulatory Policy), Sonja von Aulock PhD (Editor-in-Chief, ALTEX – Alternatives to Animal Experimentation), Anna Bal-Price PhD (Editor-in-Chief, Reproductive Toxicology), Michael D. Coleman PhD (Editor-in-Chief, Environmental Toxicology and Pharmacology), Mark T.D. Cronin PhD (Editor-in-Chief, Computational Toxicology), Paul Jennings PhD (Editor-in-Chief, Toxicology in Vitro), Angela Mally PhD (Editor-in-Chief, Toxicology Letters), Mathieu Vinken PhD (Editor-in-Chief, Toxicology and NAM Journal), Matthew C. Wright PhD (Editor-in-Chief, Food and Chemical Toxicology)

引用次数: 0

Assessment of immunotoxicity in the 21st century: Where we are and what we need to replace animals 21世纪免疫毒性评估：我们在哪里以及我们需要什么来取代动物

IF 4.6

Current opinion in toxicology

Pub Date : 2025-04-24 DOI: 10.1016/j.cotox.2025.100529

Victor J. Johnson , Dori R. Germolec , Michael I. Luster , Emanuela Corsini

The field of immunotoxicity assessment has traditionally relied on animal models, which have raised ethical concerns and presented limitations in terms of predictive accuracy and relevance to human health. This paper reviews the current state of immunotoxicity evaluation, emphasizing the importance of transitioning away from animal testing. Modern approaches, including in vitro methods, human-based studies, adverse outcome pathways (AOPs), and computational modeling, are discussed as viable alternatives. These non-animal methods offer enhanced predictive power and the potential for regulatory acceptance, though technical and practical challenges remain. Case studies demonstrate the success of non-animal methods, such as AOP-based assessments for skin sensitization and the pyrogen assay using whole blood cytokine assays. Despite these advances, further research is needed in areas like respiratory sensitization, developmental immunotoxicology (DIT), and microphysiological systems (MPS). Recommendations are provided to accelerate the adoption of new approach methodologies (NAMs), focusing on AOP frameworks. In conclusion, the paper highlights the key findings from current non-animal immunotoxicity research and issues a call to action for advancing these methods to improve safety assessment practices in the 21st century.

免疫毒性评估领域传统上依赖于动物模型，这引起了伦理问题，并在预测准确性和与人类健康的相关性方面存在局限性。本文综述了免疫毒性评价的现状，强调了从动物试验过渡到免疫毒性评价的重要性。现代方法，包括体外方法，基于人的研究，不良后果途径（AOPs）和计算模型，作为可行的替代方案进行了讨论。这些非动物方法提供了增强的预测能力和监管接受的潜力，尽管技术和实际挑战仍然存在。案例研究证明了非动物方法的成功，例如基于aop的皮肤致敏评估和使用全血细胞因子测定的热原测定。尽管取得了这些进展，但在呼吸致敏、发育免疫毒理学（DIT）和微生理系统（MPS）等领域还需要进一步的研究。本文提供了一些建议，以加速采用新的方法方法学（NAMs），重点放在AOP框架上。最后，本文重点介绍了目前非动物免疫毒性研究的主要发现，并呼吁采取行动推进这些方法，以改善21世纪的安全评估实践。

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引用次数: 0

Developmental neurotoxicity as a case example for a six-step framework for the sustainable regulatory implementation of NAMs 发育性神经毒性作为NAMs可持续监管实施六步框架的案例

IF 4.6

Current opinion in toxicology

Pub Date : 2025-04-01 DOI: 10.1016/j.cotox.2025.100528

Jonathan Blum , Kristina Bartmann , Joyce de Paula Souza , Ellen Fritsche

New Approach Methodologies (NAMs) are advancing toxicology by offering reliable, human-relevant alternatives to traditional animal methods. This review outlines a six-step framework guiding NAMs from development to regulatory approval, using the Developmental Neurotoxicity (DNT) in vitro battery (IVB) as an example.

The framework begins with the development of robust test systems with human-relevant models (step 1). Next, a NAM-based roadmap aligns testing strategies with regulatory needs and encourages early stakeholder engagement (step 2). Test method readiness is assessed for biological relevance, reproducibility, and reliability (step 3). Scientific validation includes technical characterization, independent expert review, and transparent public data sharing (step 4). OECD recognition ensures a rigorous evaluation process before NAMs are included in official guidelines (step 5). Lastly, public availability through Contract Research Organizations (CROs) guarantees compliance with Good Laboratory Practice (GLP) and facilitates regulatory adoption (step 6).

This DNT IVB lifecycle exemplifies the implementation of NAMs, continuously evolving with scientific progress. It supports initiatives like the European Roadmap towards phasing out animal testing and the Safe and Sustainable by Design (SSbD) framework under the European Green Deal. By providing a structured pathway, this lifecycle approach fosters NAM-based, human-centric risk assessments for a more sustainable future in chemical safety testing.

新方法方法（NAMs）通过提供可靠的、与人类相关的替代传统动物方法，正在推动毒理学的发展。本文以发育性神经毒性（DNT）体外电池（IVB）为例，概述了指导NAMs从开发到监管批准的六步框架。该框架从开发具有人类相关模型的健壮测试系统开始（第1步）。接下来，基于nama的路线图将测试策略与监管需求结合起来，并鼓励早期涉众参与（步骤2）。评估测试方法的生物学相关性、可重复性和可靠性（步骤3）。科学验证包括技术表征、独立专家评审和透明的公共数据共享（步骤4）。经合组织的认可确保了在NAMs被纳入官方指导方针之前的严格评估过程（步骤5）。最后，通过合同研究组织（cro）的公共可用性保证了良好实验室规范（GLP）的遵从性，并促进了监管采用（步骤6）。DNT IVB的生命周期体现了NAMs的实施，随着科学的进步而不断发展。它支持诸如逐步淘汰动物试验的欧洲路线图和欧洲绿色协议下的安全与可持续设计（SSbD）框架等倡议。通过提供结构化的途径，这种生命周期方法促进了基于nama的、以人为本的风险评估，以实现化学品安全测试更可持续的未来。

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引用次数: 0

The European Partnership PARC’s role in actively promoting the uptake of new approach methodologies and next-generation risk assessment into regulatory risk assessment practice 欧洲伙伴关系PARC在积极推动新方法方法和下一代风险评估纳入监管风险评估实践中的作用

IF 4.6

Current opinion in toxicology

Pub Date : 2025-01-29 DOI: 10.1016/j.cotox.2025.100517

Matthias Herzler , Mirjam Luijten , Philip Marx-Stoelting , Gilles Rivière

Existing approaches for human health risk assessment of chemicals have overall provided a high level of protection for EU citizens. However, the established assessment schemes face numerous challenges. Ethical and scientific concerns about using animals for safety testing have triggered awareness of the need for a paradigm shift, requiring new concepts for chemical risk assessment complementing and, in the long run, replacing existing schemes. Next-Generation Risk Assessment (NGRA) using new approach methodologies (NAMs) is commonly regarded as the way forward. However, adequately meeting regulatory needs is challenging. The European Partnership for the Assessment of Risks from Chemicals (PARC) supports the development of NGRA frameworks and their implementation at all levels, from developing adverse outcome pathways (AOPs), NAMs and integrated approaches to testing and assessments (IATAs), to designing new conceptual approaches and formulating strategic roadmaps. A particular strength of PARC is its focus on interaction and collaboration with stakeholders from all sectors of the chemical risk assessment community to promote cooperation, advance research, increase knowledge of chemical risk assessment and train methodological skills. Its results will help launch European and national strategies to reduce risks posed by hazardous chemicals, to reduce animal testing and to implement NGRA strategies in regulatory practice.

现有的化学品人类健康风险评估方法总体上为欧盟公民提供了高水平的保护。然而，现有的评估办法面临着许多挑战。对使用动物进行安全试验的伦理和科学关注已经引发了人们对范式转变的需要的认识，需要新的化学品风险评估概念来补充并从长远来看取代现有方案。采用新方法（NAMs）的下一代风险评估（NGRA）通常被认为是未来的发展方向。然而，充分满足监管需求是一项挑战。欧洲化学品风险评估伙伴关系（PARC）支持NGRA框架的发展及其在各个层面的实施，从开发不利结果路径（AOPs）、NAMs和测试和评估的综合方法（iata），到设计新的概念方法和制定战略路线图。帕洛阿尔托研究中心的一个特别优势是它注重与来自化学品风险评估界所有部门的利益相关者的互动和合作，以促进合作，推进研究，增加化学品风险评估知识和培训方法技能。其结果将有助于启动欧洲和国家战略，以减少危险化学品带来的风险，减少动物试验，并在监管实践中实施NGRA战略。

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引用次数: 0

The key characteristics concept 关键特征概念

IF 4.6

Current opinion in toxicology

Pub Date : 2024-12-27 DOI: 10.1016/j.cotox.2024.100515

Martyn T. Smith

In evaluating whether a chemical can cause cancer or another adverse outcome, three lines of evidence are typically considered: epidemiology, animal bioassays and mechanistic evidence. The key characteristics (KCs) form the basis of a uniform approach for searching, organizing, and evaluating mechanistic evidence to support hazard identification. KCs are the established properties of the toxicants themselves and are generated from our understanding of mechanisms of toxicity. KCs have been published for carcinogens, endocrine disruptors and reproductive, liver immune and cardiovascular toxicants. We noted that several KCs were common to different types of toxicants, whereas others were highly specific. Hence, there may be overlapping umbrella KCs for potentially hazardous bioactive chemicals that could be used in predictive toxicology. There are, however, also clearly unique KCs for chemicals that primarily target a specific organ and these unique KCs could be especially important to predicting target organ toxicity. It is possible that in silico approaches, in vitro tests, and in vivo biomarkers could be developed, which predict the “umbrella” and “unique” KCs of hazardous chemicals. However, given the significance of human evidence, the development of a set of biomarkers that could be used to measure the KCs in molecular epidemiology studies is also important.

在评估一种化学物质是否会导致癌症或其他不良后果时，通常会考虑三种证据：流行病学、动物生物测定和机理证据。关键特征（KCs）构成了搜索、组织和评估支持危险识别的机械证据的统一方法的基础。KCs是毒素本身的既定特性，是由我们对毒性机制的理解产生的。致癌物质、内分泌干扰物以及生殖、肝脏免疫和心血管毒物的KCs已被发表。我们注意到，几种KCs对不同类型的毒物是常见的，而其他KCs则是高度特异性的。因此，可能存在重叠的潜在危险生物活性化学品保护伞KCs，可用于预测毒理学。然而，对于主要针对特定器官的化学物质，显然也存在独特的KCs，这些独特的KCs对于预测目标器官毒性尤其重要。有可能开发出计算机方法、体外试验和体内生物标志物，以预测危险化学品的“保护伞”和“独特”KCs。然而，考虑到人类证据的重要性，在分子流行病学研究中开发一套可用于测量KCs的生物标志物也很重要。

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引用次数: 0

Advancements in the developmental zebrafish model for predictive human toxicology 斑马鱼发育模型预测人类毒理学研究进展。

IF 4.6

Current opinion in toxicology

Pub Date : 2024-12-24 DOI: 10.1016/j.cotox.2024.100516

Mackenzie L. Morshead, Robyn L. Tanguay

The rapid assessment of chemical hazards to human health, with reduced reliance on mammalian testing is essential in the 21st century. Early life stage zebrafish have emerged as a leading model in the field due to their amenability to high throughput developmental toxicity testing while retaining the benefits of using a whole vertebrate organism with high homology with humans. Zebrafish are particularly well suited for a variety of study areas that are more challenging in other vertebrate model systems, including microbiome work, transgenerational studies, gene–environment interactions, molecular responses, and mechanisms of action. The high volume of data generated from zebrafish screening studies is highly valuable for QSAR modeling and dose modeling for use in predictive hazard assessment. Recent advancements and challenges in using early life stage zebrafish for predictive human toxicology are reviewed.

在21世纪，快速评估化学品对人类健康的危害，减少对哺乳动物试验的依赖至关重要。早期生命阶段的斑马鱼已成为该领域的领先模型，因为它们易于进行高通量发育毒性测试，同时保留了使用与人类高度同源的整个脊椎动物有机体的好处。斑马鱼特别适合于在其他脊椎动物模型系统中更具挑战性的各种研究领域，包括微生物组研究、跨代研究、基因-环境相互作用、分子反应和作用机制。斑马鱼筛选研究产生的大量数据对QSAR建模和剂量建模具有很高的价值，可用于预测危害评估。本文综述了利用早期生命阶段斑马鱼预测人类毒理学的最新进展和挑战。

引用次数: 0

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