化学物毒理学资料在职业卫生中的作用

化学物毒理学特性向其理化特性一样，是化学物的基本属性之一。化学物毒理学资料的应用可以贯穿于职业中毒预防的各个层面中，如化学物的一般管理、劳动卫生调查研究、化学物现场检测、接毒人员的职业性健康监护与职业病诊断、中毒事件的应急救援、建设项目的卫生评价及评定化学物毒性、职业卫生科研、职业卫生标准的制定等。在职业卫生工作中，了解化学物的主要毒理学数据和毒作用特征，对其中毒预防管理必不可少，对中毒防治工作得以有成效开展起到重要的作用。文中还简单介绍了化学物毒性资料的获取方法，并对化学物的毒性鉴定与化学品安全性评价的意义作了简单探讨。     

毒理学研究与中毒急救

１毒性与毒理学研究化学物毒性（Ｔｏｘｉｃｉｔｙ）是化学物内在固有的特性,是指引起机体损害的能力。衡量毒性的大小可以是指测量该化学物引起实验动物某种毒效应所需的剂量或浓度,通常可用剂量－反应（效应）关系表示。引起某种效应所需的化学物剂量越小,则表明该化学物毒性越大。研究化学物的毒性和毒作用机理是毒理学的重要任务,涉及毒物在体内过程、对机体的各种可能效应与机制、效应修饰因素、作用阈限等诸多内容。不同毒物的毒性、靶器官及毒作用方式相差较大。通过常规毒性研究,可以提供与之有关的资料,这在安全性评价过程中…     

系统毒理学研究进展

系统毒理学作为毒理学领域的一门新兴学科,旨在整合生物学多层次信息,从整体解析外源化学物的毒性机制.相较于传统毒理学,它具有独特的优势.本综述介绍了系统毒理学中主要的毒代动力学和毒效动力学的概念,并系统总结了近年来毒效动力学的发展历程和研究进展.《21世纪毒性测试》报告中提出的"毒性通路"为毒性评价体系的发展指明了方向,...     

毒作用模式和有害结局路径的关系及其在风险评估中的应用

风险评估方法是保障人类健康和环境安全的必要技术手段。基于动物实验获取毒性数据的传统风险评估,由于动物实验通量低、周期长、成本高和高剂量外推至人类暴露剂量的不确定性等问题,难以满足大量化学品亟需开展风险评估的需求。毒作用模式(MOA)和有害结局路径(AOP)风险评估框架的提出为我们开发新型、高效的评价方法指明了方向。本综述介绍了MOA和AOP的基本概念、内容以及两者之间的关系,并以丙烯酰胺(AA)为例,简述MOA/AOP框架在化学物风险评估中的具体应用,以期为更好运用MOA/AOP框架进行化学物风险评估提供理论指导。     

工业化学物的神经发育毒性

神经发育性疾病，如孤独症、注意力分散、智力迟滞和脑瘫等是一类很常见的疾病，其治疗费用高昂，会引起终生残疾。这些疾病的病因大多不明。有些工业化学物（如铅、甲基汞、多氯联苯、砷和甲苯）被认为是引起神经发育性疾病和亚临床脑功能不良的原因。胚胎早期暴露于这些化学物，即使对成人无作用的剂量也可引起胚胎脑损伤。这些危险因素的认识促使人们开展以证据为基础的预防措施，比如去除汽油内的铅添加剂。虽然这些预防工作很成功，但大部分工作开展是滞后的。约200种化学物能导致成人临床神经毒作用。尽管缺乏系统的测试，但是许多化学物在动物身上已显现出神经毒作用，而这些化学物对人脑发育毒作用依然未知，对这些化学物缺乏以保护儿童为目标的管理措施。预防化学源性的神经发育缺陷存在两大主要障碍：①神经发育毒性化学物的检测不够；②相关立法所需的严谨证据不足。因此，实施以认识脑发育特有的易损性为基础的预防新方法，检测和控制化学物是必需的。     

肝毒性评价体外替代模型研究进展

随着“3R原则”及“21世纪毒理学测试：远景与策略”的提出,毒理学评价的重点从体内测试转向了体外模型的应用,从而推动了体外替代模型的发展,毒性替代模型也受到越来越多学者的关注。肝脏是外源化学物质代谢的重要场所,一些经肝脏代谢的外源化学物会引起以炎症、氧化应激和坏死为特征的肝脏损害,因此,利用肝毒性替代模型来预测外源化学物的肝毒性至关重要。本文重点概述了2D肝细胞、肝脏切片和3D肝脏肝毒性评价体外替代模型的现状和发展,同时对药物性肝损伤（drug-induced liver injury,DILI）生物标志物、DILI诊断方法以及与DILI相关的新兴技术进行了系统的阐述。     

TOPKAT和TEST软件在化学物毒性预测中的应用

目的 归纳TOPKAT、TEST两款毒性预测软件对有毒化学物健康和生态毒性的可预测性和适用范围, 探讨高效、简便、快速的毒物检测实用方法。
方法 采用简化分子线性输入规范(SMILES), 结合两款毒性预测软件对化学物的毒理学进行预测, 并将预测结果与欧洲化学品管理署公布的毒理学数据进行对比, 总结两款软件的优缺点。
结果 TOPKAT和TEST软件能预测大多数的常见化学物毒性, TEST软件的化学物预测覆盖率高于TOPKAT软件, 能预测多取代苯环类、杂环类和大分子化学物, 而TOPKAT无法预测吡啶类、部分苯酚类和苯胺类化学物的毒性。两款毒性预测软件在预测化学物是否具有毒性方面的正确率均在85%左右。TOPKAT软件对于农药类化学物的毒性预测正确率高于TEST软件, TOPKAT预测值与文献值的线性决定系数R2为0.852(健康毒性)(P < 0.01)、0.826(生态毒性)(P < 0.01)。而TEST软件对于苯系化学物的毒性预测结果略优于TOPKAT软件, TEST预测值与文献值的线性决定系数R2为0.932(P < 0.01)(健康毒性)、0.787(生态毒性)(P < 0.01)。对于酯类和醇类化学物, TOPKAT和TEST软件都显示出良好的预测能力, 预测值与文献值的线性决定系数R2为0.854~0.986(健康毒性)(P < 0.01)、0.821~0.981(生态毒性)(P < 0.01)。
结论 TOPKAT、TEST软件能高效、正确地预测大部分化学物的健康和生态毒性, 可为新化学物的健康和生态毒性评价提供依据, 为药物的早期开发提供决策支持。
     

效应生物标志物与危险度评价

效应生物标志物能够特异/灵敏地反映化学物对机体早期生物学效应,在确定化学物在体内的存在及其所产生损害的性质和程度、研究化学物作用的剂量-效应关系、阐明化学物的毒作用机制、评价预防措施的效果等方面都具有重要意义,该文简要介绍了效应分子生物标志物在危险度评价中的应用及影响因素.     

生化测定在神经毒理学中的应用

在很多情况下,神经系统成为化学物毒作用的一个靶器官,评价化学物质的神经毒性,应了解其毒性的生化机理,然而应用生化方法来测定神经毒性的文献却很少。Barnes于1965年论述了神经病的生化改变,但遗憾的是在以后的12年中,这一领域几乎无进展。近年来,     

在Tox21化学库筛查乙酰胆碱酯酶抑制剂

随着Tox21的持续发展, 体外测试系统优化和新兴替代方案开发已经成为当前化学物毒性评价的研究重点。美国国立卫生研究院(National Institutes of Health, NIH)的一项研究成果于2021年4月发表在《Environmental Health Perspectives》杂志, 该研究基于定量高通量筛查系统(quantitatively high-throughput screening, qHTS)高效、迅速筛查Tox21 10K文库中具有乙酰胆碱酯酶(acetylcholinesterase, AChE)抑制能力的化学物, 为化学物毒性评价的新兴体外实验流程提供范例。     

高内涵筛选技术在毒理学研究中的应用进展

随着各种新、老化学物质健康风险评价的需求急剧增长,基于动物实验的测试方法难以满足当前健康风险评价的需求,迫切需要研发新型的、高通量、灵敏的毒性测试方法,整合基于体外替代模型的高通量筛选技术、计算方法和信息技术的毒性测试策略。其中,高内涵筛选（HCS）利用自动化显微镜和图像分析平台,以可视化和定量的方式对体外模型进行多参...     

Bioluminescent method in studying the complex effect of sewage components

The inhibition of bacterial luminescence has been used in testing industrial enterprises sewage. The toxicity of the sewage is less than the total toxicity of separate components due to neutralization of quinone products of polyphenol oxidation in the reactions with the other phenol components of sewage. Toxicity increase is due to their influence on the cell membrane. Studies of cell ultrastructure confirm this fact. The studied mechanism of the complex effect allowed a more accurate forecast of the ecological situation during the discharge of phenol compounds and metals. It also showed the necessity of taking into account the complex effect of sewage components on contaminant discharge into water reservoirs.     

Alternative tests make the grade

Toxicity testing is absolutely necessary for assessing the safety of substances in food, air, and water, in the workplace and at home. Although there are several tried-and-true toxicity assays, the search is always on for methods that can even better predict toxic effects. As scientific understanding of the effects of environmental toxicants grows, new tests are needed to evaluate previously unexamined end points and to take advantage of advances in biotechnology and the growing knowledge of how toxicants work at the molecular and cellular levels. Another issue is how to develop tests that can reliably and accurately assess toxicity using less time, money, and materials, and with greater regard for animal welfare. The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) was established in 1997 to address these needs through the development, validation, acceptance, and harmonization of new and revised toxicological test methods throughout the federal government.     

An in situ toxicity identification evaluation method Part II: Field validation

When sediments are found to be toxic usually there is a mixture of chemicals present. Often it is important to establish which chemicals contribute to the toxicity. Establishing causality can be difficult and often requires fractionation with subsequent toxicity testing. The sample collection and manipulation process can alter chemical bioavailability and toxicity. An in situ toxicity identification evaluation (iTIE) chamber is described that was placed in sediments and fractionated pore-water chemicals into nonpolar chemicals, metals, and ammonia-type groups. This method was field tested and compared to the laboratory-based, U.S. Environmental Protection Agency (U.S. EPA) toxicity identification evaluation (TIE) method. Field studies were performed at three sites contaminated primarily with polycyclic aromatic hydrocarbons (PAHs) (Little Scioto River, OH, USA), polychlorinated biphenyls (PCBs) (Dicks Creek, OH, USA), and chlorobenzenes (Sebasticook River, ME, USA). Both the iTIE and the U.S. EPA TIE methods used Daphnia magna in 24-h exposures. Although the iTIE and TIE were conducted on sediments from the same location, there was significantly more toxicity observed in the iTIE testing. The dominant chemical classes were separated by the iTIE method and revealed which fractions contributed to toxicity. The loss of toxicity in the TIE approach did not allow for subsequent fractionation and stressor identification. Advantages of the iTIE over the TIE method were greater sensitivity and ability to detect causative toxic chemical fractions; lack of sediment collection and subsequent manipulation; and, thus, reduction in potential artifacts, more realistic exposure with slow, continual pore-water renewal in situ, ability to evaluate pore waters in sandy or rocky substrates where pore waters are difficult to collect, and a quicker phase I evaluation. Limitations of the iTIE method as compared to the TIE methods were extensive pretest assembly process, fewer phase I fractionation possibilities, and restriction to shallow waters. The results of these studies suggest that the iTIE method provides a more accurate and sensitive evaluation of pore water toxicity than the laboratory TIE method.     

Marine sediment toxicity identification evaluation methods for the anionic metals arsenic and chromium

Marine sediments accumulate a variety of contaminants and, in some cases, demonstrate toxicity because of this contamination. Toxicity identification evaluation (TIE) methods provide tools for identifying the toxic chemicals causing sediment toxicity. Currently, whole-sediment TIE methods are not available for anionic metals like arsenic and chromium. In the present paper, we describe two new anion-exchange resins used in the development of whole-sediment TIE methods for arsenic and chromium. Resins were shown to reduce whole-sediment toxicity and overlying water concentrations of the anionic metals. Sediment toxicity, expressed as the median lethal concentration, was reduced by a factor of two to a factor of nearly six between amended sediment treatments containing resin and those without resin. Aqueous concentrations of arsenic and chromium in the toxicity exposures decreased to less than the detection limits or to concentrations much lower than those measured in treatments without resin. Interference studies indicated that the anion-exchange resins had no significant effect on concentrations of the representative pesticide endosulfan and minimal effects on concentrations of ammonia. However, the anion-exchange resins did significantly reduce the concentrations of a selection of cationic metals (Cd, Cu, Ni, Pb, and Zn). These data demonstrate the utility of anion-exchange resins for determining the contribution of arsenic and chromium to whole-sediment toxicity. The present results also indicate the importance of using TIE methods in a formal TIE structure to ensure that results are not misinterpreted. These methods should be useful in the performance of marine whole-sediment TIEs.     

Alternative models in developmental toxicology

In light of various pressures, toxicologists have been searching for alternative methods for safety testing of chemicals. According to a recent policy in the European Union (Regulation, Evaluation Authorisation and Restriction of Chemicals, REACH), it has been estimated that over the next twelve to fifteen years, approximately 30,000 chemicals may need to be tested for safety, and under current guidelines such testing would require the use of approximately 7.2 million laboratory animals []. It has also been estimated that over 80%% of all animals used for safety testing under REACH legislation would be used for examining reproductive and developmental toxicity [Hofer et al., 2004]. In addition to REACH initiatives, it has been estimated that out of 5,000 to 10,000 new drug entities that a pharmaceutical company may start with, only one is finally approved by the Food and Drug Administration at a cost of over one billion dollars []. A large portion of this cost is due to animal testing. Therefore, both the pharmaceutical and chemical industries are interested in using alternative models and in vitro tests for safety testing. This review will examine the current state of three alternative models - whole embryo culture (WEC), the mouse embryonic stem cell test (mEST), and zebrafish. Each of these alternatives will be reviewed, and advantages and disadvantages of each model will be discussed. These models were chosen because they are the models most commonly used and would appear to have the greatest potential for future applications in developmental toxicity screening and testing.     

食品中典型有机污染物和重金属的毒性通路研究进展

食品污染是影响食品安全和人群健康的重要风险因素。《21世纪毒性测试愿景与战略》提出未来的毒性测试应充分考虑人群暴露可能，基于体外人源性细胞系、高通量筛选和毒性通路的毒性测试战略，试图解决传统毒性测试成本高昂、耗时费力、种属差异方面的挑战。本综述围绕我国食品污染问题突出的典型重金属和有机污染物，分析归纳了有关毒性通路研究现况，并展望未来的研究方向。     

Geostatistical methods for estimation of toxicity of marine bottom sediments based on the Gdańsk Basin area

Toxicity assessment of environmental compartments, in particular sediments as a highly complex matrix, provides a more direct way to assess potential adverse effects of pollutants present in a sample in contrast to chemical analysis estimating only a quantitative level of xenobiotics. Interactions between chemicals, formations of derivatives and the influence of chemical properties of sediments such as the organic matter content causing the intensified sorption of hydrophobic pollutants suggest that a traditional approach to the sediment quality, based only on chemical analysis may be insufficient. The presented study describes the vertical and horizontal variability of toxicity of Gdańsk Basin sediments. Based on 128 surface sediments samples and using geostatistical methods, a prediction map for the EC50 parameter was created. This allowed the evaluation of the toxicity of the surface sediment layer at any selected point of the study area. The applied analysis can be functional for many other locations worldwide. In the present study, the hypothesis about the location of toxic sediments in the vicinity of Gdańsk Deep, outer Puck Bay and close to Vistula River mouth was further confirmed.     

Alternative models in developmental toxicology

In light of various pressures, toxicologists have been searching for alternative methods for safety testing of chemicals. According to a recent policy in the European Union (Regulation, Evaluation Authorisation and Restriction of Chemicals, REACH), it has been estimated that over the next twelve to fifteen years, approximately 30,000 chemicals may need to be tested for safety, and under current guidelines such testing would require the use of approximately 7.2 million laboratory animals [ Hofer et al. 2004 ]. It has also been estimated that over 80% of all animals used for safety testing under REACH legislation would be used for examining reproductive and developmental toxicity [Hofer et al., 2004]. In addition to REACH initiatives, it has been estimated that out of 5,000 to 10,000 new drug entities that a pharmaceutical company may start with, only one is finally approved by the Food and Drug Administration at a cost of over one billion dollars [ Garg et al. 2011 ]. A large portion of this cost is due to animal testing. Therefore, both the pharmaceutical and chemical industries are interested in using alternative models and in vitro tests for safety testing. This review will examine the current state of three alternative models - whole embryo culture (WEC), the mouse embryonic stem cell test (mEST), and zebrafish. Each of these alternatives will be reviewed, and advantages and disadvantages of each model will be discussed. These models were chosen because they are the models most commonly used and would appear to have the greatest potential for future applications in developmental toxicity screening and testing.     

A large-scale categorization of sites in San Francisco Bay, USA, based on the sediment quality triad, toxicity identification evaluations, and gradient studies

Sediment quality was assessed in San Francisco Bay, California, USA, using a two-tiered approach in which 111 sites were initially screened for sediment toxicity. Sites exhibiting toxicity were then resampled and analyzed for chemical contamination, recurrent toxicity, and, in some cases, benthic community impacts. Resulting data were compared with newly derived threshold values for each of the metrics in a triad-based weight-of-evidence evaluation. Sediment toxicity test results were compared with tolerance limits derived from reference site data, benthic community data were compared with threshold values for a relative benthic index based on the presence and abundance of pollution-tolerant and -sensitive taxa, and concentrations of chemicals and chemical mixtures were compared with sediment quality guideline-based thresholds. A total of 57 sites exceeded threshold values for at least one metric, and each site was categorized based on triad inferences. Nine sites were found to exhibit recurrent sediment toxicity associated with elevated contaminant concentrations, conditions that met program criteria for regulatory attention. Benthic community impacts were also observed at three of these sites, providing triad evidence of pollution-induced degradation. Multi- and univariate correlations indicated that chemical mixtures, heavy metals, chlordanes, and other organic compounds were associated with measured biological impacts in the Bay. Toxicity identification evaluations indicated that metals were responsible for pore-water toxicity to sea urchin larvae at two sites. Gradient studies indicated that the toxicity tests and benthic community metrics employed in the study predictably tracked concentrations of chemical mixtures in Bay sediments.