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The Influence of Temperature on Toxicity 温度对毒性的影响
Pub Date : 2009-12-15 DOI: 10.1002/9780470744307.GAT032
C. Gordon, P. Rowsey
Our understanding of the effects of temperature on toxic response has seen resurgence in the past several decades, with the development of better methods to study the integration of autonomic and behavioural thermoregulatory responses in rodents and other species. Radiotelemetry provides researchers with the best tool to study the thermoregulatory responses in undisturbed rodents exposed chronically or acutely to toxic chemicals. The thermoregulatory response to acute exposure to many toxic chemicals involves a regulated hypothermic response, characterized by an increase in autonomic thermoeffectors to increase heat loss and a behavioural preference for cooler temperatures. This thermoeffector response is quickly manifested by a marked drop in the core temperature in rodents. However, in humans and other large mammals, the hypothermic response is meagre due to their large thermal inertia. A combination of exposure to cool temperatures and a moderate hypothermic response has been found to benefit survival with a variety of toxic agents. Thus, the integrated thermoregulatory response of rodents to lower their core temperature seems to be an adaptive response. On the other hand, fever or hyperthermia is often seen in humans and other large mammals exposed to various toxicants. A fever is also seen in rodents provided that core temperature is monitored without disturbing the animal (e.g. telemetry). The universal effects of temperature on chemical toxicity calls for researchers to have a better understanding of the thermoregulatory effects of environmental toxicants. Keywords: thermoregulation; autonomic; behavioural; radiotelemetry; thermal stress; organophosphate insecticides; fever
在过去的几十年里,随着研究啮齿类动物和其他物种的自主和行为体温调节反应的更好方法的发展,我们对温度对毒性反应的影响的理解已经重新抬头。无线电遥测技术为研究人员研究长期或急性暴露于有毒化学物质的未受干扰的啮齿动物的体温调节反应提供了最好的工具。急性暴露于许多有毒化学物质时的体温调节反应涉及受调节的低温反应,其特征是增加自主热效应器以增加热量损失和对较低温度的行为偏好。这种热效应反应很快表现为啮齿动物体内核心温度的显著下降。然而,在人类和其他大型哺乳动物中,由于它们的大热惯性,低温反应是微薄的。暴露于低温和适度低温反应的组合已被发现有利于生存与各种有毒物质。因此,啮齿类动物降低核心温度的综合体温调节反应似乎是一种适应性反应。另一方面,在人类和其他大型哺乳动物暴露于各种有毒物质时,经常会出现发烧或高热。如果在不干扰动物的情况下监测核心温度(例如遥测),啮齿动物也会发烧。温度对化学毒性的普遍影响要求研究人员更好地了解环境毒物的温度调节作用。关键词:温度调节;自主;行为;radiotelemetry;热应力;有机磷杀虫剂;发热
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引用次数: 5
Toxicities Associated with Parenteral Nutrition 与肠外营养有关的毒性
Pub Date : 2009-12-15 DOI: 10.1002/9780470744307.GAT053
J. Aschner, Heather M. Furlong
Parenteral nutrition is a life-sustaining therapy for patients with structural or functional intestinal diseases who are unable to tolerate sufficient enteral intake or absorb sufficient calories to support energy requirements. Despite its unquestionable value under these circumstances, prolonged dependence on parenteral nutrition is fraught with potentially life-threatening complications related to the presence of unintended chemical and microbial contaminants of parenteral nutrition solutions, and insufficient knowledge of the optimal dosing of various parenteral nutrition additives thought to be essential to human nutrition. Infants and children with congenital or acquired gastrointestinal tract diseases who are dependent on parenteral nutrition to supply essential nutrients and calories for growth and development are particularly vulnerable. This chapter will review the potential toxicities associated with both unintended contaminants in parenteral nutrition, including microbes, phthalates, bisphenol-A, particulates, lipid peroxidation products and aluminium, as well as intentional supplementation with potentially toxic substances, including trace metals, amino-acid mixtures and lipid emulsions, when provided in excessive amounts or suboptimal ratios, or when normal metabolism or excretion are altered by an underlying medical condition. Practical applications and areas in need of further laboratory and human research are highlighted. Keywords: parenteral nutrition; microbial contamination; precipitates; phthalates; bisphenol-A; aluminium; essential trace-metal toxicity; amino acids; lipid emulsions; neonate; infant
肠外营养是一种维持生命的治疗方法,适用于患有结构性或功能性肠道疾病的患者,这些患者无法耐受足够的肠内摄入或吸收足够的卡路里来支持能量需求。尽管肠外营养在这些情况下具有无可置疑的价值,但长期依赖肠外营养充满了潜在的危及生命的并发症,这些并发症与肠外营养液中意外的化学和微生物污染物的存在有关,并且对各种肠外营养添加剂的最佳剂量的了解不足被认为是人类营养所必需的。患有先天性或后天性胃肠道疾病的婴儿和儿童依赖肠外营养来提供生长发育所需的必需营养素和卡路里,这尤其容易受到伤害。本章将回顾肠外营养中意外污染物的潜在毒性,包括微生物、邻苯二甲酸盐、双酚a、微粒、脂质过氧化产物和铝,以及有意添加潜在有毒物质,包括微量金属、氨基酸混合物和脂质乳剂,当提供过量或次优比例时。或者当正常的新陈代谢或排泄被潜在的医疗状况改变时。强调了实际应用和需要进一步实验室和人类研究的领域。关键词:肠外营养;微生物污染;沉淀;邻苯二甲酸酯;双酚a;铝;必需微量金属毒性;氨基酸;脂质乳剂;新生儿;婴儿
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引用次数: 0
Poisons of Animal Origin 动物源性毒物
Pub Date : 2009-12-15 DOI: 10.1002/9780470744307.GAT148
G. Wedin, D. Keyler, E. Bilden
A great number of species in the animal kingdom possess means by which they subdue prey or defend against predators. Human encounters with these species may result in bites or stings that produce local injury or systemic toxicity ranging from local pain and varying degrees of tissue injury to systemic illness, organ failure and even death. Most of these animals deliver a dose of venom when they bite or sting, but some produce or accumulate toxin in their flesh that may produce illness if ingested. Venoms are generally complex mixtures of proteins and enzymes, but few are very well understood. Antivenoms have been produced to treat exposures to some species, but treatment generally consists of supportive measures and treatment of symptoms. This chapter presents an overview of some of more common animal species found throughout the world, the toxic syndromes they produce and current therapeutic strategies. Keywords: ants; antivenom; beaded lizard; stinging fish; gila monster; Hymenoptera; jellyfish; scorpion; shellfish; snake; spider; stingray; venom
动物王国里的许多物种都有征服猎物或抵御捕食者的手段。人类与这些物种的接触可能导致咬伤或蜇伤,造成局部损伤或全身毒性,从局部疼痛和不同程度的组织损伤到全身性疾病、器官衰竭甚至死亡。大多数这些动物在咬人或螫人时会释放一定剂量的毒液,但有些动物会在肉中产生或积累毒素,如果被摄入可能会导致疾病。毒液通常是蛋白质和酶的复杂混合物,但很少被很好地理解。已生产抗蛇毒血清来治疗某些物种的暴露,但治疗通常包括支持性措施和症状治疗。本章概述了在世界各地发现的一些更常见的动物物种,它们产生的毒性综合征和当前的治疗策略。关键词:蚂蚁;抗蛇毒素;串珠蜥蜴;刺鱼;毒蜥;膜翅目;水母;蝎子;贝类;蛇;蜘蛛;黄貂鱼;毒液
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引用次数: 1
Toxicological Considerations for Pharmaceutical Products 药品的毒理学考虑
Pub Date : 2009-12-15 DOI: 10.1002/9780470744307.GAT115
L. Reid
This chapter is designed to highlight some of the general toxicologic concepts, for example species selection, duration and dosing, which should be taken into consideration when designing a nonclinical investigatory programme intended to support development of pharmaceutical agents. The extent and types of studies needed as well as their timing relevant to the stage of clinical development are discussed. For questions regarding nonclinical development programmes for specific products, regional regulatory agencies should be consulted. Keywords: nonclinical; pharmaceutical; medicinal; drug; regulatory toxicology; ICH
本章旨在强调一些一般的毒理学概念,例如物种选择,持续时间和剂量,在设计旨在支持药物制剂开发的非临床研究计划时应考虑到这些概念。讨论了所需研究的范围和类型以及与临床发展阶段相关的时间。关于特定产品的非临床开发计划的问题,应咨询地区监管机构。关键词:临床前;制药;药用;药物;监管毒理学;我
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引用次数: 0
A Metabolomic Perspective of Small Molecule Toxicity 小分子毒性的代谢组学观点
Pub Date : 2009-12-15 DOI: 10.1002/9780470744307.GAT016
A. Patterson, J. Idle
Recent advances in small molecule profiling, including ultraperformance liquid chromatography and time-of-flight mass spectrometry, have given unprecedented views of the metabolic response to toxic stimuli. Metabolomics, the process of measuring the concentration changes in metabolites of biofluids such as urine, serum, sweat or saliva or that of intact cells, tissues or single-celled organisms, is the missing piece of the omics puzzle (genomics, transcriptomics, proteomics) necessary for providing a holistic view (DNA, RNA, protein and metabolites) of the biological response to a toxicant. Furthermore, metabolomics is an essential addition to any toxicity biomarker-screening programme, as evidenced by its strong foothold in both pharmaceutical and academic settings. Here we discuss metabolomic science with respect to its past and future contributions to the field of toxicology and describe blueprints necessary for conducting a well-designed and robust metabolomics experiment from sample collection to data acquisition and analysis. Metabolomics holds great promise as a tool for advancing the field of toxicology by uncovering novel biomarkers of toxic responses and by significantly improving xenobiotic metabolite identification. Keywords: metabolomics; metabonomics; metabolism; metabolic profiling; metabolite identification; xenobiotic; ultraperformance liquid chromatography; time-of-flight mass spectrometry; NMR; UPLC-ESI-QTOFMS
最近小分子分析的进展,包括超高效液相色谱法和飞行时间质谱法,为毒性刺激下的代谢反应提供了前所未有的视角。代谢组学是测量生物体液(如尿液、血清、汗液或唾液)或完整细胞、组织或单细胞生物的代谢物浓度变化的过程,是组学难题(基因组学、转录组学、蛋白质组学)中缺失的一块,它是提供对毒物的生物反应的整体视图(DNA、RNA、蛋白质和代谢物)所必需的。此外,代谢组学是任何毒性生物标志物筛选计划的重要补充,其在制药和学术环境中的强大立足点证明了这一点。在这里,我们将讨论代谢组学对毒理学领域的过去和未来的贡献,并描述从样本收集到数据采集和分析进行精心设计和稳健的代谢组学实验所需的蓝图。代谢组学通过发现新的毒性反应生物标志物和显著改善外源代谢物鉴定,作为推进毒理学领域的工具,具有很大的前景。关键词:代谢组学;代谢组学;新陈代谢;代谢分析;代谢物鉴定;异型生物质;超高效液相色谱法;飞行时间质谱法;核磁共振;UPLC-ESI-QTOFMS
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引用次数: 9
Genetic Toxicology Testing and its Relevance to Human Risk and Safety Evaluation 遗传毒理学测试及其与人类风险和安全评价的相关性
Pub Date : 2009-12-15 DOI: 10.1002/9780470744307.GAT076
E. Lorge
Genotoxicity is a major concern in toxicity evaluation as it may cause carcinogenicity and/or genetic diseases. Therefore genotoxicity has become a part of the toxicity regulatory assessment. Over 30 years of practice in genotoxicity, various tests and tools have been developed, validated and refined. The protocols of the most currently used tests were improved and the experimental conditions were monitored more satisfactorily. In this chapter, the main genotoxicity tests required by the current International Conference on Harmonisation (ICH) battery are reviewed, as well as the most commonly used experimental systems added to the battery for follow-up testing, with their advantages and limits. The evaluation of genotoxicity results is also extensively considered. In this exercise, it is shown how the knowledge accumulated in the last years can be used to improve results evaluation with special references to the assessment and level of cytotoxicity, metabolic activation, aneuploidy, non-DNA reacting mutagens, thresholds and risk assessment. Keywords: genotoxicity; genetic toxicology; mutagenesis; mutagen; risk assessment; toxicology
遗传毒性是毒性评价中的一个主要问题,因为它可能导致致癌性和/或遗传性疾病。因此,遗传毒性已成为毒性监管评价的一部分。30多年的遗传毒性实践已经开发、验证和改进了各种测试和工具。改进了目前常用的试验方案,对试验条件进行了更满意的监测。在本章中,回顾了当前国际协调会议(ICH)电池要求的主要遗传毒性测试,以及添加到电池中进行后续测试的最常用实验系统,以及它们的优点和局限性。遗传毒性结果的评价也被广泛考虑。在本练习中,展示了如何利用过去几年积累的知识来改进结果评估,特别参考细胞毒性,代谢激活,非整倍体,非dna反应诱变剂,阈值和风险评估的评估和水平。关键词:基因毒性;遗传毒理学;诱变;诱变剂;风险评估;毒理学
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引用次数: 1
Toxicology of the Endocrine System 内分泌系统毒理学
Pub Date : 2009-12-15 DOI: 10.1002/9780470744307.GAT072
R. Kapp, J. Thomas
The endocrine system plays a critical role in regulating virtually every aspect of the body's functions and systems, including behaviour, nutritional processes, reproduction, growth and development, gastrointestinal tract, cardiovascular system and homeostasis. It includes various endocrine glands, for example, hypothalamus, pituitary, adrenals, gonads, thyroid and pancreas, that secrete specific hormones (or messengers) as well as specific receptors in target organs throughout the body, which are activated or deactivated by a series of biochemical reactions upon contact with the proper hormone, which ultimately modifies the target organ's activity. This is a complex and interactive system and malfunctions may have serious consequences. Disorders can arise internally from overactive or underactive hormone production, or they can arise from external exposures. Both can have life-threatening effects on survival. It has been shown that many drugs and chemicals and some environmental chemicals can perturb the chemical balance of the endocrine system. Some chemicals may directly affect the normal function of the endocrine system by inhibiting specific enzymes, while others produce indirect effects that result in a pharmacological interaction between the hormone and the chemical which modulates the effect of the hormone. There are many variations on these mechanisms and effects and these are detailed in this chapter. Keywords: endocrine toxicology; hormones; biochemical regulation; endocrine disruptors; endocrine modulation; endocrine receptors; endocrine target organs
内分泌系统在调节人体功能和系统的几乎每一个方面都起着至关重要的作用,包括行为、营养过程、生殖、生长发育、胃肠道、心血管系统和体内平衡。它包括各种内分泌腺,如下丘脑、垂体、肾上腺、性腺、甲状腺、胰腺等,它们在全身的靶器官中分泌特定的激素(或信使)以及特定的受体,与适当的激素接触后,通过一系列生化反应激活或失活,最终改变靶器官的活性。这是一个复杂且相互作用的系统,故障可能会造成严重后果。紊乱可以由体内激素分泌过度活跃或不足引起,也可以由外部暴露引起。两者都可能危及生命。研究表明,许多药物和化学物质以及一些环境化学物质会扰乱内分泌系统的化学平衡。有些化学物质可能通过抑制特定的酶直接影响内分泌系统的正常功能,而另一些化学物质则产生间接影响,导致激素和调节激素作用的化学物质之间的药理学相互作用。这些机制和效果有许多变化,本章将详细介绍。关键词:内分泌毒理学;激素;生化调控;内分泌干扰物;内分泌调节;内分泌受体;内分泌靶器官
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引用次数: 1
Toxicology of the Placenta 胎盘毒理学
Pub Date : 2009-12-15 DOI: 10.1002/9780470744307.GAT088
Ramesh C. Gupta
Placental toxicology deals with the adverse effects of toxic substances on the placenta, the mother and the foetus. It is a fascinating subject which receives attention from biologists, toxicologists, teratologists, pharmacologists, physicians and regulatory agencies. Structural or functional damage to the placenta can lead to abortion, birth defects, stillbirth, premature birth and many other complications. Since the placenta is an entry organ to the foetus, and the ‘placental barrier’ is merely a false notion, the placenta remains vulnerable to the adverse effects of many toxicants. The placenta is a complex organ to study since it continually changes throughout gestation. This organ is further complicated by multiple pregnancies in many species, including humans. The placenta plays several roles in the development of the foetus by serving as the lung, gut, kidney and endocrine/exocrine gland. Additionally, it supplies vital nutrients and gases to the foetus. This chapter describes the placental toxicity of drugs of abuse, alcohol, tobacco products, metals, pesticides, environmental toxicants and mycotoxins. Keywords: placental toxicity; foetal toxicity; abused drugs; metals; mycotoxins; alcohol; smoke; pesticides; environmental contaminants
胎盘毒理学研究有毒物质对胎盘、母亲和胎儿的不良影响。这是一个引人入胜的主题,受到生物学家、毒理学家、致畸学家、药理学家、医生和监管机构的关注。胎盘的结构或功能损伤可导致流产、出生缺陷、死胎、早产和许多其他并发症。由于胎盘是胎儿的入口器官,“胎盘屏障”只是一个错误的概念,胎盘仍然容易受到许多有毒物质的不利影响。胎盘是一个复杂的器官,因为它在整个妊娠期间不断变化。在包括人类在内的许多物种中,多胎妊娠使这个器官变得更加复杂。胎盘作为肺、肠、肾和内分泌/外分泌腺在胎儿的发育过程中起着多种作用。此外,它还为胎儿提供重要的营养和气体。本章描述了滥用药物、酒精、烟草制品、金属、农药、环境毒物和真菌毒素的胎盘毒性。关键词:胎盘毒性;胎儿毒性;滥用药物;金属;真菌毒素;酒精;烟雾;农药;环境污染物
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引用次数: 20
Risk Assessment of Chemicals 化学品风险评估
Pub Date : 2009-12-15 DOI: 10.1002/9780470744307.GAT118
L. Stuchal, S. Roberts
Risk assessment of chemicals is a process that results in a quantitative and/or qualitative estimate of risk posed by chemical exposure. It includes identification of the hazard, a dose-response assessment, exposure assessment and risk characterization. The process of risk assessment continually evolves as science refines estimates of exposure and toxicity. There are two main types of risk assessment, human health and ecological, which have evolved separately to a large extent. Human health risk assessment is concerned with the protection of individuals. It considers hazard and risk to sensitive subpopulations, such as children and the elderly. Ecological risk assessment is concerned with protecting the environment and considers multiple species. Because the entity of concern is the ecosystem, the focus is on protection of populations rather than individuals. Both types of risk assessments typically utilize models to estimate the dose of chemical received and the likelihood that toxicity will occur in a particular exposure scenario. These models incorporate assumptions about exposure and toxicity, and must address both variability and uncertainty associated with risk estimates. Risk assessment is an important tool in managing potential public health and environmental impacts resulting from the use of chemicals. Keywords: risk assessment; hazard assessment; toxicity; uncertainty factors; dose-response relationship; deterministic risk; probabilistic risk; exposure; threshold dose; benchmark dose; ecological risk assessment
化学品风险评估是对化学品接触造成的风险进行定量和/或定性估计的过程。它包括识别危害、剂量反应评估、暴露评估和风险表征。随着科学对暴露和毒性的评估不断改进,风险评估过程也在不断发展。风险评估主要有两种类型,即人类健康和生态风险评估,它们在很大程度上是分开发展的。人类健康风险评估涉及对个人的保护。它考虑了对敏感亚群体(如儿童和老年人)的危害和风险。生态风险评价涉及环境保护,考虑多物种。因为关注的实体是生态系统,所以重点是保护种群而不是个人。这两种类型的风险评估通常利用模型来估计所接受的化学品剂量以及在特定接触情况下发生毒性的可能性。这些模型包含了关于暴露和毒性的假设,并且必须处理与风险估计相关的可变性和不确定性。风险评估是管理使用化学品可能造成的公共健康和环境影响的重要工具。关键词:风险评估;风险评估;毒性;不确定性因素;剂量反应关系;确定的风险;概率风险;接触;阈剂量;基准剂量;生态风险评价
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引用次数: 0
Chemical and Biological Occupational Hazards in the Toxicology Laboratory 毒理学实验室的化学和生物职业危害
Pub Date : 2009-12-15 DOI: 10.1002/9780470744307.GAT051
B. Ballantyne
In addition to the chemical, physical, flammability, thermal, electrical and radiation hazards common to laboratories in general, toxicology laboratories have specific occupational hazards that require their recognition, appreciation and development of management practices for protective and precautionary measures. These include exposure to test chemicals of poorly understood toxicology and to control chemicals of high biological potency. Additionally there may be exposure to allergenic materials such as latex or animal allergens, and to transmissible animal diseases. This chapter reviews the routes and natures of hazardous exposures in the toxicology laboratory, specific allergenic and infective problem areas, and necessary protective and precautionary measures. Keywords: animal allergens; latex; sensitization; zoonoses; protection; precautionary measures; atopy; respiratory function tests; skin-prick tests; solvents; carcinogens; laboratory safety
除了实验室普遍存在的化学、物理、可燃性、热、电和辐射危害外,毒理学实验室还有特殊的职业危害,需要它们认识、了解和制定保护和预防措施的管理做法。这些措施包括接触对毒理学知之甚少的试验化学品,以及控制具有高生物效力的化学品。此外,还可能暴露于致敏物质,如乳胶或动物过敏原,以及可传播的动物疾病。本章回顾了毒理学实验室中危险暴露的途径和性质,特定的过敏原和感染问题区域,以及必要的保护和预防措施。关键词:动物过敏原;乳胶;敏化;人畜共患病;保护;预防措施;异位性;呼吸功能检查;皮测试;溶剂;致癌物质;实验室安全
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引用次数: 0
期刊
General, Applied and Systems Toxicology
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