The mechanism of dioxin toxicity: relationship to risk assessment.
The mechanism of dioxin toxicity: relationship to risk assessment.
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二恶英毒性的机制：与风险评估的关系。
DOI：
10.1289/ehp.94102s9157
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发表时间：
1994-11
影响因子：
10.4
通讯作者：
Birnbaum, L S
中科院分区：
文献类型：
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作者：
Birnbaum, L S
风险定性包括危害识别、剂量反应关系的确定和接触评估。要改进风险评估进程，就需要纳入现有的最佳科学。最近在二恶英毒性领域的研究结果导致了重新评估其风险的重大努力。2，3，7，8-四氯二苯并对二恶英（TCDD），通常被称为“二恶英”，是一类相关化学品中毒性最强的成员，包括多卤代二苯并对二恶英、二苯并呋喃、联苯、萘、偶氮苯和氧化偶氮苯，其毒性可表示为TCDD的分数当量。这些化学物质通过与特定的细胞内蛋白质Ah受体相互作用来发挥作用。虽然与受体结合是必要的，但这不足以引起一系列事件，导致各种反应，包括酶诱导、免疫毒性、生殖和内分泌影响、发育毒性、氯痤疮、肿瘤促进等。免疫毒性和对生殖系统的影响似乎是最敏感的反应。Ah受体作为转录增强子起作用，与许多其他调节蛋白（热休克蛋白、激酶、转位酶、DNA结合物质）相互作用。与DNA中特定碱基序列的相互作用似乎受到其他生长因子、激素及其受体以及其他调节蛋白的调节。因此，二恶英似乎起着激素的作用，启动一系列依赖于每个细胞和组织环境的事件。虽然存在Ah受体变体，但所有研究的脊椎动物都证明了这种蛋白质具有相似数量的受体和对TCDD的结合亲和力。大多数物种对二恶英和相关化合物的反应相似。虽然一个给定的物种可能是一个给定的反应离群值，它会像其他动物的其他反应。对于存在动物和人类数据的体内和体外终点，如酶诱导、氯痤疮、免疫毒性、发育毒性和癌症，人类的敏感性似乎与实验动物相似。目前这类化学品的环境接触水平可能会导致处于特殊风险的人群（如自给渔民和发育中的婴儿）以及一般人群产生微妙的反应。随着对二恶英影响机制的进一步了解以及对剂量-剂量关系的阐明，正在将最佳科学纳入对四氯二苯并对二恶英及相关化合物的风险评估过程中，正在开发一种基于生物学的剂量-反应模型。
Risk characterization involves hazard identification, determination of dose-response relationships, and exposure assessment. Improvement of the risk assessment process requires inclusion of the best available science. Recent findings in the area of dioxin toxicity have led to a major effort to reassess its risk. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), commonly referred to as "dioxin," is the most toxic member of a class of related chemicals including the polyhalogenated dibenzo-p-dioxins, dibenzofurans, biphenyls, naphthalenes, azo- and azoxy-benzenes, whose toxicities can be expressed as fractional equivalencies of TCDD. These chemicals exert their effects through interaction with a specific intracellular protein, the Ah receptor. While binding to the receptor is necessary, it is not sufficient to bring about a chain of events leading to various responses including enzyme induction, immunotoxicity, reproductive and endocrine effects, developmental toxicity, chloracne, tumor promotion, etc. Some of these responses appear to be linear at low doses. Immunotoxicity and effects on the reproductive system appear to be among the most sensitive responses. The Ah receptor functions as a transcriptional enhancer, interacting with a number of other regulatory proteins (heat shock proteins, kinases, translocases, DNA binding species). Interaction with specific base sequences in the DNA appear to be modulated by the presence of other growth factors, hormones and their receptors as well as other regulatory proteins. Thus, dioxin appears to function as a hormone, initiating a cascade of events that is dependent upon the environment of each cell and tissue. While Ah receptor variants exist, all vertebrates examined have demonstrated such a protein with similar numbers of receptors and binding affinity for TCDD. Most species respond similarly to dioxin and related compounds. While a given species may be an outlier for a given response, it will behave like other animals for other responses. For both in vivo and in vitro end points where animal and human data exist, such as enzyme induction, chloracne, immunotoxicity, developmental toxicity, and cancer, the sensitivity of humans appears similar to that of experimental animals. Current levels of environmental exposure to this class of chemicals may be resulting in subtle responses in populations at special risk such as subsistence fisherman and the developing infant, as well as in the general population. Increased understanding of the mechanism of dioxin's effects as well as elucidation of exposure-dose relationships is leading to the development of a biologically based dose-response model in the ongoing process of incorporating the best science into the risk assessment of TCDD and related compounds.