三氯乙烯风险评估：综述与评论。
Trichloroethylene risk assessment: a review and commentary.
机构信息
Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
出版信息
Crit Rev Toxicol. 2009;39(9):782-97. doi: 10.3109/10408440903222177.
Trichloroethylene (TCE) is a widespread environmental contaminant that is carcinogenic when given in high, chronic doses to certain strains of mice and rats. The capacity of TCE to cause cancer in humans is less clear. The current maximum contaminant level (MCL) of 5 ppb (microg/L) is based on an US Environment Protection Agency (USEPA) policy decision rather than the underlying science. In view of major advances in understanding the etiology and mechanisms of chemically induced cancer, USEPA began in the late 1990s to revise its guidelines for cancer risk assessment. TCE was chosen as the pilot chemical. The USEPA (2005) final guidelines emphasized a "weight-of-evidence" approach with consideration of dose-response relationships, modes of action, and metabolic/toxicokinetic processes. Where adequate data are available to support reversible binding of the carcinogenic moiety to biological receptors as the initiating event (i.e., a threshold exists), a nonlinear approach is to be used. Otherwise, the default assumption of a linear (i.e., nonthreshold) dose-response is utilized. When validated physiologically based pharmacokinetic (PBPK) models are available, they are to be used to predict internal dosimetry as the basis for species and dose extrapolations. The present article reviews pertinent literature and discusses areas where research may resolve some outstanding issues and facilitate the reassessment process. Key research needs are proposed, including role of dichloroacetic acid (DCA) in TCE-induced liver tumorigenesis in humans; extension of current PBPK models to predict target organ deposition of trichloroacetic acid (TCA) and DCA in humans ingesting TCE in drinking water; use of human hepatocytes to ascertain metabolic rate constants for use in PBPK models that incorporate variability in metabolism of TCE by potentially sensitive subpopulations; measurement of the efficiency of first-pass elimination of trace levels of TCE in drinking water; and assessment of exogenous factors' (e.g., alcohol, drugs) ability to alter metabolic activation and risks at such low-level exposure.
三氯乙烯（TCE）是一种广泛存在的环境污染物，当以高剂量、慢性给予某些品系的小鼠和大鼠时会致癌。TCE 对人类致癌的能力尚不清楚。目前的最大污染物水平（MCL）为 5 ppb（微克/升），这是基于美国环境保护署（USEPA）的政策决定，而不是基础科学。鉴于对化学诱导癌症的病因和机制的理解取得了重大进展，USEPA 于 20 世纪 90 年代末开始修订其癌症风险评估指南。TCE 被选为试点化学物质。USEPA（2005 年）的最终指南强调了“证据权重”方法，同时考虑了剂量-反应关系、作用模式以及代谢/毒代动力学过程。在有充分数据支持致癌部分可逆结合生物受体作为起始事件的情况下（即存在阈值），应采用非线性方法。否则，将采用线性（即无阈值）剂量-反应的默认假设。当有经过验证的基于生理学的药代动力学（PBPK）模型可用时，应将其用于预测内部剂量，作为物种和剂量外推的基础。本文综述了相关文献，并讨论了研究可能解决一些悬而未决问题并促进重新评估过程的领域。提出了关键的研究需求，包括二氯乙酸（DCA）在 TCE 诱导人类肝脏肿瘤形成中的作用；扩展当前的 PBPK 模型，以预测人类摄入饮用水中 TCE 时目标器官中三氯乙酸（TCA）和 DCA 的沉积；使用人肝细胞确定用于纳入潜在敏感亚群 TCE 代谢变异性的 PBPK 模型的代谢率常数；测量饮用水中 TCE 痕量水平的初次消除效率；以及评估外源性因素（如酒精、药物）改变低水平暴露时代谢激活和风险的能力。
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