Department of Environmental Toxicology (Utox), Swiss Federal Institute of Aquatic Science and Technology (Eawag), Überlandstrasse 133, PO Box 611, 8600 Dübendorf, Switzerland.
Integr Environ Assess Manag. 2011 Jan;7(1):28-49. doi: 10.1002/ieam.100.
This article reviews the mechanistic basis of the tissue residue approach for toxicity assessment (TRA). The tissue residue approach implies that whole-body or organ concentrations (residues) are a better dose metric for describing toxicity to aquatic organisms than is the aqueous concentration typically used in the external medium. Although the benefit of internal concentrations as dose metrics in ecotoxicology has long been recognized, the application of the tissue residue approach remains limited. The main factor responsible for this is the difficulty of measuring internal concentrations. We propose that environmental toxicology can advance if mechanistic considerations are implemented and toxicokinetics and toxicodynamics are explicitly addressed. The variability in ecotoxicological outcomes and species sensitivity is due in part to differences in toxicokinetics, which consist of several processes, including absorption, distribution, metabolism, and excretion (ADME), that influence internal concentrations. Using internal concentrations or tissue residues as the dose metric substantially reduces the variability in toxicity metrics among species and individuals exposed under varying conditions. Total internal concentrations are useful as dose metrics only if they represent a surrogate of the biologically effective dose, the concentration or dose at the target site. If there is no direct proportionality, we advise the implementation of comprehensive toxicokinetic models that include deriving the target dose. Depending on the mechanism of toxicity, the concentration at the target site may or may not be a sufficient descriptor of toxicity. The steady-state concentration of a baseline toxicant associated with the biological membrane is a good descriptor of the toxicodynamics of baseline toxicity. When assessing specific-acting and reactive mechanisms, additional parameters (e.g., reaction rate with the target site and regeneration of the target site) are needed for characterization. For specifically acting compounds, intrinsic potency depends on 1) affinity for, and 2) type of interaction with, a receptor or a target enzyme. These 2 parameters determine the selectivity for the toxic mechanism and the sensitivity, respectively. Implementation of mechanistic information in toxicokinetic-toxicodynamic (TK-TD) models may help explain time-delayed effects, toxicity after pulsed or fluctuating exposure, carryover toxicity after sequential pulses, and mixture toxicity. We believe that this mechanistic understanding of tissue residue toxicity will lead to improved environmental risk assessment.
这篇文章回顾了毒性评估的组织残留方法的机制基础（TRA）。组织残留方法意味着全身或器官浓度（残留）作为描述水生生物毒性的剂量指标优于通常在外部介质中使用的水浓度。尽管内部浓度作为生态毒理学中的剂量指标的好处早已得到认可，但组织残留方法的应用仍然有限。造成这种情况的主要因素是测量内部浓度的难度。我们提出，如果实施机制考虑因素并明确解决毒物动力学和毒代动力学问题，环境毒理学可以取得进展。生态毒理学结果和物种敏感性的可变性部分归因于毒物动力学的差异，毒物动力学包括吸收、分布、代谢和排泄（ADME）等几个过程，这些过程会影响内部浓度。使用内部浓度或组织残留作为剂量指标可大大减少在不同条件下暴露的物种和个体之间毒性指标的可变性。只有当总内部浓度代表生物有效剂量（即靶部位的浓度或剂量）的替代物时，它们才可用作剂量指标。如果没有直接的比例关系，我们建议实施包括推导靶剂量在内的综合毒物动力学模型。根据毒性机制，靶部位的浓度可能是或可能不是毒性的充分描述符。与生物膜相关的基线毒物的稳态浓度是基线毒性毒代动力学的良好描述符。在评估特定作用和反应性机制时，需要额外的参数（例如与靶部位的反应速率和靶部位的再生）来进行特征描述。对于特定作用的化合物，内在效力取决于 1）与受体或靶酶的亲和力，以及 2）相互作用的类型。这两个参数分别决定了毒性机制的选择性和敏感性。在毒物动力学-毒代动力学（TK-TD）模型中实施机制信息可能有助于解释时滞效应、脉冲或波动暴露后的毒性、连续脉冲后的残留毒性以及混合物毒性。我们相信，这种对组织残留毒性的机制理解将导致环境风险评估的改善。
