Bogen K T, Gold L S
Health and Ecological Assessment Division, Lawrence Livermore National Laboratory, Livermore, California 94550, USA.
Regul Toxicol Pharmacol. 1997 Feb;25(1):26-42. doi: 10.1006/rtph.1996.1070.
Cancer risk assessments for trichloroethylene (TCE) based on linear extrapolation from bioassay results are questionable in light of new data on TCE's likely mechanism of action involving induced cytotoxicity, for which a threshold-type dose-response model may be more appropriate. Previous studies have shown that if a genotoxic mechanism for TCE is assumed, algebraic methods can considerably simplify the use of physiologically based pharmacokinetic (PBPK) models to estimate virtually safe environmental concentrations for humans based on rodent cancer-bioassay data. We show here how such methods can be extended to the case in which TCE is assumed to induce cancer via cytotoxicity, to estimate environmentally safe concentrations based on rodent toxicity data. These methods can be substituted for the numerical methods typically used to calculate PBPK-effective doses when these are defined as peak concentrations. We selected liver and kidney as plausible target tissues, based on an analysis of rodent TCE-bioassay data and on a review of related data bearing on mechanism. Tumor patterns in rodent bioassays are shown to be consistent with our estimates of PBPK-based, effective cytotoxic doses to mice and rats used in these studies. When used with a margin of exposure of 1000, our method yielded maximum concentration levels for TCE of 16 ppb (87 micrograms/m3) for TCE in air respired 24 hr/day, 700 ppb (3.8 mg/m3) for TCE in air respired for relatively brief daily periods (e.g., 0.5 hr while showering/bathing), and 210 micrograms/liter for TCE in drinking water assuming a daily 2-liter ingestion. Cytotoxic effective doses were also estimated for occupational respiratory exposures. These estimates indicate that the current OSHA permissible exposure limit for TCE would produce metabolite concentrations that exceed an acute no observed adverse effect level for hepatotoxicity in mice. On this basis, the OSHA TCE limit is not expected to be protective.
鉴于三氯乙烯（TCE）可能的作用机制涉及诱导细胞毒性，基于生物测定结果进行线性外推得出的TCE癌症风险评估存在疑问，对于这种情况，阈值型剂量反应模型可能更为合适。以往的研究表明，如果假定TCE存在遗传毒性机制，代数方法可以显著简化基于生理的药代动力学（PBPK）模型的使用，以便根据啮齿动物癌症生物测定数据估算对人类而言基本安全的环境浓度。我们在此展示了如何将这些方法扩展到假定TCE通过细胞毒性诱导癌症的情况，从而根据啮齿动物毒性数据估算环境安全浓度。当将这些有效剂量定义为峰值浓度时，这些方法可以替代通常用于计算PBPK有效剂量的数值方法。基于对啮齿动物TCE生物测定数据的分析以及对相关作用机制数据的综述，我们选择肝脏和肾脏作为可能的靶组织。啮齿动物生物测定中的肿瘤模式与我们对这些研究中所用小鼠和大鼠基于PBPK的有效细胞毒性剂量的估算结果一致。当暴露系数设为1000时，我们的方法得出的结果为：对于每天24小时呼吸空气中的TCE，其最大浓度水平为16 ppb（87微克/立方米）；对于每天仅短时间呼吸（例如淋浴/洗澡0.5小时）空气中的TCE，其最大浓度水平为700 ppb（3.8毫克/立方米）；假设每日饮水量为2升，饮用水中TCE的最大浓度水平为210微克/升。我们还估算了职业性呼吸道暴露的细胞毒性有效剂量。这些估算结果表明，当前美国职业安全与健康管理局（OSHA）规定的TCE允许暴露限值会导致代谢物浓度超过小鼠肝毒性的急性无观察到不良效应水平。基于此，预计OSHA的TCE限值无法起到保护作用。
