Fisher J W, Allen B C
Armstrong Laboratory, Toxicology Division, Wright-Patterson Air Force Base, Ohio 45433.
Risk Anal. 1993 Feb;13(1):87-95. doi: 10.1111/j.1539-6924.1993.tb00731.x.
Trichloroethylene (TCE) is a widespread environmental pollutant. TCE is classified as a rodent carcinogen by the U.S. Environmental Protection Agency (EPA). Using the rodent cancer bioassay findings and estimates of metabolized dose, the EPA has estimated lifetime exposure cancer risks for humans that ingest TCE in drinking water or inhale TCE. In this study, a physiologically based pharmacokinetic (PB-PK) model for mice was used to simulate selected gavage and inhalation bioassays with TCE. Plausible dose-metrics thought to be linked with the mechanism of action for TCE carcinogenesis were selected. These dose-metrics, adjusted to reflect an average amount per day for a lifetime, were metabolism of TCE (AMET, mg/kg/day) and systemic concentration of TCA (AUCTCA, mg/L/day). These dose-metrics were then used in a linearized multistage model to estimate AMET and AUCTCA values that correspond to liver cancer risks of 1 in 1 million in mice. A human PB-PK model for TCE was then used to predict TCE concentrations in drinking water and air that would provide AMET and AUCTCA values equal to the predicted mice AMET and AUCTCA values that correspond to liver cancer risks of 1 in 1 million. For the dose-metrics, AMET and AUCTCA, the TCE concentrations in air were 10.0 and 0.1 ppb TCE (continuous exposure), respectively, and in water, 7 and 4 micrograms TCE/L, respectively.
三氯乙烯（TCE）是一种广泛存在的环境污染物。美国环境保护局（EPA）将TCE归类为啮齿动物致癌物。根据啮齿动物癌症生物测定结果和代谢剂量估计，EPA估算了人类通过饮用含TCE的水或吸入TCE而终生接触致癌的风险。在本研究中，使用基于生理的小鼠药代动力学（PB-PK）模型来模拟选定的TCE灌胃和吸入生物测定。选择了被认为与TCE致癌作用机制相关的合理剂量指标。这些剂量指标经调整以反映终生每天的平均量，分别为TCE的代谢量（AMET，毫克/千克/天）和三氯乙酸的全身浓度（AUCTCA，毫克/升/天）。然后将这些剂量指标用于线性化多阶段模型，以估算与小鼠中百万分之一的肝癌风险相对应的AMET和AUCTCA值。接着使用人类TCE的PB-PK模型来预测饮用水和空气中的TCE浓度，这些浓度将提供与预测的小鼠AMET和AUCTCA值相等的值，而这些值对应于百万分之一的肝癌风险。对于剂量指标AMET和AUCTCA，空气中的TCE浓度分别为10.0和0.1 ppb TCE（持续暴露），水中的TCE浓度分别为7和4微克TCE/升。
