Casanova M, Conolly R B
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.
Fundam Appl Toxicol. 1996 May;31(1):103-16. doi: 10.1006/faat.1996.0081.
Dichloromethane (DCM) (methylene chloride; CH2Cl2) is metabolized via a glutathione S-transferase-mediated pathway to formaldehyde (HCHO), a mutagenic compound that could play a role in the carcinogenic effects of DCM observed in the liver and lungs of B6C3F1 mice at 2000 and 4000 ppm. Mice but not hamsters formed DNA-protein cross-links (DPX) in the liver at DCM concentrations ranging from approximately 500 to 4000 ppm. The formation of DPX was a nonlinear function of the airborne concentration of DCM. In addition, mice exposed to DCM (6 hr/day, 3 days) at concentrations ranging from approximately 1500 to 4000 ppm showed an increased rate of DNA synthesis in the lung indicating cell proliferation, but increased cell turnover was not detected in mouse lung at exposure concentrations of 150 or 500 ppm. Hamsters showed no evidence of cell proliferation in the lung at any concentration, and cell proliferation was not apparent in the livers of either mice or hamsters. An extended physiologically based pharmacokinetic (PBPK) model for DPX formation in mouse liver was developed, based on a published PBPK model for DCM (Andersen, M.E., Clewell, H.J., III, Gargas, M.L., Smith, F.A., and Reitz, R.H. (1987). Toxicol. Appl. Pharmacol. 87, 185-205). The extended PBPK model was fitted to the DPX data using the PBPK model-estimated area under the curve for DCM in mouse liver as the independent variable. Parameter estimates for HCHO disposition in the livers of mice exposed to dichloromethane were similar to previously published estimates for HCHO disposition in the nasal mucosa of rats exposed to formaldehyde. Using the extended PBPK model, estimates were made of the yields of DPX presumably formed in mouse liver at the DCM concentrations used in a bioassay (Mennear, J.H., McConnell, E.E., Huff, J.E., Renne, R.A., and Giddens, E. (1988). Ann. NY Acad. Sci. 534, 343-351). The tumor incidence data in mice were fitted to the DPX yields and to the airborne concentration of DCM as alternative measures of exposure using the linearized multistage (LMS) model. The two dose measures yielded similar maximum likelihood estimates for the cancer risk at concentrations from 10 to 100 ppm, but the upper 95% confidence limit on the risk was reduced by two orders of magnitude when DPX rather than the airborne concentration was used as the measure of exposure. The results demonstrate that an internal dosimeter such as DPX can markedly improve the precision of low-dose risk estimates, while having only a minor effect on the maximum likelihood estimates calculated with the LMS model.
二氯甲烷（DCM）（二氯甲烷；CH₂Cl₂）通过谷胱甘肽S-转移酶介导的途径代谢为甲醛（HCHO），甲醛是一种诱变化合物，可能在B6C3F1小鼠肝脏和肺中观察到的DCM致癌作用中发挥作用，暴露浓度分别为2000 ppm和4000 ppm。在DCM浓度约为500至4000 ppm范围内，小鼠肝脏中会形成DNA-蛋白质交联（DPX），而仓鼠则不会。DPX的形成是DCM空气浓度的非线性函数。此外，暴露于浓度约为1500至4000 ppm的DCM（每天6小时，共3天）的小鼠肺部DNA合成速率增加，表明细胞增殖，但在暴露浓度为150或500 ppm时，未在小鼠肺部检测到细胞更新增加。在任何浓度下，仓鼠肺部均未显示细胞增殖迹象，小鼠和仓鼠肝脏中也未出现明显的细胞增殖。基于已发表的DCM生理药代动力学（PBPK）模型（Andersen, M.E., Clewell, H.J., III, Gargas, M.L., Smith, F.A., and Reitz, R.H. (1987). Toxicol. Appl. Pharmacol. 87, 185 - 205），开发了一个用于小鼠肝脏中DPX形成的扩展PBPK模型。使用PBPK模型估计的小鼠肝脏中DCM曲线下面积作为自变量，将扩展PBPK模型拟合到DPX数据。暴露于二氯甲烷的小鼠肝脏中HCHO处置的参数估计值与先前发表的暴露于甲醛的大鼠鼻粘膜中HCHO处置的估计值相似。使用扩展PBPK模型，估计了生物测定中使用的DCM浓度下小鼠肝脏中可能形成的DPX产量（Mennear, J.H., McConnell, E.E., Huff, J.E., Renne, R.A., and Giddens, E. (1988). Ann. NY Acad. Sci. 534, 343 - 351）。使用线性化多阶段（LMS）模型，将小鼠的肿瘤发生率数据拟合到DPX产量和DCM空气浓度，作为暴露的替代测量指标。在浓度为10至100 ppm时，这两种剂量测量方法对癌症风险的最大似然估计值相似，但当使用DPX而非空气浓度作为暴露测量指标时，风险的95%置信上限降低了两个数量级。结果表明，诸如DPX这样的内部剂量计可以显著提高低剂量风险估计的精度，而对用LMS模型计算的最大似然估计值影响较小。
