Andersen M E, Clewell H J, Gargas M L, MacNaughton M G, Reitz R H, Nolan R J, McKenna M J
Toxic Hazards Division, Armstrong Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Ohio 45433-6573.
Toxicol Appl Pharmacol. 1991 Mar 15;108(1):14-27. doi: 10.1016/0041-008x(91)90264-f.
Dichloromethane (methylene chloride, DCM) and other dihalomethanes are metabolized to carbon monoxide (CO) which reversibly binds hemoglobin and is eliminated by exhalation. We have developed a physiologically based pharmacokinetic (PB-PK) model which describes the kinetics of CO, carboxyhemoglobin (HbCO), and parent dihalomethane, and have applied this model to examine the inhalation kinetics of CO and of DCM in rats and humans. The portion of the model describing CO and HbCO kinetics was adapted from the Coburn-Forster-Kane equation, after modification to include production of CO by DCM oxidation. DCM kinetics and metabolism were described by a generic PB-PK model for volatile chemicals (RAMSEY AND ANDERSEN, Toxicol. Appl. Pharmacol. 73, 159-175, 1984). Physiological and biochemical constants for CO were first estimated by exposing rats to 200 ppm CO for 2 hr and examining the time course of HbCO after cessation of CO exposure. These CO inhalation studies provided estimates of CO diffusing capacity under free breathing and for the Haldane coefficient, the relative equilibrium distribution ratio for hemoglobin between CO and O2. The CO model was then coupled to a PB-PK model for DCM to predict HbCO time course behavior during and after DCM exposures in rats. By coupling the models it was possible to estimate the yield of CO from oxidation of DCM. In rats only about 0.7 mol of CO are produced from 1 mol of DCM during oxidation. The combined model adequately represented HbCO and DCM behavior following 4-hr exposures to 200 or 1000 ppm DCM, and HbCO behavior following 1/2-hr exposure to 5160 ppm DCM or 5000 ppm bromochloromethane. The rat PB-PK model was scaled to predict DCM, HbCO, and CO kinetics in humans exposed either to DCM or to CO. Three human data sets from the literature were examined: (1) inhalation of CO at 50, 100, 250, and 500 ppm; (2) seven 1/2-hr inhalation exposures to 50, 100, 250, and 500 ppm DCM; and (3) 2-hr inhalation exposures to 986 ppm DCM. An additional data set from human volunteers exposed to 100 or 350 ppm DCM for 6 hr is reported here for the first time. Endogenous CO production rates and the initial amount of CO in the blood compartment were varied in each study as necessary to give the baseline HbCO value, which varied from less than 0.5% to greater than 2% HbCO. The combined PB-PK model gave a good representation of the observed behavior in all four human studies.(ABSTRACT TRUNCATED AT 400 WORDS)
二氯甲烷（二氯亚甲基，DCM）和其他二卤甲烷会代谢生成一氧化碳（CO），一氧化碳会与血红蛋白可逆性结合，并通过呼气排出体外。我们建立了一个基于生理的药代动力学（PB-PK）模型，该模型描述了CO、碳氧血红蛋白（HbCO）和母体二卤甲烷的动力学，并应用此模型研究了大鼠和人类吸入CO和DCM的动力学。描述CO和HbCO动力学的模型部分改编自Coburn-Forster-Kane方程，并进行了修改以纳入DCM氧化产生CO的过程。DCM的动力学和代谢由挥发性化学物质的通用PB-PK模型描述（拉姆齐和安德森，《毒理学与应用药理学》73卷，159 - 175页，1984年）。首先通过将大鼠暴露于200 ppm CO中2小时，并在停止CO暴露后检查HbCO的时间进程，来估算CO的生理和生化常数。这些CO吸入研究提供了自由呼吸下CO扩散容量以及哈代系数（CO与O2之间血红蛋白的相对平衡分布比）的估算值。然后将CO模型与DCM的PB-PK模型耦合，以预测大鼠暴露于DCM期间及之后HbCO的时间进程行为。通过耦合模型，可以估算DCM氧化产生CO的产量。在大鼠中，氧化过程中1摩尔DCM仅产生约0.7摩尔CO。该组合模型充分代表了大鼠暴露于200或1000 ppm DCM 4小时后以及暴露于5160 ppm DCM或5000 ppm溴氯甲烷1/2小时后HbCO和DCM的行为。大鼠PB-PK模型经缩放后用于预测暴露于DCM或CO的人类体内DCM、HbCO和CO的动力学。研究了文献中的三组人类数据集：（1）吸入50、100、250和500 ppm的CO；（2）七次1/2小时吸入暴露于50、100、250和500 ppm的DCM；（3）2小时吸入暴露于986 ppm的DCM。此处首次报告了来自人类志愿者暴露于100或350 ppm DCM 6小时的另一组数据集。在每项研究中，根据需要改变内源性CO产生速率和血液隔室中CO的初始量，以使基线HbCO值在小于0.5%至大于2% HbCO之间变化。该组合PB-PK模型很好地代表了所有四项人体研究中观察到的行为。（摘要截断于400字）
