Bolt H M, Filser J G, Buchter A
Arch Toxicol. 1981 Nov;48(4):213-28. doi: 10.1007/BF00319650.
On the basis of previous determinations of pharmacokinetic parameters for inhaled vinyl chloride in men, rhesus monkeys, and rats, and on improved pharmacokinetic models a pharmacokinetic treatment of the problem of "peak concentrations" of vinyl chloride, as occurring in industrial practice, became possible. For the calculations, metabolic elimination kinetics of vinyl chloride was assumed to be first order as experiments in different species including rhesus monkeys showed "linear" pharmacokinetics up to atmospheric exposures of 200-300 ppm. The distribution of vinyl chloride between atmosphere and organism under different conditions was evaluated using "'steady-state-kinetics". After treating the processes of "influx", "efflux", and "metabolism", the numerical values for the parameters derived from a human kinetic experiment were used to theoretically calculate the time courses of concentration of vinyl chloride in the organism and of the cumulative amount of vinyl chloride metabolized, under the conditions of (a) a 2h constant exposure to 5 ppm vinyl chloride and (b) two subsequent "peaks" of 50 ppm with a duration of 5 min each. This model calculation suggested that, regardless of the exposure profile, the amount of (reactive) metabolites formed from vinyl chloride would solely be a function of the mean atmospheric vinyl chloride concentration over time. The general validity of this suggested rule could subsequently be demonstrated. As the concentration of the reactive metabolite of vinyl chloride responsible for the carcinogenic effect at the target site must be a resultant of both formation and inactivation, an evaluation of the differential risk of different exposure profiles can reasonably be based on biochemical examinations of the "detoxifying" pathways. This points out the relevance of studies of the patterns of different metabolites of vinyl chloride in man under varying exposure profiles.
根据先前对男性、恒河猴和大鼠吸入氯乙烯的药代动力学参数的测定结果，以及改进后的药代动力学模型，对工业实践中出现的氯乙烯“峰值浓度”问题进行药代动力学处理成为可能。在计算过程中，假定氯乙烯的代谢消除动力学为一级，因为包括恒河猴在内的不同物种的实验表明，在高达200 - 300 ppm的大气暴露条件下呈现“线性”药代动力学。使用“稳态动力学”评估不同条件下氯乙烯在大气和生物体之间的分布。在处理了“流入”“流出”和“代谢”过程后，利用从人体动力学实验得出的参数数值，理论计算在以下条件下生物体中氯乙烯浓度的时间进程以及代谢的氯乙烯累积量：(a) 2小时持续暴露于5 ppm氯乙烯；(b) 两个连续的50 ppm“峰值”，每次持续5分钟。该模型计算表明，无论暴露情况如何，由氯乙烯形成的（活性）代谢物的量仅取决于随时间变化的平均大气氯乙烯浓度。随后可以证明这一建议规则的普遍有效性。由于在靶部位产生致癌作用的氯乙烯活性代谢物的浓度必须是形成和失活两者的结果，基于对“解毒”途径的生化检查，合理评估不同暴露情况的差异风险是可行的。这突出了研究不同暴露情况下人体中氯乙烯不同代谢物模式的相关性。
