Jarabek A M, Fisher J W, Rubenstein R, Lipscomb J C, Williams R J, Vinegar A, McDougal J N
U.S. Environmental Protection Agency, Environmental Criteria and Assessment Office (MD-52), Research Triangle Park, North Carolina 27711.
Risk Anal. 1994 Jun;14(3):231-50. doi: 10.1111/j.1539-6924.1994.tb00238.x.
An international consensus on the need to reduce the use of chlorofluorocarbons (CFCs) and other ozone-depleting gases such as the halons led to the adoptions of the 1987 Montreal Protocol and Title VI of the 1990 Clean Air Act Amendments, "Protecting Stratospheric Ozone." These agreements included major provisions for reducing and eventually phasing out production and use of CFCs and halons as well as advancing the development of replacement chemicals. Because of the ubiquitous use and benefits of CFCs and halons, an expeditious search for safe replacements to meet the legislative deadlines is of critical importance. Toxicity testing and health risk assessment programs were established to evaluate the health and environmental impact of these replacement chemicals. Development and implementation of these programs as well as the structural-activity relationships significant for the development of the replacement chemicals are described below. A dose-response evaluation for the health risk assessment of the replacement chemical HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) is also presented to show an innovative use of physiologically based pharmacokinetic (PBPK) modeling. This is based on a parallelogram approach using data on the anesthetic gas halothane, a structural analog to HCFC-123. Halothane and HCFC-123 both form the same metabolite, trifluoroacetic acid (TFA), indicative of the same metabolic oxidative pathway attributed to hepatotoxicity. The parallelogram approach demonstrates the application of template model structures and shows how PBPK modeling, together with judicious experimental design, can be used to improve the accuracy of health risk assessment and to decrease the need for extensive laboratory animal testing.
国际社会就减少氯氟烃（CFCs）及其他消耗臭氧层气体（如哈龙）的使用达成共识，这促成了1987年《蒙特利尔议定书》以及1990年《清洁空气法修正案》第六章“保护平流层臭氧”的通过。这些协议包含了减少并最终逐步淘汰CFCs和哈龙的生产及使用，以及推动替代化学品开发的主要条款。鉴于CFCs和哈龙的广泛使用及其带来的益处，迅速寻找安全替代品以满足立法期限至关重要。为此设立了毒性测试和健康风险评估项目，以评估这些替代化学品对健康和环境的影响。以下将描述这些项目的开发与实施，以及对替代化学品开发具有重要意义的构效关系。还给出了对替代化学品HCFC - 123（2,2 - 二氯 - 1,1,1 - 三氟乙烷）健康风险评估的剂量反应评估，以展示基于生理学的药代动力学（PBPK）模型的创新应用。这是基于一种平行四边形方法，使用了麻醉气体氟烷的数据，氟烷是HCFC - 123的结构类似物。氟烷和HCFC - 123都形成相同的代谢物三氟乙酸（TFA），这表明它们具有相同的导致肝毒性的代谢氧化途径。平行四边形方法展示了模板模型结构的应用，并说明了PBPK模型如何与明智的实验设计一起用于提高健康风险评估的准确性，并减少对大量实验动物测试的需求。
