Bond J A, Himmelstein M W, Medinsky M A
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709-2137, USA.
Int Arch Occup Environ Health. 1996;68(6):415-20. doi: 10.1007/BF00377862.
The National Research Council (NRC) recently published a report. Science and Judgment in Risk Assessment, that critiqued the current approaches to characterizing human cancer risks from exposure to chemicals. One issue raised in the report relates to the use of default options for quantitation of cancer risks. Default options are general guidelines that can be used for risk assessment when specific information about a chemical is absent. Research on 1,3-butadiene represents an interesting case study in which existing knowledge on this chemical indicates that two default options may no longer be tenable: (1) humans are as sensitive as the most sensitive animal species, and (2) the rate of metabolism is a function of body surface area rather than inherent species differences in metabolic capacity. Butadiene, a major commodity chemical used in the production of synthetic rubber, is listed as one of 189 hazardous air pollutants under the 1990 Clean Air Act Amendments. Butadiene is a carcinogen in rats and mice, with mice being substantially more sensitive than rats. The extent to which butadiene poses a cancer risk to humans exposed to this chemical is uncertain. Butadiene requires metabolic activation to DNA-reactive epoxides to exert its mutagenic and carcinogenic effects. Research is directed toward obtaining a better understanding of the cancer risks of butadiene in humans by evaluating species-dependent differences in the formation of the toxic butadiene epoxide metabolites, epoxybutene and diepoxybutane. The data include in-vitro studies on butadiene metabolism using tissues from humans, rats, and mice as well as experimental data and physiological model predictions for butadiene in blood and butadiene epoxides in blood, lung, and liver after exposure of rats and mice to inhaled butadiene. The findings suggest that humans are more like rats and less like mice regarding the formation of butadiene epoxides. The research approach employed can be a useful strategy for developing mechanistic and toxicokinetic data to supplant default options used in carcinogen risk assessments for butadiene.
美国国家研究委员会（NRC）最近发表了一份名为《风险评估中的科学与判断》的报告，该报告对当前从接触化学物质来确定人类癌症风险的方法提出了批评。报告中提出的一个问题涉及在癌症风险定量时使用默认选项。默认选项是一些通用指南，当缺乏某种化学物质的具体信息时，可用于风险评估。对1,3 - 丁二烯的研究是一个有趣的案例，关于这种化学物质的现有知识表明，两个默认选项可能不再成立：（1）人类与最敏感的动物物种一样敏感；（2）代谢速率是体表面积的函数，而不是代谢能力的固有物种差异。丁二烯是用于生产合成橡胶的一种主要化工原料，根据1990年《清洁空气法修正案》，它被列为189种有害空气污染物之一。丁二烯在大鼠和小鼠中是致癌物，小鼠比大鼠对其更为敏感。丁二烯对接触该化学物质的人类构成癌症风险的程度尚不确定。丁二烯需要代谢激活生成具有DNA反应性的环氧化物才能发挥其致突变和致癌作用。研究旨在通过评估有毒的丁二烯环氧化物代谢物环氧丁烯和1,2 - 二环氧丁烷形成过程中的物种依赖性差异，更好地了解丁二烯对人类的癌症风险。这些数据包括使用来自人类、大鼠和小鼠的组织进行的丁二烯代谢体外研究，以及大鼠和小鼠吸入丁二烯后血液中丁二烯和血液、肺和肝脏中丁二烯环氧化物的实验数据和生理模型预测。研究结果表明，在丁二烯环氧化物的形成方面，人类更像大鼠而不像小鼠。所采用的研究方法可能是一种有用的策略，可用于生成机制和毒代动力学数据，以取代丁二烯致癌物风险评估中使用的默认选项。
