Storm J E, Rozman K K
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Regul Toxicol Pharmacol. 1997 Jun;25(3):240-55. doi: 10.1006/rtph.1997.1089.
The facts that reduction of occupational vinyl chloride exposures to levels within or below the 0.5-5 ppm range has so far been successful in eliminating vinyl chloride-induced liver angiosarcoma and that humans appear to be less sensitive to the carcinogenic effect of vinyl chloride than rats offered an opportunity to verify or dispute risk assessment extrapolation models used, and proposed, by the U.S. EPA. Safe occupational vinyl chloride exposures were defined as levels associated with an incidence of one angiosarcoma in 100,000 exposed workers, determined from rat bioassay data using default no-threshold (linearized multistage model and benchmark dose approach with linear extrapolation) and threshold (NOEL/LOEL and benchmark dose uncertainty factor approaches) models, and then compared against the likely protective range of 0.5-5 ppm. Safe levels derived using either no-threshold model are equivalent and are two to three orders of magnitude below the 0.5-5 ppm range. Safe levels derived using either threshold model, when applying uncertainty factors which reflect equal or less sensitivity in humans compared to rats, fall within the 0.5-5 ppm range. Similar results were obtained for vinyl bromide and vinyl fluoride. These results undermine the U.S. EPA default assumption of no-threshold for vinyl halides as well as for other DNA-reactive carcinogens while simultaneously supporting the notion that a practical threshold exists. They further suggest that when threshold models are appropriate, the default assumption of greater sensitivity in humans compared to rats should be carefully evaluated.
将职业性氯乙烯暴露降低至0.5 - 5 ppm范围内或以下的水平，迄今为止已成功消除了氯乙烯诱发的肝血管肉瘤，而且人类似乎对氯乙烯致癌作用的敏感性低于大鼠，这为验证或质疑美国环境保护局（EPA）所使用和提出的风险评估外推模型提供了契机。安全的职业性氯乙烯暴露水平定义为，根据大鼠生物测定数据，使用默认的无阈值模型（线性化多阶段模型和采用线性外推的基准剂量法）和阈值模型（无明显有害作用水平/最低观察到有害作用水平和基准剂量不确定因素法）确定的，与100,000名暴露工人中出现一例血管肉瘤的发生率相关的水平，然后与0.5 - 5 ppm的可能保护范围进行比较。使用任何一种无阈值模型得出的安全水平是等效的，比0.5 - 5 ppm范围低两到三个数量级。当应用反映人类与大鼠相比敏感性相同或更低的不确定因素时，使用任何一种阈值模型得出的安全水平都落在0.5 - 5 ppm范围内。对于溴乙烯和氟乙烯也获得了类似结果。这些结果削弱了美国EPA关于卤化乙烯以及其他DNA反应性致癌物无阈值的默认假设，同时支持了存在实际阈值的观点。它们还进一步表明，当阈值模型适当时，应仔细评估人类比大鼠更敏感的默认假设。
