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首页> 外文期刊>Environmental toxicology and chemistry >A STRATEGY TO REDUCE THE NUMBERS OF FISH USED IN ACUTE ECOTOXICITY TESTING OF PHARMACEUTICALS
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A STRATEGY TO REDUCE THE NUMBERS OF FISH USED IN ACUTE ECOTOXICITY TESTING OF PHARMACEUTICALS

机译：减少在药物急性毒性试验中使用的鱼类数量的策略

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摘要

The pharmaceutical industry gives high priority to animal welfare in the process of drug discovery and safety assessment. In the context of environmental assessments of active pharmaceutical ingredients (APIs), existing U.S. Food and Drug Administration and draft European regulations may require testing of APIs for acute ecotoxicity to algae, daphnids, and fish (base-set ecotoxicity data used to derive the predicted no-effect concentration [PNEC_(water)] from the most sensitive of three species). Subject to regulatory approval, it is proposed that testing can be moved from fish median lethal concentration (LC50) testing (typically using ≥ 42 fish/ API) to acute threshold tests using fewer fish (typically 10 fish/API). To support this strategy, we have collated base-set ecotoxicity data from regulatory studies of 91 APIs (names coded for commercial reasons). For 73 of the 91 APIs, the algal median effect concentration (EC50) and daphnid EC50 values were lower than or equal to the fish LC50 data. Thus, for approximately 80% of these APIs, algal and daphnid acute EC50 data could have been used in the absence of fish LC50 data to derive PNEC_(water) values. For the other 18 APIs, use of an acute threshold test with a step-down factor of 3.2 is predicted to give comparable PNEC_(water) outcomes. Based on this preliminary scenario of 91 APIs, this approach is predicted to reduce the total number of fish used from 3,822 to 1,025 (～73%). The present study, although preliminary, suggests that the current regulatory requirement for fish LC50 data regarding APIs should be succeeded by fish acute threshold (step-down) test data, thereby achieving significant animal welfare benefits with no loss of data for PNEC_(water) estimates.
机译：在药物开发和安全评估过程中，制药行业高度重视动物福利。在对活性药物成分（API）进行环境评估的背景下，现有的美国食品药品监督管理局和欧洲法规草案可能要求测试API对藻类，水蚤和鱼类的急性生态毒性（用于推算预测值的基本生态毒性数据）三种物质中最敏感的一种，即无影响浓度[PNEC_（水）]。在获得监管机构批准的情况下，建议将测试从鱼类中位致死浓度（LC50）测试（通常使用≥42条鱼/ API）转移到使用更少鱼类（通常10条鱼/ API）的急性阈值测试。为了支持该策略，我们从91个API（出于商业原因而进行编码的名称）的监管研究中收集了基础设定的生态毒性数据。对于91个API中的73个，藻类中值浓度（EC50）和达芙妮EC50值低于或等于鱼的LC50数据。因此，对于这些API中的大约80％，在没有鱼类LC50数据的情况下，可以使用藻类和瑞香急性EC50数据来得出PNEC_（水）值。对于其他18种API，预计使用降压系数为3.2的急性阈值试验可得出类似的PNEC_（水）效果。根据91种API的初步情况，预计该方法将使鱼类总使用量从3,822减少到1,025（〜73％）。尽管是初步研究，但本研究表明，应通过鱼类急性阈值（降压）测试数据来满足有关API的鱼类LC50数据的当前监管要求，从而在不损失PNEC_（water）数据的情况下获得显着的动物福利。估计。

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