Pharmacology beyond the patient - The environmental risks of human drugs
Pharmacology beyond the patient - The environmental risks of human drugs
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DOI：
10.1016/j.envint.2019.04.075
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发表时间：
2019-08-01
影响因子：
11.8
通讯作者：
Tyler, Charles R.
中科院分区：
文献类型：
--
作者：
Gunnarsson, Lina;Snapk, Jason R.;Tyler, Charles R.
背景：药物在环境中的存在日益受到全球的关注，尽管欧洲和美国的新药审批需要进行环境风险评估，但当前的触发因素和基于效果的评估的充分性一直受到质疑。目的：全面分析所有符合监管规定的水生生态毒性数据，评估当前的触发因素和基于影响的环境评估，以促进开发更有效的药物毒性测试方法。方法：编制针对人类蛋白质的药物的符合监管规定的生态毒性数据，以及包括药物靶点、Cmax和亲脂性在内的药理学信息。评估了这些因素与影响生长、死亡和/或生殖的生态毒性数据之间的可能联系。结果：在975种已批准的针对人类蛋白质的小分子药物中，大多数(88%)在公共领域缺乏一套完整的符合监管规定的生态毒性数据，这突显出既需要智能方法来确定传统人类药物的优先顺序，以进行定制的环境风险评估，也需要一个透明的数据库来捕获环境数据。我们表明，药物靶向同源基因的存在/缺失对更有效的药物的易感物种具有预测作用。针对内分泌系统的药物具有最高的效力和最大的风险。然而，对于拥有全套生态毒性数据的大多数药物(80%)，在所有欧洲国家中，假设最糟糕的暴露评估的风险商数低于1，表明所评估的终点的环境风险较低。结论：我们相信所提供的分析可以指导改进当前的测试程序，并为优先选择遗留药物(即2006年前注册的药物)进行进一步的生态毒性测试提供有价值的方法。对于监管测试中没有发现可能引起关注(例如行为)的影响的药物，可能需要额外的机械测试，以提供最高的置信度，以避免对环境的影响。
Background: The presence of pharmaceuticals in the environment is a growing global concern and although environmental risk assessment is required for approval of new drugs in Europe and the USA, the adequacy of the current triggers and the effects-based assessments has been questioned.Objective: To provide a comprehensive analysis of all regulatory compliant aquatic ecotoxicity data and evaluate the current triggers and effects-based environmental assessments to facilitate the development of more efficient approaches for pharmaceuticals toxicity testing.Methods: Publicly-available regulatory compliant ecotoxicity data for drugs targeting human proteins was compiled together with pharmacological information including drug targets, Cmax and lipophilicity. Possible links between these factors and the ecotoxicity data for effects on, growth, mortality and/or reproduction, were evaluated. The environmental risks were then assessed based on a combined analysis of drug toxicity and predicted environmental concentrations based on European patient consumption data.Results: For most (88%) of the of 975 approved small molecule drugs targeting human proteins a complete set of regulatory compliant ecotoxicity data in the public domain was lacking, highlighting the need for both intelligent approaches to prioritize legacy human drugs for a tailored environmental risk assessment and a transparent database that captures environmental data. We show that presence/absence of drug-target orthologues are predictive of susceptible species for the more potent drugs. Drugs that target the endocrine system represent the highest potency and greatest risk. However, for most drugs ( > 80%) with a full set of ecotoxicity data, risk quotients assuming worst-case exposure assessments were below one in all European countries indicating low environmental risks for the endpoints assessed.Conclusion: We believe that the presented analysis can guide improvements to current testing procedures, and provide valuable approaches for prioritising legacy drugs (i.e. those registered before 2006) for further ecotoxicity testing. For drugs where effects of possible concern (e.g. behaviour) are not captured in regulatory tests, additional mechanistic testing may be required to provide the highest confidence for avoiding environmental impacts.