基于自然环境中优选药物的毒性和生态毒理风险研究

在如今超过1 500种在用原料药中,环境中发现几率明确和对环境影响明确的原料药所占比例很小。由于很难监管所有在用原料药,众多先前的研究提议将原料药按照受关注程度排序,从而可以将研究资源集中于那些最受瞩目的药物。然而这些研究都存在局限性,本文从之前优先性方法的实践经验出发,提出了一种更为全面的原料药排序方法。该方法基于对水生生物、土壤生物、鸟类、野生哺乳动物和人类的风险,综合考虑了食物链顶端存在的生态毒理学研究终点和由这些治疗性药物作用机制带来的非顶端效果。对于在英国社区以及医院设置中使用的146种活性药物的分析可以更为详细地说明该方法的运用。根据这一方法,我们将16种化合物列为优先考虑的药物。这些药物包括了抗生素、抗抑郁药、抗炎药、抗糖尿病药、抗肥胖药、雌激素类化合物以及相关的代谢产物。我们建议这种优先性方法在将来可以更广泛地应用于世界上不同的地区。
精选自Jiahua Guo, Chris J. Sinclair, Katherine Selby, Alistair B.A. Boxall. Toxicological and ecotoxicological risk based prioritisation of pharmaceuticals in the natural environment. Environmental Toxicology and Chemistry: Volume 35, Issue 7, pages 1550–1559, July 2016. DOI: 10.1002/etc.3319
详情请见http://onlinelibrary.wiley.com/doi/10.1002/etc.3319/full
     

21世纪可替代脊椎动物进行生态毒性测试的方法：过去二十年的发展和现状综述

替代脊椎动物进行化学物质和污染物危害评估的方法已成为越来越重要的需求。现在首先要考虑的是当启动一个脊椎动物生态毒性测试,必须确保不必要的脊椎动物生物的使用尽可能最小化。对于一些监管目的,脊椎动物的使用对环境风险评估(ERA)已经被禁止,而在其他情况下生物测试的数量已经大大减少了,或者测试程序严格精简了。然而,想要获得能够完全替代脊椎动物提供环境危害数据的方法仍有很长的路要走。动物替代品的发展不仅仅是基于道德的考虑,也可以降低执行脊椎动物生态毒性测试的成本以及在某些情况下能够提供更好的信息旨在改进环境风险评估。本文集中综述了在过去的几十年里生态毒性评估替代方法所发生的重大的进展。
精选自Adam Lillicrap, Scott Belanger, Natalie Burden, David Du Pasquier, Michelle R. Embry, Marlies Halder, Mark A. Lampi, Lucy Lee, Teresa Norberg-King, Barnett A. Rattner, Kristin Schirmer, Paul Thomas. Alternative approaches to vertebrate ecotoxicity tests in the 21st century: a review of developments over the last two decades and current status. Environmental Toxicology and Chemistry: Volume 35, Issue 11, pages 2637–2646, November 2016. DOI: 10.1002/etc.3603
详情请见http://onlinelibrary.wiley.com/doi/10.1002/etc.3603/full
     

保护生态系统亟需对农药进行注册后监测

现行的农药准入政策遵循一种可控的实验性分级风险评估方法,结果很难外推到实际情况。对DDT和烟碱类杀虫剂等化合物的分析清楚地表明,化学品对生态系统的实际影响比风险评估的预计更大。因此,为了管理由人工合成的化合物对生态系统造成的实际风险,提出了目前的化学药品准入政策,并通过注册后监测来补充。这种监测对于识别化合物通过多种传播途径和暴露方式对生物体产生的直接和间接影响是至关重要的。实施注册后监测可以建立在现有的监测网络上。这一方法将解决基于区域型法规与基于暴露型法规的现行政策僵局,更重要的是,将为跨部门间的风险评估提供一个安全锁,更有可能确保我们的自然环境得到保护。
精选自Vijver, M. G., Hunting, E. R., Nederstigt, T. A.P., Tamis, W. L.M., van den Brink, P. J. and van Bodegom, P. M. (2017), Postregistration monitoring of pesticides is urgently required to protect ecosystems. Environmental Toxicology and Chemistry, 36: 860–865. doi: 10.1002/etc.3721
详情请见http://onlinelibrary.wiley.com/doi/10.1002/etc.3721/full
     

蛋白组学分析揭示出阿特拉津对非洲爪蟾的生殖毒性源于其诱导生殖细胞凋亡并干扰紧密连接蛋白和代谢相关信号通路

阿特拉津可对雄性脊椎动物生殖系统造成不良影响,但其中分子机制尚不明了。本文作者将非洲爪蟾(Xenopus laevis)暴露于100 ppb的阿特拉津120 d,利用同位素标记相对和绝对定量(iTRAQ)技术检测了非洲爪蟾睾丸和卵巢中蛋白图谱的变化,结果显示100 ppb阿特拉津可影响爪蟾发育,延迟和阻碍雄性细精管的形成。组学分析显示,睾丸中143种以及卵巢中121种蛋白均表达异常,这些蛋白与细胞凋亡、细胞间紧密连接以及代谢途径相关。
精选自Xiuping Chen, Jiamei Wang, Haojun Zhu, Jiatong Ding and Yufa Peng. Proteomics analysis of Xenopus laevis gonad tissue following chronic exposure to atrazine. Environmental Toxicology and Chemistry: Volume 34, Issue 8, pages 1744–1750, August 2015. DOI: 10.1002/etc.2980
详情请见http://onlinelibrary.wiley.com/doi/10.1002/etc.2980/full     

蛋白组学分析揭示出阿特拉津对非洲爪蟾的生殖毒性源于其诱导生殖细胞凋亡并干扰紧密连接蛋白和代谢相关信号通路

阿特拉津可对雄性脊椎动物生殖系统造成不良影响，但其中分子机制尚不明了。本文作者将非洲爪蟾(Xenopus laevis)暴露于100 ppb的阿特拉津120 d，利用同位素标记相对和绝对定量(iTRAQ)技术检测了非洲爪蟾睾丸和卵巢中蛋白图谱的变化，结果显示100 ppb阿特拉津可影响爪蟾发育，延迟和阻碍雄性细精管的形成。组学分析显示，睾丸中143种以及卵巢中121种蛋白均表达异常，这些蛋白与细胞凋亡、细胞间紧密连接以及代谢途径相关。
精选自Xiuping Chen, Jiamei Wang, Haojun Zhu, Jiatong Ding and Yufa Peng. Proteomics analysis of Xenopus laevis gonad tissue following chronic exposure to atrazine. Environmental Toxicology and Chemistry: Volume 34, Issue 8, pages 1744–1750, August 2015. DOI: 10.1002/etc.2980
详情请见http://onlinelibrary.wiley.com/doi/10.1002/etc.2980/full     

蛋白组学分析揭示出阿特拉津对非洲爪蟾的生殖毒性源于其诱导生殖细胞凋亡并干扰紧密连接蛋白和代谢相关信号通路

阿特拉津可对雄性脊椎动物生殖系统造成不良影响,但其中分子机制尚不明了。本文作者将非洲爪蟾(Xenopus laevis)暴露于100 ppb的阿特拉津120 d,利用同位素标记相对和绝对定量(iTRAQ)技术检测了非洲爪蟾睾丸和卵巢中蛋白图谱的变化,结果显示100 ppb阿特拉津可影响爪蟾发育,延迟和阻碍雄性细精管的形成。组学分析显示,睾丸中143种以及卵巢中121种蛋白均表达异常,这些蛋白与细胞凋亡、细胞间紧密连接以及代谢途径相关。
精选自Xiuping Chen, Jiamei Wang, Haojun Zhu, Jiatong Ding and Yufa Peng. Proteomics analysis of Xenopus laevis gonad tissue following chronic exposure to atrazine. Environmental Toxicology and Chemistry: Volume 34, Issue 8, pages 1744–1750, August 2015. DOI: 10.1002/etc.2980
详情请见http://onlinelibrary.wiley.com/doi/10.1002/etc.2980/full     

农药暴露的机制模型：蜜蜂毒理学的重要缺失

杀虫剂在最近的蜜蜂数量减少中所扮演的角色是有争议的,部分原因是实地研究常常无法检测到实验室研究所预测的效果。这种不一致性突出了蜜蜂毒理学研究领域的一个关键空白：对蜜蜂在它们的环境中杀虫剂暴露的模式和过程知之甚少。本文作者提出蜜蜂暴露杀虫剂的2个关键过程：1)工蜂采集花蜜的过程中收集农药;2)工蜂带回的农药在蜂巢中的再分配。工蜂收集农药的过程必须被理解为环境污染和蜜蜂觅食活动之间的时空交集。这意味着农药暴露是分配的,而不是离散的,觅食工蜂的一个子集可能会获得有害剂量的农药,而群体暴露将会显得安全。蜂箱中农药的分布是一个复杂的过程,主要是由群体成员之间食物转移的相互作用而产生,而这一过程中花粉和花蜜之间有重要的区别。因此应该优先将关于蜜蜂生物学的大量文献用于发展更严谨的蜂蜜农药暴露机制模型。与效应机制模型结合,暴露机制模型具有整合蜜蜂毒理学领域的潜力,以促进风险评估和基础研究。
精选自Sponsler, D. B. and Johnson, R. M. (2017), Mechanistic modeling of pesticide exposure: The missing keystone of honey bee toxicology. Environmental Toxicology and Chemistry, 36: 871–881. doi: 10.1002/etc.3661
详情请见http://onlinelibrary.wiley.com/doi/10.1002/etc.3661/full
     

目前针对水环境化学品风险评估的方法是正确的么？

我们想要保护水生生态环境,通过测试数以千计的化学物质和成百上千的水生物种之间交互作用,得到成千上万的结果,但仍然不可能考虑到所有物质的混合情况。污染物对野生鱼类的内分泌干扰作用的课题推动了人们对如药物之类的微污染物的研究。尽管我们担心鱼类会因污染而繁殖能力下降,但并没有足够的证据表明鱼类种群处于危险之中。事实上,许多鱼类生物学家认为,在过去的30 - 40年里,鲤科的数量已经在逐步恢复中。目前的风险评估的关键在于其核心假设,也就是实验室观测或者模型预测的结果简单地适用于群体水平,显而易见这个假设是值得质疑的。 我们明白了疏于监测野生动物种群的变化成为了我们的环境保护战略的关键弱点。如果我们不知道水生野生动物物种是在减少或增加,那么我们研究的其他生态毒理行为又有多少价值呢？
精选自Andrew C. Johnson, John P. Sumpter. Are we going about chemicals risk assessment for the aquatic environment the wrong way?. Environmental Toxicology and Chemistry: Volume 35, Issue 7, pages 1609–1616, July 2016. DOI: 10.1002/etc.3441
详情请见http://onlinelibrary.wiley.com/doi/10.1002/etc.3441/full
     

依据(代)生物体对化学品的反应预测对生态系统服务功能的影响

保护生态系统服务功能越来越多地被作为风险评估的目标,但是目前生态风险评估的终点和评估生态系统服务功能受到的潜在影响之间有很大的差距。作者提出了一个框架,将常用的生态毒理学终点与对种群和群落的影响以及生态系统的服务功能联系起来。这个框架建立在机制效应模型的长足进步上,这些模型旨在跨越多种生物组织,并解释各种生物相互作用和反馈。为了说明这一点,作者引入了2个研究案例,它们采用了已完善和已验证的机制效应模型：鱼种群的inSTREAM个体模型和AQUATOX生态系统模型。他们还展示了动态能量平衡理论可以为解释组织级毒性提供一种通用货币。他们认为,一个基于机制模型的框架,可以预测化学品暴露对生态系统服务的影响,再结合经济估值,可以为环境管理提供一种有用的方法。作者强调了使用这个框架的潜在好处以及未来工作中需要解决的挑战。
精选自Forbes, V. E., Salice, C. J., Birnir, B., Bruins, R. J.F., Calow, P., Ducrot, V., Galic, N., Garber, K., Harvey, B. C., Jager, H., Kanarek, A., Pastorok, R., Railsback, S. F., Rebarber, R. and Thorbek, P. (2017), A framework for predicting impacts on ecosystem services from (sub)organismal responses to chemicals. Environmental Toxicology and Chemistry, 36: 845–859. doi: 10.1002/etc.3720
详情请见http://onlinelibrary.wiley.com/doi/10.1002/etc.3720/full
     

腐殖酸可降低纳米银的水生生物毒性

本文作者主要研究了腐殖酸对聚乙烯吡咯烷酮包覆的纳米银颗粒(polyvinylpyrrolidone-coated AgNPs)毒性的影响,受试生物涵盖了水生系统不同的营养级别,包括藻类(Raphidocelis subcapitata)、水蚤类(Chydorus sphaericus)以及淡水鱼类(Danio rerio)。结果显示,腐殖酸可降低AgNPs对本研究中所有水生生物的毒性,并具有明显的剂量效应关系。原因为：1）腐殖酸使AgNPs表面带有更多负电荷,这阻碍了AgNPs与藻细胞的接触,使毒性降低;2）腐殖酸抑制了AgNPs中Ag⁺的溶出,而本研究显示自由Ag⁺的毒性高于团聚的纳米银颗粒。
精选自Zhuang Wang, Joris T.K. Quik, Lan Song, Evert-Jan Van Den Brandhof, Marja Wouterse and Willie J.G.M. Peijnenburg. Humic substances alleviate the aquatic toxicity of polyvinylpyrrolidone-coated silver nanoparticles to organisms of different trophic levels. Environmental Toxicology and Chemistry: Volume 34, Issue 6, pages 1239–1245, June 2015. DOI: 10.1002/etc.2936
详情请见http://onlinelibrary.wiley.com/doi/10.1002/etc.2936/full
     

Pflanzenschutz: Neue Gesetze und ihr Nutzen

The debate about the revision of the EU directive 91/414 has often been characterized by unobjective criticism of the existing regulations and of the authorities involved in the regulatory procedure. This made many consumers feel uncertain and left the public with the impression that the current regulatory system for plant protection products in Europe was not safe for consumers and the environment. However, a detailed evaluation of these statements has clearly demonstrated that the current regulatory procedure is safe and recent scientific knowledge is taken into account. The risk potential calculated for aquatic and terrestrial organisms in Germany has continuously decreased since 1987. The effects and the benefits of the new regulations, which have reached a level of complexity as never before, are discussed in this context. From an industry perspective, clear legal regulations and practical implementations are essential to guarantee the transparence of the regulatory process and predictability of the outcome.     

HPLC-MS/MS in der Rückstandsanalytik von Pflanzenschutzmitteln

Goal and Scope

Increasing demands from the regulatory authorities of plant protection products for residue analytical methods on the one hand and the need for cost reduction by shorter development times on the other hand have led to a significant displacement of conventional methods (e.g. HPLC-UV or GC-MS) by HPLC-MS/MS with atmospheric pressure ionization (API) in residue analysis since the mid of the 1990s. This development started in the pharmaceutical industries where HPLC-MS/MS had already been used for the quantitation of drugs and their metabolites in plasma since the late 1980s.

Methods

The reason for the high acceptability of HPLC-MS/MS with electrospray ionisation (ESI) or chemical ionization at atmosheric pressure (APCI) compared with alternative methods are shown with respect to analytical quality parameters, compliance with international registration guidelines and economic reasons.

Results and Conclusion

HPLC-MS/MS is being applied for solving ca. 75% of all analytical problems occuring in modern residue analytical laboratories. This technique offers convincing advantages for the determination of plant protection products and their metabolites in various matrices. These are a reduced number of or no clean-up steps after extraction of the samples, high throughput besides high ruggedness, low limits of detection and a large linear measuring range. In addition, several analytes of various chemical classes can be determined within one chromatographic run. Due to the high selectivity there is only little need for additional confirmatory methods. For enforcement purposes HPLC-MS/MS is accepted by the European authorities since 2002. However, due to high costs for instrumentation and specially skilled personnel only few enforcement laboratories have invested into this technology, so far.

Recommendation and Perspective

The importance of HPLC-MS/MS in residue analysis will further increase, as new ionization techniques will enable the analysis of more analytes and as the investment costs will decrease in the future. However, proven conventional methods will still survive in some cases. New concepts, such as parallel HPLC-MS/MS or on-line purification of extracts by column switching which are already widely used in the pharmaceutical industry could help to further increase the throughput. However, for a sound evaluation with respect to their applicability in residue analysis there is so far too little experience.     

„Kochsalz verbieten?“ – ein nachdenkliches Vorwort zur Beitragsserie Regulatorische Ökotoxikologie

This series of articles titled “Regulatory Ecotoxicology” is intended to (i) elucidate the legal background, general principles and instruments of ecotoxicological risk assessment of chemicals, (ii) exemplify the thinking and functioning of regulatory decision making, (iii) illustrate the consulting and decision making processes in risk assessment of chemicals, (iv) communicate different positions on controversial regulatory topics and (v) highlight recent trends in regulatory ecotoxicology. Both discussion papers and scientific articles are contributed by authors representing all stakeholders involved (administrative bodies, industry, academia, environmental associations). The issues addressed cover all relevant substance groups, methods and regulatory instruments (biocides, plant protection products, pharmaceuticals, wastewater treatment, REACH, Water Framework Directive).     

Considerations of temperature in the context of the persistence classification in the EU

Simulation degradation studies for industrial chemicals, biocidal products and plant protection products are required in the EU to estimate half-lives in soil, water and sediment for the comparison to persistence criteria for hazard (P/vP) assessment, and for use in exposure assessments. There is a discrepancy between European regulatory approaches regarding the temperature at which degradation half-lives should be (1) measured in simulation degradation testing of environmental compartments, and (2) compared to the P/vP criteria. In this paper, an opinion is provided on the options for the experimental temperature and extrapolation to other conditions. A review of the historical development of persistence criteria did not give conclusive evidence of the temperature at which the half-lives that underpin the P-criteria were measured, but room temperature is likely. Half-lives measured at 20 °C are in line with the intentions of some international agreements, but in the EU there is a continued political debate regarding the relevant temperature for comparison with persistence criteria. Measuring degradation at 20 °C has the advantage that metabolites/transformation products can be identified with greater accuracy, and that kinetic fits to determine half-lives for parent compounds and metabolites carry less uncertainty. Extrapolation of half-lives to lower temperatures is possible for assessing environmental exposure, but the uncertainty of the persistence classification is smaller when measured half-lives are used for direct comparison with P/vP criteria, without extrapolation. Model simulations demonstrate the pattern of concentrations that can be expected for realistic worst case climate scenarios in the EU based on the half-life of 120 days in soil at 20 °C and of 40 days in water at 20 °C, and their temporal and spatial variability.     

Reply to the EFSA (2016) on the relevance of recent publications (Hofmann et al. 2014, 2016) on environmental risk assessment and management of Bt-maize events (MON810, Bt11 and 1507)

In this commentary, we respond to a report of the EFSA GMO Panel (EFSA EFSA Supp Publ, 1) that criticises the outcomes of two studies published in this journal (Hofmann et al. Environ Sci Eur 26: 24, 2; Environ Sci Eur 28: 14, 3). Both publications relate to the environmental risk assessment and management of Bt-maize, including maize events MON810, Bt11 and maize 1507. The results of Hofmann et al. (Environ Sci Eur 26: 24, 2), using standardised pollen mass filter deposition measurements, indicated that the EFSA Panel model had underestimated pollen deposition and, hence, exposure of non-target organisms to Bt-maize pollen. The results implied a need for safety buffer distances in the kilometre range for protected nature reserve areas instead of the 20–30 m range recommended by the EFSA Panel. As a result, the EFSA Panel revised their model (EFSA EFSA J 13: 4127, 4), adopting the slope of the empirical data from Hofmann et al. The intercept, however, was substantially reduced to less than 1% at one point by introducing further assumptions based on the estimates of mainly panel members, citing possible ‘uncertainty’. Hofmann et al. (Environ Sci Eur 28: 14, 3) published extensive empirical data regarding pollen deposition on leaves. These results were part of a larger 3-year study involving detailed measurements of pollen release, dispersal and deposition over the maize flowering period. The data collected in situ confirmed the previous predictions of Hofmann et al. (Environ Sci Eur 26: 24, 2). Mean levels and observed variability of pollen deposition on maize and four lepidopteran host plants exceeded the assumptions and disagreed with the conclusions of the EFSA Panel. The EFSA Panel reacted in a report (EFSA EFSA Supp Publ, 1) criticising the methods and outcomes of the two published studies of Hofmann et al. while reaffirming their original recommendations. We respond here point-by-point, showing that the critique is not justified. Based on our results on Urtica leaf pollen density, we confirm the need for specific environmental impact assessments for Bt-maize cultivation with respect to protected habitats within isolation buffer distances in the kilometre range.     

农药混配制剂环境风险评估现状与展望

本文综述了欧洲和美国农药混配制剂的环境风险评估方法。详细介绍了欧洲食品安全局(EFSA)评估体系中的2种方法,即,基础的"整体测试法"和近年来提倡的"基于组分的方法"。"基于组分的方法"的特点是以浓度加和模型(CA模型)作为默认假设进行初级评估,以独立作用模型(IA模型)等作为高级评估手段的农药混配制剂环境风险评估方法。此外,本文还介绍了模型偏差率(MDR)、毒性相似度及毒力单元(TU)等概念以及混配制剂风险评估流程。本文的目的旨在为建立我国农药混配制剂的环境风险评估方法体系提供参考。     

The Monitoring of UK Sewage Sludge Disposal Sites

In recent years there has been an increase in the intensity and frequency of environmental monitoring surveys at UK sewage sludge disposal sites. These have been carried out by the regulatory authorities and by the licensees. in order to ensure maximum efficiency, a coordinated and harmonised programme of monitoring has been developed. the programme concentrates on sediment chemical and biological quality but also includes assessments of water and fish quality

In England and Wales the Ministry of Agriculture, Fisheries and Food is the regulatory authority and the Water Authorities are the licensees. the Ministry's first priority is the collection of samples for temporal trend analysis but in addition, infrequent surveys are made to check the status of the disposal site and surrounding areas. in the periods between status surveys, regular spatial surveys designed to define the area of impact are carried out by the Water Authorities.     

Coastal protected area management and multi-tiered governance: the Cape Cod Model

Policy tools that allow for the coordination of various authorities at different levels of government are important for coastal protected areas. Frequently, multiple authorities manage these areas with varied and sometimes conflicting goals. This study examines a regulatory model implemented on the Cape Cod National Seashore in the US that uses federally-approved zoning to regulate private uses for protection of natural coastal resources. Local authorities implement the zoning which is designed to support national resource protection goals making this a prime model of cross-level governance for conservation. I use case study analysis to evaluate the program’s effectiveness by focusing on implementation and compliance in the context of multi-jurisdictional (i.e., national to local) relations. The analysis and subsequent discussion highlight the difficulties associated with implementation of intergovernmental mandates. Also, theoretical perspectives on compliance give insights about the implementation challenges of this model. The model’s limitations have implications for policymakers considering similar schemes implemented by split and hierarchical authorities with different, and possibly conflicting, coastal management goals.

Planspiel zur neuen EU-Chemikalienpolitik (REACH) in NRW

Aim and Background

In 1999, under German Presidency, the European Council asked the European Commission to set up an approach with new instruments for a new European strategy on chemicals management. In 2001, the Commission subsequently published a White Paper called ‘Strategy for a future European chemicals policy’. After intensive discussions with all involved parties, a proposal for a new Regulation, called REACH, was brought in to Council and Parliament (co-decision procedure) in October 2003. Different impact assessments concerning the strategy of the White Paper presumed dramatically increasing costs for the chemical industry. Due to these discussions, the Government of North Rhine-Westphalia decided to conduct a pilot project on workability of the new requirements in the second half of 2003. The parties involved were administrations, producers, industrial associations, unions and NGOs. The focus was not to test the entire Regulation, but to analyse the practicability of selected processes, evaluations, and communication processes connected with the registration of substances.

Results

Examining the requirements and processes with regard to their realization in practice, resulted in a list of well-founded proposals. These proposals concern modification in the Regulation itself, implementation tools required, and guidelines which will need to be available before the REACH system is launched. The pivot questions of the pilot testing were the acceptance of data of substance-effects and their evaluation in different application areas. The registration Agency (played by the German Competent Authorities) checked the presented documents concerning completeness and plausibility. For all presented papers inquiries were needed In summary, the simulation has provided concrete evidence of where and why REACH may cause problems. Lack of simple instruments and corresponding knowledge for conducting exposition scenarios were noticed. The simulation process facilitated a new communication of all parties along the supply chain. In addition, the development of new networks could be observed to ease co-operation between authorities and those active on the market. These networks continue to exist even after cessation of the pilot trial.