Greim Helmut, Arand Michael, Autrup Herman, Bolt Hermann M, Bridges James, Dybing Erik, Glomot Rémi, Foa Vito, Schulte-Hermann Rolf
Institute of Toxicology and Environmental Hygiene, Technical University of Munich, Hohenbachernstrasse 15-17, 85350 Freising-Weihenstephan, Germany.
Arch Toxicol. 2006 Mar;80(3):121-4. doi: 10.1007/s00204-005-0039-z. Epub 2006 Jan 13.
It is the ultimate goal of the intended REACH process (Registration, Evaluation and Authorization of Chemicals) of the European Union to identify substances of hazardous properties and to evaluate the risks of human and environmental exposure. During the last few months there has been a controversial discussion as to what extent in vitro studies and consideration of structure activity relationship provide sufficient information to waive repeated exposure studies. Industry as well as certain regulatory agencies or NGOs support this approach and propose that repeated dose studies may only be required beyond 100 t/a. From a toxicological point of view it has to be stressed that this discussion primarily considers the cost reduction and protection of animals, whereas protection of human health and the environment are secondary. In vitro studies only allow identification of specific hazardous properties which can be detected by the specific test system. Moreover, appropriate information on the dose response of adverse effects, identification of thresholds and NOELs that are essential for risk characterization cannot be obtained from these studies. Consequently, identification of all relevant hazardous properties and endpoints of adverse effects can only be determined in the intact animal by repeated dose studies such as 28-day or 90-day studies. In the absence of such information the hazard identification is incomplete and there is no basis for appropriate risk assessment of human exposure. Thus, any waiving of repeated dose studies in animals bears the probability of unforeseen effects in case of acute or continuous human exposure. From this the undersigning European Toxicologists conclude: 1. The intention of REACH is to identify hazardous properties in order that a reliable risk assessment can be made and measures taken to deal with chemicals posing a significant risk. 2. The recent debate has centered on ways in which the well established in vivo methods for risk assessment can be bypassed. 3. The evidence that the available alternatives would support such replacement is weak. Progress to improve their value for risk assessment purposes is bound to be slow because the issues are very complex. As a group of European Toxicologists we strongly support the need for more research support in these areas, but we believe that over claims for progress is damaging their development. 4. Under the circumstances only two options are available: to reduce very substantially the estimation of hazard and risk with inevitable adverse consequences for human health and environmental protection, or to continue the existing methods until properly validated new methods are available.
欧盟化学品注册、评估、授权和限制（REACH）程序的最终目标是识别具有危险特性的物质，并评估人类和环境暴露的风险。在过去几个月里，一直存在着一场有争议的讨论，即体外研究和结构活性关系的考量在多大程度上能够提供足够的信息来免除重复暴露研究。行业以及某些监管机构或非政府组织支持这种方法，并提议仅在年产量超过100吨时才可能需要进行重复剂量研究。从毒理学角度必须强调的是，这场讨论主要考虑的是成本降低和动物保护，而人类健康和环境保护则是次要的。体外研究仅能识别特定测试系统所能检测到的特定危险特性。此外，从这些研究中无法获得关于不良反应剂量反应、阈值识别以及无可见有害作用水平（NOELs）等对风险表征至关重要的信息。因此，所有相关危险特性和不良反应终点的识别只能通过如28天或90天的重复剂量研究在完整动物体内确定。在缺乏此类信息的情况下，危险识别是不完整的，并且没有对人类暴露进行适当风险评估的依据。因此，免除动物重复剂量研究在人类急性或持续暴露的情况下存在出现不可预见影响的可能性。据此，签署本声明的欧洲毒理学家得出以下结论：1. REACH的目的是识别危险特性，以便能够进行可靠的风险评估，并采取措施应对构成重大风险的化学品。2. 最近的辩论集中在如何绕过成熟的体内风险评估方法。3. 现有替代方法能够支持这种替代的证据不足。由于问题非常复杂，提高其用于风险评估目的的价值的进展必然缓慢。作为一群欧洲毒理学家，我们强烈支持在这些领域需要更多的研究支持，但我们认为对进展的过度宣称正在损害它们的发展。4. 在这种情况下，只有两种选择：大幅降低对危险和风险的评估，这必然会对人类健康和环境保护产生不利影响；或者继续采用现有方法，直到有经过适当验证的新方法可用。
