Sewell Fiona, Aggarwal Manoj, Bachler Gerald, Broadmeadow Alan, Gellatly Nichola, Moore Emma, Robinson Sally, Rooseboom Martijn, Stevens Alexander, Terry Claire, Burden Natalie
NC3Rs, Gibbs Building, 215 Euston Road, London NW1 2BE, UK.
Dow AgroSciences, 3B Park Square, Milton Park, Abingdon, Oxfordshire OX14 4RN, UK.
Toxicology. 2017 Aug 15;389:109-117. doi: 10.1016/j.tox.2017.07.018. Epub 2017 Aug 1.
For the purposes of chemical safety assessment, the value of using non-animal (in silico and in vitro) approaches and generating mechanistic information on toxic effects is being increasingly recognised. For sectors where in vivo toxicity tests continue to be a regulatory requirement, there has been a parallel focus on how to refine studies (i.e. reduce suffering and improve animal welfare) and increase the value that in vivo data adds to the safety assessment process, as well as where to reduce animal numbers where possible. A key element necessary to ensure the transition towards successfully utilising both non-animal and refined safety testing is the better understanding of chemical exposure. This includes approaches such as measuring chemical concentrations within cell-based assays and during in vivo studies, understanding how predicted human exposures relate to levels tested, and using existing information on human exposures to aid in toxicity study design. Such approaches promise to increase the human relevance of safety assessment, and shift the focus from hazard-driven to risk-driven strategies similar to those used in the pharmaceutical sectors. Human exposure-based safety assessment offers scientific and 3Rs benefits across all sectors marketing chemical or medicinal products. The UK's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) convened an expert working group of scientists across the agrochemical, industrial chemical and pharmaceutical industries plus a contract research organisation (CRO) to discuss the current status of the utilisation of exposure-driven approaches, and the challenges and potential next steps for wider uptake and acceptance. This paper summarises these discussions, highlights the challenges - particularly those identified by industry - and proposes initial steps for moving the field forward.
出于化学安全评估的目的，使用非动物（计算机模拟和体外）方法以及生成有关毒性效应的机制信息的价值正日益得到认可。对于体内毒性试验仍是监管要求的行业，人们同时关注如何优化研究（即减少动物痛苦并改善动物福利）、提高体内数据对安全评估过程的价值，以及在可能的情况下减少动物数量。确保成功过渡到同时利用非动物和优化安全测试的一个关键要素是更好地了解化学物质暴露情况。这包括在基于细胞的试验和体内研究过程中测量化学物质浓度、了解预测的人类暴露与测试水平之间的关系，以及利用现有的人类暴露信息来辅助毒性研究设计等方法。这些方法有望提高安全评估与人类的相关性，并将重点从危害驱动策略转向类似于制药行业所采用的风险驱动策略。基于人类暴露的安全评估为所有销售化学或医药产品的行业带来科学和3R方面的益处。英国国家动物研究替代、优化与减少中心（NC3Rs）召集了一个由农业化学、工业化学和制药行业的科学家以及一家合同研究组织（CRO）组成的专家工作组，讨论暴露驱动方法的应用现状以及更广泛采用和接受这些方法所面临的挑战与潜在的下一步措施。本文总结了这些讨论内容，突出了挑战——尤其是行业所指出的挑战，并提出了推动该领域向前发展的初步措施。
