DataSheet8_Beyond AOPs: A Mechanistic Evaluation of NAMs in DART Testing.XLSX

New Approach Methodologies (NAMs) promise to offer a unique opportunity to enable human-relevant safety decisions to be made without the need for animal testing in the context of exposure-driven Next Generation Risk Assessment (NGRA). Protecting human health against the potential effects a chemical may have on embryo-foetal development and/or aspects of reproductive biology using NGRA is particularly challenging. These are not single endpoint or health effects and risk assessments have traditionally relied on data from Developmental and Reproductive Toxicity (DART) tests in animals. There are numerous Adverse Outcome Pathways (AOPs) that can lead to DART, which means defining and developing strict testing strategies for every AOP, to predict apical outcomes, is neither a tenable goal nor a necessity to ensure NAM-based safety assessments are fit-for-purpose. Instead, a pragmatic approach is needed that uses the available knowledge and data to ensure NAM-based exposure-led safety assessments are sufficiently protective. To this end, the mechanistic and biological coverage of existing NAMs for DART were assessed and gaps to be addressed were identified, allowing the development of an approach that relies on generating data relevant to the overall mechanisms involved in human reproduction and embryo-foetal development. Using the knowledge of cellular processes and signalling pathways underlying the key stages in reproduction and development, we have developed a broad outline of endpoints informative of DART. When the existing NAMs were compared against this outline to determine whether they provide comprehensive coverage when integrated in a framework, we found them to generally cover the reproductive and developmental processes underlying the traditionally evaluated apical endpoint studies. The application of this safety assessment framework is illustrated using an exposure-led case study.

新方法学（New Approach Methodologies，NAMs）有望带来独特机遇，可在暴露驱动的下一代风险评估（Next Generation Risk Assessment，NGRA）框架下，无需开展动物试验即可做出符合人类健康相关要求的安全决策。利用NGRA评估化学品对胚胎-胎儿发育及/或生殖生物学相关领域的潜在影响，进而保护人类健康，这一过程尤具挑战性。此类影响并非单一终点或健康效应，传统风险评估历来依赖于动物发育与生殖毒性（Developmental and Reproductive Toxicity，DART）试验所产生的数据。可诱发DART的不良结局途径（Adverse Outcome Pathways，AOPs）数量繁多，这意味着为每一种AOP制定严格的测试策略以预测顶端效应终点，既非可行目标，也并非确保基于NAMs的安全评估符合适用要求的必要条件。反之，我们需要一种务实的研究路径，依托现有知识与数据，确保基于NAMs的暴露导向安全评估具备足够的健康保护效力。为此，我们对现有用于DART评估的NAMs的机制与生物学覆盖范围进行了系统评估，并明确了有待填补的研究空白，由此开发出一种聚焦于生成与人类生殖及胚胎-胎儿发育核心机制相关数据的研究方法。基于对生殖与发育关键阶段所涉及的细胞过程及信号通路的认知，我们梳理出了可用于表征DART的终点的大致框架。当将现有NAMs与该框架进行比对，以判断其在整合为一套体系时是否能实现全面覆盖时，我们发现这些NAMs大体上覆盖了传统顶端终点研究所评估的生殖与发育过程。我们通过一则暴露导向的案例研究，对该安全评估框架的实际应用进行了演示。