Knudsen Thomas B, Fitzpatrick Suzanne Compton, De Abrew K Nadira, Birnbaum Linda S, Chappelle Anne, Daston George P, Dolinoy Dana C, Elder Alison, Euling Susan, Faustman Elaine M, Fedinick Kristi Pullen, Franzosa Jill A, Haggard Derik E, Haws Laurie, Kleinstreuer Nicole C, Buck Louis Germaine M, Mendrick Donna L, Rudel Ruthann, Saili Katerine S, Schug Thaddeus T, Tanguay Robyn L, Turley Alexandra E, Wetmore Barbara A, White Kimberly W, Zurlinden Todd J
U.S. Environmental Protection Agency, ORD, Research Triangle Park, North Carolina, USA.
US Food and Drug Administration, College Park, Maryland, USA.
Toxicol Sci. 2021 Apr 12;180(2):198-211. doi: 10.1093/toxsci/kfab013.
FutureTox IV, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2018. Building upon FutureTox I, II, and III, this conference focused on the latest science and technology for in vitro profiling and in silico modeling as it relates to predictive developmental and reproductive toxicity (DART). Publicly available high-throughput screening data sets are now available for broad in vitro profiling of bioactivities across large inventories of chemicals. Coupling this vast amount of mechanistic data with a deeper understanding of molecular embryology and post-natal development lays the groundwork for using new approach methodologies (NAMs) to evaluate chemical toxicity, drug efficacy, and safety assessment for embryo-fetal development. NAM is a term recently adopted in reference to any technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment to avoid the use of intact animals (U.S. Environmental Protection Agency [EPA], Strategic plan to promote the development and implementation of alternative test methods within the tsca program, 2018, https://www.epa.gov/sites/production/files/2018-06/documents/epa_alt_strat_plan_6-20-18_clean_final.pdf). There are challenges to implementing NAMs to evaluate chemicals for developmental toxicity compared with adult toxicity. This forum article reviews the 2018 workshop activities, highlighting challenges and opportunities for applying NAMs for adverse pregnancy outcomes (eg, preterm labor, malformations, low birth weight) as well as disorders manifesting postnatally (eg, neurodevelopmental impairment, breast cancer, cardiovascular disease, fertility). DART is an important concern for different regulatory statutes and test guidelines. Leveraging advancements in such approaches and the accompanying efficiencies to detecting potential hazards to human development are the unifying concepts toward implementing NAMs in DART testing. Although use of NAMs for higher level regulatory decision making is still on the horizon, the conference highlighted novel testing platforms and computational models that cover multiple levels of biological organization, with the unique temporal dynamics of embryonic development, and novel approaches for estimating toxicokinetic parameters essential in supporting in vitro to in vivo extrapolation.
“未来毒理学IV”是毒理学学会举办的一场当代毒理学概念研讨会，于2018年11月召开。该会议以“未来毒理学I”“未来毒理学II”和“未来毒理学III”为基础，聚焦于与预测发育和生殖毒性（DART）相关的体外分析和计算机模拟建模的最新科学技术。现在已有公开的高通量筛选数据集，可用于对大量化学品库存进行广泛的生物活性体外分析。将大量的机制数据与对分子胚胎学和出生后发育的更深入理解相结合，为使用新方法学（NAMs）评估化学毒性、药物疗效以及胚胎 - 胎儿发育的安全性评估奠定了基础。NAM是最近采用的一个术语，指可用于提供化学危害和风险评估信息以避免使用完整动物的任何技术、方法、途径或其组合（美国环境保护局[EPA]，《促进有毒物质控制法案（TSCA）计划内替代测试方法的开发和实施的战略计划》，2018年，https://www.epa.gov/sites/production/files/2018-06/documents/epa_alt_strat_plan_6-20-18_clean_final.pdf）。与评估成年毒性相比，实施NAMs来评估化学品的发育毒性存在挑战。这篇论坛文章回顾了2018年研讨会的活动，强调了应用NAMs评估不良妊娠结局（如早产、畸形、低出生体重）以及出生后出现的疾病（如神经发育障碍、乳腺癌、心血管疾病、生育能力）的挑战和机遇。DART是不同监管法规和测试指南关注的重要问题。利用这些方法的进展以及随之而来的检测对人类发育潜在危害的效率，是在DART测试中实施NAMs的统一理念。尽管将NAMs用于更高层次的监管决策仍有待时日，但该会议突出了涵盖生物组织多个层次、具有胚胎发育独特时间动态的新型测试平台和计算模型，以及用于估计支持体外到体内外推所需毒代动力学参数的新方法。
