Tackling Arctic toxicology challenges using in vitro and in silico approaches to characterize and predict organism-level effects of chemical stressors

全球每年使用数十万种化学品，并生产数以千计的新化学品。其中许多会进入环境，对人类和野生动物造成不利影响。这一点在北极最为明显，在那里，土著社区和海洋哺乳动物等高营养摄食群体可以将化学物质生物放大到令人震惊的水平。《斯德哥尔摩公约》目前管理着35个以持久性、生物蓄积性、远距离迁移和毒性(PBLT)而闻名的化学基团。利用建模方法，最近的研究已经确定了3000多种威胁北极的多溴联苯化合物，称为新出现的北极关切化学品(CEAC)。其中大多数都没有监测，其毒性也是未知的。北极(和其他)毒物学家经常依赖实验室动物毒性数据，尽管这些数据伴随着一系列后勤、资金和道德限制，因为每年有数百万动物被杀害。因此，迫切需要对化学品风险评估进行重大变革。21世纪的毒理学将需要采用体外和电子计算机方法，结合新的技术，如毒素基因组学，以提供不含动物的、快速和经济有效的毒性数据。我的研究计划的长期目标是制定更好的化学品管理战略，并改进北极野生动物化学品风险评估。我将通过采用体外实验、野外野生动物研究和机械性毒物动力学和毒物动力学(TKTD)建模的独特组合来解决目前北极毒理学方面的知识差距和限制。我的短期目标是：1)建立体外毒性测试框架，并评估遗留化学品和CEAC的毒性；2)开发一个机械性的TKTD建模框架，以推断遗留化学品和CEAC的体外影响；以及3)调查遗留化学品和CEAC在北极野生动物中的体外影响。这项研究将建立下一代北极化学品和野生动物风险评估，最大限度地减少动物试验，最大限度地提高对毒性的机械性理解。这项工作填补了北极和国外缺乏CEAC毒性数据的风险评估者和监管者的一个重要知识空白。具体地说，这项研究计划着眼于在加拿大建立使用机械能源预算模型进行化学风险评估的能力。所采取的多学科方法提供了产生新知识的巨大机会，并促进了我们对生物尺度和环境中应激源影响的理解。最后，该计划将支持13名HQP在实验室工作、实地工作、统计分析和计算机建模方面备受欢迎的技能培训。HQP将通过出版物和会议演示，通过他们的研究和参与知识动员，在批判性思维、量化分析、沟通和领导能力方面发展可转移的技能。

Hundreds of thousands of chemicals are used globally and thousands of new ones produced every year. Many of these enter the environment and cause adverse effects in humans and wildlife. Nowhere is this more evident than in the Arctic where high trophic feeding populations like Indigenous communities and marine mammals can biomagnify chemicals to alarming levels. The Stockholm Convention currently regulates 35 chemical groups known for their persistence, bioaccumulation, long-range transport, and toxicity (PBLT). Using modeling approaches, recent studies have identified over 3000 PBLT chemicals that threaten the Arctic, termed Chemicals of Emerging Arctic Concern (CEACs). Most of these are unmonitored and their toxicity is unknown. Arctic (and other) toxicologists often rely on laboratory animal toxicity data, though these come with a slew of logistical, monetary, and ethical constraints as millions of animals are killed yearly. As such, a major transformation in chemical risk assessment is urgently needed. 21st century toxicology will need to adopt in vitro and in silico methods, combined with new technologies like toxicogenomics, to provide animal-free, rapid, and cost-effective toxicity data. The long-term objective of my research program is to develop strategies for better chemical management and improve wildlife chemical risk assessment in the Arctic. I will address current knowledge gaps and constraints in Arctic toxicology through adoption of a unique combination of in vitro experiments, field-based wildlife studies, and mechanistic toxicokinetic and toxicodynamic (TKTD) modeling. My short-term objectives are: 1) Establish an in vitro toxicity testing framework and assess the toxicity of legacy chemicals and CEACs; 2) Develop a mechanistic TKTD modeling framework to extrapolate in vitro effects of legacy chemicals and CEACs; and 3) Investigate the in vitro effects of legacy chemicals and CEACs in Arctic wildlife. This research will establish the next generation of Arctic chemical and wildlife risk assessment that minimizes animal testing and maximizes mechanistic understanding of toxicity. This work fills an important knowledge gap for risk assessors and regulators in the Arctic and abroad that lack toxicity data for CEACs. Specifically, this research program looks to build up capacity in Canada in the use of mechanistic energy budget modeling for chemical risk assessment. The multidisciplinary approach taken offers great opportunities to yield new knowledge and advance our understanding of stressor impacts across biological scales and environments. Finally, this program will support the training of 13 HQP in highly sought-after skillsets in laboratory work, fieldwork, statistical analysis, and computer modeling. HQP will develop transferable skills in critical thinking, quantitative analysis, communication, and leadership through their research and participation in knowledge mobilization through publications and conference presentations.