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

全球使用数十万种化学品，每年生产数千种新化学品。其中许多进入环境并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人群可以将化学物质生物放大到惊人的水平。《斯德哥尔摩公约》目前规定了35种已知具有持久性、生物蓄积性、远距离转运和毒性（PBLT）的化学基团。利用建模方法，最近的研究已经确定了超过3000种威胁北极的PBLT化学品，称为新兴北极关注化学品（CEACs）。其中大多数都没有受到监测，其毒性也不得而知。北极（和其他地区）的毒理学家通常依赖于实验室动物的毒性数据，尽管由于每年有数百万动物被杀害，这些数据受到大量后勤、金钱和道德方面的限制。因此，迫切需要在化学品风险评估方面进行重大改革。21世纪的毒理学将需要采用体外和计算机方法，结合毒物基因组学等新技术，以提供无动物、快速和具有成本效益的毒性数据。我的研究计划的长期目标是制定更好的化学品管理战略和改善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毒性动力学和毒性动力学（TKTD）建模的独特组合来解决北极毒理学目前的知识差距和限制。我的短期目标是：1)建立体外毒性测试框架，评估遗留化学品和CEACs的毒性；2)建立一个机制的TKTD模型框架，以推断遗留化学品和CEACs的体外效应；3)研究遗留化学物质和CEACs在北极野生动物体内的体外效应。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制理解。这项工作填补了北极和国外缺乏CEACs毒性数据的风险评估人员和监管机构的重要知识空白。具体来说，这个研究项目希望在加拿大建立使用机械能量预算模型进行化学品风险评估的能力。所采取的多学科方法为产生新知识和推进我们对压力源在生物尺度和环境中的影响的理解提供了巨大的机会。最后，该项目将为13名HQP提供实验室工作、实地工作、统计分析和计算机建模等急需技能的培训。HQP将通过他们的研究和通过出版物和会议发言参与知识动员，发展批判性思维、定量分析、沟通和领导方面的可转移技能。

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.