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

使用体外和计算机方法来表征和预测化学应激源对生物体水平的影响，应对北极毒理学挑战

• 批准号: RGPIN-2022-03901
• 负责人: Desforges, JeanPierre
• 金额: $ 2.11万
• 依托单位: University of Winnipeg
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=753376
• 关键词: Tackling; Arctic; toxicology; challenges; using

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.

全球使用了数十万种化学品，并且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，那里的原住民群落和海洋哺乳动物等高营养性摄食种群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》目前监管 35 种因其持久性、生物蓄积性、远距离迁移和毒性 (PBLT) 而闻名的化学物质。最近的研究利用建模方法确定了超过 3000 种威胁北极的 PBLT 化学品，称为新兴北极关注化学品 (CEAC)。其中大多数不受监控，其毒性未知。北极（和其他）毒理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、金钱和道德限制，因为每年有数百万动物被杀害。因此，化学品风险评估迫切需要进行重大转变。 21 世纪的毒理学需要采用体外和计算机方法，结合毒物基因组学等新技术，以提供非动物、快速且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策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、实地野生动物研究以及机械毒代动力学和毒效动力学 (TKTD) 建模的独特组合来解决北极毒理学当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并评估遗留化学品和CEAC的毒性； 2) 开发机械 TKTD 建模框架，以推断传统化学品和 CEAC 的体外效应； 3) 研究遗留化学品和 CEAC 对北极野生动物的体外影响。这项研究将建立下一代北极化学和野生动物风险评估，最大限度地减少动物测试并最大限度地提高对毒性的机制了解。这项工作填补了北极和国外缺乏 CEAC 毒性数据的风险评估人员和监管机构的重要知识空白。具体来说，该研究计划旨在增强加拿大使用机械能源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增进我们对跨生物尺度和环境的压力源影响的理解提供了绝佳的机会。最后，该计划将支持对 13 名 HQP 进行实验室工作、实地考察、统计分析和计算机建模等备受追捧的技能培训。 HQP 将通过出版物和会议演讲的研究和参与知识动员来培养批判性思维、定量分析、沟通和领导力方面的可转移技能。