Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, North Carolina 27709, United States.
Sciome, Durham, North Carolina 27709, United States.
Chem Res Toxicol. 2021 Feb 15;34(2):268-285. doi: 10.1021/acs.chemrestox.0c00213. Epub 2020 Oct 16.
Polycyclic aromatic compounds (PACs) are compounds with a minimum of two six-atom aromatic fused rings. PACs arise from incomplete combustion or thermal decomposition of organic matter and are ubiquitous in the environment. Within PACs, carcinogenicity is generally regarded to be the most important public health concern. However, toxicity in other systems (reproductive and developmental toxicity, immunotoxicity) has also been reported. Despite the large number of PACs identified in the environment, research attention to understand exposure and health effects of PACs has focused on a relatively limited subset, namely polycyclic aromatic hydrocarbons (PAHs), the PACs with only carbon and hydrogen atoms. To triage the rest of the vast number of PACs for more resource-intensive testing, we developed a data-driven approach to contextualize hazard characterization of PACs, by leveraging the available data from various data streams (in silico toxicity, in vitro activity, structural fingerprints, and in vivo data availability). The PACs were clustered on the basis of their in silico toxicity profiles containing predictions from 8 different categories (carcinogenicity, cardiotoxicity, developmental toxicity, genotoxicity, hepatotoxicity, neurotoxicity, reproductive toxicity, and urinary toxicity). We found that PACs with the same parent structure (e.g., fluorene) could have diverse in silico toxicity profiles. In contrast, PACs with similar substituted groups (e.g., alkylated-PAHs) or heterocyclics (e.g., N-PACs) with varying ring sizes could have similar in silico toxicity profiles, suggesting that these groups are better candidates for toxicity read-across analysis. The clusters/regions associated with certain in silico toxicity, in vitro activity, and structural fingerprints were identified. We found that genotoxicity/carcinogenicity (in silico toxicity) and xenobiotic homeostasis and stress response (in vitro activity), respectively, dominate the toxicity/activity variation seen in the PACs. The "hot spots" with enriched toxicity/activity in conjunction with availability of in vivo carcinogenicity data revealed regions of either data-poor (hydroxylated-PAHs) or data-rich (unsubstituted, parent PAHs) PACs. These regions offer potential targets for prioritization of further in vivo assessment and for chemical read-across efforts. The analysis results are searchable through an interactive web application (https://ntp.niehs.nih.gov/go/pacs_tableau), allowing for alternative hypothesis generation.
多环芳烃（PACs）是指至少含有两个六元芳香稠合环的化合物。PACs 是有机物质不完全燃烧或热分解产生的，在环境中普遍存在。在 PACs 中，致癌性通常被认为是最重要的公共卫生关注点。然而，其他系统（生殖和发育毒性、免疫毒性）的毒性也有报道。尽管环境中已经鉴定出大量的 PACs，但为了了解 PACs 的暴露和健康影响，研究重点仅集中在相对有限的一组 PACs 上，即多环芳烃（PAHs），即仅含有碳和氢原子的 PACs。为了对大量剩余的 PACs 进行更具资源密集性的测试，我们开发了一种数据驱动的方法，通过利用来自各种数据流（计算毒性、体外活性、结构指纹和体内数据可用性）的现有数据，对 PACs 的危害特征进行背景化处理。根据包含 8 个不同类别（致癌性、心脏毒性、发育毒性、遗传毒性、肝毒性、神经毒性、生殖毒性和尿毒性）预测的计算毒性特征，对 PACs 进行聚类。我们发现，具有相同母体结构（如芴）的 PACs 可能具有不同的计算毒性特征。相比之下，具有相似取代基（如烷基化-PAHs）或具有不同环大小的杂环（如 N-PACs）的 PACs 可能具有相似的计算毒性特征，这表明这些基团更适合进行毒性外推分析。确定了与特定计算毒性、体外活性和结构指纹相关的聚类/区域。我们发现，遗传毒性/致癌性（计算毒性）和外来生物稳态和应激反应（体外活性）分别主导了 PACs 中观察到的毒性/活性变化。与体内致癌性数据一起具有丰富毒性/活性的“热点”揭示了数据贫乏（羟基化-PAHs）或数据丰富（未取代、母体 PAHs）的 PAC 区域。这些区域为进一步体内评估和化学外推工作提供了潜在的优先级目标。分析结果可通过交互式网络应用程序（https://ntp.niehs.nih.gov/go/pacs_tableau）进行搜索，允许生成替代假设。
