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Abstract：
The Toxic Substances Control Act (TSCA) became law in the U.S. in 1976 and was amended in 2016. The amended law requires the U.S. EPA to perform risk-based evaluations of existing chemicals. Here, we developed a tiered approach to screen potential candidates based on their genotoxicity and carcinogenicity information to inform the selection of candidate chemicals for prioritization under TSCA. The approach was underpinned by a large database of carcinogenicity and genotoxicity information that had been compiled from various public sources. Carcinogenicity data included weight-of-evidence human carcinogenicity evaluations and animal cancer data. Genotoxicity data included bacterial gene mutation data from the Salmonella (Ames) and Escherichia coli WP2 assays and chromosomal mutation (clastogenicity) data. Additionally, Ames and clastogenicity outcomes were predicted using the alert schemes within the OECD QSAR Toolbox and the Toxicity Estimation Software Tool (TEST). The evaluation workflows for carcinogenicity and genotoxicity were developed along with associated scoring schemes to make an overall outcome determination. For this case study, two sets of chemicals, the TSCA Active Inventory non-confidential portion list available on the EPA CompTox Chemicals Dashboard (33,364 chemicals, \'TSCA Active List\') and a representative proof-of-concept (POC) set of 238 chemicals were profiled through the two workflows to make determinations of carcinogenicity and genotoxicity potential. Of the 33,364 substances on the \'TSCA Active List\', overall calls could be made for 20,371 substances. Here 46.67%% (9507) of substances were non-genotoxic, 0.5% (103) were scored as inconclusive, 43.93% (8949) were predicted genotoxic and 8.9% (1812) were genotoxic. Overall calls for genotoxicity could be made for 225 of the 238 POC chemicals. Of these, 40.44% (91) were non-genotoxic, 2.67% (6) were inconclusive, 6.22% (14) were predicted genotoxic, and 50.67% (114) genotoxic. The approach shows promise as a means to identify potential candidates for prioritization from a genotoxicity and carcinogenicity perspective.
摘要：
《有毒物质控制法》（TSCA）于1976年在美国成为法律，并于2016年进行了修订。修订后的法律要求美国环保署对现有化学品进行基于风险的评估。这里,我们开发了一种分层方法,根据潜在的候选药物的遗传毒性和致癌性信息筛选其候选药物,以便为选择TSCA下的优先次序提供信息.该方法得到了从各种公共来源汇编的大型致癌性和遗传毒性信息数据库的支持。致癌性数据包括证据重量人类致癌性评估和动物癌症数据。遗传毒性数据包括来自沙门氏菌(Ames)和大肠杆菌WP2测定的细菌基因突变数据和染色体突变(致残性)数据。此外,使用OECDQSAR工具箱和毒性估计软件工具（TEST）中的警报计划来预测Ames和Clasticgeneric结果。制定了致癌性和遗传毒性的评估工作流程以及相关的评分方案，以确定总体结果。对于这个案例研究，两套化学品,EPACompTox化学品仪表板上提供的TSCA有效库存非机密部分列表(33,364种化学品，“TSCA主动列表”）和238种具有代表性的概念验证（POC）集通过两个工作流程进行了分析，以确定致癌性和遗传毒性潜力。在“TSCA有效清单”上的33,364种物质中，总共可以调用20,371种物质。其中46.67%（9507）的物质是非基因毒性的，0.5%(103)被认为是不确定的，43.93％（8949）是预测的遗传毒性，8.9％（1812）是遗传毒性。可以对238种POC化学品中的225种进行遗传毒性的总体呼吁。其中,40.44%（91）是非基因毒性的，2.67%(6)没有定论，6.22%(14)是预测的基因毒性，50.67%（114）的遗传毒性。该方法显示出有望从遗传毒性和致癌性角度确定优先次序的潜在候选者。
