Office of Environmental Health Hazard Assessment, 7020California Environmental Protection Agency, Sacramento, CA, USA.
University of California, Davis, CA, USA.
Int J Toxicol. 2021 Jul-Aug;40(4):355-366. doi: 10.1177/10915818211010490. Epub 2021 May 4.
Per- and polyfluorinated alkyl substances (PFAS) are ubiquitous, persistent, and toxic chemicals that pose public health risks. Recent carcinogenicity concerns have arisen based on epidemiological studies, animal tumor findings, and mechanistic data. Thousands of PFAS exist; however, current understanding of their toxicity is informed by studies of a select few, namely, perfluorooctanoic acid and perfluorooctanesulfonic acid. Hence, the computational, high-throughput screening tool, the US EPA CompTox Chemical Dashboard's ToxCast, was utilized to explore the carcinogenicity potential of PFAS. Twenty-three major PFAS that had sufficient in vitro ToxCast data and covered a range of structural subclasses were analyzed with the visual analytics software ToxPi, yielding a qualitative and quantitative assessment of PFAS activity in realms closely linked with carcinogenicity. A comprehensive literature search was also conducted to check the consistency of analyses with other mechanistic data streams. The PFAS were found to induce a vast range of biological perturbations, in line with several of the International Agency for Research on Cancer-defined key carcinogen characteristics. Patterns observed varied by length of fluorine-bonded chains and/or functional group within and between each key characteristic, suggesting some structure-based variability in activity. In general, the major conclusions drawn from the analysis, that is, the most notable activities being modulation of receptor-mediated effects and induction of oxidative stress, were supported by literature findings. The study helps enhance understanding of the mechanistic pathways that underlie the potential carcinogenicity of various PFAS and hence could assist in hazard identification and risk assessment for this emerging and relevant class of environmental toxicants.
全氟和多氟烷基物质 (PFAS) 是普遍存在、持久且有毒的化学物质，对公共健康构成风险。最近，基于流行病学研究、动物肿瘤发现和机制数据，出现了对其致癌性的担忧。存在数千种 PFAS，但目前对其毒性的认识是基于对少数几种物质的研究，即全氟辛酸和全氟辛烷磺酸。因此，利用美国环保署计算、高通量筛选工具——CompTox Chemical Dashboard 的 ToxCast，探索了 PFAS 的致癌潜力。利用可视化分析软件 ToxPi 分析了具有足够体外 ToxCast 数据且涵盖多种结构子类的 23 种主要 PFAS，对与致癌性密切相关的领域中的 PFAS 活性进行了定性和定量评估。还进行了全面的文献搜索，以检查分析与其他机制数据流的一致性。研究发现，PFAS 会引起广泛的生物学扰动，与国际癌症研究机构定义的几个关键致癌特征一致。观察到的模式因氟键链的长度和/或每个关键特征内和之间的功能基团而有所不同，这表明活性存在一些基于结构的可变性。总的来说，分析得出的主要结论，即最显著的活性是调节受体介导的效应和诱导氧化应激，得到了文献发现的支持。该研究有助于增强对潜在致癌性的各种 PFAS 的潜在致癌机制途径的理解，从而有助于识别危害和评估此类新兴和相关类别的环境毒物的风险。
