Exploring Potential Carcinogenic Activity of Per- and Polyfluorinated Alkyl Substances Utilizing High-Throughput Toxicity Screening Data

Abstract

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.

Sublethal Exposure of Per‐ and Polyfluoroalkyl Substances of Varying Chain Length and Polar Functionality Results in Distinct Metabolic Responses in Daphnia magna

“…Higher chain lengths may enhance the toxicity of the pollutants to aquatic invertebrates such as D. magna by increasing the potential for bioaccumulation and biomagnification across trophic levels (Lewis et al, 2022). A previous study observed differences in the metabolic response caused by different polar functional groups (PFCAs vs. PFSAs) present in PFAS (Singh & Hsieh, 2021). Our findings also determined that sublethal exposure to PFAS pollutants of varying chemistries, PFHxA and PFHxS, resulted in differences in the observed perturbations to the extracted polar metabolite profile of D. magna (Figure 1).…”

The use of in vitro methods in assessing human health risks associated with short‐chain perfluoroalkyl and polyfluoroalkyl substances (PFAS)

“…The use of well‐characterized cell lines offers a wide array of possibilities for manipulating experimental variables to obtain a multitude of endpoints in a timely manner. The utility of screening methods employing HTS methods has already been demonstrated for PFAS chemicals (Reardon et al, 2020; Rowan‐Carroll et al, 2021; Singh & Hsieh, 2021). While not inclusive of all assays, endpoints, and cell types, Table 2 provides some examples of approaches that can be and are being used for assessing the human health effects of short‐chain PFAS.…”

“…In human health risk assessments, the weight of evidence narrative for hazard identification often includes qualitative thresholds for the carcinogenic potential of a substance (EPA). Recently, the carcinogenic potential for several PFAS chemicals with sufficient data in ToxCast was explored using the visual analytics software ToxPi (Singh & Hsieh, 2021). Short‐chain alternatives were among the chemicals assessed, and the results demonstrated that, in general, PFAS were found to induce a vast range of biological perturbations associated with carcinogenicity, but structural differences contributed to variability in the results.…”

Overview of Per- and Polyfluoroalkyl Substances (PFAS), Their Applications, Sources, and Potential Impacts on Human Health

“…Among different classes of PFAS, long-chain PFAS are the most potent due to the presence of additional C-F bonds. Those containing sulfonic acid derivatives such as sulfonamide and sulfonate PFAS have also been reported as more toxic compounds in terms of carcinogenicity [116]. Investigations found perfluorohexanoate (PFHxA; another type of PFAS) in 100% of whole blood samples, while it was not found in any of the other blood matrices.…”