Per- and polyfluoroalkyl substances (PFAS) constitute a large class of environmentally persistent chemicals used in industrial and consumer products. Human exposure to PFAS is extensive, and PFAS contamination has been reported in drinking water and food supplies as well as in the serum of nearly all people. The most well-studied member of the PFAS class, perfluorooctanoic acid (PFOA), induces tumors in animal bioassays and has been associated with elevated risk of cancer in human populations. GenX, one of the PFOA replacement chemicals, induces tumors in animal bioassays as well. Using the Key Characteristics of Carcinogens framework for cancer hazard identification, we considered the existing epidemiological, toxicological and mechanistic data for 26 different PFAS. We found strong evidence that multiple PFAS induce oxidative stress, are immunosuppressive, and modulate receptor-mediated effects. We also found suggestive evidence indicating that some PFAS can induce epigenetic alterations and influence cell proliferation. Experimental data indicate that PFAS are not genotoxic and generally do not undergo metabolic activation. Data are currently insufficient to assess whether any PFAS promote chronic inflammation, cellular immortalization or alter DNA repair. While more research is needed to address data gaps, evidence exists that several PFAS exhibit one or more of the key characteristics of carcinogens.

Drinking water contamination with per‐ and polyfluoroalkyl substances (PFAS) poses a health risk for communities across the country. The vast majority of the water systems across the United States lack both the technology and the funds to filter out PFAS. Release of PFAS with industrial wastewater from a variety of facilities is a significant contributor to PFAS contamination of drinking water. Here, we provide a screening‐level analysis of the potential for environmental PFAS releases from contaminated sites, active industrial sites, wastewater treatment plants, and waste disposal sites (including active and inactive landfills) nationwide. With specific case studies from the US states of Michigan and California, we examine how testing has identified a large number of diverse PFAS sources. Testing results alongside the list of potential sources can be used to inform state‐ or local‐level investigations as well as aid in the development of effluent guidelines and industrial pretreatment programs.Article Impact Statement: The identification of point sources and establishing per‐ and polyfluoroalkyl substances (PFAS) effluent guidelines can help mitigate the PFAS contamination of drinking water.

Hundreds of different disinfection byproducts form in drinking water following necessary treatment with chlorine and other disinfectants, and many of those byproducts can damage DNA and increase the risk of cancer. This study offers the first side-by-side comparison of cancer risk assessments based on toxicological and epidemiological studies of disinfection byproducts using a comprehensive contaminant occurrence dataset for haloacetic acids and trihalomethanes, two groups of disinfection byproducts that are regulated in drinking water. We also provide the first analysis of a new occurrence dataset for unregulated haloacetic acids that became available from the latest, fourth round of the U.S. EPA-mandated unregulated contaminant monitoring program (UCMR4). A toxicological assessment indicated that haloacetic acids, and in particular brominated haloacetic acids, are more carcinogenic and are associated with a greater number of attributable cancer cases than trihalomethanes. Based on the toxicological analysis, cumulative lifetime cancer risk due to exposure to trihalomethanes and haloacetic acids for community water systems monitored under UCMR4, estimated with standard default parameters for body weight and water intake, corresponds to 7.0 × 10⁻⁵ (3.5 × 10⁻⁵–1.3 × 10⁻⁴). The same analysis conducted with age sensitivity factors to account for elevated risk in infants and children yielded a cumulative risk estimate of 2.9 × 10⁻⁴ (1.7 × 10⁻⁴–6.2 × 10⁻⁴). Epidemiological data suggest that lifetime cancer risk from disinfection byproducts for the U.S. population served by community water systems is approximately 3.0 × 10⁻³ (2.1 × 10⁻⁴–5.7 × 10⁻³), or a lifetime cancer risk of three cases per thousand people. Overall, this analysis highlights the value of using human data in health risk assessments to the greatest extent possible.

The development of high-throughput screening methodologies may decrease the need for laboratory animals for toxicity testing. Here, we investigate the potential of assessing immunotoxicity with high-throughput screening data from the U.S. Environmental Protection Agency ToxCast program. As case studies, we analyzed the most common chemicals added to food as well as per- and polyfluoroalkyl substances (PFAS) shown to migrate to food from packaging materials or processing equipment. The antioxidant preservative tert-butylhydroquinone (TBHQ) showed activity both in ToxCast assays and in classical immunological assays, suggesting that it may affect the immune response in people. From the PFAS group, we identified eight substances that can migrate from food contact materials and have ToxCast data. In epidemiological and toxicological studies, PFAS suppress the immune system and decrease the response to vaccination. However, most PFAS show weak or no activity in immune-related ToxCast assays. This lack of concordance between toxicological and high-throughput data for common PFAS indicates the current limitations of in vitro screening for analyzing immunotoxicity. High-throughput in vitro assays show promise for providing mechanistic data relevant for immune risk assessment. In contrast, the lack of immune-specific activity in the existing high-throughput assays cannot validate the safety of a chemical for the immune system.