Per- and polyfluoroalkyl substances (PFAS or 'Forever Chemicals') are an environmental and food-borne burden worldwide. PFAS is a significant environmental and food contaminant. Of the 100’s of PFAS, there are two that have been studied in greater detail, perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), with current evidence linking PFOA as a possible endocrine disruptor and carcinogen. On the other hand, PFOS has been linked to reproductive dysfunction, affecting fertility. One question is whether these agents are cancer initiators or promotors. KRAS-related mutations have been associated with multiple forms of cancer. Linking KRAS-related mutations with exposure to PFAS as carcinogenic suggests that the pre-existing mutation may predispose individuals to increased cancer risk. The NCI has classified these agents as potential carcinogens. Current evidence has established an increased risk for cancer of the testes, kidneys, and thyroid with elevated PFOA exposure. The IARC has listed PFOA as a Group 1 ‘Carcinogenic’ agent. The Group 1 categorization is based on “sufficient evidence for cancer in experimental animals and strong mechanistic evidence (for epigenetic alterations and immunosuppression) in exposed humans.” The IARC has listed PFOS as a Group 2B, or “possibly carcinogenic to humans.” The Group 2B categorization is based on “strong mechanistic evidence across test systems, including in exposed humans (for epigenetic alterations and immunosuppression, as well as several other key characteristics of carcinogens)." The intent of this Collection, "Impact of “Forever Chemicals” on Cancer Development," is to gather data from different areas to establish a foundation for the role of PFAS in the development of cancer. This evidence would include in vivo, in vitro, and molecular studies of PFAS agents alone and in combination with other environmental pollutants or genetic mutations.

Keywords: PFOA, PFOS, Apoptosis, PFAS, Per-Polyfluoroalkyl substances, carcinogen, metastasis, genetic mutations, cellular metabolism

Traditional toxicity testing by using animal models has served its purpose reasonably well. However, due to many challenges including testing of thousands of previously untested chemical contaminants, mixture aspects as well as changes in the types of chemicals and materials produced, there is a need for improvement of the existing risk assessment paradigm.

Next-Generation Risk Assessment (NGRA) based on New Approach Methodologies (NAMs) is commonly regarded as the way forward. However, incorporating new scientific insights and innovative approaches into hazard assessment in such a way that regulatory needs are adequately met is challenging. This includes difficulties that the biology of a complete mammalian organism has to be covered by a limited number of cellular assays but also regarding standardisation and validation.

The present Collection aims at publishing manuscripts on new approach methods paving the path towards NGRA. This includes original articles as well as reviews, strategical or conceptual papers as well as reports on risk assessments done with NAM or on validation of alternative methods.

Keywords: NAM, NGRA, in vitro methods, in silico methods, risk assessment