Commentary: Understanding IARC's PFOA and PFOS carcinogenicity assessments

In November 2023, the International Agency for Research on Cancer (IARC) classified PFOA as "carcinogenic to humans" (Group 1) and PFOS as "possibly carcinogenic to humans" (Group 2B). We evaluated these classifications, considering the epidemiology, experimental animal, and mechanistic evidence. It is our opinion that the IARC Working Group overstated the available evidence for the carcinogenicity of PFOA and PFOS. Epidemiology studies have shown weak and inconsistent associations across studies. Studies reporting increased incidences of tumors in experimental animals exposed to PFOA or PFOS had statistically significant results that were driven by the presence of benign adenomas. The IARC Working Group used the key characteristics of carcinogens (KCCs, which comprise 10 chemical and/or biological properties of known human carcinogens) approach to upgrade the carcinogenicity classifications for PFOA and PFOS from initially lower classifications that were based on the strength of the epidemiology and experimental animal evidence. However, this is not a robust assessment of mechanistic evidence, as it fails to consider the quality, external validity, and relevance of the evidence. Rather than use the KCCs as a checklist of potential carcinogenic mechanisms, IARC should use a rigorous method to evaluate the plausibility and human relevance of mechanistic evidence.