Using NAMs to inform mode of action and human relevance in chemical safety assessment: A case-study involving PFAS

抄録

In risk assessment, consideration of a chemical’s mode of action (MOA) reduces uncertainties and informs human relevance. New approach methodologies (NAMs) are valuable tools to investigate the MOA of chemicals and are increasingly being applied in hazard and risk assessment. Recently, in vitro MOA studies were conducted for the short-chain PFAS, HFPO-DA. Like other PFAS, toxicity studies indicate that the liver is the primary target of toxicity in rodents following oral exposure to HFPO-DA. However, considering the structural diversity of PFAS (e.g., carbon chain length, interchain linkages), the MOA may differ between PFAS. Several MOAs have been hypothesized for HFPO-DA-mediated liver effects, including involvement of the peroxisome proliferator-activated receptor α (PPAR α), as well as cytotoxicity. It is widely accepted that PPAR α-activating compounds produce liver lesions that may progress to tumors in rodents via a MOA that is not relevant to humans; therefore, it is important to examine whether HFPO-DA-mediated liver effects in rodents are relevant to humans. In vitro MOA studies compared transcriptomic profiles between HFPO-DA and chemicals with known MOAs in rodent and human hepatocytes. Transcriptomic profiles for HFPO-DA demonstrate greatest concordance with the PPAR α activator GW7647, and a lack of concordance with known activators of PPAR γ and cytotoxicity. These in vitro data provide important information concerning the MOA and human relevance of HFPO-DA-mediated liver effects in rodents and highlight the utility of NAMs in risk assessment.