Can oral toxicity data for PFAS inform on toxicity via inhalation?

Per- and poly-fluoroalkyl substances (PFAS) are ubiquitous in the environment and are detected in wildlife and humans. With respect to human exposure, studies have shown that ingestion is the primary route of exposure; however, in certain settings, exposure via inhalation could also be a significant source of exposure. While many studies examined toxicity of PFAS via ingestion, limited information is available for PFAS toxicity via the inhalation route, translating into a lack of exposure guidelines. Consequently, this article examined whether route-to-route extrapolation to derive guidelines for inhalation exposure is appropriate for PFAS. Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) were used as exemplary PFAS given the abundance of toxicity data for these two compounds. Our evaluation determined that available toxicity and toxicokinetic data support route-to-route extrapolation for PFAS in order to derive inhalation-based standards. Results from this analysis suggest that an air concentration of 7.0 × 10^-5  mg/m³ (or 0.07 μg/m³ ) would be an appropriate RfC for PFOA and PFOS assuming the 2016 EPA RfD of 0.00002 mg/kg-day, whereas use of the interim RfDs proposed in 2022 of 1.5 × 10^-9 and 7.9 × 10^-9  mg/kg would yield much lower RfCs of 5.25 × 10^-9 and 2.77 × 10^-8  mg/m³ (or 5.25 × 10^-6 and 2.77 × 10^-5 μg/m³ ) for PFOA and PFOS, respectively.