Preliminary Modeling to Evaluate the Risk from Inhalation of Per- and Polyfluorinated Alkyl Substances (PFAS)
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While much research has focused on the toxicity from ingestion of per- and polyfluorinated alkyl substances (PFAS), their presence in indoor and outdoor air raises concern about the risks posed by inhalation exposure. To evaluate the feasibility of extrapolating ingestion risk metrics to inhalation, we performed a systematic review to identify studies reporting PFAS inhalation administration with the potential to inform pharmacokinetic modeling. This resulted in the identification of 22 studies with human evidence and 30 studies with animal evidence. We then examined a PFOA inhalation study as a test-case to understand how easily a physiologically based pharmacokinetic (PBPK) model designed for ingestion could be adapted for inhalation. We used the Multipath Particle Dosimetry (MPPD) model to predict an overall deposition fraction of 44% in rats, with 65% of the deposition occurring in the head. Smaller fractions were deposited in the tracheobronchial region (29%) and the alveolar/pulmonary region (5%). With the inhaled dose treated as an ingestion, the PBPK model performed well at the higher doses of 10 mg/m3 and 25 mg/m3, with a predicted:observed average plasma concentration ratio of 1.0 and 1.1 respectively. However, for the lowest dose of 1 mg/m3, the model underpredicted the data substantially, with a predicted:observed average plasma concentration ratio of 0.35. Overall, while the model performance was better than expected, further model development is needed to capture the nonlinear kinetics displayed in the observed inhalation data.