Stochastic Pharmacokinetic-Pharmacodynamic Modeling for Assessing the Systemic Health Risk of Perfluorooctanoate (PFOA)

Matteo Convertino, Timothy R. Church (Lead / Corresponding author), Geary W. Olsen, Yang Liu, Eddie Doyle, Clifford R. Elcombe, Anna L. Barnett, Leslie M. Samuel, Iain R. MacPherson, Thomas R. J. Evans

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Abstract

A phase 1 dose-escalation trial assessed the chemotherapeutic potential of ammonium perfluorooctanoate (APFO). Forty-nine primarily solid-tumor cancer patients who failed standard therapy received weekly APFO doses (50mg-1200mg) for six-weeks. Clinical chemistries and plasma PFOA (anionic APFO) were measured pre-dose and weekly thereafter. Several clinical measures including total cholesterol, high-density lipoproteins (HDL), thyroid stimulating hormone (TSH), and free thyroxine (fT4), relative to PFOA concentrations, were examined by: standard statistical analyses using general estimating equations (GEE) and a probabilistic analysis using probability distribution functions (pdf) at various PFOA concentrations; and a two-compartment pharmacokinetic/pharmacodynamic (PK/PD) model to directly estimate mean changes. Based on the GEE, the average rates of change in total cholesterol and fT4 associated with increasing PFOA were approximately -1.2x10-3mmol/L/μM and 2.8x10-3pmol/L/μM, respectively. The PK/PD model predicted more closely the trends observed in the data as well as the pdfs of biomarkers. A decline in total cholesterol was observed, with a clear transition in shape and range of the pdfs, manifested by the maximum value of the Kullback-Leibler (KL) divergence, that occurred at plasma PFOA between 420 and 565 μM (175,000-230,000 ng/mL). HDL was unchanged. An increase in fT4 was observed at a higher PFOA transition point, albeit TSH was unchanged. Our findings are consistent with some animal models and may motivate re-examination of the epidemiological studies to PFOA at levels several orders of magnitude lower than this study. These observational studies have reported contrary associations, but currently understood biology does not support the existence of such conflicting effects.

Original languageEnglish
Pages (from-to)293-306
Number of pages14
JournalToxicological Sciences
Volume163
Issue number1
Early online date16 Feb 2018
DOIs
Publication statusPublished - 1 May 2018

Keywords

  • APFO
  • Cholesterol
  • PFOA
  • PK/PD modeling
  • Phase 1 trial
  • Thyroid

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    Convertino, M., Church, T. R., Olsen, G. W., Liu, Y., Doyle, E., Elcombe, C. R., Barnett, A. L., Samuel, L. M., MacPherson, I. R., & Evans, T. R. J. (2018). Stochastic Pharmacokinetic-Pharmacodynamic Modeling for Assessing the Systemic Health Risk of Perfluorooctanoate (PFOA). Toxicological Sciences, 163(1), 293-306. https://doi.org/10.1093/toxsci/kfy035