Stochastic pharmacokinetic-pharmacodynamic modeling for assessing the systemic health risk of perfluorooctanoate (PFOA)

Matteo Convertino, Timothy R Church, 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 ammoniumperfluorooctanoate (APFO). Forty-nine primarily solid-tumor cancer patients who failed standard therapy received weekly APFO doses (50-1200mg) for 6 weeks. Clinical chemistries and plasma PFOA (anionic APFO) weremeasured predose and weekly thereafter. Several clinicalmeasures including total cholesterol, high-density lipoproteins (HDLs), thyroid stimulating hormone (TSH), and free thyroxine (fT4), relative to PFOA concentrations were examined by: Standard statistical analyses using generalized estimating equations (GEE) and a probabilistic analysis using probability distribution functions (pdf) at various PFOA concentrations; and a 2-compartment pharmacokinetic/pharmacodynamic (PK/PD) model to directly estimatemean changes. Based on the GEE, the average rates of change in total cholesterol and fT4 associated with increasing PFOA were approximately -1.2×10 -3 mmol/l/lMand 2.8×10 -3 pmol/l/lM, respectively. The PK/PDmodel predictedmore 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 565lM (175 000- 230 000 ng/ml). High-density lipoprotein was unchanged. An increase in fT4 was observed at a higher PFOA transition point, albeit TSH was unchanged. Our findings are consistent with some animalmodels and maymotivate re-examination of the epidemiologic studies to PFOA at levels several orders ofmagnitude 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 (US)
Pages (from-to)293-306
Number of pages14
JournalToxicological Sciences
Volume163
Issue number1
DOIs
StatePublished - May 1 2018

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Keywords

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

Cite this

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