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

doi:10.1093/toxsci/kfy035

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

Environmental Health Sciences

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

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 language	English (US)
Pages (from-to)	293-306
Number of pages	14
Journal	Toxicological Sciences
Volume	163
Issue number	1
DOIs	https://doi.org/10.1093/toxsci/kfy035
State	Published - May 1 2018

Bibliographical note

Funding Information:
This work was supported by the sponsor of this phase 1 clinical trial, CXR Biosciences (Dundee, UK). 3 M Company (St Paul, Minnesota) licensed a part of the database from CXR Biosciences for the purpose of the analyses presented herein.

Funding Information:
M.C. acknowledges the MNDrive funding at the University of Minnesota. M.C.’s current address is Complexity Group, Division of Frontier Science, Graduate School of Information Science and Technology, GI-CoRE Station for Big Data and Cybersecurity, Hokkaido University, Sapporo, Japan; Y.L. acknowledges the Bird Fellowship from the Sigma Xi Scientific Society at the University of Minnesota. The authors acknowledge the contributions of Drs. Donald Bissett (Aberdeen Royal Infirmary) and Sue Chang and John Butenhoff (3M), to this study. As of 1st March, 2017 CXR Biosciences’ trading name changed to Concept Life Sciences, to reflect group ownership. The Concept Life Sciences group comprises: Peakdale Molecular, CXR Biosciences, Agenda1, Scientific Analysis Laboratories and REC. The study authors are grateful to the study teams at the participating centers for their support of this phase 1 study in patients with advanced cancer. The Glasgow study team is supported by the Glasgow ECMC (Experimental Cancer Medicine Centre) which is funded by Cancer Research UK and the Chief Scientist’s Office, Scotland.

Funding Information:
Matteo Convertino and Timothy Church, from the University of Minnesota, are recipients of research grants from the 3M Company. Geary Olsen is an employee of 3M Company, a former manufacturer of PFOA. Eddie Doyle and Clifford Elcombe were employees of CXR Biosciences. Drs Leslie Samuel, Iain MacPherson, and Thomas Jeffrey Evans are physicians who conducted this phase 1 clinical trial that was sponsored by CXR Biosciences. Anna Barnett was the study director for CXR Biosciences for this phase 1 clinical trial study. Yang Liu has no competing interest.

Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.

Keywords

APFO
Cholesterol
PFOA
PK/PD modeling
Phase 1 trial
Thyroid

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/toxsci/kfy035

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920327

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

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.",

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author = "Matteo Convertino and Church, {Timothy R} and Olsen, {Geary W.} and Yang Liu and Eddie Doyle and Elcombe, {Clifford R.} and Barnett, {Anna L.} and Samuel, {Leslie M.} and MacPherson, {Iain R.} and Evans, {Thomas R.J.}",

note = "Funding Information: This work was supported by the sponsor of this phase 1 clinical trial, CXR Biosciences (Dundee, UK). 3 M Company (St Paul, Minnesota) licensed a part of the database from CXR Biosciences for the purpose of the analyses presented herein. Funding Information: M.C. acknowledges the MNDrive funding at the University of Minnesota. M.C.{\textquoteright}s current address is Complexity Group, Division of Frontier Science, Graduate School of Information Science and Technology, GI-CoRE Station for Big Data and Cybersecurity, Hokkaido University, Sapporo, Japan; Y.L. acknowledges the Bird Fellowship from the Sigma Xi Scientific Society at the University of Minnesota. The authors acknowledge the contributions of Drs. Donald Bissett (Aberdeen Royal Infirmary) and Sue Chang and John Butenhoff (3M), to this study. As of 1st March, 2017 CXR Biosciences{\textquoteright} trading name changed to Concept Life Sciences, to reflect group ownership. The Concept Life Sciences group comprises: Peakdale Molecular, CXR Biosciences, Agenda1, Scientific Analysis Laboratories and REC. The study authors are grateful to the study teams at the participating centers for their support of this phase 1 study in patients with advanced cancer. The Glasgow study team is supported by the Glasgow ECMC (Experimental Cancer Medicine Centre) which is funded by Cancer Research UK and the Chief Scientist{\textquoteright}s Office, Scotland. Funding Information: Matteo Convertino and Timothy Church, from the University of Minnesota, are recipients of research grants from the 3M Company. Geary Olsen is an employee of 3M Company, a former manufacturer of PFOA. Eddie Doyle and Clifford Elcombe were employees of CXR Biosciences. Drs Leslie Samuel, Iain MacPherson, and Thomas Jeffrey Evans are physicians who conducted this phase 1 clinical trial that was sponsored by CXR Biosciences. Anna Barnett was the study director for CXR Biosciences for this phase 1 clinical trial study. Yang Liu has no competing interest. Publisher Copyright: {\textcopyright} The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.",

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N2 - 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.

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access

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