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 ammonium perfluorooctanoate (APFO). Forty-nine primarily solid-tumor cancer patients who failed standard therapy received weekly APFO doses (50–1200 mg) for 6 weeks. Clinical chemistries and plasma PFOA (anionic APFO) were measured predose and weekly thereafter. Several clinical measures 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 estimate mean 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/μM and 2.8×10−3 pmol/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). 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 animal models and may motivate re-examination of the epidemiologic 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.

Outcome of a public consultation on the draft risk assessment of perfluoroalkyl substances in food

“…An explanation of this has now been added to the opinion. We agree that the study by Convertino et al (2018) has limited relevance in the assessment of causality at much lower exposure. Whilst we welcome the extension of the opinion to species beyond PFOA and PFOS, the scope is nevertheless still extremely narrow given the large number of PFAS on the market.…”

“…The CONTAM Panel agree that the study by Convertino et al (2018) suggests that very high doses of PFOA can lower serum cholesterol. The study is interesting but we note that the 3M company seems to agree on the comment in the Opinion about the study in relation to effects in humans at the much lower PFOA intake levels occurring from normal diet or contaminated drinking water.…”

Internal exposure to perfluoroalkyl substances (PFASs) and biological markers in 101 healthy 1-year-old children: associations between levels of perfluorooctanoic acid (PFOA) and vaccine response

“…Considering a high exposure to PFOA, the contamination of drinking water in West Virginia/USA, which led to a mean internal PFOA exposure in the high two-digit µg/L range (C8 cohort, Frisbee et al 2009) did not reveal evidence of any positive association between PFOA levels during pregnancy and increasing risk for any of the categories of infection reported by the 878 mothers asked about infections in their children in the previous 12 months (C8 Science Panel 2012). Furthermore, it should be noted that in a phase 1 dose-escalation trial assessing the chemotherapeutic potential of ammonium perfluorooctanoate in 49 adult cancer patients (weekly doses of 50 to 1200 mg for 6 weeks, Convertino et al 2018), obviously no breakdown of the immune system occurred despite plasma PFOA level in part above 1000 µM (approximately 420,000 µg/L).…”

PFAS Experts Symposium: Statements on regulatory policy, chemistry and analytics, toxicology, transport/fate, and remediation for per‐ and polyfluoroalkyl substances (PFAS) contamination issues

“…This modeling is a key source of uncertainty in PFAS toxicity assessments, and there is no consensus on the most appropriate method or model to use for interspecies toxicokinetic extrapolation. A recent publication (Convertino et al, ) estimated the human half‐life of PFOA based on direct serum measurements in cancer patients given known doses of PFOA as a potential therapeutic agent. The study is unique in that it evaluated a single PFAS under controlled conditions where the applied dose and urinary elimination were closely tracked.…”

“…This modeling is a key source of uncertainty in PFAS toxicity assessments, and there is no consensus on the most appropriate method or model to use for interspecies toxicokinetic extrapolation. A recent publication (Convertino et al, 2018)…”