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Estimating Safe Doses of Perfluorooctane Sulfonate (PFOS): An International Collaboration

Authors: Michael L. Dourson, Laura C. Green, Edmund A. C. Crouch, Harvey J. Clewell, Thomas Colnot, Tony Cox, Wolfgang Dekant, Linda D. Dell, James A. Deyo, Bernard K. Gadagbui, Helmut Greim, Mahesh Rachamalla Gupta, Tamara House-Knight, Ashish Jachak, Vijayavel Kannappan, Travis R. Kline, Therese Manning, Ravi Naidu, Paul Nathanail, Chijioke Onyema, Frank Pagone, Andrew Pawlisz, Tiago Severo Peixe, Katie Richardson, Anurag Sharma, James S. Smith, Nitin Verma, Andrea Wojtyniak, Jackie Wright.

Abstract: The article addresses the wide variability in estimated safe doses (reference doses, RfDs) for PFOS, a persistent and bioaccumulative chemical, ranging from 0.1 ng/kg-day (USEPA, 2024) to 60 ng/kg-day (Health Canada, 2018), with some agencies setting it at zero due to potential carcinogenicity. An international collaboration of 24 scientists from nine countries, organized by the Alliance for Risk Assessment (ARA), reviewed toxicologic and epidemiologic data to narrow this range. Epidemiologic studies were deemed unreliable for dose assessment, while animal bioassays provided usable points of departure (PODs) based on serum concentrations. After applying uncertainty factors, the teams derived a safe dose range of 20–100 ng PFOS/kg body weight/day, contrasting sharply with more precautionary estimates like USEPA's 0.1 ng/kg-day.

Introduction: PFOS, a fully fluorinated analog of octanoic acid, bioaccumulates in organisms by binding to proteins and cannot be metabolized. High exposures cause adverse effects in lab animals (e.g., hepatic issues, developmental delays), but human health impacts from low-level exposures remain uncertain. Expert groups' safe dose estimates vary widely due to differences in key studies, critical effects, PODs (“Points of Departure”), and uncertainty factors. The project aimed to estimate a plausible safe dose range to protect public health with ample safety margins, building on similar work for PFOA.

Methods: The ARA Steering Committee formed an advisory committee from nominations, which invited scientists to create three independent teams. Teams reviewed data, selected key studies for critical effects, evaluated modes of action (MOAs), and extrapolated dose-responses with uncertainty factors. Virtual meetings facilitated sharing and consensus. Epidemiologic studies (e.g., on vaccine response, cholesterol) were rejected due to inconsistencies, observational design, and confounders. Focus shifted to animal studies: a 6-month monkey bioassay (Seacat et al., 2002), a lifetime rat bioassay (Butenhoff et al., 2012), and two-generation rat studies (Lau et al., 2003; Luebker et al., 2005; Thibodeaux et al., 2003).

Human half-life data came from Li et al. (2022) and Zhang et al. (2013). PODs used benchmark dose lower confidence limits (BMDLs) or no-observed-adverse-effect levels (NOAELs) from serum concentrations, focusing on liver weight increases (15–20% benchmark response). Uncertainty factors included interspecies toxicokinetics/dynamics (1–3), intraspecies variability (2.1–3), subchronic-to-chronic extrapolation (1–3), and others (all 1). Human clearance was estimated at 0.13 ml/day-kg based on a 2.88-year half-life.

Results:
Critical effects: Hepatic lipid metabolism alterations and developmental delays in animals; unreliable evidence for human immune effects or other endpoints.

MOAs (“Potential Modes of Action”): PFOS activates nuclear receptors (e.g., PPARα), leading to peroxisome proliferation in rodents (more sensitive than primates/humans). No clear human MOA at environmental levels, but lipid disruption assumed. PODs (“Points of Departure”) (serum-based):

• Monkeys: BMDL 21.1–32.8 μg/mL for liver effects.
• Rats: BMDL/NOAEL 2.76–19.7 μg/mL for hepatotoxicity and developmental toxicity.

Safe dose estimates: 20–100 ng/kg-day across teams, implying safe drinking water levels of 140–700 ng/L (assuming 2 L/day intake and 20% relative source contribution).Key findings: Animal data provide a reliable basis; epidemiologic data do not. The range aligns with some agencies (e.g., WHO at 20 ng/kg-day) but is 200–1,000 times higher than USEPA/EFSA precautionary values.

Discussion: PFOS's persistence and ubiquity warrant caution, but low-level human harms are unproven. Rejection of epidemiology stems from inconsistencies (e.g., EFSA abandoned cholesterol endpoint; vaccine studies critiqued for thresholds). Animal serum-based extrapolation is robust, with monkeys more human-relevant. UFs are conservative yet data-informed. The 20–100 ng/kg-day range contrasts with precautionary approaches but matches several international guidelines.

Strengths: Diverse expertise, consensus on key issues. Limitations: No funding, potential regulatory bias oversight, limited animal endpoints. Future data may refine estimates.

Conclusions: The collaboration estimates a PFOS safe dose range of 20–100 ng/kg body weight/day to protect health with safety margins, based on animal serum PODs. This supports environmental guidelines (e.g., 140–700 ppt in water) and highlights epidemiologic data's inadequacy. Consensus emphasizes hepatic/developmental effects, serum extrapolation, and the need for more human-relevant research.

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EPA – Safe Dose of PFOS – “Overall, the available evidence indicates that PFOS exposure is likely to cause hepatic, immunological, cardiovascular, and developmental effects in humans given sufficient exposure conditions (e.g., at measured levels in humans as low as 0.57 to 5.0 ng/mL and at administered doses in animals as low as 0.0017 to 0.4 mg/kg/day).”.

Added Definition of Terms from The Article (Not AI Generated)

“The term “safe dose” is used throughout to be a dose-rate (of PFOS, in this case) that is estimated to lie just below the population threshold for at which any adverse health effects are expected. In other words, it is a dose-rate set to protect the (presumed) most sensitive subpopulation against harm to their health from PFOS-exposure. The USEPA currently uses the term “reference dose” to connote this safe dose-estimate. All such estimates are derived using some combination of science-based and policy-based formulas. Because of this, complete uniformity across agencies and jurisdictions is not to be expected.

"Critical effect is defined here as the first adverse effect, or its known and immediate precursor, that occurs as dose is increased. It is recognized that multiple effects may be critical (occurring at or around the same dose), and that critical effects in laboratory animals may not reflect these same effects found or expected in humans. Nonetheless, if the critical effect is prevented, then it is assumed that all other adverse effects would be prevented."

The Original Article

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