Notes from the latest meeting of the international collaboration on the #PFOA human half life conducted under the auspices of the Alliance for Risk Assessment (#ARA) can be found below.?Scientists associated with this collaboration will continue discussions via a web-based chat function, the results of which will be shared with all of you and the interested scientific community towards the end of this month.?We plan to followed these discussions with an open meeting in November where all of you will be invited to offer additional suggestions.
On behalf of the Advisory Committee,
PFOA 1/2 Life Advisory Committee:?
- Harvey Clewell, Ramboll?
- Tony Cox, Cox and Associates
- Michael Dourson, Toxicology Excellence for Risk Assessment
- Shannon Ethridge,??International Association of Plumbing and Mechanical Officials
- Ali Hamade, Oregon Health Authority
- Ravi Naidu,?Cooperative Research Centre for Contamination Assessment and Remediation of the Environment (CRC CARE)
- Nitin Verma, Chitkara University
Notes of September 7/8 International Conference Zoom Call
Michael Dourson, Toxicology Excellence for Risk Assessment
Shannon Ethridge, International Association of Plumbing and Mechanical Officials
Bernard Gadagbui, Toxicology Excellence for Risk Assessment
Mahesh Gupta, University of Saskatchewan
Hamade Ali K, Oregon Health Authority
Ravi Naidu, Cooperative Research Centre for Contamination Assessment and Remediation of the Environment
Andrew James?Prussia, Agency for Toxic Substances and Disease Registry
Lorenz Rhomberg, Gradient
James Stanley?Smith, US Navy
Nitin Verma, Chitkara University
The primary?purpose?of the call was to share findings among 3 independent groups and ask questions to gain understanding, based on the specific charge to:
- Select studies from the current?ARA?list for further review and explain why certain studies were excluded; groups were free to add studies as appropriate and explain why they were added.?
- Develop a group consensus on PFOA 1/2 life, discussing critical issues, such as, volume of distribution, 1/2 lives in different populations, and how uncertainty factors for experimental animal to human extrapolation and within human variability are affected;?groups were?free to add critical issues as appropriate.
Group?Summaries and Notes:
- The three groups differed somewhat on the selection of studies for further review as found in these?three group summaries.?Two groups focusing on a smaller selection of studies to gain an understanding of the average PFOA half life.?Up to 26% bias in the half life was possible in studies with low serum PFOA levels due to unmeasured PFOA exposures, and an argument could be made for a 20% reduction in the average half life because of this problem.?The remaining group preferred one study because of its carefully studied population although small, well established drinking water contamination and removal, similarity in the exposed group to controls, and subtraction of background PFOA level.?
- The?potential renal resorption limit is estimated as 12–24 uMoles (5 to 10 ug/ml), based on an estimated renal transporter Km of 5?μg/ml from this clinical study (ARA, 2021)*.?All human observational studies were considered to be below this resorption limit as well as the low single dose of 50 mg in the Elcombe et al. (2013) study.?Only patients with the higher weekly doses in the Elcombe et al. (2013) study were above this resorption limit making estimates of half life from this latter group of patients difficult.
- Three potential approaches can be used to determine the PFOA half-life.?In no particular order these are:
- Find a high PFOA exposure; remove exposure, and then measure PFOA serum elimination.?This is the common approach.?
- If at all possible subtract out background.?An example of where this was done is the Xu et al. (2020) study.
- Allow a sufficient time to measure serum decline; the longer the better.?An example of this might be the Olsen et al. (2007) study.
- Start with a naive population, give PFOA, and measure the time it takes to achieve a steady state.?Dividing this time by 5 approximates the half life.?An example of this might be the Elcombe et al. (2013) clinical study.
- Determine a human volume of distribution at steady state and then observe the daily clearance of PFOA in the urine, assuming that it is not eliminated elsewhere.?To date, very little human information is available on volume of distribution.?However, see an attached analysis from the Elcombe et al. (2013) clinical study which estimates this value over time.
- Questions to consider in any work in this area:
- Rat and mouse clearance is based on much higher doses than that expected in humans.?If rats or mice clear PFOA in a biphasic way as humans do, as demonstrated in the Elcombe et al. (2013) study, then a biphasic elimination in rats or mice might be expected.?If so, are we comparing toxicokinetic parameters at the same phases between the experimental animal of choice and humans?
- Does plasma binding in humans keep?PFOA from causing toxicity at expected concentrations?
- Clearance of mix-branch isomers of PFOA appear to be quicker than straight chain isomers.?If so, do human observational studies account for this?
- PFOA elimination might be increased by more fiber in the diet.?Might the large differences among half lives from human observational studies be a result of this?
Small groups will likely be meeting again to discuss presentations and discussions at this first call and perhaps develop a consensus around the given charge questions.?We anticipate this second round of discussions to occur during late September or early October where an overall consensus will be attempted among these groups.?We anticipate that this will be followed by a third round of discussions later in the fall with the broader interested community.?
* Alliance for Risk Assessment (ARA).?2021.?Beyond Science and Decisions:?From Problem Formulation to Risk Assessment.?Workshop XII.??February 24 & 25, 2021?
