International Collaboration on PFOA/S

Dear Colleagues

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Attached are meeting notes from an international consensus call based on interim findings of 3 independent science teams regarding appropriate studies for one or more of PFOA's critical effect(s).?The focus on the next effort for these 3 independent teams will be on the choice of extrapolation method to determine a range in the provisional PFOA safe dose, with a deadline of March 10 and?an international consensus call to follow.?Afterwards these teams will?identify additional data gaps with a deadline of March 31.?The sequence will then be repeated for PFOS.?

As before, your suggestions, and those of your interested colleagues, would be welcomed and valued.?Additional details can be found here:?https://tera.org/Alliance%20for%20Risk/Projects/pfoatwo.html.

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Sincerely,

Lyle Burgoon with?Raptor Pharm & Tox, Ltd, USA

Harvey Clewell with Ramboll, Global

Tony Cox with Cox Associates, USA

Michael Dourson with TERA, USA

Tamara House-Knight with GHD, Global

Ravi Naidu with CRC CARE, Australia

Paul Nathanail, United Kingdom

James S. Smith with US DoD, USA

Nitin Verma with Chitkara University, India

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Advisory Committee for?International Collaboration on the PFOA/S Safe Dose

—Alliance for Risk Assessment (ARA), building a risk assessment community

Hallmarks:?Open, collaborative,?frugal, timely and erudite

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Date: February 8-9, 2023

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Present (P)/Excused (E):

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Chair: Tony Cox with Cox Associates, USA, consultant (P)

Co-Chair: Ravi Naidu with CRC CARE, Australia, NGO (E)

Rapporteur: Michael Dourson with TERA, USA, NGO (P)

Group 1

Lyle Burgoon, RaptorPharmTox, USA, consultant (P)

Paul Nathanail, LQM, UK, consultant (E)

Shanon Ethridge,?International Association for Plumbing and Mechanical Officials Research and Testing, USA, NGO (P)

Vijay Kannappan, Cook Medical, USA, industry (E)

Michael Luster, NIOSH (retired), government, USA (P)

Therese Manning, Environmental Risk Sciences Pty Ltd, Australia, consultant (P)

Tiago Severo-Peixi, State University of Londrina, Brazil, University (E)

Andrea Wojtyniak, Geosyntec, Canada, consultant (P)

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Group 2

Harvey Clewell, Rambol, Global, consultant (P)

Tamara House-Knight,?GHD, Global, consultant (P)

Linda Dell, Ramboll, Global, consultant (P)

James Deyo, Environmental Protection Authority, New Zealand, government (E)

Bernard Gadagbui, Toxicology Excellence for Risk Assessment, USA, NGO (E)

Travis Kline, Geosyntec Consultants, USA, consultant (E)

Katie Richardson, Senversa, Australia, consultant (P)

Anurag Sharma, Nitte University, India, university (E)

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Group 3

James Smith, NMCPHC, USA, government (E)

Nitin Verma,?Chitkara University, India, university (E)

Wolfgang?Dekant, University of Würzburg (retired), Germany, university (E)

Philip Goodrum, GSI, consultant (P)

Laura Green, Green Toxicology LLC, USA, consultant (P)

Tom Jonaitis, RegTox Solutions Inc., Canada, consultant (E)

Frank Pagone, RHP Risk Management, USA, consultant (P)

Jackie Wright, Environmental Risk Sciences Pty Ltd, Australia, consultant (E)

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Michael initiated the meeting by restating the charge for this phase of the effort, a determination of the critical studies for one or more of PFOA's critical effect(s). Tony then outlined the process of the call starting with presentations and clarifying questions, and then continuing with discussion and consensus statements.?Afterwards, he invited Group 3 to present.

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Laura went over the findings of Group 3.?The group considered the following criteria in their evaluation of potential critical effects:

·?????Dose response,

·?????Known or suspected Mode of Action (MOA),

·?????Consistency,

·?????Coherence between experimental animal and epidemiology data, and

·?????Robustness of the overall response.?

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After reviewing the plethora of relevant information, Group 3 did not consider the epidemiology data, composed primarily of observational studies, to be sufficient to determine a critical effect and instead focused on experimental animal work.?

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Group 3 considered monkey studies as most relevant due to the closeness to humans with PPAR-alpha activation for potential liver effects and general physiology, and the difficulty in interpretation of rodent developmental effects:?

·?????Non-adverse liver effects were seen at all of the doses tested in monkeys (3, 10, 20, and 30 mg/kg-day).?These effects correlated roughly with some non-adverse liver effects seen in the human observational studies and was consistent with the sole human clinical study that, while short term, showed no adverse liver effects.?

·?????Although these liver effects were not considered to be adverse in monkeys, mortality was also observed in monkeys at the higher doses leading to a clear NOAEL/LOAEL boundary. ?

·?????One member of Group 3 reached out to the investigators of the monkey studies to ask for any additional data.?No additional data were available.

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Harvey then went over the findings of Group 2. ?After reviewing the relevant plethora of information, Group 2 also did not consider the epidemiology data, composed primarily of observational studies, to be sufficient to determine a critical effect. These studies were considered to be:

·?????Confounded, and confounding was not readily quantified, which created a hurdle with the use of human data, and

·?????Exposures were not significantly different from background in most studies to assign an association, much less causation

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Because of these concerns, Group 2 also focused on experimental animals for consideration of the critical effect.

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In contrast to Group 3, Group 2 selected rodent developmental studies rather than liver changes, and specifically Lau et al, 2006, as most relevant due to the consistency in response of several rodent species and the fact that the likely MOA was fatty acid mimicry.?This selection was based on:

·?????PFOA access to mid-chain fatty acid transport, and biliary and renal excretion and resorption.?

·?????While such mimicry might be readily handled by organs, such as the liver, it might more readily disturb fatty acid homeostasis in the developing organism, thus supporting its selection as the critical, or perhaps co-critical effect.?

·?????Ppar-alpha induced liver effects occurred in rodents at about a 10-fold higher dose than those evoking developmental toxicity.

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Other issues/questions raised included:

·?????Laura raised the idea that a developmental study in rabbits might also be worth considering since rodents are known not to representative human development as well.?Group 2 agreed to review the available rabbit developmental study.?

·?????Lyle raised the issue of statistical problems with the Lau et al. (2006) study in particular, and for most, if not all of the experimental animal work in general.??

·?????Several, but not all, human observational studies show a decrease in birth weight when PFOA is sampled in the 3rd trimester of pregnancy, but not at earlier sampling times.

·?????Monkey and rodent NOAEL/LOAEL interfaces are approximately the same at around 1 to 3 mg/kg-day.[1]

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Lyle then summarized the findings of Group 1, which were based on a very nice summary of studies by Jackie and Therese (attached).?Like Groups 2 and 3, Group 1 did not feel that any of the human studies were sufficiently reliable to be used to determine the critical effect, and for the various reasons already indicated.?Nor did Group 1 feel that the liver effects seen in monkeys, or perhaps other species, were appropriate, since the effects seen were not adverse.?Nor did Group 1 consider the developmental effects appropriate due to statistical issues mentioned above.

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Group 1 was of the general opinion that the overall database was insufficient at this time to make a reliable judgment of critical effect, and supported this position with the observation that different health agencies around the world have come to very different decisions.?While these differences may not be direct evidence for the overall weakness in the database, the WHO (2022) came to the same conclusion.?Specifically, the overall database was too uncertain to determine a scientifically based judgment of critical effect.?Instead WHO (2022) made a risk management recommendation.

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After these presentations, clarifying questions and discussion, the following consensus positions were developed:

§?Should human studies be used for the development of the critical effect? No, existing human observational studies cannot be used reliably for this purpose.?For example, changes in cholesterol have only a small effect and are not dose responsive.?These studies may support the choice of critical effect with some of the experimental animal work, however.

§?Should vaccine responses be used for the development of the critical effect??No, existing human observational vaccine findings are not primary immune responses and not of clinical relevance.?Moreover, higher dose worker exposures do not suggest immune responses.[2]?

§?The overall uncertainty in the database, both epidemiology and experimental animal, is sufficient to give pause to the development of a credible critical effect for PFOA.?This conclusion is similar to what WHO (2022) found and for the same or similar reasons.?However, in recognition of the importance of managing PFOA potential health risk, and despite the overall difficulties in the experimental animal studies, a provisional approach will be explored along the following lines:

o??Frank toxicity in both monkeys and rats has been observed in a dose related manner.?We might be able to tie these effects into other liver and or developmental endpoints.?TERA will conduct a Benchmark Dose (BMD) approach on the relevant monkey and rodent studies, and send this to Groups 1, 2, and 3 for consideration.?Laura asked participants to critique and improve upon her and Edmund Crouch’s work in this regard from 2019 (as submitted to MassDEP, and available at https://greentoxicology.com/Reports/PFAS_comments_to_MADEP.pdf ).

o??PFOA is the fluorinated version of the naturally occurring caprylic acid.?A big difference between these is ? life in the human body.?TERA will conduct a limited literature review on the toxicity of caprylic acid, and Groups 1, 2, and 3 will conduct a thought experiment to probe whether potential long term toxicity from caprylic acid matches any of the findings with PFOA.

o??Group 2 will look at the rabbit developmental toxicity study.

[1] The human clinical study of Elcombe et al. (2013) is in the same range and showed no overt effects (50 – 1200 mg/week ÷ 7 days ÷ 70 kg ~ 0.1 – 2.4 mg/kg-day).

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[2] Experimental animal work indicates some immune toxicity but only at doses higher than those suggested in human observational studies.?

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