Please provide 1 additional question on PFAS definition, grouping, or risk assessment approach you would like your fellow panel members to consider in Round 3 (please phrase in the form of a question)

Given the large number of PFAS compounds in commerce and the rapid pace of the introduction of new chemicals, would it be better for a governmental testing program to:
1. Generate the data needed to parameterize an in silico model of PFAS toxicity that could be applied to any PFAS structure, or
2. To systematically test a list of substances that are prioritized based on exposure, chemical properties, and existing toxicity data?

Dimensions and “certainty” or “variance” constitute a major problem since we have to deal with concentrations that vary several orders of magnitude at source/exposure but also effects (based on 48 h experiments vs. lifetime exposure). Do you wish to establish one model compound and scenario to test the practicability of the assessment? How to avoid a conclusion of our assessment that cannot be verified/validated? or "How to define "level of confidence"?

When considering the risk of PFAS should lifecycle considerations (risks during production, use and disposal) be taken into account? Yes/No. Please explain your answer.

Do we need to separate quantitative risk assessment from other reasons for grouping PFAS for chemicals managment? Yes/No. Please explain your answer.

See also answer to 1.8; the question I pose to panellists is: - will there be sufficient commonality of toxicological endpoints in conventional in vivo studies (with similar of different durations of exposure), or endpoints in NAMs (new assessment methodologies, such a zebrafish, cell culture studies, 'omics assays) that will enable robust RPFs to be developed for PFAS? What caveats would need to be placed on such an approach?

1) How would the NHANES data be utilized in PFAS risk assessment? For example NHANES 2013–2014 data reported the 95th percentile for PFBS at or below the level of detection (0.1 ng/mL), and PFBS is no longer included. Would this influence grouping which includes PFBS (this is only an example – other PFAS have different survey results)?

I am also suggesting the following:
2) Develop a problem formulation statement and provide an example of PFAS grouping, and an approach to risk assessment.

Can we group PFAS depending on the polar functional groups and then work from there for risk assessment? For example, sulfonates as one group, carboxylates as another group, fluorotelomers as a group, fluoroethers as a group, etc etc. Then assess their toxicities and then assess risk for each groups individually. If feasible, groups can be combined later, if the mode of toxicity is similar.

What is the purpose for which the risk assessment is being done?

Generally speaking a Problem Formulation is done after a process of Planning and Scoping (e.g. US EPA 2014, Framework for Human Health Risk Assessment to Inform Decision Making, as well as several other contemporary documents). A risk assessment is done to support scientifically sound choices among risk management options. A major objective of the Planning and Scoping and Problem Formulation steps is to ensure that the resulting risk assessment is fit-for-purpose -- that the assessment answers the relevant questions and provides needed information to allow intelligent choices among available risk management options. Planning and Scoping defines how the risk assessment is to be used (in the context of available risk management options) and, thus, sets ranges and boundaries for its development.

In the Problem Formulation phase, the Conceptual Model is defined, which "describes the linkages between stressors and adverse human health effects, including the stressor(s), exposure pathway(s), exposed lifestage(s)
and population(s), and endpoint(s) that will be addressed in the risk assessment" (US EPA 2014).

It was clear from reading the literature cited in the document for review that the approach to all parts of the PFAS risk assessment ought be determined by its intended use. Several papers provide useful descriptions of tiered approaches to mixtures evaluation (e.g. Meek et al. 2011; Goodrun et al. 20220 ). These tiers depend not only on the availability of data on the mixture and /or components but also on the purpose for which the risk assessment is being done. As noted in several papers a lower tier approach, for instance using Hazard Index (HI), may suffice for screening and ranking. Ranking and screening should not be considered as trivial exercises. For example by ranking PFAS groups by routes of exposure (maybe fish vs. water), or exposure scenarios (occupational vs drinking water), these groups can be ranked for immediate consideration or back-burnered based on HI.

The most appropriate groupings of chemicals, methods of mixture assessment, choice of appropriate health outcomes, all will be dependent on the purpose of the risk assessment and directed by an analysis plan founded on the Conceptual Model.

Given the lack of toxicological data and targetted analytical methods for most PFAS, do you think a screening risk assessment could be conducted by assuming the total adsorbable/extractable organic fluorine concentration is equal to the concentration of a known toxic PFAS (e.g., PFOA)?

To what extent should an understanding of a Mode of Action (or Adverse Outcome Pathway or Toxicity Pathway) be developed to support reliance on in vitro findings related to toxic effects?

Is the P-sufficient approach a management option for PFAS that is feasible?

Please consider Table 2 of https://www.epa.gov/sites/default/files/2014-11/documents/chem_mix_1986.pdf. For each category (interactions, health effects, exposure), how would you rank the quality of information for PFAS mixtures in general, and what are the implications for PFAS risk assessments going forward?