Based on USEPA (1986) Table 2 for mixtures risk assessment, please select the best classification for data quality for PFAS information on interactions

Answer Explanations

• An assumption of additivity cannot be justified, and no quantitative risk assessment can be conducted

  Expert 8

  It is not clear what the context for this question is. The problem formulation statement provided is not sufficiently detailed to provide the actual PFAS to be considered. If one is only considering the 6 PFAS included in the UCMR3 (PFOA, PFOS, PFNA, PFHxS, PFHpA and PFBS) then the first criteria applies – “An assumption of additivity cannot be justified, and no quantitative risk assessment can be conducted”. The toxicity data and MOA data do not support an additivity approach for these 6 PFAS.
  If one is considering other PFAS, I would assume the answer is the same but difficult to know in the absence of a list of the specific PFAS.

• An assumption of additivity cannot be justified, and no quantitative risk assessment can be conducted

  Expert 6

  I think we are close to accepting an assumption of additivity, but we are not yet there. When additional data is able to confirm a reasonably common mode of action (e.g. via a specific receptor) and similar toxicological outcomes, we may be able to move to the 4th dot point

• The assumption of additivity is justified based on the nature of the health effects and the number of component compounds

  Expert 3

  My answer is largely based on general knowledge of mixture components; to wit, departures from additivity in tested or known mixtures are largely high dose observations. Mixtures of PFAS likely to be in drinking water would not be considered high dose by most risk assessors. As noted in responses to the first set of charge questions, an assumption of additivity is not refuted (or even challenged) by the few published empirical results for PFAS.

  Note that the USEPA document cited above is based on the science available in1985. Since then, USEPA and several other authors have published on findings and refined theories of likelihood of interactions among components of mixtures. USEPA and others continue to opine that dose additivity can be assumed for components with the same MOA, or for the same MOA surrogate (e.g. adverse outcome commonality).

• The assumption of additivity is justified based on the nature of the health effects and the number of component compounds

  Expert 10

  Additivity can be assumed for a number of component-PFAS (e.g. the perfluoroalkyl acids, PFAAs) in a mixture. Currently risk assessments are often based on the sum of a few long-chain PFAAs which are assumed to have the similar effects and human elimination half-lives (e.g. sum of PFOS, PFOA, PFNA and PFHxS). In fact, we know enough about the elimination kinetics of multiple perfluoroalkyl acids to make more sophisticated cumulative risk assessments and include a large number of perfluoroalkyl acids (PFAAs). Consideration of precursors to PFAAs in mixture toxicity is a tricky question, however (as mentioned above).

• Expert 11

  I am not an expert in the literature on the toxicity or chemicals interactions of PFAS. I suspect the level of information varies greatly across the specific PFAS substances in the mixture. As a result, any of the five classifications could be applicable for mixtures of certain PFAS substances.

• An assumption of additivity cannot be justified, and no quantitative risk assessment can be conducted

  Expert 7

  I think this (and other questions) cannot be answered if the goal and the actors are not defined. For drinking water the spectrum of PFAS should be different from the substances regulated in wastewater or in food.
  The answers/possible ways forward/depth will depend on the role: different people/groups have different roles and responsibilities in an issue like MCL for drinking water:
  • Under discussion is only the way to establish a MCL. Afterwards, there should be no discussions until the MCL is revisited.
  • As a regulator, a limit value has to be enforced and controlled
  • As a chemical lab, the target substances must be known in a confirmatory analysis. If sum parameters are defined (for a larger number of substances) the sum has to be defined and the analtical approach as well.
  A biological lab or for bioassays, the mode of action and the endpoint have to be defined (but the identity of the PFAS will not be known).

• The assumption of additivity is justified based on the nature of the health effects and the number of component compounds

  Expert 4

  dose additivity is justified based on the current state of knowledge. Dose additivity tends to be the default assumption in the absence of data to the contrary.

• The assumption of additivity is justified based on the nature of the health effects and the number of component compounds

  Expert 1

  There is some data on PFAS mixtures in the literature that justifies additivity at low doses. For example, Wolf et al. 2014 (https://www.sciencedirect.com/science/article/pii/S0300483X13003272?via%3Dihub) observed dose additivity for PPAR activation in vitro. This is also supported by Rowan-Carroll et al. 2021 (https://pubmed.ncbi.nlm.nih.gov/33772556/) who observed similar gene expression in liver spheroids for multiple PFAS. Although the number of PFAS tested is limited in these studies, a conservative approach would be to assume dose additivity for other PFAS.

• An assumption of additivity cannot be justified, and no quantitative risk assessment can be conducted

  Expert 2

  We still do not have enough data to justify additivity, even for the two well studied PFAS namely PFOS and PFOA. Can we add toxicity of PFOS and PFOA to describe cumulative toxicity? Unless mode of action is known, additivity adds significant uncertainty to risk assessment. Again, this is complicated by - not only lack of toxicity data for mixtures, but also due to very grouping of chemicals under PFAS. I sugggestt developing subgroups of PFAS and tackle from there [ analogy would be not all "organochlorines" are the same; in that case we grouped PCBs separately from pesticides and so on].

• The assumption of additivity is justified based on the nature of the health effects and the number of component compounds

  Expert 5

  Reading the question as if it were an exam question, the "best" answer is "I", on the mixture of concern. In light of the charge to this panel, the highest-prioritized response likely to be successful seems to be "IV, the assumption of additivity". This basis for classification is one that might be testable, and may perhaps lend itself to in vitro investigations, given sufficient data that inform the mode or mechanism upon which additivity is to be tested.

• An assumption of additivity cannot be justified, and no quantitative risk assessment can be conducted

  Expert 9

  Table 1 of the USEPA (1986) mixtures risk assessment provides a key for selection of risk assessment approaches. Step 1 asks about the quality of data on interactions, health effects, and exposure. Currently, the quality of data on interactions, health effects, and exposure is inadequate for PFAS (Note that the quality of data might actually be richer than current peer-reviewed publications indicate; many papers measure multiple PFAS in serum but often run analyses on individual PFAS). According to Table 2 of the USEPA (1986) mixtures risk assessment, there are inadequate data to conduct a quantitative risk assessment.