Given the large number of PFAS in commerce and the rapid pace of the introduction of new chemicals, would it be better for a governmental testing program to:

Answer Explanations

• Other (please explain]

  Expert 11

  I think I would try to develop an approach for testing that was optimized to meet both goals. But I would favor the first goal over the second.

• To systematically test a list of substances that are prioritized based on exposure, chemical properties, and existing toxicity data?

  Expert 2

  As mentioned above, categorization of each subgroup of PFAS is the first step, which can be accomplished based on the structure. In silico models are a quick way to assess potential toxicity, but for surfactants like PFAS, with so many subgroups and functionalities, in silico models may not provide reliable data. In vitro assays are the second best alternative and with suitable/critical end points. Toxicity assessment can be performed as an initial screening approach using model in vitro system for a critical toxic end point(s). I am in favor of an in vitro system with sensitive end points for the testing program. This can be done concurrently with in silico and therefore a combination of in silico and in vitro assays provide more reliable data. However, in the end, in vivo assays are the most appropriate; for initial screening, I suggest hybrid in silico-in vitro testing but later confirmed by in vivo studies.

• Other (please explain]

  Expert 3

  I think it is impractical to rely on any governmental testing program for systematic testing of PFAS. No governmental group has the needed funding to undertake such a task. Increased resources are unlikely to be coming in the near future. By contrast there are at least some efforts among governmental and other groups, which generally address option 1 regarding parameterizing in silico models ( e.g. ToxCast, ExpoCast, and related efforts).

• To systematically test a list of substances that are prioritized based on exposure, chemical properties, and existing toxicity data?

  Expert 10

  Generating the data needed to parameterize an in silico model of PFAS toxicity that could be applied to any PFAS structure would be ideal, but it does seem unlikely in a short timeframe given the paucity of good in silico tools for PFAS and lack of data for model development for multiple PFAS. Research on development of in silico tools for estimating properties and toxicities of PFAS can be supported in the interim.

  For now, I support the approach being followed by US EPA and NIH scientists to systematically test a list of 150 PFAS to generate toxicity, toxicokinetic and other types of data to help inform decisions made about the potential health effects of PFAS. In fact, this initiative will hopefully provide the necessary data to aid the development of in silico tools in the future.

• Other (please explain]

  Expert 4

  The two choices should be done in parallel. The first would allow better management of PFAS in the future. The second would focus on substances that are a concern today based on exposure and known/predicted toxicity.

• Generate the data needed to parameterize an In silico model of PFAS toxicity that could be applied to any PFAS structure, or

  Expert 5

  An in silico model of PFAS toxicity including dose response is not an unreasonable thing to expect. Given the relatively small prediction space for computational tox models to work in, the molecular attributes of PFAS components may likely be well addressed. With adequate certainty of a mode of action, and knowledge of its biological underpinnings, it seems plausible to expect improved prediction capacity, given a reduced biological target (e.g., a receptor, or set of receptors, or a set of well conserved and well understood biological/biochemical processes). "To systematically test..." is rather a vague phrase, if "animal testing" is what is meant by "systematically test", then this further limits the alternate selection (of "To systematically test...")

• To systematically test a list of substances that are prioritized based on exposure, chemical properties, and existing toxicity data?

  Expert 1

  Although in silico models are interesting and show some potential, they are generally limited to a certain domain of applicability which may not cover new chemistries. Monitoring PFAS through a combination of targeted and untargeted analyses of drinking water would allow prioritizing chemicals to be tested in high-throughput or low-throughput assays.

• To systematically test a list of substances that are prioritized based on exposure, chemical properties, and existing toxicity data?

  Expert 8

  First of all, this is not the responsibility of the government. It is the responsibility of industry. The broad class of compounds included as “PFAS” precludes the development of a single in silico model that would be predictive of all compounds. Governments already have systems developed to look at potential use, pchem properties, some toxicity data, etc. which are used to make judgments about chemicals, including PFAS. These can be utilized and therefore I would answer: ” to systematically test a list of substances that are prioritized based on exposure, chemical properties, and existing toxicity data”. The testing does not have to be a whole series of in vivo toxicity studies, but can be targeted testing based on MOA or other toxicity information.

• Generate the data needed to parameterize an In silico model of PFAS toxicity that could be applied to any PFAS structure, or

  Expert 6

  The first option is the "holy grail" of toxicological screening. Whether or not it will be achievable remains to be seen. It may turn out that an in silico model, along with a range of other new Assessment methods (NAMs) will yield sufficient data to sufficiently characterise new and existing PFAS. If this looks more like dot point 2, then I am prepared to change my vote (sorry to be ambivalent about this!)

• Other (please explain]

  Expert 9

  It should not be the responsibility of a governmental testing program to evaluate the safety of chemicals for use in commerce. However, if forced to do so, the second choice, "To systematically test a list of substances that are prioritized based on exposure, chemical properties, and existing toxicity data" is the most appropriate choice for PFAS. Given the likelihood that PFAS operate via multiple mechanisms across tissues, an in silico model of PFAS toxicity is unlikely to be sufficiently predictive of toxicity across all PFAS.

• Other (please explain]

  Expert 7

  Second bullet: there seems to be a contradiction as to "test", do you mean "assess" since are existing data or generate new tox data? As mentioned below, I think that chemical property data need to be generated.
  a mixture of the two above. There is a need for real data and I think that rather than relying on environmental monitoring, PFAS molecules have to be tested for their chemical physical parameters under laboratory conditions rather than speculating on transport, transformation, etc.
  in vitro tests and others for toxicological parameters.
  I do not believe that there are so many PFAS in commerce. At least not the non-polymer PFAS. I would be interested in a list of permits for PFAS compounds; the latest publications do not help in this matter.
  I do not believe that an effort such as was done with the evaluation of existing substances (in the EU, at national level) is necessary.
  In addition, certain PFAS have beneficial functionality, including persistence, which should be acknowledged.